Compounds for the degradation of EGFR kinase

Abstract

Novel bifunctional compounds formed by conjugating an EGFR inhibitor moiety with an E3 ligase ligand moiety, which function to recruit a target protein to an E3 ubiquitin ligase for degradation, as well as methods for preparing and using the same, are disclosed herein.

Description

[Technical Field]

[0001] Novel bifunctional compounds formed by conjugating an EGFR inhibitor moiety with an E3 ligase ligand moiety, which function to recruit a target protein to an E3 ubiquitin ligase for degradation, as well as methods for preparing and using the same, are disclosed herein. [Background technology]

[0002] A proteolytic target chimera (PROTAC) consists of two covalently linked protein-binding molecules, one of which can associate with an E3 ubiquitin ligase, and the other which can bind to a target protein (POI) for degradation (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98:8554-9.; Sakamoto KMet al., Methods Enzymol. 2005; 399:833-847.). Rather than inhibiting the enzymatic activity of the target protein, the recruitment of the E3 ligase to a specific undesirable protein leads to ubiquitination and subsequent proteasome degradation of the target protein. The entire process of ubiquitination and proteasome degradation is known as the ubiquitin-proteasome pathway (UPP) (Ardley H. et al., Essays Biochem. 2005, 41, 15-30; Komander D. et al., Biochem. 2012, 81, 203-229; Grice GLet al., Cell Rep. 2015, 12, 545-553; Swatek KNet al., Cell Res. 2016, 26, 399-422). The proteasome is a protein complex that degrades unwanted, misfolded, or abnormal proteins into smaller peptides to maintain cellular health and productivity. Ubiquitin ligases, also called E3 ubiquitin ligases, directly catalyze the transfer of ubiquitin from E2 to target proteins for degradation.The human genome encodes over 600 putative E3 ligases, but only a limited number of E3 ubiquitin ligases, namely cereblon (CRBN), von Hippel-Lindau (VHL), mouse double minute 2 homolog (MDM2), and the cell inhibitor of apoptosis protein (cIAP) (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578), recombinant human ring finger protein 114 (RNF114) (Spradlin, JNet al. Nat. Chem. Biol. 2019, 15, 747-755), and DDB1 and CUL4-related factor 16 (DCAF16) (Zhang, X. et al. Nat. Chem. Biol. 2019, 15, 737-746), have been widely applied by small molecule PROTAC technology. For example, cereblon (CRBN) forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1) and karin 4A (CUL4A) to ubiquitinate several other proteins, followed by proteasome-mediated degradation. (Yi-An Chen, et al., Scientific Reports 2015, 5, 1-13). Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, utilize CRL4A. CRBNIt functions as a monovalent promoter of PPI by binding to the cereblon (CRBN) subunit of the E3 ligase complex and recruiting neosubstrate proteins (Matyskiela, ME et al., Nat Chem Biol 2018, 14, 981-987). As a result, the ability of thalidomide and its derivatives to recruit CRBN has been widely applied to research related to proteolytic target chimeras (PROTACs) (Christopher T. et al. ACS Chem. Biol. 2019, 14, 342-347., Honorine L. et al. ACS Cent. Sci. 2016, 2, 927-934). PROTACs have great potential to remove protein targets that are "undruggable" with conventional inhibitors, or protein targets that are non-enzymatic proteins. (Chu TT. et al., Cell Chem Biol. 2016;23:453-461. Qin C. et al., J Med Chem 2018;61:6685-6704. Winter GE. et al., Science 2015;348:1376-1381.) In recent years, PROTACs have been shown to be useful modulators, promoting the selective degradation of a wide range of target proteins in antitumor studies (Lu J. et al., Chem Biol. 2015;22(6):755-763, Ottis P. et al., Chem Biol. 2017;12(4):892-898, Crews CM et al., J Med Chem. 2018;61(2):403-404, Neklesa TK et al., Pharmacol Ther.2017,174:138-144, Cermakova K.et al.,Molecules,2018.23(8), An S.et al.,EBioMedicine,2018, Lebraud H.et al.,Essays Biochem.2017;61(5):517-527, Sun YHet al.,Cell Res.2018;28:779-81, Toure M.et al.,Angew Chem Int Ed Engl.2016;55(6):1966-1973, Yonghui Sun et al.This has been reported in Leukemia, volume 33, pages 2105-2110 (2019), Shaodong Liu et al., Medicinal Chemistry Research, volume 29, pages 802-808 (2020), and in patent publications, e.g., US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO2016197032, WO2016197114, WO2017011590, WO2017030814, This information is disclosed or discussed in WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449, WO2018071606, WO2021178920, WO2021127283, WO2021127190, WO202111871, and WO202111913.

[0003] The epidermal growth factor receptor (EGFR), belonging to the ErbB family, is a transmembrane receptor tyrosine kinase (RTK) that plays a fundamentally important role in cell proliferation, differentiation, and motility (Y. Yarden, et al., Nat. Rev. Mol. Cell Biol. 2001;2:127-137). Homodimerization or heterodimerization of EGFR and other ErbB family members activates the cytoplasmic tyrosine kinase domain, initiating intracellular signaling. Overexpression or activating mutations of EGFR are associated with the development of many types of cancer, including pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, and non-small cell lung cancer (Yewale C., et al. Biomaterials. 2013, 34(34):8690-8707). Activating mutations in the EGFR tyrosine kinase domain (L858R mutation and exon 19 deletion) have been identified as oncogenic drivers of NSCLC (Konduri, K., et al. Cancer Discovery 2016, 6(6), 601-611). First-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, are approved for NSCLC patients with EGFR activating mutations (M. Maemondo, N. Engl. J. Med. 362(2010) 2380-2388). Most patients with EGFR-mutated NSCLC respond to these therapies, but typically, patients develop resistance after an average of one year of treatment. Acquired resistance to gefitinib and erlotinib involves several mechanisms, including a secondary mutation from threonine 790 to methionine 790 (T790M), also known as the "gatekeeper" T790M mutation (Xu Y., et al. Cancer Biol Ther. 2010, 9(8):572-582.). Therefore, for the treatment of patients with the T790M mutation, the second-generation EGFR-TKI afatinib and the third-generation EGFR-TKI osimertinib (AZD9291) were developed as irreversible EGFR inhibitors that bind to Cys797. Specifically, osimertinib, which greatly preserves WT EGFR, has achieved higher clinical response rates in NSCLC patients with EGFR T790M.However, several recent studies have reported tertiary point mutations from Cys797 to Ser797 (C797S) following osimertinib clinical therapy (Thress KS, et al. Nat. Med. 2015, 21(6):560-562). There is a need for drugs that can overcome the EGFR (C797S) resistance barrier in non-small cell lung cancer (NSCLC). EGFR-targeted protacs serve as a potential strategy to overcome drug resistance mediated by these variants, as disclosed or discussed in patent publications, e.g., WO2018119441, WO2019149922, WO2019183523, WO2019121562, US20190106417, WO202157882, WO2021123087, WO2021133809, WO2021168074, WO2021208918, and WO2021216440.

[0004] However, several EGFR-targeted protacs designed to degrade EGFR mutant proteins have been published (Zhang X., et al. Eur.J.Med.Chem. 2020, 192, 112199., Zhang H, et al. Eur.J.Med.Chem. 2020, 189, 112061., Lu X, Med.Res.Rev. 2018, 38(5): 1550-1581. He K., et al. Bioorg.Med.Chem.Lett. 2020, 15, 127167.). Most of the publicly available molecules are based on first-generation, second-generation, and third-generation EGFR inhibitors (WO2021023233, WO2019121562, and WO2018119441) or allosteric EGFR inhibitors (WO2021127561). However, there is no data to show that these EGFR-targeted protacs degrade all major EGFR mutations, including Del19, L858R, Del19 / T790M, L858R / T790M, Del19 / T790M / C797S, and L858R / T790M / C797S.

[0005] This application provides novel bifunctional compounds and compositions for the treatment of severe diseases.

Summary of the Invention

[0006] One object of the present invention is to provide compounds and derivatives formed by conjugating an EGFR inhibitor moiety with an E3 ligase ligand moiety, which function to recruit target proteins to the E3 ubiquitin ligase for degradation, as well as methods for their preparation and use.

[0007] The compounds or salts thereof described herein are useful for the treatment of diseases that may be affected by EGFR regulation. The present invention provides the use of the compounds or pharmaceutically acceptable salts thereof described herein in the manufacture of a medicament for the treatment of diseases that may be affected by EGFR regulation. The present invention further provides the compounds or pharmaceutically acceptable salts thereof described herein for use in the treatment of diseases that may be affected by EGFR regulation. This application further provides a method for treating a proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof described herein.

[0008] Aspect 1. Formula (I)

Chemical formula

Chemical formula

Chemical formula

[0009] Embodiment 2. The compound is selected from formula (IIa), [ka] Preferably, the compound is selected from formula (IIb), [ka] More preferably, the compound is selected from formula (IIc), [ka] More preferably, the compound is selected from formula (IId), [ka] In the formula, R 1c and R 1d However, each is independently H, methyl, or ethyl, except R 1c and R 1d The condition is that at most one of them is H, R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , L 3 The compound according to Embodiment 1, wherein m1, m2, m3, m4, m5, and degron are as defined in Embodiment 1.

[0010] Embodiment 3. The compound is selected from formula (IIIa), [ka] In the formula, R 1c and R 1d However, each is independently H, methyl, or ethyl, except R 1c and R 1d The condition is that at most one of them is H, R 3 , R 4 , R 5 , R 6 , R 7 , R 13 , R 14 , L 1 , L 2 , L 3 , L 4 m1, m2, m3, m4, m5, Z 1 , Z 3 , X 7 , X 8 , and n6 are as defined in Embodiment 1, Preferably, the compound is selected from formula (IIIb), [ka] In the formula, R 1c and R 1d However, each is independently H, methyl, or ethyl, except R 1c and R 1d The condition is that at most one of them is H, R 13 , R 14 , L 1 , L 2 , L 3 , L 4 m1, m2, m3, m4, m5, Z 1 , Z 3 , X 7 , X 8 , and n6 are as defined in Embodiment 1, More preferably, the compound is selected from formula (IIIc) or formula (IIId), [ka] In the formula, R 1c and R 1dHowever, each is independently H, methyl, or ethyl, except R 1c and R 1d The condition is that at most one of them is H, R 13 , R 14 , L 1 , L 2 , L 3 , L 4 m4, m5, Z 1 , Z 3 , X 7 , X 8 The compound according to Embodiment 1, wherein n6 is as defined in Embodiment 1.

[0011] Appearance 4. The compound is of formula (IVa) [ka] [In the formula, R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 2a , R 2b , R 3 , R 4 , and R 5 However, each is independent of hydrogen, halogen, and -C. 1-4 Alkyl, -C 1-4 Alkoxy, -C 3-6 Cycloalkyl, or -CN, and the -C 1-4 Alkyl, the aforementioned -C 1-4 Alkoxy, or the aforementioned -C 3-6 Each cycloalkyl group can be optionally composed of hydrogen, halogen, or -C. 1-8 Alkoxy, -C 3-8 Substituted with at least one substituent selected from cycloalkyl or -CN, R 6 and R 7 However, each independently, hydrogen, -C 1-3 Alkyl, or -C 3-6 It is a cycloalkyl, and the -C 1-3Alkyl-C 3-6 Each cycloalkyl group can be optionally composed of hydrogen, halogen, or -C. 1-8 Alkoxy, -C 3-8 Substituted with at least one substituent selected from cycloalkyl or -CN, m4 and m5 are independently 0, 1, or 2, provided that m4 + m5 = 2. L 1 However, they became independent, [ka] Selected from, [ka] Each of them can choose at least one R L1c Replaced by, * L1 However, as mentioned above [ka] It refers to the position where it is joined to a part, ** L1 However, as mentioned above [ka] It refers to the position where it is joined to a part. L 2 However, they became independent, [ka] Selected from, [ka] Each of them can choose at least one R L2c Replaced by, * L2 However, as mentioned above [ka] It refers to the position where it is joined to a part, ** L2 However, as mentioned above [ka] It refers to the position where it is joined to a part. L 3 However, they became independent, [ka] Selected from, [ka] Each of them can choose at least one R L3c Replaced by, *L3 However, as mentioned above [ka] It refers to the position where it is joined to a part. **L3 However, as mentioned above [ka] It refers to the position where it is joined to a part. The aforementioned R L1c , the R L2c , and the R L3c Each of these independently exists as: non-existent, oxo (=O), halogen, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 The aryl or 5-12 member heteroaryl is the -C1-C8 alkyl, the -C1-C8 alkoxy, the -C2-C8 alkenyl, the -C2-C8 alkynyl, the C3-C8 cycloalkyl, the 3-8 member heterocyclyl, and the C6-C 12 Each of the aryl and the 5-12 member heteroaryl is optionally at least one R Lca Replaced by, R Lca However, independently, non-existent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C12 It is either an aryl, or a 5-12 member heteroaryl, or Two R's L1c However, together with the atoms to which they are bonded, they form a 3-12 membered ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally being substituted with at least one substituent halogen, hydroxyl, or C1-C8 alkyl. Two R's L2c However, together with the atoms to which they are bonded, they form a 3-12 membered ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally being substituted with at least one substituent halogen, hydroxyl, or C1-C8 alkyl. Two R's L3c However, together with the atoms to which they are bonded, they form a 3-12 membered ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally being substituted with at least one substituent halogen, hydroxyl, or C1-C8 alkyl. [ka] but, [ka] Selected from, Z 1 , Z 2 , and Z 3 However, each independently, N or CR z However, Z 1 , Z 2 , and Z 3 The condition is that not N at the same time, R z However, in each appearance, independently, non-existence, hydrogen, halogen, -C 1-8 Alkyl, -NR Za R Zb , -OR Za , -SR Za Selected from C3-C8 cycloalkyl, 3-8 membered heterocyclyl, or CN, the -C 1-8Each of the alkyl group, the C3-C8 cycloalkyl group, and the 3-8 membered heterocycline group may optionally contain at least one R Zc Replaced by, The aforementioned [ka] The part is CR z And R z Z does not exist. 1 , Z 2 , or Z 3 via any one of the above [ka] part, the above [ka] part, or the [ka] It is connected to the part, R Za and R Zb However, each is independent of: non-existent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 member heterocyclyl, C6-C 12 Selected from aryl or 5-12 member heteroaryl, and the -C 1-8 Alkyl, the C3-C8 cycloalkyl, the 3-8 membered heterocyclyl, the C6-C 12 Each of the aryl or the 5-12 member heteroaryl may optionally have at least one substituent R Zd Replaced by, R Zc and R Zd However, each is independent of halogen, hydroxyl, -C1-C8 alkyl, and -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 It is an aryl or a 5-12 member heteroaryl. R 13 and R 14 However, each is independent of non-existence, hydrogen, halogen, and -C.1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkinyl, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3-8 member heterocyclyl, C6-C 12 Aryl, 5-12 member heteroaryl, -CN, -SO2R 13a -SO2NR 13a R 13b , -COR 13a , -CO2R 13a ,-CONR 13a R 13b , -NR 13a R 13b , -NR 13a COR 13b , -NR 13a CO2R 13b , or -NR 13a SO2R 13b Selected from, -C 1-8 Alkyl, the aforementioned -C 2-8 Alkenyl, the aforementioned -C 2-8 Alkinyl, the above-C 1-8 Alkoxy, the -C3-C8 cycloalkyl, the 3-8 member heterocyclyl, the -C6-C 12 Each of the aryl or the 5-12 member heteroaryl is optionally a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkinyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 member heteroaryl, oxo, -CN, -OR 13c , -SO2R 13c -SO2NR 13c R 13d , -COR 13c , -CO2R 13c ,-CONR 13c R 13d , -NR 13c R 13d , -NR 13c COR 13d , -NR 13c CO2R 13d , or -NR 13c SO2R 13d Replaced by, In each occurrence, R 13a , R 13b , R 13c , and R 13d However, each is independent of non-existence, hydrogen, and -C. 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkinyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 It is an aryl or a 5-12 member heteroaryl. L 4 , L 5 , and L 6 However, each is independent of non-existence, single bond, -O-, and -NR. a -,-(CR a R b ) n8 -, -O(CR a R b ) n8 -, -NR a (CR a R b ) n8 - or -C(O)- is selected, In each occurrence, X 1 , X 2 , and X 7 However, each operates independently, -CR a Or selected from N, In each occurrence, X 3 , X 4 , and X 8 However, each operates independently, -NR a -, -O-, -S-, and -CR a R b - Selected from, In each occurrence, X 5 and X 6 However, each is independent of the others: non-existent, single bond, -C(O)-, -NR a -, and -O- are selected, In each occurrence, R a and R b However, each is independently hydrogen, hydroxyl, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3-8 member heterocyclyl, -C6-C12 Selected from aryls or 5-12 member heteroaryls, the -C1-C8 alkyl, the -C1-C8 alkoxy, the -C2-C8 alkenyl, the -C2-C8 alkynyl, the -C3-C8 cycloalkyl, the 3-8 member heterocyclyl, and the -C6-C 12 Each of the aryl or the 5-12 membered heteroaryl may optionally have at least one substituent: halogen, hydroxyl, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Substituted with aryl or 5-12 member heteroaryl, R a and R b However, together with the carbon atoms to which they are bonded, they form a 3- to 12-membered ring, wherein the ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally contains at least one substituent halogen, hydroxyl, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Substituted with aryl or 5-12 member heteroaryl groups, n1, n2, n3, n4, and n5 are each independently 0, 1, 2, or 3. n6, n7, and n8 are each independently 0, 1, 2, 3, or 4, however, L 1 , L 2 , or L 3 For any one of the following, X 1 If X is N, 5 The bond is single, nonexistent, -C(O)-, and / or X 2 If X is N, 6 The bond is single, nonexistent, and -C(O)-. L 1 but [ka] In this case, X 1 If X is N, 5 The bond is single, nonexistent, -C(O)-, and / or X 3 ga-CR a R b - being, X 2 If X is N, 6 The bond is single, nonexistent, -C(O)-, and / or X 4 ga-CR a R b - being, L 2 but [ka] In this case, X 1 If X is N, 5 The bond is single, nonexistent, -C(O)-, and / or X 3 ga-CR a R b - being, X 2 If X is N, 6 The bond is single, nonexistent, -C(O)-, and / or X 4 ga-CR a R b - being, L 3 but [ka] In this case, X 1 If X is N, 5 The bond is single, nonexistent, -C(O)-, and / or X 3 ga-CR a R b - being, X 2 If X is N, 6 The bond is single, nonexistent, -C(O)-, and / or X 4 ga-CR a R bThe compound according to Embodiment 1, which is selected from [conditions that it is -] or is its N-oxide, its pharmaceutically acceptable salt, its stereoisomer, its deuterated analog, or its prodrug.

[0012] Embodiment 5. The compound is selected from formula (Va), [ka] Preferably, the compound is selected from formula (Vb), [ka] More preferably, the compound is selected from formula (Vc), [ka] More preferably, the compound is selected from formula (Vd), [ka] More preferably, the compound is selected from formula (Ve), [ka] More preferably, the compound is selected from formula (Vf), [ka] R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 2a , R 2b , R 13 , R 14 , L 1 , L 2 , L 3 , L 4 m4, m5, Z 1 , Z 3 , X 7, X 8 The compound according to Embodiment 3, wherein n6 is as defined in Embodiment 3.

[0013] Appearance 6.R 6 and R 7 Each of these is independently hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and each of the methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN. Preferably, R 6 and R 7 However, each is independently hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Comfortable, R 6 However, independently, they are methyl or cyclopropyl, and R 7 The compound described in any one of the prior art, wherein the compound is hydrogen.

[0014] Appearance 7.R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 2a , R 2b , R 3 , R 4 , and R 5Each of these is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or -CN, and each of the methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN. Preferably, R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 2a , R 2b , R 3 , R 4 , and R 5 However, each is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF3, -CHF2, -CN, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, Comfortable, R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 2a , R 2b , R 3 , R 4 , and R 5However, each is independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3, or -CHF2, -CH2OCH3, and more preferably R 4 However, it is hydrogen, F, methyl, methoxy, cyclopropyl, or -CF3, and R 3 However, it is hydrogen, F, methyl, -CF3, or -CHF2, and R 5 However, R is hydrogen, F, Cl, methyl, or -CH2OCH3. 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 2a , and R 2b The compound according to any one of the prior art embodiments, wherein each is independently hydrogen, F, or methyl.

[0015] Appearance 8. The above [ka] The part, [ka] Selected from, Preferably, the above [ka] The part, [ka] A compound according to any one of the prior art, selected from the above.

[0016] Appearance 9.L 1 However, -O-, -C(O)-, -N(R a )-, *L1 -C(O)N(R a )- **L1 , *L1 -C(O)O- **L1 , *L1 -N(R a )C(O)- **L1, *L1 -OC(O)- **L1 , [ka] [ka] Selected from, [ka] [ka] Each of them can choose at least one R L1c Replaced by, The aforementioned R L1c Each of these is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and the methyl, the ethyl, the propyl Each of the following is optionally selected: butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, and 5-12 member heteroaryl, each of which optionally contains at least one R Lca Replaced by, R LcaHowever, independently, they are oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, or Two R's L1c However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. R a The hydrogen atom is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclo The compound according to any one of the preceding embodiments, wherein each octyl is optionally substituted with at least one substituent halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0017] Appearance 10.L 1 is -O-, -N(CH3)-, -C(O)-, -NH-, *L1 -C(O)N(CH3)- **L1 , *L1 -C(O)NH- **L1 , *L1 -C(O)O- **L1 , *L1 -C(O)N(C2H5)- **L1 , *L1 -C(O)N(C3H7)- **L1 , *L1 -N(CH3)C(O)- **L1 , *L1 -NHC(O)- **L1 , *L1 -OC(O)- **L1 , *L1 -N(C2H5)C(O)- **L1 , *L1 -N(C3H7)C(O)- **L1 , [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound according to any one of the prior art, selected from the above.

[0018] Appearance 11.L 2 However, -O-, -C(O)-, -N(R a )-, *L2 -C(O)N(Ra )- **L2 , *L2 -C(O)O- **L2 , *L2 -N(R a )C(O)- **L2 , *L2 -OC(O)- **L2 , [ka] [ka] Selected from, [ka] [ka] Each of them can choose at least one R L2c Replaced by, The aforementioned R L2c Each of these is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and the methyl, the ethyl, the propyl Each of the following is optionally selected: butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, and 5-12 member heteroaryl, each of which optionally contains at least one R Lca Replaced by, R LcaHowever, independently, they are oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, or Two R's L2c However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. R a The hydrogen atom is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclo The compound according to any one of the preceding embodiments, wherein each octyl is optionally substituted with at least one substituent halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0019] Appearance 12.L 2 is -O-, -N(CH3)-, -C(O)-, -NH-, *L2 -C(O)N(CH3)- **L2 , *L2 -C(O)NH- **L2 , *L2 -C(O)O- **L2 , *L2 -C(O)N(C2H5)- **L2 , *L2 -C(O)N(C3H7)- **L2 , *L2 -N(CH3)C(O)- **L2 , *L2 -NHC(O)- **L2 , *L2 -OC(O)- **L2 , *L2 -N(C2H5)C(O)- **L2 , *L2 -N(C3H7)C(O)- **L2 , [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound according to any one of the prior art, selected from the above.

[0020] Appearance 13.L 3 However, -O-, -N(R a )-, -C(O)-, *L3 -C(O)N(Ra )- **L3 , *L3 -C(O)O- **L3 , *L3 -N(R a )C(O)- **L3 , *L3 -OC(O)- **L3 , [ka] [ka] Selected from, [ka] [ka] Each of them can choose at least one R L3c Replaced by, The aforementioned R L3c Each of these is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and the methyl, the ethyl, the propyl Each of the following is optionally selected: butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, and 5-12 member heteroaryl, each of which optionally contains at least one R Lca Replaced by, R LcaHowever, independently, they are oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, or Two R's L3c However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. R a The hydrogen atom is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclo The compound according to any one of the preceding embodiments, wherein each octyl is optionally substituted with at least one substituent halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0021] Appearance 14.L 3 is -O-, -N(CH3)-, -C(O)-, -NH-, *L3 -C(O)N(CH3)- **L3 , *L3 -C(O)NH- **L3 , *L3 -C(O)O- **L3 , *L3 -C(O)N(C2H5)- **L3 , *L3 -C(O)N(C3H7)- **L3 , *L3 -N(CH3)C(O)- **L3 , *L3 -NHC(O)- **L3 , *L3 -OC(O)- **L3 , *L3 -N(C2H5)C(O)- **L3 , *L3 -N(C3H7)C(O)- **L3 , [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound according to any one of the prior art, selected from the above.

[0022] Appearance 15. The above [ka] The part, [ka] A compound according to any one of the prior art, selected from the above.

[0023] Appearance 16.L 4 However, independently, single bonds, -O-, -NR a -,-(CR a R b ) n8 -, -O(CR a R b ) n8 -, -NR a (CR a R b ) n8 - or -C(O)- is selected, In each occurrence, R a and R bEach is independently selected from hydrogen, hydroxyl, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 Each of the alkenyl, the -C2-C8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3-8 membered heterocyclyl, the phenyl, or the 5-12 membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl. Preferably, L 4 However, the compound is independently selected from single bonds, as described in any one of the prior embodiments.

[0024] Appearance 17.X 7 However, independently, -CR a Or selected from N, R aHowever, independently, hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl are selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 Each of the following is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, pentyl, hexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl: Preferably, X 7 However, independently selected from -CH, -C(CH3), or N, preferably X 7 However, independently selected from -CH, the compound according to any one of the prior embodiments.

[0025] Appearance 18.X 8 However, independently, -NR a -, -O-, -S-, and -CR a R b - Selected from, In each occurrence, R aand R b Each is independently selected from hydrogen, hydroxyl, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 Each of the alkenyl, the -C2-C8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3-8 membered heterocyclyl, the phenyl, or the 5-12 membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl. Preferably, X 8 However, independently selected from -NH- and -CH2-, preferably X 8 However, independently selected from -CH2-, the compound according to any one of the prior embodiments.

[0026] Appearance 19. [ka] but, [ka] Selected from, preferably, [ka] but, [ka] A compound according to any one of the prior art, selected from the above.

[0027] Appearance 20.Z 1 , Z 2 , and Z 3 At most one of them is N, Preferably, Z 1 , Z 2 and Z 3 However, each operates independently, CR z The compound described in any one of the prior art embodiments.

[0028] Appearance 21.R Z However, in each appearance, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -NR Za R Zb , -OR Za , -SR Za Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, or CN, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3-8 membered heterocyclyl, optionally contains at least one R Zc Replaced by, R Za and R ZbEach of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and each of the hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl may optionally have at least one substituent R Zd Replaced by, R Zc and R Zd However, each is independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl. Preferably, R z The compound according to any one of the prior art embodiments, wherein the compound is selected from H, -CH3, -C2H5, F, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -C3H7, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, -CF3, or -CH(OH)CH3.

[0029] Appearance 22.R 13 and R 14 However, each independently, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C2-8 Alkinyl, 3-8 member heterocyclyl, -C6-C 12 Aryl, 5-12 member heteroaryl, -CN, -SO2R 13a -SO2NR 13a R 13b , -COR 13a , -CO2R 13a ,-CONR 13a R 13b , -NR 13a R 13b , -NR 13a COR 13b , -NR 13a CO2R 13b , or -NR 13a SO2R 13b Selected from, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, the aforementioned -C 2-8 Alkinyl, the 3-8 membered heterocyclyl, the -C6-C 12 Each of the aryl and the 5-12 membered heteroaryls can be optionally replaced with F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkinyl, 3-8 member heterocyclyl, -C6-C 12 Aryl, 5-12 member heteroaryl, oxo, -CN, -OR 13c , -SO2R 13c -SO2NR 13c R 13d , -COR 13c , -CO2R 13c ,-CONR 13c R 13d, -NR 13c R 13d , -NR 13c COR 13d , -NR 13c CO2R 13d , or -NR 13c SO2R 13d Replaced by, R 13a , R 13b , R 13c , and R 13d However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkinyl, 3-8 member heterocyclyl, -C6-C 12 It is an aryl or a 5-12 member heteroaryl. Preferably, R 13 and R 14 The compounds described in any one of the prior embodiments, each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, or phenyl.

[0030] Appearance 23. [ka] The part, [ka] The compound described in any one of the prior art embodiments.

[0031] Appearance 24.L 5 and L 6However, each is independent of the single bond, -O-, and -NR. a -,-(CR a R b ) n8 -, -O(CR a R b ) n8 -, -NR a (CR a R b ) n8 - or -C(O)- is selected, X 8 However, -CR a R b -and, In each occurrence, R a and R bEach is independently selected from hydrogen, hydroxyl, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 Each of the alkenyl, the -C2-C8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3-8 membered heterocyclyl, the phenyl, or the 5-12 membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl. Preferably, L 5 and L 6 However, each is independent, single bond, [ka] -O-, -NH-, -NMe-, -N(CH2CH3)-, -CH2-, -CHF-, -CF2-, -C(CH3)2-, or -CO- X 8 However, it is CH2, The compound according to any one of the prior art, wherein n6 is 0 or 1.

[0032] Appearance 25.R 13 However, each independently, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkinyl, 3-8 member heterocyclyl, -C6-C 12 Aryl, 5-12 member heteroaryl, -CN, -SO2R 13a -SO2NR 13a R 13b , -COR 13a , -CO2R 13a ,-CONR 13a R 13b , -NR 13a R 13b , -NR 13a COR 13b , -NR 13a CO2R 13b , or -NR 13a SO2R 13b Selected from, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, the aforementioned -C 2-8 Alkinyl, the 3-8 membered heterocyclyl, the -C6-C 12 Each of the aryl and the 5-12 membered heteroaryls can be optionally replaced with F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C2-8 Alkenyl, -C 2-8 Alkinyl, 3-8 member heterocyclyl, -C6-C 12 Aryl, 5-12 member heteroaryl, oxo, -CN, -OR 13c , -SO2R 13c -SO2NR 13c R 13d , -COR 13c , -CO2R 13c ,-CONR 13c R 13d , -NR 13c R 13d , -NR 13c COR 13d , -NR 13c CO2R 13d , or -NR 13c SO2R 13d Replaced by, In each occurrence, R 13a , R 13b , R 13c , and R 13d However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkinyl, 3-8 member heterocyclyl, -C6-C 12 It is an aryl or a 5-12 member heteroaryl. Preferably, R 13 However, independently selected from hydrogen, F, Cl, Br, I, CN, -C1-C8 alkyl, or -C1-C8 alkoxy, preferably R 13 However, independently selected from hydrogen, F, Cl, Br, I, CN, -Me, -Et, -C3H7, -C4H9, -OMe, -OEt, -OC3H7, or -OC4H9, The compound according to any one of the prior art embodiments, wherein n7 is 0, 1, or 2.

[0033] Appearance 26. [ka] but, [ka] The compound described in any one of the prior art embodiments.

[0034] Embodiment 27. The compound according to any one of the prior embodiments, wherein the compound is selected from the following. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0035] Embodiment 28. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 27, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, together with a pharmaceutically acceptable excipient.

[0036] Embodiment 29. A method for treating a disease that may be affected by EGFR modulation, comprising administering an effective amount of a compound described in any one of Embodiments 1 to 27, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, to a subject in need thereof.

[0037] Embodiment 30. The method according to Embodiment 29, wherein the disease is selected from cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0038] Embodiment 31. Use of a compound according to any one of Embodiments 1 to 27, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, in the preparation of a medicament for the treatment of a disease that may be affected by EGFR modulation.

[0039] Embodiment 32. The use according to Embodiment 31, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer. [Modes for carrying out the invention]

[0040] The following terms have the meanings set forth throughout this specification. Unless otherwise specifically defined elsewhere in this specification, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which this invention pertains.

[0041] The following terms have the meanings set forth throughout this specification. As used herein, including in the attached claims, singular words such as "a," "an," and "the" refer to multiple objects corresponding to them unless the context otherwise clearly indicates.

[0042] The term "or" means "and / or" and is used interchangeably unless the context explicitly indicates otherwise.

[0043] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18, for example, 1 to 12, further for example, 1 to 10, even further for example, 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. 1-6Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0044] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), and 2-propyl or isopropyl ("i-Pr").

[0045] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu").

[0046] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl.

[0047] The term "hexyl" includes 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0048] The term "alkylene" includes divalent alkyl groups obtained by removing two hydrogen atoms from an alkane. Alkylenes include, but are not limited to, methylene, ethylene, and propylene.

[0049] The term "halogen" includes fluoro(F), chloro(Cl), bromo(Br), and iodine(I).

[0050] The term "alkenyl" includes a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 carbon atoms, for example, 2 to 8, and further, for example, 2 to 6. Alkenyl groups, for example, C 2-6 Examples of alkenyls include, but are not limited to, ethenyl or vinyl, propa-1-enyl, propa-2-enyl, 2-methylpropa-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl groups.

[0051] The term "alkenylene" refers to a divalent alkenyl group obtained by removing two hydrogen atoms from an alkene. Examples of alkenylenes include vinylidene and butenylene, but are not limited to these.

[0052] The term "alkynyl" includes hydrocarbon groups selected from linear and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 carbon atoms, for example, 2 to 8, and further, for example, 2 to 6. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0053] The term "alkynylene" refers to a divalent alkynyl group obtained by removing two hydrogen atoms from an alkyne. Examples of alkynylenes include ethynylene, but are not limited to these.

[0054] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including condensed, crosslinked, or spirocycloalkyl groups, as well as monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups.

[0055] For example, a cycloalkyl group may contain 3 to 12 carbon atoms, for example 3 to 10, further for example 3 to 8, further for example 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Furthermore, for example, a cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms, for example 3 to 10, further for example 3 to 8, or 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Specifically, saturated monocyclic cycloalkyl groups, for example, C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, the cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and is a monocyclic ring (C) containing 3 to 6 carbon atoms. 3-6 Bicyclic cycloalkyl groups are abbreviated as cycloalkyl groups. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms, arranged as fused bicyclic rings selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as bridging bicyclic rings selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as bicyclic rings selected from the [5,6] and [6,6] ring systems.

[0056] The term "spirocycloalkyl" refers to a cyclic structure that contains carbon atoms and is formed by at least two rings sharing one atom.

[0057] The term "condensed cycloalkyl" refers to a bicyclic cycloalkyl group as defined herein, which is saturated and formed by two or more rings sharing two adjacent atoms.

[0058] The term "crosslinked cycloalkyl" refers to a cyclic structure formed by two rings that contain carbon atoms and share two non-adjacent atoms. The term "7-10 membered crosslinked cycloalkyl" refers to a cyclic structure formed by two rings that contain 7-12 carbon atoms and share two non-adjacent atoms.

[0059] Examples of condensed cycloalkyls, condensed cycloalkenyls, or condensed cycloalkynyls include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo3- to 8-membered cycloalkyls, benzoC 4-6 This includes, but is not limited to, cycloalkenyls, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, and 1,4-dihydronaphthyl. Preferred embodiments are 8- to 9-membered condensed rings, which refer to cyclic structures containing 8- to 9 ring atoms in the examples above.

[0060] The term “aryl,” when used alone or in combination with other terms, Five-membered and six-membered carbocyclic aromatic rings, e.g., phenyl; Bicyclic ring systems, for example, 7-12 membered bicyclic ring systems, in which at least one ring is a carbon ring and an aromatic ring, such as naphthyl and indanyl, and A tricyclic ring system, such as a 10-15 membered tricyclic ring system, comprising a group selected from tricyclic ring systems, for example, fluorenyl, in which at least one ring is a carbocyclic and aromatic ring.

[0061] The terms “aromatic hydrocarbon ring” and “aryl” are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 (It is aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphtho-1-yl, naphtho-2-yl, anthracenyl, and phenantrenyl. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphtho-1-yl or naphtho-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0062] Specifically, the term "bicyclic fused aryl" refers to a bicyclic aryl ring as defined herein. A typical bicyclic fused aryl is naphthalene.

[0063] The term "heteroaryl" is defined below: A 5, 6, or 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in some embodiments 1 to 2 heteroatoms, with the remaining ring atoms being carbon; A 7-12 membered bicyclic ring comprising at least one heteroatom selected from N, O, and S, e.g., 1-4 heteroatoms, or in some embodiments 1-3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom present in the aromatic ring, and This refers to a group selected from an 11-14 membered tricyclic ring, comprising at least one heteroatom selected from N, O, and S, e.g., 1-4 heteroatoms, or in some embodiments 1-3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom located within the aromatic ring.

[0064] If the total number of S and O atoms in a heteroaryl group is greater than 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is not greater than 1. If a heteroaryl group contains more than one heteroatom ring member, these heteroatoms may be the same or different. Nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.

[0065] Specifically, the term “bicyclic condensed heteroaryl” refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9 or 10-membered condensed bicyclic heteroaryl ring as defined herein. Typically, bicyclic condensed heteroaryls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic. The group can be bonded to the rest of the molecule via any of the rings.

[0066] "Heterocyclyl," "heterocyclic," or "heterocyclic formula" are interchangeable and include non-aromatic heterocyclyl groups having one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and including monocyclic, condensed, bridging, and spirocyclic groups, i.e., monocyclic heterocyclyl, bridging heterocyclyl, spiroheterocyclyl, and condensed heterocyclic groups.

[0067] The terms "H" or "hydrogen" as disclosed herein include hydrogen and non-radioactive isotope hydrogen.

[0068] The term “at least one substituent” as disclosed herein includes 1 to 4 substituents, such as 1 to 3, or 1 or 2, as long as the theory of valence is satisfied. For example, “at least one substituent F” as disclosed herein includes 1 to 4 substituents F, such as 1 to 3, or 1 or 2.

[0069] The term "divalent" refers to a linking group that can form a covalent bond with two other parts. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogen atoms from the corresponding cycloalkane to form a linking group. The terms "divalent aryl group," "divalent heterocyclyl group," or "divalent heteroaryl group" should be understood similarly.

[0070] The compounds disclosed herein may have chiral centers and therefore may exist as enantiomers. “Enantiomer” refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed. If a compound disclosed herein has two or more chiral centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, such as substantially pure, divided enantiomers, their racemic mixtures, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specifically stated, a reference to one isomer applies to any of the possible isomers. Whenever the isomer composition is not specified, all possible isomers are included.

[0071] Where a compound disclosed herein contains an olefinic double bond, unless otherwise specified, such double bond is intended to include both E and Z geometric isomers.

[0072] Where the compounds disclosed herein include a disubstituted cyclic ring system, the substituents on such a ring system can be cis or trans. Cis formation means that both substituents are located above the arrangement of the two substituents on the carbon, while trans means they are on opposite sides. For example, the disubstituted cyclic ring system may be a cyclohexyl ring or a cyclobutyl ring.

[0073] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products from each step or series of steps are separated and / or purified to a desired degree of homogeneity (hereinafter, separated) by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, for example, reversed-phase and normal-phase, size exclusion, ion exchange, high, medium, and low-pressure liquid chromatography methods and apparatus, small-scale analysis, simulated moving bed ("SMB") and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. A person skilled in the art will be able to select and apply the technique that is most likely to achieve the desired separation.

[0074] A "diastereomer" refers to a stereoisomer of a compound that has two or more chiral centers but is not a mirror image of one another. A mixture of diastereomers can be separated into their individual diastereomers based on their physical and chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Moscher acid chloride), separating the diastereomers, and converting the individual diastereoisomers into their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of a chiral HPLC column.

[0075] A single stereoisomer, for example, a substantially pure enantiomer, can be obtained by the resolution of a racemic mixture using methods such as the formation of a diastereomer using an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH, et al. “Chromatographic resolution of enantiomers: Selective review.” J. Chromatogr., 113(3)(1975): pp.283-302). The racemic mixture of chiral compounds of the present invention can be separated and isolated by any preferred method, including (1) the formation of an ionic diastereomer salt using a chiral compound and separation by fractional crystallization or other methods; (2) the formation of a diastereomer compound using a chiral derivatization reagent, separation of the diastereomer, and conversion to a pure stereoisomer; and (3) the direct separation of substantially pure or concentrated stereoisomers under chiral conditions. See Wainer, Irving W., Ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0076] Some of the compounds disclosed herein may exist at different hydrogen bonding sites, known as tautomers. For example, a compound containing a carbonyl-CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl-CH=C(OH)- group (enol form). Where applicable, both keto and enol forms, as well as mixtures thereof, are intended to be included. In another example, a compound containing pyrazolyl may undergo tautomerism to form different rings, such as the following: [ka]

[0077] In another example, compounds containing guanidinyl within a ring can undergo tautomerism to form different rings, such as the following: [ka]

[0078] A "prodrug" refers to a derivative of an active agent that requires conversion in the body to release the active agent. In some embodiments, the conversion is enzymatic. Prodrugs are often, though not always, pharmacologically inactive until they are converted to the active agent.

[0079] A "deuterated analog" refers to a derivative of an activator in which any hydrogen atom is replaced by deuterium. In some embodiments, the deuterated site is located in the warhead portion. In some embodiments, the deuterated site is located in the linker portion. In some embodiments, the deuterated site is located in the degron portion.

[0080] A "pharmaceutically acceptable salt" means a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit / risk ratio. A pharmaceutically acceptable salt may be prepared in insights during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid, or by reacting an acidic group with a suitable base. This term also includes stereoisomers (enantiomers and / or diastereomers), tautomers, and salts of prodrugs of the compounds of the present invention.

[0081] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, addition salts such as pharmaceutically acceptable addition salts can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used without excessive experimentation to prepare non-toxic, pharmaceutically acceptable addition salts.

[0082] In this specification, the terms “administer,” “to administer,” “to treat,” and “to treat” mean, when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. Cellular treatment includes the contact of a reagent with cells, as well as the contact of a reagent with a fluid, where the fluid comes into contact with the cells. The terms “administer” and “treat” also mean in vitro and ex vivo treatments with reagents, diagnostic agents, conjugate compounds, or with other cells, e.g., cells. In this specification, the term “subject” includes any living organism, preferably an animal, more preferably a mammal (e.g., rats, mice, dogs, cats, and rabbits), most preferably a human.

[0083] As used herein, the terms “to be treated,” “to treat,” or “treatment” generally also refer to the attainment of a desired pharmacological and / or physiological effect. This effect may be prophylactic in accordance with the overall or partial prevention of the disease or its symptoms, and / or therapeutic in accordance with the partial or complete stabilization or cure of the disease, and / or side effects resulting from the disease. As used herein, “to be treated,” “to treat,” or “treatment” encompasses any treatment of a patient’s disease, including (a) the prevention of a disease or condition in a patient who is susceptible to the disease or condition but has not yet been diagnosed, (b) the suppression of the symptoms of the disease, i.e., prevention of its onset, or (c) the remission of the symptoms of the disease, i.e., causing overall or partial regression of the disease or its symptoms.

[0084] The term “effective dose” or “therapeutic dose” refers to the amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to have an effect on such treatment for the disease, disorder, or symptom. “Therapeutic dose” may vary depending on the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the symptoms of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. An appropriate amount in any given case may be obvious to those skilled in the art or can be determined by routine experimentation. In some embodiments, “therapeutic dose” is the amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug and / or at least one pharmaceutically acceptable salt thereof that is effective in “treating” the disease or disorder in a subject as defined herein. In the case of combination therapy, “therapeutic dose” refers to the total amount of the combination subject for the effective treatment of the disease, disorder, or condition.

[0085] The term “disease” refers to any illness, discomfort, disease, symptom, or indication, and may be interchangeable with the terms “disorder” or “condition.”

[0086] Throughout this specification and the following claims, unless the context otherwise requires, the term “comprise,” and variations such as “comprises” and “comprising,” are intended to identify the presence of a subsequent feature, but not to exclude the presence or addition of one or more other features. Where used herein, the term “comprising” may be replaced by the terms “containing,” “including,” or sometimes “having.”

[0087] Throughout this specification and the following claims, "C n-m " or "C n -C m The term "C" indicates a range including the endpoint, where n and m are integers and represent the number of carbon atoms. For example, C 1-8 , C 1-6 Examples include C1-C8 and C1-C6.

[0088] Unless otherwise specified, percentages, proportions, ratios, or parts as used in this application refer to weight or volume. Quantities as used in this application refer to weight or volume. Those skilled in the art can easily determine this.

[0089] The present application demonstrates its beneficial effects through the following examples. Those skilled in the art will recognize that these examples are illustrative and not limiting. These examples do not in any way limit the scope of this application. The experimental methods described in the following examples are conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.

[0090] Unless otherwise specifically defined elsewhere in this specification, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art to which this invention pertains. [Examples]

[0091] The following examples are intended to be merely illustrative and should in no way be construed as limiting. Although efforts have been made to ensure accuracy with respect to the numbers used (e.g., amounts, temperatures, etc.), some experimental error and deviation should be taken into account. Unless otherwise indicated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise indicated. Unless otherwise indicated, the reactions described below were carried out in an anhydrous solvent under a positive nitrogen or argon pressure or using a drying tube, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe, and the glassware was oven-dried and / or heat-dried.

[0092] 1 1H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. 1 1H NMR Spectra were obtained using tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm, CD3OD: 3.31 ppm, D2O: 4.79 ppm, d6-DMSO: 2.50 ppm, d6-acetone: 2.05, (CD3)3CO: 2.05) as reference standards with CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone, or (CD3)2CO as solvents. When peak multiplicities were reported, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are reported in Hertz (Hz) when provided.

[0093] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190~400nm), Mass detector: 6120 SQ Mobile phase: A: Water containing 0.1% formic acid, B: Acetonitrile containing 0.1% formic acid Column: Poroshell 120 EC-C18, 4.6×50mm, 2.7pm Gradient method: Flow rate: 1.8 mL / min Time (min) A (%) B (%) [Table 2] LC-MS, LC-MS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190~400nm), Mass detector: G6125C SQ Mobile phase: A: Water containing 0.1% formic acid, B: Acetonitrile containing 0.1% formic acid Column: Poroshell 120 EC-C18, 4.6×50mm, 2.7pm Gradient method: Flow rate: 1.8 mL / min Time (min) A (%) B (%) [Table 3] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II) Detector: MWD (190~400nm), Mass detector: G6125C SQ Mobile phase: A: Water containing 0.1% formic acid, B: Acetonitrile containing 0.1% formic acid Column: Poroshell 120 EC-C18, 4.6×50mm, 2.7pm Gradient method: Flow rate: 1.2 mL / min Time (min) A (%) B (%) [Table 4] Preparative HPLC was performed on a column (150 × 21.2 mm inner diameter, 5 pm, Gemini NXC18) at a flow rate of 20 ml / min, injection volume of 2 ml, room temperature, and UV detection at 214 nm and 254 nm.

[0094] In the following embodiments, the following abbreviations will be used. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0095] Synthesis of intermediates Intermediate 1: 3-(3,3-dimethyl-2-oxo-4-(4-oxopiperidine-1-yl)indoline-1-yl)piperidine-2,6-dione Step 1: N-(2,6-bis(benzyloxy)pyridine-3-yl)-2-(2,6-dibromophenyl)acetamide [ka] 2-(2,6-dibromophenyl)acetic acid (10 g, 34.2 mmol), 2,6-bis(benzyloxy)pyridine-3-amine (11.5 g, 37.6 mmol), and DIEA (13.3 g, 102.6 mmol) were dissolved in DMF (200 ml), to which HATU (19.5 g, 51.3 mmol) was added at 0°C. The mixture was stirred overnight at room temperature. The mixture was diluted with EA (500 mL), and the solid was filtered. The mixture was concentrated under reduced pressure to obtain the crude product (15 g, 75.7%). [M+H] + = 581.

[0096] Step 2: 1-(2,6-bis(benzyloxy)pyridine-3-yl)-4-bromoindoline-2-one [ka] A 500 mL round-bottom flask equipped with a magnetic stirring bar was packed with N-(2,6-bis(benzyloxy)pyridine-3-yl)-2-(2,6-dibromophenyl)acetamide (15 g, 25.9 mmol), K2CO3 (17.8 g, 129.5 mmol), CuCl (2.56 g, 25.9 mmol), pentane-2,4-dione (5.17 g, 51.8 mmol), and NMP (200 mL). The mixture was degassed under vacuum and purged three times with N2. The resulting mixture was stirred under N2 at 85°C for 3 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (300 mL) and then filtered through a Celite pad. The filtrate was washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography (EA / PE, 15%) to obtain the product (8.00 g, 61.8%). [M+H] + = 501.

[0097] Step 3: 1-(2,6-bis(benzyloxy)pyridine-3-yl)-4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)indoline-2-one [ka] A 120 mL solution of dioxane containing 1-(2,6-bis(benzyloxy)pyridine-3-yl)-4-bromoindorin-2-one (8 g, 15.9 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (3.43 g, 23.9 mmol), Cs2CO3 (15.62 g, 47.7 mmol), and Pd-PEPPSI-IPentCl (0.67 g, 0.80 mmol) was degassed under reduced pressure, purged five times with N2, and stirred overnight at 100°C under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL) and then filtered through a Celite pad. The filtrate was washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography (EA / PE, 40%) to obtain the product (2 g, 22.2%). [M+H] + = 564.

[0098] Step 4: 1-(2,6-bis(benzyloxy)pyridine-3-yl)-3,3-dimethyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)indoline-2-one [ka] A solution of 1-(2,6-bis(benzyloxy)pyridine-3-yl)-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)indorin-2-one (2 g, 3.55 mmol) and NaH (0.71 g, 17.75 mmol) in DMF (20 mL) was stirred at 0°C for 30 minutes. Then, while maintaining the temperature at 0°C, CH3I (2.5 g, 17.75 mmol) was added dropwise to the mixture. The resulting mixture was stirred at room temperature for 4 hours. The mixture was poured into EA (20 mL), washed sequentially with brine (20 mL), water (3 × 20 mL), and brine (20 mL), then dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica column chromatography (EA / PE, 15%) to obtain the product (1.5 g, 71.4%). [M+H] + = 592.

[0099] Step 5: 3-(3,3-dimethyl-2-oxo-4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)indoline-1-yl)piperidine-2,6-dione [ka] A 100 mL round-bottom flask equipped with a magnetic stir bar was charged with 1-(2,6-bis(benzyloxy)pyridin-3-yl)-3,3-dimethyl-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)indolin-2-one (1.5 g, 2.53 mmol), DCM / EtOH (10 mL / 20 mL), and Pd / C (10 wt%, 1.5 g). The resulting mixture was degassed under reduced pressure and purged with H2 five times, and then stirred at room temperature overnight. The mixture was diluted with DCM / MeOH (50 mL / 50 mL), then sonicated in a sonicator for 5 minutes, and subsequently filtered through a Celite pad. The filtrate was concentrated under vacuum. The residue was purified by silica column chromatography (PE / EA = 1:1) to give the product (560.1 mg, 53.6%). [M+H] + = 414. 1 H NMR (300 MHz, DMSO) δ 11.05 (s, 1H), 7.22 (t, J = 7.4 Hz, 1H), .03 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 5.21 (s, 1H), 3.93 (s, 4H), 3.32 (s, 2H), 2.87 (t, J = 5.5 Hz, 5H), 1.94 (s, 1H), 1.86 - 1.71 (m, 4H), 1.40 (s, 6H).

[0100] Step 6: 3-(3,3-Dimethyl-2-oxo-4-(4-oxopiperidin-1-yl)indolin-1-yl)piperidine-2,6-dione

Chem.

[0101] Intermediate 2: 2,6-Bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine

Chem.

[0102] Step 2: 5-Bromo-1,3-difluoro-2-iodobenzene [ka] Five reactions were carried out in parallel. 1-Bromo-3,5-difluorobenzene (1.00 kg, 5.18 mol, 595 mL) in a THF (4.00 L) solution was mixed with LDA (2 M, 2.59 L) at -70°C. The mixture was stirred at -70°C for 1 hour. Then, I2 (1.33 kg, 5.23 mol, 1.05 L) in a THF (1.00 L) solution was mixed with the mixture at -70°C. The mixture was stirred at -70°C for 1 hour. The reaction mixture was poured into H2O (5.00 L), extracted with  (3.00 L x 2), the five reaction products were combined, the combined organic layer was washed with brine (5.00 L), dried over Na2SO4, filtered, and concentrated under vacuum at 40°C to obtain the residue. The crude product was ground with petroleum ether (6.00 L). Compound 5-bromo-1,3-difluoro-2-iodobenzene (4.50 kg, 14.1 mol, yield 54.4%) was obtained. [M+H] + =318.8

[0103] Step 3: 2,6-Bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine [ka] To a solution of 5-bromo-1,3-difluoro-2-iodobenzene (4.50 kg, 14.1 mol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.89 kg, 14.1 mol) in dioxane (22.5 L) and H2O (4.50 L), Pd(PPh3)4 (1.63 kg, 1.41 mol) and K3PO4 (8.99 kg, 42.3 mol) were added. The mixture was stirred at 90°C for 12 hours. TLC (petroleum ether:ethyl acetate = 10:1, R) f (Starting material) = 0.84, R fThe product yield (0.66) indicated that the starting material was completely consumed. The mixture was filtered, the filtrate was extracted with ethyl acetate (5.00 L), the combined organic matter was washed with brine (5.00 L), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0-1:1). Compound 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (3.00 kg, 6.01 mol, yield 42.5%, purity 96.5%) was obtained. 1 ¹H NMR (400MHz, chloroform-d): 7.47-7.40 (m, 1H), 7.39-7.34 (m, 2H), 7.34-7.29 (m, 2H), 7.29-7.25 (m, 4H), 7.25-7.17 (m, 2H), 7.12-7.05 (m, 2H), 6.42 (d, J=8.0Hz, 1H), 5.32 (s, 2H), 5.28 (s, 2H); [M+H] + = 482.1.

[0104] Intermediate 3: (R)-3-(2,6-difluoro-4-(4-oxopiperidine-1-yl)phenyl)piperidine-2,6-dione Step 1: 8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] To a solution of intermediate 2 (30 g, 62.24 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (10.68 g, 74.69 mmol), and Cs2CO3 (40.58 g, 124.48 mmol) in dioxane (500 mL), Pd2(dba)3 (2.85 g, 3.11 mmol) and Xantphos (3.6 g, 6.22 mmol) were added under an N2 atmosphere. The mixture was stirred at 80°C for 16 hours under N2 protection. The mixture was diluted with siRNA and filtered. The filtrate was concentrated under vacuum and purified by silica column chromatography (EA:PE = 0-80%) to obtain the crude product. The crude product was recrystallized over MeOH and filtered. The filtration cake was dried to obtain the title compound (26.8 g, yield 79%). [M+H] + = 544.9.

[0105] Step 2: 3-(2,6-difluoro-4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione [ka] 8-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (26.8 g, 49.26 mmol) was dissolved in DMF (400 mL) and iPrOH (80 mL), to which Pd / C (27 g, 10 wt%, wet) was added. The mixture was stirred at 45°C for 16 hours under an H2 atmosphere (4 bar). The mixture was filtered, and the filter cake was washed with DMF. The combined liquid was concentrated under vacuum to obtain the title compound (15 g, yield 83.2%). [M+H] + = 367.1.

[0106] Step 3: (R)-3-(2,6-difluoro-4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione [ka] The title compound was purified by chiral HPLC (CHIRALPAK IF (2×25cm, 5um), MtBE (0.1% DEA):(MeOH:DCM=1:1)=50:50, 100 bar, 20 ml / min), and the title compound corresponded to peak A at 0.990 min / 254 nm (37% yield from 4.47 g and 12 g of racemic compound). [M+H] + = 367.1.

[0107] Step 4: (R)-3-(2,6-difluoro-4-(4-oxopiperidine-1-yl)phenyl)piperidine-2,6-dione [ka] (R)-3-(2,6-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione (1 g, 2.73 mmol) was placed in a 100 mL round-bottom flask equipped with a magnetic stirring bar. Then, 10 mL of 8N HCl aqueous solution was added. The mixture was stirred at room temperature for 30 minutes. The mixture was added dropwise to saturated NaHCO3 aqueous solution until the pH was finally adjusted to 6-7. The liquid was extracted by DCM and separated. The organic phase was concentrated under vacuum and purified by silica gel column chromatography (MeOH:DCM = 0-5%) to obtain the title compound (850 mg, yield 96.7%). [M+H] + = 323.1.

[0108] Intermediate 4: 2',6'-bis(benzyloxy)-3-fluoro-5-iodo-6-methyl-2,3'-bipyridine Step 1: 5-Fluoro-2-methylpyridine-3-amine [ka] To a solution of 2-bromo-5-fluoropyridine-3-amine (20 g, 105.26 mmol) in dioxane / H2O (200 / 40 mL), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (15.91 g, 126.32 mmol), Pd(dppf)Cl2 (8.59 g, 10.53 mmol), and K2CO3 (43.57 g, 315.79 mmol) were added. The resulting solution was stirred overnight at 120°C under an N2 atmosphere. After cooling to room temperature, the reaction products were quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with MeOH / DCM (0-10%) to obtain 5-fluoro-2-methylpyridine-3-amine (12 g, 90.1%). [M+H] + =127.1

[0109] Step 2: 6-Chloro-5-fluoro-2-methylpyridine-3-amine [ka] 6 g, 47.62 mmol of 5-fluoro-2-methylpyridine-3-amine was added to a stirred mixture of DMF (120 mL) at 0°C with NCS (8.43 g, 47.62 mmol). The mixture was stirred overnight at 60°C. After cooling to room temperature, the reaction product was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EA / PE (0-50%) to obtain 6-chloro-5-fluoro-2-methylpyridine-3-amine (3 g, 39.5%). [M+H] + =160.0

[0110] Step 3: 2',6'-bis(benzyloxy)-3-fluoro-6-methyl-[2,3'-bipyridine]-5-amine [ka] To a solution of 6-chloro-5-fluoro-2-methylpyridine-3-amine (3 g, 18.63 mmol) in dioxane / H2O (30 / 5 mL), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9.32 g, 22.36 mmol), Pd(dppf)Cl2 (1.52 g, 1.86 mmol), and K2CO3 (7.71 g, 55.89 mmol) were added. The resulting solution was stirred overnight at 100°C under an N2 atmosphere. After cooling to room temperature, it was diluted with H2O and extracted with siRNA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0-50%) to obtain 2',6'-bis(benzyloxy)-3-fluoro-6-methyl-[2,3'-bipyridine]-5-amine (5g, 64.3%). [M+H] + = 415.2.

[0111] Step 4: 2',6'-bis(benzyloxy)-3-fluoro-5-iodo-6-methyl-2,3'-bipyridine [ka] To a solution of 2',6'-bis(benzyloxy)-3-fluoro-6-methyl-[2,3'-bipyridine]-5-amine (3 g, 7.23 mmol) in ACN (30 mL), KI (6 g, 36.14 mmol), CuI (1.65 g, 8.67 mmol), and t-BuONO (3.72 g, 36.14 mmol) were added. The resulting solution was stirred overnight at 80°C under a N2 atmosphere. After cooling to room temperature, the mixture was diluted with H2O and extracted with siRNA. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0-15%) to obtain 2',6'-bis(benzyloxy)-3-fluoro-5-iodo-6-methyl-2,3'-bipyridine (2.5 g, 65.79%). [M+H] + = 527.1.

[0112] Intermediate 5: 3-(3-fluoro-6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione Step 1: 8-(2',6'-bis(benzyloxy)-3-fluoro-6-methyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] A mixture of 1,4-dioxane (50 mL) containing intermediate 4 (5.2 g, 9.89 mmol), 1,4-dioxane-8-azaspiro[4.5]decane (2.11 g, 14.83 mmol), Ruphos (0.94 g, 0.20 mmol), Pd2(dba)3 (0.9 g, 0.99 mol), and Cs2CO3 (9.7 g, 29.66 mmol) was stirred at 100°C for 8 hours under an N2 atmosphere. After cooling to room temperature, the mixture was diluted with H2O, extracted with SiO2, washed with brine, dried over Na2SO4, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0-30%) to obtain 8-(2',6'-bis(benzyloxy)-3-fluoro-6-methyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane (4.5 g, 85.0%). [M+H] + = 542.6.

[0113] Step 2: 3-(3-fluoro-6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione [ka] 8-(2',6'-bis(benzyloxy)-3-fluoro-6-methyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane (4.5 g, 8.31 mmol) was mixed in 100 mL of THF with Pd / C (10% by weight, 4.5 g). The resulting mixture was degassed under reduced pressure, purged five times with H2, and then stirred overnight at room temperature. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE, 30-50%) to obtain 3-(3-fluoro-6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione (3.53 g, 9.8 mmol, 83.0%). 1 H NMR(300MHz,DMSO)δ 10.86(s,1H), 7.35(d,J=12Hz,1H), 4.13(m,1H), 3.32(s,1H), 2.94(t,J=6Hz,4H), 2.71(m,1H), 2.62-2.50(m,1H), 2.37( d,J=3Hz,3H), 2.26-2.15(m,1H), 2.03(m,1H), 1.78(t,J=6Hz,4H), 1.36(s,1H), 1.22(d,J=12Hz,1H), 0.99-0.80(m,1H).

[0114] Step 3: 3-(3-fluoro-6-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] This compound was prepared using the same procedure as in step 4 of intermediate 3.

[0115] Intermediate 6: 3-(4,6-dimethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione Step 1: 2',6'-bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine [ka] To a solution of 3-bromo-6-chloro-2,4-dimethylpyridine (9 g, 40.91 mmol) in dioxane / H2O (100 / 20 mL), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (17.1 g, 40.91 mmol), Pd(PPh3)4 (4.64 g, 4.10 mmol), and K2CO3 (16.94 g, 122.73 mmol) were added. The resulting solution was stirred at 100°C for 5 hours under an N2 atmosphere. After cooling to room temperature, it was diluted with H2O, extracted with siRNA, washed with brine, dried over Na2SO4, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0-50%) to obtain 2',6'-bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine (12 g, 62.2%). [M+H] + =475.1

[0116] Step 2: 8-(2',6'-bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] Pd-PEPPSI-IPentCl (406.7 mg, 0.48 mmol) was added to a stirred mixture of 2',6'-bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine (2.3 g, 4.84 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (1.0 g, 7.26 mmol), and Cs2CO3 (4.7 g, 14.52 mmol) in DMF (20 mL). The resulting mixture was stirred at 100 °C for 5 hours under an N2 atmosphere. After cooling to room temperature, it was diluted with H2O, extracted with siRNA, washed with brine, dried over Na2SO4, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0-30%) to obtain 8-(2',6'-bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane (1.5 g, 57.7%). [M+H] + = 538.3.

[0117] Step 3: 3-(4,6-dimethyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione [ka] 8-(2',6'-bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane (3.4 g, 8.31 mmol) was mixed with THF (50 mL) and Pd / C (10 wt%, 3.5 g) was added. The resulting mixture was degassed under reduced pressure, purged five times with H2, and then stirred overnight at room temperature. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE = 30-50%) to obtain 3-(4,6-dimethyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione (2.09 g, 83.0%). [M+H] + =359.4 1 H NMR(300MHz,DMSO)δ 10.77(s,1H), 6.96(s,1H), 3.92(s,4H), 3.83(m,1H), 3.03(t,J=6Hz,4H), 2.62-2.51( m,2H), 2.39(s,3H), 2.26(s,3H), 2.18(m,1H), 2.12-2.00(m,1H), 1.72(t,J=6Hz,4H).

[0118] Step 4: 3-(4,6-dimethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] This compound was prepared using the same procedure as in step 4 of intermediate 3.

[0119] Intermediate 7: 3-(4-ethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione Step 1: 5-Bromo-2-chloro-4-vinylpyridine [ka] 5-Bromo-2-chloro-4-iodopyridine (16 g, 50.3 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (7.75 g, 50.3 mmol), and Na2CO3 (16.00 g, 150.9 mmol) were stirred in 1,4-dioxacyclohexane (200 mL) and H2O (40 mL) to which Pd(dpppf)Cl2 (3.65 g, 5.03 mmol) was added. The resulting mixture was degassed under reduced pressure and purged three times with N2. Then, it was stirred at 100°C for 5 hours. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by column chromatography (EA / PE = 20-30%) to obtain 5-bromo-2-chloro-4-vinylpyridine (6.8 g, 62.0%). [M+H] + = 218.

[0120] Step 2: 8-(6-chloro-4-vinylpyridine-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] 5-bromo-2-chloro-4-vinylpyridine (6.8 g, 31.2 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (4.46 g, 31.2 mmol), and Cs2CO3 (20.3 g, 62.4 mmol) were stirred in 1,4-dioxacyclohexane (140 mL) and Pd-PEPPSI-IPentCl (1.3 g, 1.56 mmol) was added. The resulting mixture was degassed under reduced pressure and purged three times with N2. This mixture was then stirred overnight at 100°C. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by column chromatography (EA / PE = 26-28%) to obtain 8-(6-chloro-4-vinylpyridine-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (4.2 g, 47.9%). [M+H] + =281.

[0121] Step 3: 8-(2',6'-bis(benzyloxy)-4-vinyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] 8-(6-chloro-4-vinylpyridine-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (4.2 g, 14.95 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.23 g, 14.95 mmol), and K2CO3 (6.19 g, 44.85 mmol) were stirred in 1,4-dioxacyclohexane (50 mL) and H2O (10 mL) to which Pd(dpppf)Cl2 (1.09 g, 1.5 mmol) was added. The resulting mixture was degassed under reduced pressure and purged three times with N2. This was then stirred at 100°C for 5 hours. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by column chromatography (EA / PE = 20-30%) to obtain 8-(2',6'-bis(benzyloxy)-4-vinyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane (6.3 g, 78.9%). [M+H] + =536

[0122] Step 4: 3-(4-ethyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione [ka] 8-(2',6'-bis(benzyloxy)-4-vinyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane (6.3 g, 11.8 mmol) was mixed in 150 mL of THF with Pd / C (10% by weight, 6.3 g). The resulting mixture was degassed under reduced pressure, purged five times with H2, and then stirred overnight at 50°C. The reaction mixture was diluted with THF / DCM (1:1) and then filtered through a Celite pad. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (PE / EA, 30-50%) to obtain 3-(4-ethyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione (3.53 g, 9.8 mmol, 83.05%). [M+H] + =360. 1 H NMR(300MHz,DMSO)δ 10.80(s,1H), 8.19(s,1H), 7.20(s,1H), 3.99-3.90(m,1H), 3.32(s,1H), 2.96(t,J=3Hz,4H) , 2.72-2.50(m,3H), 2.26-2.04(m,1H), 1.76(t,J=6Hz,4H), 1.20(t,J=9Hz,3H), 1.07(s,2H).

[0123] Step 5: 3-(4-ethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] This compound was prepared using the same procedure as in step 4 of intermediate 3.

[0124] Intermediate 8: 2-(6-(2,6-dioxopiperidine-3-yl)-2,4-dimethylpyridine-3-yl)ethylmethanesulfonate Step 1: 2',6'-bis(benzyloxy)-4,6-dimethyl-5-vinyl-2,3'-bipyridine [ka] 2',6'-bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine (3 g, 6.31 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.17 g, 7.58 mmol), and K2CO3 (2.61 g, 18.93 mmol) were mixed in 1,4-dioxane (30 mL) and H2O (6 mL) with Pd(dpppf)Cl2 (514.1 mg, 0.63 mmol). The resulting solution was stirred at 100°C for 5 hours under an N2 atmosphere. After cooling to room temperature, it was diluted with H2O, extracted with ELISA, washed with brine, dried over Na2SO4, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0-20%) to obtain 2',6'-bis(benzyloxy)-4,6-dimethyl-5-vinyl-2,3'-bipyridine (1.7 g, 63.9%). [M+H] + = 423.2.

[0125] Step 2: 2-(2',6'-bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridine]-5-yl)ethane-1-ol [ka] To a stirred mixture of 2',6'-bis(benzyloxy)-4,6-dimethyl-5-vinyl-2,3'-bipyridine (1.7 g, 4.01 mmol) in THF (20 mL), 9-BBN (0.5 M THF solution, 40 mL, 20.0 mmol) was added dropwise at 0°C. The reaction mixture was stirred overnight at room temperature, and then NaOH (2 M aqueous solution, 4 mL, 8.03 mmol) and H2O2 (30%, 40.2 mL, 12.1 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours, the mixture was diluted with H2O, extracted with EA, and the residue was purified by column chromatography (EA / PE = 0-35%) to obtain 2-(2',6'-bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridine]-5-yl)ethane-1-ol (1.4 g, 79.5%). [M+H] + = 441.2.

[0126] Step 3: 3-(5-(2-hydroxyethyl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] 2-(2',6'-bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridine]-5-yl)ethane-1-ol (1.4 g, 8.31 mmol) was mixed with THF (50 mL) and Pd / C (10 wt%, 1.5 g) was added. The resulting mixture was degassed under reduced pressure, purged five times with H2, and then stirred overnight at 50°C. The resulting mixture was filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE = 30-50%) to obtain 3-(5-(2-hydroxyethyl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione (855.7 mg, 83.0%). [M+H] + = 263.1. 1 H NMR(300MHz,DMSO)δ 10.80(s,1H), 6.96(s,1H), 4.83-4.74(m,1H), 3.83(m,1H), 3.52(m,2H), 2.78( t,J=9Hz,2H), 2.64-2.54(m,3H), 2.44(s,3H), 2.29(s,3H), 2.26-2.02(m,1H).

[0127] Step 4: 2-(6-(2,6-dioxopiperidine-3-yl)-2,4-dimethylpyridine-3-yl)ethylmethanesulfonate [ka] 3-(5-(2-hydroxyethyl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione (300 mg, 1.15 mmol) and Et3N (347 mg, 3.44 mmol) were dissolved in DCM (6 mL) and THF (6 mL). MsCl (172 mg, 1.49 mmol) was slowly added at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was quenched with water (10 mL). The organic phase was separated and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 20:1) to obtain the product (220 mg, yield 56.5%). [M+H] + = 341.5.

[0128] Intermediate 9: 3-(3-fluoro-5-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione Step 1: tert-butyl(3R,4S)-4-(4-benzylpiperazine-1-yl)-3-fluoropiperidine-1-carboxylate [ka] A solution of tert-butyl(3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (2.5 g, 11.46 mmol), N-benzyl-2-chloro-N-(2-chloroethyl)ethane-1-amine hydrochloride (3 g, 11.46 mmol), and NaHCO3 (3.85 g, 45.84 mmol) in EtOH (50 mL) was stirred at 80°C for 16 hours. After LC-MS indicated completion of the reaction, the mixture was concentrated, diluted with water, and extracted by DCM. The organic layer was separated and concentrated. The mixture was purified by silica column chromatography (MeOH:DCM = 0-4%) to obtain tert-butyl(3R,4S)-4-(4-benzylpiperazine-1-yl)-3-fluoropiperidine-1-carboxylate (2 g, 5.3 mmol, 46.3%). [M+H] + = 378.6.

[0129] Step 2: 1-Benzyl-4-((3R,4S)-3-fluoropiperidine-4-yl)piperazine [ka] To a solution of tert-butyl(3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidine-1-carboxylate (5 g, 13.2 mmol) in DCM (20 mL), TFA (10 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under vacuum. The residue was dissolved in DCM (200 mL), washed with saturated NaHCO3 solution (3 × 100 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (3 g, 81.7%). [M+H] + = 278.4.

[0130] Step 3: 2',6'-bis(benzyloxy)-5-((3R,4S)-4-(4-benzylpiperazine-1-yl)-3-fluoropiperidine-1-yl)-3-fluoro-6-methyl-2,3'-bipyridine [ka] To a stirred solution of intermediate 4 (0.95 g, 1.8 mmol) in dioxane (20 mL), Cs2CO3 (1.2 g, 3.6 mmol), 1-benzyl-4-((3R,4S)-3-fluoropiperidine-4-yl)piperazine (0.5 g, 1.8 mmol), and Pd-Ruphos-G3 (0.3 g, 0.4 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with Âi (100 mL) and washed with water (3 × 50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with MeOH / DCM (0-5%) to obtain the product (0.95 g, 78%). [M+H] + = 676.7.

[0131] Step 4: tert-butyl 4-((3R,4S)-1-(6-(2,6-dioxopiperidine-3-yl)-5-fluoro-2-methylpyridine-3-yl)-3-fluoropiperidine-4-yl)piperazine-1-carboxylate [ka] 2',6'-bis(benzyloxy)-5-((3R,4S)-4-(4-benzylpiperazine-1-yl)-3-fluoropiperidine-1-yl)-3-fluoro-6-methyl-2,3'-bipyridine (0.95 g, 1.4 mmol) and di-tert-butyl dicarbonate (1.5 g, 7 mmol) were mixed in i-PrOH (40 mL) and DMF (40 mL) and Pd carbon (1 g, wet, 10 wt%) was added. The resulting mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 24 hours. The mixture was then filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluted with MeOH / DCM (0-7%) to obtain the product (0.46 g, 64.5%). [M+H] + = 508.4.

[0132] Step 5: 3-(3-fluoro-5-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl 4-((3R,4S)-1-(6-(2,6-dioxopiperidine-3-yl)-5-fluoro-2-methylpyridine-3-yl)-3-fluoropiperidine-4-yl)piperazine-1-carboxylate (460 mg, 0.9 mmol) in DCM (10 mL), TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under vacuum. The residue was dissolved in DCM (50 mL), washed with saturated NaHCO3 solution (3 × 20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (260 mg, 70.4%). [M+H] += 408.5.

[0133] Intermediate 10: 3-(3-fluoro-5-((3S,4R)-3-fluoro-4-(piperazin-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using the same procedure as for intermediate 9.

[0134] Intermediate 11: 3-(5-((3S,4R)-3-fluoro-4-(piperazine-1-yl)piperidine-1-yl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using the same procedure as for intermediate 9.

[0135] Intermediate 12: 3-(4-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione Step 1: 2',6'-bis(benzyloxy)-5-bromo-4-methyl-2,3'-bipyridine [ka] 5-Bromo-2-iodo-4-methylpyridine (4.8 g, 16.1 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.7 g, 16.1 mmol), and K2CO3 (4.5 g, 32.2 mmol) were dissolved in 1,4-dioxane (100 mL) and H2O (20 mL). Pd(dppf)Cl2 (1.2 g, 1.61 mmol) was added to the solution. The mixture was stirred at 90°C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by silica column chromatography (PE:EA = 100:1-5:1) to obtain the product (6.7 g, 90.5%). [M+H] + = 461.5.

[0136] Step 2: 8-(2',6'-bis(benzyloxy)-4-methyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] 2',6'-bis(benzyloxy)-5-bromo-4-methyl-2,3'-bipyridine (6.7 g, 14.5 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (5.2 g, 36.3 mmol), and Cs2CO3 (9.4 g, 29.0 mmol) were dissolved in DMA (80 mL), to which Pd2(dba)3 (2.6 g, 2.9 mmol) and RuPhos (2.7 g, 5.8 mmol) were added. The mixture was stirred under a nitrogen atmosphere at 100 °C for 16 hours. The mixture was filtered through a Celite pad and washed with DCM. The filtrate was concentrated under reduced pressure to obtain the crude residue, which was purified by silica column chromatography (PE:EA = 50:1-2:1) to obtain the product (5.3 g, 69.7%). [M+H] + = 524.5.

[0137] Step 3: 3-(4-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione [ka] 8-(2',6'-bis(benzyloxy)-4-methyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane (5.3 g, 10.1 mmol) was dissolved in DMF (75 mL) and iPrOH (75 mL), to which Pd / C (2.0 g, 10 wt%, wet) was added. The mixture was stirred under a hydrogen atmosphere (balloon) at 50°C for 20 hours. The mixture was cooled to room temperature and filtered directly through Celite. The filtrate was concentrated under vacuum to obtain the desired product (2.7 g, 77.1%). [M+H] + = 346.6.

[0138] Step 4: 3-(4-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] 3-(4-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione (2.7 g, 7.8 mmol) was placed in a 250 mL round-bottom flask equipped with a magnetic stirring bar. Then, 45 mL of 8N HCl aqueous solution was added. The mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to saturated NaHCO3 aqueous solution to adjust the pH to 6-7. The liquid was extracted and separated using DCM (40 mL x 3). The combined organic phase was concentrated under vacuum and purified by combiflush (DCM:MeOH = 25:1) to obtain the title compound (2.2 g, yield 93.6%). [M+H] + = 302.5.

[0139] Intermediate 13: 3-(6-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using the same procedure as for intermediate 12.

[0140] Intermediate 14: (7 1 R,7 2 S,E)-5 6 -Brom-1 1 ,2 6 ,7 2 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one Step 1: tert-butyl((3-methylbuta-3-en-1-yl)oxy)diphenylsilane [ka] TBDPSCl (76.7 g, 278.9 mmol) was slowly added to a stirred solution of 3-methylbuta-3-en-1-ol (20 g, 232.6 mmol) and imidazole (34.8 g, 511.2 mmol) in DMF (500 mL) cooled to 0°C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with H2O (300 mL) and extracted with EA. The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by column chromatography (PE) to obtain the crude product (65 g, 200 mmol, 86%).

[0141] Step 2: Ethyl 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylcyclopropane-1-carboxylate [ka] Rh2(OAc)4 (4.08 g, 9.2 mmol) was added to a stirred solution of tert-butyl((3-methylbuta-3-en-1-yl)oxy)diphenylsilane (60 g, 184.6 mmol) in DCM (600 mL). The resulting mixture was degassed under reduced pressure and purged three times with N2. 2-ethyl diazo (84.2 g, 738.5 mmol) was added dropwise to the mixture cooled to -10°C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated. The residue was purified by column chromatography (EA / PE = 0-5%) to obtain the crude product (60 g, 121.7 mmol, 65.9%). [M+H] + = 411.

[0142] Step 3: (2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylcyclopropyl) methanol [ka] To a stirred solution of ethyl 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylcyclopropane-1-carboxylate (36 g, 87.6 mmol) cooled to 0°C in THF (700 mL), LiAlH4 (6.66 g, 175.2 mmol) was added in small amounts. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with sodium sulfate decahydrate at 0°C for 30 minutes. This was then diluted with DCM / MEOH, filtered, and concentrated. The residue was purified by column chromatography (EA / PE = 18-20%) to obtain the product (3.1 g, 8.4 mmol, 9.6%). [M+H] + =369.

[0143] Step 4: 2-((2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylcyclopropyl)methyl)isoindoline-1,3-dione [ka] (2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylcyclopropyl)methanol (3.1 g, 8.4 mmol) and isoindoline-1,3-dione (1.23 g, 8.4 mmol) were mixed in a stirred solution of THF (60 ml) to which PPh3 (4.4 g, 16.8 mmol) was added. The resulting mixture was degassed under reduced pressure and purged three times with N2. DIAD (2.5 g, 12.6 mmol) was added dropwise to the mixture cooled to 0°C. The resulting mixture was then stirred at room temperature for 5 hours. The reaction mixture was diluted with H2O and extracted with EA. The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by column chromatography (EA / PE, 7-9%) to obtain the product (2.8 g, 5.6 mmol, 66.7%). [M+H] + = 498.

[0144] Step 5: (2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylcyclopropyl)methanamine [ka] 2-((2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylcyclopropyl)methyl)isoindoline-1,3-dione (2.8 g, 5.6 mmol) was mixed with EtOH (60 mL) and N2H4·H2O (1.12 g, 22.4 mmol) was added. The resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product (2.0 g, 5.4 mmol). The product was used directly in the next step without purification. [M+H] + = 368.

[0145] Step 6: 2-(2-(((5-bromo-2-nitrophenyl)amino)methyl)-1-methylcyclopropyl)ethane-1-ol [ka] (2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-methylcyclopropyl)methaneamine (2.0 g, 5.4 mmol) and 4-bromo-2-fluoro-1-nitrobenzene (1.3 g, 5.94 mmol) were mixed in DMSO (20 mL) and DIEA (2.1 g, 16.3 mmol) was added. The resulting mixture was degassed under reduced pressure and purged three times with N2. It was then stirred at 80°C for 4 hours. The reaction mixture was diluted with H2O and extracted with EA. The combined organic layers were washed with brine, dried, filtered, and concentrated. The residue was purified by column chromatography (EA / PE = 25-30%) to obtain the product (1.1 g, 3.3 mmol, 61.1%). [M+H] + = 329.

[0146] Step 7: 2-((1S,2R)-2-(((5-bromo-2-nitrophenyl)amino)methyl)-1-methylcyclopropyl)ethane-1-ol [ka] The crude product (1.1 g) from Step 6 was purified by preparative chiral HPLC under the following conditions (column: CHIRALPAK IG-3 (4.6 × 50 mm, 3 μm), mobile phase: Hex (0.1% DEA): EtOH = 75:25, flow rate: 1.0 mL / min, temperature: 25 °C, retention time: 2.759 min) to obtain 2-((1S,2R)-2-(((5-bromo-2-nitrophenyl)amino)methyl)-1-methylcyclopropyl)ethane-1-ol (442.6 mg, 1.3 mmol, 40.2%, enantiomeric excess = 100%). [M+H] + = 329. 1 H NMR(400MHz,CDCl3)δ 8.16(s,1H), 8.03(d,J=8Hz,1H), 6.98(d,J=4.0Hz,1H), 6.74(dd,J=9.1,2.0Hz,1H), 3.94-3.84(m,1H), 3.88-3.79(m,1H), 3.53(m, 1H), 2.97(m,1H), 1.83-1.72(m,1H), 1.37(m,1H), 1.16(s,3H), 1.20-1.08(m,1H), 0.68(dd,J=8.7,4.8Hz,1H), 0.27(t,J=4Hz,1H).

[0147] Step 8: Methyl 2-(5-(2-((1S,2R)-2-(((5-bromo-2-nitrophenyl)amino)methyl)-1-methylcyclopropyl)ethoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] 2-((1S,2R)-2-(((5-bromo-2-nitrophenyl)amino)methyl)-1-methylcyclopropyl)ethane-1-ol (3.5 g, 10.6 mmol), methyl 2-(5-hydroxy-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (2.9 g, 11.7 mmol), and PPh3 (3.4 g, 12.8 mmol) were mixed in THF (70 mL) and DIAD (2.6 g, 12.8 mmol). The mixture was then stirred at room temperature for 2 hours. The mixture was then concentrated and purified by silica gel column chromatography eluted with SiO2 / PE (0-80%) to obtain the product (6.2 g) mixed with PPh3O. [M+H] + = 558.3.

[0148] Step 9: Methyl 2-(5-(2-((1S,2R)-2-(((2-amino-5-bromophenyl)amino)methyl)-1-methylcyclopropyl)ethoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] Raney nickel (3.0 g) was added to a stirred solution of methyl 2-(5-(2-((1S,2R)-2-(((5-bromo-2-nitrophenyl)amino)methyl)-1-methylcyclopropyl)ethoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (6.2 g, 11.1 mmol) in THF (70 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 2 hours. The mixture was then filtered, and the filtrate was concentrated. The resulting mixture (5.5 g) was used in the next step without purification. [M+H] + = 528.3.

[0149] Step 10: Methyl 2-(5-(2-((1S,2R)-2-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)-1-methylcyclopropyl)ethoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate [Chemical formula] A solution of methyl 2-(5-(2-((1S,2R)-2-(((2-amino-5-bromophenyl)amino)methyl)-1-methylcyclopropyl)ethoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (5.5 g, 10.4 mmol) and BrCN (1.7 g, 15.6 mmol) in MeOH (50 mL) was stirred at room temperature for 4 hours. Then, the mixture was concentrated, diluted with DCM (200 mL), and then washed with saturated aqueous NaHCO3 (3 × 100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (0 - 15%) to give the product (4.5 g, 78.1%). [M+H] + = 553.4.

[0150] Step 11: (7 1 R,7 2 S,E)-5 6 -bromo-1 1 ,2 6 ,7 2 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [Chemical formula] To a stirred solution of methyl 2-(5-(2-((1S,2R)-2-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)-1-methylcyclopropyl)ethoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (4.5 g, 8.1 mmol) in THF (80 mL), LiHMDS (1N THF solution, 20.3 mL) was added at room temperature for 15 minutes. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then diluted with EA (100 mL) and washed with saturated NH4Cl aqueous solution (2 × 100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in EA (100 mL) and stirred at room temperature for 1 hour. The mixture was then filtered to obtain the product (3.2 g, 75.5%). [M+H] + = 521.2.

[0151] Intermediate 15: (7 1 S,7 2 R,E)-5 6 -Brom-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] Step 1: (Buta-3-en-1-yloxy)(tert-butyl)diphenylsilane [ka] A 500 mL round-bottom flask equipped with a magnetic stirring bar was packed with buta-3-en-1-ol (5.0 g, 69.4 mmol), TBDPSCl (28.65 g, 104.6 mmol), imidazole (10.39 g, 152.7 mmol), and DMF (80 mL). The resulting mixture was degassed under reduced pressure, purged three times with N2, and then stirred overnight at room temperature. The mixture was diluted with EA (200 mL), washed with water (2 × 100 mL) and brine (100 mL), dried, and concentrated. The residue was purified by column chromatography (pure PE:PE / EA = 10:1) to obtain the crude product (15 g, 48.2 mmol, 69.4%). 1 H NMR(300MHz,DMSO-d6)δ ppm 7.68-7.58(m,4H), 7.53-7.37(m,6H), 5.82(ddt,J=17.1,10.2,6.8Hz,1H), 5.1 3-4.97(m,2H), 3.69(t,J=6.6Hz,2H), 2.28(qt,J=6.6,1.4Hz,2H), 0.99(s,9H).

[0152] Step 2: Ethyl 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropane-1-carboxylate [ka] A three-necked round-bottom flask equipped with a magnetic stirring bar was packed with (buta-3-en-1-yloxy)(tert-butyl)diphenylsilane (10 g, 32.2 mmol), Rh2(OAc)4 (1.42 g, 3.22 mmol), and DCM (200 ml). The mixture was degassed under reduced pressure and purged three times with N2. DCM (20 ml) of 2-ethyl 2-diazoethyl acetate (18.34 g, 160.7 mmol) was poured into the flask, the flask was degassed, purged once more with N2, and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with EA, washed with water and brine, dried, and concentrated. The residue was purified by column chromatography (pure PE:PE / EA = 20:1) to obtain the crude product (6 g, 15.1 mmol, 46.8%). [M+H] + =397.5

[0153] Step 3: (2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methanol [ka] A round-bottom flask equipped with a magnetic stirring bar was packed with ethyl 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropane-1-carboxylate (4.0 g, 10.1 mmol) and THF (70 mL). The temperature was reduced to 0°C. While maintaining the temperature at 0°C, LiAlH4 (1.15 g, 30.3 mmol) was added to the mixture in small amounts, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was quenched with sodium sulfate decahydrate at 0°C for 30 minutes. Then, it was diluted with DCM / MEOH (50 ml / 50 ml) and concentrated. The residue was purified by column chromatography (PE / EA = 10:1-6:1) to obtain the product (730 mg, 2.05 mmol, 20.8%). [M+H] + = 355.5.

[0154] Step 4: 2-((2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methyl)isoindoline-1,3-dione [ka] A round-bottom flask equipped with a magnetic stirring bar was packed with (2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methanol (680 mg, 1.91 mmol), isoindoline-1,3-dione (564 mg, 3.82 mmol), PPh3 (1.01 g, 3.82 mmol), and THF (10 ml). The mixture was degassed under reduced pressure and purged three times with N2. DIAD (774.6 mg, 3.82 mmol) was added to the flask, the flask was degassed and purged once more with N2, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA, washed with water and brine, dried, and concentrated. The residue was purified by column chromatography (PE / EA = 10:1-7:1) to obtain the product (850 mg, 1.76 mmol, 85.4%). [M+H] + = 484.5.

[0155] Step 5: 2-(((1R,2S)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methyl)isoindoline-1,3-dione [ka] The crude product (20 g) was purified by preparative SFC under the following conditions (column: chiral ND(2) 3.0 × 100 mm, 3 μm, solvent A: CO2, solvent B: IPA (0.1% DEA), gradient (B): 5%-20% over 2 minutes, held at 20% for 1 minute, retention time 1.704 minutes) to obtain 2-(((1R,2S)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methyl)isoindoline-1,3-dione (8.12 g, 40.6%, enantiomer excess = 98.58%). 1H NMR(300MHz,DMSO-d6)δ ppm 7.84(s,4H), 7.52(td,J=8.1,1.6Hz,4H), 7.45-7.36(m,6H), 3.61-3.47(m,3H), 3.35(dd,J=14.2,7.5Hz,1H), 1.52(dq,J=12.6,6.4H z,1H), 1.32-1.19(m,1H), 0.98(d,J=7.1Hz,1H), 0.92(s,9H), 0.84(s,2H), 0.49(dt,J=8.8,4.6Hz,1H), 0.30(dt,J=9.6,5.0Hz,1H). [M+H] + = 484.5.

[0156] Step 6: 2-(((1S,2R)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methyl)isoindoline-1,3-dione [ka] The crude product (20 g) was purified by preparative SFC under the following conditions (column: chiral ND(2) 3.0 × 100 mm, 3 μm, solvent A: CO2, solvent B: IPA (0.1% DEA), gradient (B): 5%-20% over 2 minutes, held at 20% for 1 minute, retention time 2.041 minutes) to obtain 2-(((1S,2R)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methyl)isoindoline-1,3-dione (9.98 g, 49.9%, enantiomeric excess = 99.56%). 1 H NMR(300MHz,DMSO-d6)δ ppm 7.84(s,4H), 7.52(td,J=8.1,1.6Hz,4H), 7.45-7.36(m,6H), 3.61-3.47(m,3H), 3.35(dd,J=14.2,7.5Hz,1H), 1.52(dq,J=12.6,6.4H z,1H), 1.32-1.19(m,1H), 0.98(d,J=7.1Hz,1H), 0.92(s,9H), 0.84(s,2H), 0.49(dt,J=8.8,4.6Hz,1H), 0.30(dt,J=9.6,5.0Hz,1H). [M+H] + = 484.5.

[0157] Step 7: ((1S,2R)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methanamine [ka] Hydrazine hydrate (6 mL) was added to a solution of 2-(((1S,2R)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methyl)isoindoline-1,3-dione (3.5 g, 7.2 mmol) in EtOH (100 mL). The resulting mixture was stirred at 70°C for 2 hours. After LC-MS indicated completion of the reaction, the mixture was filtered to remove the solid. The filtrate was concentrated under reduced pressure to obtain the product (2.4 g, 93.7%). [M+H] + = 354.5.

[0158] Step 8: 5-Bromo-N-(((1S,2R)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methyl)-2-nitroaniline [ka] ((1S,2R)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methaneamine (1.0 g, 2.8 mmol) and 4-bromo-2-fluoro-1-nitrobenzene (684 mg, 3.1 mmol) were dissolved in MeCN (30 mL), to which DIEA (728 mg, 5.6 mol) was added at 25 °C. The mixture was stirred at 60 °C for 12 hours. The reaction product was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (PE:EA = 10:1) to obtain the product (1.4 g, yield 89.7%). [M+H] + = 553.5

[0159] Step 9: 2-((1R,2S)-2-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopropyl)ethane-1-ol [ka] 5-Bromo-N-(((1S,2R)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)cyclopropyl)methyl)-2-nitroaniline (1.4 g, 2.5 mmol) was dissolved in THF (10 mL) and TBAF (1.0 mol / L in THF, 4.0 mL) was added. The resulting mixture was stirred at room temperature for 3 hours. After LC-MS indicated completion of the reaction, the reaction product was concentrated under reduced pressure to obtain a crude residue, which was purified by silica column chromatography (PE:EA = 2:1) to obtain the product (670 mg, 84.1%). [M+H] + = 315.5.

[0160] Step 10: Methyl 2-(5-(2-((1R,2S)-2-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopropyl)ethoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] DIAD (554 mg, 2.7 mmol) was added dropwise at 15°C to a solution of 2-((1R,2S)-2-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopropyl)ethane-1-ol (665 mg, 2.1 mmol), methyl 2-(5-hydroxy-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (576 mg, 2.3 mmol), and PPh3 (719 mg, 2.7 mmol) in THF (30 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by column chromatography (DCM:EA=3:1) to obtain the product (1.0 g, yield 86.9%). [M+H] + = 544.5.

[0161] Step 11: Methyl 2-(5-(2-((1R,2S)-2-(((2-amino-5-bromophenyl)amino)methyl)cyclopropyl)ethoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] The title compound was prepared using the same procedure as in step 4 of Example 9. [M+H] + = 514.5.

[0162] Step 12: Methyl 2-(5-(2-((1R,2S)-2-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)cyclopropyl)ethoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] The title compound was prepared using the same procedure as in step 5 of Example 9. [M+H] + = 539.5.

[0163] Step 13: (7 1 S,7 2 R,E)-5 6 -Brom-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] To a solution of methyl 2-(5-(2-((1R,2S)-2-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)cyclopropyl)ethoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (900 mg, 1.7 mmol) in DMF (30 mL), LiHMDS (1.0 mol / L in THF, 4.0 mL) was added dropwise at 0°C. The mixture was stirred at room temperature for 10 minutes. The mixture was quenched with NH4Cl / water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude residue, which was purified by silica column chromatography (DCM:MeOH = 20:1) to obtain the product (420 mg, 49.6%). [M+H] + = 507.5.

[0164] Intermediate 16: (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -(3-(tetrahydrofuran-3-yl)piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one Step 1: 2-(tetrahydrofuran-3-yl)pyrazine [ka] To a DMA (100 mL) solution of 2-bromopyrazine (5.0 g, 31.4 mmol) and 3-iodotetrahydrofuran (9.3 g, 47.2 mmol), NiI2 (2.94 g, 9.42 mmol), picolinimidamide (HCl salt, 2.47 g, 15.7 mmol), Mn (5.2 g, 94.2 mmol), and TFA (1.07 g, 9.42 mmol) were added. The mixture was stirred under N2 at 100°C for 16 hours. After LCMS indicated completion of the reaction, the mixture was filtered and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (DCM:MeOH=100:1-95:5) to obtain the product (820 mg, 18.2%). [M+H] + = 151.4.

[0165] Step 2: 2-(tetrahydrofuran-3-yl)piperazine (AcOH salt) [ka] PtO2 (150 mg) was added at room temperature to a solution of 2-(tetrahydrofuran-3-yl)pyrazine (310 mg, 2.06 mmol) in AcOH / MeOH (6 mL / 6 mL). The mixture was then changed three times with H2 and stirred at 40°C for 20 hours under an H2 atmosphere. The reaction was monitored by LC-MS. The mixture was filtered through a Celite pad and washed with MeOH (20 mL). The filtrate was concentrated under vacuum to obtain the crude title product without purification. [M+H] + = 157.5.

[0166] Step 3: (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -(3-(tetrahydrofuran-3-yl)piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] To a solution of intermediate 15 (200.0 mg, 0.394 mmol), 2-(tetrahydrofuran-3-yl)piperazine (AcOH salt) (crude product, 200 mg), and t-BuONa (189 mg, 1.97 mmol) in DMA (10 mL), Pd2(dba)3 (72 mg, 0.079 mmol) and RuPhos (73 mg, 0.158 mmol) were added. The mixture was stirred under N2 at 90°C for 1.5 hours. After LCMS indicated completion of the reaction, the mixture was diluted with aqueous NH4Cl solution (20 mL) and extracted with DCM (25 mL x 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (2% NH4OH, DCM:MeOH = 100:1-80:20) to obtain the product (150 mg, 65.5%). [M+H] + = 583.4.

[0167] Intermediate 17: (7 1 S,7 2 R,E)-5 6 -((S)-4-(azetidine-3-yl)-2-methylpiperazine-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one Step 1: tert-butyl(S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,53 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)-3-methylpiperazine-1-carboxylate [ka] (7 1 S,7 2 R,E)-5 6 -Brom-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one (1.5g, 2.96mmol), tert-butyl(S)-3-methylpiperazine-1-carboxylate (890mg, 4.45mmol), Pd2(dba)3 (275mg, 0.3mmol), Ruphos (286mg, 0.6mmol), and NaO t Bu (568 mg, 5.92 mmol) was dissolved in DMA (30 mL). The resulting mixture was stirred at 100°C for 6 hours. The reaction product was concentrated under vacuum, and the residue was purified by silica gel column (DCM:CH3OH=15:1) to obtain tert-butyl(S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6-yl)-3-methylpiperazine-1-carboxylate (1.3g, 70.1%) was obtained. [M+H] + = 627.

[0168] Step 2: (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -((S)-2-methylpiperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] tert-butyl(S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 TFA (7 mL) was added to a mixture of (1.3 g, 2.07 mmol)-3-methylpiperazine-1-carboxylate (-yl) in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours, and the resulting mixture was concentrated under vacuum. The residue was treated with saturated NaHCO3 solution to pH = 7-8, and then extracted with DCM:MeOH (10:1) (100 mL x 3). The combined organic phase was washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6-((S)-2-methylpiperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one (800 mg, 73.4%) was obtained. [M+H] + = 527.

[0169] Step 3: tert-butyl 3-((S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 (-yl)-3-methylpiperazine-1-yl)azetidine-1-carboxylate [ka] (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -((S)-2-methylpiperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1STAB (483 mg, 2.28 mmol) was added to a mixture of H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one (600 mg, 1.14 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (390 mg, 2.28 mmol) in DCE (25 mL). The reaction mixture was stirred at 50°C for 3 hours, and the resulting mixture was quenched with saturated NaHCO3 solution (20 mL), and then extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried with Na2SO4, filtered, concentrated under vacuum, and the residue was purified by silica gel column (DCM:CH3OH=15:1) to obtain tert-butyl3-((S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 (-yl)-3-methylpiperazine-1-yl)azetidine-1-carboxylate (500 mg, 64.4%) was obtained. [M+H] + = 682.

[0170] Step 4: (7 1 S,7 2 R,E)-5 6 -((S)-4-(azetidine-3-yl)-2-methylpiperazine-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] tert-butyl3-((S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 TFA (6 mL) was added to a mixture of (500 mg, 0.73 mmol)-3-methylpiperazine-1-yl)azetidine-1-carboxylate in DCM (30 mL). The reaction mixture was stirred at room temperature for 1 hour, and the resulting mixture was concentrated under vacuum. The residue was treated with saturated NaHCO3 solution to pH 7-8, and then extracted with DCM:MeOH (10:1) (40 mL x 3). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain (7 1 S,7 2 R,E)-5 6 -((S)-4-(azetidine-3-yl)-2-methylpiperazine-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one (400 mg, 93.9%) was obtained. [M+H] + = 582.

[0171] Intermediate 18: (7 1 S,7 2 R,E)-5 6 -(5-(azetidine-3-yl)-2,5-diazabicyclo[2.2.2]octane-2-yl)-11 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] Intermediate 18 was prepared in the same manner as intermediate 17. [M+H] + = 594.5

[0172] Intermediate 19: (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -((S)-2-methylpiperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one Step 1: tert-butyl(S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)-3-methylpiperazine-1-carboxylate [ka] Intermediate 15 (280 mg, 0.55 mmol), tert-butyl(S)-3-methylpiperazine-1-carboxylate (320 mg, 1.38 mmol), and t-BuONa (180 mg, 1.65 mmol) were dissolved in DMA (10 mL), to which Pd-PEPPSI-IPentCl (105 mg, 0.11 mmol) was added. The resulting mixture was stirred under N2 at 100 °C for 2 hours. After LC-MS indicated completion of the reaction, the mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by silica column chromatography (DCM:MeOH = 100:1-20:1) to obtain the product (330 mg, 95.3%). [M+H] + = 627.5.

[0173] Step 2: (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -((S)-2-methylpiperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] tert-butyl(S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6To a solution of -yl-3-methylpiperazine-1-carboxylate (330 mg, 0.53 mmol) in DCM (4 mL), TFA (1 mL) was added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated, basicized with aqueous NaHCO3 solution, and extracted with DCM (3 × 20 mL). The combined organic phase was washed with brine (1 × 15 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the desired product (260 mg, 93.8%), which was used without further purification. [M+H] + = 527.5.

[0174] Intermediate 20: ((3R)-1-(6-(2,6-dioxopiperidine-3-yl)-2-methylpyridine-3-yl)pyrrolidine-3-yl)methylmethanesulfonate Step 1: 3-Bromo-6-iodo-2-methylpyridine [ka] TMSI (7.97 g, 39.85 mmol) was added to a mixture of 3,6-dibromo-2-methylpyridine (50 g, 199.2 mmol) and NaI (59.76 g, 398.4 mmol) in ACN (500 ml). The resulting mixture was degassed under reduced pressure and purged three times with N2. It was then stirred overnight at 95°C. The reaction mixture was cooled to room temperature and diluted with a 1:1 mixture of EA and H2O. The mixture was stirred for 15 minutes, after which the aqueous and organic phases were separated. The organic layer was sequentially washed with an equal volume of saturated sodium bicarbonate aqueous solution, sodium thiosulfate (5% aqueous solution), and brine. The organic layer was dried, filtered, and concentrated under reduced pressure to obtain 3-bromo-6-iodo-2-methylpyridine (50 g, 84.51%), which was used directly in the next step without purification. [M+H] + = 298.

[0175] Step 2: 2',6'-bis(benzyloxy)-5-bromo-6-methyl-2,3'-bipyridine [ka] Pd(PPh3)4 (1.05 g, 0.91 mmol) was added to a solution of 3-bromo-6-iodo-2-methylpyridine (5 g, 16.84 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (7.37 g, 17.67 mmol), and dioxane (125 ml) in a 2 M, 25 ml aqueous solution of K2CO3. The resulting mixture was stirred at 100°C for 3 hours. The reaction mixture was diluted with water and extracted with EA. The combined organic layers were washed with water, then with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using PE / EA (19:1) elution to obtain 2',6'-bis(benzyloxy)-5-bromo-6-methyl-2,3'-bipyridine (4.6050 g, 59.57%). [M+H] + = 461.1.

[0176] Step 3: (R)-(1-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridine]-5-yl)pyrrolidine-3-yl)methanol [ka] (R)-pyrrolidine-3-ylmethanol (3 g, 29.7 mmol), 2',6'-bis(benzyloxy)-5-bromo-6-methyl-2,3'-bipyridine (16.4 g, 35.6 mmol), and K3PO4 (18.9 g, 89.1 mmol) were stirred in 1,4-dioxacyclohexane (160 mL) to which Pd2(dba)3 (2.7 g, 3.0 mmol) and Johnphos (1.8 g, 5.9 mmol) were added. The resulting mixture was degassed under reduced pressure and purged three times with N2. Then, it was stirred overnight at 100°C. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by column chromatography using PE / EA (2:3) elution to obtain (R)-(1-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridine]-5-yl)pyrrolidine-3-yl)methanol (2.8 g, 19.55%). [M+H] + = 482.

[0177] Step 4: 3-(5-((R)-3-(hydroxymethyl)pyrrolidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] (R)-(1-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridine]-5-yl)pyrrolidine-3-yl)methanol (2.8 g, 5.81 mmol) was mixed with THF (60 mL) and Pd / C (10 wt%, 6.3 g) was added. The resulting mixture was degassed under reduced pressure, purged 5 times with H2, and then stirred overnight at 50°C. The reaction mixture was diluted with THF / DCM (1:1) and then filtered through a Celite pad. The filtrate was concentrated under vacuum. The residue was purified by column chromatography eluting with DCM / MeOH (19:1) to obtain 3-(5-((R)-3-(hydroxymethyl)pyrrolidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione (613.4 mg, 34.85%). [M+H] + =304.

[0178] Step 5: ((3R)-1-(6-(2,6-dioxopiperidine-3-yl)-2-methylpyridine-3-yl)pyrrolidine-3-yl)methylmethanesulfonate [ka] 3-(5-((R)-3-(hydroxymethyl)pyrrolidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione (303 mg, 1.0 mmol) and TEA (303 mg, 3.0 mmol) were dissolved in DCM (10 mL), to which methanesulfonic anhydride (348 mg, 2.0 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by silica column chromatography (DCM:MeOH = 100:1-20:1) to obtain the desired product (340 mg, 89.0%). [M+H] += 382.5.

[0179] Intermediate 21: (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -(4-oxopiperidine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] Step 1: (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] (7 1 S,7 2 R,E)-5 6 -Brom-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one (3.0 g, 5.9 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (1.7 g, 11.8 mmol), and t-BuONa (1.2 g, 11.8 mmol) were dissolved in DMA (80 mL) and Pd2(dba)3 (540 mg, 0.59 mmol) and RuPhos (550 mg, 1.18 mmol) were added. The mixture was stirred under N2 at 100°C for 3 hours. The mixture was diluted with water and extracted with SiO2. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (DCM:MeOH = 100:1-15:1) to obtain the product (2.9 g, 85.8%). [M+H] + = 570.5.

[0180] Step 2: (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -(4-oxopiperidine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one (2.9 g, 5.1 mmol) was placed in a 250 mL round-bottom flask equipped with a magnetic stirring bar. Then, 45 mL of 8N HCl aqueous solution was added. The mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to saturated NaHCO3 aqueous solution until the pH was finally adjusted to 6-7. The liquid was extracted and separated using DCM. The organic phase was concentrated under vacuum and purified by combiflush (DCM:MeOH = 20:1) to obtain the title compound (2.5 g, yield 93.6%). [M+H] + = 526.5.

[0181] Intermediate 22: 3-(5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione Step 1: tert-butyl 8-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridine]-5-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] To a solution of 2',6'-bis(benzyloxy)-5-bromo-6-methyl-2,3'-bipyridine (1 g, 2.17 mmol) in dioxane (30 mL), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (691 mg, 3.26 mmol), Pd2(dba)3 (393 mg, 0.43 mmol), Ruphos (400 mg, 0.86 mmol), and Cs2CO3 (1.4 g, 4.3 mmol) were added. The resulting solution was stirred at 100°C for 16 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ELISA. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to obtain tert-butyl 8-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridine]-5-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (800 mg, 62.3%). [M+H] + = 593.4

[0182] Step 2: tert-butyl8-(6-(2,6-dioxopiperidine-3-yl)-2-methylpyridine-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] To a solution of tert-butyl 8-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridine]-5-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (800 mg, 1.35 mmol) in i-PrOH (15 mL) and DMF (15 mL), Pd / C (20 wt%, 160 mg) was added. The resulting mixture was stirred at 50°C for 16 hours under an H2 atmosphere. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica column chromatography (DCM:MeOH = 10:1) to obtain tert-butyl 8-(6-(2,6-dioxopiperidine-3-yl)-2-methylpyridine-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (300 mg, 54%). [M+H] + = 415.3.

[0183] Step 3: 3-(5-(3,8-diazabicyclo[3.2.1]octan-8-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl 8-(6-(2,6-dioxopiperidine-3-yl)-2-methylpyridine-3-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (300 mg, 0.72 mmol) in DCM (10 mL), HCl (4 M dioxane solution, 5 mL) was added. The mixture was stirred in a flask at room temperature for 2 hours. The mixture was evaporated under vacuum to obtain the crude product (200 mg, 88.5%), which was used in the next step without further purification.

[0184] Intermediate 23: 3-(5-((R)-3,3-difluoro-4-(piperazin-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using the same procedure as for intermediate 9.

[0185] Intermediate 24: 3-(5-((3R,4S)-3-fluoro-4-(piperazine-1-yl)piperidine-1-yl)-4-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using the same procedure as for intermediate 9.

[0186] Intermediate 25: (1-(1-(2,6-dioxopiperidine-3-yl)-3,3-dimethyl-2-oxoindorin-5-yl)azetidine-3-yl)methyl-4-methylbenzenesulfonate Step 1: Methyl 2-(2,5-dibromophenyl)-2-methylpropanoate [ka] To a stirred solution of 2-(2,5-dibromophenyl)acetic acid (15.0 g, 51.0 mmol) in dry DMF (300 mL), NaH (60 wt%, 10.2 g, 255 mmol) was added in small amounts at 0°C. The mixture was degassed under reduced pressure, purged three times with N2, and then stirred at 0°C for 30 minutes. MeI (43.4 g, 306 mmol) was added to the mixture while maintaining vigorous stirring at 0°C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched by adding 1N HCl while maintaining vigorous stirring at 0°C. The mixture was extracted with EA, washed with water and brine, dried, and concentrated. The residue was purified by silica column chromatography PE / EA (9:1) to obtain methyl 2-(2,5-dibromophenyl)-2-methylpropanoate (12.0 g, 70%). [M+H] + =335.0.

[0187] Step 2: 2-(2,5-dibromophenyl)-2-methylpropanoic acid [ka] A 250 mL round-bottom flask equipped with a magnetic stirring bar was filled with a solution of methyl 2-(2,5-dibromophenyl)-2-methylpropanoate (12.0 g, 35.7 mmol), MeOH (150 mL), and NaOH solution (14.3 g, 357 mmol) in 15 mL of water. The resulting mixture was stirred overnight at 70 °C. After cooling to room temperature, the mixture was acidified with 1 N HCl, and then the MeOH was removed by evaporation. The residue was diluted with EA, washed with water and brine, dried, and concentrated. The residue was ground with PE to obtain the product (11.0 g, 96%). [M+H] + =321.0.

[0188] Step 3: N-(2,6-bis(benzyloxy)pyridine-3-yl)-2-(2,5-dibromophenyl)-2-methylpropanamide [ka] To a stirred mixture of 2,6-bis(benzyloxy)pyridine-3-aminium chloride (12.6 g, 41.2 mmol) and 2-(2,5-dibromophenyl)-2-methylpropanoic acid (11 g, 34.3 mmol) in dry MeCN (200 mL), 1-methyl-1H-imidazole (14.2 g, 171.5 mmol) was added by syringe under N2. The mixture was stirred at room temperature for 10 minutes, after which a solution of N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (11.5 g, 41.2 mmol) in dry MeCN (50 mL) was added to the mixture by syringe. The mixture was stirred at 50°C for 4 hours under N2. After cooling to room temperature, the reaction was quenched by adding water, and then the mixture was concentrated under vacuum using an evaporator. The residue was purified by column chromatography PE / EA (19:1) to obtain N-(2,6-bis(benzyloxy)pyridine-3-yl)-2-(2,5-dibromophenyl)-2-methylpropanamide (18 g, 86.1%). [M+H] + = 609.1.

[0189] Step 4: 1-(2,6-bis(benzyloxy)pyridine-3-yl)-5-bromo-3,3-dimethylindoline-2-one [ka] CuCl (1.62 g, 16.4 mmol) was added to a stirred mixture of N-(2,6-bis(benzyloxy)pyridine-3-yl)-2-(2,5-dibromophenyl)-2-methylpropanamide (10.0 g, 16.4 mmol) and K2CO3 (11.3 g, 81.9 mmol) in NMP (150 mL). The suspension was degassed under vacuum and purged three times with N2. Pentane-2,4-dione (3.28 g, 32.8 mmol) was added to the mixture using a syringe. The suspension was stirred under N2 at 85°C for 2 hours. After cooling to room temperature, the mixture was poured into EA, washed sequentially with brine, water, and brine, then dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography PE / EA (9:1) to obtain 1-(2,6-bis(benzyloxy)pyridine-3-yl)-5-bromo-3,3-dimethylindorin-2-one (6.0 g, 69.2%). [M+H] + = 529.1.

[0190] Step 5: 5-(3-((benzyloxy)methyl)azetidine-1-yl)-1-(2,6-bis(benzyloxy)pyridine-3-yl)-3,3-dimethylindoline-2-one [ka] A solution of 1-(2,6-bis(benzyloxy)pyridine-3-yl)-5-bromo-3,3-dimethylindorin-2-one (6.0 g, 11.3 mmol), 3-((benzyloxy)methyl)azetidine (2.02 g, 11.3 mmol), Cs2CO3 (11.1 g, 34.0 mmol), Pd2(dba)3 (1.04 g, 1.13 mmol), and RuPhos (1.06 g, 2.26 mmol) in dioxane (80 mL) was degassed under reduced pressure, purged five times with N2, and stirred overnight at 100°C under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate and then filtered through a Celite pad. The filtrate was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography PE / EA (3:2) to obtain 5-(3-((benzyloxy)methyl)azetidine-1-yl)-1-(2,6-bis(benzyloxy)pyridine-3-yl)-3,3-dimethylindorin-2-one (4g, 56.3%). [M+H] + = 626.3.

[0191] Step 6: 3-(5-(3-(hydroxymethyl)azetidine-1-yl)-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione [ka] A 100 mL round-bottom flask equipped with a magnetic stirring bar was packed with 5-(3-((benzyloxy)methyl)azetidine-1-yl)-1-(2,6-bis(benzyloxy)pyridine-3-yl)-3,3-dimethylindorin-2-one (4, 4.79 mmol), i-PrOH / DMF (50 mL / 50 mL), and dried Pd / C (4.0 g). The resulting mixture was degassed under reduced pressure, purged five times with H2, and then stirred overnight at 50°C. The mixture was diluted with i-PrOH / DMF (1:1), sonicated in an ultrasonic cleaner for 5 minutes, and then filtered through a Celite pad. The filtrate was concentrated under vacuum. The residue was purified by C18 column chromatography (mobile phase A: water, mobile phase B: MeCN) to obtain 3-(5-(3-(hydroxymethyl)azetidine-1-yl)-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione (1.63 g, 73.1%). [M+H] + = 358.1.

[0192] Step 7: (1-(1-(2,6-dioxopiperidine-3-yl)-3,3-dimethyl-2-oxoindolin-5-yl)azetidine-3-yl)methyl-4-methylbenzenesulfonate [ka] A pyridine (5 mL) solution of 3-(5-(3-(hydroxymethyl)azetidine-1-yl)-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione (100 mg, 0.28 mmol) and TosCl (80 mg, 0.42 mmol) was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to obtain the product (120 mg, 83.8%). [M+H] + = 512.4.

[0193] Intermediate 26: 3-(6-ethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using the same procedure as for intermediate 7.

[0194] Intermediate 27: (R)-2-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)acetaldehyde Step 1: Ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate [ka] To a solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (10 g, 43.1 mmol) in THF (150 mL), LDA (2 M THF solution, 24 mL, 48 mmol) was added dropwise over 20 minutes at -65°C. The reaction solution was then stirred at this temperature for 1 hour. Subsequently, ethyl 3-bromopropanoate (9.4 g, 51.7 mmol) in THF (30 mL) was added dropwise over 10 minutes. The resulting solution was stirred at -65°C for 30 minutes and then allowed to warm naturally to room temperature. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (50 mL) and extracted with siRNA (100 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the product (13.8 g, 96.5%). [M+H] + = 332.0.

[0195] Step 2: 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoic acid [ka] To a solution of ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate (13.5 g, 40.7 mmol) in THF / H2O (90 mL / 30 mL), LiOH (2.9 g, 0.122 mol) was added. The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with water and extracted with HCl (50 mL × 2). The pH of the aqueous phase was adjusted to 4-5 with 1N HCl (10 mL) and extracted with HCl (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the product (10.2 g, 82.5%). [M+H] + = 304.2.

[0196] Step 3: 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione [ka] 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoic acid (10.2 g, 33.5 mmol) was added to a stirred solution of toluene (100 mL) with concentrated H₂SO₄ (2 mL, 36.9 mmol). The resulting solution was stirred at 100°C for 3 hours. The reaction mixture was concentrated under vacuum, and then the mixture was poured into water. The pH was adjusted to 7-8 with saturated NaHCO₃ (40 mL) aqueous solution, and the resulting solution was extracted with RINKAN (50 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the product (8.2 g, 80.4%). [M+H] + = 304.3.

[0197] Step 4: (R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (8.2 g, 27.0 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.4 g, 32.4 mmol) were mixed in DMF / H2O (100 mL / 20 mL) and Pd(dtbpf)Cl2 (883 mg, 1.35 mmol) and CsF (8.2 g, 54.0 mmol) were added. The resulting mixture was stirred under a nitrogen atmosphere at 80°C for 2 hours. The reaction solution was diluted with water and extracted with siRNA (100 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SFC (IH (3×25cm, 5um), 13%EtOH / 87%CO2, 100 bar, 100 ml / min), and the title compound corresponded to peak A at 1.679 min / 254 nm (3.1 g, 39.0%). [M+H] + = 296.1.

[0198] Step 5: (R)-2-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)acetaldehyde [ka] (R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione (3.1 g, 10.4 mmol) was dissolved in FA (50 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness to obtain the product (2.6 g, 91.8%). [M+H] + = 268.1.

[0199] Intermediate 28: (7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] The title compound was prepared using the same procedure as for intermediate 19. [M+H] + = 513.5.

[0200] Intermediate 29: 3-(5-((3S,4R)-3-fluoro-4-(piperazin-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using the same procedure as for intermediate 9.

[0201] Intermediate 30: (7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafan-3-one [ka] The title compound was prepared using the same procedure as for intermediate 19. [M+H] + = 527.5

[0202] Intermediate 31: 3-(5-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using the same procedure as for intermediate 9.

[0203] Intermediate 33: 3-(4-((3S,4R)-3-fluoro-4-(piperazine-1-yl)piperidine-1-yl)-3,3-dimethyl-2-oxoindorin-1-yl)piperidine-2,6-dione Step 1: N-(2,6-bis(benzyloxy)pyridine-3-yl)-2-(2,6-dibromophenyl)acetamide [ka] 2-(2,6-dibromophenyl)acetic acid (10 g, 34.2 mmol), 2,6-bis(benzyloxy)pyridine-3-amine (11.5 g, 37.6 mmol), and DIEA (13.3 g, 102.6 mmol) were dissolved in DMF (200 ml), to which HATU (19.5 g, 51.3 mmol) was added at 0°C. The mixture was stirred overnight at room temperature. The mixture was diluted with EA (500 mL), and the solid was filtered. The mixture was concentrated under reduced pressure to obtain the crude product (15 g, 75.7%). [M+H] + = 581.

[0204] Step 2: 1-(2,6-bis(benzyloxy)pyridine-3-yl)-4-bromoindoline-2-one [ka] A 500 mL round-bottom flask equipped with a magnetic stirring bar was packed with N-(2,6-bis(benzyloxy)pyridine-3-yl)-2-(2,6-dibromophenyl)acetamide (15 g, 25.9 mmol), ((2-bromoethoxy)methyl)benzene (15.4 g, 71.5 mmol), K2CO3 (17.8 g, 129.5 mmol), CuCl (2.56 g, 25.9 mmol), pentane-2,4-dione (5.17 g, 51.8 mmol), and NMP (200 mL). The mixture was degassed under vacuum and purged three times with N2. The resulting mixture was stirred under N2 at 85°C for 3 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (300 mL) and then filtered through a Celite pad. The filtrate was washed with brine (300 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica column chromatography (EA / PE, 15%) to obtain the product (8.00 g, 61.8%). [M+H] + = 501.

[0205] Step 3: 4-((3S,4R)-4-(4-benzylpiperazine-1-yl)-3-fluoropiperidine-1-yl)-1-(2,6-bis(benzyloxy)pyridine-3-yl)indoline-2-one [ka] 1-(2,6-bis(benzyloxy)pyridine-3-yl)-4-bromoindoline-2-one (1 g, 2 mmol, see step 2 of the synthesis of intermediate 10), 1-benzyl-4-((3S,4R)-3-fluoropiperidine-4-yl)piperazine (831 mg, 3 mmol, prepared in the same manner as intermediate 20), t-A DMA (15 mL) solution of BuONa (576 mg, 6 mmol) and Pd-PEPPSI-IPentCl (195 mg, 0.2 mmol) was degassed under reduced pressure, purged five times with N2, and stirred at 90°C for 1 hour under N2. After cooling to room temperature, the mixture was diluted with DCM (100 mL) and then filtered through a Celite pad. The filtrate was washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column chromatography (EA / PE, 40%) to obtain the product (810 mg, 60%). [M+H] + = 698.3.

[0206] Step 4: 4-((3S,4R)-4-(4-benzylpiperazine-1-yl)-3-fluoropiperidine-1-yl)-1-(2,6-bis(benzyloxy)pyridine-3-yl)-3,3-dimethylindoline-2-one [ka] A solution of 4-((3S,4R)-4-(4-benzylpiperazine-1-yl)-3-fluoropiperidine-1-yl)-1-(2,6-bis(benzyloxy)pyridine-3-yl)indorin-2-one (697 mg, 1 mmol) in DMF (10 mL) was stirred at 0°C under N2. NaH (100 mg, 2.5 mmol, 60% in oil) was added at this temperature. After 30 minutes, CH3I (355 mg, 2.5 mmol) was added, and the mixture was stirred at room temperature under N2 for 1 hour. The reaction solution was quenched with 20 mL of water and extracted by DCM. The organic layer was washed with brine, saturated sodium thiosulfate aqueous solution, and water, and dried over anhydrous sodium sulfate. This was filtered, and the resulting residue was concentrated and purified by column chromatography (EA / PE, 40%) to obtain the product (500 mg, 69%). [M+H]+=726.5.

[0207] Step 5: tert-butyl 4-((3S,4R)-1-(1-(2,6-dioxopiperidine-3-yl)-3,3-dimethyl-2-oxoindoline-4-yl)-3-fluoropiperidine-4-yl)piperazine-1-carboxylate [ka] Under N2 conditions, 4-((3S,4R)-4-(4-benzylpiperazine-1-yl)-3-fluoropiperidine-1-yl)-1-(2,6-bis(benzyloxy)pyridine-3-yl)-3,3-dimethylindorin-2-one (726 mg, 1 mmol) DMF / i- To a PrOH (5 mL / 5 mL) solution, 10% Pd / C (100 mg) and (Boc)2O were added at room temperature. The mixture was then changed twice with H2 and stirred at 50°C for 15 hours under an H2 atmosphere. The mixture was filtered through a Celite pad and washed with MeOH (50 mL). The filtrate was concentrated under vacuum to obtain the product (500 mg, 90%). [M+H] + = 558.5.

[0208] Step 6: 3-(4-((3S,4R)-3-fluoro-4-(piperazine-1-yl)piperidine-1-yl)-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl 4-((3S,4R)-1-(1-(2,6-dioxopiperidine-3-yl)-3,3-dimethyl-2-oxoindolin-4-yl)-3-fluoropiperidine-4-yl)piperazine-1-carboxylate (279 mg, 0.5 mmol) in DCM (3 mL), TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under vacuum. The residue was dissolved in DCM (20 mL), washed with saturated NaHCO3 solution (3 × 20 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (180 mg, 78.6%). [M+H]+=458.5.

[0209] Intermediate 34: 3-(5-((3S,4R)-3-fluoro-4-(piperazine-1-yl)piperidine-1-yl)-4-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using the same procedure as for intermediate 9.

[0210] Compound synthesis Example 1: 3-(5-(4-(3-(((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)amino)azetidine-1-yl)piperidine-1-yl)4-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 3. 1H NMR(500MHz,DMSO)δ 12.27(s,1H), 10.73(s,1H), 8.64(s,1H), 8.07(s,2H), 7.81(s,1H), 7.42(s,1H), 7.18(d,J=8.6Hz,1H), 7.07(s,1H), 6.51(s,1H), 6.45(d,J=8.5Hz,1H), 6.06(s,1H), 4.24-4.10(m,3H), 4.08-3.97(m,2H), 3.8 0-3.75(m,3H), 3.68(s,3H), 3.06-3.01(m,3H), 2.67-2.59(m,3H), 2.21-2.03(m,11H), 1.81-1.69(m,3H) ), 1.39-1.28(m,3H), 1.25-1.22(m,1H), 1.10-1.02(m,1H), 0.50-0.40(m,1H), 0.36-0.28(m,1H);[M+H] + = 784.5.

[0211] Example 2: 3-(5-(4-((R)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)-3-methylpiperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 3. 1H NMR(500MHz,DMSO)δ 12.44(s,1H), 10.78(s,1H), 8.71(s,1H), 7.88(s,1H), 7.51(s,1H), 7.36(dd,J=8.3,6.0Hz,2H), 7.10(d,J=8.1Hz,1H), 7.04(s,1H) , 6.88(d,J=7.8Hz,1H), 4.35-4.21(m,3H), 4.11(s,1H), 3.89(dd,J=9.5,5.3Hz,2H), 3.75(s,3H), 3.14(d,J=9.6Hz,4H), 3.01(s,1H) , 2.91(d,J=9.8Hz,1H), 2.74-2.55(m,8H), 2.43-2.35(m,5H), 2.25-2.18(m,1H), 2.14-2.03(m,2H), 1.91(s,2H), 1.71-1.56(m,2H) , 1.50-1.38(m,1H), 1.32(d,J=4.4Hz,1H), 1.19-1.11(m,1H), 0.98(d,J=6.3Hz,3H), 0.58-0.46(m,1H), 0.38(dd,J=8.3,4.7Hz,1H). [M+H] + = 812.6.

[0212] Example 3: 3-(5-(4-((S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)-3-methylpiperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] STAB (95 mg, 0.45 mmol) was added to a solution of intermediate 19 (80 mg, 0.15 mmol) and intermediate 13 (65 mg, 0.21 mmol) in DCE (8 mL). The mixture was then stirred overnight at 50°C. The reaction product was quenched with aqueous NaHCO3 solution and extracted with DCM (3 × 15 mL). The combined organic phase was washed with brine (1 × 10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:CH3OH = 10:1), followed by preparative HPLC chromatography to obtain the title product (32 mg, 26.1%). 1 H NMR(500MHz,DMSO)δ 12.44(s,1H), 10.78(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.36(d,J=8.2Hz,2H), 7.11(d,J=8.1Hz,1H), 7.04(s,1H), 6.89(d,J=8.5Hz,1H), 4.35-4.21(m,3H), 4.11(t,J=7.0Hz,1H), 3.94-3.84(m,2H), 3.75(s,3H), 3.14(d,J=9.6Hz,3H), 3.01(t, J=9.1Hz,1H), 2.90(s,1H), 2.74-2.53(m,9H), 2.43-2.35(m,5H), 2.26-2.17(m,1H), 2.08(d,J=6.7Hz,2H), 1.91(s,2H), 1.71-1 .55(m,2H), 1.50-1.39(m,1H), 1.33(d,J=4.5Hz,1H), 1.19-1.09(m,1H), 0.98(d,J=6.2Hz,3H), 0.52(s,1H), 0.41-0.31(m,1H). [M+H] + = 812.6.

[0213] Example 4: 3-(5-(3-(1-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 (-yl)piperidine-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 21 and 22 in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 12.43(s,1H), 10.76(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.34(d,J=8.7Hz,1H), 7.21(d,J=8.0Hz,1H), 7.08-6.98(m,2H) ), 6.90(d,J=9.4Hz,1H), 4.34-4.23(m,1H), 4.11(s,1H), 3.85(d,J=8.9Hz,1H), 3.75(s,3H), 3.69-3.66(m,2H), 3.31-3.28(m,3H), 2.80-2.78(m,4H), 2.54-2.51(m,6H), 2.46-2.44(m,4H), 2.36(s,2H), 2.25-2.15(m,1H), 2.09(d,J=5.2Hz,2H), 1.88(d,J=11.9Hz) ,2H), 1.81(d,J=7.3Hz,2H), 1.75(s,2H), 1.61(d,J=10.7Hz,2H), 1.44(s,1H), 1.33(s,1H), 1.15(s,1H), 0.53(s,1H), 0.38(s,1H). [M+H] + =824.0

[0214] Example 5: 3-(5-(5-(1-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperidine-4-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 3. 1H NMR(500MHz,DMSO)δ 12.43(s,1H), 10.76(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.34(d,J=8.6Hz,2H), 7.04(d,J=8.4Hz,2H), 6.90(d,J=8.9Hz,1H), 4. 35-4.20(m,3H), 4.11(d,J=6.9Hz,1H), 3.85(dd,J=8.7,5.3Hz,1H), 3.75(s,3H), 3.64(d,J=8.4Hz,2H), 3.56(t,J=11.0Hz,1H), 3.17(d,J=9) .8Hz,2H), 3.09(s,1H), 2.89(d,J=8.8Hz,1H), 2.79(t,J=11.1Hz,2H), 2.65-2.54(m,7H), 2.38(s,3H), 2.19(dt,J=14.8,7.5Hz,1H), 2.15- 1.88(m,6H), 1.71(d,J=10.0Hz,2H), 1.58-1.40(m,3H), 1.34(d,J=4.5Hz,1H), 1.19-1.09(m,1H), 0.53(d,J=3.8Hz,1H), 0.44-0.33(m,1H). [M+H] + =824.5

[0215] Example 6: 3-(5-(4-(5-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 (-yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 12.34(s,1H), 10.77(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.35(d, J=8.0Hz,1H), 7.31(d,J=8.7Hz,1H), 7.09(d,J=8.1Hz,1H), 6.72(s,1H), 6.6 1(d,J=8.7Hz,1H), 4.35-4.19(m,3H), 4.16-4.08(m,1H), 4.06-3.98(m,1H), 3.88(dd,J=9.3,5.4Hz,1H), 3.75(s,3H), 3.62(d,J=8.7Hz,1H), 3.24(d,J=9. 3Hz,2H), 3.13-3.09(m,2H), 3.04-2.96(m,2H), 2.63(t,J=11.1Hz,2H), 2.59 -2.54(m,6H), 2.39-2.35(m,3H), 2.25-2.16(m,1H), 2.06-2.01(m,5H), 1.91 -1.84(m,1H), 1.84-1.75(m,1H), 1.64-1.61(m,1H), 1.56-1.41(m,3H), 1.36 -1.32(m,1H), 1.20-1.10(m,1H), 0.57-0.50(m,1H), 0.41-0.33(m,1H);[M+H] + = 824.5.

[0216] Example 7: 3-(5-(4-(8-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3-dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 12.36(s,1H), 10.77(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.32(t,J=9.3Hz,2H), 7.08(d,J=8.1Hz,1H), 6.95(s,1H), 6.79(d,J=8.4Hz,1H), 4.36-4.21(m,5H), 4.16-4.07(m,1H), 3.87(dd,J=9.1,5.3Hz,1H), 3.75(s,3H) , 3.06(d,J=10.9Hz,2H), 2.64-2.54(m,11H), 2.36(s,3H), 2.25-2.15(m,2H), 2.10-2.07(m,2H), 1.95-1.74(m,6H) ), 1.61-1.50(m,2H), 1.48-1.45(m,1H), 1.37-1.28(m,1H), 1.15(s,1H), 0.53(s,1H), 0.37(d,J=3.8Hz,1H);[M+H] + = 824.5.

[0217] Example 8: 3-(5-((R)-4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 (-yl)piperazine-1-yl)-3,3-difluoropiperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 23 and 15 in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.57(s,1H), 10.87(s,1H), 8.86(s,1H), 8.04(s,1H), 7.69(s,1H), 7.56(s,1H), 7.40(d,J=8.6Hz, 1H), 7.26(s,1H), 7.17(d,J=15.6Hz,1H), 6.97(d,J=9.3Hz,1H), 4.38-4.25(m,4H), 4.18(s,1H), 3. 99(s,2H), 3.78(s,3H), 3.28-3.05(m,6H), 2.89(s,1H), 2.68-2.53(m,7H), 2.46-2.41(m,5H), 2.25 (s,1H), 2.13-2.02(m,4H), 1.48(s,1H), 1.33(s,1H), 1.17(s,1H), 0.53(s,1H), 0.42-0.35(m,1H). [M+H] + = 834.7.

[0218] Example 9: 3-(5-((S)-3-((4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6-yl)piperazine-1-yl)methyl)pyrrolidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] Intermediate 28 (90 mg, 0.17 mmol), intermediate 20 (80 mg, 0.21 mmol), and KI (65 mg, 0.35 mmol) were dissolved in MeCN (5 mL) and DMSO (2 mL) to which DIEA (67 mg, 0.52 mmol) was added. The resulting mixture was heated overnight at 80 °C under N2. After LC-MS indicated completion of the reaction, the mixture was quenched with water and extracted with DCM (3 × 20 mL). The combined organic phases were washed with brine (1 × 15 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude residue, which was purified by silica column chromatography (DCM:MeOH = 100:1-10:1), followed by preparative HPLC chromatography to obtain the title product (21 mg, 15%). 1 H NMR(500MHz,DMSO)δ 12.43(s,1H), 10.75(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.34(s,1H), 7.15(d,J=8.3Hz,1H), 7.06(s,1H), 7.02(d, J=8.2Hz,1H), 6.90(d,J=7.6Hz,1H), 4.35-4.20(m,3H), 4.11(t,J=6.7Hz,1H), 3.84(dd,J=8.9,5.3Hz,1H), 3.75(s,3H), 3.25 -3.14(m,7H), 3.04(d,J=9.6Hz,1H), 2.66-2.54(m,10H), 2.47-2.36(m,5H), 2.20(dd,J=10.8,6.4Hz,1H), 2.09(d,J=3.9Hz,3 H), 1.66(d,J=6.7Hz,1H), 1.49-1.40(m,1H), 1.34(d,J=4.2Hz,1H), 1.19-1.10(m,1H), 0.56-0.50(m,1H), 0.41-0.34(m,1H). [M+H] + = 798.6.

[0219] Example 10: (R)-3-(4-(4-(3-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 (-yl)piperazine-1-yl)azetidine-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 27. 1 H NMR(500MHz,DMSO)δ 12.44(s,1H), 10.87(s,1H), 8.70(s,1H), 7.88(s,1H), 7.50(s,1H), 7.35(d,J=8.7Hz,1H), 7.05(s,1H), 6.89(d,J=8.0Hz, 1H), 6.62(d,J=13.1Hz,2H), 4.35-4.21(m,3H), 4.11(t,J=6.7Hz,1H), 4.04(dd,J=12.4,4.7Hz,1H), 3.75(s,3H), 3.63(s,2) H), 3.45(s,1H), 3.21-3.13(m,4H), 2.98-2.73(m,6H), 2.64-2.53(m,4H), 2.47-2.39(m,4H), 2.09(d,J=12.0Hz,2H), 2.00- 1.92(m,1H), 1.71(s,3H), 1.45(d,J=5.8Hz,1H), 1.34(d,J=4.6Hz,1H), 1.27-1.13(m,4H), 0.53(s,1H), 0.42-0.35(m,1H). [M+H] + = 874.6.

[0220] Example 11: 3-(5-((3R,4S)-4-(4-((7 1 S,7 2 R,E)-11 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)-3-fluoropiperidine-1-yl)-4-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 15 and 24 in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.43(s,1H), 10.81(s,1H), 8.71(s,1H), 8.16(s,1H), 7.88(s,1H), 7.51(s,1H), 7.35(d,J=8.7Hz,1H), 7.15(s,1H), 7.07(s ,1H), 6.91(d,J=8.6Hz,1H), 5.17-5.03(m,1H), 4.36-4.22(m,3H), 4.11(t,J=6.8Hz,1H), 3.90(dd,J=8.8,5.4Hz,1H), 3.75(s ,3H), 3.27-3.15(m,6H), 3.00-2.79(m,6H), 2.64-2.53(m,6H), 2.28(s,3H), 2.20(d,J=7.3Hz,1H), 2.15-1.98(m,3H), 1.83(d ,J=10.2Hz,1H), 1.51-1.40(m,1H), 1.34(d,J=4.8Hz,1H), 1.19-1.12(m,1H), 0.59-0.51(m,1H), 0.39(dd,J=8.5,4.8Hz,1H). [M+H] + = 816.6.

[0221] Example 12: 3-(5-((3S,4R)-4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-52 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)-3-fluoropiperidine-1-yl)-4-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.43(s,1H), 10.81(s,1H), 8.71(s,1H), 8.16(s,1H), 7.88(s,1H), 7.51(s,1H), 7.35(d,J=8.7Hz,1H), 7.15(s,1H), 7.07(s ,1H), 6.91(d,J=8.6Hz,1H), 5.17-5.03(m,1H), 4.36-4.22(m,3H), 4.11(t,J=6.8Hz,1H), 3.90(dd,J=8.8,5.4Hz,1H), 3.75(s ,3H), 3.27-3.15(m,6H), 3.00-2.79(m,6H), 2.64-2.53(m,6H), 2.28(s,3H), 2.20(d,J=7.3Hz,1H), 2.15-2.01(m,3H), 1.83(d ,J=10.2Hz,1H), 1.51-1.40(m,1H), 1.34(d,J=4.8Hz,1H), 1.19-1.12(m,1H), 0.59-0.51(m,1H), 0.39(dd,J=8.5,4.8Hz,1H). [M+H] + = 816.6.

[0222] Example 13: 3-(5-(3-((4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)methyl)azetidine-1-yl)-3,3-dimethyl-2-oxoindoline-1-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 28 and 25 in the same manner as in Example 9. 1 H NMR(500MHz,DMSO)δ 12.37(s,1H), 10.96(s,1H), 8.64(s,1H), 7.81(s,1H), 7.44(s,1H), 7.28(d,J=8.6Hz,1H), 6.98(s,1H), 6.82(d ,J=8.5Hz,1H), 6.69(d,J=7.6Hz,1H), 6.48(s,1H), 6.19(d,J=8.0Hz,1H), 5.07(s,1H), 4.30-4.12(m,3H), 4.09- 3.96(m,1H), 3.92-3.72(m,2H), 3.68(s,3H), 3.41-3.19(m,6H), 3.09(s,3H), 2.91-2.75(m,2H), 2.59-2.50(m,5 H), 2.43(s,3H), 2.13-1.96(m,1H), 1.91-1.77(m,1H), 1.38-1.06(m,9H), 0.53-0.38(m,1H), 0.37-0.22(m,1H). [M+H] + = 852.7.

[0223] Example 14: 3-(5-(4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-56 -yl)piperazine-1-yl)piperidine-1-yl)-6-ethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 28 and 26 in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 12.43(s,1H), 10.79(d,J=4.8Hz,1H), 8.71(s,1H), 7.91-7.84(m,1H), 7.50(d,J=4.4Hz,1H), 7.44-7.30 (m,2H), 7.12(dd,J=7.7,3.9Hz,1H), 7.05(s,1H), 6.90(s,1H), 4.35-4.21(m,3H), 4.11(s,1H), 3.91(s,1 H), 3.76-3.73(m,2H), 3.21-3.05(m,6H), 2.84-2.54(m,15H), 2.39(s,1H), 2.20-2.08(m,3H), 1.97-1.86 (m,2H), 1.63(s,2H), 1.44(s,1H), 1.33(s,1H), 1.21-1.13(m,3H), 0.56-0.50(m,1H), 0.41-0.34(m,1H). [M+H] + = 812.6.

[0224] Example 15: 3-(5-(4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 28 and 6 in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 12.44(s,1H), 10.78(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.35(d,J=8.7Hz,1H), 7.05(s,1H), 6.90(d,J=8.7Hz,2H), 4 .28(dd,J=11.7,4.7Hz,3H), 4.11(t,J=6.6Hz,1H), 3.84(dd,J=9.2,5.3Hz,1H), 3.75(s,3H), 3.20-3.07(m,6H), 2.95(d,J=13.2H) z,2H), 2.78-2.68(m,4H), 2.60-2.54(m,5H), 2.41(d,J=7.6Hz,4H), 2.28(s,3H), 2.22-2.03(m,3H), 1.86(d,J=10.4Hz,2H), 1.5 9(d,J=8.2Hz,2H), 1.44(dd,J=14.3,6.3Hz,1H), 1.34(d,J=4.6Hz,1H), 1.18-1.11(m,1H), 0.56-0.50(m,1H), 0.42-0.34(m,1H). [M+H] + = 812.6.

[0225] Example 16: 3-(5-(4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)-3-fluoro-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 28 and 5 in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 12.44(s,1H), 10.87(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.37-7.31(m,2H), 7.05(d,J=1.2Hz,1H ), 6.90(dd,J=8.8,1.7Hz,1H), 4.36-4.22(m,3H), 4.18-4.08(m,2H), 3.75(s,3H), 3.18(s,6H), 2.74-2.63(m ,7H), 2.58-2.52(m,4H), 2.42-2.37(m,4H), 2.30-2.20(m,1H), 2.15-2.01(m,2H), 1.98-1.91(m,2H), 1.68- 1.58(m,2H), 1.49-1.41(m,1H), 1.38-1.31(m,1H), 1.19-1.11(m,1H), 0.58-0.52(m,1H), 0.41-0.35(m,1H). [M+H] + = 816.70.

[0226] Example 17: (R)-3-(2,6-difluoro-4-(4-(4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 30 and 3 in the same manner as in Example 3. 1H NMR(500MHz,DMSO)δ 12.46(s,1H), 10.87(s,1H), 8.52(s,1H), 7.87(s,1H), 7.53(s,1H), 7.36(d,J=8.8Hz,1H), 7.17(s,1H), 6.88(d,J=8.8Hz ,1H), 6.64(d,J=12.8Hz,2H), 4.57(d,J=13.4Hz,2H), 4.14-4.02(m,2H), 3.90(dd,J=13.7,9.2Hz,1H), 3.81(d,J=12.7Hz, 2H), 3.74(s,3H), 3.16(d,J=4.6Hz,4H), 2.82-2.75(m,4H), 2.69(s,3H), 2.65-2.53(m,6H), 2.12-2.05(m,1H), 2.00-1.93 (m,1H), 1.88(d,J=11.1Hz,2H), 1.52-1.41(m,7.7Hz,3H), 1.36(s,3H), 1.05(d,J=14.7Hz,1H), 0.75(s,1H), 0.60(s,1H). [M+H] + =833.6

[0227] Example 18: 3-(4-(4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)-3,3-dimethyl-2-oxoindoline-1-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 28 and 1 in the same manner as in Example 3. 1H NMR(500MHz,DMSO)δ 12.44(s,1H), 11.06(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.36(d,J=8.7Hz,1H), 7.24(t,J=7.9Hz,1H), 7.08-7.01( m,2H), 6.91(d,J=8.9Hz,1H), 6.80(s,1H), 5.21(s,1H), 4.38-4.21(m,3H), 4.11(s,1H), 3.75(s,3H), 3.19(s,3H), 2.93-2.87 (m,3H), 2.80-2.73(m,2H), 2.73(s,3H), 2.64-2.60(m,2H), 2.58-2.54(m,5H), 2.44-2.39(m,1H), 2.13-2.09(m,1H), 1.95-1. 93(m,3H), 1.65-1.58(m,2H), 1.47-1.42(m,7H), 1.36-1.34(m,1H), 1.19-1.15(m,1H), 0.56-0.52(m,1H), 0.43-0.35(m,1H). [M+H] + = 866.8.

[0228] Example 19: 3-(6-methyl-5-(4-(4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 3. 11H NMR (500MHz, DMSO) δ 12.62(s,1H), 10.88(s,1H), 8.65(s,1H), 7.99(s,1H), 7.68(s,1H), 7. 56(s,1H), 7.45(d,J=8.7Hz,1H), 7.31(s,1H), 7.27(s,1H), 7.01(d,J=8 .7Hz,1H), 4.62(d,J=13.7Hz,1H), 4.57(dd,J=9.8,4.2Hz,1H), 4.13(s,2H), 4.01-3.89(m,4H), 3.77(s,3H), 3.72(s,2H), 3.48(s,1H), 3.29(d ,J=10.6Hz,4H), 3.10-3.03(m,2H), 2.74(t,J=11.5Hz,2H), 2.64(s,3H), 2.61-2.53(m,2H), 2.48(s,3H), 2.25(d,J=9.5Hz,3H), 2.09(dd,J=13 .2,5.2Hz,1H), 1.91-1.85(m,2H), 1.46(dd,J=14.2,8.4Hz,1H), 1.39(s,3H), 1.08(d,J=15.1Hz,1H), 0.75(t,J=4.4Hz,1H), 0.65-0.56(m,1H). [M+H] + =812.5

[0229] Example 20: 3-(5-(4-(3-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)azetidine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 27. 11H NMR (500MHz, DMSO) δ 12.44(s,1H), 10.78(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.36( d,J=4.5Hz,1H), 7.34(d,J=4.9Hz,1H), 7.09(d,J=8.2Hz,1H), 7.05(s,1H) , 6.90(dd,J=8.9,1.7Hz,1H), 4.30(d,J=6.9Hz,3H), 4.11(t,J=6.8Hz,1H) , 3.88(dd,J=9.4,5.3Hz,1H), 3.75(s,3H), 3.43(t,J=5.8Hz,2H), 3.17(s, 4H), 3.02(s,2H), 2.92(dd,J=12.3,6.1Hz,1H), 2.87(d,J=6.2Hz,2H), 2.6 5-2.53(m,7H), 2.44(s,4H), 2.37(s,3H), 2.24-2.14(m,2H), 2.13-2.03(m ,2H), 1.77(d,J=10.0Hz,2H), 1.50-1.41(m,1H), 1.35(d,J=8.9Hz,3H), 1. 15(dt,J=8.4,4.4Hz,1H), 0.58-0.50(m,1H), 0.38(dt,J=9.2,4.6Hz,1H). [M+H] + = 853.6.

[0230] Example 21: 3-(5-(2-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)ethyl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 8 and 28 in the same manner as in Example 9. 1 H NMR(500MHz,DMSO)δ 12.44(s,1H), 10.79(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.35(d,J=8.7Hz,1H), 7.07(s,1H), 6.98(s,1H), 6.91( d,J=8.8Hz,1H), 4.29(d,J=9.0Hz,3H), 4.14-4.10(m,1H), 3.86-3.83(m,1H), 3.75(s,3H), 3.21(s,3H), 2.84-2.79(m,2H), 2.69-2.66(m,4H), 2.65-2.62(m,1H), 2.59-2.56(m,3H), 2.55(s,4H), 2.47(s,3H), 2.39-2.34(m,1H), 2.33(s,2H), 2.25-2 .19(m,1H), 2.12-2.05(m,2H), 1.45(s,1H), 1.35(s,1H), 1.15(d,J=3.5Hz,1H), 0.58-0.52(m,1H), 0.41-0.36(m,1H);[M+H] + =757.4

[0231] Example 22: 3-(5-(4-(3-((S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)-3-methylpiperazine-1-yl)azetidine-1-yl)piperidine-1-yl)4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 27. 11H NMR (500MHz, DMSO) δ 12.45(s,1H), 10.78(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7. 36(d,J=8.6Hz,1H), 7.05(s,1H), 6.96(d,J=32.4Hz,1H), 6.94-6.85(m ,1H), 4.36-4.20(m,3H), 4.16-4.07(m,1H), 3.95-3.86(m,1H), 3.85-3 .81(m,1H), 3.78-3.72(m,3H), 3.53-3.49(m,2H), 3.21(s,1H), 3.07-2. 88(m,7H), 2.71-2.63(m,1H), 2.60-2.56(m,6H), 2.48-2.44(m,2H), 2. 40-2.37(m,4H), 2.30-2.26(m,3H), 2.23-2.15(m,2H), 2.13-2.02(m,2H) ), 1.83-1.70(m,2H), 1.50-1.41(m,1H), 1.40-1.27(m,3H), 1.18-1.16 (m,1H), 0.99-0.97(m,3H), 0.56-0.48(m,1H), 0.41-0.34(m,1H);[M+H] + = 881.5.

[0232] Example 24: 3-(5-(4-(3-((R)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)-3-methylpiperazine-1-yl)azetidine-1-yl)piperidine-1-yl)4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 27. 1 1H NMR (500MHz, DMSO) δ 12.45(s,1H), 10.78(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.3 6(d,J=8.7Hz,1H), 7.05(s,1H), 6.97-6.92(m,1H), 6.88(d,J=8.0Hz,1H) , 4.35-4.21(m,3H), 4.16-4.06(m,1H), 3.96-3.88(m,1H), 3.83(dd,J=9 .2,5.3Hz,1H), 3.75(s,3H), 3.55-3.39(m,2H), 3.25-3.17(m,1H), 3.07- 2.75(m,8H), 2.69-2.64(m,1H), 2.61-2.54(m,5H), 2.47-2.43(m,1H), 2 .39-2.35(m,4H), 2.26-2.23(m,3H), 2.22-2.14(m,2H), 2.14-2.02(m,3H ), 1.83-1.65(m,2H), 1.50-1.39(m,1H), 1.37-1.25(m,3H), 1.19-1.11(m ,1H), 0.98(d,J=6.1Hz,3H), 0.58-0.49(m,1H), 0.42-0.33(m,1H);[M+H] + = 881.5.

[0233] Example 25: 3-(6-ethyl-5-(4-(4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 3. 1 1H NMR (500MHz, DMSO) δ 12.59-12.26(m,1H), 10.79(s,1H), 8.59-8.48(m,1H), 7.95-7.82(m,1H), 7.53(s,1H), 7.47-7.39(m,1H), 7.39-7.32(m,1H), 7.19(s,1H), 7.12(d,J =8.1Hz,1H), 6.90(d,J=8.8Hz,1H), 4.58(d,J=13.7Hz,2H), 4.09(t,J=7.0 Hz,1H), 3.97-3.86(m,2H), 3.74(s,3H), 3.18(d,J=4.5Hz,4H), 3.11-3.03 (m,2H), 2.84-2.76(m,1H), 2.75-2.60(m,7H), 2.59-2.53(m,6H), 2.39(t, J=11.7Hz,1H), 2.23-2.08(m,2H), 1.92(d,J=10.3Hz,2H), 1.63(d,J=11.3 Hz,2H), 1.44(dd,J=14.0,7.5Hz,1H), 1.37(s,3H), 1.18(t,J=7.4Hz,3H), 1.06(d,J=14.3Hz,1H), 0.76(t,J=4.3Hz,1H), 0.61(dd,J=7.7,3.3Hz,1H). [M+H] + = 826.6.

[0234] Example 26: (R)-3-(2,6-difluoro-4-(4-((S)-2-(methoxymethyl)-4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 12.44(s,1H), 10.87(s,1H), 8.52(s,1H), 7.87(s,1H), 7.53(s,1H), 7.37(d,J=8.7Hz,1H), 7.13(s,1H), 6.86(d,J=8.6Hz,1H), 6.65(s,1H), 6.63(s,1H), 4.63-4.51(m,2H), 4.13-4.0 0(m,2H), 3.90(dd,J=13.7,9.2Hz,1H), 3.83(d,J=11.8Hz,2H), 3.74(s,3H), 3.57(dd,J=9. 4,4.2Hz,1H), 3.50(dd,J=9.5,5.7Hz,1H), 3.29(s,3H), 3.27(s,1H), 3.22-3.14(m,1H), 3. 11-3.01(m,2H), 2.98(dd,J=11.0,6.8Hz,1H), 2.90(t,J=11.0Hz,1H), 2.85-2.70(m,4H), 2 .70-2.62(m,1H), 2.59-2.51(m,5H), 2.09(qd,J=12.9,3.6Hz,1H), 1.99-1.92(m,1H), 1.88 (d,J=10.9Hz,1H), 1.74(d,J=11.1Hz,1H), 1.62(ddd,J=12.4,9.3,4.7Hz,1H), 1.49-1.39( m,2H), 1.37(s,3H), 1.05(d,J=14.5Hz,1H), 0.77-0.68(m,1H), 0.61(dd,J=7.7,3.2Hz,1H). [M+H] + = 877.7.

[0235] Example 27: (R)-3-(2,6-difluoro-4-(4-(3-((S)-3-methyl-4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)azetidine-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 17 and 3 in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 12.47(s,1H), 10.86(s,1H), 8.52(s,1H), 7.87(s,1H), 7.53(s,1H), 7.37(d,J=8.7Hz,1H), 7.2 1(s,1H), 6.86(d,J=7.8Hz,1H), 6.63(s,1H), 6.60(s,1H), 4.57(dd,J=12.8,7.3Hz,2H), 4.09(t ,J=6.9Hz,1H), 4.04(dd,J=12.5,4.8Hz,1H), 3.89(dd,J=13.1,8.8Hz,2H), 3.74(s,3H), 3.59(d ,J=12.5Hz,2H), 3.44-3.38(m,2H), 3.19(d,J=11.4Hz,1H), 2.99(t,J=8.7Hz,1H), 2.87(dd,J=1 3.1,7.7Hz,4H), 2.81-2.74(m,2H), 2.62(d,J=10.7Hz,1H), 2.56(s,3H), 2.54(d,J=2.2Hz,2H), 2.38(dd,J=25.2,7.7Hz,2H), 2.20(d,J=10.2Hz,2H), 2.08(qd,J=13.7,4.4Hz,1H), 2.00-1.92( m,1H), 1.69(d,J=10.8Hz,2H), 1.44(dd,J=14.7,8.4Hz,1H), 1.36(s,3H), 1.21(d,J=9.6Hz,2H) , 1.06(d,J=13.6Hz,1H), 0.94(d,J=6.2Hz,3H), 0.78-0.71(m,1H), 0.61(dd,J=7.8,3.3Hz,1H). [M+H] + =902.7.

[0236] Example 28: 3-(5-(4-(3-(5-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)azetidine-1-yl)piperidine-1-yl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 18 and 6 in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 12.34(s,1H), 10.77(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.31(d,J=8.7Hz,1H), 6.98-6.91(m,1H), 6.72(s,1H), 6. 60(d,J=7.8Hz,1H), 4.34-4.21(m,3H), 4.15-4.09(m,1H), 4.02(s,1H), 3.87-3.80(m,1H), 3.75(s,3H), 3.60-3.58(m,1H), 3.2 4-3.22(m,1H), 3.11-2.70(m,9H), 2.59-2.53(m,5H), 2.37(s,3H), 2.29-2.22(m,3H), 2.21-2.01(m,4H), 1.99-1.84(m,3H), 1 .82-1.57(m,3H), 1.50-1.46(m,2H), 1.38-1.29(m,2H), 1.23(s,3H), 1.18-1.11(m,1H), 0.57-0.49(m,1H), 0.41-0.34(m,1H). [M+H] + = 893.7.

[0237] Example 29: (R)-3-(2,6-difluoro-4-((1-(1-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperidine-4-carbonyl)piperidine-4-yl)oxy)phenyl)piperidine-2,6-dione Step 1: 2,6-Bis(benzyloxy)-3-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (35 g, 72.8 mmol) in dioxane (300 mL), B(pin)2 (37.0 g, 145.5 mmol), Pd(dppf)Cl2 (5.3 g, 7.3 mmol), and K2CO3 (30.1 g, 218.3 mmol) were added. The resulting solution was stirred overnight at 100°C under an N2 atmosphere. After cooling to room temperature and filtering, the filter cake was washed with EA. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA:PE = 0-10%) to obtain 2,6-bis(benzyloxy)-3-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (30g, 77.94%). [M+H] + =530.39

[0238] Step 2: 4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenol [ka] 2,6-bis(benzyloxy)-3-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridine (30 g, 56.7 mmol) was mixed with AcOH (100 mL) and THF (100 mL) and H2O2 (100 mL) was added in small amounts at 0°C. The mixture was stirred overnight at room temperature. Then, saturated aqueous Na2S2O3 was added, and the mixture was extracted with EA. The organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica column chromatography (EA:PE = 0-30%) to obtain 4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenol (21 g, 88.4%). [M+H] + = 420.4.

[0239] Step 3: tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenoxy)piperidine-1-carboxylate [ka] A 500 mL round-bottom flask equipped with a magnetic stirring bar was packed with 4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenol (20.5 g, 48.9 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (20.5 g, 73.4 mmol), Cs2CO3 (47.8 g, 146.6 mmol), and DMF (210 mL). The resulting mixture was degassed under reduced pressure, purged three times with N2, and then stirred at 110°C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with siRNA. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (EA / PE, 12-16%) to obtain tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenoxy)piperidine-1-carboxylate (14 g, 23.3 mmol, 47.6%). [M+H] + = 603.0.

[0240] Step 4: tert-butyl 4-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenoxy)piperidine-1-carboxylate [ka] A 500 mL round-bottom flask equipped with a magnetic stirring bar was packed with tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenoxy)piperidine-1-carboxylate (14 g, 23.3 mmol), dry THF (240 ml), and Pd / C (10 wt%, 27 g). The resulting mixture was degassed under reduced pressure, purged five times with H2, and then stirred overnight at 50°C. The mixture was diluted with THF / DCM / MeOH (200 mL / 200 mL / 200 mL), sonicated in an ultrasonic cleaner for 5 minutes, and then filtered through a Celite pad. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (EA / PE, 40-50%) to obtain tert-butyl 4-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenoxy)piperidine-1-carboxylate (6.9 g, 70.0%). [M+H] + = 425.

[0241] Step 5: tert-butyl(R)-4-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenoxy)piperidine-1-carboxylate [ka] The crude product (6.7 g) was purified by chiral SFC under the following conditions (column: chiralpak AD-3 3×100 mm, 3 mm, 10%-50% over 2.0 min, retention at 50% for 1.0 min, MeOH (0.1% DEA), retention time 1.612 min) to obtain tert-butyl(R)-4-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenoxy)piperidine-1-carboxylate. [M+H] + = 425.

[0242] Step 6: (R)-3-(2,6-difluoro-4-(piperidine-4-yloxy)phenyl)piperidine-2,6-dione [ka] To a 10 mL solution of tert-butyl(R)-4-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenoxy)piperidine-1-carboxylate (500 mg, 1.18 mmol) in DCM, 3 mL of HCl (4 M dioxane solution) was added. The mixture was stirred in a flask at room temperature for 2 hours. The mixture was evaporated under vacuum to obtain the crude product (350 mg, 91.6%), which was used in the next step without further purification. [M+H] + = 325.

[0243] Step 7: tert-butyl(R)-4-(4-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenoxy)piperidine-1-carbonyl)piperidine-1-carboxylate [ka] To a solution of (R)-3-(2,6-difluoro-4-(piperidine-4-yloxy)phenyl)piperidine-2,6-dione (350 mg, 1.08 mmol) in DCM (5 mL), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (370 mg, 1.62 mmol), DIEA (278 mg, 2.16 mmol), and T3P (50% by weight in EA) (1.37 g, 682.2 mmol) were added. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (10:1) to obtain tert-butyl(R)-4-(4-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenoxy)piperidine-1-carbonyl)piperidine-1-carboxylate (300 mg, 52%). [M+H] + = 536.2.

[0244] Step 8: (R)-3-(2,6-difluoro-4-((1-(piperidine-4-carbonyl)piperidine-4-yl)oxy)phenyl)piperidine-2,6-dione [ka] To a 10 mL solution of tert-butyl(R)-4-(4-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenoxy)piperidine-1-carbonyl)piperidine-1-carboxylate (300 mg, 0.56 mmol) in DCM, HCl (4 M dioxane solution, 3 mL) was added. The mixture was stirred in a flask at room temperature for 2 hours. The mixture was evaporated under vacuum to obtain the crude product (200 mg, 81.9%), which was used in the next step without further purification. [M+H] + = 436.2.

[0245] Step 9: (R)-3-(2,6-difluoro-4-((1-(1-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperidine-4-carbonyl)piperidine-4-yl)oxy)phenyl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 30. 1H NMR(500MHz,DMSO)δ 12.45(s,1H), 10.92(s,1H), 8.52(s,1H), 7.87(s,1H), 7.53(s,1H), 7.36(d,J=8.7Hz,1H), 7.18(s,1H), 6.9 1(d,J=8.5Hz,1H), 6.84(d,J=10.8Hz,2H), 4.70(s,1H), 4.58(d,J=13.0Hz,2H), 4.18-4.08(m,2H), 3.89-3. 86(m,5H), 3.74(s,3H), 2.86-2.73(m,6H), 2.56(s,3H), 2.17-2.07(m,2H), 1.97-1.95(m,4H), 1.75(s,5H), 1.62(s,1H), 1.43(d,J=6.2Hz,1H), 1.36(s,3H), 1.06(d,J=12.4Hz,1H), 0.75(s,1H), 0.61(d,J=4.9Hz,1H). [M+H] + =876.0

[0246] Example 30: 3-(5-((3R,4S)-4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)-3-fluoropiperidine-1-yl)-3-fluoro-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] To a DMA (5 mL) stirred solution of intermediate 15 (100 mg, 0.2 mmol), t-BuONa (38 mg, 0.4 mmol), Pd2(dba)3 (36 mg, 0.04 mmol), Ruphos (37 mg, 0.08 mmol), and intermediate 9 (80 mg, 0.2 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C for 10 minutes under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with  (100 mL) and washed with water (3 × 50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with MeOH / DCM (0-5%) to obtain the product (23.3 mg, 14.2%). 1 H NMR(500MHz,DMSO)δ 12.58(s,1H), 10.89(s,1H), 8.81(s,1H), 7.99(s,1H), 7.63(s,1H), 7.45(d,J=11.3Hz,1H), 7.42(d,J=8.7Hz,1H), 7.23(s,1 H), 7.00(d,J=8.6Hz,1H), 5.52-5.42(m,1H), 4.39-4.24(m,5H), 4.19-4.15(m,3H), 3.91(s,3H), 3.64(s,2H), 3.34(s,3H), 3 .14(s,2H), 3.03-2.93(m,1H), 2.88-2.83(m,1H), 2.76-2.70(m,1H), 2.63(s,3H), 2.60-2.52(m,2H), 2.43(s,3H), 2.35-2.2 2(m,2H), 2.13-2.03(m,3H), 1.54-1.44(m,1H), 1.38-1.33(m,1H), 1.19-1.16(m,1H), 0.57-0.50(m,1H), 0.41-0.38(m,1H). [M+H] + = 834.6.

[0247] Example 31: 3-(5-((3R,4S)-4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)-3-fluoropiperidine-1-yl)-6-ethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.44(s,1H), 10.80(s,1H), 8.71(s,1H), 7.88(s,1H), 7.51(s,1H), 7.43(d,J=8.1Hz,1H), 7.35(t,J=7.0Hz,1H), 7.14( d,J=8.1Hz,1H), 7.06(d,J=11.0Hz,1H), 6.94-6.89(m,1H), 5.17-5.03(m,1H), 4.37-4.21(m,3H), 4.11(t,J=6.6Hz,1H), 3.92(dd,J=7.9,5.6Hz,1H), 3.75(s,3H), 3.22-3.12(m,5H), 2.91-2.71(m,8H), 2.65-2.54(m,8H), 2.24-2.02(m,4H), 1. 82(d,J=12.4Hz,1H), 1.49-1.41(m,1H), 1.34(d,J=4.5Hz,1H), 1.20-1.15(m,3H), 0.57-0.51(m,1H), 0.42-0.35(m,1H). [M+H] + = 830.6.

[0248] Example 32: 3-(5-((3S,4R)-4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)-3-fluoropiperidine-1-yl)-6-ethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.60(s,1H), 10.84(s,1H), 8.85(s,1H), 8.04(s,1H), 7.68(s,1H), 7.54(d,J=8.2Hz,1H), 7.43(d,J=8.7Hz,1H), 7.23(s,1H), 7.21(s,1H) ), 7.01(dd,J=8.8,1.7Hz,1H), 5.51-5.42(m,1H), 4.40-4.26(m,3H), 4.18(t,J=7.1Hz,1H), 3.97(dd,J=8.3,5.4Hz,2H), 3.78(s,3H), 3.5 0-3.31(m,7H), 3.24(d,J=10.9Hz,1H), 3.14(s,1H), 3.07-2.72(m,5H), 2.65(s,3H), 2.59(t,J=6.6Hz,2H), 2.30(d,J=10.8Hz,1H), 2.26- 2.03(m,4H), 1.56-1.45(m,1H), 1.35(qd,J=9.4,4.9Hz,1H), 1.25-1.14(m,4H), 0.53(dt,J=8.5,4.3Hz,1H), 0.39(dt,J=9.1,4.7Hz,1H). [M+H] + = 830.6.

[0249] Example 33: 3-(5-((3S,4R)-4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 (-yl)piperazine-1-yl)-3-fluoropiperidine-1-yl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 10.72(s,1H), 8.64(s,1H), 7.81(s,1H), 7.44(s,1H), 7.29(d,J=8.8Hz,1H), 7.00-6.96(m,2H), 6.86-6. 84(m,2H), 4.37-4.12(m,4H), 4.06-4.04(m,1H), 3.81-3.76(m,2H), 3.68(s,3H), 3.14-2.96(m,6H), 2.94 -2.89(m,2H), 2.77(s,5H), 2.58-2.52(m,3H), 2.30(d,J=5.3Hz,2H), 2.22(d,J=13.9Hz,4H), 2.12(s,1H) , 2.08-1.90(m,3H), 1.67(s,1H), 1.40(s,1H), 1.28(s,1H), 1.11-1.06(m,2H), 0.48(s,1H), 0.32(s,1H). [M+H] + =830.6

[0250] Example 34: 3-(5-((3S,4R)-4-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6-yl)piperazine-1-yl)-3-fluoropiperidine-1-yl)-3-fluoro-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using the same procedure as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.45(s,1H), 10.87(s,1H), 8.71(s,1H), 7.88(s,1H), 7.51(s,1H), 7.36-7.32(m,2H), 7.06(s,1H), 6.91 (d,J=8.6Hz,1H), 5.16-5.06(m,1H), 4.29-4.27(m,3H), 4.21-4.00(m,2H), 3.75(s,3H), 3.43(s,2H), 3.2 3-3.18(m,4H), 2.96-2.77(m,6H), 2.75-2.68(m,1H), 2.57(d,J=12.5Hz,5H), 2.40(s,2H), 2.26(d,J=9.6 Hz,1H), 2.12-2.06(m,3H), 1.84(s,1H), 1.46-1.35(m,2H), 1.23-1.08(m,2H), 0.54(s,1H), 0.38(s,1H). [M+H] + =834.6

[0251] Example 35: (3R)-3-(4-(2-(4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 (-yl)-2-(tetrahydrofuran-3-yl)piperazine-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 16 and 27 in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 10.96(s,1H), 8.71(s,1H), 8.31(s,1H), 7.88(s,1H), 7.50(s,1H), 7.36(d,J=6.4Hz,1H), 7.07(d,J=3.5Hz,1H), 7.05(d ,J=3.3Hz,1H), 6.90(d,J=8.6Hz,1H), 4.35-4.27(m,2H), 4.22-4.18(m,2H), 3.75(s,4H), 3.65-3.57(m,1H), 3.51-3.47 (m,3H), 3.23(s,2H), 3.20-3.18(m,2H), 2.99-2.93(m,2H), 2.85-2.78(m,5H), 2.64(s,2H), 2.59-2.51(m,5H), 2.15-2. 09(m,2H), 2.02-1.97(m,1H), 1.92(s,1H), 1.75-1.71(m,1H), 1.55-1.38(m,1H), 1.21-1.05(m,2H), 0.39(s,1H);[M+H] + =834.6

[0252] Example 36: 3-(5-(4-(3-((S)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)-3-methylpiperazine-1-yl)azetidine-1-yl)piperidine-1-yl)6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 27. 1 H NMR(500MHz,DMSO)δ 12.44(s,1H), 10.78(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.37-7.35(m,2H), 7.16-6.98(m,2H), 6.88(d,J=8.6Hz,1H), 4.33-4 .24(m,3H), 4.13-4.10(m,1H), 3.90-3.87(m,2H), 3.75(s,3H), 3.43(s,2H), 3.21(d,J=11.7Hz,1H), 3.04-2.98(m,3H), 2.90-2.80(m,3H) , 2.69-2.59(m,3H), 2.55(s,3H), 2.54(s,2H), 2.45-2.43(m,1H), 2.37(s,3H), 2.33(d,J=8.4Hz,1H), 2.24-2.14(m,3H), 2.12-2.04(m,2H) ), 1.76(s,2H), 1.51-1.40(m,1H), 1.35(d,J=8.7Hz,3H), 1.20-1.06(m,1H), 0.97(d,J=6.2Hz,3H), 0.56-0.47(m,1H), 0.43-0.29(m,1H). [M+H] + =867.7

[0253] Example 37: 3-(5-(4-(3-((R)-4-((7 1 S,7 2 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)-3-methylpiperazine-1-yl)azetidine-1-yl)piperidine-1-yl)6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in Example 27. 1H NMR(500MHz,DMSO)δ 12.44(s,1H), 10.78(s,1H), 8.71(s,1H), 7.88(s,1H), 7.50(s,1H), 7.37-7.35(m,2H), 7.16-6.98(m,2H), 6.88(d,J=8.6Hz,1H), 4.33-4 .24(m,3H), 4.13-4.10(m,1H), 3.90-3.87(m,2H), 3.75(s,3H), 3.43(s,2H), 3.21(d,J=11.7Hz,1H), 3.04-2.98(m,3H), 2.90-2.80(m,3H) , 2.69-2.59(m,3H), 2.55(s,3H), 2.54(s,2H), 2.45-2.43(m,1H), 2.37(s,3H), 2.33(d,J=8.4Hz,1H), 2.24-2.14(m,3H), 2.12-2.04(m,2H) ), 1.76(s,2H), 1.51-1.40(m,1H), 1.35(d,J=8.7Hz,3H), 1.20-1.06(m,1H), 0.97(d,J=6.2Hz,3H), 0.56-0.47(m,1H), 0.43-0.29(m,1H). [M+H] + =867.7

[0254] Example 43: 3-(3-fluoro-5-((3S,4R)-3-fluoro-4-(4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 14 and 10 in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.54(s,1H), 10.82(s,1H), 8.53(s,1H), 7.91(s,1H), 7.54(s,1H), 7.42(s,2H), 7.29(s,1H), 6.97(s,1H), 5.57-5.47(m,1H), 4.68- 4.52(m,2H), 4.16(dd,J=11.2,5.1Hz,1H), 4.11(d,J=6.5Hz,1H), 3.97-3.84(m,2H), 3.81-3.69(m,5H), 3.62-3.58(m,1H), 3.37(s,2H) ), 3.21(s,2H), 3.02-2.82(m,3H), 2.76-2.68(m,1H), 2.62-2.53(m,6H), 2.42(s,3H), 2.34-2.14(m,2H), 2.10-2.00(m,1H), 1.46(d,J =5.7Hz,1H), 1.37(s,3H), 1.15(d,J=5.8Hz,1H), 1.10-1.04(m,1H), 0.95(dd,J=15.1,5.9Hz,1H), 0.76(s,1H), 0.61(d,J=4.6Hz,1H). [M+H] + =848.7

[0255] Example 49: 3-(5-((3S,4R)-3-fluoro-4-(4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 14 and 29 in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.46(s,1H), 10.79(s,1H), 8.52(s,1H), 7.87(s,1H), 7.53(s,1H), 7.39(d,J=6.9Hz,1H), 7.37(s,1H), 7.20(d,J=1.7Hz,1H), 7.1 2(d,J=8.2Hz,1H), 6.91(dd,J=8.8,1.9Hz,1H), 5.16-5.06(m,1H), 4.58(d,J=13.5Hz,2H), 4.10(t,J=6.8Hz,1H), 3.94-3.84(m,2H) ), 3.74(s,3H), 3.25-3.08(m,6H), 2.92-2.75(m,6H), 2.60-2.53(m,7H), 2.42(s,3H), 2.26-2.16(m,1H), 2.14-2.01(m,2H), 1.84( d,J=9.7Hz,1H), 1.44(dd,J=14.6,8.5Hz,1H), 1.37(s,3H), 1.06(d,J=15.3Hz,1H), 0.78-0.71(m,1H), 0.61(dd,J=8.0,3.6Hz,1H). [M+H] + = 830.7.

[0256] Example 54: 3-(3-fluoro-6-methyl-5-(4-(4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 30 and 5 in the same manner as in Example 3. 1 H NMR(500MHz,DMSO)δ 12.47(s,1H), 10.87(s,1H), 8.52(s,1H), 7.87(s,1H), 7.53(s,1H), 7.37(d,J=8.7Hz,1H), 7.32(d,J=11.5Hz,1H), 7.19(s,1H), 6.90(dd, J=8.8,1.7Hz,1H), 4.58(d,J=13.5Hz,2H), 4.14(dd,J=11.1,5.2Hz,1H), 4.10(t,J=6.8Hz,1H), 3.91(dd,J=13.8,9.0Hz,1H), 3.74(s,3H) , 3.18(d,J=4.3Hz,6H), 2.79-2.61(m,7H), 2.59-2.53(m,5H), 2.43-2.34(m,4H), 2.30-2.18(m,1H), 2.08-2.00(m,1H), 1.94(d,J=10.0Hz) ,2H), 1.64(d,J=9.9Hz,2H), 1.44(dd,J=14.5,7.9Hz,1H), 1.37(s,3H), 1.11-1.01(m,1H), 0.78-0.73(m,1H), 0.61(dd,J=8.1,3.6Hz,1H). [M+H] + = 830.7.

[0257] Example 57: 3-(4-((3S,4R)-3-fluoro-4-(4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)-3,3-dimethyl-2-oxoindoline-1-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 14 and 33 in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.44(s,1H), 11.06(s,1H), 8.52(s,1H), 7.87(s,1H), 7.53(s,1H), 7.38(d,J=8.7Hz,1H), 7.25(t,J=7.8Hz,1H), 7.20(s,1H), 7.07( d,J=8.0Hz,1H), 6.91(d,J=9.2Hz,1H), 6.83(s,1H), 5.30-5.18(m,1H), 5.15-5.05(m,1H), 4.59-4.52(m,2H), 4.10(t,J=7.4Hz,1H), 3.92(d,J=7.3Hz,1H), 3.74(s,3H), 3.25-3.04(m,6H), 3.02-2.76(m,8H), 2.65-2.60(m,2H), 2.56(s,4H), 2.06-2.02(m,1H), 1.97-1 .94(m,1H), 1.88-1.78(m,1H), 1.43(dd,J=8.2,3.8Hz,7H), 1.37(s,3H), 1.12-1.01(m,1H), 0.76(t,J=4.2Hz,1H), 0.65-0.57(m,1H). ;[M+H] + = 898.7.

[0258] Example 59: 3-(5-((3S,4R)-3-fluoro-4-(4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)-4-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 14 and 34 in the same manner as in Example 30. 1 1H NMR (500MHz, DMSO) δ 12.60(s,1H), 10.88(s,1H), 8.63(s,1H), 8.25(s,1H), 7.98(s,1H), 7.66( s,1H), 7.45(d,J=8.7Hz,1H), 7.31(s,1H), 7.28(s,1H), 7.01(d,J=8.3Hz, 1H), 5.57-5.37(m,1H), 4.68-4.53(m,2H), 4.13(t,J=6.0Hz,1H), 3.98(dd ,J=9.2,5.4Hz,1H), 3.95-3.90(m,1H), 3.77(s,3H), 3.73-3.70(m,1H), 3.6 7-3.61(m,2H), 3.33-3.21(m,6H), 3.10(dd,J=14.1,5.6Hz,1H), 3.05-3.0 0(m,1H), 2.99-2.91(m,1H), 2.67-2.53(m,7H), 2.38-2.28(m,4H), 2.27-2 .19(m,1H), 2.18-2.07(m,2H), 1.46(dd,J=13.9,8.0Hz,1H), 1.38(s,3H), 1.08(d,J=14.0Hz,1H), 0.75(t,J=3.9Hz,1H), 0.62(dd,J=7.4,3.1Hz,1H). [M+H] + = 830.7.

[0259] Example 61: 3-(3-fluoro-5-((3R,4S)-3-fluoro-4-(4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-56-yl)piperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 14 and 9 in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.46(s,1H), 10.87(s,1H), 8.52(s,1H), 7.87(s,1H), 7.53(s,1H), 7.36(dd,J=14.3,10.1Hz,2H), 7.20(s,1H), 6.91(d,J= 8.9Hz,1H), 5.18-5.04(m,1H), 4.58(d,J=13.6Hz,2H), 4.18-4.06(m,2H), 3.91(dd,J=13.6,8.9Hz,1H), 3.74(s,3H), 3.25- 3.16(m,5H), 2.94-2.79(m,6H), 2.75-2.54(m,8H), 2.40(s,3H), 2.26(dd,J=20.4,11.8Hz,1H), 2.05(dd,J=11.6,7.1Hz,2H ), 1.84(d,J=11.0Hz,1H), 1.48-1.41(m,1H), 1.37(s,3H), 1.06(d,J=14.4Hz,1H), 0.76(t,J=4.4Hz,1H), 0.64-0.57(m,1H). [M+H] + = 848.6.

[0260] Example 62: 3-(5-((3R,4S)-3-fluoro-4-(4-((7 1 R,7 2 S,E)-1 1 ,2 6 ,7 2 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-10-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,2)-cyclopropanacyclodecafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 14 and 31 in the same manner as in Example 30. 1 H NMR(500MHz,DMSO)δ 12.45(s,1H), 10.79(s,1H), 8.52(s,1H), 7.87(s,1H), 7.53(s,1H), 7.38(dd,J=8.4,4.8Hz,2H), 7.20(s,1H), 7.12(d,J=8.1Hz,1H), 6 .91(d,J=8.7Hz,1H), 5.16-5.05(m,1H), 4.61-4.56(m,2H), 4.10(t,J=6.9Hz,1H), 3.93-3.87(m,2H), 3.74(s,3H), 3.39-3.36(m,1H), 3.19(s,5H), 2.88-2.76(m,6H), 2.63-2.57(m,2H), 2.56-2.55(m,4H), 2.54-2.51(m,1H), 2.42(s,3H), 2.25-2.17(m,1H), 2.11-2.01( [M+H] + =830.5

[0261] cell line H1975-Clone No. 8 (L858R / C797S): EGFR-L858R / C797S were stably expressed in the H1975 cell line via lentiviral-mediated overexpression. Subsequently, EGFR-overexpressing cells were knocked out, and EGFR-targeting sgRNAs were designed to target only endogenous EGFR copies while preserving exogenous EGFR copies. Following knockout, edited H1975 cells were seeded at a concentration of 1 cell / cell in 96-well plates and cultured for approximately 2 weeks to enable single clone formation. The formed clones were screened by DNA sequencing and whole-exome sequencing for the desired editing. H1975-Clone No. 8 was ultimately confirmed as a homozygous L858R / C797S EGFR clone.

[0262] BaF3-L858R (abbreviated as L858R) cells were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.

[0263] cell degradation Cell processing On day 1, H1975-clone number 8 (L858R / C797S) cells were seeded at a rate of 5000 cells / well in Corning 96-well plates (catalog number 3599) in cell culture medium [RPMI1640 (Gibco, catalog number 72400-047), 10% heat-inactive FBS, 1% PS (Gibco, catalog number 10378)].

[0264] On day 2, BaF3-L858R cells were seeded at a rate of 50,000 cells / well and a volume of 54 μl / well in Corning 96-well plates (catalog no. 3799) in cell culture medium [RPMI1640 (Gibco, phenol red-free, catalog no. 11835-030), 10% heat-inactive FBS, 1% PS (Gibco, catalog no. 10378)].

[0265] H1975-number 8 cells and BaF3-L858R cells were treated with the compound diluted in 0.1% DMSO cell culture medium on day 2 and incubated at 37°C and 5% CO2 for 16 hours. The final concentration of the compound in all assays was 10 μM, starting at a 5-fold dilution, and included a total of 8 doses.

[0266] HTRF assay After 16 hours of processing, for H1975-number 8 cells, add 100 μl of 1x HTRF lysis buffer to each well; for BaF3-L858R cells, add 20 μl of 4x lysis buffer to each well, seal the plate, and incubate on a plate shaker at room temperature for 1 hour. Once the cells are lysed, transfer 16 μl of the cell lysate to a PE38 4-well HTRF detection plate and add 4 μl of premixed HTRF antibody to each well. Cover the plate with a plate sealer and rotate at 1000 rpm for 1 minute. Incubate overnight at room temperature. Read using a BMG PheraStar with the HTRF protocol (337 nm-665 nm-620 nm).

[0267] The inhibition (degradation) percentage of the compounds was calculated using the following formula: Inhibition Percentage of Compound = 100 - 100 × (Signal - Low Control) / (High Control - Low Control) [wherein signal = each test compound group] Low control = lysis buffer containing no cells (indicating that EGFR is completely degraded). High control = Cells treated with DMSO and free of the compound (shows microplate readings without EGFR degradation). Dmax is the maximum inhibition (degradation) percentage.

[0268] Compound IC 50 (DC 50 The value can be obtained by fitting the following formula. Y = Bottom + (Top - Bottom) / (1 + ((IC) 50 / X)^hill gradient)) In the formula, X and Y are known values, and IC 50The hill gradient, top, and bottom are parameters obtained through software-based fitting. Y is the inhibition percentage (calculated from the formula), X is the concentration of the compound, and IC is the IC. 50 IC is the concentration of the compound at which 50% inhibition is achieved. 50 The smaller the value, the stronger the inhibitory ability of the compound. The opposite is also true for IC. 50 The higher the value, the weaker the inhibitory ability of the compound. The hill gradient is generally about 1 * The curve's slope is represented by the bottom, which is generally 0% ± 20% and represents the minimum value of the curve obtained through data fitting, while the top, which is generally 100% ± 20% and represents the maximum value of the curve obtained through data fitting. Experimental data was fitted by calculation and analysis using Dotmatics data analysis software. [Table 6-1] [Table 6-2]

Claims

1. Equation (I) 【Chemistry 1】 [In the formula, R １ａ 、 R １ｂ 、 R １ｃ 、 R １ｄ 、 R １ｅ 、 R １ｆ 、 R １ｇ 、 R １ｈ 、 R ２ａ 、 R ２ｂ 、 R ３ 、 R ４ 、 and R ５ are each independently hydrogen, halogen, -C １－４ alkyl, -C １－４ alkoxy, -C ３－６ cycloalkyl, or -CN, wherein each of said -C １－４ alkyl, said -C １－４ alkoxy, or said -C ３－６ cycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkoxy, -C ３－８ cycloalkyl, or -CN. R ６ and R ７ However, each independently, hydrogen, -C １－３ Alkyl, or -C ３－６ It is a cycloalkyl, and the -C １－３ Alkyl-C ３－６ Each cycloalkyl group can be optionally composed of hydrogen, halogen, or -C. １－８ Alkoxy, -C ３－８ Substituted with at least one substituent selected from cycloalkyl or -CN, m1, m2, and m3 are each independently 0, 1, or 2, provided that m1 + m2 + m3 = 4 or less and m1 + m2 + m3 = 1 or greater. m4 and m5 are independently 0, 1, or 2, provided that m4 + m5 = 2. L １ However, independently, -C １－３ Alkylene-, -O-, -NR ａ -, -C(O)-, ＊Ｌ１ -C(O)NR ａ - ＊＊Ｌ１ , ＊Ｌ１ -C(O)O- ＊＊Ｌ１ , ＊Ｌ１ -NR ａ C(O)- ＊＊Ｌ１ , ＊Ｌ１ -OC(O)- ＊＊Ｌ１ , 【Chemistry 2】 Selected from, the above-C １－３ Alkylene-, 【Transformation 3】 Each of them can optionally choose at least one R Ｌ１ｃ Replaced by, ＊Ｌ１ However, as mentioned above 【Chemistry 4】 It refers to the position where it is joined to a part. ＊＊Ｌ１ However, as mentioned above 【Transformation 5】 It refers to the position where it is joined to a part. L ２ However, independently, -C １－３ Alkylene-, -O-, -NR ａ -, -C(O)-, ＊Ｌ２ -C(O)NR ａ - ＊＊Ｌ２ , ＊Ｌ２ -C(O)O- ＊＊Ｌ２ , ＊Ｌ２ -NR ａ C(O)- ＊＊Ｌ２ , ＊Ｌ２ -OC(O)- ＊＊Ｌ２ , 【Transformation 6】 Selected from, the above-C １－３ Alkylene-, 【Transformation 7】 Each of them can optionally choose at least one R Ｌ２ｃ Replaced by, ＊Ｌ２ However, as mentioned above 【Transformation 8】 It refers to the position where it is joined to a part. ＊＊Ｌ２ However, as mentioned above 【Chemistry 9】 It refers to the position where it is joined to a part. L ３ However, independently, -C １－３ Alkylene-, -O-, -NR ａ -, -C(O)-, ＊Ｌ３ -C(O)NR ａ - ＊＊Ｌ３ , ＊Ｌ３ -C(O)O- ＊＊Ｌ３ , ＊Ｌ３ -NR ａ C(O)- ＊＊Ｌ３ , ＊Ｌ３ -OC(O)- ＊＊Ｌ３ , 【Chemistry 10】 Selected from, the above-C １－３ Alkylene-, 【Chemistry 11】 Each of them can optionally choose at least one R Ｌ３ｃ Replaced by, ＊Ｌ３ However, as mentioned above 【Chemistry 12】 It refers to the position where it is joined to a part. ＊＊Ｌ３ However, as mentioned above 【Chemistry 13】 It refers to the position where it is joined to a part. said R Ｌ１ｃ said R Ｌ２ｃ said R Ｌ３ｃ each of which is independently non - existent, oxo(=O), halogen, hydroxy, -CN, -C １ -C ８ alkyl, -C[[ID=ii]] １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3 - 8 - membered heterocyclyl, C ６ -C １２ aryl, or 5 - 12 - membered heteroaryl, and each of said -C １ -C ８ alkyl, said -C １ -C ８ alkoxy, said -C ２ -C ８ alkenyl, said -C ２ -C ８ alkynyl, said C ３ -C ８ cycloalkyl, said 3 - 8 - membered heterocyclyl, said C ６ -C １２ aryl, and said 5 - 12 - membered heteroaryl is optionally substituted with at least one R Ｌｃａ ; R Ｌｃａ However, independently, non-existent, oxo (=O), halogen, hydroxy, -CN, -C １ -C ８ Alkyl, -C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ It is either an aryl, or a 5- to 12-membered heteroaryl, or Two R's Ｌ１ｃ However, together with the atoms to which they are bonded, they form a 3- to 12-membered ring, the ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally having at least one substituent halogen, hydroxyl, or -C １ -C ８ Substituted with alkyl, Two R's Ｌ２ｃ However, together with the atoms to which they are bonded, they form a 3- to 12-membered ring, the ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally having at least one substituent halogen, hydroxyl, or -C １ -C ８ Substituted with alkyl, Two R's Ｌ３ｃ However, together with the atoms to which they are bonded, they form a 3- to 12-membered ring, the ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally having at least one substituent halogen, hydroxyl, or -C １ -C ８ Substituted with alkyl, 【Chemistry 14】 but, 【Chemistry 15】 Selected from, Z １ Z ２ , and Z ３ However, each independently, N or CR ｚ However, Z １ Z ２ , and Z ３ Provided that both are not N, R ｚ However, in each appearance, independently, non-existence, hydrogen, halogen, and -C are present. １－８ Alkyl, -NR Ｚａ R Ｚｂ , -OR Ｚａ ,-SR Ｚａ , C ３ -C ８ Selected from cycloalkyl, 3-8 membered heterocyclyl, or CN, the -C １－８ alkyl, the C ３ -C ８ Each of the cycloalkyl group and the 3-8 membered heterocyclyl group optionally contains at least one R Ｚｃ Replaced by, The aforementioned 【Chemistry 16】 The part is CR ｚ And R ｚ Z does not exist. １ Z ２ , or Z ３ via any one of the above 【Chemistry 17】 part, the above [Chemistry 18] part, or the 【Chemistry 19】 It is connected to the part, R Ｚａ and R Ｚｂ However, each is independent of non-existence, hydrogen, and -C. １ -C ８ Alkyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Selected from aryl or 5- to 12-membered heteroaryl, and the -C １－８ alkyl, the C ３ -C ８ Cycloalkyl, the 3-8 membered heterocyclyl, the C ６ -C １２ Each of the aryl or the 5- to 12-membered heteroaryl may optionally have at least one substituent R Ｚｄ Replaced by, R Ｚｃ and R Ｚｄ However, each independently, halogen, hydroxyl, and -C １ -C ８ Alkyl, -C １－８ Alkoxy, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ It is an aryl or a 5- to 12-membered heteroaryl. R １３ and R １４ However, each is independent of non-existence, hydrogen, halogen, and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C １－８ Alkoxy, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, -CN, -SO ２ R １３ａ , -SO ２ NR １３ａ R １３ｂ , -COR １３ａ , -CO ２ R １３ａ , -CONR １３ａ R １３ｂ , -NR １３ａ R １３ｂ , -NR １３ａ COR １３ｂ , -NR １３ａ CO ２ R １３ｂ , or -NR １３ａ SO ２ R １３ｂ Selected from, the above-C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Alkinyl, the above-C １－８ Alkoxy, the above-C ３ -C ８ Cycloalkyl, the 3-8 membered heterocyclyl, the -C ６ -C １２ Each of the aryl or the 5- to 12-membered heteroaryl is optionally a halogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Aryl, 5-12 member heteroaryl, oxo, -CN, -OR １３ｃ , -SO ２ R １３ｃ , -SO ２ NR １３ｃ R １３ｄ , -COR １３ｃ , -CO ２ R １３ｃ , -CONR １３ｃ R １３ｄ , -NR １３ｃ R １３ｄ , -NR １３ｃ COR １３ｄ , -NR １３ｃ CO ２ R １３ｄ , or -NR １３ｃ SO ２ R １３ｄ Replaced by, In each occurrence, R １３ａ , R １３ｂ , R １３ｃ , and R １３ｄ However, each is independent of non-existence, hydrogen, and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ It is an aryl or a 5- to 12-membered heteroaryl. L ４ , L ５ , and L ６ However, each is independent of non-existence, single bond, -O-, and -NR. ａ -, - (CR ａ R ｂ ) ｎ８ -, -O(CR ａ R ｂ ) ｎ８ -, -NR ａ (CR ａ R ｂ ) ｎ８ - or -C(O)- is selected, In each occurrence, X １ , X ２ , and X ７ However, each operates independently, -CR ａ Or selected from N, In each occurrence, X ３ , X ４ , and X ８ However, each is independent of -NR ａ -, -O-, -S-, and -CR ａ R ｂ - Selected from, In each occurrence, X ５ and X ６ However, each is independent of non-existence, single bond, -C(O)-, and -NR ａ - and -O- are selected, In each occurrence, R ａ and R ｂ However, each is independent of hydrogen, hydroxyl, halogen, CN, and -C. １ -C ８ Alkyl, -C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Selected from aryl or 5- to 12-membered heteroaryl, and the -C １ -C ８ Alkyl, the above-C １ -C ８ Alkoxy, the above-C ２ -C ８ Alkenyl, the above-C ２ -C ８ Alkinyl, the above-C ３ -C ８ Cycloalkyl, the 3-8 membered heterocyclyl, the -C ６ -C １２ Each of the aryl or the 5- to 12-membered heteroaryl is optionally substituted with at least one halogen, hydroxyl, halogen, or -C substituent. １ -C ８ Alkyl, -C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Substituted with aryl or 5- to 12-membered heteroaryl, R ａ and R ｂ However, together with the carbon atoms to which they are bonded, they form a 3- to 12-membered ring, the ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally containing at least one substituent halogen, hydroxyl, -C １ -C ８ Alkyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, -C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Substituted with aryl or 5- to 12-membered heteroaryl groups, n1, n2, n3, n4, and n5 are each independently 0, 1, 2, or 3. n6, n7, and n8 are each independently 0, 1, 2, 3, or 4, however, L １ , L ２ , or L ３ For any one of the following, X １ If X is N, ５ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ２ If X is N, ６ The bond is a single bond, nonexistent, and -C(O)-. L １ but 【Chemistry 20】 In that case, X １ If X is N, ５ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ３ ga-CR ａ R ｂ - being X ２ If X is N, ６ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ４ ga-CR ａ R ｂ - that is, L ２ but 【Chemistry 21】 In that case, X １ If X is N, ５ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ３ ga-CR ａ R ｂ - being X ２ If X is N, ６ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ４ ga-CR ａ R ｂ - that is, L ３ but 【Chemistry 22】 In that case, X １ If X is N, ５ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ３ ga-CR ａ R ｂ - being X ２ If X is N, ６ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ４ ga-CR ａ R ｂ A compound of [subject to the condition that], its N-oxide, its pharmaceutically acceptable salt, its stereoisomer, its deuterated analog, or its prodrug.

2. The compound is selected from formula (IIa), 【Chemistry 23】 Preferably, the compound is selected from formula (IIb), 【Chemistry 24】 More preferably, the compound is selected from formula (IIc), 【Chemistry 25】 More preferably, the compound is selected from formula (IId), 【Chemistry 26】 In the formula, R １ｃ and R １ｄ However, each is independently H, methyl, or ethyl, except R １ｃ and R １ｄ The condition is that at most one of them is H, R ３ , R ４ , R ５ , R ６ , R ７ , L １ , L ２ , L ３ The compound according to claim 1, wherein m1, m2, m3, m4, m5, and degron are as defined in claim 1.

3. The compound is selected from formula (IIIa), 【Chemistry 27】 In the formula, R １ｃ and R １ｄ However, each is independently H, methyl, or ethyl, except R １ｃ and R １ｄ The condition is that at most one of them is H, R ３ , R ４ , R ５ , R ６ , R ７ , R １３ , R １４ , L １ , L ２ , L ３ , L ４ , m1, m2, m3, m4, m5, Z １ Z ３ , X ７ , X ８ , and n6 are as defined in claim 1, Preferably, the compound is selected from formula (IIIb), 【Chemistry 28】 In the formula, R １ｃ and R １ｄ However, each is independently H, methyl, or ethyl, except R １ｃ and R １ｄ The condition is that at most one of them is H, R １３ , R １４ , L １ , L ２ , L ３ , m1, m2, m3, m4, m5, Z １ Z ３ , X ７ , X ８ , and n6 are as defined in claim 1, More preferably, the compound is selected from formula (IIIc) or formula (IIId), 【Chemistry 29】 In the formula, R １ｃ and R １ｄ However, each is independently H, methyl, or ethyl, except R １ｃ and R １ｄ The condition is that at most one of them is H, R １３ , R １４ , L １ , L ２ , L ３ m4, m5, Z １ Z ３ , X ７ , X ８ The compound according to claim 1, wherein n6 is as defined in claim 1.

4. The aforementioned compound is of formula (IVa) 【Transformation 30】 [In the formula, R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ , R １ｆ , R １ｇ , R １ｈ , R ２ａ , R ２ｂ , R ３ , R ４ , and R ５ However, each independently, hydrogen, halogen, and -C １－４ Alkyl, -C １－４ Alkoxy, -C ３－６ Cycloalkyl, or -CN, and the -C １－４ Alkyl, the above-C １－４ Alkoxy, or the aforementioned -C ３－６ Each cycloalkyl group can be optionally composed of hydrogen, halogen, or -C. １－８ Alkoxy, -C ３－８ Substituted with at least one substituent selected from cycloalkyl or -CN, R ６ and R ７ However, each independently, hydrogen, -C １－３ Alkyl, or -C ３－６ It is a cycloalkyl, and the -C １－３ Alkyl-C ３－６ Each cycloalkyl group can be optionally composed of hydrogen, halogen, or -C. １－８ Alkoxy, -C ３－８ Substituted with at least one substituent selected from cycloalkyl or -CN, m4 and m5 are independently 0, 1, or 2, provided that m4 + m5 = 2. L １ However, they became independent, 【Chemistry 31】 Selected from the above, 【Chemistry 32】 Each of them can optionally choose at least one R Ｌ１ｃ Replaced by, ＊Ｌ１ However, as mentioned above 【Transformation 33】 It refers to the position where it is joined to a part. ＊＊Ｌ１ However, as mentioned above 【Transformation 34】 It refers to the position where it is joined to a part. L ２ However, they became independent, 【Chemistry 35】 Selected from the above, 【Transformation 36】 Each of them can optionally choose at least one R Ｌ２ｃ Replaced by, ＊Ｌ２ However, as mentioned above 【Chemistry 37】 It refers to the position where it is joined to a part. ＊＊Ｌ２ However, as mentioned above 【Transformation 38】 It refers to the position where it is joined to a part. L ３ However, they became independent, 【Chemistry 39】 Selected from, 【Chemistry 40】 Each of them can optionally choose at least one R Ｌ３ｃ Replaced by, ＊Ｌ３ However, as mentioned above 【Chemistry 41】 It refers to the position where it is joined to a part. ＊＊Ｌ３ However, as mentioned above 【Chemistry 42】 It refers to the position where it is joined to a part. The aforementioned R Ｌ１ｃ , the R Ｌ２ｃ , and the R Ｌ３ｃ Each of these independently represents non-existence, oxo (=O), halogen, hydroxyl, -CN, and -C. １ -C ８ Alkyl, -C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ The aryl or 5- to 12-membered heteroaryl, and the -C １ -C ８ Alkyl, the above-C １ -C ８ Alkoxy, the above-C ２ -C ８ Alkenyl, the above-C ２ -C ８ Alkinyl, the C ３ -C ８ Cycloalkyl, the 3-8 membered heterocyclyl, the C ６ -C １２ Each of the aryl and the 5- to 12-membered heteroaryl is optionally at least one R Ｌｃａ Replaced by, R Ｌｃａ However, independently, non-existent, oxo (=O), halogen, hydroxy, -CN, -C １ -C ８ Alkyl, -C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ It is either an aryl, or a 5- to 12-membered heteroaryl, or Two R's Ｌ１ｃ However, together with the atoms to which they are bonded, they form a 3- to 12-membered ring, the ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally having at least one substituent halogen, hydroxyl, or -C １ -C ８ Substituted with alkyl, Two R's Ｌ２ｃ However, together with the atoms to which they are bonded, they form a 3- to 12-membered ring, the ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally having at least one substituent halogen, hydroxyl, or -C １ -C ８ Substituted with alkyl, Two R's Ｌ３ｃ However, together with the atoms to which they are bonded, they form a 3- to 12-membered ring, the ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally having at least one substituent halogen, hydroxyl, or -C １ -C ８ Substituted with alkyl, 【Chemistry 43】 but, 【Chemistry 44】 Selected from, Z １ Z ２ , and Z ３ However, each independently, N or CR ｚ However, Z １ Z ２ , and Z ３ Provided that both are not N, R ｚ However, in each appearance, independently, non-existence, hydrogen, halogen, and -C are present. １－８ Alkyl, -NR Ｚａ R Ｚｂ , -OR Ｚａ ,-SR Ｚａ , C ３ -C ８ Selected from cycloalkyl, 3-8 membered heterocyclyl, or CN, the -C １－８ alkyl, the C ３ -C ８ Each of the cycloalkyl group and the 3-8 membered heterocyclyl group optionally contains at least one R Ｚｃ Replaced by, The aforementioned 【Chemistry 45】 The part is CR ｚ And R ｚ Z does not exist. １ Z ２ , or Z ３ via any one of the above 【Chemistry 46】 part, the above 【Chemistry 47】 part, or the 【Chemistry 48】 It is connected to the part, R Ｚａ and R Ｚｂ However, each is independent of non-existence, hydrogen, and -C. １ -C ８ Alkyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Selected from aryl or 5- to 12-membered heteroaryl, and the -C １－８ alkyl, the C ３ -C ８ Cycloalkyl, the 3-8 membered heterocyclyl, the C ６ -C １２ Each of the aryl or the 5- to 12-membered heteroaryl may optionally have at least one substituent R Ｚｄ Replaced by, R Ｚｃ and R Ｚｄ However, each independently, halogen, hydroxyl, and -C １ -C ８ Alkyl, -C １－８ Alkoxy, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ It is an aryl or a 5- to 12-membered heteroaryl. R １３ and R １４ However, each is independent of non-existence, hydrogen, halogen, and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C １－８ Alkoxy, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, -CN, -SO ２ R １３ａ , -SO ２ NR １３ａ R １３ｂ , -COR １３ａ , -CO ２ R １３ａ , -CONR １３ａ R １３ｂ , -NR １３ａ R １３ｂ , -NR １３ａ COR １３ｂ , -NR １３ａ CO ２ R １３ｂ , or -NR １３ａ SO ２ R １３ｂ Selected from, the above-C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Alkinyl, the above-C １－８ Alkoxy, the above-C ３ -C ８ Cycloalkyl, the 3-8 membered heterocyclyl, the -C ６ -C １２ Each of the aryl or the 5- to 12-membered heteroaryl is optionally a halogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Aryl, 5-12 member heteroaryl, oxo, -CN, -OR １３ｃ , -SO ２ R １３ｃ , -SO ２ NR １３ｃ R １３ｄ , -COR １３ｃ , -CO ２ R １３ｃ , -CONR １３ｃ R １３ｄ , -NR １３ｃ R １３ｄ , -NR １３ｃ COR １３ｄ , -NR １３ｃ CO ２ R １３ｄ , or -NR １３ｃ SO ２ R １３ｄ Replaced by, In each occurrence, R １３ａ , R １３ｂ , R １３ｃ , and R １３ｄ However, each is independent of non-existence, hydrogen, and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ It is an aryl or a 5- to 12-membered heteroaryl. L ４ , L ５ , and L ６ However, each is independent of non-existence, single bond, -O-, and -NR. ａ -, - (CR ａ R ｂ ) ｎ８ -, -O(CR ａ R ｂ ) ｎ８ -, -NR ａ (CR ａ R ｂ ) ｎ８ - or -C(O)- is selected, In each occurrence, X １ , X ２ , and X ７ However, each operates independently, -CR ａ Or selected from N, In each occurrence, X ３ , X ４ , and X ８ However, each is independent of -NR ａ -, -O-, -S-, and -CR ａ R ｂ - Selected from, In each occurrence, X ５ and X ６ However, each is independent of non-existence, single bond, -C(O)-, and -NR ａ - and -O- are selected, In each occurrence, R ａ and R ｂ However, each is independent of hydrogen, hydroxyl, halogen, CN, and -C. １ -C ８ Alkyl, -C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Selected from aryl or 5- to 12-membered heteroaryl, and the -C １ -C ８ Alkyl, the above-C １ -C ８ Alkoxy, the above-C ２ -C ８ Alkenyl, the above-C ２ -C ８ Alkinyl, the above-C ３ -C ８ Cycloalkyl, the 3-8 membered heterocyclyl, the -C ６ -C １２ Each of the aryl or the 5- to 12-membered heteroaryl is optionally substituted with at least one halogen, hydroxyl, halogen, or -C substituent. １ -C ８ Alkyl, -C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, -C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, -C ６ -C １２ Substituted with aryl or 5- to 12-membered heteroaryl, R ａ and R ｂ However, together with the carbon atoms to which they are bonded, they form a 3- to 12-membered ring, the ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring optionally containing at least one substituent halogen, hydroxyl, -C １ -C ８ Alkyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, -C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Substituted with aryl or 5- to 12-membered heteroaryl groups, n1, n2, n3, n4, and n5 are each independently 0, 1, 2, or 3. n6, n7, and n8 are each independently 0, 1, 2, 3, or 4, however, L １ , L ２ , or L ３ For any one of the following, X １ If X is N, ５ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ２ If X is N, ６ The bond is a single bond, nonexistent, and -C(O)-. L １ but 【Chemistry 49】 In that case, X １ If X is N, ５ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ３ ga-CR ａ R ｂ - being X ２ If X is N, ６ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ４ ga-CR ａ R ｂ - that is, L ２ but [Transformation 50] In that case, X １ If X is N, ５ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ３ ga-CR ａ R ｂ - being X ２ If X is N, ６ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ４ ga-CR ａ R ｂ - that is, L ３ but 【Chemistry 51】 In that case, X １ If X is N, ５ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ３ ga-CR ａ R ｂ - being X ２ If X is N, ６ The fact that it is a single bond, nonexistent, -C(O)-, and / or X ４ ga-CR ａ R ｂ The compound according to claim 1, which is selected from [conditions that it is -], or is its N-oxide, its pharmaceutically acceptable salt, its stereoisomer, its deuterated analog, or its prodrug.

5. The compound is selected from formula (Va), 【Chemistry 52】 Preferably, the compound is selected from formula (Vb), 【Chemistry 53】 More preferably, the compound is selected from formula (Vc), 【Chemistry 54】 More preferably, the compound is selected from formula (Vd), 【Transformation 55】 More preferably, the compound is selected from formula (Ve), 【Transformation 56】 More preferably, the compound is selected from formula (Vf), 【Chemistry 57】 R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ , R １ｆ , R １ｇ , R １ｈ , R ２ａ , R ２ｂ , R １３ , R １４ , L １ , L ２ , L ３ , L ４ m4, m5, Z １ Z ３ , X ７ , X ８ The compound according to claim 3, wherein n6 is as defined in claim 3.

6. R ６ and R ７ Each of these is independently hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and each of the methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN. Preferably, R ６ and R ７ However, each is independently hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More specifically, R ６ However, independently, they are methyl or cyclopropyl, and R ７ The compound according to any one of the prior claims, wherein the compound is hydrogen.

7. R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ , R １ｆ , R １ｇ , R １ｈ , R ２ａ , R ２ｂ , R ３ , R ４ , and R ５ Each of these is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or -CN, and each of the methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN. Preferably, R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ , R １ｆ , R １ｇ , R １ｈ , R ２ａ , R ２ｂ , R ３ , R ４ , and R ５ However, each is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF ３ ,-CHF ２ -CN, -CH ２ OCH ３ ien-CH ２ OCH ２ CH ３ ien-CH ２ CH ２ OCH ３ ien-CH ２ CH ２ OCH ２ CH ３ And, More specifically, R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ , R １ｆ , R １ｇ , R １ｈ , R ２ａ , R ２ｂ , R ３ , R ４ , and R ５ However, each independently, hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF ３ , or -CHF ２ ien-CH ２ OCH ３ And more preferably, R ４ However, hydrogen, F, methyl, methoxy, cyclopropyl, or -CF ３ And R ３ However, hydrogen, F, methyl, -CF ３ , or -CHF ２ And R ５ However, hydrogen, F, Cl, methyl, or -CH ２ OCH ３ And R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ , R １ｆ , R １ｇ , R １ｈ , R ２ａ , and R ２ｂ The compound according to any one of the prior claims, wherein each is independently hydrogen, F, or methyl.

8. The aforementioned 【Transformation 58】 The part, 【Chemistry 59】 Selected from, Preferably, the above 【Transformation 60】 The part, 【Chemistry 61】 A compound selected from any one of the prior claims.

9. L １ が、-O-、-C(O)-、-N(R ａ )-、 ＊Ｌ１ -C(O)N(R ａ )- ＊＊Ｌ１ 、 ＊Ｌ１ -C(O)O- ＊＊Ｌ１ 、 ＊Ｌ１ -N(R ａ )C(O)- ＊＊Ｌ１ 、 ＊Ｌ１ -OC(O)- ＊＊Ｌ１ 、 【Chemistry 62-1】 【Chemistry 62-2】 Selected from, 【Chemistry 63-1】 【Chemistry 63-2】 Each of them can optionally choose at least one R Ｌ１ｃ Replaced by, The aforementioned R Ｌ１ｃ Each of these independently represents oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, the above-C ２ -C ８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl may optionally contain at least one R Ｌｃａ Replaced by, R Ｌｃａ is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, or Two R's Ｌ１ｃ However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. R ａ is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and wherein each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said methoxy, said -C ２ -C ８ alkenyl, said -C ２ -C ８ alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclyl, phenyl, or 5 to 12-membered heteroaryl, a compound according to any one of the preceding claims.

10. L １ が、-O-、-N(CH ３ )-、-C(O))-、-NHH-、 ＊Ｌ１ -C(O)N(CH) ３ )- ＊＊Ｌ１ 、 ＊Ｌ１ -C(O)NH- ＊＊Ｌ１ 、 ＊Ｌ１ -C(O)O- ＊＊Ｌ１ 、 ＊Ｌ１ -C(O)N(C) ２ H ５ )- ＊＊Ｌ１ 、 ＊Ｌ１ -C(O)N(C) ３ H ７ )- ＊＊Ｌ１ 、 ＊Ｌ１ -N(CH) ３ )C(O)- ＊＊Ｌ１ 、 ＊Ｌ１ -NHC(O)- ＊＊Ｌ１ 、 ＊Ｌ１ -OC(O)- ＊＊Ｌ１ 、 ＊Ｌ１ -N(C) ２ H ５ )C(O)- ＊＊Ｌ１ 、 ＊Ｌ１ -N(C) ３ H ７ )C(O)- ＊＊Ｌ１ 、 【Chemistry 64-1】 【Chemistry 64-2】 【Chemistry 64-3】 【Chemistry 64-4】 【Chemistry 64-5】 【Chemistry 64-6】 【Chemistry 64-7】 A compound selected from any one of the prior claims.

11. L ２ が、-O-、-C(O)-、-N(R ａ )-、 ＊Ｌ２ -C(O)N(R ａ )- ＊＊Ｌ２ 、 ＊Ｌ２ -C(O)O- ＊＊Ｌ２ 、 ＊Ｌ２ -N(R ａ )C(O)- ＊＊Ｌ２ 、 ＊Ｌ２ -OC(O)- ＊＊Ｌ２ 、 【Chemistry 65-1】 【Chemistry 65-2】 Selected from, 【Chemistry 66-1】 【Chemistry 66-2】 Each of them can optionally choose at least one R Ｌ２ｃ Replaced by, Said R Ｌ２ｃ each independently is oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said methoxy, said ethoxy, said propoxy, said butoxy, said pentoxy, said hexoxy, said heptyloxy, said octyloxy, said -C ２ -C ８ alkenyl, said -C ２ -C ８ alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said 3- to 8-membered heterocyclyl, said phenyl, and said 5- to 12-membered heteroaryl is each optionally substituted with at least one R Ｌｃａ and R Ｌｃａ However, independently, oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, or Two R's Ｌ２ｃ However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. R ａ However, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, and -C ２ -C ８ Alkenyl, the above-C ２ -C ８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, and -C ２ -C ８ Alkenyl, -C ２ -C ８ The compound according to any one of the prior claims, substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

12. L ２ が、-O-、-N(CH ３ )-、-C(O))-、-NHH-、 ＊Ｌ２ -C(O)N(CH) ３ )- ＊＊Ｌ２ 、 ＊Ｌ２ -C(O)NH- ＊＊Ｌ２ 、 ＊Ｌ２ -C(O)O- ＊＊Ｌ２ 、 ＊Ｌ２ -C(O)N(C) ２ H ５ )- ＊＊Ｌ２ 、 ＊Ｌ２ -C(O)N(C) ３ H ７ )- ＊＊Ｌ２ 、 ＊Ｌ２ -N(CH) ３ )C(O)- ＊＊Ｌ２ 、 ＊Ｌ２ -NHC(O)- ＊＊Ｌ２ 、 ＊Ｌ２ -OC(O)- ＊＊Ｌ２ 、 ＊Ｌ２ -N(C) ２ H ５ )C(O)- ＊＊Ｌ２ 、 ＊Ｌ２ -N(C) ３ H ７ )C(O)- ＊＊Ｌ２ 、 【Chemistry 67-1】 【Chemistry 67-2】 【Chemistry 67-3】 【Chemistry 67-4】 【Chemistry 67-5】 【Transformation 67-6】 【Transformation 67-7】 A compound selected from any one of the prior claims.

13. L ３ が、-O-、-N(R ａ )-、-C(O)-、 ＊Ｌ３ -C(O)N(R ａ )- ＊＊Ｌ３ 、 ＊Ｌ３ -C(O)O- ＊＊Ｌ３ 、 ＊Ｌ３ -N(R ａ )C(O)- ＊＊Ｌ３ 、 ＊Ｌ３ -OC(O)- ＊＊Ｌ３ 、 【Chemistry 68-1】 【Chemistry 68-2】 Selected from, 【Chemistry 69-1】 【Chemistry 69-2】 Each of them can optionally choose at least one R Ｌ３ｃ Replaced by, The aforementioned R Ｌ３ｃ Each of these independently represents oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, the above-C ２ -C ８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl may optionally contain at least one R Ｌｃａ Replaced by, R Ｌｃａ However, independently, oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, or Two R's Ｌ３ｃ However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the ring is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl. R ａ However, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, and -C ２ -C ８ Alkenyl, the above-C ２ -C ８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, and -C ２ -C ８ Alkenyl, -C ２ -C ８ The compound according to any one of the prior claims, substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

14. L ３ が、-O-、-N(CH ３ )-、-C(O))-、-NHH-、 ＊Ｌ３ -C(O)N(CH) ３ )- ＊＊Ｌ３ 、 ＊Ｌ３ -C(O)NH- ＊＊Ｌ３ 、 ＊Ｌ３ -C(O)O- ＊＊Ｌ３ 、 ＊Ｌ３ -C(O)N(C) ２ H ５ )- ＊＊Ｌ３ 、 ＊Ｌ３ -C(O)N(C) ３ H ７ )- ＊＊Ｌ３ 、 ＊Ｌ３ -N(CH) ３ )C(O)- ＊＊Ｌ３ 、 ＊Ｌ３ -NHC(O)- ＊＊Ｌ３ 、 ＊Ｌ３ -OC(O)- ＊＊Ｌ３ 、 ＊Ｌ３ -N(C) ２ H ５ )C(O)- ＊＊Ｌ３ 、 ＊Ｌ３ -N(C) ３ H ７ )C(O)- ＊＊Ｌ３ 、 【Chemistry 70-1】 【Chemistry 70-2】 【Chemistry 70-3】 【Chemistry 70-4】 【Transformation 70-5】 【Transformation 70-6】 【Transformation 70-7】 A compound selected from any one of the prior claims.

15. The aforementioned 【Chemistry 71】 The part, 【Chemistry 72】 A compound selected from any one of the prior claims.

16. L ４ However, independently, single bond, -O-, -NR ａ -, - (CR ａ R ｂ ) ｎ８ -, -O(CR ａ R ｂ ) ｎ８ -, -NR ａ (CR ａ R ｂ ) ｎ８ - or -C(O)- is selected, In each occurrence, R ａ and R ｂ However, each independently, hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, the above-C ２ -C ８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, or -C ２ -C ８ Alkenyl, -C ２ -C ８ Substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, Preferably, L ４ However, the compound according to any one of the prior claims, independently selected from single bonds.

17. X ７ However, independently, -CR ａ Or selected from N, R ａ However, independently, hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, the above-C ２ -C ８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, or -C ２ -C ８ Alkenyl, -C ２ -C ８ Substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, Preferably, X ７ However, independently, -CH, -C(CH) ３ ), or selected from N, preferably X ７ However, independently selected from -CH, the compound according to any one of the prior claims.

18. X ８ However, independently, -NR ａ -, -O-, -S-, and -CR ａ R ｂ - Selected from, In each occurrence, R ａ and R ｂ However, each independently, hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, the above-C ２ -C ８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, or -C ２ -C ８ Alkenyl, -C ２ -C ８ Substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, Preferably, X ８ However, independently, -NH- and -CH ２ - Selected from, preferably X ８ However, independently, -CH ２ A compound selected from any one of the prior claims. 【Request Item 19】 【Chemistry 73】 but, 【Chemistry 74】 Selected from, preferably, 【Chemistry 75】 but, 【Transformation 76】 A compound selected from any one of the prior claims.

20. Z １ Z ２ , and Z ３ At most one of them is N, Preferably, Z １ Z ２ and Z ３ However, each operates independently, CR ｚ The compound according to any one of the prior claims.

21. R Ｚ However, in each appearance, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR Ｚａ R Ｚｂ , -OR Ｚａ ,-SR Ｚａ Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, or CN, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3-8 membered heterocyclyl, optionally contains at least one R Ｚｃ Replaced by, R Ｚａ and R Ｚｂ Each of these is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and each of the hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally coupled with at least one substituent R Ｚｄ Replaced by, R Ｚｃ and R Ｚｄ However, each is independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl. Preferably, R ｚ However, H, -CH ３ , -C ２ H ５ , F, -CH ２ F, -CHF ２ , -CF ３ , -OCH ３ , -OC ２ H ５ , -C ３ H ７ , -OCH ２ F, -OCHF ２ , -OCH ２ CF ３ , -OCF ３ , -SCF ３ , -CF ３ , or -CH(OH)CH ３ A compound selected from any one of the prior claims.

22. R １３ and R １４ However, each independently, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, 3-8 membered heterocyclyl, -C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, -CN, -SO ２ R １３ａ , -SO ２ NR １３ａ R １３ｂ , -COR １３ａ , -CO ２ R １３ａ , -CONR １３ａ R １３ｂ , -NR １３ａ R １３ｂ , -NR １３ａ COR １３ｂ , -NR １３ａ CO ２ R １３ｂ , or -NR １３ａ SO ２ R １３ｂ Selected from, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, the above-C ２－８ Alkinyl, the 3-8 membered heterocyclyl, the -C ６ -C １２ Each of the aryl and the 5-12 membered heteroaryls can be optionally replaced with F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, 3-8 membered heterocyclyl, -C ６ -C １２ Aryl, 5-12 member heteroaryl, oxo, -CN, -OR １３ｃ , -SO ２ R １３ｃ , -SO ２ NR １３ｃ R １３ｄ , -COR １３ｃ , -CO ２ R １３ｃ , -CONR １３ｃ R １３ｄ , -NR １３ｃ R １３ｄ , -NR １３ｃ COR １３ｄ , -NR １３ｃ CO ２ R １３ｄ , or -NR １３ｃ SO ２ R １３ｄ Replaced by, R １３ａ , R １３ｂ , R １３ｃ , and R １３ｄ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, 3-8 membered heterocyclyl, -C ６ -C １２ It is an aryl or a 5- to 12-membered heteroaryl. Preferably, R １３ and R １４ However, each independently, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -CH ２ F, -CHF ２ , -CF ３ , -OCH ２ F, -OCHF ２ , -OCH ２ CF ３ , -OCF ３ , -SCF ３ A compound according to any one of the prior claims, selected from , or phenyl. 【Request Item 23】 【Chemistry 77】 but, 【Transformation 78】 The compound according to any one of the prior claims.

24. L ５ and L ６ However, each is independent of a single bond, -O-, and -NR ａ -, - (CR ａ R ｂ ) ｎ８ -, -O(CR ａ R ｂ ) ｎ８ -, -NR ａ (CR ａ R ｂ ) ｎ８ - or -C(O)- is selected, X ８ However, -CR ａ R ｂ - and In each occurrence, R ａ and R ｂ However, each independently, hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, the above-C ２ -C ８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl is optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, or -C ２ -C ８ Alkenyl, -C ２ -C ８ Substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, Preferably, L ５ and L ６ However, each is independent, single bond, 【Transformation 79】 -O-、-NH-、-NMe-、-N(CH ２ CH ３ ) -, -CH ２ -、-CHF-、-CF ２ -, -C(CH ３ ) ２ -, or -CO-, X ８ However, CH ２ And, The compound according to any one of the prior claims, wherein n6 is 0 or 1.

25. R １３ However, independently, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, 3-8 membered heterocyclyl, -C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, -CN, -SO ２ R １３ａ , -SO ２ NR １３ａ R １３ｂ , -COR １３ａ , -CO ２ R １３ａ , -CONR １３ａ R １３ｂ , -NR １３ａ R １３ｂ , -NR １３ａ COR １３ｂ , -NR １３ａ CO ２ R １３ｂ , or -NR １３ａ SO ２ R １３ｂ Selected from, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, the above-C ２－８ Alkinyl, the 3-8 membered heterocyclyl, the -C ６ -C １２ Each of the aryl and the 5-12 membered heteroaryls can be optionally replaced with F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, 3-8 membered heterocyclyl, -C ６ -C １２ Aryl, 5-12 member heteroaryl, oxo, -CN, -OR １３ｃ , -SO ２ R １３ｃ , -SO ２ NR １３ｃ R １３ｄ , -COR １３ｃ , -CO ２ R １３ｃ , -CONR １３ｃ R １３ｄ , -NR １３ｃ R １３ｄ , -NR １３ｃ COR １３ｄ , -NR １３ｃ CO ２ R １３ｄ , or -NR １３ｃ SO ２ R １３ｄ Replaced by, In each occurrence, R １３ａ , R １３ｂ , R １３ｃ , and R １３ｄ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, 3-8 membered heterocyclyl, -C ６ -C １２ It is an aryl or a 5- to 12-membered heteroaryl. Preferably, R １３ However, independently, hydrogen, F, Cl, Br, I, CN, -C １ -C ８ Alkyl, or -C １ -C ８ Selected from alkoxys, preferably R １３ However, independently, hydrogen, F, Cl, Br, I, CN, -Me, -Et, -C ３ H ７ , -C ４ H ９ 、-OMe、-OEt、-OC ３ H ７ , or -OC ４ H ９ Selected from, n ７ The compound according to any one of the prior claims, wherein the coefficient is 0, 1, or 2. 【Request Item 26】 【Chemistry 80】 but, 【Chemistry 81】 The compound according to any one of the prior claims.

27. The compound is selected from the following, according to any one of the prior claims. Table 1-1 Table 1-2 Table 1-3 Table 1-4

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, together with a pharmaceutically acceptable excipient.

29. A method for treating a disease that may be affected by EGFR modulation, comprising administering an effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, to a subject in need thereof.

30. The method according to claim 29, wherein the disease is selected from cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

31. Use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, in the preparation of a medicament for the treatment of a disease that may be affected by EGFR modulation.

32. The use according to claim 31, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

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