Compounds for the degradation of EGFR kinase

Abstract

Disclosed herein are novel bifunctional compounds formed by conjugating an EGFR inhibitor moiety with an E3 ligase ligand moiety, methods for preparing the same, and uses thereof.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to International Application PCT / CN2023 / 097387 filed on 31 May 2023, International Application PCT / CN2023 / 125498 filed on 19 October 2023, and International Application PCT / CN2024 / 090756 filed on 30 April 2024, the disclosures of which are incorporated herein by reference in their entirety.

[0002] Disclosed herein are 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. [Background technology]

[0003] A target protein degradation-inducing chimeric molecule (PROTAC) consists of two covalently bonded protein-binding molecules: one capable of engaging with an E3 ubiquitin ligase, and the other binding to the 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, which are then subsequently degraded via the proteasome. (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 the neosubstrate protein (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.) PROTAC as a useful modulator that promotes the selective degradation of a wide range of target proteins is being studied in antitumor research (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., US2016 / 0045607, US2017 / 0008904, US2018 / 0050021, US2018 / 0072711, WO2002 / 020740, WO2014 / 108452, WO2016 / 146985, WO2016 / 149668, WO2016 / 197032, WO2016 / 197114, WO2017 / 011590, WO2017 / 03 This is disclosed or discussed in 0814, WO2017 / 079267, WO2017 / 182418, WO2017 / 197036, WO2017 / 197046, WO2017 / 197051, WO2017 / 197056, WO2017 / 201449, WO2018 / 071606, WO2021 / 178920, WO2021 / 127283, WO2021 / 127190, WO2021 / 11871, and WO2021 / 11913.

[0004] 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 have been 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 point mutations from tertiary Cys797 to Ser797 (C797S) in osimertinib clinical therapy (Thress KS, et al. Nat. Med. 2015, 21(6):560-562). Therefore, there is a need for a drug 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., WO2018 / 119441, WO2019 / 149922, WO2019 / 183523, WO2019 / 121562, US2019 / 0106417, WO2021 / 57882, WO2021 / 123087, WO2021 / 133809, WO2021 / 168074, WO2021 / 208918, and WO2021 / 216440.

[0005] 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 these publicly available molecules are based on first-generation, second-generation, and third-generation EGFR inhibitors (WO2021 / 023233, WO2019 / 121562, and WO2018 / 119441) or allosteric EGFR inhibitors (WO2021 / 127561). 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.

[0006] This application provides novel bifunctional compounds and compositions for the treatment of severe diseases affected by EGFR regulation, particularly for the treatment of cancers selected preferably from pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, and non-small cell lung cancer.

Summary of the Invention

[0007] One object of the present disclosure is to provide compounds and derivatives formed by conjugating an EGFR inhibitor moiety with an E3 ligase ligand moiety, which function to mobilize a target protein to an E3 ubiquitin ligase for degradation, as well as methods for their preparation and use.

[0008] The compounds or salts thereof described herein are useful for the treatment of diseases that can be affected by EGFR regulation. The present disclosure provides the use of the compounds or pharmaceutically acceptable salts thereof described herein in the manufacture of medicaments for the treatment of diseases that can be affected by EGFR regulation. The present disclosure further provides the compounds or pharmaceutically acceptable salts thereof described herein for use in the treatment of diseases that can be affected by EGFR regulation. This application further provides a method for treating a proliferative disorder, which comprises administering to a subject in need thereof a therapeutically effective amount of the compounds or pharmaceutically acceptable salts thereof described herein.

[0009] Aspect 1. A compound of formula (I):

Chemical formula

[0010] Embodiment 2. The compound is of formula (IIa) [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 The compound according to Embodiment 1, wherein s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0011] In one embodiment, the compound is of formula (IIb): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0012] In one embodiment, the compound is of formula (IIc): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0013] In one embodiment, the compound is of formula (IId): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0014] In one embodiment, the compound is given by formula (IIe): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0015] In one embodiment, the compound is given by formula (IIf): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0016] In one embodiment, the compound is of formula (IIg): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0017] In one embodiment, the compound is of formula (IIh): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0018] In one embodiment, the compound is given by formula (IIi): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0019] In one embodiment, the compound is given by formula (IIj): [ka] A compound selected from the following, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug, In the formula, R 1a , R 1b , R 2a , R 2b , R3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0020] Embodiment 3. The compound is of formula (IIIa): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 The compound according to Embodiment 1, wherein s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0021] In one embodiment, the compound is given by formula (IIIb): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0022] In one embodiment, the compound is given by formula (IIIc): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0023] In one embodiment, the compound is given by formula (IIId): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0024] In one embodiment, the compound is given by formula (IIIe): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0025] In one embodiment, the compound is given by formula (IIIf): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0026] In one embodiment, the compound is of formula (IIIg): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0027] In one embodiment, the compound is of formula (IIIh): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a, R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0028] In one embodiment, the compound is given by formula (IIIi): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0029] In one embodiment, the compound is of formula (IIIj): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0030] In one embodiment, the compound is given by formula (IIIk): [ka] A compound selected from or thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug thereof, where R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L2 , L 3 s1, s2, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, and degron are as defined in Embodiment 1.

[0031] In one embodiment, the compound is of formula (IIIm): [ka] Selected from the compounds, in the formula, R 7 However, each is independent of non-existence, hydrogen, halogen, or -C. 1-3 It is alkyl, R 8 and R 9 However, each is independently selected from hydrogen, halogen, and -C1-C3 alkyl, R 10 However, each is independently selected from hydrogen, halogen, or -C1-C3 alkyl, L 1 but, [ka] Selected from, the [ka] Each of them has at least one R L1c It is arbitrarily replaced with, *L1 but, [ka] It refers to the position where a part is joined. **L1 but, [ka] It refers to the position where a part is joined. L 2 but, [ka] Selected from, the [ka] Each of them has at least one R L2c It is arbitrarily replaced with, *L2 but, [ka] It refers to the position where a part is joined. **L2 but, [ka] It refers to the position where a part is joined. The R L1c and R L2c Each of these is independently non-existent, oxo (=O), halogen, hydroxy, -C1-C3 alkyl, or -C1-C3 alkoxy, and each of the -C1-C3 alkyl and -C1-C3 alkoxy is at least one R Lca It is arbitrarily replaced with, R Lca However, each is independently either absent, halogenated, hydroxylated, or C1-C3 alkoxy, or 2 R L1c However, together with the atoms to which they bond, they form a 3-5 membered ring, and this ring independently contains 0-1 heteroatoms selected from nitrogen and oxygen. 2 R L2c However, together with the atoms to which they bond, they form a 3-5 membered ring, and this ring independently contains 0-1 heteroatoms selected from nitrogen and oxygen. R z However, in each appearance, independently, non-existence, hydrogen, halogen, -C 1-3 Alkyl or C1-C3 alkoxy, R 14 However, in each appearance, independently, non-existence, hydrogen, halogen, -C 1-3 Alkyl or C1-C3 alkoxy, In each occurrence, X 1 and X 2 However, each is independently -CH or N, In each occurrence, X 3 and X4 However, each is independently -NH- and -CH2-, In each occurrence, X 5 and X 6 However, each is independent of the others: non-existent, single bond, -C(O)-, or -NR. a -and, In each occurrence, R a However, independently, hydrogen and -C1-C3 alkyl are selected, n1, n2, n3, and n4 are each independently 0, 1, or 2. s5, s6, and s7 are each independently 0, 1, or 2.

[0032] Embodiment 4. A compound according to any one of the above embodiments, wherein m1 + m2 + m3 + m4 ≤ 3.

[0033] Embodiment 5. The compound according to any one of the embodiments described above, wherein m1+m2+m3+m4=0, 1, 2, or 3. In one embodiment, m1+m2+m3+m4=0, 1, or 2. In one embodiment, m1+m2+m3+m4=0. In one embodiment, m1+m2+m3+m4=1. In one embodiment, m1+m2+m3+m4=2.

[0034] Appearance 6. [ka] The compound according to any one of the above embodiments, wherein the total number of -CH2- groups in the portion is 4 or less.

[0035] In one embodiment, [ka] The total number of -CH2- groups in the part is 3 or less.

[0036] In one embodiment, [ka] The total number of -CH2- groups in the portion is 2 or less.

[0037] Appearance 7.R 3 and R 4 The compound according to any one of the above embodiments, wherein each is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, hydroxyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy.

[0038] In one embodiment, R 3 is -C 1-3 It is alkyl, and the -C 1-3 Alkyl or -C 3-8 Cycloalkyls are composed of hydrogen, hydroxyl, halogen, and -C 1-6 It is optionally substituted with at least one substituent selected from alkoxys. In one embodiment, R 3 is -C 1-3 It is alkyl. In one embodiment, R 4 is hydrogen, and in one embodiment, R 3 and R 4 These are, independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, and hexyl. In one embodiment, R 3 and R 4 Each of these is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. In one embodiment, R 3 R is independently methyl and 4 It is hydrogen.

[0039] Appearance 8.R 1a , R 1b , R 2a , and R 2bis, independently of each other, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN, and each said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl are optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN, a compound according to any one of the前述の態様のいずれか1つに記載の化合物.

[0040] In one embodiment, R 1a , R 1b , R 2a , and R 2b are, independently of each other, absent, hydrogen, halogen, or -C 1-6 alkyl. In one embodiment, R 1a , R 1b , R 2a , and R 2b are, independently of each other, hydrogen, halogen, or -C 1-3 alkyl. In one embodiment, R 1a , R 1b , R 2a , and R 2b are, independently of each other, hydrogen, or -C 1-3 alkyl.

[0041] In one embodiment, R1a , R 1b , R 2a , and R 2b is, independently of each other, 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, -CF3, -CHF2, -CN, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3.

[0042] In one embodiment, R 1a , R 1b , R 2a , and R 2b is, independently of each other, hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3, or -CHF2, or -CH2OCH3.

[0043] In one embodiment, R 1a , R 1b , R 2a , and R 2b is, independently of each other, hydrogen.

[0044] Embodiment 9. R 5 and R 6 are, independently of each other, 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, -CF3, -CHF2, -CN, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3, a compound according to any one of the foregoing embodiments.

[0045] In one embodiment, R 5 and R 6 are, independently of each other, hydrogen, halogen, -C 1-6Alkyl, -C 1-6 Alkoxy, -C 3-6 It is a cycloalkyl or -CN, and each of the -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C 3-6 Cycloalkyls are composed of hydrogen, halogen, and -C 1-8 Alkoxy, -C 3-8 It is optionally substituted with at least one substituent selected from cycloalkyl or -CN.

[0046] In one embodiment, R 5 and R 6 These are, independently, hydrogen, halogen, and -C. 1-3 Alkyl, -C 1-3 Alkoxy, or -C 3-6 It is a cycloalkyl group.

[0047] In one embodiment, R 5 and R 6 Each of these is independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3-CHF2, or -CH2OCH3.

[0048] Appearance 10.R 5 and R 6 The compound according to any one of the above embodiments, wherein, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently comprises 0 to 3 heteroatoms selected from nitrogen, oxygen, and 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.

[0049] In one embodiment, R 5 and R 6 Together with the carbon atoms to which they are bonded, they form a 3, 4, 5, or 6-membered ring, which is optionally substituted with at least one substituent selected from F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0050] Appearance 11.R 7 The compound according to any one of the above embodiments, wherein each is 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, -CF3, -CHF2, -CN, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3. In one embodiment, R 7 These are, independently, non-existent, hydrogen, halogen, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-6 It is a cycloalkyl or -CN, and each of the -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C 3-6 Cycloalkyls are composed of hydrogen, halogen, and -C 1-6 Alkoxy, -C 3-6 It is optionally substituted with at least one substituent selected from cycloalkyl and -CN.

[0051] In one embodiment, R 7 These are, independently, non-existent, hydrogen, halogen, and -C. 1-3 Alkyl, or -C 1-3 It is an alkoxy.

[0052] In one embodiment, R 7 These are, independently, hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3, or -CHF2, -CH2OCH3.

[0053] In one embodiment, R 7 Each of them is independently hydrogen.

[0054] Apparatus 12.2 R 7The compound according to any one of the above embodiments, wherein, together with the carbon atoms (or more) to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently comprises 0 to 3 heteroatoms selected from nitrogen, oxygen, and 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.

[0055] In one embodiment, two R 7 These, together with the carbon atoms to which they are bonded, form a 3, 4, 5, or 6-membered ring, which is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl.

[0056] Appearance 13.R 8 and R 9 The compound according to any one of the above embodiments, wherein each is independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, hydroxy, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy.

[0057] In one embodiment, R 8 and R 9 Each is independently selected from hydrogen, halogen, and -C1-C6 alkyl, and the -C1-C6 alkyl is hydrogen, halogen, hydroxyl, and -C 1-6 It is optionally substituted with at least one substituent selected from alkoxys.

[0058] In one embodiment, R 8 and R 9is independently selected from hydrogen, halogen, and -C1-C3 alkyl, and the -C1-C3 alkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, and hydroxy.

[0059] In one embodiment, R 8 and R 9 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CF3, -CHF2, -CH2OH, or -CH2CH2OH.

[0060] In one embodiment, R 8 is independently hydrogen, methyl, -CF3, -CHF2, or -CH2OH, and R 9 is F, methyl, or -CH2OH.

[0061] Aspect 14. R 10 is each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -NR 10a R 10b 、-OR 10a 、-SR 10a 、-C(O)R 10a 、-CO2R 10a 、-C(O)NR 10a R 10b 、-NR 10a COR 10b 、-NR 10a CO2R 10b -NR 10a SO2R 10b 、and -CN, and methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, and phenyl each have at least one R 10c It is arbitrarily replaced with, R 10a and R 10b However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, and phenyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the following molecules may have at least one substituent R: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, or phenyl 10d It is arbitrarily replaced with, R 10c and R 10d However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo(=O), -NR 10e R 10f , -OR 10e , -SR 10e , -SO2R 10e -SO2NR 10e R 10f , -C(O)R 10e , -CO2R 10e -C(O)NR 10e R 10f , -NR 10e COR10f , -NR 10e CO2R 10f , -NR 10e SO2R 10f Selected from , and -CN, R 10e and R 10f However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 A compound according to any one of the above embodiments, selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl.

[0062] In one embodiment, R 10 These are, independently, hydrogen, halogen, -C1-C6 alkyl, -C3-C6 cycloalkyl, and -NR. 10a R 10b , -OR 10a , -C(O)R 10a , -CO2R 10a -C(O)NR 10a R 10b Selected from -CN, and each of the -C1-C6 alkyl or -C3-C6 cycloalkyl groups, has at least one R 10c It is arbitrarily replaced with, R 10a and R 10b These are, independently, hydrogen, -C1-C6 alkyl, -C3-C6 cycloalkyl, 3-8 member heterocycline, and C6-C 12 Selected from aryls and 5-12 membered heteroaryls, the C1-C6 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, and C6-C 12 Each aryl or 5- to 12-membered heteroaryl has at least one substituent R 10d It is arbitrarily replaced with, R 10c and R 10d These are, independently, halogen, hydrogen, -C1-C6 alkyl, -C1-C6 alkoxy, -C3-C6 cycloalkyl, oxo (=O), and -NR. 10eR 10f , -OR 10e , -CO2R 10e -C(O)NR 10e R 10f , -NR 10e COR 10f Selected from , and -CN, R 10e and R 10f These are, independently, hydrogen, -C1-C3 alkyl, -C3-C6 cycloalkyl, 3-8 member heterocycline, and C6-C 12 Selected from aryls and 5- to 12-membered heteroaryls.

[0063] In one embodiment, R 10 These are, independently, hydrogen, halogen, -C1-C3 alkyl, -C3-C6 cycloalkyl, and -NR. 10a R 10b , -OR 10a , -C(O)R 10a , -CO2R 10a -C(O)NR 10a R 10b Selected from -CN, and -C1-C6 alkyl or -C3-C6 cycloalkyl, each of which contains at least one halogen, hydrogen, oxo (=O), -NR 10e R 10f , or -OR 10e It is arbitrarily replaced with, R 10a and R 10b Each is independently selected from hydrogen, -C1-C3 alkyl, and -C3-C6 cycloalkyl, and each of the -C1-C3 alkyl or -C3-C6 cycloalkyl has at least one substituent halogen, hydrogen, oxo (=O), -NR 10e R 10f , or -OR 10e It is arbitrarily replaced with, R 10e and R 10f Each of these is independently selected from hydrogen or a -C1-C3 alkyl group.

[0064] In one embodiment, R 10These are, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, and -NR. 10a R 10b , -OR 10a , -SR 10a , -C(O)R 10a , -CO2R 10a -C(O)NR 10a R 10b , -NR 10a COR 10b , -NR 10a CO2R 10b , -NR 10a SO2R 10b Selected from -CN, and -Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the following compounds contains at least one R 10c It is arbitrarily replaced with, R 10a and R 10b These are, independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. 2-8 Alkenyl, -C 2-8 Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, and phenyl, R 10c These are, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. 2-8 Alkenyl, -C 2-8 Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo(=O), -NR 10e R10f , -OR 10e Selected from , and -CN, R 10e and R 10f 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, and 5-12 membered heteroaryl.

[0065] In one embodiment, R 10 These are, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-8 membered heterocyclyl, and -NR. 10a R 10b , -OR 10a , -CO2R 10a , and -C(O)NR 10a R 10b Selected from, each of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 3- to 8-membered heterocyclyl, has at least one R 10c It is arbitrarily replaced with, R 10a and R 10b Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, and 6-membered heterocyclyl. R 10c These are, independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxo(=O), and -NR. 10e R 10f , -OR 10e Selected from , and -CN, R 10e and R 10fEach of these is independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and cyclopentyl.

[0066] In one embodiment, R 10 These are, independently, H, F, Cl, Br, methyl, ethyl, propyl (n-propyl or iso-propyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, [ka] Selected from -COOH, -CONH2, -CH2OCH3, and -CH2OH.

[0067] Appearance 15. [ka] The part, [ka] [ka] A compound according to any one of the above embodiments, selected from the above.

[0068] In one embodiment, [ka] The part is, [ka] That is the case.

[0069] In one embodiment, [ka] The part is, [ka] That is the case.

[0070] In one embodiment, [ka] The part is, [ka] That is the case.

[0071] In one embodiment, [ka] The part is, [ka] That is the case.

[0072] In another embodiment, [ka] The part is, [ka] That is the case.

[0073] In another embodiment, [ka] The part is, [ka] That is the case.

[0074] In another embodiment, [ka] The part is, [ka] That is the case.

[0075] In another embodiment, [ka] The part is, [ka] That is the case.

[0076] In another embodiment, [ka] The part is, [ka] That is the case.

[0077] Appearance 16.R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d However, each is independent of oxo, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkinyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8The compound according to any one of the above embodiments, optionally substituted with at least one substituent selected from alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, or -CN.

[0078] In one embodiment, R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d These are, independently, non-existent, oxo, hydrogen, halogen, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, or -C 3-6 It is a cycloalkyl, and the -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C 3-6 Each of the cycloalkyl groups consists of hydrogen, halogen, and -C. 1-6 It is optionally substituted with at least one substituent selected from alkoxy and -CN.

[0079] In one embodiment, R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d These are, independently, non-existent, oxo, hydrogen, halogen, and -C. 1-3 Alkyl, or -C 1-3 It is an alkoxy.

[0080] In one embodiment, R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12dEach is independently oxo, 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, or cyclooctyl, preferably R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d Each of these is independently oxo, hydrogen, F, Cl, Br, I, methyl, ethyl, or propyl.

[0081] In one embodiment, R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d Each of these is independently either hydrogen or methyl.

[0082] Appearance 17.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, The [ka] [ka] Each of them has at least one R L1c It is arbitrarily replaced with, The R L1c Each of these can independently be 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 Each of the following is a heteroaryl compound: 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, and 5-12 member heteroaryl compounds, each containing at least one R Lca It is arbitrarily replaced with, R Lca However, 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 2 R L1cHowever, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently contains 0, 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and 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 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 each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is a hydrogen atom. The compound according to any one of the above embodiments, optionally substituted with at least one substituent selected from C, -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, and 5- to 12-membered heteroaryl.

[0083] In one embodiment, L 1 -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] Selected from.

[0084] Appearance 18.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] [ka] A compound according to any one of the above embodiments, selected from the above.

[0085] In one embodiment, L 1 teeth, [ka] Selected from.

[0086] Appearance 19.L 2 However, -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 , [ka] [ka] Selected from, The [ka] [ka] Each of them has at least one R L2c It is arbitrarily replaced with, The R L2cEach of these can independently be 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 Each of the following is a heteroaryl compound: 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, and 5-12 member heteroaryl compounds, each containing at least one R Lca It is arbitrarily replaced with, R Lca However, 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 2 R L2c However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently contains 0, 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and 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 aHowever, 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, each of which is present in small amounts. The compound according to any one of the above embodiments, which is optionally substituted with at least one substituent 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.

[0087] In one embodiment, L 2 -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 , [ka] Selected from.

[0088] Appearance 20.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] [ka] A compound according to any one of the above embodiments, selected from the above.

[0089] In one embodiment, L 2 teeth, [ka] Selected from.

[0090] Appearance 21.L 3 However, -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 , [ka] [ka] Selected from, The [ka] [ka] Each of them has at least one R L3c It is arbitrarily replaced with, The R L3c Each of these can independently be 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 Each of the following is a heteroaryl compound: 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, and 5-12 member heteroaryl compounds, each containing at least one R Lca It is arbitrarily replaced with, 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 2 R L3c However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently contains 0, 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and 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 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 each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is hydroxyl The compound according to any one of the above embodiments, optionally substituted with at least one substituent selected from -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, and 5-12 membered heteroaryl.

[0091] In one embodiment, L3 -O-, -C(O)-, -N(R a )-, *L3 -C(O)N(R a )- **L3 , *L3 -C(O)O- **L3 , *L3 -N(R a )C(O)- **L3 , *L3 -OC(O)- **L3 , [ka] Selected from.

[0092] Appearance 22.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] [ka] A compound according to any one of the above embodiments, selected from the above.

[0093] In one embodiment, L 3 teeth, [ka] Selected from.

[0094] Appearance 23. [ka] The part, [ka] [ka] [ka] [ka] A compound according to any one of the above embodiments, selected from the above.

[0095] Appearance 24.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-, and -C(O)- are selected, In each occurrence, R a and R b However, each is independently selected from 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, and 5-12 member heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl The compound according to any one of the above embodiments, wherein each of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl is optionally substituted with at least one substituent selected from 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, and 5-12 membered heteroaryl.

[0096] In one embodiment, L 4 These are independently selected from single bonds.

[0097] In one embodiment, L 4 These are selected independently from -O-.

[0098] In one embodiment, L 4 -NR is independent. a - Selected from, Ra This is independently selected from hydrogen, methyl, ethyl, or propyl.

[0099] In one embodiment, L 4 It is selected independently from -NH-.

[0100] In one embodiment, L 4 It is independently selected from -NCH3-.

[0101] In one embodiment, L 4 Independently, -(CR a R b ) n8 - Selected from, R a and R b Each of these is independently selected from hydrogen, methyl, ethyl, or propyl, and n8 is 1 or 2.

[0102] In one embodiment, L 4 It is independently selected from -CH2-.

[0103] Appearance 25.X 7 However, independently, -CR a Selected from , and N, R aHowever, independently selected from 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, and 5-12 member heteroaryl, said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl The compound according to any one of the above embodiments, wherein each of quinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent 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- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl.

[0104] In one embodiment, X 7 This is independently selected from -CH, -C(CH3), or N. In one embodiment, X 7 It is selected independently from -CH.

[0105] Appearance 26.X 8 However, independently, -NR a -, -O-, -S-, and -CR a R b - Selected from, In each occurrence, R a and R bHowever, each is independently selected from 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, and 5-12 member heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl The compound according to any one of the above embodiments, wherein each of the following is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl.

[0106] In one embodiment, X 8 These are independently selected from -NH- and -CH2-.

[0107] In one embodiment, X 8 It is independently selected from -CH2-.

[0108] Appearance 27. [ka] but, [ka] A compound according to any one of the above embodiments, selected from the above.

[0109] In one embodiment, [ka] teeth, [ka] Selected from.

[0110] In one embodiment, [ka] teeth, [ka] Selected from.

[0111] Appearance 28.Z 1 , Z 2 , and Z 3 A compound according to any one of the above embodiments, wherein at most one of the atoms is N.

[0112] In one embodiment, Z 1 , Z 2 , and Z 3 Each of them operates independently, CR z That is the case.

[0113] In one embodiment, Z 1 is N, and Z 2 and Z 3 Each of them operates independently, CR z That is the case.

[0114] Appearance 29.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 , -SRZa Selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, and CN, each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3-8 membered heterocyclyl, with at least one R Zc It is arbitrarily replaced with, 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 member heterocyclyl, phenyl, and 5-12 member heteroaryl, and each of these hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 member heterocyclyl, phenyl, or 5-12 member heteroaryl has at least one substituent R Zd It is arbitrarily replaced with, R Zc and R Zd The compound according to any one of the above embodiments, wherein 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.

[0115] In one embodiment, R z The molecule is selected from H, -CH3, -C2H5, F, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -C3H7, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, -CF3, or -CH(OH)CH3.

[0116] In one embodiment, R z is H. In one embodiment, R z is -CH3. In one embodiment, R z It is F.

[0117] Appearance 30.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 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 , and -NR 13a SO2R 13b Selected from 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 12Each of the aryl and 5-12 membered heteroaryls is 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 It is arbitrarily replaced with, 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 The compound according to any one of the above embodiments, which is an aryl or a 5-12 membered heteroaryl.

[0118] In one embodiment, R 13 and R 14These are, 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, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF 3、 - Selected from SCF3 or phenyl.

[0119] In one embodiment, R 13 and R 14 Each of these is independently selected from hydrogen, fluorine, and methyl.

[0120] In one embodiment, R 13 These are independently selected from hydrogen, fluorine, and methyl.

[0121] In one embodiment, R 14 These are independently selected from hydrogen, fluorine, and methyl.

[0122] Appearance 31. [ka] but, [ka] The compound described in any one of the above embodiments.

[0123] Appearance 32.L 5 and L 6 However, 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 -, and -C(O)- are selected, X 8 However, -CR a R b -and, In each occurrence, R a and R b However, each is independently selected from 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, and 5-12 member heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 The compound according to any one of the above embodiments, wherein each of lukinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent 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- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0124] In one embodiment, L 5 and L 6 These are, independently, single bonds, -O-, and -NR bonds. a -,-(CR a R b ) n8 -, or -C(O)-, R a and R bThese are, independently, hydrogen and -C. 1-3 Selected from alkyl groups, n8 is 1.

[0125] In one embodiment, L 5 and L 6 Each is independently, with a single bond. [ka] -O-, -NH-, -NMe-, -N(CH2CH3)-, -CH2-, -CHF-, -CF2-, -C(CH3)2-, or -CO- X 8 It is CH2, n6 is either 0 or 1.

[0126] Appearance 33.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 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 , and -NR 13a SO2R 13bSelected from 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 Each of the aryl and 5-12 membered heteroaryls is 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 It is arbitrarily replaced with, 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 2-8Alkinyl, 3-8 member heterocyclyl, -C6-C 12 The compound according to any one of the above embodiments, which is an aryl or a 5-12 membered heteroaryl.

[0127] In one embodiment, R 13 The elements are independently selected from hydrogen, F, Cl, Br, I, CN, -C1-C8 alkyl, and -C1-C8 alkoxy, preferably R 13 These are independently selected from hydrogen, F, Cl, Br, I, CN, -Me, -Et, -C3H7, -C4H9, -OMe, -OEt, -OC3H7, and -OC4H9. n7 is 0, 1, or 2.

[0128] Appearance 34. [ka] but, [ka] [ka] The compound described in any one of the above embodiments.

[0129] Appearance 35. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] A compound according to any one of the above embodiments, selected from the above.

[0130] Embodiment 36. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 35, or an N-oxide, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a deuterated analog, or a prodrug, together with a pharmaceutically acceptable excipient.

[0131] In one embodiment, a pharmaceutical composition comprising a compound described in any one of embodiments 1 to 35, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, together with a pharmaceutically acceptable excipient.

[0132] In one embodiment, a pharmaceutical composition comprising a compound described in any one of embodiments 1 to 35 together with a pharmaceutically acceptable excipient. In one embodiment, a pharmaceutical composition comprising a compound described in any one of embodiments 1 to 35, or a pharmaceutically acceptable salt, together with a pharmaceutically acceptable excipient. In one embodiment, a pharmaceutical composition comprising a compound described in any one of embodiments 1 to 35, or a pharmaceutically acceptable stereoisomer, together with a pharmaceutically acceptable excipient. In one embodiment, a pharmaceutical composition comprising a compound described in any one of embodiments 1 to 35, or a pharmaceutically acceptable tautomer, together with a pharmaceutically acceptable excipient.

[0133] Embodiment 37. A method for treating a disease that may be affected by EGFR modulation, comprising administering to a subject in need of such treatment an effective amount of a compound described in any one of Embodiments 1 to 35, or its N-oxide, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a deuterated analog, or a prodrug.

[0134] In one embodiment, a method for treating a disease that may be affected by EGFR modulation includes administering to a subject in need an effective amount of the compound described in any one of embodiments 1 to 35, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0135] In one embodiment, a method for treating a disease that may be affected by EGFR modulation includes administering an effective amount of the compound described in any one of embodiments 1 to 35 to a subject in need. In one embodiment, a method for treating a disease that may be affected by EGFR modulation includes administering an effective amount of the compound described in any one of embodiments 1 to 35, or a pharmaceutically acceptable salt thereof, to a subject in need. In one embodiment, a method for treating a disease that may be affected by EGFR modulation includes administering an effective amount of the compound described in any one of embodiments 1 to 35, or a pharmaceutically acceptable stereoisomer thereof, to a subject in need. In one embodiment, a method for treating a disease that may be affected by EGFR modulation includes administering an effective amount of the compound described in any one of embodiments 1 to 35, or a pharmaceutically acceptable tautomer thereof, to a subject in need.

[0136] Embodiment 38. The method according to Embodiment 37, wherein the disease is selected from cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0137] Applicable aspect 39. Use of a compound according to any one of Applicable aspects 1 to 35, 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.

[0138] Embodiment 40. The use according to Embodiment 39, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0139] 5-membered ring part [ka] This makes the molecule of this application have much lower toxicity than a 3- or 4-membered ring molecule. Toxicity can be tested by methods common in the art. 5-membered ring portion [ka] This allows the molecule of this application to have far superior activity against the EGFR L858R mutation and the L858R / C797S double mutation than a 3 or 4-membered ring molecule. At the same time, the 5-membered ring portion [ka] The present invention provides the molecule to have equivalent or superior activity to EGFR Del19 single mutant, Del19 / C797S double mutant, Del19 / T790M / C797S triple mutant, and L858R / T790M / C797S triple mutant than a 3 or 4-membered ring molecule. Degradation activity can be tested by the method described in this application. 5-membered ring portion [ka] This invention provides the molecule of this application with a rat PK that is superior to that of a 3- or 4-membered ring molecule. [Modes for carrying out the invention]

[0140] 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 the present invention pertains.

[0141] 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.

[0142] The term "or" means "and / or" and is used interchangeably unless the context explicitly indicates otherwise.

[0143] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms, for example, 1 to 12, even more 1 to 10, even more 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. 1-6 Examples 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.

[0144] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), and 2-propyl or isopropyl ("i-Pr").

[0145] 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").

[0146] 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.

[0147] 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.

[0148] The term "alkylene" refers to a divalent alkyl group formed by removing two hydrogen atoms from an alkane. Examples of alkylenes include methylene, ethylene, and propylene, but are not limited to these.

[0149] The term "halogen" includes fluoro(F), chloro(Cl), bromo(Br), and iodine(I).

[0150] 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, e.g., 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.

[0151] The term "alkenylene" refers to a divalent alkenyl group formed by removing two hydrogen atoms from an alkene. Examples of alkenylenes include vinylidene and butenylene, but are not limited to these.

[0152] 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. 2-6Examples of alkynyl groups include, but are not limited to, ethynnyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0153] 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.

[0154] 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.

[0155] For example, a cycloalkyl group may contain 3 to 12 carbon atoms, for example, 3 to 10, even more for example, 3 to 8, even more for example, 3 to 6, 3 to 5, or 3 to 4. Furthermore, for example, a cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms, for example, 3 to 10, even more for example, 3 to 8, or 3 to 6. 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. 3-6Bicyclic 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.

[0156] The term "spirocycloalkyl" includes cyclic structures that contain carbon atoms and are formed by at least two rings sharing one atom.

[0157] The term "condensed cycloalkyl" includes, as defined herein, bicyclic cycloalkyl groups that are saturated and formed by two or more rings sharing two adjacent atoms. 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 benzo-3 to 8-membered cycloalkyls, benzo-C 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.

[0158] The term "crosslinked cycloalkyl" includes cyclic structures formed by two rings that contain carbon atoms and share two non-adjacent atoms. The term "7-10 membered crosslinked cycloalkyl" includes cyclic structures formed by two rings that contain 7-12 carbon atoms and share two non-adjacent atoms.

[0159] The term "aryl," used alone or in combination with other terms, includes groups selected from five- and six-membered carbocyclic aromatic rings, e.g., phenyl; bicyclic ring systems, e.g., seven- to twelve-membered bicyclic ring systems, where at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and tricyclic ring systems, e.g., ten- to fifteen-membered tricyclic ring systems, where at least one ring is carbocyclic and aromatic, e.g., fluorenyl.

[0160] 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.

[0161] Specifically, the term “bicyclic fused aryl” includes bicyclic aryl rings as defined herein. A typical bicyclic fused aryl is naphthalene.

[0162] The term "heteroaryl" means 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, for example, 1-4 heteroatoms, or 1-3 heteroatoms in some embodiments, or 1 or 2 heteroatoms in other embodiments, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom present in the aromatic ring, and The group comprises a group selected from an 11-14 membered tricyclic ring, which includes at least one heteroatom selected from N, O, and S, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms are carbon, at least one ring is aromatic, and at least one heteroatom is located within the aromatic ring.

[0163] If the total number of S and O atoms in a heteroaryl group is greater than one, 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 two. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is not greater than one. 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 a heteroaryl group may be oxidized to form N-oxides.

[0164] Specifically, the term “bicyclic condensed heteroaryl” includes, as defined herein, 7- to 12-membered, preferably 7- to 10-membered, more preferably 9 or 10-membered condensed bicyclic heteroaryl rings. Typically, bicyclic condensed heteroaryls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic. The groups can be bonded to the rest of the molecule via any of the rings.

[0165] "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.

[0166] The terms "H" or "hydrogen" as disclosed herein include hydrogen and non-radioactive isotope hydrogen.

[0167] The term “at least one substituent” as disclosed herein includes 1 to 4 substituents, such as 1 to 3, and 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, and 1 or 2.

[0168] 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.

[0169] 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 classification of stereoisomers. All such possible stereoisomers are intended to be included, such as substantially pure decomposed 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.

[0170] 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.

[0171] 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 or cyclobutyl ring.

[0172] It may be advantageous to separate 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.

[0173] 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.

[0174] 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 with 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.

[0175] 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: [ka] In another example, compounds containing guanidinyl within a ring can undergo tautomerism to form different rings, such as: [ka]

[0176] 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.

[0177] "Deuterated analogues" are any 1 This refers to a derivative of the activator in which a hydrogen atom is substituted with 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.

[0178] 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.

[0179] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basicizing 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.

[0180] 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.

[0181] 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.

[0182] 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 influence such treatment for the disease, disorder, or symptom. “Therapeutic dose” can vary depending on the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity 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 customary experimentation. In some embodiments, “therapeutic dose” is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, which is effective for “treatment” of 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 agent for effective treatment of the disease, disorder, or condition.

[0183] The term “disease” refers to any illness, discomfort, disease, symptom, or indication, and may be interchangeable with the terms “disorder” or “condition.”

[0184] Throughout this specification and the following claims, unless contextually required, the term “comprise,” and variations such as “comprises” and “comprising,” are intended to identify the presence of the following features, but not to exclude the presence or addition of one or more other features. As used herein, the term “comprising” may be replaced by the terms “containing,” “including,” or sometimes “having.”

[0185] Throughout this specification and the following claims, "C n-m " or "C n -C mThe term "C" indicates a range including the endpoints, where n and m are integers representing the number of carbon atoms. For example, C 1-8 , C 1-6 Examples include C1-C8 and C1-C6.

[0186] Unless otherwise specified, percentages, proportions, ratios, or parts used in this application refer to weight or volume. Those skilled in the art can easily determine this.

[0187] 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.

[0188] 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 the present invention pertains. [Examples]

[0189] The following examples are intended to be illustrative only and should not be considered limiting. While efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantities, 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 anhydrous solvents under positive pressure of nitrogen or argon, or using a drying tube, with rubber diaphragms fitted to the reaction flasks for introducing substrates and reagents by syringe, and the glassware was dried in an oven and / or heated.

[0190] The 1H NMR spectrum was recorded using an Agilent instrument operating at 400 MHz. 1 1H NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, with 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. When peak multiplicity is reported, the following abbreviations are used: s (singular), d (double), t (tripular), q (quadular), qn (quintular), sx (hexatular), m (multiple), br (spread), dd (double double), dt (double triple). Given coupling constants are reported in Hertz (Hz).

[0191] 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: 1.8mL / min Time (min) A(%) B(%) [Table 2]

[0192] LCMS-2: 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: 1.8mL / min Time (min) A(%) B(%) [Table 3]

[0193] LCMS-3: 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: 1.2mL / min Time (min) A(%) B(%) [Table 4]

[0194] 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.

[0195] In the following embodiments, the following abbreviations may be useful: [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0196] General synthesis for intermediates The compounds and salts disclosed herein can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0197] The reactions for preparing the compounds disclosed herein may be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially inactive with the starting materials, intermediates, or products at the temperature in which the reaction is carried out, for example, at temperatures varying from the boiling point of the solvent. A given reaction may be carried out in one solvent or a mixture of solvents.

[0198] The selection of an appropriate protecting group can be easily determined by those skilled in the art. Some protection / deprotection steps are not shown in the synthetic scheme and may be incorporated before, after, or between any of the steps. The protecting groups shown in the synthetic scheme may or may not be used depending on the reaction conditions. The order of the reactions may vary, but similar results will be obtained.

[0199] The reaction can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. The compound can be purified by various methods, including preparative HPLC and silica gel chromatography. Unless otherwise specified, preparative HPLC uses a buffered acetonitrile / water system, and silica gel chromatography (including column chromatography and preparative TLC) uses a PE / Ã, Ã / MeOH, or DCM / MeOH system as the mobile phase. The NMR spectrum is recorded using a Bruker or Varian instrument with a preset pulse sequence. Scheme I: General Route 1 [ka]

[0200] The intermediates can be synthesized via general route 1, such as intermediates 1, 57, or 75. Scheme II: General Route 2 [ka]

[0201] The intermediate can be synthesized via general route 2, such as intermediate 135. Scheme III: General Route 3 [ka]

[0202] The intermediate can be synthesized via general pathway 3, such as intermediate 134. Scheme IV: General Route 4 [ka]

[0203] The intermediates can be synthesized via general pathway IV, such as intermediate 137.

[0204] Synthesis of intermediates Intermediate 1: (7 1 R,7 3 S,E)-5 6 -Brom-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)--benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one

[0205] Step 1: 3-Oxabicyclo[3.2.1]Octane-2,4-dione [ka] A 2 L round-bottom flask equipped with a magnetic stirring bar was packed with cis-cyclopentane-1,3-dicarboxylic acid (100 g, 633 mmol) and Ac2O (600 ml). The mixture was stirred at 140°C for 12 hours. The mixture was concentrated under reduced pressure. The residue was ground with PE to obtain the crude product (70 g, 496.4 mmol, 78.5%). 1H NMR(400 MHz,DMSO)δ 3.18(q,J=3.9 Hz,2H),2.35(d,J=12.4 Hz,1H),2.17-2.01(m,2H),1.90(t,J=7.5 Hz,2H),1.69(dt,J=12.4,4.2 Hz,1H).

[0206] Step 2: cis-3-carbamoylcyclopentane-1-carboxylic acid [ka] A 2 L round-bottom flask equipped with a magnetic stirring bar was packed at 0°C with (1R,5S)-3-oxabicyclo[3.2.1]octane-2,4-dione (70 g, 496.4 mmol), THF (700 ml), and NH3-MeOH 7M (4 equivalents). The mixture was stirred at room temperature for 12 hours. The residue was quenched at 0°C with MeOH (500 ml). The mixture was concentrated under reduced pressure to obtain the crude product (56 g, 354.4 mmol, 74.4%). [M+H] + = 158.

[0207] Step 3: Methylcis-3-carbamoylcyclopentane-1-carboxylate [ka] A 1 L round-bottom flask equipped with a magnetic stirring bar was packed with cis-3-carbamoylcyclopentane-1-carboxylic acid (56 g, 354.4 mmol) and MeOH (600 mL). The temperature was lowered to 0°C, and H2SO4 (34.7 g, 354 mmol) was added dropwise to the mixture while maintaining the temperature at 0°C. The resulting mixture was stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure to obtain the crude product (49 g, 284.8 mmol, 80.3%). [M+H] + = 172.

[0208] Step 4: ((cis)-3-(aminomethyl)cyclopentyl) methanol [ka] A 1 L round-bottom flask equipped with a magnetic stirring bar was packed with methyl cis-3-carbamoylcyclopentane-1-carboxylate (49 g, 284.8 mmol) and THF (500 mL). The temperature was lowered to 0°C, and BH3-THF (1140 ml, 1140 mmol) was added dropwise to the mixture while maintaining the temperature at 0°C. The resulting mixture was stirred at room temperature for 24 hours. The residue was quenched with MeOH (500 ml) at 0°C. The mixture was concentrated under reduced pressure to obtain the crude product (35 g, 269.2 mmol, 79.5%). [M+H] + =130.

[0209] Step 5: ((cis)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopentyl)methanol [ka] A 1 L round-bottom flask equipped with a magnetic stirring bar was packed with ((cis)-3-(aminomethyl)cyclopentyl)methanol (35 g, 269.2 mmol), 4-bromo-2-fluoro-1-nitrobenzene (64.8 g, 295.9 mmol), DIEA (104.2 g, 807.8 mmol), and DMSO (500 mL). The mixture was stirred under N2 at 80°C for 4 hours. After cooling to room temperature, the mixture was poured into EA (500 mL), washed sequentially with brine (200 mL), water (3 / 200 mL), and brine (200 mL), then dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (EA / PE, 24%) to obtain the title product (20 g, 60.8 mmol, 22.6%). [M+H] + =329.

[0210] Step 6: ((1S,3R)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopentyl)methanol [ka] The crude product (20 g) was purified by preparative SFC under the following conditions ((Lux 3uCellulose-3 4.6*50 mm, 3 μm), temperature: 35°C, flow rate (mL / min): 4, solvent A: CO2, solvent B: IPA (0.5% 2 mM NH3-MeOH), gradient (B%): 10% to 50% over 2.0 minutes, maintained at 50% for 1.0 minute, retention time 0.971 minutes) to obtain ((1S,3R)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopentyl)methanol (5.6 g, 28.1%, ee=96.08%). [M+H] + =329. The crude product can also be purified by chiral HPLC under the following conditions: column (chiralpak IC-3 4.6×50 mm, 3 mm), mobile phase (Hex(0.1%DEA):EtOH=80:20), flow rate 1.0 mL / min, temperature 25°C, retention time 2.836 min. 1 H NMR(300 MHz,DMSO-d6)δ 8.14(t,J=5.6 Hz,1H),7.98(d,J=9.1 Hz,1H),7.27(d,J=2.1 Hz,1H),6.83(dd,J=9.1,2.0 Hz,1H),4.45(t,J=5.3 Hz,1H),4.34(s,1H),3.43(s,1H),2.23(dt,J=15.3,7.5 Hz,1H),2.11-1.83(m,2H),1.81-1.54(m,1H),1.45-1.20(m,2H),1.06(t,J=7.0 Hz,2H),1.00-0.71(m,1H).

[0211] Step 7: Methyl 2-(5-(((1S,3R)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopentyl)methoxy)1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] DIAD (3.8 g, 18.6 mmol) was added to a stirred solution of ((1S,3R)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopentyl)methanol (5.1 g, 15.5 mmol), methyl 2-(5-hydroxy-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (4.2 g, 17.0 mmol), and PPh3 (4.9 g, 18.6 mmol) in THF (100 mL). The mixture was then stirred at room temperature for 2 hours. The mixture was then concentrated and purified by silica gel column chromatography, and eluted with ELISA (0-80%) to obtain the product (9.3 g) mixed with PPh3O; [M+H] + =558.3.

[0212] Step 8: Methyl 2-(5-(((1S,3R)-3-(((2-amino-5-bromophenyl)amino)methyl)cyclopentyl)methoxy)1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] Raney nickel (4.5 g) was added to a stirred solution of methyl 2-(5-(((1S,3R)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopentyl)methoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (9.3 g, 16.7 mmol) in THF (100 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 (8.4 g) was used in the next step without purification. [M+H] + =528.3.

[0213] Step 9: Methyl 2-(5-(((1S,3R)-3-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] A solution of methyl 2-(5-(((1S,3R)-3-(((2-amino-5-bromophenyl)amino)methyl)cyclopentyl)methoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (8.4 g, 15.9 mmol) and BrCN (2.5 g, 23.8 mmol) in MeOH (50 mL) was stirred at room temperature for 4 hours. The mixture was then concentrated, diluted with DCM (200 mL), and 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 and eluted with MeOH / DCM (0-15%) to obtain the product (7.1 g, 80.7%); [M+H] + =553.4.

[0214] Step 10: (7 1 R,7 3 S,E)-5 6 -Brom-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)--benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] To a stirred solution of methyl 2-(5-(((1S,3R)-3-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (3.2 g, 5.8 mmol) in 80 mL of THF, LiHMDS (1N in THF, 14.5 mL) was added at room temperature over 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 aqueous solution NH4Cl (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 (2.6 g, 86.2%); [M+H] + =521.2.

[0215] Intermediate 2: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one Step 1: tert-butyl 4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-carboxylate [ka] Intermediate 1 (1.0 g, 1.92 mmol), tert-butylpiperazine-1-carboxylate (535 mg, 2.88 mmol), Pd2(dba)3 (360 mg, 0.4 mmol), Ruphos (360 mg, 0.8 mmol), and NaO in DMA (30 mL). t A solution of Bu (550 mg, 5.75 mmol) was stirred at 100°C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column (DCM:CH3OH=15:1) to obtain tert-butyl 4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-carboxylate (1.0 g, 83.2%) was obtained. [M+H] + =627.

[0216] Step 2: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] tert-butyl 4-((7) in DCM (20 mL) 1 R,7 3 S,E)-1 1 ,2 6-dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 A mixture of (-yl)piperazine-1-carboxylate (1.0 g, 1.6 mmol) was mixed with TFA (7 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 aqueous solution NaHCO3 to pH 7-8 and 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 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one (700 mg, 83.3%) was obtained. [M+H] + = 527.

[0217] Intermediate 3: (7 1 R,7 3 S,E)-5 6 -((S)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + = 571.5

[0218] Intermediate 4: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(2-oxa-5,8-diazaspiro[3.5]nonan-5-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + = 569.5

[0219] Intermediate 5: (7 1 S,7 3 R,E)-1 1 ,2 6 -dimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + = 527.5

[0220] Intermediate 6: 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine Step 1: 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] The four reactants were tested in parallel.

[0221] To a solution of 2,6-benzyloxy-3-bromopyridine (2.00 kg, 5.40 mol, 1.00 equivalent) in dioxane (12.0 L), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (760 g, 5.94 mol, 862 mL, 1.10 equivalent) and TEA (1.09 kg, 10.8 mol, 1.50 L, 2.00 equivalent) were added, the mixture was degassed, purged with N2, and Pd(PPh3)2Cl2 (189 g, 270 mmol, 0.05 equivalent) was added to the mixture. The mixture was stirred at 90°C for 16 hours. The reaction mixture was filtered and concentrated. The four reaction products were combined. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1). 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (5.80 kg, 13.9 mol, 64.3% yield) was obtained. [M+H] + =418.3

[0222] Step 2: 5-Bromo-1,3-difluoro-2-iodobenzene [ka] The five reactants were tested in parallel.

[0223] To a solution of 1-bromo-3,5-difluorobenzene (1.00 kg, 5.18 mol, 595 mL) in THF (4.00 L), LDA (2 M, 2.59 L) was added at -70°C. The mixture was stirred at -70°C for 1 hour. Next, a solution of I2 (1.33 kg, 5.23 mol, 1.05 L) in THF (1.00 L) was added to 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 ethyl acetate (3.00 L x 2), the five reactants 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, 54.4% yield) was obtained. [M+H] + =318.8.

[0224] 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. The mixture was filtered, and the filtrate was extracted with ELISA (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 to 1:1). Compound 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (3.00 kg, 6.01 mol, 42.5% yield, 96.5% purity) was obtained. 1H NMR(400 MHz, 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=8.0 Hz,1H),5.32(s,2H),5.28(s,2H);[M+H] + =482.1.

[0225] Intermediate 7: (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 6 (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 500 mL of dioxane, Pd2(dba)3 (2.85 g, 3.11 mmol) and xanthophos (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 SiO2 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, 79% yield); [M+H] + =544.9.

[0226] Step 2: 3-(2,6-difluoro-4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)phenyl)piperidine-2,6-dione [ka] To a solution of 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) in 400 mL of DMF and 80 mL of iPrOH, 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, 83.2% yield); [M+H] + =367.1.

[0227] 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 racemic mixture); [M+H] + =367.1.

[0228] 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 aqueous HCl was added. The mixture was stirred at room temperature for 30 minutes. The mixture was added dropwise to a saturated aqueous NaHCO3 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, 96.7% yield); [M+H] + =323.1.

[0229] Intermediate 9: 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: 4-((3S,4R)-4-(4-benzylpiperazine-1-yl)-3-fluoropiperidine-1-yl)-1-(2,6-bis(benzyloxy)pyridine-3-yl)indoline-2-one [ka] DMA (15 mL) contains 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 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 on 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.

[0230] Step 2: 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] 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 aqueous sodium thiosulfate, and water, and dried on 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.

[0231] Step 3: 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, DMF / i- To a solution of 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) in PrOH (5 mL / 5 mL), 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.

[0232] Step 4: 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.

[0233] Intermediate 10: 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] To a solution of 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) in DMF (200 ml), 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.

[0234] 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 on 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.

[0235] 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 solution of 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) in dioxane (120 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 (100 mL) and then filtered through a Celite pad. The filtrate was washed with brine (150 mL), dried on 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.

[0236] 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, CH3I (2.5 g, 17.75 mmol) was added dropwise to the mixture while maintaining the temperature at 0°C. 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.

[0237] 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 stirring bar was packed with 1-(2,6-bis(benzyloxy)pyridine-3-yl)-3,3-dimethyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)indorin-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, purged 5 times with H2, and then stirred overnight at room temperature. The mixture was diluted with DCM / MEOH (50 mL / 50 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 silica column chromatography (PE / EA = 1:1) to obtain the product (560.1 mg, 53.6%). [M+H] + =414. 1H NMR(300 MHz,DMSO)δ 11.05(s,1H),7.22(t,J=7.4 Hz,1H),7.03(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).

[0238] Step 6: 3-(3,3-dimethyl-2-oxo-4-(4-oxopiperidine-1-yl)indoline-1-yl)piperidine-2,6-dione [ka] The compound was prepared using the same procedure as in step 4 of intermediate 7.

[0239] Intermediate 11: 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 mixture was 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 and eluted with MeOH / DCM (0-10%) to obtain 5-fluoro-2-methylpyridine-3-amine (12 g, 90.1%). [M+H] + =127.1

[0240] Step 2: 6-Chloro-5-fluoro-2-methylpyridine-3-amine [ka] To a stirred mixture of 5-fluoro-2-methylpyridine-3-amine (6 g, 47.62 mmol) in DMF (120 mL), NCS (8.43 g, 47.62 mmol) was added at 0°C. 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 and eluted with EA / PE (0-50%) to obtain 6-chloro-5-fluoro-2-methylpyridine-3-amine (3 g, 39.5%). [M+H] + =161.0.

[0241] 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]+ =416.2

[0242] 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 an 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

[0243] Intermediate 12: 3-(3-fluoro-6-methyl-5-(4-oxopiperidine-1-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 intermediate 11 (5.2 g, 9.89 mmol), 1,4-dioxane (50 mL), 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] + =542.0

[0244] 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] To a stirred solution of 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) in THF (100 mL), Pd / C (10 wt%, 4.5 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-(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%). 1H NMR(300 MHz,DMSO)δ 10.86(s,1H),7.35(d,J=12 Hz,1H),4.13(m,1H),3.32(s,1H),2.94(t,J=6 Hz,4H),2.71(m,1H),2.62-2.50(m,1H),2.37(d,J=3 Hz,3H),2.26-2.15(m,1H),2.03(m,1H),1.78(t,J=6 Hz,4H),1.36(s,1H),1.22(d,J=12 Hz,1H),0.99-0.80(m,1H).

[0245] Step 3: 3-(3-fluoro-6-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] The compound was prepared using the same procedure as in step 4 of intermediate 7.

[0246] Intermediate 13: 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 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 = 0-50%) to obtain 2',6'-bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine (12 g, 62.2%). [M+H] + =475.1

[0247] 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

[0248] 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] To a stirred solution of 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) in THF (50 mL), 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 filtrate 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] + =360.2. 1H NMR(300 MHz,DMSO)δ 10.77(s,1H),6.96(s,1H),3.92(s,4H),3.83(m,1H),3.03(t,J=6 Hz,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=6 Hz,4H).

[0249] Step 4: 3-(4,6-dimethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] The compound was prepared using the same procedure as in step 4 of intermediate 7.

[0250] Intermediate 14: 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] To a solution of 1,4-dioxane and 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) in 20 mL of H2O, Pd(dppf)Cl2 (1.2 g, 1.61 mmol) was added. 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.

[0251] Step 2: 8-(2',6'-bis(benzyloxy)-4-methyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] To a solution of 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) in 80 mL of DMA, 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.

[0252] Step 3: 3-(4-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione [ka] To a solution of 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) in 75 mL of DMF and 75 mL of iPrOH, Pd / C (2.0 g, 10 wt%, wet) was added. The mixture was stirred at 50°C for 20 hours under a hydrogen atmosphere (balloon). 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.

[0253] 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 aqueous HCl was added. The mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to saturated aqueous NaHCO3 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, 93.6% yield). [M+H] + =302.5.

[0254] Intermediate 15: 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 14.

[0255] Intermediate 16: 3-(4-ethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione Step 1: 5-Bromo-2-chloro-4-vinylpyridine [ka] Pd(dppf)Cl2 (3.65 g, 5.03 mmol) was added to a stirred mixture of 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) in 1,4-dioxacyclohexane (200 mL) and H2O (40 mL). The resulting mixture was degassed under reduced pressure and purged three times with N2. The mixture 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 5-bromo-2-chloro-4-vinylpyridine (6.8 g, 62.0%). [M+H] + =218.

[0256] Step 2: 8-(6-chloro-4-vinylpyridine-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] Pd-PEPPSI-IPentCl (1.3g, 1.56 mmol) was added to a stirred mixture of 5-bromo-2-chloro-4-vinylpyridine (6.8g, 31.2 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (4.46g, 31.2 mmol), and Cs2CO3 (20.3g, 62.4 mmol) in 1,4-dioxacyclohexane (140 mL). The resulting mixture was degassed under reduced pressure and purged three times with N2. It 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 (4.2g, 47.9%). [M+H] + =281.

[0257] Step 3: 8-(2',6'-bis(benzyloxy)-4-vinyl-[2,3'-bipyridine]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] Pd(dppf)Cl2 (1.09 g, 1.5 mmol) was added to a stirred mixture of 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) in 1,4-dioxacyclohexane (50 mL) and H2O (10 mL). The resulting mixture was degassed under reduced pressure and purged three times with N2. It 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 (6.3g, 78.9%). [M+H] + = 536.

[0258] Step 4: 3-(4-ethyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)piperidine-2,6-dione [ka] To a stirred solution of 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) in THF (150 mL), Pd / C (10 wt%, 6.3 g) was added. 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 (EA / PE, 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. (3.53g, 9.8mmol, 83.05%). [M+H] + =360. 1 H NMR(300 MHz,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=3 Hz,4H),2.72-2.50(m,3H),2.26-2.04(m,1H),1.76(t,J=6 Hz,4H),1.20(t,J=9 Hz,3H),1.07(s,2H).

[0259] Step 5: 3-(4-ethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] The compound was prepared using the same procedure as in step 4 of intermediate 14.

[0260] Intermediate 17: 3-(6-ethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] The compound was prepared using the same procedure as for intermediate 16.

[0261] Intermediate 18: (1-(6-(2,6-dioxopiperidine-3-yl)-2,4-dimethylpyridine-3-yl)azetidine-3-yl)methylmethanesulfonate Step 1: 2',6'-bis(benzyloxy)-5-(3-((benzyloxy)methyl)azetidine-1-yl)-4,6-dimethyl-2,3'-bipyridine [ka] A solution of 2',6'-bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine (5g, 10.5 mmol), 3-((benzyloxy)methyl)azetidine (2.81g, 15.79 mmol), Cs2CO3 (10.29g, 31.59 mmol), and Pd-PEPPSI-IPentCl (0.44g, 0.53 mmol) in DMF (60 ml) was degassed under reduced pressure, purged five times with N2, and stirred at 100°C for 5 hours under N2. After cooling to room temperature, the mixture was poured into EA (100 mL), washed sequentially with brine (100 mL), water (3'100 mL), and brine (100 mL), then dried on anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica column chromatography PE / EA (6:1) to obtain 2',6'-bis(benzyloxy)-5-(3-((benzyloxy)methyl)azetidine-1-yl)-4,6-dimethyl-2,3'-bipyridine (3.7 g, 61.4%). [M+H] + = 572.

[0262] Step 2: 3-(5-(3-(hydroxymethyl)azetidine-1-yl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] A 250 mL round-bottom flask equipped with a magnetic stirring bar was packed with 2',6'-bis(benzyloxy)-5-(3-((benzyloxy)methyl)azetidine-1-yl)-4,6-dimethyl-2,3'-bipyridine (3.7 g, 6.49 mmol), THF (50 mL), and Pd / C (10 wt%, 3.7 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 (100 mL), then sonicated in an ultrasonic cleaner for 5 minutes, and subsequently filtered through a Celite pad. The filtrate was concentrated under vacuum. The residue was ground with PE to obtain 3-(5-(3-(hydroxymethyl)azetidine-1-yl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione (1.03 g, 52.6%). [M+H] + =304.

[0263] Step 3: (1-(6-(2,6-dioxopiperidine-3-yl)-2,4-dimethylpyridine-3-yl)azetidine-3-yl)methylmethanesulfonate [ka] This compound was prepared in the same manner as in step 5 of intermediate 19.

[0264] Intermediate 19: 2-(6-(2,6-dioxopiperidine-3-yl)-2,4-dimethylpyridine-3-yl)ethylmethanesulfonate 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, 40.9 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, 40.9 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 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 = 0-50%) to obtain 2',6'-bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine (12 g, 62.2%). [M+H] + =475.1.

[0265] Step 2: 2',6'-bis(benzyloxy)-4,6-dimethyl-5-vinyl-2,3'-bipyridine [ka] Pd(dppf)Cl2 (514.1 mg, 0.63 mmol) was added to a stirred mixture of 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) in 1,4-dioxane (30 mL) and H2O (6 mL). 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 ethyl acetate, 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] +=423.0

[0266] Step 3: 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 in THF, 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 in water, 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

[0267] Step 4: 3-(5-(2-hydroxyethyl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] To a stirred solution of 2-(2',6'-bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridine]-5-yl)ethane-1-ol (1.4 g, 8.31 mmol) in THF (50 mL), 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 filtrate 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(300 MHz,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=9 Hz,2H),2.64-2.54(m,3H),2.44(s,3H),2.29(s,3H),2.26-2.02(m,1H).

[0268] Step 5: 2-(6-(2,6-dioxopiperidine-3-yl)-2,4-dimethylpyridine-3-yl)ethylmethanesulfonate [ka] To a solution of 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) 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, 56.5% yield). [M+H] + =341.5.

[0269] Intermediate 20: 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 50 mL of EtOH was stirred at 80°C for 16 hours. 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.

[0270] 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.

[0271] 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 11 (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 under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 100 °C for 12 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with toluene (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 and eluted with DCM / MeOH (0-5%) to obtain the product (0.95 g, 78%). [M+H] + =676.7.

[0272] Step 4: tert-butyl4-((3R,4S)-1-(6-(2,6-dioxopiperidine-3-yl)-5-fluoro-2-methylpyridine-3-yl)-3-fluoropiperidine-4-yl)piperazine-1-carboxylate [ka] To a stirred mixture of 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) in i-PrOH (40 mL) and DMF (40 mL), 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 and eluted with MeOH / DCM (0-7%) to obtain the product (0.46 g, 64.5%). [M+H] + =508.4.

[0273] 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.

[0274] Intermediate 21: 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 in the same manner as intermediate 20.

[0275] Intermediate 22: 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 in the same manner as intermediate 20.

[0276] Intermediate 23: 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 in the same manner as intermediate 20.

[0277] Intermediate 24: 3-(5-((3R,4S)-3-fluoro-4-(piperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 20.

[0278] Intermediate 25: 3-(5-((R)-3,3-difluoro-4-(piperazine-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 20.

[0279] Intermediate 26: 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 20.

[0280] Intermediate 27: 3-(5-((3S,4R)-3-fluoro-4-(piperazin-1-yl)piperidine-1-yl)-4-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 20.

[0281] Intermediate 28: 1-(6-(2,6-dioxopiperidine-3-yl)-2-methylpyridine-3-yl)piperidine-4-carbaldehyde [ka] The title compound was prepared in the same manner as intermediate 14.

[0282] Intermediate 29: 1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)azetidine-3-carbaldehyde [ka] Step 1: Methyl 2-cyano-4-(3-(hydroxymethyl)azetidine-1-yl)benzoate [ka] To a stirred mixture of methyl 2-cyano-5-fluorobenzoate (20 g, 112 mmol) and azetidine-3-yl methanol (hydrogen chloride) (14 g, 112 mmol) in DMSO (100 mL), DIEA (29 g, 223 mmol) was added at 60°C within 3 hours. The resulting mixture was extracted with SiO2 (500 mL). The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Methyl 2-cyano-4-(3-(hydroxymethyl)azetidine-1-yl)benzoate (18 g, 66.7%) was obtained. [M+H] + =247.0.

[0283] Step 2: Methyl 2-formyl-4-(3-(hydroxymethyl)azetidine-1-yl)benzoate [ka] To a stirred mixture of methyl 2-cyano-4-(3-(hydroxymethyl)azetidine-1-yl)benzoate (18 g, 72.9 mmol) in AcOH (150 mL) and H2O (75 mL), Raney nickel (15 g) was gradually added over 4 hours at 40°C under an air atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM and MeOH (300 mL). The filtrate was concentrated under reduced pressure. The filtrate was extracted with ELISA (500 mL). The combined organic layers were washed with brine (500 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (9:1). Methyl 2-formyl-4-(3-(hydroxymethyl)azetidine-1-yl)benzoate (10 g, 55.6%) was obtained. [M+H] + =250.1.

[0284] Step 3: 3-(5-(3-(hydroxymethyl)azetidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] A mixture of 3-aminopiperidine-2,6-dione (hydrogen chloride) (9.9 g, 60.2 mmol) and DIEA (10.4 g, 80.3 mmol) in DMF (90 mL) was stirred at room temperature for 5 hours. The mixture was acidified to pH < 7 with AcOH (12 g, 201 mmol), and then methyl 2-formyl-4-(3-(hydroxymethyl)azetidine-1-yl)benzoate (10 g, 40.2 mmol) in DMF (10 mL) was added at room temperature. The resulting mixture was stirred overnight at room temperature. NaBH3CN (7.5 g, 119.35 mmol) was gradually added to the above mixture at room temperature. The resulting mixture was stirred for a further 2 hours at room temperature. The reaction product was quenched with water at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (10:1) to obtain the crude product. The residue was purified by grinding using DCM. This yielded 3-(5-(3-(hydroxymethyl)azetidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (4g, 30.8%). 1 H NMR(300 MHz,DMSO)δ 10.94(s,1H),7.48(d,J=8 Hz,1H),6.52-6.42(m,2H),5.04(m,1H),4.81(t,J=8 Hz,1H),4.30(d,J=16 Hz,1H),4.18(d,J=20 Hz,1H),3.93(m,2H),3.65(m,2H),3.59(t,J=8 Hz,2H),2.97-2.76(m,2H),2.64-2.53(m,1H),2.35(m,1H),1.95(m,1H).[M+H] + =330.1.

[0285] Step 4: 1-(2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-5-yl)azetidine-3-carbaldehyde [ka] The title compound was prepared in the same manner as in step 2 of intermediate 33. [M+H] + =328.1

[0286] Intermediate 30: (7 1 R,7 3 S,E)-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + = 571.5

[0287] Intermediate 31: 3-(4-(4-oxopiperidine-1-yl)phenoxy)piperidine-2,6-dione [ka] Step 1: 3-(4-bromophenoxy)piperidine-2,6-dione [ka] A solution of 4-bromophenol (2 g, 11.6 mmol), 3-bromopiperidine-2,6-dione (4.4 g, 23.1 mmol), and Cs2CO3 (11.3 g, 34.7 mmol) in DMF (50 mL) was stirred at 60°C for 5 hours, then diluted with siRNA (400 mL) and washed with brine (3 × 150 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / EA (0-30%) to obtain the product (1 g, 30.5%); [M+H] + =284.2.

[0288] Step 2: 3-(4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)phenoxy)piperidine-2,6-dione [ka] To a stirred solution of 3-(4-bromophenoxy)piperidine-2,6-dione (900 mg, 3.2 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (544 mg, 1.3 mmol) in DMA (20 mL), Cs2CO3 (2 g, 6.3 mmol), Ruphos (591 mg, 0.24 mmol), and Pd2(dba)3 (580 mg, 0.6 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 6 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  (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 and eluted with DCM / MeOH (25:1) to obtain the product (130 mg, 11.9%); [M+H] + =347.3.

[0289] Step 3: 3-(4-(4-oxopiperidine-1-yl)phenoxy)piperidine-2,6-dione [ka] A solution of 3-(4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenoxy)piperidine-2,6-dione (130 mg, 0.4 mmol) in aqueous HCl (8N, 5 mL) was stirred at room temperature for 2 hours, and DCM (100 mL) was added. The resulting mixture was adjusted to pH=7 with aqueous NaHCO3, the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product (100 mg, 88.1%); [M+H] + =303.2.

[0290] Intermediate 32: 3-((3-fluoro-4-(4-oxopiperidine-1-yl)phenyl)amino)piperidine-2,6-dione [ka] Step 1: 8-(2-fluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] To a solution of 1,2-difluoro-4-nitrobenzene (3.0 g, 18.9 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (4.0 g, 28.3 mmol) in 60 mL of DMF, K2CO3 (5.2 g, 37.8 mmol) was added. The resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into water (150 mL), the precipitate was filtered, washed with water, and dried under air to obtain the crude product (5.3 g, 96.2%). [M+H] + =283.5.

[0291] Step 2: 3-Fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline [ka] To a solution of 8-(2-fluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (5.1 g, 18.0 mmol) in 40 mL of DCM and 40 mL of MeOH, Pd / C (2.5 g, 10 wt%, wet) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere (balloon). The mixture was filtered through a Celite pad and washed with DCM. The filtrate was concentrated under vacuum to obtain the crude product (4.4 g, 96.5%). [M+H] + =253.5.

[0292] Step 3: 3-((3-fluoro-4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)phenyl)amino)piperidine-2,6-dione [ka] To a solution of 3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline (700 mg, 2.8 mmol) and 3-bromopiperidine-2,6-dione (525 mg, 2.8 mmol) in 10 mL of DMF, Na2CO3 (595 mg, 5.6 mmol) was added. The resulting mixture was heated at 70°C for 16 hours. The mixture was quenched with water and extracted with EA (2 × 50 mL). The combined organic phase was washed with brine (2 × 30 mL), concentrated under vacuum, and purified by combiflush (DCM:EA = 1:2) to obtain the title compound (345 mg, 34.5%). [M+H] + =364.5.

[0293] Step 4: 3-((3-fluoro-4-(4-oxopiperidine-1-yl)phenyl)amino)piperidine-2,6-dione [ka] 3-((3-fluoro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)piperidine-2,6-dione (345 mg, 0.95 mmol) was placed in a 100 mL round-bottom flask equipped with a magnetic stirring bar. Then, 10 mL of 8N aqueous HCl was added. The mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to a saturated aqueous NaHCO3 solution until the pH was finally adjusted to 6-7. The liquid was extracted with DCM (2 × 50 mL). The combined organic phase was concentrated under vacuum and purified by combiflush (DCM:MeOH = 25:1) to obtain the title compound (300 mg, 99.0%). [M+H] + =320.5.

[0294] Intermediate 33: 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-carbaldehyde [ka] Step 1: 2-(2,6-dioxopiperidine-3-yl)-5-(3-(hydroxymethyl)azetidine-1-yl)isoindoline-1,3-dione [ka] A mixture of 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione (2.76 g, 1 mmol), azetidine-3-yl methanol (870 mg, 1 mmol), and DIEA (2.85 g, 2 mmol) in DMSO (30 mL) was stirred in a round-bottom flask at 100°C under N2 for 12 hours. The mixture was diluted with H2O and extracted with ELISA (100 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (10:1). 2-(2,6-dioxopiperidine-3-yl)-5-(3-(hydroxymethyl)azetidine-1-yl)isoindoline-1,3-dione (3 g, 87%) was obtained. [M+H] + =344.3

[0295] Step 2: 1-(2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindorin-5-yl)azetidine-3-carbaldehyde [ka] A mixture of 2-(2,6-dioxopiperidine-3-yl)-5-(3-(hydroxymethyl)azetidine-1-yl)isoindorin-1,3-dione (1.71 g, 0.5 mmol) and 2-iodoxybenzoic acid (2.8 g, 1 mmol) in DMSO (15 mL) was stirred in a round-bottom flask at 25°C under N2 for 12 hours. The mixture was diluted with H2O and extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (10:1) to obtain the title compound (1.5 g, 88%). [M+H] + =342.3

[0296] Intermediate 34: (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared using intermediate 39 in the same manner as intermediate 40. [M+H] + = 541.5.

[0297] Intermediate 35: (7 1 R,7 3 S,E)-5 6 -((R)-3-(hydroxymethyl)piperazine-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + =557.5.

[0298] Intermediate 36: 3-(5-((3S,4S)-3-fluoro-4-(piperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 20. [M+H] + =390.3.

[0299] Intermediate 37: (7 1 R,7 3 S,E)-5 6 -((S)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,2 6 -dimethyl-1 3 -(trifluoromethyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =639.5.

[0300] Intermediate 38: 2-(6-(2,6-dioxopiperidine-3-yl)-5-fluoro-2-methylpyridine-3-yl)acetaldehyde [ka] Step 1: 2',6'-bis(benzyloxy)-5-(2,2-dimethoxyethyl)-3-fluoro-6-methyl-2,3'-bipyridine [ka] A mixture of 2',6'-bis(benzyloxy)-5-bromo-3-fluoro-6-methyl-2,3'-bipyridine (700 mg, 1.5 mmol, obtained by the same method as WO2023 / 098656A1), 3-bromo-1,1-dimethoxypropane (400 mg, 2.2 mmol), NiI2 (91 mg, 0.3 mmol), HCl salt of picoline imidamide (46 mg, 0.3 mmol), NaI (87 mg, 0.58 mmol), and Mn (160 mg, 3 mmol) in DMA (15 mL) was mixed with TFA (25 mg, 0.25 mmol) under N2 conditions. The resulting mixture was heated to 100°C for 3 hours under N2 conditions. After cooling to room temperature, the reaction mixture was diluted with EA (60 mL), then washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column (PE:EA = 5:1) to obtain the product (560 mg, 78.5%); [M+H] + =489.6.

[0301] Step 2: 3-(5-(2,2-dimethoxyethyl)-3-fluoro-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] Under N2 conditions, a solution of 2',6'-bis(benzyloxy)-5-(2,2-dimethoxyethyl)-3-fluoro-6-methyl-2,3'-bipyridine (560 mg, 1.15 mmol) in DMF (10 mL) / i-PrOH (10 mL) was mixed with 10% Pd / C (500 mg) at 25°C. The mixture was then changed twice with H2 and stirred at 50°C for 12 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 crude product (120 mg, 33.7%). [M+H] + =311.4.

[0302] Step 3: 2-(6-(2,6-dioxopiperidine-3-yl)-5-fluoro-2-methylpyridine-3-yl)acetaldehyde [ka] A solution of 3-(5-(2,2-dimethoxyethyl)-3-fluoro-6-methylpyridine-2-yl)piperidine-2,6-dione (120 mg, 0.4 mmol) in aqueous HCl (8 N, 5 mL) was stirred at room temperature for 2 hours, and DCM (100 mL) was added. The resulting mixture was adjusted to pH=7 with aqueous NaHCO3, the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (100 mg, 97.8%); [M+H] + =265.2.

[0303] Intermediate 39: (7 1 R,7 3 S,E)-5 6 -Brom-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] Step 1: Methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] To a solution of methyl 2-chloro-6-methylisonicotinate (1.85 g, 10 mmol), 1,3-dimethyl-1H-pyrazole-5-ol (2.24 g, 20 mmol), and Na2CO3 (2.12 g, 20 mmol) in 50 mL of anisole, Pd(dppf)Cl2 (1.46 g, 2 mmol) was added under an N2 atmosphere. The mixture was stirred at 130°C for 16 hours under an N2 atmosphere. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica column chromatography (MeOH:DCM = 0-7%) to obtain methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate (990 mg, 3.79 mmol, 37.9% yield). [M+H] + =262.2.

[0304] Step 2: Methyl 2-(5-(((1S,3R)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] To a solution of methyl 2-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate (990 mg, 3.79 mmol), ((1S,3R)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopentyl)methanol (1.24 g, 3.79 mmol), and PPh3 (1.19 g, 4.55 mmol) in 30 mL of THF, DIAD (920 mg, 4.55 mmol) was added at 0°C. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum and purified by silica column chromatography (MeOH:DCM = 0-5%) to obtain methyl 2-(5-(((1S,3R)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopentyl)methoxy)1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate (2.6 g of crude product containing PPh3O). [M+H] += 572.2.

[0305] Step 3: Methyl 2-(5-(((1S,3R)-3-(((2-amino-5-bromophenyl)amino)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] Raney nickel was added to a solution of methyl 2-(5-(((1S,3R)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate (2.6 g of crude product containing PPh3O) in 50 mL of THF. The mixture was stirred at room temperature under an H2 atmosphere for 1 hour. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum to obtain methyl 2-(5-(((1S,3R)-3-(((2-amino-5-bromophenyl)amino)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate (2.5 g of crude product). [M+H] += 542.2.

[0306] Step 4: Methyl 2-(5-(((1S,3R)-3-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] To a solution of methyl 2-(5-(((1S,3R)-3-(((2-amino-5-bromophenyl)amino)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate (2.5 g crude) in 30 mL of MeOH, BrCN (630 mg, 6 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum. The residue was dissolved in DCM (100 mL), washed with saturated aqueous solution K2CO3 (50 mL x 3), and separated. The organic layer was dried, concentrated, and purified by silica column chromatography (MeOH:DCM = 0-8%) to obtain methyl 2-(5-(((1S,3R)-3-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate (1.6 g, 2.83 mmol). [M+H] + =567.2.

[0307] Step 5: (7 1 R,7 3 S,E)-5 6 -Brom-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] To a solution of methyl 2-(5-(((1S,3R)-3-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)-1,3-dimethyl-1H-pyrazole-4-yl)-6-methylisonicotinate (1.6 g, 2.83 mmol) in 30 mL of THF, 5 mL of 1N LiHMDS in THF was added. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated aqueous solution NH4Cl (30 mL) and concentrated. The residue was dissolved in DCM (70 mL) and washed with brine (40 mL x 3). The organic layer was separated, concentrated, and purified by silica column chromatography (MeOH:DCM = 0-4%). 1 R,7 3 S,E)-5 6 -Brom-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one (780 mg, 1.46 mmol, 51.6% yield). [M+H] + = 535.2.

[0308] Intermediate 40: (7 1 R,7 3 S,E)-5 6 -((S)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared using intermediate 39 in the same manner as intermediate 2. [M+H] + =585.1.

[0309] Intermediate 41: 3-(5-((S)-3,3-difluoro-4-(piperazine-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 20. [M+H] + =408.1.

[0310] Intermediate 42: 3-(2,6-difluoro-4-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] Step 1: 1-Benzyl-4-((3R,4S)-1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)-3-fluoropiperidine-4-yl)piperazine [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (1.0 g, 2.1 mmol), 1-benzyl-4-((3R,4S)-3-fluoropiperidine-4-yl)piperazine (694 mg, 2.5 mmol), and Cs2CO3 (2.0 g, 6.3 mmol) in 20 mL of 1,4-dioxane, Pd-G3 RuPhos (351 mg, 0.42 mmol) and RuPhos (392 mg, 0.84 mmol) were added. The mixture was stirred under N2 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 (DCM:MeOH = 100:1 to 20:1) to obtain the product (1.1 g, 78.0%). [M+H] + =679.5.

[0311] Step 2: tert-butyl 4-((3R,4S)-1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)-3-fluoropiperidine-4-yl)piperazine-1-carboxylate [ka] To a solution of 1-benzyl-4-((3R,4S)-1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)-3-fluoropiperidine-4-yl)piperazine (1.1 g, 1.6 mmol) and (Boc)2O (1.0 g, 4.8 mmol) in 20 mL of DMF and 20 mL of iPrOH, Pd / C (0.8 g, 10 wt%, wet) was added. The mixture was stirred under a hydrogen atmosphere (balloon) at 50°C for 16 hours. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under vacuum to obtain the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0~20:1) to obtain the product (790 mg, 95.5%). [M+H] + =511.5.

[0312] Step 3: 3-(2,6-difluoro-4-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] To a solution of 4-((3R,4S)-1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)-3-fluoropiperidine-4-yl)piperazine-1-carboxylate (790 mg, 1.5 mmol) in DCM (6 mL), TFA (2 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and basicized with saturated aqueous solution NaHCO3. The liquid was extracted with DCM / CF3CH2OH (3 × 30 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title product (600 mg, 94.5%). [M+H] + =411.5.

[0313] Intermediate 43: (7 1 R,7 3 S,E)-1 3 -(difluoromethyl)-5 6 -((S)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 40. [M+H] + =621.3.

[0314] Intermediate 44: (R)-1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)azetidine-3-carbaldehyde [ka] Step 1: Methyl 1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate [ka] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (3.00 g, 6.22 mmol), methylazetidine-3-carboxylate hydrochloride (1.41 g, 9.33 mmol), Cs2CO3 (6.06 g, 18.7 mmol), and RuPhos Pd G3 (520.7 mg, 0.62 mmol) in toluene (50 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was diluted with brine (300 mL) and extracted with toluene (100 mL x 3). 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 and eluted with PE / toluene (2:1) to obtain the product (1.7 g, 53%). [M+H] + =517.1.

[0315] Step 2: 1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid [ka] To a stirred mixture of methyl 1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate (1.7 g, 3.29 mmol) in THF (20 mL), 168 mg, 4 mmol of LiOH·H2O (10 mL) in water was added dropwise at room temperature. The mixture was then stirred for 2 hours. The resulting mixture was concentrated under vacuum. The aqueous layer was adjusted to pH < 5 with 1 N HCl and then extracted with ELISA (3 × 40 mL). 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 (1.4 g, 85%), which was used in the next step without further purification. [M+H] + =503.2.

[0316] Step 3: (R)-1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid [ka] To a solution of 1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (1.40 g, 2.79 mmol) in iPrOH (20 mL) and DCM (20 mL), Pd / C (1.0 g, 10 wt%) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 48 hours. The resulting mixture was filtered, and the filtrate was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure and purified by chiral HPLC (analytical method: CHIRALPAK AD-3 3.0*100 mm, 3 μm, MeOH (0.1% DEA)). The title compound corresponded to peak A at 1.849 min / 254 nm (190 mg, 22%). [M+H] + =325.3.

[0317] Step 4: (R)-3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidine-1-yl)phenyl)piperidine-2,6-dione [ka] To a solution of (R)-1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (6.5 g, 20 mmol) in THF, BH3.THF (30 mL, 1 M in THF) was added dropwise at 0°C. The reaction mixture was stirred overnight at room temperature. The mixture was then quenched with MeOH (20 mL), diluted with DCM (150 mL), and 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 to obtain the crude product, which was purified by silica gel column chromatography and eluted with DCM / MeOH (30:1~15:1) to obtain the title product (3.8 g, 61.2%). [M+H] + =311.2.

[0318] Step 5: (R)-1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)azetidine-3-carbaldehyde [ka] A mixture of (R)-3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidine-1-yl)phenyl)piperidine-2,6-dione (3.8 g, 12.3 mmol) and IBX (6.8 g, 24.6 mmol) in DMSO (80 mL) was stirred overnight at room temperature in a flask. The reaction mixture was quenched with water, and the mixture was extracted with DCM (60 mL x 3). The combined organic layer was washed with saturated aqueous Na2S2O3 (100 mL), saturated aqueous NaHCO3 (100 mL x 2), and saturated aqueous NaCl (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the product (2.3 g, 70.1%), which was used without further purification. [M+H] + =309.1.

[0319] Intermediate 45: (7 1 R,7 3 S,E)-5 5 -Fluoro-5 6 -((S)-3-(methoxymethyl)piperazine-1-yl)-1 1,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =589.3.

[0320] Intermediate 46: 3-(3-fluoro-4-(4-oxopiperidine-1-yl)phenoxy)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 31. [M+H] + =321.2

[0321] Intermediate 47: (7 1 R,7 3 S,E)-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] Step 1: tert-butyl(R)-2-(methoxymethyl)-4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-carboxylate [ka] To a solution of intermediate 39 (150 mg, 0.28 mmol), tert-butyl(R)-2-(methoxymethyl)piperazine-1-carboxylate (129 mg, 0.56 mmol), and tBuONa (135 mg, 1.4 mmol) in 5 mL of DMA, Pd2(dba)3 (51 mg, 0.056 mmol) and RuPhos (52 mg, 0.12 mmol) were added. The mixture was stirred at 90°C for 1 hour. The mixture was concentrated under vacuum and purified by silica column chromatography (MeOH:DCM = 0-4%) to obtain the title compound (180 mg, 93.8%). [M+H] + =685.2.

[0322] Step 2: (7 1 R,7 3 S,E)-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] tert-butyl(R)-2-(methoxymethyl)-4-((7) in 2 mL of DCM 1 R,7 3S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 To a solution of (180 mg, 0.26 mmol) of (-yl)piperazine-1-carboxylate, 2 mL of TFA was added. This mixture was stirred at room temperature for 15 minutes. The mixture was concentrated and dissolved in DCM (20 mL). The residue was washed with saturated aqueous NaHCO3 (10 mL x 3) and separated. The organic layer was concentrated and purified by silica column chromatography ((MeOH + 2% NH3.H2O): DCM = 0-15%) to obtain the title compound (130 mg, 84.6%). [M+H] + =585.2.

[0323] Intermediate 48: 3-((3,5-difluoro-4-(4-oxopiperidine-1-yl)phenyl)amino)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 32. [M+H] + =338.2.

[0324] Intermediate 49: (7 1 R,7 3 S,E)-5 6 -((R)-2-(hydroxymethyl)piperazine-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + =557.2.

[0325] Intermediate 50: (7 1 R,7 3 S,E)-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 1 ,2 6 -dimethyl-1 3 -(trifluoromethyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 47 [M+H]. + =639.3.

[0326] Intermediate 51: (7 1 R,7 3 S,E)-5 6 -((S)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,2 6 ,5 5 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =585.3.

[0327] Intermediate 52: 3-((6-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)amino)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 32. [M+H] + =317.2.

[0328] Intermediate 53: (7 1 R,7 3 S,E)-1 3 -(difluoromethyl)-1 1 ,2 6 -dimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =577.3.

[0329] Intermediate 54: (7 1 R,7 3 S,E)-5 5 -Fluoro-1 1 ,2 6 -dimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + = 545.3.

[0330] Intermediate 55: 3-((3-chloro-4-(4-oxopiperidine-1-yl)phenyl)amino)piperidine-2,6-dione [ka] Step 1: 8-(2-chloro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] To a stirred solution of 2-chloro-1-fluoro-4-nitrobenzene (2 g, 11.5 mmol) in DMF (30 mL), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 g, 13.8 mmol) and K2CO3 (3.2 g, 23 mmol) were added. The resulting mixture was stirred at 80°C for 12 hours. The mixture was cooled to room temperature. The resulting mixture was poured into water (50 mL), filtered, and the filter cake was washed with water to obtain the product (3 g, 87%). [M+H] + =299.3.

[0331] Step 2: 3-Chloro-4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)aniline [ka] Raney nickel (1 g) was added to a stirred solution of 8-(2-chloro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (3 g, 10.1 mmol) in THF (40 mL). The resulting mixture was stirred under H2 at room temperature for 1 hour. The mixture was filtered and concentrated under vacuum to obtain the product (2.6 g, 95%). [M+H] + =269.3.

[0332] Step 3: 3-((3-chloro-4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)phenyl)amino)piperidine-2,6-dione [ka] To a solution of 3-chloro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline (2.6 g, 9.7 mmol) in DMF (40 mL), 3-bromopiperidine-2,6-dione (3.7 g, 19.4 mmol) and Na2CO3 (3.1 g, 29.1 mmol) were added. The resulting mixture was stirred at 70°C for 12 hours. The mixture was poured into water 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 reduced pressure to obtain the crude residue, which was purified by silica column chromatography (DCM:MeOH = 100:1~10:1) to obtain the product (1.8 g, 49%). [M+H] + =380.3.

[0333] Step 4: 3-((3-chloro-4-(4-oxopiperidine-1-yl)phenyl)amino)piperidine-2,6-dione [ka] A solution of 3-((3-chloro-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)piperidine-2,6-dione (1 g, 2.6 mmol) in HCl (8 M, 10 mL) was stirred at room temperature for 2 hours. Saturated aqueous solution NaHCO3 was added dropwise to the mixture to adjust the pH to 6-7. The liquid was extracted with DCM (30 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (800 mg, 92%). [M+H] + =336.2.

[0334] Intermediate 56: 3-(5-((S)-3,3-difluoro-4-(piperazin-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 20. [M+H] + =408.2.

[0335] Intermediate 57: (7 1 R,7 3 S,E)-5 6 -Brom-1 1 ,2 6 ,5 5 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared using the same procedure as for intermediate 1. [M+H] + = 535.2.

[0336] Intermediate 58: (7 1 R,7 3 S,E)-1 3 -(difluoromethyl)-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =621.2.

[0337] Intermediate 59: 3-(5-(4-(methoxymethyl)-4-(piperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 20. [M+H] + =416.5.

[0338] Intermediate 61: (7 1 R,7 3 S,E)-5 6 -((S)-4-(azetidine-3-yl)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] Step 1: tert-butyl 3-((S)-4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 (-yl)-2-(methoxymethyl)piperazine-1-yl)azetidine-1-carboxylate [ka] To a solution of intermediate 3 (80 mg, 0.14 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (50 mg, 0.28 mmol) in DCE (6 mL), STAB (89 mg, 0.42 mmol) was added. The mixture was then stirred overnight at room temperature. The reaction product was quenched with saturated aqueous NaHCO3 (15 mL) 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 = 20:1) to obtain the title product (95 mg, 93.1%). [M+H] + =726.6.

[0339] Step 2: (7 1 R,7 3 S,E)-5 6 -((S)-4-(azetidine-3-yl)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] tert-butyl 3-((S)-4-((7) in DCM (5 mL) 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6To a solution of (-yl)-2-(methoxymethyl)piperazine-1-yl)azetidine-1-carboxylate (95 mg, 0.13 mmol), TFA (1 mL) was added. The mixture was stirred at room temperature for 60 minutes. The mixture was concentrated and basicized with saturated aqueous solution NaHCO3. The liquid was extracted with DCM / MeOH (3 × 20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title product (78 mg, 95.1%). [M+H] + =626.6.

[0340] Intermediate 62: 3-(3,5-difluoro-4-(4-oxopiperidine-1-yl)phenoxy)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 31. [M+H] + =339.3.

[0341] Intermediate 63: 3-(4-(azetidine-3-ylamino)-2,6-difluorophenyl)piperidine-2,6-dione [ka] Step 1: tert-butyl 3-((4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate [ka] To a solution of intermediate 6 (3.0 g, 6.2 mmol), tert-butyl 3-aminoazetidine-1-carboxylate (2.1 g, 12.4 mmol), and Cs2CO3 (4.0 g, 12.4 mmol) in 80 mL of 1,4-dioxane, Pd2(dba)3 (1.1 g, 1.24 mmol) and xanthophos (1.4 g, 2.48 mmol) were added. The mixture was stirred under N2 at 100°C for 16 hours. The mixture was filtered through a Celite pad and washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to obtain the crude residue, which was purified by silica gel column chromatography (PE:EA = 100:1-2:1) to obtain the product (3.4 g, 95.0%). [M+H] + = 574.5.

[0342] Step 2: tert-butyl 3-((4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate [ka] To a solution of tert-butyl 3-((4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate (3.4 g, 5.9 mmol) in 40 mL of DMF and 40 mL of iPrOH, Pd / C (2.0 g, 10 wt%, wet) was added. The mixture was stirred under a hydrogen atmosphere (balloon) at 50°C for 48 hours. The mixture was cooled to room temperature and filtered directly through Celite. The filtrate was concentrated under vacuum to obtain the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0~20:1) to obtain the product (1.8 g, 76.9%). [M+H] + =396.5.

[0343] Step 3: 3-(4-(azetidine-3-ylamino)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of tert-butyl 3-((4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)amino)azetidine-1-carboxylate (530 mg, 1.3 mmol) in DCM (6 mL), TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 60 minutes. The mixture was concentrated under vacuum to obtain the title product as the TFA salt (395 mg, 99.5%). [M+H] + =296.5.

[0344] Intermediate 64: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(4-oxopiperidine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] Step 1: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-5 2 ,5 3 -Dihydro-11H,51H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] To a solution of intermediate 1 (1 g, 1.92 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (549 mg, 3.84 mmol), and t-BuONa (369 mg, 3.84 mmol) in 20 mL of DMA, Pd2(dba)3 (348 mg, 0.38 mmol) and RuPhos (177 mg, 0.38 mmol) were added. The mixture was stirred under N2 at 80°C for 0.5 hours. The reaction product was quenched with NH4Cl / H2O (15 mL) and extracted with DCM (3 × 15 mL). The combined organic phase was washed with brine (1 × 15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column (DCM:CH3OH = 15:1) to obtain the title product (1 g, 88.5%). [M+H] + =584.3.

[0345] Step 2: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(4-oxopiperidine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-5 2 ,5 3A solution of -dihydro-11H,51H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclonononaphane-3-one (1 g, 2.6 mmol) was stirred at room temperature for 2 hours. Saturated aqueous solution NaHCO3 was added dropwise to the mixture to adjust the pH to 6-7. The liquid was extracted with DCM (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (800 mg, 87%). [M+H] + =540.3.

[0346] Intermediate 65: (R)-3-(2,6-difluoro-4-(piperidine-4-yloxy)phenyl)piperidine-2,6-dione [ka] 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 intermediate 6 (35 g, 72.8 mmol) in dioxane (300 mL), B(pin)2 (37.0 g, 146 mmol), Pd(dppf)Cl2 (5.28 g, 7.30 mmol), and K2CO3 (30.1 g, 218 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 (100 mL). 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 (30 g, 77.9%). [M+H] + =530.4.

[0347] Step 2: 4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenol [ka] To a stirred solution of 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) in AcOH (100 mL) and THF (100 mL), H2O2 (100 mL) was gradually added at 0°C. The mixture was stirred overnight at room temperature. Then, saturated aqueous solution Na2S2O3 (150 mL) was added, and the mixture was extracted with EA (50 mL x 3). The organic layer was washed with brine and dried on 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, 88.48%). [M+H] + =420.43.

[0348] 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 product was quenched with water (400 mL) and extracted with siRNA (100 mL x 3). The combined organic layer was washed with brine (100 mL x 3) 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, 47.6%). [M+H] + =603.3.

[0349] 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 under an H2 atmosphere. The mixture was diluted with THF / DCM / MEOH (200 mL / 200 mL / 200 mL), then sonicated in an ultrasonic cleaner for 5 minutes, and subsequently 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] + =425.3.

[0350] 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 preparative SFC under the following conditions (column: CHIRALPAK IC 5*25 cm, 5 μm; mobile phase A: CO2; mobile phase B: MeOH (1% 2 mM NH3-MeOH); gradient A:B = 40:60; flow rate 130 mL / min; column temperature 30 °C) to obtain tert-butyl(R)-4-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenoxy)piperidine-1-carboxylate, which corresponds to peak A at 8.45 min. [M+H] + =425.3.

[0351] Step 6: (R)-3-(2,6-difluoro-4-(piperidine-4-yloxy)phenyl)piperidine-2,6-dione [ka] To a 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 (10 mL), HCl (4 M in dioxane, 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 (350 mg, 91.6%), which was used in the next step without further purification. [M+H] + =325.2.

[0352] Intermediate 66: 3-(5-(4-(hydroxymethyl)-4-(piperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 20. [M+H] + =402.3.

[0353] Intermediate 67: 3-(3-fluoro-4-((3S,4R)-3-fluoro-4-(piperazine-1-yl)piperidine-1-yl)phenoxy)piperidine-2,6-dione [ka] Step 1: 1-Benzyl-4-((3S,4R)-1-(4-(benzyloxy)-2-fluorophenyl)-3-fluoropiperidine-4-yl)piperazine [ka] To a stirred solution of 4-(benzyloxy)-1-bromo-2-fluorobenzene (1 g, 3.6 mmol) and 1-benzyl-4-((3S,4R)-3-fluoropiperidine-4-yl)piperazine (986 mg, 3.6 mmol, prepared in the same manner as in steps 1-2 of intermediate 20) in dioxane (20 mL), Cs2CO3 (2.2 g, 7.1 mmol), Ruphos (663 mg, 1.42 mmol), and Pd2(dba)3 (651 mg, 0.7 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 100 °C for 6 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with ELISA (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 and eluted with DCM / MeOH (15:1) to obtain the product (700 mg, 41.2%); [M+H]+=478.3.

[0354] Step 2: tert-butyl 4-((3S,4R)-3-fluoro-1-(2-fluoro-4-hydroxyphenyl)piperidine-4-yl)piperazine-1-carboxylate [ka] Under N2 conditions, a solution of 1-benzyl-4-((3S,4R)-1-(4-(benzyloxy)-2-fluorophenyl)-3-fluoropiperidine-4-yl)piperazine (700 mg, 1.5 mmol) and di-tert-butyl dicarbonate (640 mg, 2.9 mmol) in DMF (10 mL) / i-PrOH (10 mL) was mixed with 10% Pd / C (700 mg) at 25 °C. The mixture was then changed twice with H2 and stirred at 50 °C for 12 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. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (20:1) to obtain the product (460 mg, 79%); [M+H]+=398.4.

[0355] Step 3: tert-butyl 4-((3S,4R)-1-(4-((2,6-dioxopiperidine-3-yl)oxy)-2-fluorophenyl)-3-fluoropiperidine-4-yl)piperazine-1-carboxylate [ka] A solution of tert-butyl 4-((3S,4R)-3-fluoro-1-(2-fluoro-4-hydroxyphenyl)piperidine-4-yl)piperazine-1-carboxylate (450 mg, 1.1 mmol), 3-bromopiperidine-2,6-dione (434 mg, 2.3 mmol), and Cs2CO3 (1.1 g, 3.4 mmol) in DMSO (15 mL) was stirred at 50°C for 5 hours, diluted with ELISA (400 mL), and washed with brine (3 × 150 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with DCM / MeOH (10:1) to obtain the product (210 mg, 36.5%); [M+H] + =509.6.

[0356] Step 4: 3-(3-fluoro-4-((3S,4R)-3-fluoro-4-(piperazine-1-yl)piperidine-1-yl)phenoxy)piperidine-2,6-dione [ka] To a solution of tert-butyl 4-((3S,4R)-1-(4-((2,6-dioxopiperidine-3-yl)oxy)-2-fluorophenyl)-3-fluoropiperidine-4-yl)piperazine-1-carboxylate (210 mg, 0.4 mmol) in DCM (5 mL), TFA (2 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 (100 mL), washed with saturated aqueous NaHCO3 (3 × 50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (130 mg, 77%); [M+H] + =409.5.

[0357] Intermediate 68: 3-(2,6-difluoro-4-(piperidine-4-ylamino)phenyl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 63. [M+H] + =324.2.

[0358] Intermediate 69: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(2,6-diazaspiro[3.3]heptane-2-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + = 539.5.

[0359] Intermediate 70: 3-((3-methyl-4-(4-oxopiperidine-1-yl)phenyl)amino)piperidine-2,6-dione [ka] Step 1: 8-(2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] To a stirred solution of 1-fluoro-2-methyl-4-nitrobenzene (2 g, 12.9 mmol) in DMF (30 mL), 1,4-dioxa-8-azaspiro[4.5]decane (2.2 g, 15.5 mmol) and K2CO3 (3.6 g, 25.8 mmol) were added. The resulting mixture was stirred at 80°C for 12 hours. The mixture was cooled to room temperature. The resulting mixture was poured into water (30 mL), filtered, and the filter cake was washed with water (30 mL) to obtain the product (3.2 g, 89%). [M+H] + =279.3.

[0360] Step 2: 3-Methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline [ka] Raney nickel (1 g) was added to a stirred solution of 8-(2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (3.2 g, 11.5 mmol) in THF (40 mL). The resulting mixture was stirred under H2 at room temperature for 1 hour. The mixture was filtered and concentrated under vacuum to obtain the product (2.7 g, 95%). [M+H] + =249.3.

[0361] Step 3: 2,6-Bis(benzyloxy)-N-(3-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)pyridine-3-amine [ka] To a solution of 3-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)aniline (2 g, 8.1 mmol) in dioxane (40 mL), 2,6-bis(benzyloxy)-3-bromopyridine (3.3 g, 8.9 mmol), Pd2(dba)3 (1.5 g, 1.6 mmol), RuPhos (745 mg, 1.6 mmol), and Cs2CO3 (5.3 g, 16.2 mmol) were added. The mixture was stirred under N2 at 100°C for 12 hours. The mixture was diluted with water (60 mL) and extracted with RINKAN (40 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (PE:EA = 10:1-5:1) to obtain the product (3.5 g, 80%). [M+H]+=538.4.

[0362] Step 4: 3-((3-methyl-4-(1,4-dioxa-8-azapiro[4.5]decane-8-yl)phenyl)amino)piperidine-2,6-dione [ka] To a stirred solution of 2,6-bis(benzyloxy)-N-(3-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)pyridine-3-amine (3.5 g, 6.5 mmol) in DMF / i-PrOH (100 mL / 40 mL), Pd / C (3.5 g, 10 wt%, wet) was added. The resulting mixture was stirred under H2 at 50°C for 16 hours. The mixture was filtered and concentrated under vacuum to obtain the product (2.0 g, 86%). [M+H] + =360.3.

[0363] Step 5: 3-((3-methyl-4-(4-oxopiperidine-1-yl)phenyl)amino)piperidine-2,6-dione [ka] A solution of 3-((3-methyl-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)amino)piperidine-2,6-dione (1 g, 2.8 mmol) in HCl (8 M, 10 mL) was stirred at room temperature for 2 hours. Saturated aqueous solution NaHCO3 was added dropwise to the mixture to adjust the pH to 6-7. The liquid was extracted with DCM (20 mL x 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (800 mg, 89%). [M+H] + =316.2.

[0364] Intermediate 71: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -((S)-3-methylpiperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + =541.2.

[0365] Intermediate 72: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(2,7-diazaspiro[3.5]nonan-7-il)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + = 567.5.

[0366] Intermediate 73:(7 1 R,7 3 S,E)-5 6 -((S)-4-(azetidine-3-yl)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 61. [M+H] + =640.5.

[0367] Intermediate 74: Methyl 2-(1-(2-(benzyloxy)ethyl)-5-hydroxy-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] Step 1: (2-(benzyloxy)ethyl)hydrazine [ka] To a stirred mixture of ((2-bromoethoxy)methyl)benzene (10 g, 46.7 mmol) in EtOH (100 mL), hydrazine hydrate (58 mL, 467 mmol) was added dropwise at 0°C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure and extracted with EA. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. The crude product (10 g) was used directly in the next step without further purification. [M+H] + =167.1.

[0368] Step 2: Methyl 2-(4-bromo-6-methylpyridine-2-yl)acetate [ka] To a stirred mixture of 4-bromo-2,6-dimethylpyridine (20 g, 108.1 mmol) in THF (200 mL), LDA (108.1 mL, 2 M in THF) was added dropwise at -78°C. The resulting mixture was stirred at -78°C for 30 minutes under an N2 atmosphere. Dimethyl carbonate (9.73 g, 108.1 mmol) was added dropwise to the above mixture over 10 minutes at -78°C. The resulting mixture was stirred at room temperature for a further 2 hours. The reaction mixture was quenched with NH4Cl (aqueous solution) and extracted with EA. 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 and eluted with PE / EA (3:1) to obtain methyl 2-(4-bromo-6-methylpyridine-2-yl) acetate (9 g, 34%). [M+H]+=244.1.

[0369] Step 3: Methyl(Z)-2-(4-bromo-6-methylpyridine-2-yl)-3-(dimethylamino)acrylate [ka] A mixture of methyl 2-(4-bromo-6-methylpyridine-2-yl) acetate (9 g, 37.0 mmol) and 1,1-dimethoxy-N,N-dimethylmethaneamine (5.29 g, 44.4 mmol) in DMF (100 mL) was stirred overnight at 80°C. The resulting mixture was concentrated under reduced pressure. The crude product (11 g) was used directly in the next step without further purification. [M+H] + =299.2.

[0370] Step 4: 1-(2-(benzyloxy)ethyl)-4-(4-bromo-6-methylpyridine-2-yl)-1H-pyrazole-5-ol [ka] A mixture of methyl(Z)-2-(4-bromo-6-methylpyridine-2-yl)-3-(dimethylamino)acrylate (11 g crude, 36.9 mmol) and (2-(benzyloxy)ethyl)hydrazine (9.1 g crude, 55.35 mmol) in MeOH was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5:1) to obtain 1-(2-(benzyloxy)ethyl)-4-(4-bromo-6-methylpyridine-2-yl)-1H-pyrazole-5-ol (3.8 g, 27.1%). [M+H] + =388.3.

[0371] Step 5: Methyl 2-(1-(2-(benzyloxy)ethyl)-5-hydroxy-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] A mixture of 1-(2-(benzyloxy)ethyl)-4-(4-bromo-6-methylpyrazole-2-yl)-1H-pyrazole-5-ol (3.4 g, 8.78 mmol), Pd(dppf)Cl2 (0.72 g, 0.88 mmol), and DIEA (5.65 g, 43.8 mmol) in MeOH (30 mL) was stirred at 100°C for 3 hours under a CO (20 atm) atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (3:1) to obtain methyl 2-(1-(2-(benzyloxy)ethyl)-5-hydroxy-1H-pyrazole-4-yl)-6-methylisonicotinate (3 g, 93.8%). [M+H] + =368.2. 1 H NMR(400 MHz,DMSO)δ 7.99(s,1H),7.91(s,1H),7.52(s,1H),7.35-7.21(m,5H),4.47(s,2H),4.04(t,J=4 Hz,2H),3.91(s,3H),3.73(t,J=4 Hz,2H),2.56(s,3H).

[0372] Intermediate 75: (7 1 R,7 3 S,E)-1 1 -(2-(benzyloxy)ethyl-5 6 -Brom-2 6 -methyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared using intermediate 74 in the same manner as intermediate 1.

[0373] Intermediate 76:(7 1 R,7 3 S,E)-1 1 -(2-hydroxyethyl)-26 -methyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] Step 1: tert-butyl 4-((7 1 R,7 3 S,E)-1 1 -(2-(benzyloxy)ethyl)-2 6 -methyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-carboxylate [ka] To a solution of intermediate 75 (300 mg, 0.47 mmol), tert-butylpiperazine-1-carboxylate (175 mg, 0.94 mmol), and t-BuONa (135 mg, 1.41 mmol) in 8 mL of DMA, Pd2(dba)3 (86 mg, 0.09 mmol) and RuPhos (84 mg, 0.18 mmol) were added. The resulting mixture was stirred at 90°C for 1 hour under N2. The mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:1~20:1) to obtain the product (265 mg, 75.7%). [M+H] + =747.5.

[0374] Step 2: (7 1 R,7 3 S,E)-1 1-(2-hydroxyethyl)-2 6 -methyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] tert-butyl 4-((7) in 10 mL of DCM 1 R,7 3 S,E)-1 1 -(2-(benzyloxy)ethyl-2 6 -methyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 To a solution of (-yl)piperazine-1-carboxylate (265 mg, 0.35 mmol), BBr3 in DCM (1 M, 1.0 mL) was added. After stirring at room temperature for 1 hour, the reaction mixture was quenched with aqueous NaHCO3 and extracted with DCM (3 × 30 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:1~5:1) to obtain the product (90 mg, 45.7%). [M+H] + =557.5.

[0375] Intermediate 77:(7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(3-(methylamino)azetidine-1-yl)-5 2 ,5 3 -dihydro-1 1H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + = 527.5.

[0376] Intermediate 78: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -(2,7-diazaspiro[3.5]nonan-2-il)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + =567.5

[0377] Intermediate 79: (R)-3-(2,6-difluoro-4-(3-oxoazetidine-1-yl)phenyl)piperidine-2,6-dione [ka] Step 1: 2,6-Bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidine-1-yl)-2,6-difluorophenyl)pyridine [ka] A solution of intermediate 6 (20 g, 41.49 mmol), 3-(benzyloxy)azetidine hydrochloride (9.96 g, 49.79 mmol), Pd2(dba)3 (3.79 g, 4.15 mmol), RuPhos (3.88 g, 8.3 mmol), and Cs2CO3 (40.58 g, 124.47 mmol) in dioxane (400 mL) was stirred at 100 °C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with water and extracted with SiO2. The combined organic layer was washed with brine and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / SiO(10:1) to obtain 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidine-1-yl)-2,6-difluorophenyl)pyridine (17g, 72.6%). [M+H] + =565.6.

[0378] Step 2: 3-(2,6-difluoro-4-(3-hydroxyazetidine-1-yl)phenyl)piperidine-2,6-dione [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidine-1-yl)-2,6-difluorophenyl)pyridine (17 g, 30.09 mmol) in DCM / THF (200 mL / 200 mL), Pd / C (10 wt%, wet, 34 g) was added. The mixture was stirred at 65°C for 2 days under a hydrogen atmosphere. After cooling to room temperature, the resulting mixture was filtered, and the filter cake was washed with iPrOH. The filtrate was concentrated under reduced pressure and purified by grinding with DCM / MeOH (10 / 1) to obtain 3-(2,6-difluoro-4-(3-hydroxyazetidine-1-yl)phenyl)piperidine-2,6-dione (8 g, 89.9%). [M+H] + =297.1

[0379] Step 3: 3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A solution of 3-(2,6-difluoro-4-(3-hydroxyazetidine-1-yl)phenyl)piperidine-2,6-dione (11 g, 37.16 mmol), TBSCl (11.15 g, 74.32 mmol), and imidazole (7.58 g, 111.49 mmol) in DMF (200 mL) was stirred at room temperature for 2 hours. The resulting mixture was diluted with saturated aqueous NaHCO3 (500 mL) and extracted with EA (200 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. The residue was purified by silica gel column chromatography and eluted with PE / EA (10:1) to obtain 3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (11 g, 72.4%). [M+H] + =411.2

[0380] Step 4: (R)-3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The crude product (11g) was purified by preparative SFC, and the title compound corresponds to (CHIRALPAK IF-3, 4.6*50mm, 3μm, MtBE (0.1% DEA):(MeOH:DCM=1:1)=80:20, peak A at 1.084 min). (4g, 36%, ee=100%). [M+H] + =411.2

[0381] Step 5: (R)-3-(2,6-difluoro-4-(3-hydroxyazetidine-1-yl)phenyl)piperidine-2,6-dione [ka] (R)-3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (2.6 g, 6.3 mmol) was placed in a 250 mL round-bottom flask equipped with a magnetic stirring bar. Then, 60 mL of THF and 60 mL of 1 M HCl were added at 0°C. The mixture was stirred at room temperature for 3 hours. The mixture was added dropwise to saturated aqueous solution NaHCO3 to adjust the pH to 6-7. The liquid was extracted and separated using DCM (50 mL x 3). The combined organic phase was concentrated under vacuum and purified by combiflush (DCM:MeOH = 20:1) to obtain the title compound (1.8 g, 95% yield). [M+H] + =297.2.

[0382] Step 6: (R)-3-(2,6-difluoro-4-(3-oxoazetidine-1-yl)phenyl)piperidine-2,6-dione [ka] To a stirred solution of (R)-3-(2,6-difluoro-4-(3-hydroxyazetidine-1-yl)phenyl)piperidine-2,6-dione (1.8 g, 6.0 mmol) in DCM (60 mL), Dess Martin periodinane (3.8 g, 9.0 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with DCM (100 mL) and washed with saturated aqueous Na2S2O3 (100 mL), saturated aqueous NaHCO3 (3 × 100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product (2.0 g), which was used without further purification. [M+H] + =295.2.

[0383] Intermediate 80: (R)-1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)piperidine-4-carbaldehyde [ka] The title compound was prepared in the same manner as intermediate 7. [M+H] + =337.2

[0384] Intermediate 82:1-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclonononaphane-56-yl)piperidine-4-carbaldehyde [ka] The title compound was prepared in the same manner as intermediate 64. [M+H] + = 554.5

[0385] Intermediate 83: 3-((3,5-difluoro-4-(4-oxopiperidine-1-yl)phenyl)amino)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 32. [M+H] + =338.2

[0386] Intermediate 84:(7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -((R)-3-methylpiperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared using intermediate 39 in the same manner as intermediate 2. [M+H] + = 555.3

[0387] Intermediate 85: (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -((S)-3-methylpiperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared using intermediate 39 in the same manner as intermediate 2. [M+H] + = 555.3

[0388] Intermediate 86:(7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(4-(methylamino)piperidine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared using intermediate 39 in the same manner as intermediate 2. [M+H] + = 569.3

[0389] Intermediate 87: 3-((6-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)oxy)piperidine-2,6-dione [ka] Step 1: 2,6-Bis(benzyloxy)pyridine-3-ol [ka] A solution of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (20.0 g, 47.96 mmol) and NaOH (3.8 g, 95.92 mmol) in DCM (200 mL) was mixed with H2O2 (40 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 0-6%) to obtain 2,6-bis(benzyloxy)pyridine-3-ol (10.0 g, 68.02% yield). [M+H] + =308.12

[0390] Step 2: 2,6-Bis(benzyloxy)-3-((5-bromo-6-methylpyridine-2-yl)oxy)pyridine [ka] To a solution of 2,6-bis(benzyloxy)pyridine-3-ol (10.0 g, 32.57 mmol) and 3-bromo-6-fluoro-2-methylpyridine (6.1 g, 32.57 mmol) in DMSO (100 mL), Cs2CO3 (31.7 g, 97.71 mmol) was added. The reaction mixture was stirred overnight at 80 °C. The reaction mixture was diluted with H2O and extracted with RINKAN. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE = 0-3%) to obtain 2,6-bis(benzyloxy)-3-((5-bromo-6-methylpyridine-2-yl)oxy)pyridine (13.0 g, 83.87% yield). [M+H] + =477.07

[0391] Step 3: 8-(6-((2,6-bis(benzyloxy)pyridine-3-yl)oxy)-2-methylpyridine-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] A mixture of 2,6-bis(benzyloxy)-3-((5-bromo-6-methylpyridine-2-yl)oxy)pyridine (13 g, 27.31 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (5.85 g, 41.0 mmol), Pd2(dba)3 (2.49 g, 2.73 mmol), Ruphos (2.59 g, 5.46 mmol), and Cs2CO3 (26.6 g, 81.9 mmol) in dioxane (130 mL) was stirred overnight at 100°C under a nitrogen atmosphere. The reaction mixture was diluted with H2O and extracted with butyl. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE = 0-20%) to obtain 8-(6-((2,6-bis(benzyloxy)pyridine-3-yl)oxy)-2-methylpyridine-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (6.0 g, 40.8% yield). [M+H] + =540.24

[0392] Step 4: 6-Methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-ol [ka] A 250 mL round-bottom flask equipped with a magnetic stirring bar was packed with 8-(6-((2,6-bis(benzyloxy)pyridine-3-yl)oxy)-2-methylpyridine-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (6.0 g, 11.1 mmol), THF (60.0 mL), and Pd / C (60 wt%, 6.0 g). The resulting mixture was degassed under reduced pressure, purged five times with H2, and then stirred overnight at 50°C. The mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to obtain 6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-ol (2.1 g, 75.5%). [M+H] + =251.13

[0393] Step 5: 3-((6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)oxy)piperidine-2,6-dione [ka] To a solution of 6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-ol (2.1 g, 8.39 mmol) and 3-bromopiperidine-2,6-dione (2.0 g, 10.5 mmol) in THF (21 mL), NaH (671.6 mg, 16.78 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous solution NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE = 0-60%) to obtain 3-((6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridine-2-yl)oxy)piperidine-2,6-dione (1.25 g, 41.6%). [M+H] + =362.2

[0394] Step 6: 3-((6-methyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)oxy)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in step 4 of intermediate 7. [M+H] + =318.2

[0395] Intermediate 88:(7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(4-((methylamino)methyl)piperidine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared using intermediate 39 in the same manner as intermediate 2. [M+H] + = 583.5

[0396] Intermediate 89: 3-(3-methyl-4-(4-oxopiperidine-1-yl)phenoxy)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 31. [M+H] + =317.2

[0397] Intermediate 90: (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(methyl(piperidine-4-yl)amino)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + = 569.5

[0398] Intermediate 91: 3-(4-((3S,4R)-3-fluoro-4-(piperazine-1-yl)piperidine-1-yl)phenoxy)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediates 31 and 20. [M+H] + =391.3

[0399] Intermediate 93: (7 1 S,7 3R,E)-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =585.4.

[0400] Intermediate 94: (7 1 R,7 3 S,E)-5 5 -Methoxy-5 6 -((S)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =615.4.

[0401] Intermediate 95: (7 1 R,7 3 S,E)-5 5 -Methoxy-1 1 ,1 3 ,2 6 -trimethyl-5 6-(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + = 571.5.

[0402] Intermediate 96: (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(3-(methylamino)azetidine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + = 541.5.

[0403] Intermediate 98: (7 1 R,7 3 S,E)-1 1 -(2-hydroxyethyl)-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 3 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 75 and 76. [M+H] + =615.5.

[0404] Intermediate 99: (7 1 R,7 3 S,E)-1 1 -(2-hydroxyethyl)-5 6 -((S)-3-(methoxymethyl)piperazine-1-yl)-1 3 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 75 and 76. [M+H] + =615.5.

[0405] Intermediate 100: 3-(4-(3-aminoazetidine-1-yl)-3,5-difluorophenoxy)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediates 31 (step 1) and 63 (steps 1 and 3). [M+H] + =312.5.

[0406] Intermediate 101: (7 1 R,7 3 S,E)-1 1 ,1 3,2 6 -trimethyl-5 6 -(4-oxopiperidine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 64. [M+H] + =554.3.

[0407] Intermediate 102: 3-((4,6-dimethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)amino)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 32. [M+H] + =331.3.

[0408] Intermediate 103: (7 1 R,7 3 S,E)-1 1 -(2-methoxyethyl)-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 3 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 74, 75, and 2. [M+H] + =629.6.

[0409] Intermediate 104: (7 1 R,7 3 S,E)-1 1 -(2-methoxyethyl)-1 3 ,2 6 -dimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 74, 75, and 2. [M+H] + = 585.5.

[0410] Intermediate 105: (7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-5 6 -((R)-3-methylpiperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + = 541.5.

[0411] Intermediate 106: 2-((S)-4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6-trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-56-yl)piperazine-2-yl)acetonitrile [ka] The title compound was prepared in the same manner as intermediate 2. [M+H] + =580.4.

[0412] Intermediate 107: 3-(2,6-difluoro-4-(4-(2-oxopiperazine-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] Step 1: tert-butyl4-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)piperidine-4-yl)-3-oxopiperazine-1-carboxylate [ka] To a stirred solution of intermediate 6 (1.5 g, 3.1 mmol) and tert-butyl 3-oxo-4-(piperidine-4-yl)piperazine-1-carboxylate (1.2 g, 4.2 mmol) in DMA (30 mL), Cs2CO3 (3.17 g, 9.75 mmol), Pd2(dba)3 (300 mg, 0.325 mmol), and Ruphos (300 mg, 0.65 mmol) were added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred under a nitrogen atmosphere at 100 °C for 16 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with ELISA (200 mL) and washed with water (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 and eluted with PE / Â(4:1) to obtain the product (360 mg, 16.9%); [M+H] + =685.7.

[0413] Step 2: tert-butyl4-(1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)piperidine-4-yl)-3-oxopiperazine-1-carboxylate [ka] 360 mg, 0.53 mmol of tert-butyl 4-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)piperidine-4-yl)-3-oxopiperazine-1-carboxylate was dissolved in 8 mL of DMF and 4 mL of iPrOH. 350 mg, 10% by weight, wet Pd / C was added to the solution all at once. The resulting mixture was stirred overnight at 50°C under a hydrogen atmosphere (1 atm). The solid was removed by filtration, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography and eluted with DMC / MeOH (20:1) to obtain the product (200 mg, 75.1%); [M+H] + =507.5.

[0414] Step 3: 3-(2,6-difluoro-4-(4-(2-oxopiperazine-1-yl)piperidine-1-yl)phenyl)piperidine-2,6-dione [ka] In a 100 mL round-bottom flask equipped with a magnetic stirring bar, tert-butyl 4-(1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)piperidine-4-yl)-3-oxopiperazine-1-carboxylate (200 mg, 0.53 mmol), DCM (6 mL), and TFA (2 mL) were added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to obtain the product (270 mg) as the TFA salt, which was used without further purification. [M+H] + =407.4.

[0415] Intermediate 108: (7 1 R,7 3 S,E)-5 5 -Fluoro-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =603.5.

[0416] Intermediate 109: 3-((4,6-dimethyl-5-(4-oxopiperidine-1-yl)pyridine-2-yl)oxy)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 87. [M+H] + =332.2.

[0417] Intermediate 110: (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -(4-methyl-4-((methylamino)methyl)piperidine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =597.6.

[0418] Intermediate 111: (7 1 R,7 3 S,E)-5 5 -Fluoro-5 6 -((S)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =603.5.

[0419] Intermediate 112: (7 1 R,7 3 S,E)-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 1 ,1 3 ,2 6 ,5 5 -Tetramethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =599.5.

[0420] Intermediate 113: (7 1 R,7 3 S,E)-5 6 -((S)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,1 3 ,2 6 ,5 5 -Tetramethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =599.5.

[0421] Intermediate 114: (7 1 R,7 3 S,E)-2 6 -Chloro-1 1,1 3 -dimethyl-5 6 -(piperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =561.3.

[0422] Intermediate 115: (R)-2-(1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)piperidine-4-yl)acetaldehyde [ka] The title compound was prepared in the same manner as intermediate 44. [M+H] + =350.2.

[0423] Intermediate 116: (R)-1-(4-((R)-2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbaldehyde [ka] Step 1: (R)-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-yl)methanol [ka] To a solution of (R)-pyrrolidine-3-ylmethanol (9.2 g, 91.0 mmol) in dioxane (600 mL), intermediate 6 (52.5 g, 109 mmol), Pd2(dba)3 (8.3 g, 9.0 mmol), Johnphos (5.39 g, 18.0 mmol), and K3PO4 (57.8 g, 272 mmol) were added. The resulting mixture was stirred overnight at 110 °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 = 0-25%) to obtain (R)-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-yl)methanol (33.5 g, 73.1%). [M+H] + = 503.21

[0424] Step 2: (R)-3-(2,6-difluoro-4-((R)-3-(hydroxymethyl)pyrrolidine-1-yl)phenyl)piperidine-2,6-dione [ka] A 1000 mL round-bottom flask equipped with a magnetic stirring bar was packed with (R)-(1-(4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-yl)methanol (33.5 g, 66.7 mmol), dry THF (400 ml), and Pd / C (10 wt%, 34 g). The resulting mixture was degassed under reduced pressure, purged three times with H2, and then stirred overnight at 40°C. The mixture was diluted with THF / EA (1 / 1), sonicated in an ultrasonic cleaner for 10 minutes, and then filtered through a Celite pad. The filtrate was concentrated under vacuum, and the residue was purified by grinding (PE / EA = 1 / 1) to obtain 3-(2,6-difluoro-4-((R)-3-(hydroxymethyl)pyrrolidine-1-yl)phenyl)piperidine-2,6-dione (16.5 g, 76.7%). The title compound was purified by preparative chiral SFC and analyzed at 0.999 min under the following conditions corresponding to peak A: [M+H]+=325.0 Injection volume (μL): 1.00 Column name: (S,S)WHELK-01 4.6*50mm, 3.5μm Solvent A: CO2 Solvent B: MeOH (0.1% DEA) Temperature (℃):35 Flow rate (mL / min): 4 Gradient (B%): 10% to 50% in 2.0 minutes, hold at 50% for 1.0 minute. Back pressure (psi): 1500

[0425] Step 3: (R)-1-(4-((R)-2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbaldehyde [ka] The title compound was prepared in the same manner as in step 2 of intermediate 33. [M+H] + =323.0.

[0426] Intermediate 117: 3-(2,6-difluoro-4-((S)-3-(piperazin-1-yl)pyrrolidine-1-yl)phenyl)piperidine-2,6-dione [ka] Step 1: tert-butyl((1R,3S)-3-(4-benzylpiperazine-1-yl)cyclopentyl)carbamate [ka] A mixture of tert-butyl((1R,3S)-3-aminocyclopentyl)carbamate (7 g, 35 mmol), benzyl-bis(2-chloroethyl)amine hydrochloride (9.38 g, 35 mmol), KI (581 mg, 3.5 mmol), and K2CO3 (24.2 g, 175 mmol) in acetonitrile (140 mL) was stirred overnight at 80°C. After cooling the reaction mixture, it was diluted with dichloromethane and extracted with 1N HCl. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (ACN / water (0.05% TFA) = 0-30%) to obtain tert-butyl((1R,3S)-3-(4-benzylpiperazin-1-yl)cyclopentyl)carbamate (5.3 g, 42.0%). [M+H] + =360.3

[0427] Step 2: (1R,3S)-3-(4-benzylpiperazine-1-yl)cyclopentane-1-aminetrifluoroacetate [ka] To a solution of tert-butyl((1R,3S)-3-(4-benzylpiperazine-1-yl)cyclopentyl)carbamate (5.3 g, 14.8 mmol) in dichloromethane (40 mL), trifluoroacetic acid (20 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by grinding (PE / EA = 10 / 1) to obtain (1R,3S)-3-(4-benzylpiperazine-1-yl)cyclopentan-1-aminetrifluoroacetate (5.4 g, 98.1%). [M+H] + =260.11

[0428] Step 3: N-((1R,3S)-3-(4-benzylpiperazine-1-yl)cyclopentyl)-4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluoroaniline [ka] A mixture of intermediate 6 (6.0 g, 12.5 mmol), (1R,3S)-3-(4-benzylpiperazin-1-yl)cyclopentan-1-aminetrifluoroacetate (5.5 g, 15.0 mmol), Pd2(dba)3 (1.1 g, 1.24 mmol), Ruphos (593.7 mg, 1.24 mmol), and Cs2CO3 (12.1 g, 37.4 mmol) in dioxane (60 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA / PE = 50%~100%) to obtain a crude solid. Next, the residue was purified by reverse-phase column chromatography (ACN / water (0.05% TFA) = 0-50%) to obtain N-((1R,3S)-3-(4-benzylpiperazin-1-yl)cyclopentyl)-4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluoroaniline (5.3g, 64.3%). [M+H] + =661.33.

[0429] Step 4: tert-butyl 4-((1S,3R)-3-((4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)amino)cyclopentyl)piperazine-1-carboxylate [ka] A mixture of N-((1R,3S)-3-(4-benzylpiperazine-1-yl)cyclopentyl)-4-(2,6-bis(benzyloxy)pyridine-3-yl)-3,5-difluoroaniline (5.0 g, 7.57 mmol), Boc2O (2.0 g, 9.08 mmol), and Pd / C (5.0 g) in THF (80 mL) was stirred overnight at 50°C under an H2 atmosphere. After cooling the reaction mixture, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH / DCM = 0-5%) to obtain tert-butyl 4-((1S,3R)-3-((4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)amino)cyclopentyl)piperazine-1-carboxylate (2.64 g, 71.3%). [M+H] + =493.25

[0430] Step 5: 3-(2,6-difluoro-4-((S)-3-(piperazin-1-yl)pyrrolidine-1-yl)phenyl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as in step 2 of intermediate 2. [M+H] + =379.2.

[0431] Intermediate 118: (7 1 R,7 3 S,E)-5 6 -((R)-3-ethylpiperazin-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =569.2.

[0432] Intermediate 119: (7 1 R,7 3 S,E)-5 6 -((S)-3-ethylpiperazin-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =569.2.

[0433] Intermediate 120: (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -((R)-2-methylpiperazine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =555.2.

[0434] Intermediate 121: (7 1 R,7 3S,E)-5 6 -((2R,5S)-2,5-dimethylpiperazine-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =569.2.

[0435] Intermediate 122: (7 1 R,7 3 S,E)-5 6 -(2,5-diazabicyclo[2.2.2]octan-2-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =567.4

[0436] Intermediate 123: (7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-5 6 -((S)-2-methylpiperazine-1-yl)-5 2 ,53 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + = 555.3

[0437] Intermediate 124: (7 1 R,7 3 S,E)-5 6 -((2R,5R)-2,5-dimethylpiperazine-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =569.2.

[0438] Intermediate 125: (7 1 R,7 3 S,E)-5 6 -((2S,5S)-2,5-dimethylpiperazine-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =569.2.

[0439] Intermediate 126: (7 1 R,7 3 S,E)-5 6 -((2S,6S)-2,6-dimethylpiperazine-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =569.2.

[0440] Intermediate 127: (7 1 R,7 3 S,E)-5 6 -((2S,5R)-2,5-dimethylpiperazine-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =569.2.

[0441] Intermediate 128: (7 1 R,7 3 S,E)-5 6 -((S)-2-(fluoromethyl)piperazin-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + = 573.6.

[0442] Intermediate 129: (7 1 R,7 3 S,E)-5 6 -((S)-3-(difluoromethyl)piperazin-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =591.5.

[0443] Intermediate 130: (7 1 R,7 3 S,E)-5 6 -((R)-4-(azetidine-3-yl)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 61. [M+H] + =640.5.

[0444] Intermediate 131: (7 1 R,7 3 S,E)-5 6 -((R)-4-(azetidine-3-yl)-3-(methoxymethyl)piperazine-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediate 61. [M+H] + =626.6

[0445] Intermediate 132: (7 1 R,7 3 S,E)-5 6 -((R)-3-(fluoromethyl)piperazin-1-yl)-11 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + = 573.5.

[0446] Intermediate 133: (7 1 R,7 3 S,E)-5 6 -((R)-2-(fluoromethyl)piperazin-1-yl)-1 1 ,1 3 ,2 6 -trimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + = 573.6.

[0447] Intermediate 134: (R)-3-(2,6-difluoro-4-(piperidine-4-ylamino)phenyl)piperidine-2,6-dione [ka] The title compound was prepared in the same manner as intermediate 63. [M+H] + =324.2.

[0448] Intermediate 135: tert-butyl(S)-4-(2-imino-3-(((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1-methyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)2,3-dihydro-1H-benzo[d]imidazole-5-yl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] Step 1: ((1S,3R)-3-(((5-fluoro-2-nitrophenyl)amino)methyl)cyclopentyl)methanol [ka] 2,4-Difluoronitrobenzene (1.15 g, 7.26 mmol, 1.1 equivalents) was added to a 50 mL three-necked round-bottom flask, and toluene (10 mL, 10 volumes) was added. Then, TEA (1.40 g, 13.9 mmol, 2.1 equivalents) was added, followed by ((1S,3R)-3-(aminomethyl)cyclopentyl)methanol hydrochloride (1.1 g, 6.6 mmol, 1.0 equivalent). The mixture was heated to 75°C and stirred overnight at 75°C. The reaction mixture was cooled to room temperature and washed with water (approximately 2 × 10 volumes). The organic layer was collected, and the solvent was changed from toluene to acetonitrile. The compound in acetonitrile (5 volumes) was used directly in the next step. [M+H] + =269.2

[0449] Step 2: tert-butyl(S)-4-(3-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] ((1S,3R)-3-(((5-fluoro-2-nitrophenyl)amino)methyl)cyclopentyl)methanol in acetonitrile was mixed with TEA (1.0 g, 9.9 mmol, 1.5 equivalents), followed by tert-butyl(S)-2-(methoxymethyl)piperazine-1-carboxylate (1.27 g, 8.0 mmol, 1.2 equivalents). The mixture was heated to 75°C and stirred at 75°C for 24 hours. The reaction mixture was cooled to room temperature and diluted with DCM (10-15 vols) to dissolve the product. The mixture was washed with water (approximately 2 × 10 vols). The organic layer was concentrated and purified by silica column chromatography (EA / DCM = 0-30%) to obtain tert-butyl(S)-4-(3-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate. [M+H] + =479.3

[0450] Step 3: tert-butyl(S)-4-(3-((((1R,3S)-3-(((4-(4-((methoxycarbonyl)-6-methylpyridine-2-yl)-1-methyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] In a 50 mL flask, tert-butyl(S)-4-(3-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate (1.14 g, 2.38 mmol, 1.0 equivalent) and methyl 2-(5-hydroxy-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (588 mg, 2.38 mmol, 1.0 equivalent) were added. Then, THF (10 mL, 10 volumes) was added to obtain a slurry. Next, triphenylphosphine (750 mg, 2.86 mmol, 1.2 equivalents) was added. Then, DIAD (578 mg, 2.86 mmol, 1.2 equivalents) was slowly added using a syringe, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by silica column chromatography (EA / DCM = 0-30%) to obtain tert-butyl(S)-4-(3-((((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1-methyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate (1.55 g, 92.0% yield). [M+H] + =708.4

[0451] Step 4: tert-butyl(S)-4-(4-amino-3-((((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1-methyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)phenyl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] A stainless steel reactor was packed with tert-butyl(S)-4-(3-((((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1-methyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate (1.55 g, 2.2 mmol, 1.00 equivalent) and (5 wt% Pt, 62.5% H2O, Kaili Catalyst & New Materials Co., Ltd) Pt / V / C (826 mg, 0.13 mmol, 0.06 equivalent). The reactor was evacuated and packed with N2 for 3 cycles. 25 ml (15V) of anhydrous THF was transferred to the reactor. The reactor was purged with N2 3 times and with H2 3 times. The reactor was pressurized with hydrogen at 0.4 MPa and stirred at 40°C for 24 hours. The mixture was filtered, and the solvent was concentrated to obtain tert-butyl(S)-4-(4-amino-3-((((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1-methyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)phenyl)-2-(methoxymethyl)piperazine-1-carboxylate (1.35 g, 90.9% yield). [M+H] + =678.4

[0452] Step 5: tert-butyl(S)-4-(2-imino-3-(((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1-methyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)2,3-dihydro-1H-benzo[d]imidazole-5-yl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] A solution of tert-butyl(S)-4-(4-amino-3-((((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1-methyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)phenyl)-2-(methoxymethyl)piperazine-1-carboxylate (1.35 g, 2.0 mmol) and BrCN (0.25 g, 2.4 mmol) in 30 mL of MeOH was stirred at room temperature for 2 hours. The mixture was extracted with DCM, washed with aqueous saturated NaHCO3, and separated. The organic layer was concentrated and purified by silica column chromatography (EA / DCM = 0-30%) to obtain tert-butyl(S)-4-(2-imino-3-(((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1-methyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)2,3-dihydro-1H-benzo[d]imidazole-5-yl)-2-(methoxymethyl)piperazine-1-carboxylate (1.30 g, 92.9% yield). [M+H] + =703.4

[0453] Intermediate 136: Methyl 2-(5-(((1S,3R)-3-((2-amino-6-bromo-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate [ka] Step 1: Methyl 2-(5-(((1S,3R)-3-((6-bromo-2-((ethoxycarbonyl)amino)-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)-1-methyl- 1 H-pyrazole-4-yl)-6-methylisonicotinate [ka] To a solution of methyl 2-(5-(((1S,3R)-3-(((2-amino-5-bromophenyl)amino)methyl)cyclopentyl)methoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (4.2 g, 8.07 mmol, 1 equivalent) (product of step 8 of intermediate 1) in THF (40 ml, 10 volumes), 1.05 equivalents of O-ethyl carboisothiocyanate were added in two batches to the reactor, and the mixture was stirred at 30°C for 30 minutes after each addition. The reaction mixture was stirred at room temperature for 1 hour to obtain the intermediate ([M+H] += 659.6). Next, DIPEA (1.56 g, 12.1 mmol, 1.5 equivalents) and EDCI (1.86 g, 9.68 mmol, 1.2 equivalents) were added. The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with H2O and extracted with DCM. After removing the DCM, the crude product was purified by column chromatography (5% MeOH / DCM) to obtain methyl 2-(5-(((1S,3R)-3-((6-bromo-2-((ethoxycarbonyl)amino)-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (4.6 g, 93% yield). [M+H] += 625.5.

[0454] Step 2: Methyl 2-(5-(((1S,3R)-3-((2-amino-6-bromo-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)-1-methyl- 1 H-pyrazole-4-yl)-6-methylisonicotinate [ka] A solution of methyl 2-(5-(((1S,3R)-3-((6-bromo-2-((ethoxycarbonyl)amino)-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (4.6 g, 7.37 mmol) in CH3CN (46 ml, 10 volumes) and H2O (4.6 ml, 1 volume) was stirred at 80°C for 20 hours. The mixture was concentrated to obtain methyl 2-(5-(((1S,3R)-3-((2-amino-6-bromo-1H-benzo[d]imidazole-1-yl)methyl)cyclopentyl)methoxy)-1-methyl-1H-pyrazole-4-yl)-6-methylisonicotinate (3.9 g, 95.8% yield). [M+H] + = 553.5.

[0455] Intermediate 137: tert-butyl(R)-4-(2-imino-3-(((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)2,3-dihydro-1H-benzo[d]imidazole-5-yl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] Step 1: tert-butyl(R)-4-(3-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] ((1S,3R)-3-(((5-fluoro-2-nitrophenyl)amino)methyl)cyclopentyl)methanol in acetonitrile was mixed with TEA (1.0 g, 9.9 mmol, 1.5 equivalents), followed by tert-butyl(R)-2-(methoxymethyl)piperazine-1-carboxylate (1.27 g, 8.0 mmol, 1.2 equivalents). The mixture was heated to 75°C and stirred at 75°C for 24 hours. The reaction mixture was cooled to room temperature and diluted with DCM (10-15 vols) to dissolve the product. The mixture was washed with water (approximately 2 × 10 vols). The organic layer was concentrated and purified by silica column chromatography (EA / DCM = 0-30%) to obtain tert-butyl(R)-4-(3-(((( 1 R, 3 S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate was obtained. [M+H] + =479.3

[0456] Step 2: tert-butyl(R)-4-(3-((((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] In a 50 mL flask, combine tert-butyl(R)-4-(3-((((1R,3S)-3-(hydroxymethyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate (1.14 g, 2.38 mmol, 1.0 equivalent) and methyl 2-(5-hydroxy-1,3-dimethyl- 1H-pyrazole-4-yl)-6-methylisonicotinate (588 mg, 2.38 mmol, 1.0 equivalent) was added. Then, THF (10 mL, 10 volumes) was added to obtain a slurry. Next, triphenylphosphine (750 mg, 2.86 mmol, 1.2 equivalents) was added. Then, DIAD (578 mg, 2.86 mmol, 1.2 equivalents) was slowly added using a syringe and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by silica column chromatography (EA / DCM = 0-30%) to obtain tert-butyl(R)-4-(3-((((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate (1.55 g, 92.0% yield). [M+H] + =722.4

[0457] Step 3: tert-butyl(R)-4-(4-amino-3-((((1R,3S)-3-(((4-(((4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)phenyl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] A stainless steel reactor was packed with tert-butyl(R)-4-(3-((((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate (1.55 g, 2.2 mmol, 1.00 equivalent) and (5 wt% Pt, 62.5% H2O, Kaili Catalyst & New Materials Co., Ltd) Pt / V / C (826 mg, 0.13 mmol, 0.06 equivalent). The reactor was evacuated and packed with N2 for 3 cycles. 25 ml (15V) of anhydrous THF was transferred to the reactor. The reactor was purged with N2 3 times and with H2 3 times. The reactor was pressurized with hydrogen at 0.4 MPa and stirred at 40°C for 24 hours. The mixture was filtered, and the solvent was concentrated to obtain tert-butyl(R)-4-(4-amino-3-((((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)phenyl)-2-(methoxymethyl)piperazine-1-carboxylate (1.35 g, 90.9% yield). [M+H] + =692.4

[0458] Step 4: tert-butyl(R)-4-(2-((ethoxycarbonyl)amino)-1-(((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)1H-benzo[d]imidazole-6-yl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl(R)-4-(4-amino-3-((((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)amino)phenyl)-2-(methoxymethyl)piperazine-1-carboxylate (1.35 g, 1.95 mmol, 1 equivalent) in THF (15 ml, 10 volumes), O-ethylcarboisothiocyanate (1.05 equivalents) was added in two batches to the reactor, and after each addition, the mixture was stirred at 30°C for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour to obtain the intermediate ([M+H] + =823.4). Next, DIPEA (377 mg, 2.9 mmol, 1.5 equivalents) and EDCI (450 mg, 2.34 mmol, 1.2 equivalents) were added. The resulting reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with H2O and extracted with DCM. After removing the DCM, the crude product was purified by column chromatography (5% MeOH / DCM) to obtain tert-butyl(R)-4-(2-((ethoxycarbonyl)amino)-1-(((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)-1H-benzo[d]imidazole-6-yl)-2-(methoxymethyl)piperazine-1-carboxylate (1.38 g, 89% yield). [M+H] + =789.4

[0459] Step 5: tert-butyl(R)-4-(2-imino-3-(((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)2,3-dihydro-1H-benzo[d]imidazole-5-yl)-2-(methoxymethyl)piperazine-1-carboxylate [ka] A solution of tert-butyl(R)-4-(2-((ethoxycarbonyl)amino)-1-(((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)-1H-benzo[d]imidazole-6-yl)-2-(methoxymethyl)piperazine-1-carboxylate (1.38 g, 1.75 mmol) in CH3CN (14 ml, 10 volumes) and H2O (1.5 ml, 1 volume) was stirred at 80°C for 20 hours. The mixture was concentrated to obtain tert-butyl(R)-4-(2-imino-3-(((1R,3S)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridine-2-yl)-1,3-dimethyl-1H-pyrazole-5-yl)oxy)methyl)cyclopentyl)methyl)2,3-dihydro-1H-benzo[d]imidazole-5-yl)-2-(methoxymethyl)piperazine-1-carboxylate (1.15 g, 91.7% yield). [M+H] + =717.4

[0460] Intermediate 138: (7 1 R,7 3 S,E)-1 3 -ethyl-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 1 ,2 6 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =599.5.

[0461] Intermediate 139: (7 1 R,7 3 S,E)-26 -Chloro-5 6 -((R)-3-(methoxymethyl)piperazin-1-yl)-1 1 ,1 3 -dimethyl-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared in the same manner as intermediates 1 and 2. [M+H] + =605.3.

[0462] Intermediate 140: (7 1 R,7 3 S,E)-1 1 -(2-hydroxyethyl)-2 6 -methyl-5 6 -(4-oxopiperidine-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-3-one [ka] The title compound was prepared using intermediate 75 in the same manner as intermediate 64. [M+H] + =570.3.

[0463] Compound synthesis Example 1: (R)-3-(4-(4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 (-yl)piperazine-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of intermediate 2 (80 mg, 0.15 mmol) and intermediate 7 (68 mg, 0.21 mmol) in DCE (8 mL), STAB (95 mg, 0.45 mmol) was added. The mixture was then stirred overnight at 50°C. The reaction product was quenched with saturated aqueous NaHCO3 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) and subsequently by preparative HPLC chromatography to obtain the title product (33 mg, 26.1%). 1 H NMR(500 MHz,DMSO)δ 12.42(s,1H),10.87(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.36(d,J=8.7 Hz,1H),7.01(s,1H),6.90(d,J=8.7 Hz,1H),6.66(s,1H),6.63(s,1H),4.30(s,1H),4.19(s,1H),4.05(dd,J=12.5,5.0 Hz,3H),3.81(d,J=12.1 Hz,2H),3.74(s,3H),3.16(s,4H),2.77(dd,J=15.1,7.7 Hz,3H),2.68(s,4H),2.65-2.57(m,2H),2.55(s,3H),2.53(d,J=4.0 Hz,2H),2.49-2.40(m,2H),2.09(qd,J=13.4,4.9 Hz,1H),1.99-1.79(m,6H),1.67(s,1H),1.54-1.43(m,2H).[M+H] + =833.7

[0464] Example 2: 3-(5-(4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-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 2 and 15 in the same manner as in Example 1. 1 H NMR(500 MHz,DMSO)δ 12.56(s,1H),10.88(s,1H),8.64(s,1H),8.02(s,1H),7.60(s,1H),7.56(d,J=8.1 Hz,1H),7.44(d,J=8.7 Hz,1H),7.27(d,J=7.9 Hz,1H),7.17(s,1H),7.01(d,J=8.3 Hz,1H),4.33(s,1H),4.22(s,1H),4.13(s,2H),4.00(dd,J=9.8,5.2 Hz,1H),3.95(d,J=11.6 Hz,2H),3.77(s,3H),3.72(d,J=10.9 Hz,2H),3.41-3.39(m,2H),3.29(d,J=10.7 Hz,4H),3.08(d,J=11.8 Hz,2H),2.74(t,J=11.4 Hz,2H),2.67-2.58(m,7H),2.48(s,3H),2.25(d,J=10.1 Hz,3H),2.09(dd,J=13.3,5.2 Hz,1H),1.96-1.80(m,6H),1.68(s,1H).[M+H] + =812.7

[0465] Example 3: 3-(5-(4-(4-((7 1 S,7 3 R,E)-11 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-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 5 and 15 in the same manner as in Example 1. 1 H NMR(500 MHz,DMSO)δ 12.56(s,1H),10.88(s,1H),8.64(s,1H),8.02(s,1H),7.60(s,1H),7.56(d,J=8.1 Hz,1H),7.44(d,J=8.7 Hz,1H),7.27(d,J=7.9 Hz,1H),7.17(s,1H),7.01(d,J=8.3 Hz,1H),4.33(s,1H),4.22(s,1H),4.13(s,2H),4.00(dd,J=9.8,5.2 Hz,1H),3.95(d,J=11.6 Hz,2H),3.77(s,3H),3.72(d,J=10.9 Hz,2H),3.41-3.39(m,2H),3.29(d,J=10.7 Hz,4H),3.08(d,J=11.8 Hz,2H),2.74(t,J=11.4 Hz,2H),2.67-2.58(m,7H),2.48(s,3H),2.25(d,J=10.1 Hz,3H),2.09(dd,J=13.3,5.2 Hz,1H),1.96-1.79(m,6H),1.68(s,1H).[M+H] + =812.6

[0466] Example 4: 3-(5-(4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,53 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)-6-ethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 2 and 17 in the same manner as in Example 1. 1 H NMR(500 MHz,DMSO)δ 12.39(s,1H),10.79(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.40(d,J=8.2 Hz,1H),7.37(d,J=8.7 Hz,1H),7.11(d,J=8.2 Hz,1H),7.02(s,1H),6.91(dd,J=8.8,1.7 Hz,1H),4.30(s,1H),4.19(t,J=8.0 Hz,1H),4.09(s,2H),3.91(dd,J=7.7,5.6 Hz,1H),3.75(d,J=5.0 Hz,3H),3.18(s,4H),3.07(s,2H),2.80(td,J=14.8,7.4 Hz,1H),2.75-2.52(m,15H),2.43-2.34(m,1H),2.23-2.09(m,2H),1.99-1.75(m,6H),1.70-1.57(m,3H),1.18(t,J=7.4 Hz,3H).[M+H] + =826.6.

[0467] Example 5: 3-(4-(4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-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 2 and 10 in the same manner as in Example 1. 1 H NMR(500 MHz,DMSO)δ 12.40(s,1H),11.06(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.37(d,J=8.7 Hz,1H),7.23(t,J=7.9 Hz,1H),7.05(d,J=8.2 Hz,1H),7.03(s,1H),6.92(d,J=9.0 Hz,1H),6.80(s,1H),5.31-5.09(m,1H),4.32(ddd,J=14.6,11.5,5.9 Hz,1H),4.19(t,J=7.7 Hz,1H),4.14-4.01(m,2H),3.74(s,3H),3.23-3.13(m,4H),2.94-2.86(m,3H), 2.85-2.77(m,3H),2.72(s,4H),2.67-2.57(m,4H),2.55(s,3H),2.52(d,J=1.4 Hz,1H),2.41(t,J=10.7 Hz,1H),1.96-1.90(m,4H),1.87-1.79(m,2H),1.68-1.57(m,3H),1.42(s,3H),1.41(s,3H).[M+H] + =880.7.

[0468] Example 6: 3-(5-(4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-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 2 and 12 in the same manner as in Example 1. 1 H NMR(500 MHz,DMSO)δ 12.41(s,1H),10.87(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.37(d,J=8.7 Hz,1H),7.32(d,J=11.6 Hz,1H),7.03(s,1H),6.92(dd,J=8.8,1.9 Hz,1H),4.39-4.25(m,1H),4.23-4.17(m,1H),4.14(dd,J=11.2,5.3 Hz,1H),4.11-4.05(m,1H),3.74(s,3H),3.23-3.14(m,7H),2.76-2.71(m,5H),2.68(d,J=5.2 Hz,1H),2.66(s,1H),2.64-2.62(m,1H),2.59-2.56(m,1H),2.55(s,3H),2.54-2.5 2(m,2H),2.44-2.35(m,5H),2.28-2.19(m,1H),2.08-2.01(m,1H),1.94(d,J=11.3 Hz,3H),1.87-1.79(m,2H),1.70-1.58(m,3H).[M+H] + =830.7.

[0469] Example 7: 3-(5-(2-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)ethyl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] DMSO (2 mL) was added to a solution of intermediate 2 (90 mg, 0.17 mmol), intermediate 19 (70 mg, 0.21 mmol), and KI (65 mg, 0.35 mmol) in MeCN (5 mL) and DIEA (67 mg, 0.52 mmol). The resulting mixture was heated overnight at 80°C under N2. 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) and subsequently by preparative HPLC chromatography to obtain the title product (21 mg, 16%). 1 H NMR(500 MHz,DMSO)δ 12.42(s,1H),10.79(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.37(d,J=8.7 Hz,1H),7.04(s,1H),6.98(s,1H),6.92(d,J=8.8 Hz,1H),4.37-4.26(m,1H),4.19(t,J=7.9 Hz,1H),4.13-4.02(m,2H),3.85(dd,J=9.3,5.3 Hz,1H),3.74(s,3H),3.26-3.18(m,4H),2.86-2.79(m,2H),2.73-2.66(m,4H),2.64-2.56(m,5H),2.55(s,3H),2.52(s,2H),2.47(s,3H) ),2.39-2.35(m,1H),2.32(s,3H),2.25-2.16(m,1H),2.12-2.04(m,1H),1.97-1.89(m,1H),1.87-1.79(m,2H),1.71-1.63(m,1H).[M+H] + =771.6.

[0470] Example 8: 3-(5-(3-((4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)methyl)azetidine-1-yl)-4,6-dimethylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 2 and 18 in the same manner as in Example 7. 1 H NMR(500 MHz,DMSO)δ 10.72(s,1H),8.52(s,1H),7.89(s,1H),7.44(s,1H),7.36(d,J=8.7 Hz,1H),7.03(d,J=1.7 Hz,1H),6.91(dd,J=8.8,2.0 Hz,1H),6.74(s,1H),4.36-4.28(m,1H),4.25(t,J=7.4 Hz,2H),4.19(t,J=8.1 Hz,1H),4.14-4.00(m,2H),3.78(t,J=6.5 Hz,2H),3.74(s,3H),3.72(d,J=5.3 Hz,1H),3.17(s,4H),2.79(dt,J=13.7,6.7 Hz,1H),2.68-2.52(m,15H),2.35(s,3H),2.23(s,3H),2.20-2.11(m,1H),2.0 9-2.01(m,1H),1.96-1.88(m,1H),1.86-1.78(m,2H),1.73-1.62(m,1H).[M+H] + =812.6.

[0471] Example 9: (R)-3-(4-(4-((S)-4-((7 1 R,73 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 (-yl)-2-(methoxymethyl)piperazine-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 3 and 7 in the same manner as in Example 1. 1 H NMR(500 MHz,DMSO)δ 12.41(s,1H),10.87(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.37(d,J=8.7 Hz,1H),6.98(s,1H),6.87(d,J=8.8 Hz,1H),6.65(s,1H),6.63(s,1H),4.36-4.25(m,1H),4.19(t,J=7.9 Hz,1H),4.13-4.08(m,1H),4.05(dd,J=12.6,5.2 Hz,2H),3.83(d,J=11.9 Hz,2H),3.74(s,3H),3.57(dd,J=9.6,4.3 Hz,1H),3.51(dd,J=9.7,5.9 Hz,1H),3.30(s,3H),3.28(d,J=3.0 Hz,1H),3.24-3.16(m,1H),3.10-3.01(m,2H),2.98(dd,J=11.1,7.1 Hz,1H),2.94-2.86(m,1H),2.86-2.68(m,7H),2.67-2.57(m,3H),2.55(s,3H),2.09(qd,J=12.9,3.8 Hz,1H),2.00-1.81(m,5H),1.74(d,J=11.9 Hz,1H),1.68-1.57(m,2H),1.44(ddd,J=15.2,12.4,3.6 Hz,1H).[M+H] + =877.6.

[0472] Example 10: (R)-3-(4-(4-(5-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 (-yl)-2-oxa-5,8-diazaspiro[3.5]nonane-8-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 4 and 7 in the same manner as in Example 1. 1 H NMR(500 MHz,DMSO)δ 12.50(s,1H),10.87(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.40(d,J=8.5 Hz,1H),7.02(s,1H),6.75(dd,J=8.5,1.6 Hz,1H),6.66(s,1H),6.63(s,1H),4.53(d,J=6.1 Hz,2H),4.38(d,J=6.2 Hz,2H),4.35-4.27(m,1H),4.19(t,J=8.2 Hz,1H),4.10(t,J=8.4 Hz,1H),4.05(dd,J=12.6,5.1 Hz,2H),3.80(d,J=12.5 Hz,2H),3.74(s,3H),3.26-3.18(m,2H),2.99(s,2H),2.84-2.74(m,3H),2.65-2.51(m,7H),2.49-2.46(m,4H),2.09(qd,J=13.0,3.7 Hz,1H),2.00-1.89(m,2H),1.83(d,J=10.1 Hz,4H),1.75-1.66(m,1H),1.56-1.46(m,2H).[M+H] + =875.7.

[0473] Example 11: 3-(4-((3S,4R)-4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)-3-fluoropiperidine-1-yl)-3,3-dimethyl-2-oxoindoline-1-yl)piperidine-2,6-dione [ka] Intermediate 1 (104 mg, 0.2 mmol), Intermediate 9 (137 mg, 0.3 mmol), Pd2dba3 (36.6 mg, 0.04 mmol), Ruphos (36.8 mg, 0.08 mmol), and in DMA (5 mL) t- A mixture of BuONa (76.8 mg, 0.8 mmol) was stirred in a round-bottom flask under N2 at 90°C for 1 hour. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL x 3). The combined organic layer was dried over Na2SO4. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to obtain the product (40 mg, 22%). 1H NMR(500 MHz,DMSO)δ 12.43(s,1H),11.07(s,1H),8.53(s,1H),7.89(s,1H),7.45(s,1H),7.38(d,J=8.7 Hz,1H),7.25(t,J=8.0 Hz,1H),7.10-7.00(m,2H),6.95-6.90(m,1H),6.83(s,1H),5.25-5.21(m,1H),5 .15-5.06(m,1H),4.38-4.25(m,1H),4.22-4.16(m,1H),4.14-4.02(m,2H),3.74( s,3H),3.24-3.17(m,4H),3.15-2.97(m,2H),2.96-2.80(m,7H),2.64-2.54(m,9 H),2.09-1.99(m,1H),1.98-1.76(m,6H),1.69-1.65(m,1H),1.43(dd,J=8.3,3.8 Hz,6H);[M+H] + =898.6.

[0474] Example 12: 3-(5-((3S,4R)-4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)-3-fluoropiperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 1 and 26 in the same manner as in Example 11. 1H NMR(500 MHz,DMSO)δ 12.36(s,1H),10.79(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.40(s,1H),7.37(d,J=8.6 Hz,1H),7.12(d,J=8.1 Hz,1H),7.04(s,1H),6.93(d,J=8.8 Hz,1H),5.16-5.06(m,1H),4.38-4.26(m,1H),4.23-4.16(m,1H),4.14-4.01(m,2H),3.90(dd,J=9.5,5.3 Hz,1H),3.74(s,3H),3.19(d,J=4.4 Hz,5H),2.92-2.79(m,6H),2.65-2.63(m,1H),2.62-2.56(m,4H),2.54(dd,J=6.1,2.4 Hz,5H),2.44-2.42(m,3H),2.26-2.17(m,1H),2.12-2.00(m,2H),1.96-1.75(m,5H),1.72-1.62(m,1H).[M+H] + =830.6.

[0475] Example 13: 3-(5-((3S,4R)-4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-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 using intermediates 1 and 22 in the same manner as in Example 11. 1H NMR(500 MHz,DMSO)δ 12.37(s,1H),10.79(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.37(d,J=8.7 Hz,1H),7.07-6.90(m,3H),5.07-4.97(m,1H),4.37-4.25(m,1H),4.19(t,J=7.5 Hz,1H),4.14-4.02(m,2H),3.85(dd,J=8.1,5.8 Hz,1H),3.74(s,3H),3.25-3.07(m,6H),3.01-2.94(m,1H),2.88-2.78(m,4H),2.66-2.53(m,10H),2.47-2.35(m,3H),2.28(d,J=13.9 Hz,3H),2.25-2.14(m,1H),2.12-1.99(m,2H),1.97-1.59(m,6H).[M+H] + =844.6.

[0476] Example 14: 3-(5-((3S,4R)-4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-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 intermediates 1 and 21 in the same manner as in Example 11. 1H NMR(500 MHz,DMSO)δ 12.43(s,1H),10.87(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.37(d,J=8.9 Hz,1H),7.34(s,1H),7.04(s,1H),6.93(d,J=9.1 Hz,1H),5.16-5.06(m,1H),4.31(s,1H),4.24-4.03(m,4H),3.74(s,3H),3.23-3. 15(m,4H),2.94-2.80(m,6H),2.76-2.67(m,2H),2.64-2.57(m,5H),2.54(d,J=3.8 Hz,4H),2.40(s,3H),2.32-2.20(m,1H),2.09-1.99(m,2H),1.96-1.66(m,6H).[M+H] + =848.7.

[0477] Example 15: 3-(5-((3R,4S)-4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)-3-fluoropiperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 1 and 24 in the same manner as in Example 11. 1H NMR(500 MHz,DMSO)δ 12.42(s,1H),10.79(s,1H),8.53(s,1H),7.89(s,1H),7.45(s,1H),7.38(t,J=8.2 Hz,2H),7.12(d,J=8.3 Hz,1H),7.04(s,1H),6.93(d,J=9.1 Hz,1H),4.31(s,1H),4.19(s,1H),4.10(s,1H),3.90(dd,J=9.4,5.4 Hz,1H),3.74(s,3H),3.45(s,2H),3.41-3.36(m,4H),3.19(s,4H),2.83(s,4H),2.62-2.61(m,1H),2.59-2.56(m,2H),2.55(s,3H),2.42(s ,3H),2.25-2.18(m,1H),2.10-2.03(m,2H),1.96-1.91(m,1H),1.85- 1.80(m,2H),1.70-1.65(m,1H),1.24(s,3H),0.88-0.83(m,2H);[M+H] + =830.6

[0478] Example 21: 3-(5-((3S,4R)-4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-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 1 and 27 in the same manner as in Example 11. 1H NMR(500 MHz,DMSO)δ 12.36(s,1H),10.80(s,1H),8.52(s,1H),8.16(s,1H),7.89(s,1H),7.45(s,1H),7.37(d,J=8.8 Hz,1H),7.15(s,1H),7.04(s,1H),6.93(d,J=8.7 Hz,1H),5.18-5.00(m,1H),4.32(dd,J=12.3,10.5 Hz,1H),4.19(t,J=7.1 Hz,1H),4.14-4.03(m,2H),3.90(dd,J=8.8,5.4 Hz,1H),3.74(s,3H),3.29-3.17(m,6H),3.01-2.79(m,7H),2.65-2.56(m,6H),2.55(s,3H),2.28(s,3H),2.23-2 .16(m,1H),2.13-2.08(m,1H),2.04-1.98(m,1H),1.95-1.90(m,1H),1.87-1.79(m,3H),1.71-1.61(m,1H).[M+H] + =830.7.

[0479] Example 23: 3-(5-(4-((4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)methyl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 2 and 28 in the same manner as in Example 1. 1H NMR(500 MHz,DMSO)δ 12.42(s,1H),10.78(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.37(dd,J=8.4,2.5 Hz,2H),7.10(d,J=8.2 Hz,1H),7.03(s,1H),6.92(d,J=8.9 Hz,1H),4.36-4.27(m,1H),4.20(dd,J=12.3,8.2 Hz,1H),4.11-4.07(m,2H),3.89(dd,J=9.3,5.3 Hz,1H),3.74(s,4H),3.18(s,4H),3.08(d,J=11.1 Hz,3H),2.60-2.58(m,5H),2.57-2.51(m,7H),2.39(s,3H),2.28(d,J=7.2 Hz,2H),2.23-2.19(m,1H),2.12-2.07(m,1H),1.97-1.78(m,6H),1.74-1.64(m,2H),1.34-1.29(m,2H);[M+H]+=826.7.

[0480] Example 27: 3-(5-((3R,4S)-4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-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 intermediates 1 and 20 in the same manner as in Example 11. 1H NMR(500 MHz,DMSO)δ 12.42(s,1H),10.87(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.36(dd,J=12.3,10.2 Hz,2H),7.04(s,1H),6.93(d,J=8.8 Hz,1H),5.18-5.04(m,1H),4.38-4.01(m,5H),3.74(s,3H),3.43(s,1H),3.26-3.1 6(m,5H),2.94-2.78(m,6H),2.75-2.54(m,9H),2.40(s,3H),2.26(dd,J=20.2,11.4 Hz,1H),2.05(dd,J=11.6,7.1 Hz,2H),1.97-1.62(m,6H).[M+H] + =848.6.

[0481] Example 35: 3-(5-(3-((4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)methyl)azetidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 2 and 29 in the same manner as in Example 1. 1H NMR(500 MHz,DMSO)δ 12.41(s,1H),10.93(s,1H),8.52(s,1H),7.89(s,1H),7.49(d,J=8.2 Hz,1H),7.45(s,1H),7.37(d,J=8.7 Hz,1H),7.03(s,1H),6.92(d,J=8.6 Hz,1H),6.52(s,1H),6.49(d,J=8.3 Hz,1H),5.03-4.99(m,1H),4.35-4.26(m,2H),4.18-4.15(m,2H),4.06-4.02(m,4H), 3.74-3.71(m,3H),3.60-3.56(m,2H),3.18-3.15(m,4H),3.06-3.01(m,1H),2.96-2. 84(m,1H),2.67-2.64(m,2H),2.62-2.59(m,6H),2.57-2.54(m,3H),2.53-2.49(m,3H ),2.35-2.32(m,1H),1.95-1.92(m,2H),1.84-1.79(m,2H),1.71-1.66(m,1H);[M+H] + =838.7.

[0482] Example 57: 3-(4-(4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)phenoxy)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 2 and 31 in the same manner as in Example 1. 1H NMR(500 MHz,DMSO)δ 12.42(s,1H),10.88(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.36(d,J=8.7 Hz,1H),7.02(s,1H),6.95-6.85(m,5H),5.02-4.49(m,1H),4.30(s,1H),4.18(d,J=8.0 Hz,1H),4.09(s,2H),3.74(s,3H),3.61-3.58(m,2H),3.17(s,4H),2.78-2.63(m,6H),2.62-2.56(m,5H),2.55(s,3H),2.51(s,1H) ),2.38-2.34(m,1H),2.20-2.14(m,1H),2.13-2.05(m,1H),1.91-1.98(m,3H),1.83(s,2H),1.67(s,1H),1.60-1.53(m,2H).[M+H] + =813.6.

[0483] Example 59: 3-((4-(4-(4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)-3-fluorophenyl)amino)piperidine-2,6-dione [ka] To a solution of intermediate 2 (60 mg, 0.11 mmol) and intermediate 32 (50 mg, 0.16 mmol) in DCE (6 mL), STAB (72 mg, 0.33 mmol) was added. The mixture was then stirred overnight at 50°C. The reaction product was quenched with saturated aqueous NaHCO3 (15 mL) 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 (31 mg, 33.1%). 1 H NMR(500 MHz,DMSO)δ 12.41(s,1H),10.78(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.36(s,1H),7.02(s,1H),6.91(dd,J=8.9,1.9 Hz,1H),6.84(t,J=9.4 Hz,1H),6.51(dd,J=15.0,2.4 Hz,1H),6.42(dd,J=8.7,2.1 Hz,1H),5.79(d,J=7.6 Hz,1H),4.35-4.16(m,3H),4.10(s,2H),3.74(s,3H),3.23-3.14(m,6H),2.76-2.66(m,5H),2.65 -2.52(m,9H),2.39-2.32(m,1H),2.12-2.05(m,1H),1.95-1.75(m,7H),1.73-1.54(m,3H).[M+H] + =830.6.

[0484] Example 63: 3-(5-(3-(((S)-4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6(-yl)-2-(methoxymethyl)piperazine-1-yl)methyl)azetidine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 3 and 29 in the same manner as in Example 1. 1 H NMR(500 MHz,DMSO)δ 12.43(s,1H),10.93(s,1H),8.52(s,1H),7.89(s,1H),7.49(d,J=8.3 Hz,1H),7.45(s,1H),7.38(d,J=8.7 Hz,1H),7.01(s,1H),6.89(dd,J=8.8,1.6 Hz,1H),6.52(s,1H),6.48(dd,J=8.4,1.6 Hz,1H),5.04(dd,J=13.3,5.1 Hz,1H),4.35-4.25(m,2H),4.21-4.14(m,2H),4.12-3.97(m,4H),3.74(s,3H),3 .63-3.54(m,3H),3.51-3.44(m,1H),3.43-3.37(m,1H),3.32(s,5H),3.11-2.81 (m,7H),2.73-2.69(m,1H),2.65-2.58(m,3H),2.57(s,3H),2.46-2.41(m,1H),2 .40-2.30(m,2H),1.98-1.88(m,2H),1.87-1.80(m,2H),1.72-1.61(m,1H);[M+H] + =882.7.

[0485] Example 64: (R)-3-(4-(4-((R)-4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6(-yl)-2-(methoxymethyl)piperazine-1-yl)piperidine-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of intermediate 30 (85 mg, 0.15 mmol) and intermediate 7 (67 mg, 0.21 mmol) in DCE (6 mL), STAB (96 mg, 0.45 mmol) was added. The mixture was then stirred overnight at 50°C. The reaction product was quenched with saturated aqueous NaHCO3 (15 mL) 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 (30 mg, 23.0%). 1 H NMR(500 MHz,DMSO)δ 12.42(s,1H),10.87(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.37(d,J=8.7 Hz,1H),6.97(s,1H),6.87(d,J=8.7 Hz,1H),6.64(d,J=12.8 Hz,2H),4.35-4.25(m,1H),4.23-4.15(m,1H),4.11-3.96(m,3H),3.82(d,J=12.4 Hz,2H),3.74(s,3H),3.61-3.55(m,1H),3.53-3.48(m,1H),3.32(s,5H),3.27(d,J=9.6 Hz,1H),3.23-3.16(m,1H),3.09-2.96(m,3H),2.90(t,J=9.9 Hz,1H),2.85-2.70(m,5H),2.69-2.64(m,1H),2.59(d,J=6.9 [M+H] + =877.7.

[0486] Example 65: 3-(5-(4-((R)-4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 (-yl)-2-(methoxymethyl)piperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 30 and 15 in the same manner as in Example 1. 1 H NMR(500 MHz,DMSO)δ 12.35(s,1H),10.78(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.38(dd,J=8.4,3.8 Hz,2H),7.11(d,J=8.1 Hz,1H),6.99(s,1H),6.89(d,J=9.7 Hz,1H),4.37-4.25(m,1H),4.22-4.18(m,1H),4.11-4.07(m,2H),3.91-3.87(m,1H),3.74(s,3H),3. 61-3.55(m,1H),3.52-3.49(m,1H),3.28-3.22(m,1H),3.19-3.11(m,2H),3.09-3.05(m,2H),3.01-2. 97(m,1H),2.94-2.80(m,2H),2.72-2.69(m,2H),2.65-2.51(m,14H),2.41(s,3H),2.25-2.15(m,1H), 2.13-2.04(m,1H),1.99-1.89(m,2H),1.86-1.73(m,4H),1.73-1.64(m,1H),1.63-1.53(m,1H);[M+H] + =856.7.

[0487] Example 69: 5-(3-(((S)-4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)-2-(methoxymethyl)piperazine-1-yl)methyl)azetidine-1-yl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione [ka] To a solution of intermediate 3 (85 mg, 0.15 mmol) and intermediate 33 (72 mg, 0.21 mmol) in DCE (6 mL), STAB (96 mg, 0.45 mmol) was added. The mixture was then stirred overnight at room temperature. The reaction product was quenched with saturated aqueous NaHCO3 (15 mL) 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 (60 mg, 45%). 1H NMR(500 MHz,DMSO)δ 12.55(s,1H),11.08(s,1H),8.61(s,1H),7.99(s,1H),7.70(d,J=8.3 Hz,1H),7.57(s,1H),7.43(d,J=8.7 Hz,1H),7.13(d,J=17.3 Hz,1H),7.00(t,J=7.5 Hz,1H),6.84(d,J=1.6 Hz,1H),6.71(dd,J=8.4,1.9 Hz,1H),5.07(dd,J=12.7,5.4 Hz,1H),4.37-4.18(m,5H),4.15-4.04(m,3H),3.88-3.81(m,10H),3.76-3. 72(m,3H),3.69-3.62(m,2H),3.58-3.51(m,1H),3.48-3.42(m,1H),3.32-3 .21(m,2H),3.09-2.99(m,2H),2.94-2.84(m,1H),2.64-2.55(m,6H),2.06- 1.99(m,1H),1.93-1.88(m,1H),1.84-1.79(m,2H),1.68-1.59(m,1H);[M+H] + =896.7.

[0488] Example 70: 3-(5-(4-((S)-4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 (-yl)-2-(methoxymethyl)piperazine-1-yl)piperidine-1-yl)-3-fluoro-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 3 and 12 in the same manner as in Example 1. 1H NMR(500 MHz,DMSO)δ 12.43(s,1H),10.86(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.37(d,J=8.6 Hz,1H),7.33(d,J=11.6 Hz,1H),6.99(s,1H),6.89(d,J=8.4 Hz,1H),4.36-4.26(m,1H),4.23-4.19(m,1H),4.16-4.04(m,3H),3.74(s,3H),3.60-3.55(m,1 H),3.53-3.49(m,1H),3.27-3.24(m,1H),3.21-3.16(m,2H),3.09-3.03(m,2H),3.01-2.96(m,1 H),2.92-2.82(m,3H),2.76-2.67(m,6H),2.65-2.60(m,5H),2.55(s,4H),2.38(s,3H),2.29-2 .20(m,1H),2.06-1.99(m,1H)),1.98-1.91(m,2H),1.87-1.72(m,5H),1.63-1.59(m,1H);[M+H] + =874.7.

[0489] Example 71: 3-(5-(4-((R)-4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 (-yl)-2-(methoxymethyl)piperazine-1-yl)piperidine-1-yl)-3-fluoro-6-methylpyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 30 and 12 in the same manner as in Example 1. 1H NMR(500 MHz,DMSO)δ 12.43(s,1H),10.86(s,1H),8.52(s,1H),7.89(s,1H),7.45(s,1H),7.37(d,J=8.6 Hz,1H),7.33(d,J=11.6 Hz,1H),6.99(s,1H),6.89(d,J=8.4 Hz,1H),4.36-4.26(m,1H),4.23-4.19(m,1H),4.16-4.05(m,3H),3.74(s,3H),3.60-3.55(m,1 H),3.53-3.49(m,1H),3.27-3.24(m,1H),3.21-3.16(m,2H),3.11-3.03(m,2H),3.01-2.96(m,1 H),2.92-2.82(m,3H),2.76-2.67(m,6H),2.65-2.61(m,5H),2.55(s,4H),2.38(s,3H),2.29-2 .20(m,1H),2.06-1.99(m,1H)),1.98-1.91(m,2H),1.88-1.72(m,5H),1.63-1.59(m,1H);[M+H] + =874.7.

[0490] Example 72: 3-(6-methyl-5-(4-(4-((7 1 R,7 3 S,E)-1 1 ,1 3 ,2 6 -trimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 -yl)piperazine-1-yl)piperidine-1-yl)pyridine-2-yl)piperidine-2,6-dione [ka] The title compound was prepared using intermediates 34 and 15 in the same manner as in Example 1. 1H NMR(500 MHz,DMSO)δ 12.42(s,1H),10.78(s,1H),8.54(s,1H),7.45(s,1H),7.37(d,J=8.9 Hz,2H),7.11(d,J=8.2 Hz,1H),7.03(s,1H),6.95-6.89(m,1H),4.35-3.98(m,4H),3.89(dd,J=9.4,5.3 Hz,1H),3.67(s,3H),3.22-3.11(m,7H),2.76-2.70(m,4H),2.68-2.53(m,10 H),2.48(s,2H),2.42-2.35(m,4H),2.25-2.17(m,1H),2.08(dd,J=12.8,6.0 Hz,1H),1.97-1.76(m,6H),1.69-1.57(m,3H).[M+H] + =826.6.

[0491] Example 73: 3-(5-(4-((S)-4-((7 1 R,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-Oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclopentanacyclononafane-5 6 (-yl)-2-(methoxymethyl)piperazine-1-yl)piperidine-1-yl)-6-methylpyridine-2-yl)piperidine-2,6-di...

Claims

1. Equation (I): 【Chemistry 1】 A compound thereof, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug, During the ceremony, E １ However, N or CR ５ And, E ２ However, N or CR ６ And, R １ａ 、R １ｂ 、R ２ａ 、and R ２ｂ are each independently non-existent, hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, -C ３－８ cycloalkyl, or -CN, and each said -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -C ３－８ cycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkoxy, -C ３－８ cycloalkyl, and -CN, R ３ and R ４ However, each independently, hydrogen, -C １－６ Alkyl, or -C ３－８ It is a cycloalkyl, and each of the -C １－６ Alkyl or -C ３－８ Cycloalkyls are hydrogen, hydroxyl, halogen, and -C １－６ Optionally substituted with at least one substituent selected from alkoxys, R ５ and R ６ 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 ３－８ Cycloalkyl, or -CN, each of the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C １－８ Alkoxy, or -C ３－８ Cycloalkyl groups contain hydrogen, halogens, and -C １－８ Alkoxy, -C ３－８ It may be optionally substituted with at least one substituent selected from cycloalkyl and -CN, or R ５ and R ６ However, together with the carbon atoms to which they are bonded, they form a 3- to 12-membered ring, and the ring independently contains 0 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur, and the ring contains halogens, hydroxyls, and -C １ -C ８ Optionally substituted with at least one substituent selected from alkyl groups, R ７ 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 ３－８ Cycloalkyl, or -CN, each of the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C １－８ Alkoxy, or -C ３－８ Cycloalkyl groups contain hydrogen, halogens, and -C １－８ Alkoxy, -C ３－８ It may be optionally substituted with at least one substituent selected from cycloalkyl and -CN, or Two R ７ However, together with the carbon atoms (or more) to which they are bonded, they form a 3- to 12-membered ring, and the ring independently contains 0 to 3 heteroatoms selected from nitrogen, oxygen, or sulfur, and the ring contains halogens, hydroxyls, and -C １ -C ８ Optionally substituted with at least one substituent selected from alkyl groups, R ８ and R ９ However, each independently, hydrogen, halogen, and -C １ -C ６ Alkyl and C ３ -C ８ Selected from cycloalkyl, -C １ -C ６ Alkyl or C ３ -C ８ Each of the cycloalkyl groups consists of hydrogen, halogen, hydroxyl, and -C. １－６ Optionally substituted with at least one substituent selected from alkoxys, R １０ is, independently of each other, hydrogen, halogen, -C １ -C ８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, 5- to 12-membered heteroaryl, -NR １０ａ R １０ｂ , -OR １０ａ , -SR １０ａ , -C(O)R １０ａ , -CO ２ R １０ａ , -C(O)NR １０ａ R １０ｂ , -NR １０ａ COR １０ｂ , -NR １０ａ CO ２ R １０ｂ , -NR １０ａ SO ２ R １０ｂ , and -CN, and each of -C １ -C ８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one R １０ｃ , R １０ａ and R １０ｂ However, each independently, hydrogen, -C １ -C ８ Alkyl, -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 aryls and 5- to 12-membered heteroaryls, the -C １ -C ８ Alkyl, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Each of the aryl or 5- to 12-membered heteroaryl has at least one substituent R １０ｄ It is arbitrarily replaced with, R １０ｃ and R １０ｄ However, each is independent of halogen, hydrogen, 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 Aryl, 5-12 member heteroaryl, oxo (=O), -NR １０ｅ R １０ｆ , -OR １０ｅ , -SR １０ｅ , -SO ２ R １０ｅ , -SO ２ NR １０ｅ R １０ｆ , -C(O)R １０ｅ , -CO ２ R １０ｅ , -C(O)NR １０ｅ R １０ｆ , -NR １０ｅ COR １０ｆ , -NR １０ｅ CO ２ R ８ｆ , -NR １０ｅ SO ２ R １０ｆ Selected from , and -CN, R １０ｅ and R １０ｆ However, each independently, hydrogen, -C １ -C ８ Alkyl, -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 aryls or 5- to 12-membered heteroaryls, R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , and R １２ｄ However, each is independent of non-existence, oxo, hydrogen, halogen, and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C １－８ Alkoxy, or -C ３－８ It is a cycloalkyl, and the -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C １－８ Alkoxy, or -C ３－８ Each of the cycloalkyl groups is hydrogen, halogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, -C １－８ Optionally substituted with at least one substituent selected from alkoxy and -CN, L １ が、-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, 【Transformation 3】 Each of them has at least one R Ｌ１ｃ It is arbitrarily replaced with, ＊Ｌ１ but, 【Chemistry 4】 It refers to the position where a part is joined. ＊＊Ｌ１ but, 【Transformation 5】 It refers to the position where a part is joined. L ２ が、-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, 【Transformation 7】 Each of them has at least one R Ｌ２ｃ It is arbitrarily replaced with, ＊Ｌ２ but, 【Transformation 8】 It refers to the position where a part is joined. ＊＊Ｌ２ but, 【Chemistry 9】 It refers to the position where a part is joined. L ３ が、-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, 【Chemistry 11】 Each of them has at least one R Ｌ３ｃ It is arbitrarily replaced with, ＊Ｌ３ but, 【Chemistry 12】 It refers to the position where a part is joined. ＊＊Ｌ３ but, 【Chemistry 13】 It refers to the position where a part is joined. The aforementioned R Ｌ１ｃ , R Ｌ２ｃ , and 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, -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 Each of the aryl and 5- to 12-membered heteroaryls has at least one R Ｌｃａ It is arbitrarily replaced with, 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 Ｌ１ｃ However, together with the atoms to which they bond, they form a 3- to 12-membered ring, and the ring independently contains 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the ring contains halogens, hydroxyls, and -C １ -C ８ Optionally substituted with at least one substituent selected from alkyl groups, Two R Ｌ２ｃ However, together with the atoms to which they bond, they form a 3- to 12-membered ring, and the ring independently contains 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the ring contains halogens, hydroxyls, and -C １ -C ８ Optionally substituted with at least one substituent selected from alkyl groups, Two R Ｌ３ｃ However, together with the atoms to which they bond, they form a 3- to 12-membered ring, and the ring independently contains 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the ring contains halogens, hydroxyls, and -C １ -C ８ Optionally substituted with at least one substituent selected from alkyl groups, 【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 However, at the same time, 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 It is a cycloalkyl, 3- to 8-membered heterocyclyl, or CN, and -C １－８ Alkyl, C ３ -C ８ Each of the cycloalkyl and 3- to 8-membered heterocyclyl groups has at least one R Ｚｃ It is arbitrarily replaced with, 【Chemistry 16】 The part is CR ｚ And R ｚ Z does not exist. １ or Z ２ via any one of the following 【Chemistry 17】 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 The aryl or 5- to 12-membered heteroaryl, and the -C １－８ Alkyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocyclyl, C ６ -C １２ Each of the aryl or 5- to 12-membered heteroaryl has at least one substituent R Ｚｄ It is arbitrarily replaced with, 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 They are aryl or 5- to 12-membered heteroaryl compounds. 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 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 Each of the aryl or 5- to 12-membered heteroaryl groups is 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 It is arbitrarily replaced with, 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 They are aryl or 5- to 12-membered heteroaryl compounds. 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)-, In each occurrence, X １ , X ２ , and X ７ However, each operates independently, -CR ａ , or N, In each occurrence, X ３ , X ４ , and X ８ However, each is independent of -NR ａ -, -O-, -S-, or -CR ａ R ｂ - and In each occurrence, X ５ and X ６ However, each is independent of non-existence, single bond, -C(O)-, and -NR ａ - or -O-, 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 The aryl and 5- to 12-membered heteroaryls, and the -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 Each of the aryl or 5- to 12-membered heteroaryl groups may be a halogen, hydroxyl, halogen, or -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 may be optionally substituted with at least one substituent selected from aryls and 5- to 12-membered heteroaryls, or R ａ and R ｂ However, together with the carbon atoms to which they are bonded, they form a 3- to 12-membered ring, and the ring independently contains 0 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the ring contains halogens, hydroxyls, and -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 Optionally substituted with at least one substituent selected from aryls and 5- to 12-membered heteroaryls, m1, m2, m3, and m4 are each independently 0, 1, or 2, provided that m1 + m2 + m3 + m4 ≤ 4. m5, m6, and m7 are each independently 0, 1, or 2, provided that m5 + m6 + m7 ≥ 1. n1, n2, n3, n4, and n5 are each independently 0, 1, 2, or 3. n6 is independently 0, 1, 2, 3, or 4. n7 and n8 are independently 0, 1, 2, or 3. s1 and s2 are independently 0, 1, 2, or 3. s5, s6, and s7 are each independently 0, 1, 2, or 3. however, L １ , L ２ , or L ３ For any one of the following, X １ If X is N, ５ However, it is a single bond, absent, or -C(O)- and / or X ２ If X is N, ６ However, it is either a single bond, absent, or -C(O)-, L １ but, [Chemistry 18] If X １ If X is N, ５ However, it is a single bond, absent, or -C(O)-, X ３ However, -CR ａ R ｂ - and X ２ If X is N, ６ However, it is a single bond, absent, or -C(O)- and / or X ４ However, -CR ａ R ｂ - and L ２ but, 【Chemistry 19】 If X １ If X is N, ５ However, it is a single bond, absent, or -C(O)- and / or X ３ However, -CR ａ R ｂ - and X ２ If X is N, ６ However, it is a single bond, absent, or -C(O)- and / or X ４ However, -CR ａ R ｂ - and L ３ but, 【Chemistry 20】 If X １ If X is N, ５ However, it is a single bond, absent, or -C(O)- and / or X ３ However, -CR ａ R ｂ - and X ２ If X is N, ６ However, it is a single bond, absent, or -C(O)- and / or X ４ However, -CR ａ R ｂ - The compound, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug.

2. The aforementioned compound is of formula (IIa) 【Chemistry 21】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog.

3. The aforementioned compound is of formula (IIb): 【Chemistry 22】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog.

4. The aforementioned compound is of formula (IIc): 【Chemistry 23】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog.

5. The aforementioned compound is of formula (IId): 【Chemistry 24】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated analog, or prodrug.

6. The aforementioned compounds are of formulas (IIe) and (IIf): 【Chemistry 25】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog.

7. The aforementioned compounds are of formulas (IIg) and (IIh): 【Chemistry 26】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog.

8. The aforementioned compounds are of formulas (IIIi) and (IIj): 【Chemistry 27】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog.

9. The aforementioned compound is of formula (IIIa): 【Chemistry 28】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog.

10. The aforementioned compound is of formula (IIIb): 【Chemistry 29】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog.

11. The aforementioned compound is of formula (IIIc): 【Transformation 30】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog.

12. The aforementioned compounds are of formulas (IIId) and (IIIe): 【Chemistry 31】 A compound according to claim 1, selected from the compounds, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog.

13. The aforementioned compound is of formula (IIIm): 【Chemistry 32】 Selected from the compounds, in the formula, R ７ However, each is independent of non-existence, hydrogen, halogen, or -C. １－３ It is alkyl, R ８ and R ９ However, each is independent of hydrogen, halogen, and -C. １ -C ３ Selected from alkyl groups, R １０ However, each independently produces hydrogen, halogen, or -C. １ -C ３ Selected from alkyl groups, L １ but, 【Transformation 33】 Selected from, The aforementioned 【Transformation 34】 Each of them has at least one R Ｌ１ｃ It is arbitrarily replaced with, ＊Ｌ１ but, 【Chemistry 35】 It refers to the position where a part is joined. ＊＊Ｌ１ but, 【Transformation 36】 It refers to the position where a part is joined. L ２ but, 【Chemistry 37】 Selected from the above, 【Transformation 38】 Each of them has at least one R Ｌ２ｃ It is arbitrarily replaced with, ＊Ｌ２ but, 【Chemistry 39】 It refers to the position where a part is joined. ＊＊Ｌ２ but, 【Chemistry 40】 It refers to the position where a part is joined. The aforementioned R Ｌ１ｃ and R Ｌ２ｃ Each of these independently represents non-existence, oxo (=O), halogen, hydroxyl, and -C. １ -C ３ Alkyl, or -C １ -C ３ It is an alkoxy, and the -C １ -C ３ Alkyl and -C １ -C ３ Each alkoxy has at least one R Ｌｃａ It is arbitrarily replaced with, R Ｌｃａ However, each is independent of the others: absent, halogen, hydroxyl, or -C. １ -C ３ It is alkoxy, or Two R Ｌ１ｃ However, together with the atoms to which they bond, they form a 3- to 5-membered ring, and the ring independently contains 0 to 1 heteroatom selected from nitrogen and oxygen. Two R Ｌ２ｃ However, together with the atoms to which they bond, they form a 3- to 5-membered ring, and the ring independently contains 0 to 1 heteroatom selected from nitrogen and oxygen. R ｚ However, in each appearance, independently, non-existence, hydrogen, halogen, and -C are present. １－３ Alkyl, or -C １ -C ３ It is an alkoxy, R １４ However, in each appearance, independently, non-existence, hydrogen, halogen, and -C are present. １－３ Alkyl, or -C １ -C ３ It is an alkoxy, In each occurrence, X １ and X ２ However, each is independently -CH or N, In each occurrence, X ３ and X ４ However, each is independent of -NH- or -CH ２ - and In each occurrence, X ５ and X ６ However, each is independent of non-existence, single bond, -C(O)-, or -NR ａ - and In each occurrence, R ａ However, independently, hydrogen or -C １ -C ３ It is alkyl, n1, n2, n3, and n4 are each independently 0, 1, or 2. The compound according to claim 1, wherein s5, s6, and s7 are each independently 0, 1, or 2.

14. The compound according to any one of claims 1 to 12, wherein m1 + m2 + m3 + m4 ≤ 3.

15. The compound according to any one of claims 1 to 12, wherein m1 + m2 + m3 + m4 = 0, 1, or 2. 【Request Item 16】 【Chemistry 41】 -CH in the part ２ - The compound according to any one of claims 1 to 12, wherein the total number of groups is 4 or less. 【Request Item 17】 【Chemistry 42】 -CH in the part ２ - The compound according to any one of claims 1 to 12, wherein the total number of groups is 3 or less.

18. R ３ and R ４ The compound according to any one of claims 1 to 6 and 9 to 10, wherein each is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, hydroxyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy.

19. R ３ and R ４ The compound according to any one of claims 1 to 6 and 9 to 10, wherein each is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

20. R ３ However, it is methyl, and R ４ The compound according to any one of the prior claims, wherein the compound is hydrogen.

21. R １ａ , R １ｂ , R ２ａ , and R ２ｂ However, each is independent of hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or -CN, each of which is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or -C. ２－８ Alkenyl, -C ２－８ The compound according to any one of claims 1 to 4 and 9 to 10, wherein alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl are 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.

22. R １ａ , R １ｂ , R ２ａ , and R ２ｂ 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, -CF ３ ,-CHF ２ -CN, -CH ２ OCH ３ ien-CH ２ OCH ２ CH ３ ien-CH ２ CH ２ OCH ３ , or -CH ２ CH ２ OCH ２ CH ３ The compound according to any one of claims 1 to 4 and 9 to 10.

23. R １ａ , R １ｂ , R ２ａ , and R ２ｂ However, each independently, hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF ３ ,-CHF ２ , or -CH ２ OCH ３ The compound according to any one of claims 1 to 4 and 9 to 10.

24. R １ａ , R １ｂ , R ２ａ , and R ２ｂ The compound according to any one of claims 1 to 4 and 9 to 10, wherein each is independently hydrogen.

25. R ５ and R ６ 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, -CF ３ ,-CHF ２ -CN, -CH ２ OCH ３ ien-CH ２ OCH ２ CH ３ ien-CH ２ CH ２ OCH ３ , or -CH ２ CH ２ OCH ２ CH ３ The compound according to any one of claims 1 to 2 and 9.

26. R ５ and R ６ However, each independently, hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF ３ ,-CHF ２ , and -CH ２ OCH ３ The compound according to any one of claims 1 to 2 and 9.

27. R ７ 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, -CF ３ ,-CHF ２ -CN, -CH ２ OCH ３ ien-CH ２ OCH ２ CH ３ ien-CH ２ CH ２ OCH ３ , or -CH ２ CH ２ OCH ２ CH ３ The compound according to any one of claims 1 to 6 and 9 to 13.

28. R ７ However, each independently, hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF ３ ,-CHF ２ , or -CH ２ OCH ３ The compound according to any one of claims 1 to 6 and 9 to 13.

29. R ７ The compound according to any one of claims 1 to 6 and 9 to 13, wherein each is independently hydrogen.

30. R ８ and R ９ The compound according to any one of claims 1 to 7 and 9 to 13, wherein each is independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, hydroxy, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy.

31. R ８ and R ９ However, each independently, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CF ３ ,-CHF ２ ien-CH ２ OH, or -CH ２ CH ２ The compound according to any one of claims 1 to 7 and 9 to 13, wherein it is an OH group.

32. R ８ However, hydrogen, methyl, -F, -Cl, -CF ３ ,-CHF ２ , or -CH ２ OH and R ９ However, F, methyl, or -CH ２ The compound according to any one of claims 1 to 7 and 9 to 13, wherein it is an OH group.

33. R １０ However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -NR １０ａ R １０ｂ , -OR １０ａ , -SR １０ａ , -C(O)R １０ａ , -CO ２ R １０ａ , -C(O)NR １０ａ R １０ｂ , -NR １０ａ COR １０ｂ , -NR １０ａ CO ２ R １０ｂ , -NR １０ａ SO ２ R １０ｂ Selected from , and -CN, including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the following is an R: １０ｃ It is arbitrarily replaced with, R １０ａ and R １０ｂ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, and phenyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the following molecules is an alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, or phenyl molecule, with at least one substituent R １０ｄ It is arbitrarily replaced with, R １０ｃ and R １０ｄ However, each independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo(=O), -NR １０ｅ R １０ｆ , -OR １０ｅ , -SR １０ｅ , -SO ２ R １０ｅ , -SO ２ NR １０ｅ R １０ｆ , -C(O)R １０ｅ , -CO ２ R １０ｅ , -C(O)NR １０ｅ R １０ｆ , -NR １０ｅ COR １０ｆ , -NR １０ｅ CO ２ R １０ｆ , -NR １０ｅ SO ２ R １０ｆ Selected from , and -CN, R １０ｅ and R １０ｆ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ A compound according to any one of claims 1 to 13, selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl.

34. R １０ However, each independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, -NR １０ａ R １０ｂ , -OR １０ａ , -SR １０ａ , -C(O)R １０ａ , -CO ２ R １０ａ , -C(O)NR １０ａ R １０ｂ , -NR １０ａ COR １０ｂ , -NR １０ａ CO ２ R １０ｂ , -NR １０ａ SO ２ R １０ｂ Selected from , and -CN, including methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the following is an R: １０ｃ It is arbitrarily replaced with, R １０ａ and R １０ｂ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, and phenyl, R １０ｃ However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo(=O), -NR １０ｅ R １０ｆ , -OR １０ｅ Selected from , and -CN, R １０ｅ and R １０ｆ The compound according to any one of claims 1 to 13, wherein each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl.

35. R １０ However, each independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-8 membered heterocyclyl, -NR １０ａ R １０ｂ , -OR １０ａ , -CO ２ R １０ａ , and -C(O)NR １０ａ R １０ｂ Selected from, each of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a 3- to 8-membered heterocycline, each having at least one R １０ｃ It is arbitrarily replaced with, R １０ａ and R １０ｂ However, each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, and 6-membered heterocyclyl. R １０ｃ However, each independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxo (=O), -NR １０ｅ R １０ｆ , -OR １０ｅ Selected from , and -CN, R １０ｅ and R １０ｆ The compound according to any one of claims 1 to 13, wherein each is independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and cyclopentyl.

36. R １０ However, each independently, H, F, Cl, Br, methyl, ethyl, propyl (n-propyl or iso-propyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 【Chemistry 43】 -COOH, -CONH ２ ien-CH ２ OCH ３ , and -CH ２ A compound according to any one of claims 1 to 13, selected from OH. 【Request Item 37】 【Chemistry 44】 The part, 【Chemistry 45-1】 【Chemistry 45-2】 A compound according to claim 1, selected from the following.

38. The aforementioned 【Chemistry 46】 The part, 【Chemistry 47】 A compound according to claim 1, selected from the following.

39. R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , and R １２ｄ However, each is independent of oxo, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the aforementioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Each of the following is a compound: alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, each containing hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ The compound according to any one of claims 1 to 12, optionally substituted with at least one substituent selected from alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, and -CN.

40. R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , and R １２ｄ However, each is independently oxo, 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, or cyclooctyl, preferably R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , and R １２ｄ The compound according to any one of claims 1 to 12, wherein each is independently oxo, hydrogen, F, Cl, Br, I, methyl, ethyl, or propyl.

41. R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , and R １２ｄ The compound according to any one of the prior claims, wherein each is independently hydrogen or methyl.

42. 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 48-1】 【Chemistry 48-2】 Selected from, The aforementioned 【Chemistry 49-1】 【Chemistry 49-2】 Each of them has at least one R Ｌ１ｃ It is arbitrarily replaced with, 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, and the aforementioned 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 Each of the following is at least one R: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl Ｌｃａ It is arbitrarily replaced with, 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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, or Two R Ｌ１ｃ However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently comprises 0, 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and 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, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of the following is a compound: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, each of which is 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 The compound according to any one of claims 1 to 13, which is optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl.

43. 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 、 [Transformation 50] Selected from, The aforementioned 【Chemistry 51】 Each of them has at least one R Ｌ１ｃ It is arbitrarily replaced with, Said R Ｌ１ｃ each independently being 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, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, and each of said 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, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl being optionally substituted by at least one R Ｌｃａ ; 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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, or Two R Ｌ１ｃ However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently comprises 0, 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and 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, -C ２ -C ８ Alkenyl, -C ２ -C ８ Each of the following is a compound: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, each of which is 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 The compound according to any one of claims 1 to 13, which is optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl.

44. 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 52-1】 【Chemistry 52-2】 【Chemistry 52-3】 【Chemistry 52-4】 【Chemistry 52-5】 【Chemistry 52-6】 【Chemistry 52-7】 【Chemistry 52-8】 A compound according to any one of claims 1 to 13, selected from the above.

45. L １ but, 【Chemistry 53】 A compound according to any one of claims 1 to 13, selected from the above.

46. 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 54-1】 【Chemistry 54-2】 Selected from, The aforementioned 【Chemistry 55-1】 【Chemistry 55-2】 Each of them has at least one R Ｌ２ｃ It is arbitrarily replaced with, The aforementioned R Ｌ２ｃ 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, and the aforementioned 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 Each of the following is at least one R: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl Ｌｃａ It is arbitrarily replaced with, 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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, or Two R Ｌ２ｃ However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently contains 0, 1, 2, or 3 heteroatoms 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, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl are each 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 claims 1 to 13, which is optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

47. 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 、 【Transformation 56】 Selected from, The aforementioned 【Chemistry 57】 Each of them has at least one R Ｌ２ｃ It is arbitrarily replaced with, The aforementioned R Ｌ２ｃ 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, and the aforementioned 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 Each of the following is at least one R: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl Ｌｃａ It is arbitrarily replaced with, 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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, or Two R Ｌ２ｃ However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently contains 0, 1, 2, or 3 heteroatoms 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, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl are each 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 claims 1 to 13, which is optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

48. 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 58-1】 【Chemistry 58-2】 【Chemistry 58-3】 【Chemistry 58-4】 【Chemistry 58-5】 【Chemistry 58-6】 【Chemistry 58-7】 【Chemistry 58-8】 A compound according to any one of claims 1 to 13, selected from the above.

49. L ２ but, 【Chemistry 59】 A compound according to any one of claims 1 to 13, selected from the above.

50. 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 60-1】 【Chemistry 60-2】 Selected from, The aforementioned 【Chemistry 61-1】 【Chemistry 61-2】 Each of them has at least one R Ｌ３ｃ It is arbitrarily replaced with, 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, and the aforementioned 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 Each of the following is at least one R: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl Ｌｃａ It is arbitrarily replaced with, 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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, or Two R Ｌ３ｃ However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently comprises 0, 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the ring is optionally substituted with at least one substituent selected from F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and 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, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl are each of the following: 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 claims 1 to 12, which is optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl.

51. L ３ が、-O-、-C(O)-、-N(R ａ )-、 ＊Ｌ３ -C(O)N(R ａ )- ＊＊Ｌ３ 、 ＊Ｌ３ -C(O)O- ＊＊Ｌ３ 、 ＊Ｌ３ -N(R ａ )C(O)- ＊＊Ｌ３ 、 ＊Ｌ３ -OC(O)- ＊＊Ｌ３ 、 【Transformation 62】 Selected from, The aforementioned 【Transformation 63】 Each of them has at least one R Ｌ３ｃ It is arbitrarily replaced with, 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, and the aforementioned 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 Each of the following is at least one R: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl Ｌｃａ It is arbitrarily replaced with, 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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl, or Two R Ｌ３ｃ However, together with the carbon atoms to which they are bonded, they form a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently comprises 0, 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and the ring is optionally substituted with at least one substituent selected from F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and 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, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl are each of the following: 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 claims 1 to 12, optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl.

52. 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 64-1】 【Chemistry 64-2】 【Chemistry 64-3】 【Chemistry 64-4】 【Chemistry 64-5】 【Chemistry 64-6】 【Chemistry 64-7】 【Transformation 64-8】 A compound according to any one of claims 1 to 12, selected from the above.

53. L ３ but, 【Transformation 65】 A compound according to any one of claims 1 to 12, selected from the above. 【Request Item 54】 【Transformation 66】 The part, 【Chemistry 67-1】 【Chemistry 67-2】 【Chemistry 67-3】 【Chemistry 67-4】 A compound according to claim 1, selected from the following.

55. 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 - and -C(O)- are 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, and 5-12 membered heteroaryl, and the aforementioned 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 Each of the following is a halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cycloheptyl, hexoxy, heptyloxy, octyl, -C, -C, -C ２ -C ８ Alkenyl, -C ２ -C ８ The compound according to any one of claims 1 to 9, which is optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl.

56. L ４ However, the compound according to any one of claims 1 to 9, which is independently selected from single bonds.

57. X ７ However, independently, -CR ａ Selected from , and 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, and 5-12 membered heteroaryl, and the aforementioned 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 Each of the following is a halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cycloheptyl, hexoxy, heptyloxy, octyl, -C, -C, -C ２ -C ８ Alkenyl, -C ２ -C ８ The compound according to any one of claims 1 to 9, which is optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl.

58. X ７ However, independently, -CH, -C(CH) ３ ), or selected from N, preferably X ７ However, the compound according to any one of claims 1 to 9, independently selected from -CH.

59. 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, and 5-12 membered heteroaryl, and the aforementioned 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 Each of the following is a halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cycloheptyl, hexoxy, heptyloxy, octyl, -C, -C, -C ２ -C ８ Alkenyl, -C ２ -C ８ The compound according to any one of claims 1 to 9, which is optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl.

60. X ８ However, independently, -NH- and -CH ２ - Selected from, preferably X ８ However, independently, -CH ２ A compound according to any one of claims 1 to 9, selected from -. 【Request Item 61】 【Transformation 68】 but, 【Transformation 69】 A compound selected from any one of claims 1 to 8. 【Request Item 62】 【Chemistry 70】 but, 【Chemistry 71】 A compound selected from any one of claims 1 to 8. 【Request Item 63】 【Chemistry 72】 but, 【Transformation 73】 A compound selected from any one of claims 1 to 8.

64. Z １ Z ２ , and Z ３ The compound according to any one of claims 1 to 8, wherein at most one of the atoms is N.

65. Z １ Z ２ , and Z ３ However, each operates independently, CR ｚ is, or Z １ However, N is Z ２ and Z ３ However, each operates independently, CR ｚ The compound according to any one of claims 1 to 8.

66. 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, and CN, each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and 3-8 membered heterocyclyl, having at least one R Ｚｃ It is arbitrarily replaced with, 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, and 5-12 membered heteroaryl, and each of the above hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl has at least one substituent R Ｚｄ It is arbitrarily replaced with, R Ｚｃ and R Ｚｄ The compound according to any one of claims 1 to 8, wherein 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.

67. 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 , and -CH(OH)CH ３ A compound selected from any one of claims 1 to 8.

68. 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 , and -NR １３ａ SO ２ R １３ｂ Selected from 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 Each of the aryl and 5-12 membered heteroaryls is 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 It is arbitrarily replaced with, 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 The compound according to any one of claims 1 to 8, wherein it is an aryl or a 5- to 12-membered heteroaryl.

69. 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 claims 1 to 8, selected from , or phenyl. 【Request Item 70】 【Chemistry 74】 but, 【Chemistry 75】 The compound according to any one of claims 1 to 8.

71. 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 - and -C(O)- are 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, and 5-12 membered heteroaryl, and the aforementioned 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 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, and 5-12 membered heteroaryl compounds has 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, and -C ２ -C ８ Alkenyl, -C ２ -C ８ The compound according to any one of claims 1 to 8, which is optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

72. L ５ and L ６ However, each is independent, single bond, 【Transformation 76】 -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 claims 1 to 8, wherein n6 is 0 or 1.

73. 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 , and -NR １３ａ SO ２ R １３ｂ Selected from 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 Each of the aryl and 5-12 membered heteroaryls is 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 It is arbitrarily replaced with, 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 The compound according to any one of claims 1 to 8, wherein it is an aryl or a 5- to 12-membered heteroaryl.

74. R １３ However, independently, hydrogen, F, Cl, Br, I, CN, -C １ -C ８ Alkyl, or -C １ -C ８ A compound according to any one of claims 1 to 8, selected from alkoxys.

75. 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 claims 1 to 8, wherein the coefficient is 0, 1, or 2. 【Request Item 76】 【Chemistry 77】 but, 【Chemistry 78-1】 【Chemistry 78-2】 The compound according to any one of claims 1 to 8.

77. Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 21, Compound 22, Compound 23, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, Compound 36, Compound 37, Compound 38, Compound 39, Compound 40, Compound 41, Compound 42, Compound 43, Compound 44, Compound 45, Compound 46, Compound 47, Compound 49, Compound 50, Compound 51, Compound 54, Chemical Compounds 55, 56, 57, 58, 59, 60, 61, 63, 64, 65, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 98, 99, 100, 101, and 102. 102, Compound 103, Compound 104, Compound 105, Compound 106, Compound 108, Compound 111, Compound 112, Compound 113, Compound 114, Compound 115, Compound 116, Compound 117, Compound 118, Compound 119, Compound 120, Compound 121, Compound 122, Compound 123, Compound 124, Compound 125, Compound 126, Compound 127, Compound 129, Compound 131, Compound 132, Compound 133, Compound 134, Compound 135, Compound 136, Compound 137, Compound 138, Compound 140, Compound 141, Compound 142, Compound 143, Chemical Compounds 144, 147, 150, 151, 152, 153, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 167, 168, 169, 172, 173, 175, 176, 179, 182, 183, 184, 186, 188, 189, 190, 191, 192, 193, 195, and 196.A compound according to claim 1, selected from compound 197, compound 198, compound 199, compound 200, compound 202, compound 205, compound 206, compound 207, compound 208, compound 210, compound 211, compound 213, and compound 214.

78. A pharmaceutical composition comprising a compound according to any one of claims 1 to 77, or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, or prodrug, together with a pharmaceutically acceptable excipient.

79. 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 77, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, to a subject in need thereof.

80. The method according to claim 79, wherein the disease is selected from cancers, preferably from pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, and non-small cell lung cancer.

81. Use of a compound according to any one of claims 1 to 77, 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.

82. The use according to claim 81, wherein the disease is cancer, preferably selected from pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, and non-small cell lung cancer.

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