Pyridine-containing polycyclic derivative inhibitors, methods of making and use thereof

Abstract

The present application relates to pyridine polycyclic derivative inhibitors, their preparation methods and uses. In particular, the present application relates to compounds of general formula (V), their preparation methods and pharmaceutical compositions containing the compounds, and their uses as EGFR inhibitors in the treatment of cancer-related diseases, wherein each substituent in general formula (V) is the same as defined in the specification.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a pyridine polycyclic derivative inhibitor and a preparation method and application thereof. BACKGROUND

[0002] EGFR (Epidermal Growth Factor Receptor) is a member of transmembrane receptor tyrosine kinase ErbB family, which is activated by binding with its ligand epidermal growth factor (EGF) or transforming growth factor alpha (TGFa). The activated EGFR forms homodimers on the cell membrane, or forms heterodimers with other receptors (such as ErbB-2, ErbB-3, or ErbB-4) in the family, causing phosphorylation of key tyrosine residues in the cell, thereby activating the downstream signaling pathway in the cell, playing an important role in cell proliferation, survival and anti-apoptosis. The activation mutation, overexpression or gene amplification of EGFR can lead to the overactivation of EGFR, promote the transformation of cells to tumor cells, and play an important role in the proliferation, invasion, metastasis and vascularization of tumor cells, and is an important target for the development of anti-cancer drugs, especially lung cancer treatment drugs.

[0003] The first generation of small molecule EGFR inhibitors includes gefitinib (Iressa) and erlotinib (Tarceva), which show good efficacy in lung cancer treatment and have been used as first-line drugs for the treatment of non-small cell lung cancer (NSCLC) with EGFR activating mutations (including L858R and delE746_A750). However, after 10-12 months of treatment with the first generation of small molecule EGFR inhibitors, almost all NSCLC patients develop resistance to the first generation of small molecule inhibitors, and more than half of the resistance mechanisms are due to the secondary mutation of EGFR gatekeeper residue T790M.

[0004] Osimertinib (AZD9291) is a third-generation EGFR TKI inhibitor, which has a high response rate and good therapeutic effect on drug resistance caused by EGFR T790M mutation, and was approved for marketing by the US FDA in November 2015. It can effectively treat patients with advanced non-small cell lung cancer with EGFR T790M drug-resistant mutation in clinic. Although Osimertinib has achieved great success in the treatment of non-small cell lung cancer with EGFR T790M mutation in clinic, drug resistance still occurs after 9-14 months of treatment. Studies have shown that up to 20-40% of drug-resistant patients are due to EGFR C797S mutation. EGFR C797S mutation changes the 797th half-amino acid to serine, which prevents Osimertinib from forming a covalent bond with the EGFR protein, thereby causing drug resistance. There is currently no effective inhibitor for EGFR C797S drug-resistant mutation in clinic. Therefore, it is urgent to develop new high-activity EGFR inhibitors to solve the problem of drug resistance caused by EGFR C797S mutation.

[0005] Novartis reported a compound EAI0450 against EGFR C797S drug resistance, which is an EGFR allosteric inhibitor. When combined with EGFR monoclonal antibody drugs such as cetuximab, it showed good antitumor effect in a mouse in vivo pharmacodynamic model of L858R / T790M / C797S mutation, but the compound had no effect as a single drug and could not inhibit C797S drug resistance containing deIE746_A750, and failed to enter clinical research. In 2017, Ken Uchibori et al. reported that Brigatinib (AP26113) combined with EGFR monoclonal antibody (such as cetuximab) can overcome the third-generation EGFR inhibitor drug resistance caused by C797S mutation, and shows good antitumor effect in PC9 (EGFR-C797S / T790M / de119) mouse pharmacodynamic model, but Brigatinib also faces the problems of low in vitro activity and no significant antitumor activity in vivo, and also has no further clinical research.

[0006] Lung cancer is a major disease that threatens human health, and the mortality rate of lung cancer has ranked first among all malignant tumors. In China, the incidence of lung cancer is increasing year by year, with about 700,000 new cases each year. In China, cases of lung cancer with EGFR activating mutation account for about 35% of all NSCLC, and the use of first-generation or third-generation EGFR inhibitors can achieve good therapeutic effect, but new drug-resistant mutations will occur in the later stage. Therefore, the development of a new generation of high-activity anti-drug-resistant EGFR inhibitors has great clinical and market value. SUMMARY

[0007] The object of the present application is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

[0008]

[0009] wherein:

[0010] R 1 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n R aa , -(CH2) n OR aa , -(CH2) n C(O)R aa , -(CH2) n C(O)OR aa , -(CH2) n OC(O)R aa , -(CH2) n S(O) m R aa , -(CH2) n NR aa R bb , -(CH2) n NR aa C(O)R bb , -(CH2) n NR aa C(O)OR bb , -(CH2) n C(O)NR aa R bb or -(CH2) n NR aa S(O) m R bb , said amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally can be further substituted;

[0011] R 2 is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally can be further substituted;

[0012] Ring A is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0013] R a is independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n1 R A1 , -(CH2) n1 OR A1 , -(CH2) n1 C(O)R A1 , -(CH2) n1 C(O)OR A1 , -(CH2) n1 OC(O)R A1 , -(CH2) n1 S(O) m1 R A1 , -(CH2) n1 NR A1 R A2 , -(CH2) n1 NR A1 C(O)R A2 , -(CH2) n1 NR A1 C(O)OR A2 , -(CH2) n1 C(O)NR A1 R A2 , -(CH2) n1 NR A1 S(O) m1 R A2 , -(CH2) n1 O(CH2) n2 R A1 , or -(CH2) n1 NR A1 (CH2) n2 NR A1 R A2 , said amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups optionally can be further substituted;

[0014] Ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0015] R bindependently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally can be further substituted;

[0016] or, any two of R 1 , R 2 , and R b are linked to form a heterocyclyl or heteroaryl, said cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally can be further substituted;

[0017] R aa , R bb , R A1 , and R A2 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, oxo, thioxo, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally can be further substituted;

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

[0019] y is 1, 2, 3, or 4;

[0020] z is 1, 2, 3, or 4;

[0021] m is 0, 1, or 2;

[0022] m1 is 0, 1, or 2;

[0023] n is 0, 1, 2, 3, or 4;

[0024] n1 is 0, 1, 2, 3, or 4; and

[0025] n2 is 0, 1, 2, 3, or 4.

[0026] In further preferred embodiments of the present application, the compound structure is as shown in formula (II):

[0027]

[0028] Ring D is selected from 7-20 membered heterocyclyl;

[0029] R is selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1-6 alkyl, C1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, optionally, further substituted by deutero, halo, amino, hydroxy, cyano, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, one or more substituents of which are substituted; preferably hydrogen or C 1-6 alkyl; more preferably hydrogen or C 1-3 alkyl; further preferably hydrogen or methyl;

[0030] or, any two R are linked to form, together with the atoms to which they are attached, a C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, said C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, optionally can be further substituted; preferably C 3-8 cycloalkyl; more preferably C 3-6 cycloalkyl; further preferably cyclopropyl;

[0031] s is an integer from 0 to 12.

[0032] In a further preferred embodiment of the present application, the compound has the structure according to formula (III):

[0033]

[0034] wherein:

[0035] M1is selected from -CR1-, -CR1R2-, N, -NR1-, -S-, or -O-;

[0036] M2is selected from -CR3R4-, -NR3-, -NR3-C(O)-, -S-, or -O-;

[0037] R1, R2, R3, and R4are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, or 5-14 membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, optionally, further substituted with deuterium, halogen, amino, hydroxyl, cyano, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, one or more substituents of which are selected from deuterium, halogen, amino, hydroxyl, cyano, oxo, thioxo, C 1-6 alkyl; more preferably C 1-3 alkyl; further preferably methyl;

[0038] optionally, R or R3 may be linked to form a ring; 1 may be linked to form a ring;

[0039] and t is 0, 1, 2, 3, or 4.

[0040] In a further preferred embodiment of the application, the compound has the structure according to formula (IV):

[0041]

[0042] wherein:

[0043] ring C is selected from C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; preferably 3-12 membered heterocyclyl containing 1-3 N, O or S atoms; further preferably a group selected from:

[0044]

[0045] R c selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl, -(CH2) n5 R A5 , -(CH2) n5 OR A5 , -(CH2) n5 C(O)R A5 , -(CH2) n5 C(O)OR A5 , -(CH2) n5 OC(O)R A5 , -(CH2) n5 S(O) m3 R A5 , -(CH2) n5 NR A5 R A6 , -(CH2) n5 NR A5 C(O)R A6 , -(CH2) n5 NRA5 C(O)OR A6 -(CH2) n5 C(O)NR A5 R A6 -(CH2) n5 NR A5 S(O) m3 R A6 -(CH2) n5 O(CH2) n6 R A5 Or -(CH2) n5 O(CH2) n6 OR A5 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0046] Preferred groups include deuterium, halogen, amino, hydroxyl, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 heteroaryl, -(CH2) n5 R A5 -(CH2) n5 ORA5 -(CH2) n5 C(O)R A5 -(CH2) n5 S(O) m3 R A5 -(CH2) n5 NR A5 R A6 -(CH2) n5 NR A5 C(O)R A6 -(CH2) n5 C(O)NR A5 R A6 Or -(CH2) n5 O(CH2) n6 R A5 The amino group, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl or 5-14 heteroaryl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 The aryl group is substituted by one or more substituents in the 5-14 membered heteroaryl group;

[0047] Further preferred groups include deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, oxacyclobutyl, -CH2F, -CH2CH2F, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -CH2CN, -CH2OCH3, -CH2CH2OCH3, -OCH3, -OCH2CH3, -C(O)CH3, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)CH3, -N(CH3)C(O)CH3, -S(O)2CH3, or

[0048] R A5 and R A6 each independently is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, optionally, further substituted with one or more substituents selected from deuterium, halogen, amino, hydroxyl, cyano, oxo, thia, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl; 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl;

[0049] u is 0, 1, 2, 3, 4, or 5;

[0050] m3 is 0, 1, or 2;

[0051] n5 is 0, 1, 2, 3, or 4; and

[0052] n6 is 0, 1, 2, 3, or 4.

[0053] In further preferred embodiments of the application, the compound has a structure according to Formula (V):

[0054]

[0055] wherein:

[0056] R 3 one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, said amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl or 5- to 14-membered heteroaryl, optionally, further substituted by deuterium, halogen, amino, hydroxyl, cyano, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 halogenated alkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl; preferably C 1-6 alkyl; more preferably C 1-3 alkyl; further preferably methyl, ethyl or propyl.

[0057] In a further preferred embodiment of the present application, the compound has the structure according to formula (VI):

[0058]

[0059] The present application also provides a preferred embodiment, and is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I) as shown above, and stereoisomers thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0060] The present application further relates to the use of any of the compounds of the general formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition for the preparation of MEK inhibitors, EGFR inhibitors, and EGFR monoclonal antibodies and their combination related drugs.

[0061] The present application also provides a preferred aspect, and further relates to the use of the compounds of each of the general formulae, and stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition for the preparation of the treatment of cancer related diseases; wherein the cancer diseases are selected from lung cancer.

[0062] The present application further relates to the use of the compounds of each of the general formulae, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition for the preparation of the treatment of cancer related diseases.

[0063] The present application also relates to the method of treating cancer related diseases, which comprises administering to the mammal a therapeutically effective amount of the compounds of the present application or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof.

[0064] In some embodiments, the present method relates to the treatment of cancer related conditions.

[0065] The treatment methods provided herein include administering to a subject a therapeutically effective amount of the compounds of the present application. In one embodiment, the present application provides a method of treating cancer related diseases in a mammal. The method comprises administering to the mammal a therapeutically effective amount of the compounds of the present application, or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof.

[0066] Detailed description of the invention

[0067] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0068] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate, with methyl, ethyl, i-propyl, t-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxyl-substituted alkyl being preferred.

[0069] The term "alkylene" refers to an alkyl group with one hydrogen atom further replaced by a substituent, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0070] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 8 carbon atoms. Monocyclic cycloalkyl groups comprise 3 to 12 carbon atoms, preferably comprising 3 to 8 carbon atoms, more preferably comprising 3 to 6 carbon atoms; non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0071] The cycloalkyl ring can be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring that is attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. The cycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0072] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) ma ring member, which is a heteroatom (e.g., -O-, -S-, or -NR- (wherein R is hydrogen or C1-6alkyl), but not -O-O-, -O-S-, or -S-S-, the remaining ring members are carbon. Preferably, the heterocyclyl group contains 3 to 12 ring members, of which 1 to 4 are heteroatoms; more preferably, the heterocyclyl group contains 3 to 10 ring members; more preferably, the heterocyclyl group contains 3 to 8 ring members; most preferably, the heterocyclyl group contains 3 to 8 ring members; further preferably, the 3-8 membered heterocyclyl group contains 1-3 N, O, or S atoms, optionally substituted with 1-2 oxo groups, including nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spirocyclic heterocyclyl groups, or nitrogen-containing fused heterocyclyl groups.

[0073] Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepinyl, 1,4-diazepinyl, 1,4-oxazepinyl, pyranyl, oxazolinyl, tetrahydrooxazolinyl, dihydropyrazinyl, dihydropyrazinonyl, oxazinyl, and dihydrooxazinyl, and the like, preferably oxetanyl, azetidinyl, tetrahydropyrrolidinyl, tetrahydrooxazolyl, piperazinyl, morpholinyl, or 1,4-oxazepinyl. Polycyclic heterocyclyl groups include spirocyclic, fused, and bridged heterocyclyl groups; wherein the spirocyclic, fused, and bridged heterocyclyl groups are optionally connected to other groups by a single bond, or further annelated to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups through any two or more atoms on the ring.

[0074] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between two single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m a ring member, which is a heteroatom (e.g., -O-, -S-, or -NR- (wherein R is hydrogen or C1-6alkyl), but not -O-O-, -O-S-, or -S-S-, the remaining ring members are carbon. Preferably, the heterocyclyl group contains 3 to 12 ring members, of which 1 to 4 are heteroatoms; more preferably, the heterocyclyl group contains 3 to 10 ring members; more preferably, the heterocyclyl group contains 3 to 8 ring members; most preferably, the heterocyclyl group contains 3 to 8 ring members; further preferably, the 3-8 membered heterocyclyl group contains 1-3 N, O, or S atoms, optionally substituted with 1-2 oxo groups, including nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spirocyclic heterocyclyl groups, or nitrogen-containing fused heterocyclyl groups.

[0075] and the like.

[0076] The term "fused heterocyclyl" refers to a polycyclic heterocyclic radical of 5 to 20 members, each ring in the system sharing a pair of adjacent atoms with another ring in the system, one or more rings can contain one or more double bonds, but no ring has a completely conjugated pi-electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m wherein m is an integer from 0 to 2, the remaining ring atoms are carbon. Preferably, 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings comprising the ring system, it can be a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 5 / 5 or 5 / 6 bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl groups include:

[0077] and the like.

[0078] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic radical of 5 to 14 members, any two rings sharing two non-adjacent atoms, which can contain one or more double bonds, but no ring has a completely conjugated pi-electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m wherein m is an integer from 0 to 2, the remaining ring atoms are carbon. Preferably, 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings comprising the ring system, it can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0079] and the like.

[0080] The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0081] and the like.

[0082] The heterocyclyl group can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0083] The term "aryl" means a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring systems having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclyl is a heterocyclic ring containing 1-3 nitrogen atoms, oxygen atoms, sulfur atoms; or also a three-membered nitrogen-containing fused ring containing a benzene ring.

[0084] The term "heteroaryl" means a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl and pyrazinyl, and the like, preferably oxazolyl, thiazolyl, pyridyl, pyrazolyl, pyrazinyl, triazolyl, thienyl, imidazolyl or pyrimidinyl; more preferably oxazolyl, thiazolyl, pyridyl, pyrazolyl or pyrazinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring which is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0085] and the like.

[0086] The term "alkoxy" means -O-(alkyl) and -O-(non-substituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group can be optionally substituted or non-substituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0087] The term "alkylthio" refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl is defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. The alkylthio group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0088] "Alkylaminocarbonyl" refers to (alkyl)-N-C(O)-, wherein alkyl is defined above.

[0089] "Haloalkyl" refers to an alkyl group as defined above substituted by one or more halogens.

[0090] "Haloalkoxy" refers to an alkoxy group as defined above substituted by one or more halogens.

[0091] "Haloalkylthio" refers to an alkylthio group as defined above substituted by one or more halogens.

[0092] "Hydroxyalkyl" refers to an alkyl group as defined above substituted by a hydroxyl group.

[0093] "Cyanoalkyl" refers to an alkyl group as defined above substituted by a cyano group.

[0094] "Alkenyl" refers to an alkenyl group, also known as an alkene group, wherein the alkenyl group can be further substituted by other relevant groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0095] "Alkynyl" refers to (CH≡C-), wherein the alkynyl group can be further substituted by other relevant groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0096] The term "alkynylcarbonyl" means -C(O)-(alkynyl), wherein alkynyl is as defined above. Non-limiting examples of alkynylcarbonyl include: ethynylcarbonyl, propynylcarbonyl, butynylcarbonyl. The alkynylcarbonyl group can be optionally substituted or unsubstituted, and when substituted, the substituent(s) are preferably one or more independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0097] "Halogen" means fluorine, chlorine, bromine, or iodine. "Amino" means -NH2. "Cyano" means -CN. "Nitro" means -NO2. "Carbonyl" means -C(O)-. "Carboxyl" means -C(O)OH. "THF" means tetrahydrofuran. "EtOAc" means ethyl acetate. "MeOH" means methanol. "DMF" means N,N-dimethylformamide. "DIPEA" means diisopropylethylamine. "TFA" means trifluoroacetic acid. "MeCN" means acetonitrile. "DMA" means N,N-dimethylacetamide. "Et2O" means diethyl ether. "DCE" means 1,2 dichloroethane. "DIPEA" means N,N-diisopropylethylamine. "NBS" means N-bromosuccinimide. "NIS" means N-iodosuccinimide. "Cbz-Cl" means benzyl chloroformate. "Pd2(dba)3" means tris(dibenzylideneacetone)dipalladium. "Dppf" means 1,1'-bis(diphenylphosphino) ferrocene. "HATU" means 2-(7-oxadiazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. "KHMDS" means potassium hexamethyldisilazide. "LiHMDS" means lithium bis(trimethylsilyl)amide. "MeLi" means methyllithium. "n-BuLi" means n-butyllithium. "NaBH(OAc)3" means sodium triacetoxyborohydride.

[0098] The phrases "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," "X is A, B, and C," and the like are used interchangeably and have the same meaning, i.e., X can be any one of A, B, or C, or any combination thereof.

[0099] Any hydrogen atom described herein can be replaced by its isotope deuterium. Any hydrogen atom in the compounds of the embodiments described herein can be replaced by deuterium.

[0100] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and that the description includes instances where the heterocyclyl group is substituted with alkyl and instances where the heterocyclyl group is not substituted with alkyl.

[0101] "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced with the corresponding number of substituents. It is understood that substituents are only in their possible chemical positions and can be determined (experimentally or theoretically) by one skilled in the art without undue effort as to what is possible or impossible. For example, an amino or hydroxyl group with a free hydrogen can be unstable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0102] "pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The goal of a pharmaceutical composition is to facilitate administration to an organism and to facilitate absorption of the active ingredient(s) to elicit the biological activity.

[0103] "pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are safe and effective for use in a mammal and possess the desirable biological activity. DETAILED DESCRIPTION

[0104] The present application is further described in connection with the following examples, which are not intended to limit the scope of the application.

[0105] Examples

[0106] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are made on a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0107] LC-MS measurements are made on an Agilent 1200 Infinity Series Mass Spectrometer. HPLC measurements are made using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 x 4.6 mm column).

[0108] Thin layer chromatography silica gel plates were used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, TLC plates were 0.15mm-0.20mm in thickness, and thin layer chromatography separation and purification product plates were 0.4mm-0.5mm in thickness. Column chromatography generally used Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0109] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized using or according to methods known in the art.

[0110] Unless otherwise specified, all reactions of the present application were carried out under continuous magnetic stirring under a dry nitrogen or argon atmosphere, with dry solvents, and the reaction temperature was in degrees Celsius.

[0111] Example 1

[0112] (R,E)-5 6 -((3-(methoxymethyl)azetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoloazol-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecan-3-one

[0113]

[0114] First step: Preparation of methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6- methylisonicotinate

[0115]

[0116] Methyl 2-chloro-6-methylisonicotinate (5.0 g, 27 mmol), 1-methyl-1H-pyrazol-5-ol (5.3 g, 54 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (661 mg, 0.81 mmol) and sodium carbonate (7.2 g, 67.5 mmol) were dissolved in anisole (60 mL) at room temperature, warmed to 130°C, and stirred for 16 h. Cooled to room temperature, filtered with diatomite, added 4M hydrochloric acid dioxane solution (10 mL) to the filtrate, filtered out the solid, and washed the solid with toluene and n-hexane to obtain the title compound methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (6.7 g, yield: 100%).

[0117] MS m / z (ESI): 248.2 [M+H] + .

[0118] Second step: Preparation of tert-pentyl (R)-(2,6-dimethylhept-5-en-1-yl)carbamate

[0119]

[0120] To a solution of (R)-3,7-dimethyloct-6-enoic acid (2.9 g, 20 mmol) in tert-pentanol (20 mL) was added azidophosphonic acid diphenyl ester (5 g, 20 mmol) and triethylamine (5 g, 20 mmol) successively, and the mixture was heated to 110 °C for 8 h. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound tert-pentyl (R)-(2,6-dimethylhept-5-en-1-yl)carbamate (4.9 g, yield: 91%).

[0121] MS m / z (ESI): 256.2 [M+H] + .

[0122] Third step: Preparation of (R)-2,6-dimethylhept-5-en-1-amine

[0123]

[0124] Tert-pentyl (R)-(2,6-dimethylhept-5-en-1-yl)carbamate (2.55 g, 10 mmol) was dissolved in tetrahydrofuran (40 mL), and potassium tert-butoxide (40 mL, 1 mol / L) was added. The mixture was stirred at 90 °C for 3 h. After concentration under reduced pressure, saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated to give the title compound (R)-2,6-dimethylhept-5-en-1-amine, which was used directly in the next step.

[0125] MS m / z (ESI): 142.2 [M+H] + .

[0126] Fourth step: Preparation of (R)-5-bromo-N-(2,6-dimethylhept-5-en-1-yl)-2-nitroaniline

[0127]

[0128] To a solution of 4-bromo-2-fluoro-1 -nitrobenzene (2.2 g, 10 mmol) and (R)-2,6-dimethylhept-5-ene-1 -amine (1.9 g, 10 mmol) in DMF (10 mL) was added potassium carbonate (2.7 g, 20 mmol) and stirred at room temperature for 16 h. Water was added and extracted with ethyl acetate. The organic phase was washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate and the organic solvent was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the title compound (R)-5-bromo-N-(2,6-dimethylhept-5-en-1 -yl)-2-nitroaniline (3.1 g, yield: 91 %).

[0129] MS m / z (ESI): 341.1 [M+H] + .

[0130] Fifth step: Preparation of 5-bromo-N-((2R)-4-(3,3-dimethyl oxetan-2-yl)-2- methylbutyl)-2-nitroaniline

[0131]

[0132] To a solution of (R)-5-bromo-N-(2,6-dimethylhept-5-en-1 -yl)-2-nitroaniline (3.1 g, 9.1 mmol) in dichloromethane (25 mL) was added m-chloroperoxybenzoic acid (1.7 g, 10.0 mmol) in portions under ice bath condition and stirred for 1 h. Saturated sodium carbonate solution was added and extracted with ethyl acetate. The organic phase was washed with saturated brine and separated. The organic phase was dried over anhydrous sodium sulfate and the organic solvent was concentrated under reduced pressure to obtain the title compound 5-bromo-N-((2R)-4-(3,3-dimethyl oxetan-2-yl)-2-methylbutyl)-2-nitroaniline as crude which was used directly for the next reaction.

[0133] MS m / z (ESI): 357.2 [M+H] + .

[0134] Sixth step: Preparation of (R)-5-((5-bromo-2-nitrophenyl)amino)-4- methylpentanal

[0135]

[0136] To a solution of 5-bromo-N-((2R)-4-(3,3-dimethyl oxetan-2-yl)-2- methylbutyl)-2-nitroaniline (3.3 g, 9.1 mmol) in tetrahydrofuran / ethyl ether (25 mL / 13 mL) was added periodic acid (2.1 g, 10.0 mmol) in portions under ice bath condition and stirred for 1 h. Ice water was added and the organic phase was extracted with ethyl ether. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the crude product was purified by column chromatography to give the title compound (R)-5-((5-bromo-2-nitrophenyl)amino)-4- methylpentanal (1.7 g, yield: 61%).

[0137] MS m / z (ESI): 315.2 [M+H] + .

[0138] Step 7: Preparation of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentan-1- ol

[0139]

[0140] To a solution of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentanal (1.7 g, 5.4 mmol) in methanol (20 mL) was added sodium borohydride (0.2 g, 5.4 mmol) in portions under ice bath condition and stirred for 1 h. Methanol was concentrated under reduced pressure and water was added. The organic phase was extracted with ethyl acetate and washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentan-1-ol (1.45 g, yield: 85%).

[0141] MS m / z (ESI): 317.2 [M+H] + .

[0142] Step 8: Preparation of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate

[0143]

[0144] To a solution of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentan-1-ol (1.45 g, 4.6 mmol) and triethylamine (697 mg, 6.9 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (632 mg, 5.5 mmol) dropwise at ice bath condition and stirred for 1 h. Saturated sodium bicarbonate solution was added and the organic phase was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate (1.68 g, yield: 93%).

[0145] MS m / z (ESI): 395.2 [M+H] + .

[0146] Ninth Step: Preparation of methyl (R)-2-(5-((5-((5-bromo-2-nitrophenyl)amino)-4- methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate

[0147]

[0148] To a solution of (R)-5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl methanesulfonate (1.68 g, 4.3 mmol) and methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6- methylisonicotinate (1.06 g, 4.3 mmol) in dimethylformamide (20 mL) was added potassium carbonate (1.48 g, 10.8 mmol) at room temperature and stirred at 60 °C for 16 h. Water was added and the organic phase was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the organic solvent was concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound methyl (R)-2-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (2.1 g, yield: 90%).

[0149] MS m / z (ESI): 546.2 [M+H] + .

[0150] Tenth Step: Preparation of methyl (R)-2-(5-((5-((2-amino-5-bromophenyl)amino)-4- methylpentyl)oxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate

[0151]

[0152] Methyl (R)-2-(5-((5-((5-bromo-2-nitrophenyl)amino)-4-methylpentyl)oxy)-l- methyl-lH-pyrazol-4-yl)-6-methylisonicotinate (2.1 g, 3.9 mmol) was dissolved in ethanol / water solution (20 mL / 7 mL) at room temperature, and reduced iron powder (1.76 g, 31.2 mmol) and ammonium chloride (835 mg, 15.6 mmol) were added sequentially, and the reaction was warmed to 90 °C for 5 h. The organic solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain the title compound methyl (R)-2-(5-((5-((2-amino-5-bromophenyl)amino)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinate (1.6 g, yield: 81%).

[0153] MS m / z (ESI): 516.2 [M+H] + .

[0154] Tenth Step: Preparation of methyl (R)-2-(5-((5-(2-amino-6-bromo-lH- benzo[d]imidazol-l-yl)-4-methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6- methylisonicotinate

[0155] Methyl (R)-2-(5-((5-((2-amino-5-bromophenyl)amino)-4-methylpentyl)oxy)-l- methyl-lH-pyrazol-4-yl)-6-methylisonicotinate (1.6 g, 3.1 mmol) was dissolved in dichloromethane / tert-butanol solution (20 mL / 4 mL) at room temperature, and cyanogen bromide (394 mg, 3.7 mmol) was added, and the reaction was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added, and dichloromethane was extracted, and the organic phase was separated, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain the title compound methyl (R)-2-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l-yl)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinate (1.47 g, yield: 88%).

[0156] MS m / z (ESI): 541.2 [M+H] + .

[0157] Twelfth Step: Preparation of (R)-2-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l- yl)-4-methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinic acid

[0158]

[0159] (R)-2-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l-yl)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinic acid (1.35 g, 2.6 mmol) was dissolved in dichloromethane (15 mL) at room temperature, triethylamine (1.05 g, 10.4 mmol) and 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (1.25 g, 3.9 mmol) were added sequentially and stirred at room temperature for 2 h. Water was added and extracted with dichloromethane, the organic solvent was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (R,E)-5

[0160] MS m / z (ESI): 527.2 [M+H] + .

[0161] Thirteenth step: (R,E)-5 6 -bromo-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2, 1)-benzo[d]imidazoloazol-2(2,4)-pyridine-l(4,5)-pyrazole cycloundecan-3-one

[0162] (R)-2-(5-((5-(2-amino-6-bromo-lH-benzo[d]imidazol-l-yl)-4- methylpentyl)oxy)-l-methyl-lH-pyrazol-4-yl)-6-methylisonicotinic acid (1.35 g, 2.6 mmol) was dissolved in dichloromethane (15 mL) at room temperature, triethylamine (1.05 g, 10.4 mmol) and 2-(lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (1.25 g, 3.9 mmol) were added sequentially and stirred at room temperature for 2 h. Water was added and extracted with dichloromethane, the organic solvent was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (R,E)-5 6 -bromo-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazoloundecan-3-one (858 mg, yield: 65%).

[0163] MS m / z (ESI): 509.2 [M+H]+. + .

[0164] Fourteenth step: (R,E)-1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazoloundecan-5 6 -formaldehyde

[0165] (R,E)-5 6 -bromo-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazoloundecan-3-one (858 mg, 1.7 mmol), palladium acetate (38 mg, 0.17 mmol), bis(1-adamantyl)norbornylphosphine (183 mg, 0.51 mmol) and tetramethylethylenediamine (394 mg, 3.4 mmol) were dissolved in dioxane (15 mL), purged with carbon monoxide three times, warmed to 110 °C, stirred for 16 h at 80 psi pressure. Cooled to room temperature, concentrated the organic solvent under reduced pressure, purified by column chromatography to give the title compound (R,E)-1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazoloundecan-5 6 -formaldehyde (701 mg, yield: 90%).

[0166] MS m / z (ESI): 509.2 [M+H]+.

[0167] Step 15: (R,E)-5 6 -((3-(methoxymethyl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0168]

[0169] At room temperature, (R,E)-1 1 ,2 6 7-Trimethyl-3-carbonyl-5 2 5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolecycloundecane-5 6 Formaldehyde (701 mg, 1.5 mmol) and 3-(methoxymethyl)acetidine trifluoroacetate (297 mg, 1.5 mmol) were dissolved in dichloroethane (15 mL). Two drops of acetic acid were added dropwise, and the mixture was stirred for 1 h. Then, sodium borohydride acetate (636 mg, 3.0 mmol) was added in portions, and the mixture was stirred overnight. The mixture was extracted with saturated sodium bicarbonate solution and dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound (R,E)-5. 6 -((3-(methoxymethyl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolecycloundecane-3-one (537 mg, yield: 66%).

[0170] 1H NMR(400MHz, CDCl3)δ0.94(d,J=6.0Hz,3H),1.95-1.96(m,2H),2.13-2.26(m,2H),2.64(s,3H),2.77-2.99(m,2H),3.28-3.52(m,7H) ),3.66-4.10(m,9H),4.35-4.45(m,2H),7.18-7.19(m,1H),7.27-7.35(m,2H),7.65(s,1H),8.16(s,1H),8.48(s,1H),12.01(s,1H);

[0171] MS m / z (ESI): 544.2 [M+H] + .

[0172] Example 2

[0173] (R,E)-5 6 -((3-methoxyacryl-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0174]

[0175] (R,E)-5 6 -((3-methoxyacryl-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0176] MS m / z (ESI): 530.2 [M+H] + .

[0177] Example 3

[0178] (R,E)-5 6 -((3-ethoxyacryl-1-yl)methyl)-1 1 ,2 67-trimethyl-5 2 5 3 - dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazepinozole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecan-3-one

[0179]

[0180] (R,E)-5 6 -((3-ethoxyazetidin-1-yl)methyl)-1 1 ,2 6 - dihydro-1 2 ,5 3 - dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazepinozole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecan-3-one

[0181] MS m / z (ESI): 544.2 [M+H] + .

[0182] Example 4

[0183] (R,E)-1-((1 1 ,2 6 - dihydro-1 2 ,5 3 - dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazepinozole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecan-5 6 -yl)methyl)azetidine-3-carbonitrile

[0184]

[0185] (R,E)-1-((1 1 ,2 6 - dihydro-1 2 ,5 3 - dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazepinozole-2(2,4)-pyridine-1(4,5)-pyrazolocycloundecan-5 6 -yl)methyl)azetidine-3-carbonitrile

[0186] MS m / z (ESI): 525.2 [M+H] + .

[0187] Example 5

[0188] (R,E)-2-(1-((1 1 ,2 6 7-Trimethyl-3-carbonyl-5 2 5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-5 6 Preparation of 3-yl)methyl)acetidine-3-yl)acetonitrile

[0189]

[0190] (R,E)-2-(1-((1 1 ,2 6 7-Trimethyl-3-carbonyl-5 2 5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-5 6 The preparation method of (-yl)methyl)acetidine-3-yl)acetonitrile is as described in Example 1.

[0191] MS m / z (ESI): 539.2 [M+H] + .

[0192] Example 6

[0193] (R,E)-2-(3-methyl-1-((1 1 ,2 6 7-Trimethyl-3-carbonyl-5 2 5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[ d Imidazolozo-2(2,4)-pyridine-1(4,5)-pyrazolecycloundecane-5 6 Preparation of 3-yl)methyl)acetidine-3-yl)acetonitrile

[0194]

[0195] (R,E)-2-(3-methyl-1-((1 1 ,2 6 7-Trimethyl-3-carbonyl-5 2 5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[ d Imidazolozo-2(2,4)-pyridine-1(4,5)-pyrazolecycloundecane-5 6 The preparation method of (-yl)methyl)acetidine-3-yl)acetonitrile is as described in Example 1.

[0196] MS m / z (ESI): 553.2 [M+H] + .

[0197] Example 7

[0198] (R,E)-5 6 -((3-(dimethylamino)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0199]

[0200] (R,E)-5 6 -((3-(dimethylamino)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0201] MS m / z (ESI): 543.2 [M+H] + .

[0202] Example 8

[0203] (R,E)-5 6 -((3-(diethylamino)acetidin-1-yl)methyl)-11 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0204]

[0205] (R,E)-5 6 -((3-(diethylamino)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0206] MS m / z (ESI): 571.2 [M+H] + .

[0207] Example 9

[0208] (R,E)-5 6 -((3-(ethyl(methyl)amino)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0209]

[0210] (R,E)-5 6 -((3-(ethyl(methyl)amino)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1The preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)- pyridine-1(4,5)-pyrazolacycloundecan-3-one was carried out according to the procedure described in Example 1.

[0211] MS m / z (ESI): 557.2 [M+H] + .

[0212] Example 10

[0213] (R,E)-N-methyl-N-(1-((1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-5 6 -yl)methyl)azetidin-3-yl)acetamide

[0214]

[0215] (R,E)-N-methyl-N-(1-((1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-5 6 -yl)methyl)azetidin-3-yl)acetamide was prepared according to the procedure described in Example 1.

[0216] MS m / z (ESI): 571.2 [M+H] + .

[0217] Example 11

[0218] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((3-(methyl(oxetan-3-yl)amino)azetidin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0219]

[0220] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((3-(methyl(oxobutylcyclo-3-yl)amino)acetidin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0221] MS m / z (ESI): 585.2 [M+H] + .

[0222] Example 12

[0223] (R,E)-5 6 -((3-aminoacetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0224]

[0225] (R,E)-5 6 -((3-aminoacetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0226] MS m / z (ESI): 515.2 [M+H] + .

[0227] Example 13

[0228] (R,E)-5 6 -((3-hydroxyazetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2, 1)-benzo[d] imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolocycloundecan-3-one

[0229]

[0230] (R,E)-5 6 -((3-hydroxyazetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2, 1)-benzo[d] imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolocycloundecan-3-one

[0231] MS m / z (ESI): 516.2 [M+H] + .

[0232] Example 14

[0233] (R,E)-5 6 -((3-hydroxy-3-methylazetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2, 1)-benzo[d] imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolocycloundecan-3-one

[0234]

[0235] (R,E)-5 6 -((3-hydroxy-3-methylazetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-52 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0236] MS m / z (ESI): 530.2 [M+H] + .

[0237] Example 15

[0238] (R,E)-5 6 -((3-(hydroxymethyl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0239]

[0240] (R,E)-5 6 -((3-(hydroxymethyl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0241] MS m / z (ESI): 530.2 [M+H] + .

[0242] Example 16

[0243] (R,E)-5 6 -((3-(2-hydroxypropan-2-yl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one

[0244]

[0245] (R,E)-5 6 -((3-(2-oxoazetidin-1-yl)methyl)-1 1 ,2 6 ,7-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 The method of preparing H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one is described in reference example 1.

[0246] MS m / z (ESI): 558.2 [M+H] + .

[0247] Example 17

[0248] (R,E)-5 6 -((3-(hydroxymethyl)-3-methylazetidin-1-yl)methyl)-1 1 ,2 6 ,7-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 The method of preparing H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one is described in reference example 1.

[0249]

[0250] (R,E)-5 6 -((3-(hydroxymethyl)-3-methylazetidin-1-yl)methyl)-1 1 ,2 6 ,7-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 The method of preparing H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one is described in reference example 1.

[0251] MS m / z (ESI): 544.2 [M+H]+ .

[0252] Example 18

[0253] (R,E)-5 6 -((3-(methoxymethyl)-3-methylazetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolacycloundecan-3-one

[0254]

[0255] (R,E)-5 6 -((3-(methoxymethyl)-3-methylazetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolacycloundecan-3-one

[0256] MS m / z (ESI): 558.2 [M+H] + .

[0257] Example 19

[0258] (R,E)-5 6 -((3-fluoro-3-(hydroxymethyl)azetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolacycloundecan-3-one

[0259]

[0260] (R,E)-5 6 -((3-fluoro-3-(hydroxymethyl)azetidin-l-yl)methyl)-l1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0261] MS m / z (ESI): 548.2 [M+H] + .

[0262] Example 20

[0263] (R,E)-5 6 -((3-fluoro-3-(2-hydroxypropane-2-yl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0264]

[0265] (R,E)-5 6 -((3-fluoro-3-(2-hydroxypropane-2-yl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0266] MS m / z (ESI): 576.2 [M+H] + .

[0267] Example 21

[0268] (R,E)-5 6 -((3-fluoro-3-(methoxymethyl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 53 - dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)-pyrazolacycloundecan-3-one

[0269]

[0270] (R,E)-5 6 -((3-fluoro-3-(methoxymethyl)azetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 - dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)-pyrazolacycloundecan-3-one

[0271] MS m / z (ESI): 562.2 [M+H] + .

[0272] Example 22

[0273] (R,E)-5 6 -((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 - dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)-pyrazolacycloundecan-3-one

[0274]

[0275] (R,E)-5 6 -((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 - dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)-pyrazolacycloundecan-3-one

[0276] MS m / z (ESI): 548.2 [M+H] + .

[0277] Example 23

[0278] (R,E)-5 6 -((4-acetylpiperazin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolacycloundecan-3-one

[0279]

[0280] (R,E)-5 6 -((4-acetylpiperazin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolacycloundecan-3-one

[0281] MS m / z (ESI): 571.2 [M+H] + .

[0282] Example 24

[0283] (R,E)-l 1 ,2 6 ,7-trimethyl-5 6 -((4-methyl-2-oxopiperazin-l-yl)methyl)-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolacycloundecan-3-one

[0284]

[0285] (R,E)-l 1 ,26 7-methyl-5 6 -((4-methyl-2-oxopiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 The preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one is described in Example 1.

[0286] MS m / z (ESI): 557.2 [M+H] + .

[0287] Example 25

[0288] (R,E)-1 1 ,2 6 7-methyl-5 6 -((4-methyl-3-oxopiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 The preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one is described in Example 1.

[0289]

[0290] (R,E)-1 1 ,2 6 7-methyl-5 6 -((4-methyl-3-oxopiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 The preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one is described in Example 1.

[0291] MS m / z (ESI): 557.2 [M+H] + .

[0292] Example 26

[0293] (R,E)-1 1 ,2 6 7-methyl-5 6 -(morpholinomethyl)-5 2 ,5 3- dihydro-1 1 H, 5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one

[0294]

[0295] (R,E)-1 1 ,2 6 ,7-Trimethyl-5 6 -(morpholinomethyl)-5 2 ,5 3 - dihydro-1 1 H, 5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one

[0296] MS m / z (ESI): 530.2 [M+H] + .

[0297] Example 27

[0298] (R,E)-5 6 -((1,4-oxazepan-4-yl)methyl)-1 1 ,2 6 ,7-Trimethyl-5 2 ,5 3 - dihydro-1 1 H, 5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one

[0299]

[0300] (R,E)-5 6 -((1,4-oxazepan-4-yl)methyl)-1 1 ,2 6 ,7-Trimethyl-5 2 ,5 3 - dihydro-1 1 H, 5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one

[0301] MS m / z (ESI): 544.2 [M+H]+ .

[0302] Example 28

[0303] (R,E)-5 6 -((4- cyclopropylpiperazin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one

[0304]

[0305] (R,E)-5 6 -((4- cyclopropylpiperazin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one

[0306] MS m / z (ESI): 569.2 [M+H] + .

[0307] Example 29

[0308] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one

[0309]

[0310] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)-pyrazolacycloundecan-3-one was prepared according to the procedure described in Example 1.

[0311] MS m / z (ESI): 585.2 [M+H] + .

[0312] Example 30

[0313] (R,E)-5 6 -((4-(2-fluoroethyl)piperazin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)-pyrazolacycloundecan-3-one was prepared according to the procedure described in Example 1.

[0314]

[0315] (R,E)-5 6 -((4-(2-fluoroethyl)piperazin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)-pyrazolacycloundecan-3-one was prepared according to the procedure described in Example 1.

[0316] MS m / z (ESI): 575.2 [M+H] + .

[0317] Example 31

[0318] (R,E)-5 6 -((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolocycloundecan-3-one

[0319]

[0320] (R,E)-5 6 -((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolocycloundecan-3-one

[0321] MS m / z (ESI): 573.2 [M+H] + .

[0322] Example 32

[0323] (R,E)-5 6 -((4-(2-methoxyethyl)piperazin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolocycloundecan-3-one

[0324]

[0325] (R,E)-5 6 -((4-(2-methoxyethyl)piperazin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolocycloundecan-3-one

[0326] MS m / z (ESI): 586.2 [M+H] + .

[0327] Example 33

[0328] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -(pyrrolidine-1-ylmethyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0329]

[0330] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -(pyrrolidine-1-ylmethyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0331] MS m / z (ESI): 514.2 [M+H] + .

[0332] Example 34

[0333] (R,E)-5 6 -((diethylamino)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0334]

[0335] (R,E)-5 6 -((diethylamino)methyl)-1 1 ,2 6 ,7-trimethyl-52 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0336] MS m / z (ESI): 516.2 [M+H] + .

[0337] Example 35

[0338] (R,E)-5 6- (((R)-3-methoxypyrrolidine-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0339]

[0340] (R,E)-5 6- (((R)-3-methoxypyrrolidine-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0341] MS m / z (ESI): 544.2 [M+H] + .

[0342] Example 36

[0343] (R,E)-5 6 -(((S)-3-methoxypyrrolidine-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0344]

[0345] (R,E)-5 6 -(((S)-3-methoxypyrrolidine-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0346] MS m / z (ESI): 544.2 [M+H] + .

[0347] Example 37

[0348] (R,E)-5 6 -(((R)-3-(dimethylamino)pyrrolidone-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0349]

[0350] (R,E)-5 6 -(((R)-3-(dimethylamino)pyrrolidone-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0351] MS m / z (ESI): 557.2 [M+H] +.

[0352] Example 38

[0353] (R,E)-5 6 -(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one

[0354]

[0355] (R,E)-5 6 -(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one

[0356] MS m / z (ESI): 557.2 [M+H] + .

[0357] Example 39

[0358] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((2-oxazolidin-3-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one

[0359]

[0360] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6-((2-carbonyloxazolidin-3-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 The preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo oxazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one is described in Example 1.

[0361] MS m / z (ESI): 530.2 [M+H] + .

[0362] Example 40

[0363] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((2-carbonyl-1,3-oxazepan-3-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 The preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo oxazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one is described in Example 1.

[0364]

[0365] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((2-carbonyl-1,3-oxazepan-3-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 The preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo oxazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one is described in Example 1.

[0366] MS m / z (ESI): 544.2 [M+H] + .

[0367] Example 41

[0368] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-5 2 ,5 3- dihydro-1 1 H, 5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridino-1(4,5)- pyrazolacycloundecan-3-one-3-one

[0369]

[0370] (R,E)-1 1 ,2 6 ,7-Trimethyl-5 6 -(((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-5 2 ,5 3 - dihydro-1 1 H, 5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridino-1(4,5)- pyrazolacycloundecan-3-one-3-one

[0371] MS m / z (ESI): 555.2 [M+H] + .

[0372] Example 42

[0373] (R,E)-1 1 ,2 6 ,7-Trimethyl-5 6 -(((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-5 2 ,5 3 - dihydro-1 1 H, 5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridino-1(4,5)- pyrazolacycloundecan-3-one

[0374]

[0375] (R,E)-1 1 ,2 6 ,7-Trimethyl-5 6 -(((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-5 2 ,5 3 - dihydro-1 1 H, 5 1The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0376] MS m / z (ESI): 555.2 [M+H] + .

[0377] Example 43

[0378] (7R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0379]

[0380] (7R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0381] MS m / z (ESI): 555.2 [M+H] + .

[0382] Example 44

[0383] (7R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0384]

[0385] (7R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0386] MS m / z (ESI): 555.2 [M+H] + .

[0387] Example 45

[0388] (R,E)-5 6 -(((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0389]

[0390] (R,E)-5 6 -(((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0391] MS m / z (ESI): 556.2 [M+H] + .

[0392] Example 46

[0393] (R,E)-5 6 -(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one

[0394]

[0395] (R,E)-5 6 -(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one

[0396] MS m / z (ESI): 556.2 [M+H] + .

[0397] Example 47

[0398] (R,E)-5 6 -(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one

[0399]

[0400] (R,E)-5 6 -(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one was prepared according to the procedure described in Example 1.

[0401] MS m / z (ESI): 545.2 [M+H] + .

[0402] Example 48

[0403] (R,E)-5 6 -(((3aR,6aS)-5-acetylpyrrolizidin-2(lH)-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one was prepared according to the procedure described in Example 1.

[0404]

[0405] (R,E)-5 6 -(((3aR,6aS)-5-acetylpyrrolizidin-2(lH)-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazacycloundecan-3-one was prepared according to the procedure described in Example 1.

[0406] MS m / z (ESI): 597.2 [M+H] + .

[0407] Example 49

[0408] (R,E)-11 ,2 6 ,7-trimethyl-5 6 -(((3aR,6aS)-5-(methanesulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0409]

[0410] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -(((3aR,6aS)-5-(methanesulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0411] MS m / z (ESI): 633.2 [M+H] + .

[0412] Example 50

[0413] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0414]

[0415] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6-(((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)methyl)-5 2 ,5 3 - dihydro-l 1 H,5 1 The preparation of H- 11 -oxa-4-aza-5(2, 1 )-benzo[d]imidazoazol-2(2,4)- pyridine- 1 (4,5)-pyrazolacycloundecan-3-one is described in Example 1.

[0416] 1 H NMR (400 MHz, CDC13) δ 0.94 (d, J = 5.8 Hz, 3H), 1.83 - 2.16 (m, 3H), 2.21 - 2.55 (m, 3H), 2.65 (s, 3H), 2.76 - 3.13 (m, 4H), 3.58 - 3.93 (m, 12H), 4.26 - 4.61 (m, 2H), 7.20 - 7.22 (m, 2H), 7.29 - 7.30 (m, 1H), 7.66 (s, 1H), 8.16 (s, 1H), 8.48 (s, 1H), 11.99 (s, 1H);

[0417] MS m / z (ESI): 556.2 [M+H] + .

[0418] Example 51

[0419] (R,E)-5 6 -((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 - dihydro-l 1 H,5 1 The preparation of H- 11 -oxa-4-aza-5(2, 1 )-benzo[d]imidazoazol-2(2,4)- pyridine- 1 (4,5)-pyrazolacycloundecan-3-one is described in Example 1.

[0420]

[0421] (R,E)-5 6 -((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 - dihydro-l 1 H,5 1The preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolodecan-3-one is described in Example 1.

[0422] MS m / z (ESI): 570.2 [M+H] + .

[0423] Example 52

[0424] (R,E)-5 6 -((6-oxa-2-azaspiro[3.4]octan-2-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolodecan-3-one

[0425]

[0426] (R,E)-5 6 -((6-oxa-2-azaspiro[3.4]octan-2-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolodecan-3-one

[0427] MS m / z (ESI): 556.2 [M+H] + .

[0428] Example 53

[0429] (E)-1 1 ,2 6 ,7,7-tetramethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolodecan-3-one

[0430]

[0431] (E)-1 1 ,2 6 ,7,7-Tetramethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0432] MS m / z (ESI): 557.2 [M+H] + .

[0433] Example 54

[0434] (E)-5 6 -((3-(dimethylamino)acetidin-1-yl)methyl)-1 1 ,2 6 ,7,7-Tetramethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0435]

[0436] (E)-5 6 -((3-(dimethylamino)acetidin-1-yl)methyl)-1 1 ,2 6 ,7,7-Tetramethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0437] MS m / z (ESI): 557.2 [M+H] + .

[0438] Example 55

[0439] (E)-2-(1-((11 ,2 6 7,7-Tetramethyl-3-carbonyl-5 2 5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-5 6 Preparation of 3-yl)methyl)acetidine-3-yl)acetonitrile

[0440]

[0441] (E)-2-(1-((1 1 ,2 6 7,7-Tetramethyl-3-carbonyl-5 2 5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-5 6 The preparation method of (-yl)methyl)acetidine-3-yl)acetonitrile is as described in Example 1.

[0442] MS m / z (ESI): 553.2 [M+H] + .

[0443] Example 56

[0444] (E)-5 6 -((3-(methoxymethyl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7,7-Tetramethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0445]

[0446] (E)-5 6 -((3-(methoxymethyl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7,7-Tetramethyl-5 2 5 3 -dihydro-1 1 H,5 1The preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazoazol-2(2,4)- pyridino(4,5)-pyrazolo undecan-3-one was carried out according to Example 1.

[0447] MS m / z (ESI): 558.2 [M+H] + .

[0448] Example 57

[0449] (E)-5 6 -((3-methoxyazetidin-l-yl)methyl)-l 1 ,2 6 ,7,7-tetramethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazoazol-2(2,4)- pyridino(4,5)-pyrazolo undecan-3-one

[0450]

[0451] (E)-5 6 -((3-methoxyazetidin-l-yl)methyl)-l 1 ,2 6 ,7,7-tetramethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazoazol-2(2,4)- pyridino(4,5)-pyrazolo undecan-3-one

[0452] MS m / z (ESI): 544.2 [M+H] + .

[0453] Example 58

[0454] (E)-5 6 -(((3aR,6aS)-5-acetylpyrrolizidin-2(lH)-yl)methyl)-l 1 ,2 6 ,7,7-tetramethyl-5 2 ,5 3 -dihydro-l 1 H,5 1Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolodecan-3-one

[0455]

[0456] (E)-5 6 -(((3aR,6aS)-5-ethoxycarbonylhexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l 1 ,2 6 ,7,7-tetramethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 The method for preparing H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolodecan-3-one is described in reference example 1.

[0457] MS m / z (ESI): 611.2 [M+H] + .

[0458] Example 59

[0459] (E)-1 1 ,2 6 ,7,7-tetramethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 The method for preparing H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolodecan-3-one is described in reference example 1.

[0460]

[0461] (E)-1 1 ,2 6 ,7,7-tetramethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 The method for preparing H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolodecan-3-one is described in reference example 1.

[0462] MS m / z (ESI): 647.2 [M+H] + .

[0463] Example 60

[0464] (E)-1 1 ,2 6 ,7,7-Tetramethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0465]

[0466] (E)-1 1 ,2 6 ,7,7-Tetramethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0467] MS m / z (ESI): 570.2 [M+H] + .

[0468] Example 61

[0469] (E)-5 6 -((3-fluoro-3-(2-hydroxypropane-2-yl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7,7-Tetramethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0470]

[0471] (E)-5 6 -((3-Fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-1 1 ,2 6 ,7,7-Tetramethyl-5 2 ,5 3 -Dihydro-1 1 H,5 1 H-11-Oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridino-1(4,5)- pyrazacycloundecan-3-one was prepared according to the procedure described in Example 1.

[0472] MS m / z (ESI): 590.2 [M+H] + .

[0473] Example 62

[0474] (E)-1',6'-Dimethyl-6'-((4-methylpiperazin-1-yl)methyl)spiro[cyclopropane-1,7'- 11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridino-1(4,5)-pyrazacycloundecan]- 3'-one was prepared according to the procedure described in Example 1.

[0475]

[0476] (E)-1',6'-Dimethyl-6'-((4-methylpiperazin-1-yl)methyl)spiro[cyclopropane-1,7'- 11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridino-1(4,5)-pyrazacycloundecan]- 3'-one was prepared according to the procedure described in Example 1.

[0477] MS m / z (ESI): 555.2 [M+H] + .

[0478] Example 63

[0479] (E)-6'-((3-(Dimethylamino)azetidin-1-yl)methyl)-1',6'-dimethylspiro[cyclopropane- 1,7'-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridino-1(4,5)-pyrazacycloundecan]- 3'-one was prepared according to the procedure described in Example 1.

[0480]

[0481] The preparation of (E)-6'-((3-(dimethylamino)azetidin-l-yl)methyl)-l',6'- dimethylspiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)- pyridine-l(4,5)-pyrazolodecane]-3'-one is described in Example 1.

[0482] MS m / z (ESI): 555.2 [M+H] + .

[0483] Example 64

[0484] The preparation of (E)-2-(l-((l',6'-dimethyl-3'-carbonylspiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)-pyrazolodecane]-6'- yl)methyl)azetidin-3-yl)acetonitrile is described in Example 1.

[0485]

[0486] The preparation of (E)-2-(l-((l',6'-dimethyl-3'-carbonylspiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)-pyrazolodecane]-6'- yl)methyl)azetidin-3-yl)acetonitrile is described in Example 1.

[0487] MS m / z (ESI): 551.2 [M+H] + .

[0488] Example 65

[0489] The preparation of (E)-6'-((3-(dimethylamino)azetidin-l-yl)methyl)-l',6'- dimethylspiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)- pyridine-l(4,5)-pyrazolodecane]-3'-one is described in Example 1.

[0490]

[0491] The preparation of (E)-6'-((3-(dimethylamino)azetidin-l-yl)methyl)-l',6'- dimethylspiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)- pyridine-l(4,5)-pyrazolodecane]-3'-one is described in Example 1.

[0492] MS m / z (ESI): 556.2 [M+H]+ .

[0493] Example 66

[0494] Preparation of (E)-6'-((3-methoxyazetidin-l-yl)methyl)-l',6'-dimethylspiro[cyclopropane-l,7'- 11-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)-pyrazacycloundecan]-3'-one

[0495]

[0496] The preparation of (E)-6'-((3-methoxyazetidin-l-yl)methyl)-l',6'-dimethylspiro[cyclopropane-l,7'- 11-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)-pyrazacycloundecan]-3'-one follows the procedure of Example 1.

[0497] MS m / z (ESI): 542.2 [M+H] + .

[0498] Example 67

[0499] Preparation of (E)-6'-(((3aR,6aS)-5-acetyloctahydro pyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l',6'- dimethylspiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine- 1(4,5)-pyrazacycloundecan]-3'-one

[0500]

[0501] The preparation of (E)-6'-(((3aR,6aS)-5-acetyloctahydro pyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l',6'- dimethylspiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine- 1(4,5)-pyrazacycloundecan]-3'-one follows the procedure of Example 1.

[0502] MS m / z (ESI): 609.2 [M+H] + .

[0503] Example 68

[0504] Preparation of (E)-1',6'-dimethyl-6'-(((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)spiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)- pyridine-l(4,5)-pyrazacycloundecan]-3'-one

[0505]

[0506] The preparation of (E)-1',6'-dimethyl-6'-(((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)spiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)- pyridine-l(4,5)-pyrazacycloundecan]-3'-one follows the procedure of Example 1.

[0507] MS m / z (ESI): 645.2 [M+H] + .

[0508] Example 69

[0509] The preparation of (E)-1',6'-dimethyl-6'-(((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)- yl)methyl)spiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazacycloundecan]-3'-one follows the procedure of Example 1.

[0510]

[0511] The preparation of (E)-1',6'-dimethyl-6'-(((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)- yl)methyl)spiro[cyclopropane-l,7'-l l-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazacycloundecan]-3'-one follows the procedure of Example 1.

[0512] MS m / z (ESI): 568.2 [M+H] + .

[0513] Example 70

[0514] Preparation of (E)-6'-((3-fluoro-3-(2-hydroxypropane-2-yl)acetidin-1-yl)methyl)-1',6'-dimethylspiro[cyclopropane-1,7'-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridin-1(4,5)-pyrazolium-1,7'-cyclopropane]-3'-one

[0515]

[0516] The preparation method of (E)-6'-((3-fluoro-3-(2-hydroxypropane-2-yl)acetidin-1-yl)methyl)-1',6'-dimethylspiro[cyclopropane-1,7'-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolium-1,7'-one is as described in Example 1.

[0517] MS m / z (ESI): 588.2 [M+H] + .

[0518] Example 71

[0519] (S,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0520]

[0521] (S,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0522] MS m / z (ESI): 545.2 [M+H] + .

[0523] Example 72

[0524] (S,E)-5 6 -((3-(dimethylamino)azetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 Preparation of H-8, 11-dioxa-4-aza-5(2, 1)-benzo[d] imidazoloazol-2(2, 4)- pyridine- 1(4, 5)-pyrazolacycloundecan-3-one

[0525]

[0526] (S,E)-5 6 -((3-(dimethylamino)azetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 Preparation of H-8, 11-dioxa-4-aza-5(2, 1)-benzo[d] imidazoloazol-2(2, 4)- pyridine- 1(4, 5)-pyrazolacycloundecan-3-one

[0527] MS m / z (ESI): 545.2 [M+H] + .

[0528] Example 73

[0529] (S,E)-2-(l-((l 1 ,2 6 ,7-trimethyl-3-carbonyl-5 2 ,5 3 -dihydro-l 1 H,5 1 Preparation of H-8, 11-dioxa-4-aza-5(2, 1)-benzo[d] imidazoloazol-2(2, 4)- pyridine- 1(4, 5)-pyrazolacycloundecan-5 6 -yl)methyl)azetidin-3-yl)acetonitrile

[0530]

[0531] (S,E)-2-(l-((l 1 ,2 6 ,7-trimethyl-3-carbonyl-5 2 ,5 3 -dihydro-l 1H,5 1 H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-5 6 The preparation method of (S)-5-((3-(methoxymethyl)azetidin-1-yl)methyl)-1- ((2-methoxyethoxy)methyl)-1H-1,2,4-triazole-3-carboxamide refers to Example 1.

[0532] MS m / z (ESI): 541.2 [M+H] + .

[0533] Example 74

[0534] (S,E)-5 6 -((3-(methoxymethyl)azetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 The preparation of H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)- pyridine-1(4,5)-pyrazolacycloundecan-3-one

[0535]

[0536] (S,E)-5 6 -((3-(methoxymethyl)azetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 The preparation method of H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)- pyridine-1(4,5)-pyrazolacycloundecan-3-one refers to Example 1.

[0537] MS m / z (ESI): 546.2 [M+H] + .

[0538] Example 75

[0539] (S,E)-5 6 -((3-((3-(methoxymethyl)azetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1Preparation of H-8, 11-dioxa-4-aza-5(2, 1)-benzo[d] imidazoxazol-2(2, 4)- pyridino- 1(4, 5)-pyrazacycloundecan-3-one

[0540]

[0541] (S,E)-5 6 -((3- methoxyazetidin- 1 -yl)methyl)- 1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro- 1 1 H,5 1 The method of preparing H-8, 11-dioxa-4-aza-5(2, 1)-benzo[d] imidazoxazol-2(2, 4)- pyridino- 1(4, 5)-pyrazacycloundecan-3-one is described in reference example 1.

[0542] MS m / z (ESI): 532.2 [M+H] + .

[0543] Example 76

[0544] (S,E)-5 6 -(((3aR,6aS)-5-acetylpiperazino[3,4-c]pyrrol-2(lH)-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 The method of preparing H-8, 11-dioxa-4-aza-5(2, 1)-benzo[d] imidazoxazol-2(2, 4)- pyridino- 1(4, 5)-pyrazacycloundecan-3-one is described in reference example 1.

[0545]

[0546] (S,E)-5 6 -(((3aR,6aS)-5-acetylpiperazino[3,4-c]pyrrol-2(lH)-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 The method of preparing H-8, 11-dioxa-4-aza-5(2, 1)-benzo[d] imidazoxazol-2(2, 4)- pyridino- 1(4, 5)-pyrazacycloundecan-3-one is described in reference example 1.

[0547] MS m / z (ESI): 599.2 [M+H] + .

[0548] Example 77

[0549] (S,E)-1 1 ,2 6 ,7-trimethyl-5 6 -(((3aR,6aS)-5-(methanesulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0550]

[0551] (S,E)-1 1 ,2 6 ,7-trimethyl-5 6 -(((3aR,6aS)-5-(methanesulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0552] MS m / z (ESI): 635.2 [M+H] + .

[0553] Example 78

[0554] (S,E)-1 1 ,2 6 ,7-trimethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0555]

[0556] (S,E)-1 1 ,2 6 ,7-trimethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0557] MS m / z (ESI): 558.2 [M+H] + .

[0558] Example 79

[0559] (S,E)-5 6 -((3-fluoro-3-(2-hydroxypropane-2-yl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0560]

[0561] (S,E)-5 6 -((3-fluoro-3-(2-hydroxypropane-2-yl)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-8,11-dioxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0562] MS m / z(ESI): 578.2 [M+H] + .

[0563] Example 80

[0564] (R,E)-1 1 ,2 6 ,7-trimethyl-5 5 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-thieno[2,3-d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0565]

[0566] (R,E)-1 1 ,2 6 ,7-trimethyl-5 5 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-thieno[2,3-d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0567] MS m / z (ESI): 549.2 [M+H] + .

[0568] Example 81

[0569] (R,E)-5 5 -((3-(dimethylamino)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-thieno[2,3-d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0570]

[0571] (R,E)-5 5 -((3-(dimethylamino)acetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 5 3- dihydro-1 1 H, 5 1 The preparation of (R,E)-2-(1-((1

[0572] MS m / z (ESI): 549.2 [M+H] + .

[0573] Example 82

[0574] (R,E)-2-(1-((1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 - dihydro-1 1 H, 5 1 The preparation of (R,E)-2-(1-((1

[0575]

[0576] (R,E)-2-(1-((1 1 ,2 6 ,7-trimethyl-3-oxo-5 2 ,5 3 - dihydro-1 1 H, 5 1 The preparation of (R,E)-2-(1-((1

[0577] MS m / z (ESI): 545.2 [M+H] + .

[0578] Example 83

[0579] (R,E)-5 5 -((3-(methoxymethyl)azetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 - dihydro-1 1 H, 5 1Preparation of H-11-oxa-4-aza-5(2,1)-thieno[2,3-d]imidazo-2(2,4)-pyridino-1(4,5)- pyrazolodecan-3-one

[0580]

[0581] (R,E)-5 5 -((3-(methoxymethyl)azetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 The method of preparing H-11-oxa-4-aza-5(2,1)-thieno[2,3-d]imidazo-2(2,4)-pyridino-1(4,5)- pyrazolodecan-3-one is described in reference example 1.

[0582] MS m / z (ESI): 550.2 [M+H] + .

[0583] Example 84

[0584] (R,E)-5 5 -((3-methoxyazetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 The method of preparing H-11-oxa-4-aza-5(2,1)-thieno[2,3-d]imidazo-2(2,4)-pyridino-1(4,5)- pyrazolodecan-3-one

[0585]

[0586] (R,E)-5 5 -((3-methoxyazetidin-1-yl)methyl)-1 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 The method of preparing H-11-oxa-4-aza-5(2,1)-thieno[2,3-d]imidazo-2(2,4)-pyridino-1(4,5)- pyrazolodecan-3-one is described in reference example 1.

[0587] MS m / z (ESI): 536.2 [M+H]+ .

[0588] Example 85

[0589] (R,E)-5 5 -(((3aR,6aS)-5-acetyloctahydro pyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,l)-thieno[2,3-d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolocycloundecan-3-one

[0590]

[0591] (R,E)-5 5 -(((3aR,6aS)-5-acetyloctahydro pyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,l)-thieno[2,3-d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolocycloundecan-3-one

[0592] MS m / z (ESI): 603.2 [M+H] + .

[0593] Example 86

[0594] (R,E)-l 1 ,2 6 ,7-trimethyl-5 5 -(((3aR,6aS)-5-(methylsulfonyl)octahydro pyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-5 2 ,5 3 -dihydro-l 1 H,5 1 H-11-oxa-4-aza-5(2,l)-thieno[2,3-d]imidazoazol-2(2,4)-pyridine-l(4,5)- pyrazolocycloundecan-3-one

[0595]

[0596] (R,E)-1 1 ,2 6 ,7-trimethyl-5 5 -(((3aR,6aS)-5-(methanesulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-thieno[2,3-d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0597] MS m / z (ESI): 639.2 [M+H] + .

[0598] Example 87

[0599] (R,E)-1 1 ,2 6 ,7-trimethyl-5 5 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-thieno[2,3-d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0600]

[0601] (R,E)-1 1 ,2 6 ,7-trimethyl-5 5 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-11-oxa-4-aza-5(2,1)-thieno[2,3-d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one is as described in Example 1.

[0602] MS m / z (ESI): 562.2 [M+H] + .

[0603] Example 88

[0604] (R,E)-5 5 -((3-Fluoro-3-(2-hydroxypropan-2-yl)azetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,l)-thieno[2,3-d]imidazoazol-2(2,4)- pyridine-l(4,5)-pyrazolacycloundecan-3-one

[0605]

[0606] (R,E)-5 5 -((3-Fluoro-3-(2-hydroxypropan-2-yl)azetidin-l-yl)methyl)-l 1 ,2 6 ,7-trimethyl-5 2 ,5 3 -dihydro-l 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,l)-thieno[2,3-d]imidazoazol-2(2,4)- pyridine-l(4,5)-pyrazolacycloundecan-3-one

[0607] MS m / z (ESI): 582.2 [M+H] + .

[0608] Example 89

[0609] (5 2 E,7Z)-l 1 ,2 6 ,7-trimethyl-5 6 -((4-Methylpiperazin-l-yl)methyl)-5 2 ,5 3 -dihydro-l 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,l)-benzo[d]imidazoazol-2(2,4)-pyridine- l(4,5)-pyrazolacycloundecan-7-en-3-one

[0610]

[0611] (5 2 E,7Z)-l 1 ,2 6 ,7-trimethyl-5 6-((4-methylpiperazin- 1 -yl)methyl)-5 2 ,5 3 - dihydro- 1 1 H,5 1 H- 11 -oxa-4-aza-5(2, 1 )-benzo[d] imidazoazol-2(2,4)-pyridine- 1 (4,5)- pyrazolacycloundec-7-ene-3-one was prepared according to the procedure described in Example 1.

[0612] MS m / z (ESI): 541.2 [M+H] + .

[0613] Example 90

[0614] (5 2 E,7E)-1 1 ,2 6 - dihydro- 1 6 -((4-methylpiperazin- 1 -yl)methyl)-5 2 ,5 3 - dihydro- 1 1 H,5 1 H- 11 -oxa-4-aza-5(2, 1 )-benzo[d] imidazoazol-2(2,4)-pyridine- 1 (4,5)- pyrazolacycloundec-7-ene-3-one was prepared according to the procedure described in Example 1.

[0615]

[0616] (5 2 E,7E)-1 1 ,2 6 - dihydro- 1 6 -((4-methylpiperazin- 1 -yl)methyl)-5 2 ,5 3 - dihydro- 1 1 H,5 1 H- 11 -oxa-4-aza-5(2, 1 )-benzo[d] imidazoazol-2(2,4)-pyridine- 1 (4,5)- pyrazolacycloundec-7-ene-3-one was prepared according to the procedure described in Example 1.

[0617] MS m / z (ESI): 527.2 [M+H] + .

[0618] Example 91

[0619] Preparation of (E)-2-methyl-4-(l-methyl-lH-pyrazol-4-yl)-l l-((4- methylpiperazin- 1 -yl)methyl)-7,8-dihydro-6H-benzo[4,5] imidazo[2, 1 - f]pyrido[3,4-b][l,5,7]oxadiazocin-16(14H)-one

[0620]

[0621] The method of preparing (E)-2-methyl-4-(l-methyl-lH-pyrazol-4-yl)-l l-((4- methylpiperazin- 1 -yl)methyl)-7,8-dihydro-6H-benzo[4,5] imidazo[2, 1 - f]pyrido[3,4-b][l,5,7]oxadiazocin-16(14H)-one is described in Reference Example 1.

[0622] MS m / z (ESI): 501.2 [M+H] + .

[0623] Example 92

[0624] Preparation of (E)-2-methyl-4-(l-methyl-lH-pyrazol-4-yl)-l l-((4- methylpiperazin- 1 -yl)methyl)-7,8-dihydro-6H-benzo[4,5] imidazo[2, 1 - f]pyrido[3,4-b][l,5,7]oxadiazocin-16(14H)-one

[0625]

[0626] The method of preparing (E)-2-methyl-4-(l-methyl-lH-pyrazol-4-yl)-l l-((4- methylpiperazin- 1 -yl)methyl)-7,8-dihydro-6H-benzo[4,5] imidazo[2, 1 - f]pyrido[3,4-b][l,5,7]oxadiazocin-16(14H)-one is described in Reference Example 1.

[0627] MS m / z (ESI): 515.2 [M+H] + .

[0628] Example 93

[0629] Preparation of (E)-2-methyl-4-(l-methyl-lH-pyrazol-4-yl)-l l-((4- methylpiperazin- 1 -yl)methyl)-7,8-dihydro-6H-benzo[4,5] imidazo[2, 1 - f]pyrido[3,4-b][l,5,7]oxadiazocin-16(14H)-one

[0630]

[0631] The preparation method of (E)-2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-13-((4-methylpiperazin-1-yl)methyl)-7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[2,1-f]pyrido[3,4-b][1]oxa[5,7]diazacyclododecano-18(16H)-one is as described in Example 1.

[0632] MS m / z (ESI): 529.2 [M+H] + .

[0633] Example 94

[0634] Preparation of (E)-1,23-dimethyl-12-((4-methylpiperazin-1-yl)methyl)-1,15,16,17,18,20-hexahydro-4,6-(azaene-bridged)-5,19-methylenebenzo[4,5]imidazo[2,1-b]pyrazolo[3,4-j][1,3,8]triacrondecadecin-7(9H)-one

[0635]

[0636] The preparation method of (E)-1,23-dimethyl-12-((4-methylpiperazin-1-yl)methyl)-1,15,16,17,18,20-hexahydro-4,6-(azene-bridged)-5,19-methylenebenzo[4,5]imidazo[2,1-b]pyrazolo[3,4-j][1,3,8]triacrondecadecin-7(9H)-one is described in Example 1.

[0637] MS m / z (ESI): 540.2 [M+H] + .

[0638] Example 95

[0639] (1 3 Z,5 2 E)-2 6 -Methyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 Preparation of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one

[0640]

[0641] (1 3 Z,5 2 E)-2 6 -Methyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 The preparation method of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one is as described in Example 1.

[0642] MS m / z (ESI): 540.2 [M+H] + .

[0643] Example 96

[0644] (E)-2 6 -Methyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 5 ,1 6 5 2 5 3 -Tetrahydro-1 4 H,5 1 Preparation of H-10-oxa-4-aza-5(2,1)-benzo[d]imidazo[1,4]-pyrrolo[1,2-b]pyranoacazol-2(2,4)-pyridinecyclodecane-3-one

[0645]

[0646] (E)-2 6 -Methyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 5 ,1 6 5 2 5 3 -Tetrahydro-1 4 H,5 1 The preparation method of H-10-oxa-4-aza-5(2,1)-benzo[d]imidazo[1,2-b]pyrrolo[1,2-b]pyrano[2,4]pyridinecyclodecane-3-one is as described in Example 1.

[0647] MS m / z (ESI): 541.2 [M+H] + .

[0648] Example 97

[0649] (E)-2 6 -methyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-4-aza-5(2,1)-benzo[d]imidazoazol-1(2,1)-indol-2(2,4)- pyridine cycloundecan-3-one

[0650]

[0651] (E)-2 6 -methyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-4-aza-5(2,1)-benzo[d]imidazoazol-1(2,1)-indol-2(2,4)- pyridine cycloundecan-3-one

[0652] MS m / z (ESI): 562.2 [M+H] + .

[0653] Example 98

[0654] (E)-1 1 ,2 6 -dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-1(5,4),5(2,1)-diazolo-2(2,4)-pyridine cycloundecan-3-one

[0655]

[0656] (E)-1 1 ,2 6 -dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1The preparation of H-11-oxa-4-aza-1 (5,4), 5(2,1)-diazolyl-2(2,4)- pyridinocycloundecan-3-one is described in reference example 1.

[0657] MS m / z (ESI): 579.2 [M+H] + .

[0658] Example 99

[0659] (E)-1 2 ,2 6 -dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 2 H,5 1 H-11-oxa-4-aza-1 (5,4), 5(2,1)-diazolyl-2(2,4)- pyridinocycloundecan-3-one

[0660]

[0661] (E)-1 2 ,2 6 -dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 2 H,5 1 H-11-oxa-4-aza-1 (5,4), 5(2,1)-diazolyl-2(2,4)- pyridinocycloundecan-3-one

[0662] MS m / z (ESI): 579.2 [M+H] + .

[0663] Example 100

[0664] (E)-2 6 -methyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 ,5 2 ,5 3 -tetrahydro-5 1 H-11-oxa-4-aza-5 (2,1)-benzo[d]imidazolyl-2(2,4)- pyridin-1 (6,5)-benzo[b][1,4]dioxinocyclododecan-3-one

[0665]

[0666] (E)-2 6 - methyl -5 6 - ((4-methylpiperazin- 1 -yl)methyl) - 1 2 , 1 3 , 5 2 , 5 3 - tetrahydro -5 1 The preparation of H- 11 -oxa-4-aza-5(2, 1)-benzo[d] imidazoazol-2(2, 4)- pyridine- 1(6, 5)-benzo[b][l, 4]dioxine -3 -one is described in Example 1.

[0667] MS m / z (ESI): 583.2 [M+H] + .

[0668] Example 101

[0669] (E)-2 6 - methyl -5 6 - ((4-methylpiperazin- 1 -yl)methyl) - 1 2 , 5 3 - dihydro -5 1 The preparation of H- 11 -oxa-4-aza-5(2, 1)-benzo[d] imidazoazol-2(2, 4)- pyridine- 1(5, 4)-benzo[d][l, 3]dioxolane-3 -one is described in Example 1.

[0670]

[0671] (E)-2 6 - methyl -5 6 - ((4-methylpiperazin- 1 -yl)methyl) - 1 2 , 5 3 - dihydro -5 1 The preparation of H- 11 -oxa-4-aza-5(2, 1)-benzo[d] imidazoazol-2(2, 4)- pyridine- 1(5, 4)-benzo[d][l, 3]dioxolane-3 -one is described in Example 1.

[0672] MS m / z (ESI): 569.2 [M+H] + .

[0673] Example 102

[0674] (E)-2 6 - methyl -5 6 - ((4-methylpiperazin- 1 -yl)methyl) - 1 2 , 5 3 - dihydro -5 1Preparation of H-11-oxa-4-aza-1 (6, 5)-quinoxaline-5 (2, 1)-benzo[d] imidazoazol-2 (2, 4)- pyridine cycloundecan-3-one

[0675]

[0676] (E)-2 6 - methyl-5 6 - ((4-methylpiperazin-1-yl)methyl)-5 2 , 5 3 - dihydro-5 1 The preparation of H-11-oxa-4-aza-1 (6, 5)-quinoxaline-5 (2, 1)-benzo[d] imidazoazol-2 (2, 4)- pyridine cycloundecan-3-one is according to Example 1.

[0677] MS m / z (ESI): 577.2 [M+H] + .

[0678] Example 103

[0679] (1 3 Z, 1 4 E, 5 2 (E)-2 6 - methyl-5 6 - ((4-methylpiperazin-1-yl)methyl)-5 2 , 5 3 - dihydro-5 1 The preparation of H-10-oxa-4-aza-1 (3, 5), 5 (2, 1)-dipyrazolo[1, 5-a]pyridine-2 (2, 4)- pyridine cycloundecan-3-one is according to Example 1.

[0680]

[0681] (1 3 Z, 1 4 E, 5 2 (E)-2 6 - methyl-5 6 - ((4-methylpiperazin-1-yl)methyl)-5 2 , 5 3 - dihydro-5 1 The preparation of H-10-oxa-4-aza-1 (3, 5), 5 (2, 1)-dipyrazolo[1, 5-a]pyridine-2 (2, 4)- pyridine cycloundecan-3-one is according to Example 1.

[0682] MS m / z (ESI): 551.2 [M+H] + .

[0683] Example 104

[0684] (E)-2 6 - methyl -5 6 - ((4-methylpiperazin- 1 -yl)methyl) - 1 3 , 1 4 , 5 2 , 5 3 - tetrahydro- 1 2 H, 5 1 H-4-aza- 1 (6,4)- benzo [b] [ 1,4] oxazin-5 (2, 1)- benzo [d] imidazoazol-2 (2,4)- pyridine cycloundecan-3-one

[0685]

[0686] (E)-2 6 - methyl -5 6 - ((4-methylpiperazin- 1 -yl)methyl) - 1 3 , 1 4 , 5 2 , 5 3 - tetrahydro- 1 2 H, 5 1 H-4-aza- 1 (6,4)- benzo [b] [ 1,4] oxazin-5 (2, 1)- benzo [d] imidazoazol-2 (2,4)- pyridine cycloundecan-3-one

[0687] MS m / z (ESI): 566.2 [M+H] + .

[0688] Example 105

[0689] (E)-1 4 , 2 6 - dimethyl -5 6 - ((4-methylpiperazin- 1 -yl)methyl) - 1 1 , 1 2 , 1 3 , 1 4 , 5 2 , 5 3 - hexahydro- 5 1 H-4-aza- 1 (7, 1)- quinoxaline-5 (2, 1)- benzo [d] imidazoazol-2 (2,4)- pyridine cyclodecan-3-one

[0690]

[0691] (E)-1 4 , 2 6 - dimethyl -5 6-((4-methylpiperazin- 1 -yl)methyl)- 1 1 ,1 2 ,1 3 ,1 4 ,5 2 ,5 3 - hexahydro-5 1 The preparation of H-4-aza- 1 (7, 1)-quinoxalino-5(2, 1)-benzo[d] imidazoazol-2(2,4)- pyridine- 1 (4,5)-pyrazacycloundecan-3-one was carried out according to Example 1.

[0692] MS m / z (ESI): 579.2 [M+H] + .

[0693] Example 106

[0694] (R,E)-2 6 - cyclopropyl- 1 1 ,7-dimethyl-5 6 -((4-methylpiperazin- 1 -yl)methyl)-5 2 ,5 3 - dihydro- 1 1 H,5 1 The preparation of H- 11 -oxa-4-aza-5(2, 1)-benzo[d]imidazoazol-2(2,4)-pyridine- 1 (4,5)- pyrazacycloundecan-3-one was carried out according to Example 1.

[0695]

[0696] (R,E)-2 6 - cyclopropyl- 1 1 ,7-dimethyl-5 6 -((4-methylpiperazin- 1 -yl)methyl)-5 2 ,5 3 - dihydro- 1 1 H,5 1 The preparation of H- 11 -oxa-4-aza-5(2, 1)-benzo[d]imidazoazol-2(2,4)-pyridine- 1 (4,5)- pyrazacycloundecan-3-one was carried out according to Example 1.

[0697] 1H NMR(400MHz,CD3Cl)δ0.91(d,J=6.6Hz,3H),0.97-1.02(m,2H),1.10-1.16(m,2H),1.45-1.57(m,3H) ,1.91-2.01(m,2H),2.10-2.20(m,2H),2.23-2.31(m,1H),2.41-2.49(m,3H),2.59-2.74(m,5H),2.81 -2.89(m,1H),3.64-3.76(m,3H),3.78(s,3H),3.84-3.92(m,1H),4.31-4.40(m,1H),4.42-4.51(m,1H ),7.19-7.23(m,1H),7.27-7.34(m,2H),7.63(s,1H),8.10(s,1H),8.41(s,1H),11.89-12.06(m,1H);

[0698] MS m / z (ESI): 569.2 [M+H] + .

[0699] Example 107

[0700] (R,E)-1 1 ,7-Dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-3-carbonyl-5 2 5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-2 6 Preparation of formonitrile

[0701]

[0702] (R,E)-1 1 ,7-Dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-3-carbonyl-5 2 5 3 -dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-2 6 - The preparation method of formonitrile is as described in Example 1.

[0703] MS m / z (ESI): 554.2 [M+H] + .

[0704] Example 108

[0705] (R,E)-1 1 ,7- dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-2 6 -(trifluoromethyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazoloazepin-2(2,4)- pyridine-1(4,5)-pyrazolacycloundecan-3-one

[0706]

[0707] (R,E)-1 1 ,7- dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-2 6 -(trifluoromethyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazoloazepin-2(2,4)- pyridine-1(4,5)-pyrazolacycloundecan-3-one

[0708] MS m / z (ESI): 597.2 [M+H] + .

[0709] Example 109

[0710] (R,E)-1 1 ,7- dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-2 6 -phenyloxy-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d] imidazoloazepin-2(2,4)- pyridine-1(4,5)-pyrazolacycloundecan-3-one

[0711]

[0712] (R,E)-1 1 ,7- dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-2 6Phenoxy-5 2 ,5 3 Dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one was prepared according to Example 1.

[0713] MS m / z (ESI): 621.2 [M+H] + .

[0714] Example 110

[0715] (R,E)-1 1 ,7-Dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-2 6 -(phenylamino)-5 2 ,5 3 Dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one was prepared according to Example 1.

[0716]

[0717] (R,E)-1 1 ,7-Dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-2 6 -(phenylamino)-5 2 ,5 3 Dihydro-1 1 H,5 1 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one was prepared according to Example 1.

[0718] MS m / z (ESI): 620.2 [M+H] + .

[0719] Example 111

[0720] (1 3 Z,5 2 E,7R)-2 6 ,7-Dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,17 ,5 2 ,5 3 - hexahydro-5 1 Preparation of H-4-aza-1 (3, 5)- pyrazolo [1, 5-a] pyrazine-5 (2, 1)- benzo [d] imidazolazol-2 (2, 4)- pyridinocyclononan-3-one

[0721]

[0722] (1 3 Z,5 2 E,7R)-2 6 ,7- dimethyl-5 6 - ((4-methylpiperazin-1-yl) methyl)-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 Preparation of H-4-aza-1 (3, 5)- pyrazolo [1, 5-a] pyrazine-5 (2, 1)- benzo [d] imidazolazol-2 (2, 4)- pyridinocyclononan-3-one

[0723] MS m / z (ESI): 554.2 [M+H] + .

[0724] Example 112

[0725] (1 3 Z,5 2 E,7R)-5 6 - ((3-(dimethylamino) azetidin-1-yl) methyl)-2 6 ,7- dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 Preparation of H-4-aza-1 (3, 5)- pyrazolo [1, 5-a] pyrazine-5 (2, 1)- benzo [d] imidazolazol-2 (2, 4)- pyridinocyclononan-3-one

[0726]

[0727] (1 3 Z,5 2 E,7R)-5 6 - ((3-(dimethylamino) azetidin-1-yl) methyl)-2 67-dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 The preparation of H-4-aza-1 (3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)- benzo[d]imidazolazol-2(2,4)-pyridinocyclononan-3-one is described in Example 1.

[0728] MS m / z (ESI): 554.2 [M+H] + .

[0729] Example 113

[0730] 2-(1-(((1 3 Z,5 2 E,7R)-2 6 ,7-dimethyl-3-oxo-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 The preparation of H-4-aza-1 (3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)- benzo[d]imidazolazol-2(2,4)-pyridinocyclononan-5 6 -yl)methyl)azetidin-3-yl)acetonitrile is described in Example 1.

[0731]

[0732] 2-(1-(((1 3 Z,5 2 E,7R)-2 6 ,7-dimethyl-3-oxo-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 The preparation of H-4-aza-1 (3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)- benzo[d]imidazolazol-2(2,4)-pyridinocyclononan-5 6 -yl)methyl)azetidin-3-yl)acetonitrile is described in Example 1.

[0733] MS m / z (ESI): 550.2 [M+H] + .

[0734] Example 114

[0735] (1 3 Z,5 2 E,7R)-5 6 -((3-(methoxymethyl)azetidin-l-yl)methyl)-2 6 ,7-dimethyl-l 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -hexahydro-5 1 Preparation of H-4-aza-l(3,5)-pyrazolo[l,5-a]pyrazine-5(2,l)-benzo[d]imidazoloxazol-2(2,4)- pyridinonan-3-one

[0736]

[0737] (1 3 Z,5 2 E,7R)-5 6 -((3-(methoxymethyl)azetidin-l-yl)methyl)-2 6 ,7-dimethyl-l 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -hexahydro-5 1 Preparation of H-4-aza-l(3,5)-pyrazolo[l,5-a]pyrazine-5(2,l)-benzo[d]imidazoloxazol-2(2,4)- pyridinonan-3-one

[0738] MS m / z (ESI): 555.2 [M+H] + .

[0739] Example 115

[0740] (1 3 Z,5 2 E,7R)-5 6 -((3-(methoxymethyl)azetidin-l-yl)methyl)-2 6 ,7-dimethyl-l 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -hexahydro-5 1Preparation of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one

[0741]

[0742] (1 3 Z,5 2 E,7R)-5 6 -((3-methoxyacryl-1-yl)methyl)-2 6 ,7-Dimethyl-1 4 ,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 The preparation method of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one is as described in Example 1.

[0743] MS m / z (ESI): 541.2 [M+H] + .

[0744] Example 116

[0745] (1 3 Z,5 2 E,7R)-5 6 -(((3aR,6aS)-5-acetylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-2 6 ,7-Dimethyl-1 4 ,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 Preparation of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one

[0746]

[0747] (1 3 Z,5 2 E,7R)-5 6 -(((3aR,6aS)-5-acetylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-2 6 ,7-Dimethyl-1 4,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 The preparation method of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one is as described in Example 1.

[0748] MS m / z (ESI): 608.2 [M+H] + .

[0749] Example 117

[0750] (1 3 Z,5 2 E,7R)-2 6 ,7-Dimethyl-5 6 -(((3aR,6aS)-5-(methanesulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 Preparation of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one

[0751]

[0752] (1 3 Z,5 2 E,7R)-2 6 ,7-Dimethyl-5 6 -(((3aR,6aS)-5-(methanesulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 The preparation method of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one is as described in Example 1.

[0753] MS m / z (ESI): 644.2 [M+H] + .

[0754] Example 118

[0755] (1 3 Z,5 2 E,7R)-2 6 ,7-Dimethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 Preparation of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one

[0756]

[0757] (1 3 Z,5 2 E,7R)-2 6 ,7-Dimethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 The preparation method of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one is as described in Example 1.

[0758] MS m / z (ESI): 567.2 [M+H] + .

[0759] Example 119

[0760] (1 3 Z,5 2 E,7R)-5 6 -((3-fluoro-3-(2-hydroxypropane-2-yl)acetidin-1-yl)methyl)-2 6 ,7-Dimethyl-1 4 ,1 5 ,1 6 ,1 7 5 2,5 3 - Hexahydro-5 1 Preparation of H-4-aza-1 (3,5)-pyrazolo[1,5-a]pyrazin-5(2,1)- benzo[d]imidazoazol-2(2,4)-pyridinocyclononan-3-one

[0761]

[0762] (1 3 Z,5 2 E,7R)-5 6 -((3-fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - Hexahydro-5 1 Preparation of H-4-aza-1 (3,5)-pyrazolo[1,5-a]pyrazin-5(2,1)- benzo[d]imidazoazol-2(2,4)-pyridinocyclononan-3-one

[0763] MS m / z (ESI): 587.2 [M+H] + .

[0764] Example 120

[0765] (R,E)-2 6 ,7-dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 ,5 2 ,5 3 - Tetrahydro-1 1 H,5 1 Preparation of H-4-aza-5(2,1)-benzo[d]imidazoazolo-1 (7,1)- imidazo[1,2-b]pyranazol-2(2,4)-pyridinocyclodecan-3-one

[0766]

[0767] (R,E)-2 6 ,7-dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 2 ,1 3 ,5 2 ,5 3 - Tetrahydro-1 1 H,5 1The preparation of H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)- imidazo[1,2-b]pyranazol-2(2,4)-pyridinecyclodecan-3-one is described in Example 1.

[0768] MS m / z (ESI): 554.2 [M+H] + .

[0769] Example 121

[0770] (R,E)-5 6 -((3-(dimethylamino)azetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 2 ,1 3 ,5 2 ,5 3 -tetrahydro-1 1 H,5 1 Preparation of H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)- imidazo[1,2-b]pyranazol-2(2,4)-pyridinecyclodecan-3-one

[0771]

[0772] (R,E)-5 6 -((3-(dimethylamino)azetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 2 ,1 3 ,5 2 ,5 3 -tetrahydro-1 1 H,5 1 Preparation of H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)- imidazo[1,2-b]pyranazol-2(2,4)-pyridinecyclodecan-3-one

[0773] MS m / z (ESI): 554.2 [M+H] + .

[0774] Example 122

[0775] (R,E)-2-(1-((2 6 ,7-dimethyl-3-oxo-1 2 ,1 3 ,5 2 ,5 3 -tetrahydro-1 1 H,5 1H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)-imidazo[1,2-b]pyranazol-2(2,4)- pyridine cyclo decan-5 6 Preparation of (E)-2-(1-((2

[0776]

[0777] (R,E)-2-(1-((2 6 ,7- dimethyl-3-oxo-1 2 ,1 3 ,5 2 ,5 3 - tetrahydro-1 1 H,5 1 H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)-imidazo[1,2-b]pyranazol-2(2,4)- pyridine cyclo decan-5 6 The preparation method of (E)-2-(1-((2

[0778] MS m / z (ESI): 550.2 [M+H] + .

[0779] Example 123

[0780] (R,E)-5 6 -((3-(methoxymethyl)azetidin-1-yl)methyl)-2 6 ,7- dimethyl-1 2 ,1 3 ,5 2 ,5 3 - tetrahydro-1 1 H,5 1 H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)-imidazo[1,2-b]pyranazol-2(2,4)- pyridine cyclo decan-5

[0781]

[0782] (R,E)-5 6 -((3-(methoxymethyl)azetidin-1-yl)methyl)-2 6 ,7- dimethyl-1 2 ,1 3 ,5 2 ,5 3 - tetrahydro-1 1 H,5 1The preparation of H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)- imidazo[1,2-b]pyranazol-2(2,4)-pyridinecyclodecan-3-one is described in Example 1.

[0783] MS m / z (ESI): 555.2 [M+H] + .

[0784] Example 124

[0785] (R,E)-5 6 -((3-methoxyazetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 2 ,1 3 ,5 2 ,5 3 -tetrahydro-1 1 H,5 1 Preparation of H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)- imidazo[1,2-b]pyranazol-2(2,4)-pyridinecyclodecan-3-one

[0786]

[0787] (R,E)-5 6 -((3-methoxyazetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 2 ,1 3 ,5 2 ,5 3 -tetrahydro-1 1 H,5 1 Preparation of H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)- imidazo[1,2-b]pyranazol-2(2,4)-pyridinecyclodecan-3-one

[0788] MS m / z (ESI): 541.2 [M+H] + .

[0789] Example 125

[0790] (R,E)-5 6 -(((3aR,6aS)-5-acetylpyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-2 6 ,7-dimethyl-1 2 ,1 3 ,5 2 ,5 3 -tetrahydro-1 1 H,51 Preparation of H-4-aza-5(2,1)-benzo[d]imidazozozo-1(7,1)-imidazo[1,2-b]pyranoacazol-2(2,4)-pyridinecyclodecane-3-one

[0791]

[0792] (R,E)-5 6 -(((3aR,6aS)-5-acetylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-2 6 ,7-Dimethyl-1 2 ,1 3 5 2 5 3 -Tetrahydro-1 1 H,5 1 The preparation method of H-4-aza-5(2,1)-benzo[d]imidazozozo-1(7,1)-imidazo[1,2-b]pyrano-acazol-2(2,4)-pyridinecyclodecane-3-one is as described in Example 1.

[0793] MS m / z (ESI): 608.2 [M+H] + .

[0794] Example 126

[0795] (R,E)-2 6 ,7-Dimethyl-5 6 -(((3aR,6aS)-5-(methanesulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-1 2 ,1 3 5 2 5 3 -Tetrahydro-1 1 H,5 1 Preparation of H-4-aza-5(2,1)-benzo[d]imidazozozo-1(7,1)-imidazo[1,2-b]pyranoacazol-2(2,4)-pyridinecyclodecane-3-one

[0796]

[0797] (R,E)-2 6 ,7-Dimethyl-5 6 -(((3aR,6aS)-5-(methanesulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)methyl)-1 2 ,1 3 5 2 5 3 -Tetrahydro-1 1 H,51 The preparation method of H-4-aza-5(2,1)-benzo[d]imidazozozo-1(7,1)-imidazo[1,2-b]pyrano-acazol-2(2,4)-pyridinecyclodecane-3-one is as described in Example 1.

[0798] MS m / z (ESI): 644.2 [M+H] + .

[0799] Example 127

[0800] (R,E)-2 6 ,7-Dimethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-1 2 ,1 3 5 2 5 3 -Tetrahydro-1 1 H,5 1 Preparation of H-4-aza-5(2,1)-benzo[d]imidazozozo-1(7,1)-imidazo[1,2-b]pyranoacazol-2(2,4)-pyridinecyclodecane-3-one

[0801]

[0802] (R,E)-2 6 ,7-Dimethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl)-1 2 ,1 3 5 2 5 3 -Tetrahydro-1 1 H,5 1 The preparation method of H-4-aza-5(2,1)-benzo[d]imidazozozo-1(7,1)-imidazo[1,2-b]pyrano-acazol-2(2,4)-pyridinecyclodecane-3-one is as described in Example 1.

[0803] MS m / z (ESI): 567.2 [M+H] + .

[0804] Example 128

[0805] (R,E)-5 6 -((3-fluoro-3-(2-hydroxypropane-2-yl)acetidin-1-yl)methyl)-2 6 ,7-Dimethyl-1 2 ,1 3 52 ,5 3 - Tetrahydro-1 1 H,5 1 H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)-imidazo[1,2-b]pyranazol-2(2,4)- pyridacyclodecane-3-one

[0806]

[0807] (R,E)-5 6 -((3-fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 2 ,1 3 ,5 2 ,5 3 - Tetrahydro-1 1 H,5 1 H-4-aza-5(2,1)-benzo[d]imidazoazolo-1(7,1)-imidazo[1,2-b]pyranazol-2(2,4)- pyridacyclodecane-3-one

[0808] MS m / z (ESI): 587.2 [M+H] + .

[0809] Example 129

[0810] (R,E)-2 6 ,7-dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - Hexahydro-5 1 H-4-aza-1(3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)-benzo[d]imidazoazolo-2(2,4)- pyridacyclodecane-3-one

[0811]

[0812] (R,E)-2 6 ,7-dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3hexahydro-5 1 The preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)- benzo[d]imidazoloxazol-2(2,4)-pyridinocyclodecan-3-one was prepared according to Example 1.

[0813] MS m / z (ESI): 568.2 [M+H] + .

[0814] Example 130

[0815] (R,E)-5 6 -((3-(dimethylamino)azetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 hexahydro-5 1 The preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)- benzo[d]imidazoloxazol-2(2,4)-pyridinocyclodecan-3-one

[0816]

[0817] (R,E)-5 6 -((3-(dimethylamino)azetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 hexahydro-5 1 The preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)- benzo[d]imidazoloxazol-2(2,4)-pyridinocyclodecan-3-one was prepared according to Example 1.

[0818] MS m / z (ESI): 568.2 [M+H] + .

[0819] Example 131

[0820] (R,E)-2-(1-((2 6 ,7-dimethyl-3-oxo-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3hexahydro-5 1 H-4-azepin-1 (3,4)-pyrazolo[1,5-a]pyrimidin-5(2,1)-benzo[d]imidazoloxazol-2(2,4)- pyridinocyclodecan-5 6 Process for the preparation of (E)-2-(1-((3-(methoxymethyl)azetidin-1-yl)methyl)-2- oxazetidin-3-yl)acetonitrile

[0821]

[0822] (R,E)-2-(1-((2 6 ,7-dimethyl-3-oxo-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 hexahydro-5 1 H-4-azepin-1 (3,4)-pyrazolo[1,5-a]pyrimidin-5(2,1)-benzo[d]imidazoloxazol-2(2,4)- pyridinocyclodecan-5 6 Process for the preparation of (E)-2-(1-((3-(methoxymethyl)azetidin-1-yl)methyl)-2- oxazetidin-3-yl)acetonitrile

[0823] MS m / z (ESI): 564.2 [M+H] + .

[0824] Example 132

[0825] (R,E)-5 6 -((3-(methoxymethyl)azetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 hexahydro-5 1 H-4-azepin-1 (3,4)-pyrazolo[1,5-a]pyrimidin-5(2,1)-benzo[d]imidazoloxazol-2(2,4)- pyridinocyclodecan-3-one

[0826]

[0827] (R,E)-5 6 -((3-(methoxymethyl)azetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 hexahydro-51 A process for the preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidin-5(2,1)- benzo[d]imidazoloxazol-2(2,4)-pyridinocyclodecan-3-one is described in Example 1.

[0828] MS m / z (ESI): 569.2 [M+H] + .

[0829] Example 133

[0830] (R,E)-5 6 -((3-methoxyazetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -hexahydro-5 1 A process for the preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidin-5(2,1)- benzo[d]imidazoloxazol-2(2,4)-pyridinocyclodecan-3-one is described in Example 1.

[0831]

[0832] (R,E)-5 6 -((3-methoxyazetidin-1-yl)methyl)-2 6 ,7-dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -hexahydro-5 1 A process for the preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidin-5(2,1)- benzo[d]imidazoloxazol-2(2,4)-pyridinocyclodecan-3-one is described in Example 1.

[0833] MS m / z (ESI): 555.2 [M+H] + .

[0834] Example 134

[0835] (R,E)-5 6 -(((3aR,6aS)-5-acetyloxazolopyrrolidin-2(1H)-yl)methyl)-2 6 ,7-dimethyl-1 4 ,1 5 ,1 6 ,1​7 ,5 2 ,5 3 - hexahydro-5 1 Preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)-benzo[d]imidazoazol-2(2,4)- pyridinocyclodecan-3-one

[0836]

[0837] (R,E)-5 6 -(((3aR,6aS)-5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-2 6 ,7-dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 Method of preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)-benzo[d]imidazoazol-2(2,4)- pyridinocyclodecan-3-one refers to Example 1.

[0838] MS m / z (ESI): 622.2 [M+H] + .

[0839] Example 135

[0840] (R,E)-2 6 ,7-dimethyl-5 6 -(((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 Preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)-benzo[d]imidazoazol-2(2,4)- pyridinocyclodecan-3-one

[0841]

[0842] (R,E)-2 6 ,7-dimethyl-5 6 -(((3aR,6aS)-5-(methylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-1 4 ,15 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 The preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)- benzo[d]imidazoloxazol-2(2,4)-pyridinocyclodecan-3-one is described in Example 1.

[0843] MS m / z (ESI): 658.2 [M+H] + .

[0844] Example 136

[0845] (R,E)-2 6 ,7-dimethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 The preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)- benzo[d]imidazoloxazol-2(2,4)-pyridinocyclodecan-3-one is described in Example 1.

[0846]

[0847] (R,E)-2 6 ,7-dimethyl-5 6 -(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 The preparation of H-4-aza-1 (3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)- benzo[d]imidazoloxazol-2(2,4)-pyridinocyclodecan-3-one is described in Example 1.

[0848] MS m / z (ESI): 581.2 [M+H] + .

[0849] Example 137

[0850] (R,E)-56 -((3-Fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-2 6 ,7-Dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -Hexahydro-5 1 Preparation of H-4-aza-1 (3, 4)-pyrazolo [1, 5-a] pyrimidine-5 (2, 1)-benzo [d] imidazoloxazol-2 (2, 4)-pyridinocyclodecan-3-one

[0851]

[0852] (R, E)-5 6 -((3-Fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)-2 6 ,7-Dimethyl-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -Hexahydro-5 1 Preparation of H-4-aza-1 (3, 4)-pyrazolo [1, 5-a] pyrimidine-5 (2, 1)-benzo [d] imidazoloxazol-2 (2, 4)-pyridinocyclodecan-3-one

[0853] MS m / z (ESI): 601.2 [M+H] + .

[0854] Example 138

[0855] (1 3 Z,1 7 S,5 2 E,7R)-1 7 ,2 6 ,7-Trimethyl-5 6 -((4-Methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -Hexahydro-5 1 Preparation of H-4-aza-1 (3, 5)-pyrazolo [1, 5-a] pyrazine-5 (2, 1)-benzo [d] imidazoloxazol-2 (2, 4)-pyridinocyclononan-3-one

[0856]

[0857] (1 3 Z,1 7 S,5 2 E,7R)-1 7 ,2 6 ,7-trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 The preparation method of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one is as described in Example 1.

[0858] MS m / z (ESI): 568.2 [M+H] + .

[0859] Example 139

[0860] (1 3 Z,1 7 R,5 2 E,7R)-1 7 ,2 6 ,7-trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 5 2 5 3 -hexahydro-5 1 Preparation of H-4-aza-1(3,5)-pyrazolo[1,5-a]pyrazine-5(2,1)-benzo[d]imidazozozol-2(2,4)-pyridinecyclononane-3-one

[0861]

[0862] (1 3 Z,1 7 R,5 2 E,7R)-1 7 ,2 6 ,7-trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 5 2 53 - Hexahydro-5 1 The preparation of H-4-aza-1 (3,5)-pyrazolo[1,5-a]pyrazin-5(2,1)- benzo[d]imidazoazol-2(2,4)-pyridinocyclononan-3-one is described in Example 1.

[0863] MS m / z (ESI): 568.2 [M+H] + .

[0864] Example 140

[0865] (1 3 S,7R,E)-1 3 ,2 6 ,7-Trimethyl-5 6 -((4-methylpiperazin-1 -yl)methyl)-1 2 ,1 3 ,5 2 ,5 3 -Tetrahydro-1 1 H,5 1 The preparation of H-4-aza-5(2,1)-benzo[d]imidazoazolo-1 (7,1)- imidazo[1,2-b]pyranoazol-2(2,4)-pyridinocyclodecan-3-one is described in Example 1.

[0866]

[0867] (1 3 S,7R,E)-1 3 ,2 6 ,7-Trimethyl-5 6 -((4-methylpiperazin-1 -yl)methyl)-1 2 ,1 3 ,5 2 ,5 3 -Tetrahydro-1 1 H,5 1 The preparation of H-4-aza-5(2,1)-benzo[d]imidazoazolo-1 (7,1)- imidazo[1,2-b]pyranoazol-2(2,4)-pyridinocyclodecan-3-one is described in Example 1.

[0868] MS m / z (ESI): 568.2 [M+H] + .

[0869] Example 141

[0870] (1 3 R,7R,E)-1 3 ,2 6 ,7-Trimethyl-5 6- ((4-methylpiperazin- 1 -yl)methyl)- 1 2 ,1 3 ,5 2 ,5 3 - tetrahydro- 1 1 H,5 1 H-4-aza-5(2, 1)-benzo[d]imidazoazolo- 1(7, 1)-imidazo[l,2-b]pyranazol-2(2,4)- pyridacyclodecane-3-one

[0871]

[0872] (1 3 R,7R,E)-1 3 ,2 6 ,7- trimethyl-5 6 - ((4-methylpiperazin- 1 -yl)methyl)- 1 2 ,1 3 ,5 2 ,5 3 - tetrahydro- 1 1 H,5 1 H-4-aza-5(2, 1)-benzo[d]imidazoazolo- 1(7, 1)-imidazo[l,2-b]pyranazol-2(2,4)- pyridacyclodecane-3-one

[0873] MS m / z (ESI): 568.2 [M+H] + .

[0874] Example 142

[0875] (1 7 S,7R,E)-1 7 ,2 6 ,7- trimethyl-5 6 - ((4-methylpiperazin- 1 -yl)methyl)- 1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 - hexahydro-5 1 H-4-aza- 1(3,4)-pyrazolo[l,5-a]pyrimidine-5(2, 1)-benzo[d]imidazoazolo-2(2,4)- pyridacyclodecane-3-one

[0876]

[0877] (1 7 S,7R,E)-1 7 ,2 6,7-Trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -Hexahydro-5 1 The preparation of H-4-aza-1(3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)-benzo[d]imidazoazol-2(2,4)- pyridacyclodecan-3-one is described in Example 1.

[0878] MS m / z (ESI): 582.2 [M+H] + .

[0879] Example 143

[0880] (1 7 R,7R,E)-1 7 ,2 6 ,7-Trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -Hexahydro-5 1 The preparation of H-4-aza-1(3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)-benzo[d]imidazoazol-2(2,4)- pyridacyclodecan-3-one

[0881]

[0882] (1 7 R,7R,E)-1 7 ,2 6 ,7-Trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-1 4 ,1 5 ,1 6 ,1 7 ,5 2 ,5 3 -Hexahydro-5 1 The preparation of H-4-aza-1(3,4)-pyrazolo[1,5-a]pyrimidine-5(2,1)-benzo[d]imidazoazol-2(2,4)- pyridacyclodecan-3-one is described in Example 1.

[0883] MS m / z (ESI): 582.2 [M+H] + .

[0884] Example 144

[0885] (R,E)-2 6 -methoxy-1 1 ,7-dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one

[0886]

[0887] (R,E)-2 6 -methoxy-1 1 ,7-dimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-4-aza-5(2,1)-benzo[d]imidazoazol-2(2,4)-pyridine-1(4,5)- pyrazolacycloundecan-3-one

[0888] 1 H NMR (400 MHz, CD3Cl) δ 0.91 (d, J = 6.5 Hz, 3H), 1.47-1.58 (m, 1H), 1.92-2.01 (m, 3H), 2.11-2.18 (m, 1H), 2.23-2.31 (m, 1H), 2.38 (s, 3H), 2.52-2.65 (m, 6H), 2.80-2.92 (m, 1H), 3.59-3.69 (m, 2H), 3.69-3.75 (m, 1H), 3.79 (s, 3H), 3.85-3.92 (m, 1H), 4.03 (s, 3H), 4.31-4.39 (m, 1H), 4.46-4.54 (m, 1H), 7.18-7.23 (m, 1H), 7.27-7.33 (m, 3H), 8.11 (s, 1H), 8.26 (s, 1H), 11.91-12.10 (m, 1H);

[0889] MS m / z (ESI): 559.2 [M+H] + .

[0890] Example 145

[0891] (R,E)-1 1 ,2 6 ,7,10-Tetramethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-4,10-diaza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3,11-dione

[0892]

[0893] (R,E)-1 1 ,2 6 ,7,10-Tetramethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 The preparation method of H-4,10-diaza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3,11-dione is as described in Example 1.

[0894] MS m / z (ESI): 570.2 [M+H] + .

[0895] Example 146

[0896] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-3-thia-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3,3-dioxide

[0897]

[0898] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1H,5 1 The preparation method of H-11-oxa-3-thia-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolecycloundecane-3,3-dioxide is as described in Example 1.

[0899] MS m / z (ESI): 579.2 [M+H] + .

[0900] Example 147

[0901] Preparation of (R,E)-1',6',7'-trimethyl-6'-((4-methylpiperazin-1-yl)methyl)spiro[oxobutane-3,3'-11-oxa-4-aza-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5]-pyrazolium-1,5-cycloundecane]

[0902]

[0903] The preparation method of (R,E)-1',6',7'-trimethyl-6'-((4-methylpiperazin-1-yl)methyl)spiro[oxobutane-3,3'-11-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolium-1 / undecane] is as described in Example 1.

[0904] MS m / z (ESI): 571.2 [M+H] + .

[0905] Example 148

[0906] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,5 1 Preparation of H-11-oxa-5(2,1)-benzo[d]imidazo[2,4]-pyridine-1(4,5)-pyrazolecycloundecane-3-one

[0907]

[0908] (R,E)-1 1 ,2 6 ,7-trimethyl-5 6 -((4-methylpiperazin-1-yl)methyl)-5 2 5 3 -dihydro-1 1 H,51 The preparation method of H-11-oxa-5(2, 1)-benzo[d]imidazoazol-2(2, 4)-pyridine-1(4, 5)- pyrazolocycloundecan-3-one is referred to Example 1.

[0909] MS m / z (ESI): 542.2 [M+H] + .

[0910] Biological test evaluation

[0911] The application will be further described in connection with the following test examples, which are not meant to limit the scope of the application.

[0912] Test Example 1, determination of the inhibitory effect of the compound of the application on the kinase activity of EGFR wild type, EGFR del19 / T790M / C797S, EGFR del 746-750 / T790M / C797S and EGFR L858R / T790M / C797S mutations

[0913] Purpose of the experiment: the purpose of this test example is to test the activity of the compound on the inhibition of the kinase activity of EGFR wild type, EGFR del19 / T790M / C797S, EGFR del 746-750 / T790M / C797S and EGFR L858R / T790M / C797S mutations.

[0914] Experimental instruments: centrifuge (5810R) purchased from Eppendorf company, pipette purchased from Eppendorf or Rainin company, microplate reader purchased from BioTek company in the United States, model SynergyH1 full function microplate reader.

[0915] Experimental method: in this experiment, the HTRF kinase assay method of Cisbio company (Cisbio #62TK0PEB) is used. The substrate polypeptide TK and ATP undergo catalytic reaction in the presence of tyrosine kinase EGFR wild type, EGFR del19 / T790M / C797S, EGFR del 746-750 / T790M / C797S or EGFR L858R / T790M / C797S mutation, the substrate is phosphorylated, the content of the phosphorylated substrate generated in the reaction is determined to characterize the activity of the kinase, and the half inhibitory concentration IC50 of the compound on the inhibition of the kinase activity of EGFR wild type, EGFR del 746-750 / T790M / C797S, EGFR del19 / T790M / C797S or EGFR L858R / T790M / C797S mutation is obtained. 50 .

[0916] The specific experimental operation is as follows:

[0917] The kinase reaction was carried out in a white 384-well plate (Perkin Elmer #6008280), 1-5 μL of different concentrations of compounds diluted with ddH2O containing 1% DMSO was added to each well, 1-5 μL of ddH2O containing 1% DMSO was added to the positive control well, then 1-5 μL of 0.5-5 nM 4x EGFR wild-type, EGFR del19 / T790M / C797S, EGFR del746-750 / T790M / C797S or EGFR L858R / T790M / C797S mutant kinase solution diluted with Dilution buffer (5x kinase buffer, MgCl26.65 mM, MnCl21.33 mM, DTT 1.33 mM) was added to each well, 1-5 μL of Dilution buffer was added to the negative control well, 1-5 μL of 4 μM 4x substrate TK solution prepared with 10x Dilution buffer was added to all wells, and finally 1-5 μL of 24 μM 4x ATP solution diluted with Dilution buffer was added to start the reaction, and the reaction was carried out at room temperature for 120 minutes. After reaction, 10 μL of detection solution (TK antibody 16 nM, XL665 0.5 μM) was added to each well, and the chemiluminescence value was detected by BioTek Synergy H1 microplate reader after reaction at room temperature for 20 minutes.

[0918] Experimental data processing method:

[0919] The percentage inhibition data of the wells treated with compounds was calculated by the positive control wells (DMSO control wells) and the negative control wells (without adding kinase) on the plate {% inhibition = 100-[(test compound value-negative control value)] / (positive control value-negative control value) x 100}. The IC 50 values were calculated by fitting different concentrations and corresponding percentage inhibition data to the 4-parameter nonlinear logistic formula using GraphPad prism.

[0920] Experimental conclusion:

[0921] The compounds shown in the present application show biological activity of about 1 nM to 1000 nM or more (IC 50 ) in the activity test of EGFR wild-type kinase by the above scheme.

[0922] In some embodiments, the IC 50 of the compounds of the present application for the activity of EGFR L858R / T790M / C797S drug-resistant mutant kinase is less than about 100 nM, preferably less than about 10 nM, further preferably less than about 1 nM, more preferably less than about 0.1 nM.

[0923] In some embodiments, the compounds of the present application have an IC50for the activity of del 746-750 / T790M / C797S drug resistant mutant kinase of less than about 100 nM, preferably less than about 10 nM, more preferably less than about 1 nM, more preferably less than about 0.1 nM. 50 less than about 100 nM, preferably less than about 10 nM, more preferably less than about 1 nM, more preferably less than about 0.1 nM.

[0924] The inhibition of kinase activity of the partial example compounds against EGFR wild type, EGFR del746-750 / T790M / C797S and EGFR L858R / T790M / C797S mutations are shown in Table 1.

[0925] Table 1 Inhibition activity of partial example compounds

[0926]

[0927] Test Example 2: Cell proliferation inhibition experiment

[0928] Purpose of the experiment: The purpose of this test example is to test the activity of the compounds on cell proliferation inhibition.

[0929] Experimental instruments: Pipettor was purchased from Eppendorf company, CO2 incubator was purchased from Thermo company in the United States, microplate reader was purchased from BioTek company in the United States, model Synergy H1 full function microplate reader.

[0930] Experimental method: In this experiment, CTG (CELL TITER-GLO) luminescence method was used to detect the proliferation inhibition activity of the compounds on A431 cells and Ba / F3 (EGFR del19 / T790M / C797S) cells, and the half inhibitory concentration IC50of the compounds on cell proliferation activity was calculated. 50 .

[0931] The specific experimental operation is as follows:

[0932] For A431 cells: On the first day, 90 μL of A431 cell suspension was plated in a 96-well test plate, with 3000 cells per well, and the negative control was not added with cells. The plate was placed in a 37°C incubator containing 5% CO2 and cultured overnight. On the second day, 10 μL of gradient diluted compound solution was added to each well, and the positive and negative control wells were only added with 10 μL of culture medium containing DMSO. The plate was placed in a carbon dioxide incubator for incubation for 72 hours. After 72 hours of culture, 50 μL of CellTiter Glo was added to each well of the cell plate, and the plate was shaken in the dark for 2 min and then placed for 10 min. Then the luminescence value was detected in BioTek Synergy H1 microplate reader, the inhibition rate was calculated by chemiluminescence signal value, and the IC50of the compound was calculated by curve fitting according to the inhibition rate of different concentrations.50 .

[0933] For Ba / F3 (EGFR del19 / T790M / C797S) suspension cells:

[0934] In 96-well assay plates, 90 μL of Ba / F3 cell suspension was plated at 3000 cells per well, and no cells were added to the negative control wells. After 2 h, 10 μL of the gradient-diluted compound solution was added to each well, and 10 μL of the DMSO-containing medium was added to the positive and negative control wells. After incubation in a carbon dioxide incubator for 72 h, CTG detection was performed according to the method described above for A431 cells.

[0935] Experimental data processing method:

[0936] The percentage inhibition data of the wells treated with the compounds was calculated by using the positive control wells (DMSO control wells) and the negative control wells (no cells added) on the plate {% inhibition = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) x 100}. The IC 50 values were calculated by fitting the different concentrations and the corresponding percentage inhibition data to a 4-parameter nonlinear logistic formula using GraphPad Prism.

[0937] Experimental conclusion:

[0938] The compounds shown in the present application showed a biological activity of about 1 nM to 1000 nM (IC 50 ) in the proliferation inhibition activity test of A431 cells according to the above scheme.

[0939] The compounds shown in the present application showed a biological activity of about 0.01 nM to 100 nM (IC 50 ) in the proliferation inhibition activity test of Ba / F3 (EGFR del19 / T790M / C797S) cells according to the above scheme.

[0940] In some embodiments, the compounds of the present application have an IC 50 of less than about 100 nM, preferably less than about 10 nM, further preferably less than about 5 nM, more preferably less than about 1 nM, and most preferably less than 0.1 nM or even less than about 0.01 nM for the proliferation inhibition activity of Ba / F3 (EGFR del19 / T790M / C797S) cells.

Claims

1. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in general formula (VI): in: Ring C is selected from R c Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 Alkyne group, -(CH2) n5 OR A5 -(CH2) n5 C(O)R A5 -(CH2) n5 C(O)OR A5 -(CH2) n5 OC(O)R A5 -(CH2) n5 S(O) m3 R A5 -(CH2) n5 NR A5 R A6 -(CH2) n5 NR A5 C(O)R A6 -(CH2) n5 NR A5 C(O)OR A6 -(CH2) n5 C(O)NR A5 R A6 -(CH2) n5 NR A5 S(O) m3 R A6 -(CH2) n5 O(CH2) n6 R A5 Or -(CH2) n5 O(CH2) n6 OR A5 ; R A5 and R A6 Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Alkylthio; u can be 0, 1, 2, 3, 4 or 5; m3 is 0, 1, or 2; n5 can be 0, 1, 2, 3 or 4; n6 is 0, 1, 2, 3, or 4; and The compound is not 2. The compound according to claim 1, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R c Selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Cyanoalkyl, C 1-3 Alkyl group, -(CH2) n5 OR A5 -(CH2) n5 C(O)R A5 -(CH2) n5 S(O) m3 R A5 -(CH2) n5 NR A5 R A6 Or -(CH2) n5 NR A5 C(O)R A6 .

3. The compound according to claim 2, its stereoisomers, or its pharmaceutically acceptable salts, characterized in that, R c It is selected from methyl, ethyl, n-propyl, isopropyl, -CH2OCH3, -CH2CH2OCH3, -OCH3, -OCH2CH3, -N(CH3)2, -N(CH2CH3)2 or -N(CH2CH3)CH3.

4. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from the following compounds:

5. A pharmaceutical composition comprising a therapeutically effective dose of the compound shown in any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

6. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, or the pharmaceutical composition according to claim 5, in the preparation of MEK inhibitors, EGFR inhibitors, and EGFR monoclonal antibodies and their combination with related drugs.

7. The use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, or the pharmaceutical composition according to claim 5, in the preparation of a medicament for treating cancer-related diseases; wherein the cancer is lung cancer.

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