Compounds for the Degradation of EGFR Kinase

Abstract

Disclosed herein are novel bifunctional compounds of formula (I) formed by conjugating an EGFR inhibitor moiety and an E3 ligase ligand moiety, which function to recruit target proteins to E3 ubiquitin ligases for degradation, as well as methods for their preparation and use. [Formula 1] TIFF2025538190000823.tif43170

Description

[Technical Field]

[0001] Disclosed herein are novel bifunctional compounds formed by conjugating an EGFR inhibitor moiety and an E3 ligase ligand moiety, which function to recruit target proteins to E3 ubiquitin ligases for degradation, as well as methods for their preparation and use. [Background technology]

[0002] Targeted protein degradation inducer chimeric molecules (PROTACs) consist of two covalently linked protein-binding molecules: one capable of engaging with an E3 ubiquitin ligase, and the other capable of binding to a protein of interest (POI) for degradation (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98:8554-9; Sakamoto KM et al., Methods Enzymol. 2005;399:833-847). Rather than inhibiting the enzymatic activity of the target protein, the recruitment of E3 ligase to specific unwanted proteins results in ubiquitination and subsequent degradation of the target protein by the proteasome. The entire process of ubiquitination and proteasomal 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 G. Lett. et al., Cell Rep. 2015, 12, 545-553; Swatek K. Nett. et al., Cell Res. 2016, 26, 399-422). The proteasome is a protein complex that degrades unnecessary, misfolded, or abnormal proteins into small peptides to maintain cellular health and productivity. Ubiquitin ligases, also known as E3 ubiquitin ligases, directly catalyze the transfer of ubiquitin from E2s to target proteins for degradation.Although the human genome encodes over 600 putative E3 ligases, only a limited number of E3 ubiquitin ligases have been widely applied by small molecule PROTAC technology: cereblon (CRBN), von Hippel-Lindau (VHL), mouse double minute 2 homolog (MDM2), and cellular inhibitor of apoptosis proteins (cIAPs) (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578), recombinant human RING finger protein 114 (RNF114) (Spradlin, J. Net al. Nat. Chem. Biol. 2019, 15, 747-755), and DDB1 and CUL4-associated factor 16 (DCAF16) (Zhang, X. et al. Nat. Chem. Biol. 2019, 15, 737-746). For example, cereblon (CRBN) forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1) and cullin 4A (CUL4A) to ubiquitinate several other proteins, which are then degraded via the proteasome (Yi-An Chen, et al., Scientific Reports 2015, 5, 1-13). Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, inhibit CRL4A. CRBNThalidomide functions as a monovalent promoter of PPIs by binding to the cereblon (CRBN) subunit of the E3 ligase complex and recruiting neo-substrate proteins (Matyskiela, ME et al., Nat Chem Biol 2018, 14, 981-987). As a result, the ability of thalidomide and its derivatives to recruit CRBN has been widely applied in research related to targeted proteolysis-inducing chimeric molecules (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 for eliminating protein targets that are "undruggable" by conventional inhibitors or that are non-enzymatic. (Chu TT. et al., Cell Chem Biol. 2016;23:453-461, Qin C. et al., J Med Chem 2018;61:6685-6704, Winter GE. et al., Science 2015;348:1376-1381.) In recent years, PROTACs have been reported as useful modulators in anti-tumor research, promoting the selective degradation of a wide range of target proteins.(Lu J.et al.,Chem Biol.2015;22(6):755-763, Ottis P.et al.,Chem Biol.2017;12(4):892-898, Crews CMet al.,J MedChem.2018;61(2):403-404, Neklesa TKet 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., Leukemia, volume 33, pp. 2105-2110 (2019), Shaodong Liu et al., Medicinal Chemistry Research, volume 29, pp. 802-808 (2020), and are disclosed or discussed in patent publications, such as US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO2016197032, WO2016197114, WO201701 1590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449, WO2018071606, WO2021178920, WO2021127283, WO2021127190, WO202111871, and WO202111913.

[0003] The epidermal growth factor receptor (EGFR), a member of the ErbB family, is a transmembrane receptor tyrosine kinase (RTK) that plays a fundamental 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 with 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). The first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, have been approved for patients with NSCLC harboring EGFR-activating mutations (M. Maemondo, N. Engl. J. Med. 362(2010)2380-2388). While most patients with EGFR-mutated NSCLC respond to these therapies, resistance typically develops after an average of one year of treatment. There are several mechanisms underlying acquired resistance to gefitinib and erlotinib, including a secondary mutation of 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. Notably, osimertinib, which has little effect on wild-type EGFR, has achieved higher clinical response rates in NSCLC patients with EGFR T790M mutation.However, several recent studies have reported a tertiary Cys797 to Ser797 (C797S) point mutation in osimertinib clinical therapy (Thress KS, et al. Nat. Med. 2015, 21(6):560-562). There is a need for drugs that can overcome the barrier of EGFR (C797S) resistance in non-small cell lung cancer (NSCLC). EGFR-targeted PROTACs serve as a potential strategy to overcome drug resistance mediated by these mutations, as disclosed or discussed in, for example, the following patent publications: WO2018119441, WO2019149922, WO2019183523, WO2019121562, US20190106417, WO202157882, WO2021123087, WO2021133809, WO2021168074, WO2021208918, and WO2021216440.

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

[0005] The present application provides novel bifunctional compounds and compositions for the treatment of serious diseases. Summary of the Invention

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

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

[0008] Aspect 1. A compound of formula (I): [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, During the ceremony, E 1 But N or CR 5 and E 2 But N or CR 6 and R 1a , R 1b , R 2a , and R 2b each independently represents absence, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C2-8 Alkynyl, -C 1-8 Alkoxy, -C 3-8 cycloalkyl, or -CN, and each of the -C 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Alkynyl, said -C 1-8 Alkoxy, or the -C 3-8 Cycloalkyl is optionally selected from hydrogen, halogen, -C 1-8 Alkoxy, -C 3-8 cycloalkyl, or -CN; R 3 and R 4 are each independently hydrogen, -C 1-6 Alkyl, or -C 3-8 cycloalkyl, and each of the -C 1-6 Alkyl or -C 3-8 Cycloalkyl is optionally selected from hydrogen, halogen, -C 1-6 substituted with at least one substituent selected from alkoxy; R 5 and R 6 each independently represents absence, 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 of the -C 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Alkynyl, said -C 1-8 Alkoxy, or the -C 3-8 Cycloalkyl is optionally selected from hydrogen, halogen, -C 1-8 Alkoxy, -C 3-8 cycloalkyl, or -CN; or R 5 and R 6taken together with the carbon atoms to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl; R 7 each independently represents absence, 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 of the -C 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Alkynyl, said -C 1-8 Alkoxy, or the -C 3-8 Cycloalkyl is optionally selected from hydrogen, halogen, -C 1-8 Alkoxy, -C 3-8 cycloalkyl, or -CN; or The Two R's 7 taken together with the carbon atom(s) to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl; R 8 and R 9 are each independently selected from hydrogen, halogen, —C1-C6 alkyl, or C3-C8 cycloalkyl, wherein each of said —C1-C6 alkyl or said C3-C8 cycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, —C1-C6 alkoxy; R 10 are each independently hydrogen, halogen, -C1-C8 alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12Aryl, 5-12 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 or -NR 10a SO2R 10b or -CN, wherein said -C1-C8 alkyl, said -C 2-8 alkenyl, said -C 2-8 alkynyl, the C3-C8 cycloalkyl, the 3- to 8-membered heterocyclyl, the C6-C 12 aryl, or each of said 5- to 12-membered heteroaryl optionally contains at least one R 10c is replaced by R 10a and R 10b are each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; and 12 aryl, or each of said 5- to 12-membered heteroaryl optionally contains at least one substituent R 10d is replaced by R 10c and R 10d each independently represents halogen, hydrogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo (=O), -NR 10e R 10f , -OR 10e , -SR 10e , -SO2R10e , -SO2NR 10e R 10f , -C(O)R 10e , -CO2R 10e , -C(O)NR 10e R 10f , -NR 10e COR 10f , -NR 10e CO2R 8f or -NR 10e SO2R 10f , or -CN, R 10e and R 10f are each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d each independently represents absent, oxo, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, or -C 3-8 cycloalkyl, wherein the -C 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Alkynyl, said -C 1-8 Alkoxy, or the -C 3-8 Each cycloalkyl is optionally selected from hydrogen, halogen, —C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 substituted with at least one substituent selected from -alkoxy, -CN, L 1 However, independently, -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 , [ka] and [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] and the above [ka] each optionally containing at least one R L1c is replaced by In the formula, * L1 However, [ka] ** indicates the position where the molecule is attached to the L1 However, [ka] refers to the position where the molecule is attached to the moiety, L 2 However, independently, -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 , [ka] and [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] and the above [ka] each optionally containing at least one R L2c is replaced by In the formula, * L2 However, [ka] ** indicates the position where the molecule is attached to the L2 However, [ka] refers to the position where the molecule is attached to the moiety, L 3 However, independently, -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 , [ka] and [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] and the above [ka] each optionally containing at least one R L3c is replaced by In the formula, * L3 However, [ka] ** indicates the position where the molecule is attached to the L3 However, [ka] refers to the position where the molecule is attached to the moiety, R L1c , the R L2c , and the R L3c each independently represents absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl, and the —C1-C8 alkyl, the —C1-C8 alkoxy, the —C2-C8 alkenyl, the —C2-C8 alkynyl, the C3-C8 cycloalkyl, the 3- to 8-membered heterocyclyl, the C6-C 12 aryl, and each of the 5- to 12-membered heteroaryl optionally contains at least one R Lca is replaced by R Lca are independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; The Two R's L1c together with the atoms to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent halogen, hydroxy, -C1-C8 alkyl; The Two R's L2ctogether with the atoms to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent halogen, hydroxy, -C1-C8 alkyl; The Two R's L3c together with the atoms to which they are attached form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent halogen, hydroxy, -C1-C8 alkyl; Z 1 and Z 2 are each independently N or CR z and R z may, in each occurrence, independently represent absence, hydrogen, halogen, -C 1-8 Alkyl, -NR Za R Zb , -OR Za , -SR Za , C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, or CN, 1-8 alkyl, the C3-C8 cycloalkyl, and the 3- to 8-membered heterocyclyl may each optionally be selected from the group consisting of at least one R Zc is replaced by R Za and R Zb each independently represents absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; 1-8 alkyl, the C3-C8 cycloalkyl, the 3- to 8-membered heterocyclyl, the C6-C 12 aryl, or each of said 5- to 12-membered heteroaryl optionally contains at least one substituent R Zd is replaced by R Zc and R Zd each independently represents halogen, hydroxy, -C1-C8 alkyl, -C 1-8Alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; R 13 each independently represents absence, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 Aryl, 5-12 membered heteroaryl, -CN, -SO2R 13a , -SO2NR 13a R 13b , -COR 13a , -CO2R 13a , -CONR 13a R 13b , -NR 13a R 13b , -NR 13a COR 13b , -NR 13a CO2R 13b , or -NR 13a SO2R 13b -C is selected from 1-8 Alkyl, said -C 2-8 alkenyl, said -C 2-8 Alkynyl, said -C 1-8 alkoxy, the -C3-C8 cycloalkyl, the 3- to 8-membered heterocyclyl, the -C6-C 12 aryl, or each of said 5- to 12-membered heteroaryls is optionally selected from halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 13c , -SO2R 13c , -SO2NR 13c R 13d , -COR 13c , -CO2R 13c , -CONR 13c R 13d , -NR 13c R13d , -NR 13c COR 13d , -NR 13c CO2R 13d , or -NR 13c SO2R 13d is replaced by In each occurrence, R 13a , R 13b , R 13c , and R 13d are each independently absent, hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; In each occurrence, X 1 , X 2 , and X 7 However, each independently, -CR a , or N, In each occurrence, X 3 , X 4 , and X 8 are each independently -NR a -, -O-, -S-, and -CR a R b - selected from In each occurrence, X 5 and X 6 each independently represents absence, a single bond, -C(O)-, or -NR a -, and -O-; In each occurrence, R a and R b are each independently hydrogen, hydroxy, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5- to 12-membered heteroaryl; and 12Aryl, or each of said 5- to 12-membered heteroaryl, optionally has at least one substituent halogen, hydroxy, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 substituted with aryl, or 5- to 12-membered heteroaryl; R a and R b are taken together with the carbon atoms to which they are attached to form a 3- to 12-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said ring optionally contains at least one substituent halogen, hydroxy, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl or 5- to 12-membered heteroaryl; 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 are independently 0, 1, 2, 3, or 4 at each occurrence; s1 and s2 are each independently 0, 1, 2, or 3; s3 and s4 are each independently 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 1 If N, then X 5 is a single bond, absent, -C(O)-, and / or X2 If N, then X 6 is a single bond, absent, -C(O)-, L 1 but [ka] If X 1 If N, then X 5 is a single bond, absent, -C(O)-, and / or X 3 But, -CR a R b - and X 2 If N, then X 6 is a single bond, absent, -C(O)-, and / or X 4 But, -CR a R b - and L 2 but [ka] If X 1 If N, then X 5 is a single bond, absent, -C(O)-, and / or X 3 But, -CR a R b - and X 2 If N, then X 6 is a single bond, absent, -C(O)-, and / or X 4 But, -CR a R b - and L 3 but [ka] If X 1 If N, then X 5 is a single bond, absent, -C(O)-, and / or X 3 But, -CR a R b - and X 2 If N, then X 6 is a single bond, absent, -C(O)-, and / or X4 But, -CR a R b - or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, provided that:

[0009] Aspect 2. The compound is selected from formula (IIa) or (IIb): [ka] [ka] In the formula, 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 , R 13 , L 1 , L 2 , L 3 , Z 1 , s1, s2, s3, s4, s5, s6, s7, m1, m2, m3, m4, m5, m6, and m7 are as defined in any one of the preceding aspects; More preferably, the compound is selected from formula (IIIa) or (IIIb): [ka] [ka] In the formula, 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 , R 13 , L 1 , L 2 , L 3 , s1, s2, s3, s4, s5, s6, s7, m1, m2, m3, m4, m5, m6, and m7 are as defined in any one of the preceding aspects; Even more preferably, the compound is selected from formula (IVa) or (IVb): [ka] [ka] In the formula, 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 13 , L 1 , L 2 , L 3 , s1, s2, s3, s4, s5, s6, s7, m1, m2, m3, m4, m5, m6, and m7 are as defined in any one of the preceding aspects; Even more preferably, the compound is selected from formula (Va) or (Vb): [ka] [ka] In the formula, R 10 , R 13 , L 1 , L 2 , L 3 , s7, m1, m2, m3, m4, m5, m6, and m7 are as defined in any one of the preceding embodiments.

[0010] Aspect 3. The compound is selected from formula (VIa): [ka] Preferably, the compound is selected from formula (VIb), (VIc) or (VIc'), [ka] [ka] [ka] More preferably, the compound is selected from formula (VId) or (VIe): [ka] [ka] More preferably, the compound is selected from formula (VIf) or (VIg), [ka] [ka] Even more preferably, the compound is selected from formula (VIh) or (VIi): [ka] [ka] Even more preferably, the compound is selected from formula (VIj), (VIk), (VIl), or (VIm), [ka] [ka] [ka] [ka] Even more preferably, the compound is selected from formula (VIn), (VIo), (VIp), or (VIq), [ka] [ka] [ka] [ka] In the formula, 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 , R 13, L 1 , L 2 , L 3 , s1, s2, s3, s4, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, n6, Z 1 , Z 2 , X 7 , and X 8

[0023] The compound of any one of the preceding aspects, wherein

[0011] Embodiment 4. The compound according to any one of the preceding embodiments, wherein m1 + m2 + m3 + m4 ≦3.

[0012] Embodiment 5. A compound according to any one of the preceding embodiments, wherein m1+m2+m3+m4=0, 1, 2, or 3, and preferably m1+m2+m3+m4=0, 1, or 2.

[0013] Aspect 6. [ka] The compound according to any one of the preceding aspects, wherein the number of -CH2- in the moiety is 4 or less, preferably 3 or less, and even more preferably 2 or less.

[0014] Aspect 7.R 3 and R 4 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, wherein said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, or said cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy; Preferably, R 3 and R 4are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and preferably R 3 are independently methyl, and R 4 The compound of any one of the preceding embodiments, wherein is hydrogen.

[0015] Aspect 8.R 1a , R 1b , R 2a , and R 2b are each independently 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, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or —CN, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C 2-8 alkenyl, said -C 2-8 The compound of any one of the preceding aspects, wherein alkynyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, and the 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.

[0016] Aspect 9.R 1a , R 1b , R 2a , and R 2bare 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, -CF3, -CHF2, -CN, -CHOCH3, -CHOCHCH3, -CHCHOCH3, -CHCHOCHCH3; Preferably, R 1a , R 1b , R 2a , and R 2b

[0039] The compound of any one of the preceding embodiments, wherein each is independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3, or -CHF2, -CH2OCH3.

[0017] Aspect 10.R 5 and R 6 are 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, -CF3, -CHF2, -CN, -CHOCH3, -CHOCHCH3, -CHCHOCH3, -CHCHOCHCH3; Preferably, R 5 and R 6

[0039] The compound of any one of the preceding embodiments, wherein each is independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3, or -CHF2, -CH2OCH3.

[0018] Aspect 11.R 5 and R 6together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; Preferably, R 5 and R 6 are taken together with the carbon atoms to which they are attached to form a 3-, 4-, 5-, or 6-membered ring, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl.

[0019] Aspect 12.R 7 are 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, -CF3, -CHF2, -CN, -CHOCH3, -CHOCHCH3, -CHCHOCH3, -CHCHOCHCH3; Preferably, R 7

[0039] The compound of any one of the preceding embodiments, wherein each is independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3, or -CHF2, -CH2OCH3.

[0020] Aspect 13. Two R 7 together with the carbon atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; Preferably, two R 7 together with the carbon atom(s) to which they are attached form a 3-, 4-, 5-, or 6-membered ring, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl.

[0021] Aspect 14.R 8 and R 9 are each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, wherein said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, or said cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy; Preferably, R 8 and R 9 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and preferably R 8 are independently hydrogen, and R 9 The compound of any one of the preceding embodiments, wherein is F or methyl.

[0022] Aspect 15.R 10 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, 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 , -CO2R 10a , -C(O)NR 10a R 10b , -NR 10a COR 10b , -NR 10a CO2R 10b or -NR 10a SO2R 10b or —CN, wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the —C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, or the phenyl optionally contains at least one R 10c is replaced by R 10a and R 10b each independently represents hydrogen, 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, or phenyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or -C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, or the phenyl optionally contains at least one substituent R 10d is replaced by R 10c and R 10d are 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 Alkynyl, 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 COR 10f , -NR 10e CO2R 10f or -NR 10e SO2R 10f , or -CN, R 10e and R 10f each independently represents 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- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, R 10 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, -NR 10a R 10b , -OR10a , -SR 10a , -C(O)R 10a , -CO2R 10a , -C(O)NR 10a R 10b , -NR 10a COR 10b , -NR 10a CO2R 10b or -NR 10a SO2R 10b or —CN, wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the —C 2-8 alkenyl, said -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, or the phenyl optionally contains at least one R 10c is replaced by R 10a and R 10b each independently represents 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- to 8-membered heterocyclyl, or phenyl; R 10c each independently represents 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, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, oxo (=O), -NR 10e R 10f , -OR 10e , or -CN, R 10e and R 10fare each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; More preferably, R 10 each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclyl, -NR 10a R 10b , -OR 10a , -CO2R 10a , or -C(O)NR 10a R 10b wherein each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, or said 3- to 8-membered heterocyclyl optionally comprises at least one R 10c is replaced by R 10a and R 10b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, or 6-membered heterocyclyl; R 10c each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxo (=O), -NR 10e R 10f , -OR 10e , or -CN, R 10e and R 10f are each independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and cyclopentyl; Even more preferably, R 10are 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, [ka] The compound of any one of the preceding embodiments, wherein the compound is selected from —COOH, —CONH 2 , —CH 2 OCH 3 , or —CH 2 OH.

[0023] Aspect 16. The above [ka] The part is, [ka] The compound of any one of the preceding aspects, selected from:

[0024] Aspect 17. The above [ka] The part is, [ka] The compound of any one of the preceding aspects, selected from:

[0025] Aspect 18.R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d each independently represents oxo, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or -C 2-8 alkenyl, said -C 2-8 Each of alkynyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, or the cyclooctyl is optionally selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 substituted with at least one substituent selected from alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, or -CN; Preferably, R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d are each 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, and preferably R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12dare each independently oxo, hydrogen, F, Cl, Br, I, methyl, ethyl, or propyl, more preferably R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d

[0039] The compound of any one of the preceding embodiments, wherein each is independently hydrogen or methyl.

[0026] Aspect 19.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] [ka] is selected from The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] and the above [ka] each optionally containing at least one R L1c is replaced by R L1ceach 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, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and , the butyl, the pentyl, the hexyl, the heptyl, the octyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the -C2-C8 alkenyl, the -C2-C8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, and the 5- to 12-membered heteroaryl may each optionally be selected from the group consisting of phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, methoxy, ethoxy, phenyl ... Lca is replaced by R Lca are independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; The Two R's L1c together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; R ais 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 wherein said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said methoxy, said -C2-C8 alkenyl, said -C2-C8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, and said cyclooctyl are independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, said -C2-C8 alkenyl, said -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The compound of any one of the preceding aspects, wherein each octyl is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0027] Aspect 20.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] The compound of any one of the preceding aspects, selected from:

[0028] Aspect 21.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] [ka] is selected from The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] each optionally containing at least one R L2c is replaced by R L2c each 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, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and , the butyl, the pentyl, the hexyl, the heptyl, the octyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the -C2-C8 alkenyl, the -C2-C8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, and the 5- to 12-membered heteroaryl may each optionally be selected from the group consisting of phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, methoxy, ethoxy, phenyl ... Lca is replaced by R Lca are independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; The Two R's L2ctogether with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; R a 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 wherein said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said methoxy, said -C2-C8 alkenyl, said -C2-C8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, and said cyclooctyl are independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, said -C2-C8 alkenyl, said -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The compound of any one of the preceding aspects, wherein each octyl is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0029] Aspect 22.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] The compound of any one of the preceding aspects, selected from:

[0030] Aspect 23.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] is selected from The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] The aforementioned [ka] and the above [ka] each optionally containing at least one R L3c is replaced by R L3c each 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, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and , the butyl, the pentyl, the hexyl, the heptyl, the octyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the -C2-C8 alkenyl, the -C2-C8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, and the 5- to 12-membered heteroaryl may each optionally be selected from the group consisting of phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, phenyl, methoxy, ethoxy, phenyl ... Lca is replaced by R Lcaare independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; The Two R's L3c together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; R a 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 wherein said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said methoxy, said -C2-C8 alkenyl, said -C2-C8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, and said cyclooctyl are independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, said -C2-C8 alkenyl, said -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The compound of any one of the preceding aspects, wherein each octyl is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0031] Aspect 24.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] The compound of any one of the preceding aspects, selected from:

[0032] Aspect 25. [ka] The part is, [ka] [ka] The compound of any one of the preceding aspects, selected from:

[0033] Aspect 26. The above [ka] The part is, [ka] The compound of any one of the preceding aspects, selected from:

[0034] Aspect 27.X 7 But independently, -CR a or N, R aare 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- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the -C2-C8 alkynyl, each of the -C2-C8 alkenyl, the -C2-C8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, or the 5- to 12-membered heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, X 7 is independently selected from -CH, -C(CH), or N, preferably X 7 is independently selected from —CH.

[0035] Aspect 28.X 8 But independently, -NR a -, -O-, -S-, and -CR a R b - selected from In each occurrence, R aand R b are each 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- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each independently represents a 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; each of the -C2-C8 alkenyl, the -C2-C8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, or the 5- to 12-membered heteroaryl is optionally substituted by at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, X 8 is independently selected from -NH- and -CH2-, preferably X 8 is independently selected from -CH2-.

[0036] Aspect 29. [ka] but, [ka] is selected from, preferably [ka] but, [ka] The compound of any one of the preceding aspects, selected from:

[0037] Aspect 30.Z 1 and Z 2 At most one of Z is N, and preferably 1 and Z 2 However, each independently, CR z

[0023] The compound of any one of the preceding aspects, wherein

[0038] Aspect 31.R Z is, in each occurrence, independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR Za R Zb , -OR Za , -SR Za , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, or CN, wherein each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, or said 3- to 8-membered heterocyclyl optionally comprises at least one R Zc is replaced by R Za and R Zbare each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of the hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may optionally be selected from at least one substituent R Zd is replaced by R Zc and R Zd are each 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- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, R z is selected from H, —CH3, —C2H5, F, —CH2F, —CHF2, —CF3, —OCH3, —OC2H5, —C3H7, —OCH2F, —OCHF2, —OCH2CF3, —OCF3, —SCF3, —CF3, or —CH(OH)CH3.

[0039] Aspect 32.R 13 are 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 2-8Alkynyl, 3-8 membered heterocyclyl, -C6-C 12 Aryl, 5-12 membered heteroaryl, -CN, -SO2R 13a , -SO2NR 13a R 13b , -COR 13a , -CO2R 13a , -CONR 13a R 13b , -NR 13a R 13b , -NR 13a COR 13b , -NR 13a CO2R 13b , or -NR 13a SO2R 13b and is selected from the group consisting of 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, said -C 2-8 alkynyl, the 3- to 8-membered heterocyclyl, the -C6-C 12 aryl, each of the 5- to 12-membered heteroaryls is optionally selected from 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 Alkynyl, 3-8 membered heterocyclyl, -C6-C 12 Aryl, 5-12 membered heteroaryl, oxo, -CN, -OR 13c , -SO2R 13c , -SO2NR 13c R 13d , -COR 13c , -CO2R 13c , -CONR 13c R 13d , -NR13c R 13d , -NR 13c COR 13d , -NR 13c CO2R 13d , or -NR 13c SO2R 13d is replaced by R 13a , R 13b , R 13c , and R 13d each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, or 5- to 12-membered heteroaryl; Preferably, R 13 are each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, —CN, —CHF, —CHF, —CF, —OCHF, —OCHF, —OCHCF, —OCF, —SCF, or phenyl.

[0040] Aspect 33. [ka] but, [ka]

[0023] The compound of any one of the preceding aspects, wherein

[0041] Aspect 34. [ka] but, [ka]

[0023] The compound of any one of the preceding aspects, wherein

[0042] Aspect 35. The following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The compound of any one of the preceding aspects, selected from:

[0043] Embodiment 36. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, together with a pharmaceutically acceptable excipient.

[0044] Embodiment 37. A method of treating a disease that can be affected by EGFR modulation, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

[0045] Embodiment 38. The method of embodiment 34, wherein said disease is selected from cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0046] Embodiment 39. Use of a compound according to any one of embodiments 1 to 32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in the preparation of a medicament for treating a disease that can be affected by EGFR modulation.

[0047] Aspect 40. The use according to aspect 36, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer. DETAILED DESCRIPTION OF THE INVENTION

[0048] The following terms have the meanings indicated throughout this specification: Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0049] The following terms have the meanings indicated throughout this specification: As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0050] The term "or" means, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0051] The term "alkyl" includes hydrocarbon groups selected from straight-chain and branched-chain saturated hydrocarbon groups containing 1 to 18, for example, 1 to 12, further for example, 1 to 10, and even further for example, 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6 Examples of alkyl 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.

[0052] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0053] 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").

[0054] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.

[0055] 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.

[0056] The term "alkylene" refers to a divalent alkyl group formed by removing two hydrogens from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, and the like.

[0057] The term "halogen" includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0058] The term "alkenyl" includes hydrocarbon groups selected from straight-chain and branched-chain hydrocarbon groups containing at least one C=C double bond and 2 to 18, for example, 2 to 8, further for example, 2 to 6 carbon atoms. Alkenyl groups, for example, C 2-6Examples of alkenyl include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0059] The term "alkenylene" refers to a divalent alkenyl group formed by removing two hydrogens from an alkene. Alkenylene includes, but is not limited to, vinylidene, butenylene, and the like.

[0060] The term "alkynyl" includes hydrocarbon groups selected from straight-chain and branched-chain hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, for example, 2 to 8, further for example, 2 to 6 carbon atoms. Alkynyl groups, for example, C 2-6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0061] The term "alkynylene" refers to a divalent alkynyl group formed by removing two hydrogens from an alkyne. Alkynylene includes, but is not limited to, ethynylene, and the like.

[0062] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0063] For example, the cycloalkyl group can contain 3 to 12, such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Still further, for example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Specifically, saturated monocyclic cycloalkyl groups, such as C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl is a monocyclic ring (C) containing 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring 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 a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0064] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings that share one atom.

[0065] The term "fused cycloalkyl" includes bicyclic cycloalkyl groups, as defined herein, that are saturated and formed by two or more rings sharing two adjacent atoms.

[0066] The term "bridged cycloalkyl" includes a cyclic structure containing carbon atoms and formed by two rings that share two non-adjacent atoms. The term "7-10 membered bridged cycloalkyl" includes a cyclic structure containing 7-12 carbon atoms and formed by two rings that share two non-adjacent atoms.

[0067] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl 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 3-8 membered benzocycloalkyl, benzoC 4-6 Examples include, but are not limited to, cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused rings, referring to ring structures containing 8-9 ring atoms in the above examples.

[0068] The term "aryl" used alone or in combination with other terms, 5- and 6-membered carbocyclic aromatic rings, for example, phenyl; Bicyclic ring systems, for example, 7- to 12-membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and Tricyclic ring systems, such as 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, include groups selected from, for example, fluorenyl.

[0069] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10(aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0070] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0071] The term "heteroaryl" includes groups selected from: a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), e.g., 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms, and in some embodiments, 1 to 2 heteroatoms, with the remaining ring atoms being carbon; a 7-12 membered bicyclic ring containing at least one heteroatom selected from N, O, and S, e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring; and An 11-14 membered tricyclic ring containing at least one heteroatom selected from N, O, and S, e.g., 1-4, or in some embodiments 1-3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being present in an aromatic ring.

[0072] When the total number of S and O atoms in the heteroaryl group exceeds 1, the heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form an N-oxide.

[0073] Specifically, the term "bicyclic fused heteroaryl" includes 7- to 12-membered, preferably 7- to 10-membered, and more preferably 9- or 10-membered fused bicyclic heteroaryl rings as defined herein. Typically, bicyclic fused heteroaryls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclics. Groups can be attached to the remainder of the molecule through either ring.

[0074] "Heterocyclyl," "heterocycle," or "heterocyclic ring" are interchangeable and include non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro rings, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0075] The term "H" or "hydrogen" as disclosed herein includes hydrogen and the non-radioactive isotope deuterium.

[0076] The term "at least one substituent" disclosed herein includes 1 to 4 substituents, such as 1 to 3, or even 1 or 2, as long as valence theory is satisfied. For example, "at least one substituent F" disclosed herein includes 1 to 4, such as 1 to 3, or even 1 or 2 substituents F.

[0077] The term "divalent" refers to a linking group that can form a covalent bond with two other moieties. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkane to form the linking group. The terms "divalent aryl group," "divalent heterocyclyl group," or "divalent heteroaryl group" should be understood similarly.

[0078] The compounds disclosed herein may have asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, including substantially purely resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0079] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, it is intended that such double bond include both E and Z geometric isomers.

[0080] When the compounds disclosed herein comprise a disubstituted cyclic ring system, the substituents found in such ring system can adopt cis and trans configuration.Cis configuration means that both substituents are found on the upper side of the arrangement of the two substituents on the carbon, while trans means that they are on the opposite side.For example, the disubstituted cyclic ring system can be a cyclohexyl or cyclobutyl ring.

[0081] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse-phase and normal-phase, size exclusion, ion exchange, high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus, small-scale analytical, simulated moving bed ("SMB"), and preparative thin- or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. One skilled in the art will be able to select and apply the techniques most likely to achieve the desired separation.

[0082] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0083] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as the formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review," J. Chromatogr., 113(3)(1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) the formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) the formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) the direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0084] Some of the compounds disclosed herein may exist at different points of hydrogen attachment, called tautomers. For example, compounds containing a carbonyl -CHC(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both the keto and enol forms (individually and in mixtures) are intended to be included. In another example, compounds containing pyrazolyl may undergo tautomerism to form different rings, such as: [ka]

[0085] In another example, compounds containing guanidinyl in a ring may undergo tautomerism to form different rings as shown below. [ka]

[0086] "Prodrug" refers to a derivative of an active agent that requires a transformation within the body to release the active agent. In some embodiments, the transformation is enzymatic. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the active agent.

[0087] "Deuterated analog" refers to a derivative of an active agent in which any hydrogen has been replaced with deuterium. In some embodiments, the deuteration site is in the Warhead moiety. In some embodiments, the deuteration site is in the Linker moiety. In some embodiments, the deuteration site is in the Degron moiety.

[0088] "Pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that corresponds to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or can be prepared separately by reacting a free base functional group with a suitable organic acid, or an acidic group with a suitable base. The term also includes salts of stereoisomers (enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the invention.

[0089] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0090] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with a cell as well as contact of a reagent with a biological fluid, where the biological fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell, with a reagent, diagnostic, binding compound, or another cell. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0091] As used herein, the terms "treated," "treating," or "treatment" also generally refer to the achievement of a desired pharmacological and / or physiological effect. This effect may be preventative, according to the total or partial prevention of a disease or its symptoms, and / or therapeutic, according to the partial or complete stabilization or cure of a disease and / or side effects resulting from a disease. As used herein, "treated," "treating," or "treatment" encompasses any treatment for a disease in a patient, including (a) the prevention of a disease or condition in a patient who may be predisposed to the disease or condition but has not yet been diagnosed, (b) the inhibition of symptoms of the disease, i.e., preventing its onset, or (c) the amelioration of symptoms of the disease, i.e., causing a total or partial regression of the disease or condition.

[0092] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" can vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case will be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug thereof and / or at least one pharmaceutically acceptable salt thereof that is effective in "treating" a disease or disorder, as defined herein, in a subject. In the case of a combination therapy, the term "therapeutically effective amount" refers to the total amount of the combined entities for effective treatment of a disease, disorder, or condition.

[0093] The term "disease" refers to any disease, ailment, illness, symptom, or indication, and may be used interchangeably with the terms "disorder" or "condition."

[0094] Throughout this specification and the claims that follow, unless the context otherwise requires, the word "comprise," as well as variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the word "comprising" may be substituted with the words "containing," "including," or, in some cases, "having."

[0095] Throughout this specification and the claims that follow, "C n-m " or "C n -C m The term "" denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 , C1-C8, C1-C6, etc.

[0096] Unless otherwise specified, percentages, ratios, proportions, or portions used in this application are by weight or volume. Quantities used in this application are by weight or volume, which can be readily determined by one skilled in the art.

[0097] Hereinafter, the present application will demonstrate the beneficial effects of the present application through examples. Those skilled in the art will recognize that these examples are illustrative and not limiting. These examples in no way limit the scope of the present 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.

[0098] Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. [Example]

[0099] The following examples are intended to be merely illustrative and should not be construed as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be expected. Temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and were used without further purification unless otherwise indicated. Unless otherwise indicated, reactions described below were carried out in anhydrous solvents under a positive pressure of nitrogen or argon or using drying tubes; reaction flasks were equipped with rubber septa for introduction of substrates and reagents via syringe; and glassware was oven-dried and / or heat-dried.

[0100] 1 1 H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. 1 HNMR Spectra were obtained in CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, using tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm, CD3OD: 3.31 ppm, DO: 4.79 ppm, d6-DMSO: 2.50 ppm, d6-acetone: 2.05 ppm, (CD3)3CO: 2.05 ppm) as reference standards. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broadened), dd (double doublet), and dt (double triplet). Coupling constants given are reported in Hertz (Hz).

[0101] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190-400 nm), 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 x 50 mm, 2.7 pm Gradient method: Flow rate: 1.8 mL / min Time (min) A (%) B (%) [Table 1]

[0102] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190-400 nm), 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 x 50 mm, 2.7 pm Gradient method: Flow rate: 1.8 mL / min Time (min) A (%) B (%) [Table 2]

[0103] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II) Detector: MWD (190-400 nm), 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 x 50 mm, 2.7 pm Gradient method: Flow rate: 1.2 mL / min Time (min) A (%) B (%) [Table 3]

[0104] Preparative HPLC was performed on a column (150 x 21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml / min, injection volume of 2 ml, room temperature, and UV detection at 214 nm and 254 nm.

[0105] In the examples below, the following abbreviations are used: [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0106] Intermediate 1: (7 1 s,7 3 s,E)-5 6 -Bromo-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)-cyclobutanacyclononaphan-3-one Step 1: Methyl (1s,3s)-3-formylcyclobutane-1-carboxylate [ka] To a stirred solution of methyl 3-(hydroxymethyl)cyclobutane-1-carboxylate (100 g, 693 mmol) in DCM (1000 mL) was added Dess-Martin periodinane (353 g, 832 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was then diluted with DCM (1000 mL) and washed with saturated aqueous NaHCO (3 × 1000 mL) and brine (1000 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product as a mixture of cis and trans isomers. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (100:12) to give the title compound (cis) (45 g, 45.6%) and the trans product (30 g, 30.4%). 1 H NMR (500MHz, CDCl3) δ 9.70 (s, 1H), 3.69 (s, 3H), 3.23 - 3.07 (m, 2H), 2.57 - 2.51 (m, 2H), 2.45 - 2.39 (m, 2H).

[0107] Step 2: Methyl (1s,3s)-3-(((tert-butylsulfinyl)amino)methyl)cyclobutane-1-carboxylate [ka] To a stirred solution of methyl (1s,3s)-3-formylcyclobutane-1-carboxylate (45 g, 318 mmol) in DCM (200 mL) was added 2-methylpropane-2-sulfinamide (42.2 g, 348 mmol) and 5 mL of AcOH at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated and diluted with MeOH (200 mL). NaBH (24 g, 633 mmol) was then added, and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated, diluted with DCM (1000 mL), and washed with brine (500 mL × 2). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to give the product (48 g, 61.3%). [M+H] + =248.2.

[0108] Step 3: Methyl (1s,3s)-3-(aminomethyl)cyclobutane-1-carboxylate hydrochloride [ka] A solution of methyl (1s,3s)-3-(((tert-butylsulfinyl)amino)methyl)cyclobutane-1-carboxylate (48 g, 194 mmol) in 100 mL of HCl (4N in dioxane) was stirred at room temperature for 4 hours. The resulting mixture was concentrated to give the product (38 g) as the hydrochloride salt. [M+H] + =144.1.

[0109] Step 4: Methyl (1s,3s)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutane-1-carboxylate [ka] A solution of (1s,3s)-3-(aminomethyl)cyclobutane-1-carboxylate hydrochloride (38 g, 265 mmol), 4-bromo-2-fluoro-1-nitrobenzene (87.6 g, 398 mmol), and DIEA (137 g, 1.06 mol) in MeCN (500 mL) was stirred at 80 °C for 16 h. The mixture was then concentrated, diluted with DCM (1000 mL), and washed with saturated aqueous NH4Cl (3 × 500 mL) and brine (500 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (0–20%) to give the product (45 g, 49.4%). [M+H] + =343.2.

[0110] Step 5: ((1s,3s)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutyl)methanol [ka] A solution of methyl (1s,3s)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutane-1-carboxylate (45 g, 131 mmol) in 600 mL of THF was cooled to −20 °C. LiAlH (2.4 M in THF, 60 mL) was added at −20 °C for 15 min. The resulting mixture was stirred at −20 °C for 1 h. The mixture was then diluted with EA (600 mL) and washed with saturated aqueous NH Cl (3 × 500 mL) and brine (500 mL). The organic layer was dried over anhydrous Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (0–60%) to give the product (37 g, 89.5%). [M+H] + =315.1.

[0111] Step 6: Methyl 2-(5-(((1s,3s)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate [ka] To a stirred solution of ((1s,3s)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutyl)methanol (37 g, 117 mmol), methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (27.4 g, 117 mmol), and PPh3 (37 g, 141 mmol) in THF (500 mL) was added DIAD (28.5 g, 141 mmol). The mixture was then stirred at room temperature for 2 h. The mixture was then concentrated and purified by silica gel column chromatography eluting with EtOAc / PE (0-80%) to give the product (72 g) in admixture with PPh3O. [M+H] + =544.3.

[0112] Step 7: Methyl 2-(5-(((1s,3s)-3-(((2-amino-5-bromophenyl)amino)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate [ka] To a stirred solution of methyl 2-(5-(((1s,3s)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (72 g, 132 mmol) in THF (1000 mL) was added Raney nickel (39 g, 661 mmol). The resulting mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (1 atm). The mixture was then filtered and the filtrate was concentrated. The resulting mixture (66 g) was used in the next step without purification. [M+H] + =514.3.

[0113] Step 8: Methyl 2-(5-(((1s,3s)-3-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate [ka] Methyl 2-(5-(((1s,3s)-3-(((2-amino-5-bromophenyl)amino)methyl)) in MeOH (200 mL) A solution of (cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (66 g, 128 mmol) and BrCN (41 g, 384 mmol) was stirred at room temperature for 4 hours. The mixture was then concentrated, diluted with DCM (1000 mL), and then washed with saturated aqueous NaHCO3 (3 x 500 mL) and brine (500 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (0-15%) to give the product (37 g, 43.5%). [M+H] + =539.4.

[0114] Step 9: (7 1 s,7 3 s,E)-5 6 -Bromo-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)-cyclobutanacyclononaphan-3-one [ka] To a stirred solution of methyl 2-(5-(((1s,3s)-3-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (37 g, 69.6 mmol) in 600 mL of THF was added LiHMDS (1N in THF, 137 mL) at room temperature for 15 min. The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with EA (600 mL) and washed with saturated aqueous NH4Cl (2 x 500 mL) and brine (500 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in 100 mL of EA and stirred at room temperature for 1 h. The mixture was then filtered to give the product (26 g, 74.7%). [M+H] + =507.2.

[0115] Intermediate 2: (7 1 r,7 3 r,E)-5 6 -Bromo-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)-cyclobutanacyclononaphan-3-one [ka] The title compound was prepared in a similar manner to Intermediate 1. [M+H] + =507.2.

[0116] Intermediate 3: (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid Step 1: Methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate [ka] A mixture of intermediate 16 (3.00 g, 6.22 mmol), methyl azetidine-3-carboxylate hydrochloride (1.41 g, 9.33 mmol), CsCO (6.06 g, 18.66 mmol), and RuPhos Pd G (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 EtOAc (100 mL × 3). The combined organic layer was washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2:1) to give the product (1.7 g, 53%). [M+1] + =517.1.

[0117] Step 2: 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid [ka] To a stirred mixture of methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate (1.7 g, 3.29 mmol) in THF (20 mL) was added LiOH·HO (168 mg, 4 mmol) in 10 mL of water dropwise at room temperature. The mixture was then stirred for 2 h. The resulting mixture was concentrated in vacuo. The aqueous layer was adjusted to pH < 5 with 1 N HCl and then extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the product (1.4 g, 85%), which was used in the next step without further purification. [M+1] + =503.2.

[0118] Step 3: (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid [ka] To a solution of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (1.40 g, 2.79 mmol) in iPrOH (20 mL) and DCM (20 mL) was added Pd / C (1.0 g, 10% wt), and the mixture was stirred under a hydrogen atmosphere at room temperature for 48 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure and purified by SFC (CHIRALPAK AD-3 3.0 × 100 mm, 3 μm, MeOH (0.1% DEA)) to give the title compound corresponding to Peak A at 1.849 min / 254 nm (190 mg, 22%). [M+1] + =325.3.

[0119] Intermediate 4: (S)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylic acid Step 1: Methyl (S)-4,4-dimethylpyrrolidine-3-carboxylate [ka] To a stirred solution of (S)-4,4-dimethylpyrrolidine-3-carboxylic acid (2 g, 13.96 mmol) in MeOH (30 mL) was added SOCl (1.66 g, 13.96 mmol) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at a temperature of 60° C. for 2 hours. The resulting mixture was concentrated under reduced pressure to give the product (2.1 g, 95.8%), which was used in the next step without further purification. [M+H] + =158.1

[0120] Steps 2-4: (S)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylic acid [ka] The title compound was prepared in a similar manner to the synthesis of Intermediate 3 (Steps 1-3). [M+H] + =367.4.

[0121] Intermediate 5: (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde Step 1: Ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate [ka] To a solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (10 g, 43.1 mmol) in THF (150 mL) was added LDA (2 M in THF, 24 mL, 48 mmol) dropwise over 20 minutes at −65° C. The reaction solution was stirred at this temperature for 1 hour, and then ethyl 3-bromopropanoate (9.4 g, 51.7 mmol) in THF (30 mL) was added dropwise over 10 minutes. The resulting solution was stirred at −65° C. for 30 minutes and then allowed to warm to room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (13.8 g, 96.5%). [M+H] + =332.0.

[0122] Step 2: 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoic acid [ka] To a solution of ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate (13.5 g, 40.7 mmol) in THF / HO (90 mL / 30 mL) was added LiOH (2.9 g, 0.122 mol). The reaction mixture was stirred at room temperature for 12 hours. The resulting mixture was diluted with water and extracted with EtOAc (50 mL x 2). The pH of the aqueous phase was adjusted to 4-5 with 1N HCl (10 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the product (10.2 g, 82.5%). [M+H] + =304.2.

[0123] Step 3: 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a stirred solution of 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoic acid (10.2 g, 33.5 mmol) in toluene (100 mL) was added concentrated H2SO4 (2 mL, 36.9 mmol). The resulting solution was stirred at 100 °C for 3 h. The reaction mixture was concentrated in vacuo, and then the mixture was poured into water. The pH was adjusted to 7-8 using saturated aqueous NaHCO3 (40 mL), and the resulting solution was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the product (8.2 g, 80.4%). [M+H] + =304.3.

[0124] Step 4: (R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a stirred solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (8.2 g, 27.0 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.4 g, 32.4 mmol) in DMF / HO (100 mL / 20 mL) was added Pd(dtbpf)Cl (883 mg, 1.35 mmol) and CsF (8.2 g, 54.0 mmol). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction solution was diluted with water and extracted with EtOAc (100 mL × 2). The combined organic layer was washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by SFC (IH (3 x 25 cm, 5 μm), 13% EtOH / 87% CO2, 100 bar, 100 ml / min) to give the title compound corresponding to peak A (1.679 min / 254 nm). (3.1 g, 39.0%). [M+H] + =296.1.

[0125] Step 5: (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde [ka]

[0126] (R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione (3.1 g, 10.4 mmol) was dissolved in FA (50 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction solution was evaporated to dryness to give the product (2.6 g, 91.8%). [M+H] + =268.1.

[0127] Intermediate 6: (R)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione Step 1: 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] To a solution of intermediate 16 (30 g, 62.24 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (10.68 g, 74.69 mmol), and CsCO (40.58 g, 124.48 mmol) in 500 mL of dioxane, Pd(dba) (2.85 g, 3.11 mmol) and Xantphos (3.6 g, 6.22 mmol) were added under N atmosphere. The mixture was stirred at 80 °C under N protection for 16 h. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo and purified by silica column chromatography (EA:PE = 0-80%) to give the crude product. The crude material was recrystallized with MeOH and filtered. The filter cake was dried to give the title compound (26.8 g, 79% yield). [M+H] + =544.9.

[0128] Step 2: 3-(2,6-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione [ka]

[0129] To a solution of 8-(4-(2,6-bis(benzyloxy)pyridin-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 was added Pd / C (27 g, 10 wt %, wet). The mixture was stirred at 45° C. under a H atmosphere (4 bar) for 16 hours. The mixture was filtered and the filter cake was washed with DMF. The combined liquids were concentrated in vacuo to give the title compound (15 g, 83.2% yield). [M+H] + =367.1.

[0130] Step 3: (R)-3-(2,6-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione [ka] The title compound was purified by chiral HPLC (CHIRALPAK IF (2 x 25 cm, 5 μm), MtBE (0.1% DEA): (MeOH: DCM = 1:1) = 50:50, 100 bar, 20 ml / min) (4.47 g, 37% yield from 12 g of racemate). [M+H] + =367.1.

[0131] The title compound could also be purified by chiral HPLC (CHIRALPAK IF (4.6 × 50 mm, 3 μm), MtBE (0.1% DEA): (MeOH: DCM = 1:1) = 50:50, 1 ml / min), and the title compound corresponded to peak A at 0.990 min / 254 nm.

[0132] Step 4: (R)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione [ka]

[0133] (R)-3-(2,6-Difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-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 stirrer. Then, 10 mL of 12 N aqueous HCl was added. The mixture was stirred at room temperature for 30 minutes. The mixture was added dropwise to saturated aqueous NaHCO3 solution until the pH reached 6-7. The liquid was extracted with DCM and separated. The organic phase was concentrated in vacuo and purified by silica gel column chromatography (MeOH:DCM = 0-5%) to give the title compound (850 mg, 96.7% yield). [M+H] + =323.1.

[0134] Intermediate 7: (R)-3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione Step 1: 2,6-Bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidin-1-yl)-2,6-difluorophenyl)pyridine [ka] A solution of intermediate 16 (20 g, 41.49 mmol), 3-(benzyloxy)azetidine hydrochloride (9.96 g, 49.79 mmol), Pd(dba) (3.79 g, 4.15 mmol), RuPhos (3.88 g, 8.3 mmol), and CsCO (40.58 g, 124.47 mmol) in dioxane (400 mL) was stirred at 100 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidin-1-yl)-2,6-difluorophenyl)pyridine (17 g, 72.6%). [M+H] + =565.6.

[0135] Step 2: 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidin-1-yl)-2,6-difluorophenyl)pyridine (17 g, 30.09 mmol) in DCM / THF (200 mL / 200 mL) was added Pd / C (10 wt%, wet, 34 g). The mixture was stirred under a hydrogen atmosphere at 65° C. for 2 days. After cooling to room temperature, the resulting mixture was filtered, and the filter cake was washed with IPA. The filtrate was concentrated under reduced pressure and purified by trituration with DCM / MeOH (10 / 1) to give 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (8 g, 89.9%). [M+H] + =297.1

[0136] Step 3: 3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A solution of 3-(2,6-difluoro-4-(3-hydroxyazetidin-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 NaHCO (500 mL) and extracted with EA (200 mL × 3). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (11 g, 72.4%). [M+H] + =411.2

[0137] Step 4: (R)-3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The crude product (11 g) was purified by preparative HPLC to give the title compound (CHIRALPAK IF-3, 4.6 x 50 mm, 3 μm, MtBE (0.1% DEA): (MeOH: DCM = 1:1) = 80:20, flow rate 1.0 mL / min, peak A at 1.084 min). (4 g, 36%, ee = 100%). [M+H] + =411.2

[0138] Step 5: (R)-3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione [ka] (R)-3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidin-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 stirrer. 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 h. The mixture was added dropwise to saturated aqueous NaHCO3 solution to adjust the pH to 6-7. The liquid was extracted with DCM (50 mL x 3) and separated. The combined organic phase was concentrated in vacuo and purified by Combiflash (DCM:MeOH = 20:1) to give the title compound (1.8 g, 95% yield). [M+H] + =297.2.

[0139] Step 6: (R)-3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione [ka] To a stirred solution of (R)-3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (1.8 g, 6.0 mmol) in DCM (60 mL) was added Dess-Martin periodinane (3.8 g, 9.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was then diluted with DCM (100 mL) and washed with saturated aqueous NaSO (100 mL), saturated aqueous NaHCO (3 × 100 mL), and brine (100 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product (2.0 g), which was used without further purification. [M+H] + =295.2.

[0140] Intermediate 8: (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbaldehyde Step 1: (R)-3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)piperidine-2,6-dione [ka] To a solution of intermediate 3 (6.5 g, 20 mmol) in THF was added BH3.THF (30 mL, 1 M in THF) dropwise at 0 °C. The reaction mixture was stirred at room temperature overnight. The mixture was then quenched with MeOH (20 mL), diluted with DCM (150 mL), and washed with saturated aqueous NaHCO3 (3 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography eluting with DCM / MeOH (30:1 to 15:1) to give the title product (3.8 g, 61.2%). [M+H] + =311.2.

[0141] Step 2: (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbaldehyde [ka] A mixture of (R)-3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-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 in a flask at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with DCM (60 mL × 3). The combined organic layers were washed with saturated aqueous NaSO (100 mL), saturated aqueous NaHCO (100 mL × 2), saturated aqueous NaCl (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the product (2.3 g, 70.1%), which was used without further purification. [M+H] + =309.1.

[0142] Intermediate 9: 3-(3-fluoro-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione Step 1: 8-(6-chloro-5-fluoropyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] To a solution of 5-bromo-2-chloro-3-fluoropyridine (2.0 g, 9.5 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (2.0 g, 14.25 mmol), and CsCO (9.26 g, 28.5 mmol) in 80 mL of 1,4-dioxane, Pd(dba) (871 mg, 0.95 mmol) and XantPhos (880 mg, 1.9 mmol) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. After LCMS showed the reaction was complete, the mixture was filtered through a Celite pad and washed with DCM. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by silica column chromatography (PE:EA = 50:1 to 2:1) to give the product (1.7 g, 65.8%). [M+H] + =273.5.

[0143] Step 2: 8-(2',6'-bis(benzyloxy)-3-fluoro-[2,3'-bipyridin]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] To a solution of 8-(6-chloro-5-fluoropyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane (1.6 g, 5.87 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0 g, 7.04 mmol), and KCO (2.43 g, 17.61 mmol) in 40 mL of 1,4-dioxane and 8 mL of HO was added Pd(dppf)Cl (858 mg, 1.17 mmol). The mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was filtered through a Celite pad and washed with DCM. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by silica column chromatography (PE:EA=50:1 to 2:1) to give the product (2.7 g, 90.1%). [M+H] + =528.5.

[0144] Step 3: 3-(3-fluoro-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)piperidine-2,6-dione [ka] 8-(2',6'-Bis(benzyloxy)-3-fluoro-[2,3'-bipyridin]-5-yl)-1,4-dioxa-8-azaspiro[4.5]decane (2.7 g, 5.12 mmol) was dissolved in DMF (40 mL) and iPrOH (20 mL). Pd / C (2.7 g, 10 wt%, wet) was added to the solution in one portion. The resulting mixture was stirred overnight at 50°C under a hydrogen atmosphere (1 atm). The solids were filtered off, and the filtrate was concentrated to give the crude product. The crude was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the product (1.6 g, 89.8%). [M+H] + =350.5.

[0145] Step 4: 3-(3-fluoro-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] 3-(3-Fluoro-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)piperidine-2,6-dione (500 mg, 1.43 mmol) was placed in a 25 mL round-bottom flask equipped with a magnetic stirrer. 5 mL of concentrated aqueous HCl was then added. The mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to saturated aqueous NaHCO3 solution to adjust the pH to 6-7. The liquid was extracted with DCM (20 mL x 3) and separated. The combined organic phase was concentrated in vacuo and purified by Combiflash (DCM:MeOH = 20:1) to give the title compound (350 mg, 80.2% yield). [M+H] + =306.5.

[0146] Intermediate 10: 3-(4-methyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione Step 1: 2',6'-Bis(benzyloxy)-5-bromo-4-methyl-2,3'-bipyridine [ka] To a solution of 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 KCO (4.5 g, 32.2 mmol) in 100 mL of 1,4-dioxane and 20 mL of HO was added Pd(dppf)Cl (1.2 g, 1.61 mmol). The mixture was stirred at 90 °C for 16 h. The mixture was concentrated under reduced pressure to give a crude residue, which was purified by silica column chromatography (PE:EA = 100:1 to 5:1) to give the product (6.7 g, 90.5%). [M+H] + =461.5.

[0147] Step 2: 8-(2',6'-bis(benzyloxy)-4-methyl-[2,3'-bipyridin]-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 CsCO (9.4 g, 29.0 mmol) in 80 mL of DMA, Pd(dba) (2.6 g, 2.9 mmol) and RuPhos (2.7 g, 5.8 mmol) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was filtered through a Celite pad and washed with DCM. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by silica column chromatography (PE:EA = 50:1 to 2:1) to give the product (5.3 g, 69.7%). [M+H] + =524.5.

[0148] Step 3: 3-(4-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)piperidine-2,6-dione [ka] To a solution of 8-(2',6'-bis(benzyloxy)-4-methyl-[2,3'-bipyridin]-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 was added Pd / C (2.0 g, 10 wt %, wet). The mixture was stirred at 50°C under a hydrogen atmosphere (balloon) for 20 hours. The mixture was cooled to room temperature and filtered directly through Celite. The filtrate was concentrated in vacuo to give the desired product (2.7 g, 77.1%). [M+H] + =346.6.

[0149] Step 4: 3-(4-methyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] 3-(4-Methyl-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-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 stirrer. 45 mL of 8N aqueous HCl was then added. The mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to saturated aqueous NaHCO3 solution to adjust the pH to 6-7. The liquid was extracted with DCM (40 mL x 3) and separated. The combined organic phase was concentrated in vacuo and purified by Combiflash (DCM:MeOH = 25:1) to give the title compound (2.2 g, 93.6% yield). [M+H] + =302.5.

[0150] Intermediate 11: 3-(5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Intermediate 10. [M+H] + =288.2.

[0151] Intermediate 12: 3-(6-methyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Intermediate 10. [M+H] + =302.5.

[0152] Intermediate 13: 2-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)ethyl methanesulfonate Step 1: 2-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)ethan-1-ol [ka] To a solution of intermediate 16 (180 g, 374 mmol), 2-aminoethan-1-ol (45.6 g, 748 mmol), and KPO (158.6 g, 748 mmol) in 1 L of DMSO, CuI (7.1 g, 37.4 mmol) and L-proline (4.3 g, 37.4 mmol) were added under N protection. The mixture was stirred at 90 °C for 16 h. The mixture was diluted with EtOAc and filtered. The filtrate was washed with saturated aqueous NaCl and concentrated in vacuo. The crude product was purified by silica column chromatography (EA:PE = 0-70%) to give the title compound (109 g, 63% yield). [M+H] + =463.6.

[0153] Step 2: 3-(2,6-difluoro-4-((2-hydroxyethyl)amino)phenyl)piperidine-2,6-dione [ka] To a solution of 2-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)ethan-1-ol (108 g, 234 mmol) in 200 mL of DCM and 1600 mL of IPA was added Pd / C (108 g, 10% wt). The mixture was stirred at 45° C. under an H atmosphere for 16 hours. The mixture was filtered through Celite. The filter cake was washed twice with DMF and the combined filtrates were concentrated in vacuo to give the title compound (45.6 g, 68% yield). [M+H] + =285.6.

[0154] Step 3: 2-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)ethyl methanesulfonate [ka] To a solution of 3-(2,6-difluoro-4-((2-hydroxyethyl)amino)phenyl)piperidine-2,6-dione (5.1 g, 18 mmol) and EtN (5.4 g, 54 mmol) in 100 mL of DCM was added MsCl (4.1 g, 36 mmol). The mixture was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The mixture was concentrated in vacuo and purified by silica column chromatography (MeOH:DCM = 0-3%) to give the title compound (4.2 g, 64% yield). [M+H] + =363.6.

[0155] Intermediate 14: (R)-3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione [ka] Step 1: Benzyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperazine-1-carboxylate [ka] To a solution of intermediate 16 (4.8 g, 10 mmol), benzylpiperazine-1-carboxylate (2.4 g, 11 mmol), and CsCO (6.5 g, 20 mmol) in 100 mL of dioxane, Pd(dba) (457 mg, 0.5 mmol) and Xantphos (578 mg, 1 mmol) were added. The mixture was stirred at 90 °C under a N atmosphere for 18 h. After LCMS showed the reaction was complete, the mixture was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo, and the crude product was purified by silica column chromatography (EA:PE = 0-50%) to give the desired product (5.9 g, 95%). [M+H] + =622.7.

[0156] Step 2: (R)-3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione [ka] To a solution of benzyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperazine-1-carboxylate (5.9 g, 9.5 mmol) in 5 mL of DCM and 100 mL of IPA was added Pd / C (5.9 g, 10% wt). The mixture was stirred under an H atmosphere at 45° C. for 18 hours. After LCMS showed the reaction was complete, the mixture was filtered through Celite. The filter cake was suspended in 50 mL of DMF and filtered. The filtrates were combined and concentrated in vacuo. The crude product was washed with MeOH and purified by chiral HPLC (IF (2×25 cm, 5 μm), 60% MtBE / 40% MeOH:DCM=1:1, 80 bar, 20 ml / min) (2.5 g, 85%). [M+H] + =310.7.

[0157] The title compound could also be purified by chiral SFC (column: chiral ND(2) 3.0 × 100 mm, 3 μm; solvent A: CO2, solvent B: IPA (0.1% DEA), gradient (B%): 10% to 50% in 2.0 min, hold at 50% for 1.0 min, flow rate 2 mL / min, retention time 1.979 min).

[0158] Intermediate 15: Step 3: 3-(6-methyl-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione Step 1: tert-butyl 4-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridin]-5-yl)piperazine-1-carboxylate [ka] To a solution of 2',6'-bis(benzyloxy)-5-bromo-6-methyl-2,3'-bipyridine (4.0 g, 8.7 mmol) (compound obtained by a similar method to Step 1 of Intermediate 10), tert-butyl piperazine-1-carboxylate (4.0 g, 17.4 mmol), and CsCO (5.7 g, 17.4 mmol) in 80 mL of DMA, Pd(dba) (1.6 g, 1.74 mmol) and RuPhos (1.6 g, 3.48 mmol) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was filtered through a Celite pad and washed with DCM. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by silica column chromatography (PE:EA = 50:1 to 2:1) to give the product (1.9 g, 38.8%). [M+H] + =567.5.

[0159] Step 2: tert-Butyl 4-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridin]-5-yl)piperazine-1-carboxylate (1.9 g, 3.7 mmol) in 25 mL of DMF and 25 mL of iPrOH was added Pd / C (1.2 g, 10 wt%, wet). The mixture was stirred at 50°C under a hydrogen atmosphere (balloon) for 16 hours. The mixture was cooled to room temperature and filtered directly through Celite. The filtrate was concentrated in vacuo to give the desired product (1.2 g, 92.3%). [M+H] + =389.5.

[0160] Step 3: 3-(6-methyl-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] To a 50 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl 4-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperazine-1-carboxylate (400 mg, 1.0 mmol) and HCl / 1,4-dioxane (10 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to give the product (as the hydrochloride salt) (350 mg), which was used without further purification. [M+H] + =289.5.

[0161] Intermediate 16: 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] Four reactions were carried out in parallel.

[0162] To a solution of 2,6-dibenzyloxy-3-bromo-pyridine (2.00 kg, 5.40 mol, 1.00 equiv.) in dioxane (12.0 L) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (760 g, 5.94 mol, 862 mL, 1.10 equiv.) and TEA (1.09 kg, 10.8 mol, 1.50 L, 2.00 equiv.), degassed, and purged with N. Then, Pd(PPh)Cl (189 g, 270 mmol, 0.05 equiv.) was added to the mixture. The mixture was stirred at 90 °C for 16 h. TLC (petroleum ether / ethyl acetate = 10 / 1, R f (starting material) = 0.50, R f The (product) = 0.55) indicated complete consumption of the starting material. The reaction mixture was filtered and concentrated. The four reactions were combined. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 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

[0163] Step 2: 5-Bromo-1,3-difluoro-2-iodobenzene [ka] Five reactions were carried out in parallel.

[0164] To a solution of 1-bromo-3,5-difluoro-benzene (1.00 kg, 5.18 mol, 595 mL) in THF (4.00 L) was added LDA (2 M, 2.59 L) at −70° C. The mixture was stirred at −70° C. for 1 hour. Then, to the mixture was added a solution of I2 (1.33 kg, 5.23 mol, 1.05 L) in THF (1.00 L) at −70° C. The mixture was stirred at −70° C. for 1 hour. TLC (petroleum ether:ethyl acetate=1:0, R f (starting material) = 0.86, R f(Product) = 0.80) indicated that the starting material was completely consumed. The reaction mixture was poured into HO (5.00 L) and extracted with EtOAc (3.00 L × 2). The five reactions were combined, and the combined organic layer was washed with brine (5.00 L), dried over NaSO, filtered, and concentrated in vacuo at 40 °C to give a residue. The crude product was triturated with petroleum ether (6.00 L). The compound 5-bromo-1,3-difluoro-2-iodo-benzene (4.50 kg, 14.1 mol, 54.4% yield) was obtained. [M+H] + =318.8

[0165] Step 3: 2,6-Bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine [ka] To a solution of 5-bromo-1,3-difluoro-2-iodo-benzene (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 HO (4.50 L) was added Pd(PPh) (1.63 kg, 1.41 mol) and KPO (8.99 kg, 42.3 mol). The mixture was stirred at 90 °C for 12 h. TLC (petroleum ether:ethyl acetate = 10:1, R f (starting material) = 0.84, R f The (product) = 0.66) indicated complete consumption of the starting material. The mixture was filtered, and the filtrate was extracted with EtOAc (5.00 L). The combined organics were washed with brine (5.00 L), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 1:0 to 1:1). The compound 2,6-dibenzyloxy-3-(4-bromo-2,6-difluorophenyl)pyridine (3.00 kg, 6.01 mol, 42.5% yield, 96.5% purity) was obtained. 1H NMR(400MHz,chloroform-d) 7.47 - 7.40 (m, 1H), 7.39 - 7.34 (m, 2H), 7.34 - 7.29 (m, 2H), 7.29 - 7.25 (m, 4H), 7.25 - 7.17 (m, 2H), 7.12 - 7.05 (m, 2H), 6.42 (d, J = 8.0 Hz, 1H), 5.32 (s, 2H), 5.28 (s, 2H);[M+H] + =482.1.

[0166] Intermediate 17: 1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)azetidine-3-carbaldehyde [ka] The title compound was prepared in a similar manner to intermediates 8 and 10. [M+H] + =288.3.

[0167] Intermediate 18: 2',6'-bis(benzyloxy)-3-fluoro-5-iodo-6-methyl-2,3'-bipyridine Step 1: 5-Fluoro-2-methylpyridin-3-amine [ka] To a solution of 2-bromo-5-fluoropyridin-3-amine (20 g, 105.26 mmol) in dioxane / HO (200 / 40 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (15.91 g, 126.32 mmol), Pd(dppf)Cl (8.59 g, 10.53 mmol), and KCO (43.57 g, 315.79 mmol). The resulting solution was stirred overnight at 120 °C under a N atmosphere. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (0-10%) to give 5-fluoro-2-methylpyridin-3-amine (12 g, 90.1%). [M+H] + =127.1.

[0168] Step 2: 6-Chloro-5-fluoro-2-methylpyridin-3-amine [ka] To a stirred mixture of 5-fluoro-2-methylpyridin-3-amine (6 g, 47.62 mmol) in DMF (120 mL) was added NCS (8.43 g, 47.62 mmol) at 0 °C. The mixture was stirred at 60 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc. 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 eluting with EA / PE (0-50%) to give 6-chloro-5-fluoro-2-methylpyridin-3-amine (3 g, 39.5%). [M+H] + =161.3.

[0169] 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-methylpyridin-3-amine (3 g, 18.63 mmol) in dioxane / HO (30 mL / 5 mL) was added 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)Cl (1.52 g, 1.86 mmol), and KCO (7.71 g, 55.89 mmol). The resulting solution was stirred overnight at 100 °C under a N atmosphere. After cooling to room temperature, it was diluted with HO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0-50%) to give 2',6'-bis(benzyloxy)-3-fluoro-6-methyl-[2,3'-bipyridine]-5-amine (5 g, 64.3%). [M+H] + =416.2.

[0170] 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) was added KI (6 g, 36.14 mmol), CuI (1.65 g, 8.67 mmol), and t-BuONO (3.72 g, 36.14 mmol). The resulting solution was stirred overnight at 80 °C under a N atmosphere. After cooling to room temperature, the mixture was diluted with HO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0-15%) to give 2',6'-bis(benzyloxy)-3-fluoro-5-iodo-6-methyl-2,3'-bipyridine (2.5 g, 65.79%). [M+H] + =527.1.

[0171] Intermediate 19: 3-(3-fluoro-5-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione Step 1: tert-Butyl (3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidine-1-carboxylate [ka] A solution of tert-butyl (3R,4S)-4-amino-3-fluoropiperidine-1-carboxylate (2.5 g, 11.5 mmol), N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine hydrochloride (3 g, 11.5 mmol), and NaHCO3 (3.85 g, 45.8 mmol) in 50 mL of EtOH was stirred at 80 °C for 16 h. After LCMS showed the reaction was complete, the mixture was concentrated, diluted with DCM, and washed with water. The organic layer was separated and concentrated. The mixture was purified by silica column chromatography (MeOH:DCM = 0-4%) to give tert-butyl (3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidine-1-carboxylate (2 g, 5.3 mmol, 46.3%). [M+H] + =378.6.

[0172] Step 2: 1-benzyl-4-((3R,4S)-3-fluoropiperidin-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) was added TFA (10 mL). The reaction was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (200 mL), washed with saturated aqueous NaHCO (3 × 100 mL) and brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the product (3 g, 81.7%). [M+H] + =278.4.

[0173] Step 3: 2',6'-Bis(benzyloxy)-5-((3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidin-1-yl)-3-fluoro-6-methyl-2,3'-bipyridine [ka] To a stirred solution of intermediate 18 (0.95 g, 1.8 mmol) in dioxane (20 mL) was added CsCO (1.2 g, 3.6 mmol), 1-benzyl-4-((3R,4S)-3-fluoropiperidin-4-yl)piperazine (0.5 g, 1.8 mmol), and Pd-Ruphos-G (0.3 g, 0.4 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with water (3 × 50 mL) and brine (50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (0–5%) to give the product (0.95 g, 78%). [M+H] + =676.7.

[0174] Step 4: tert-Butyl 4-((3R,4S)-1-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin-3-yl)-3-fluoropiperidin-4-yl)piperazine-1-carboxylate [ka] To a stirred mixture of 2',6'-bis(benzyloxy)-5-((3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidin-1-yl)-3-fluoro-6-methyl-2,3'-bipyridine (0.95 g, 1.4 mmol), di-tert-butyl dicarbonate (1.5 g, 7 mmol) in i-PrOH (40 mL) and DMF (40 mL) was added Pd / C (10 wt%, 1 g). The resulting mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 24 hours. The mixture was then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (0-7%) to give the product (0.46 g, 64.5%). [M+H] + =508.4.

[0175] Step 5: 3-(3-fluoro-5-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl 4-((3R,4S)-1-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin-3-yl)-3-fluoropiperidin-4-yl)piperazine-1-carboxylate (460 mg, 0.9 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with saturated aqueous NaHCO (3×20 mL) and brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the product (260 mg, 70.4%). [M+H]+ =408.5.

[0176] Intermediate 20: 3-(5-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 19.

[0177] Intermediate 21: 3-(4-methyl-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 15.

[0178] Intermediate 22: 3-(4-methyl-5-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 15.

[0179] Intermediate 23: 3-(5-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 15.

[0180] Intermediate 24: 3-(5-((R)-3,3-difluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 19.

[0181] Intermediate 25: (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(4-oxopiperidin-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)-cyclobutanacyclononaphan-3-one Step 1: (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(1,4-dioxa-8-azaspiro[4.5]decan-8-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)-cyclobutanacyclononaphan-3-one [ka] To a solution of intermediate 1 (3.0 g, 5.9 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (1.7 g, 11.8 mmol), and t-BuONa (1.2 g, 11.8 mmol) in 80 mL of DMA, Pd(dba) (540 mg, 0.59 mmol) and RuPhos (550 mg, 1.18 mmol) were added. The mixture was stirred at 100 °C under N for 3 h. After LCMS showed the reaction was complete, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (DCM:MeOH = 100:1 to 15:1) to give the product (2.5 g, 73.2%). [M+H] + =570.4.

[0182] Step 2: (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(4-oxopiperidin-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)-cyclobutanacyclononaphan-3-one [ka] (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(1,4-dioxa-8-azaspiro[4.5]decan-8-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)-cyclobutanacyclononaphan-3-one (300 mg, 0.53 mmol) was placed in a 25 mL round-bottom flask equipped with a magnetic stir bar. 4 mL of concentrated aqueous HCl was then added. The mixture was stirred at room temperature for 2 hours. Saturated aqueous NaHCO3 was added dropwise to the mixture to adjust the pH to 6-7. The liquid was extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, concentrated in vacuo, and purified by CombiFlash (DCM:MeOH = 20:1) to give the title compound (120 mg, 43.2% yield). [M+H] + =526.5.

[0183] Intermediate 26: 2-(6-(2,6-dioxopiperidin-3-yl)-2,4-dimethylpyridin-3-yl)ethyl methanesulfonate 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 / HO (100 / 20 mL) was added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (17.1 g, 40.9 mmol), Pd(PPh) (4.64 g, 4.10 mmol), and KCO (16.94 g, 122.73 mmol). The resulting solution was stirred at 100 °C for 5 h under a N atmosphere. After cooling to room temperature, it was diluted with HO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0-50%) to give 2',6'-bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine (12 g, 62.2%). [M+H] + =475.1.

[0184] Step 2: 2',6'-Bis(benzyloxy)-4,6-dimethyl-5-vinyl-2,3'-bipyridine [ka] 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 KCO (2.61 g, 18.93 mmol) in 1,4-dioxane (30 mL) and HO (6 mL) was added Pd(dpppf)Cl (514.1 mg, 0.63 mmol). The resulting solution was stirred at 100 °C under a N atmosphere for 5 h. After cooling to room temperature, it was diluted with HO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0-20%) to give 2',6'-bis(benzyloxy)-4,6-dimethyl-5-vinyl-2,3'-bipyridine (1.7 g, 63.9%). [M+H] + =423.0.

[0185] Step 3: 2-(2',6'-bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridin]-5-yl)ethan-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) was added 9-BBN (0.5 M in THF, 40 mL, 20.0 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature overnight, and then NaOH (2 M solution in water, 4 mL, 8.03 mmol) and HO (30%, 40.2 mL, 12.1 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with HO and extracted with EA. The residue was purified by column chromatography (EA / PE = 0-35%) to give 2-(2',6'-bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridin]-5-yl)ethan-1-ol (1.4 g, 79.5%). [M+H] + =441.0.

[0186] Step 4: 3-(5-(2-hydroxyethyl)-4,6-dimethylpyridin-2-yl)piperidine-2,6-dione [ka] To a stirred solution of 2-(2',6'-bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridin]-5-yl)ethan-1-ol (1.4 g, 8.31 mmol) in THF (50 mL) was added Pd / C (10 wt%, 1.5 g). The resulting mixture was degassed under reduced pressure, purged with H2 five times, and then stirred at 50 °C overnight. 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 give 3-(5-(2-hydroxyethyl)-4,6-dimethylpyridin-2-yl)piperidine-2,6-dione (855.7 mg, 83.0%). [M+H] + =263.1. 1H 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).

[0187] Step 5: 2-(6-(2,6-dioxopiperidin-3-yl)-2,4-dimethylpyridin-3-yl)ethyl methanesulfonate [ka] To a solution of 3-(5-(2-hydroxyethyl)-4,6-dimethylpyridin-2-yl)piperidine-2,6-dione (300 mg, 1.15 mmol) and EtN (347 mg, 3.44 mmol) in DCM (6 mL) and THF (6 mL) was added MsCl (172 mg, 1.49 mmol) slowly at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The mixture was quenched with water (10 mL). The organic phase was separated and concentrated in vacuo. The residue was purified by preparative TLC (DCM:MeOH = 20:1) to give the product (220 mg, 56.5% yield). [M+H] + =341.5.

[0188] Intermediate 27: 2-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)ethyl methanesulfonate [ka] This compound was prepared in a similar manner to Intermediate 26.

[0189] Intermediate 28: 3-(5-((3S,4R)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The compound was prepared in a similar manner to Intermediate 19.

[0190] Intermediate 29: 3-(5-((3R,4R)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 19.

[0191] Intermediate 30: 3-(6-methyl-5-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 15.

[0192] Intermediate 31: 3-(5-((S)-3,3-difluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 19.

[0193] Intermediate 32: 3-(5-((3S,4R)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 19.

[0194] Intermediate 33: 3-(5-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 19.

[0195] Intermediate 34: 3-(2,6-difluoro-4-((3S,4R)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)phenyl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 19.

[0196] Intermediate 35: 3-(5-((3R,4R)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 19.

[0197] Intermediate 36: 3-(6-ethyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 10.

[0198] Intermediate 37: 3-(4,6-dimethyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 10.

[0199] Intermediate 38: 3-(3-fluoro-6-methyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] This compound was prepared in a similar manner to Intermediate 10.

[0200] Intermediate 39: (7 1 s,7 3 s,E)-5 6 -(4-(azetidin-3-yl)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)-cyclobutanacyclononaphan-3-one Step 1: tert-Butyl 3-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)azetidine-1-carboxylate [ka] (7 in 10 mL of DMA 1 s,7 3 s,E)-5 6 -Bromo-1 1 ,2 6 -Dimethyl-5 2 ,5 3 -dihydro-1 1H,5 1 To a solution of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphan-3-one (507.0 mg, 1.0 mmol), tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (313.0 mg, 1.3 mmol), and t-BuONa (288 mg, 3.0 mmol), Pd(dba) (183 mg, 0.2 mmol) and RuPhos (186 mg, 0.4 mmol) were added. The mixture was stirred at 90 °C under N for 1.5 h. The mixture was diluted with aqueous NHCl (20 mL) and extracted with DCM (25 mL × 2). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (DCM:MeOH = 100:1 to 90:10) to give the product (450 mg, 67.5%). [M+H] + =668.7.

[0201] Step 2: (7 1 s,7 3 s,E)-5 6 -(4-(azetidin-3-yl)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)-cyclobutanacyclononaphan-3-one [ka] tert-Butyl 3-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 To a solution of (-yl)piperazin-1-yl)azetidine-1-carboxylate (400 mg, 0.599 mmol) was added TFA (2 mL). The reaction solution was stirred at room temperature for 1.5 hours and then concentrated in vacuo. The residue was dissolved in DCM and then washed with saturated NaHCO3 solution (5 mL) and brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the product (290 mg, 85.2%). [M+H] + =568.7.

[0202] Intermediate 40: 3-(5-(4-((R)-3,3-difluoropiperidin-4-yl)piperazin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione Step 1: tert-Butyl (S)-4-(4-benzylpiperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate [ka] A solution of tert-butyl (S)-4-amino-3,3-difluoropiperidine-1-carboxylate (2.5 g, 10.6 mmol), N-benzyl-2-chloro-N-(2-chloroethyl)ethan-1-amine hydrochloride (2.84 g, 11.6 mmol), and NaHCO3 (3.56 g, 42.4 mmol) in 50 mL of EtOH was stirred at 80 °C for 16 h. LCMS showed the reaction was complete, and the mixture was concentrated, diluted with water, and extracted with DCM. The organic layer was separated and concentrated. The mixture was purified by silica column chromatography (MeOH:DCM = 0-4%) to give tert-butyl (S)-4-(4-benzylpiperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate (2 g, 5.0 mmol, 47.2%). [M+H] + = 396.3.

[0203] Step 2: tert-Butyl (S)-3,3-difluoro-4-(piperazin-1-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl (S)-4-(4-benzylpiperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate (2 g, 5.06 mmol) in MeOH (30 mL) was added Pd / C (20 wt%, 400 mg). The reaction was stirred at room temperature for 2 hours. The reaction was filtered, and the filtrate was concentrated to give the product tert-butyl (S)-3,3-difluoro-4-(piperazin-1-yl)piperidine-1-carboxylate (1.2 g, 77.5%). [M+H] + =306.4.

[0204] Step 3: tert-Butyl (S)-4-(4-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridin]-5-yl)piperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate [ka] To a solution of 2',6'-bis(benzyloxy)-5-bromo-6-methyl-2,3'-bipyridine 4 (1 g, 2.17 mmol) in dioxane (20 mL) was added CsCO (1.4 g, 4.34 mmol), tert-butyl (S)-3,3-difluoro-4-(piperazin-1-yl)piperidine-1-carboxylate (997 mg, 3.26 mmol), Pd(dba) (393 mg, 0.43 mmol), and RuPhos (400 mg, 0.86 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (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 eluting with MeOH / DCM (0-5%) to give the product tert-butyl (S)-4-(4-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridin]-5-yl)piperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate (800 mg, 53.7%). [M+H] + =686.7.

[0205] Step 4: tert-Butyl (4S)-4-(4-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate [ka] To a stirred mixture of tert-butyl (S)-4-(4-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridin]-5-yl)piperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate (800 mg, 1.17 mmol) in i-PrOH (10 mL) and DMF (10 mL) was added Pd / C (20 wt%, 160 mg). The resulting mixture was stirred at 50°C under a hydrogen atmosphere (1 atm) for 24 h. The mixture was then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (0-7%) to give the product (400 mg, 67.4%). [M+H] + =508.6.

[0206] Step 5: 3-(5-(4-((S)-3,3-difluoropiperidin-4-yl)piperazin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] To a solution of tert-butyl (4S)-4-(4-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate (400 mg, 0.79 mmol) in DCM (10 mL) was added HCl (4 M in dioxane) (5 mL). The reaction was stirred at room temperature for 2 hours and then concentrated in vacuo to give the product (260 mg, 80.8%). [M+H] + =408.5.

[0207] Example 1: 3-(5-(4-((R)-4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 33.

[0208] 1 H NMR (500 MHz, DMSO) δ 12.34 (s, 1H), 10.73 (s, 1H), 8.59 (s, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.07 (s, 1H), 6.94 (s, 1H), 6.82 (d, J = 8.7 Hz, 1H), 3.89 - 3.81 (m, 3H), 3.65 (s, 3H), 3.15 - 3.11 (m, 3H), 3.01 - 2.90 (m, 2H), 2.88 - 2.82 (m, 4H), 2.70 - 2.63 (m, 5H), 2.59 - 2.54 (m, 4H), 2.49 (s, 5H), 2.31 (d, J = 12.6 Hz, 2H), 2.19 (s, 3H), 2.16 - 2.09 (m, 1H), 2.07 - 2.00 (m, 1H), 1.84 (s, 2H), 1.64 - 1.45 (m, 2H), 0.91 (d, J = 6.1 Hz, 3H). [M+H] + =812.7.

[0209] Example 2: (R)-3-(4-((S)-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)-cyclobutanacyclononaphane-5 6 -yl)methyl)piperazine-1-carbonyl)-3,3-dimethylpyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 3 using Intermediate 4.

[0210] 1 H NMR (500 MHz, DMSO) δ 12.61 (s, 1H), 10.83 (s, 1H), 8.46 (s, 1H), 7.87 (s, 1H), 7.49 - 7.43 (m, 3H), 7.23 - 7.21 (m, 1H), 6.23 - 6.20 (m, 2H), 4.77 - 4.68 (m, 1H), 4.59 - 4.46 (m, 1H), 4.30 - 4.24 (m, 1H), 4.18 - 4.12 (m, 1H), 4.04 - 3.98 (m, 1H), 3.73 (s, 3H), 3.68 - 3.64 (m, 1H), 3.60 - 3.56 (m, 4H), 3.53 - 3.48 (m, 3H), 3.47 - 3.40 (m, 2H), 3.25 - 3.21 (m, 1H), 2.86 - 2.60 (m, 2H), 2.54 (s, 4H), 2.45 - 2.41 (m, [M+H] + =875.8.

[0211] Example 3: (R)-3-(4-(3-(4-(((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)methyl)piperazine-1-carbonyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: Tert-butyl 4-(3-fluoro-4-nitrobenzyl)piperazine-1-carboxylate [ka] To a solution of 3-fluoro-4-nitrobenzaldehyde (5 g, 29.6 mmol) and tert-butyl piperazine-1-carboxylate (6.6 g, 35.5 mmol) in DCE (100 mL) was added STAB (12.55 g, 59.2 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated aqueous NaHCO (60 mL), and the resulting mixture was extracted with DCM (100 mL × 3). The combined organic phase was washed with brine (130 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (PE:EA = 1:1) to give tert-butyl 4-(3-fluoro-4-nitrobenzyl)piperazine-1-carboxylate (8.6 g, 86%). [M+H] + =340.2.

[0212] Step 2: Tert-butyl 4-(3-((((1s,3s)-3-(methoxycarbonyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piperazine-1-carboxylate [ka] To a mixture of tert-butyl 4-(3-fluoro-4-nitrobenzyl)piperazine-1-carboxylate (4 g, 11.8 mmol) and methyl (1s,3s)-3-(aminomethyl)cyclobutane-1-carboxylate hydrochloride (2.0 g, 14.1 mmol) in CHCN (80 mL) was added DIEA (6.1 g, 47.0 mmol). The reaction was stirred at 70 °C for 16 hours. After cooling to room temperature, the reaction was concentrated in vacuo. The residue was purified by silica gel column (PE:EA = 1:2) to give tert-butyl 4-(3-((((1s,3s)-3-(methoxycarbonyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piperazine-1-carboxylate (4.3 g, 79.6%). [M+H] + =463.5.

[0213] Step 3: Tert-butyl 4-(3-((((1s,3s)-3-(hydroxymethyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piperazine-1-carboxylate [ka] A solution of tert-butyl 4-(3-((((1s,3s)-3-(methoxycarbonyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piperazine-1-carboxylate (2.0 g, 4.3 mmol) in THF (50 mL) was cooled to 0 °C, and then LiAlH (246 mg, 6.5 mmol) was added. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated aqueous NH Cl (50 mL), and the resulting mixture was extracted with DCM (40 mL × 3). The combined organic phases were washed with brine (50 mL), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel column (PE:EA=1:2) to give tert-butyl 4-(3-((((1s,3s)-3-(hydroxymethyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piperazine-1-carboxylate (1.6 g, 84.2%). [M+H] + =435.4.

[0214] Step 4: Tert-butyl 4-(3-((((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(3-((((1s,3s)-3-(hydroxymethyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piperazine-1-carboxylate (499 mg, 1.15 mmol) and methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (312 mg, 1.26 mmol) in THF (10 mL) was added PPh3 (453 mg, 1.73 mmol) and DIAD (349 mg, 1.73 mmol). The reaction was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and the residue was purified by silica gel column (DCM:CHOH=20:1) to give tert-butyl 4-(3-((((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piperazine-1-carboxylate (550 mg, 72.1%). [M+H] + =664.6.

[0215] Step 5: Tert-butyl 4-(4-amino-3-((((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)benzyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(3-((((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piperazine-1-carboxylate (550 mg, 0.83 mmol) in THF (15 mL) was added Raney nickel (220 mg). The reaction was stirred under an atmosphere of H at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated in vacuo to give tert-butyl 4-(4-amino-3-((((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)benzyl)piperazine-1-carboxylate (500 mg, 95.2%). [M+H] + =634.6.

[0216] Step 6: Tert-butyl 4-((2-imino-3-(((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-amino-3-((((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)benzyl)piperazine-1-carboxylate (500 mg, 0.79 mmol) in DCM (5 mL) and CHOH (2 mL) was added BrCN (166 mg, 1.58 mmol). The reaction was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was purified by silica gel column (DCM:MeOH=8:1) to give tert-butyl 4-((2-imino-3-(((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperazine-1-carboxylate (490 mg, 94%). [M+H] + =659.5.

[0217] Step 7: 2-(5-(((1s,3s)-3-((6-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid [ka] To a solution of tert-butyl 4-((2-imino-3-(((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)piperazine-1-carboxylate (490 mg, 0.74 mmol) in THF (15 mL) and HO (5 mL) was added LiOH monohydrate (156 mg, 3.72 mmol). The reaction was stirred at room temperature for 5 h. The pH of the reaction mixture was adjusted to 5-6 with 1 N HCl solution and then extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(5-(((1s,3s)-3-((6-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (450 mg, 94.3%). [M+H] + =645.6.

[0218] Step 8: Tert-butyl 4-(((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)methyl)piperazine-1-carboxylate [ka] To a solution of 2-(5-(((1s,3s)-3-((6-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-imino-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (450 mg, 0.7 mmol) in DMF (10 mL) was added HATU (265 mg, 0.7 mmol) and DIEA (181 mg, 1.4 mmol). The reaction was stirred at room temperature for 30 min. The reaction was quenched with water (10 mL), and the resulting mixture was extracted with EA (15 mL × 3). The combined organic phases were washed with brine (10 mL × 3), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH=15:1) to give tert-butyl 4-(((7 1 s,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)-cyclobutanacyclononaphane-5 6 (-yl)methyl)piperazine-1-carboxylate (220 mg, 50.1%) was obtained. [M+H] + =627.5.

[0219] Step 9: (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(piperazin-1-ylmethyl)-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)-cyclobutanacyclononaphan-3-one [ka] tert-Butyl 4-(((7 1 s,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)-cyclobutanacyclononaphane-5 6 To a solution of (7-yl)methyl)piperazine-1-carboxylate (220 mg, 0.35 mmol) was added TFA (2 mL). The reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo. The residue was dissolved in DCM (15 mL), washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(piperazin-1-ylmethyl)-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)-cyclobutanacyclononaphan-3-one (170 mg, 92%) was obtained. [M+H] + =527.4.

[0220] Step 10: (R)-3-(4-(3-(4-(((7 1 s,7 3 s,E)-11,26-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)-cyclobutanacyclononaphane-5 6 -yl)methyl)piperazine-1-carbonyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] in DCM (5 mL) 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(piperazin-1-ylmethyl)-5 2 ,5 3 -dihydro-1 1 H,5 1 To a solution of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphan-3-one (50 mg, 0.10 mmol) and Intermediate 3 (36.9 mg, 0.11 mmol) was added T3P (90 mg, 0.14 mmol, 50% in EA) and DIEA (24.5 mg, 0.19 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL), and the resulting mixture was extracted with DCM (10 mL × 3). The combined organic phase was washed with brine (10 mL × 3), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (DCM:CH3OH=12:1) to give (R)-3-(4-(3-(4-(((7 1 s,7 3 s,E)-11,26-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)-cyclobutanacyclononaphane-5 6To the obtained product, (24 mg, 30.4%)-2,6-difluorophenyl)piperazine-1-carbonyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione was obtained. 1 H NMR (500 MHz, DMSO) δ 12.62 (s, 1H), 10.85 (s, 1H), 8.66 (s, 1H), 7.90 (s, 1H), 7.48 - 7.46 (m, 2H), 7.39 (s, 1H), 7.23 - 7.21 (m, 1H), 6.16 (d, J = 11.1 Hz, 2H), 4.88 - 4.46 (m, 2H), 4.04 - 4.01 (m, 3H), 3.89 - 3.84 (m, 2H), 3.82 - 3.76 (m, 1H), 3.72 (s, 3H), 3.59 (s, 2H), 3.50 (s, 2H), 3.43 - 3.40(m, 2H), 3.00 - 2.82 (m, 2H), 2.81 - 2.75 (m, 1H), 2.56 (s, 3H), 2.55 - 2.52 (m, 2H), 2.49 - 2.44 (m, 4H), 2.43 - 2.29 (m, 5H), 2.11 - 2.03 (m, 1H), 1.99 - 1.84 (m, 1H);[M+H] + =833.6.

[0221] Example 4: (R)-3-(4-((S)-4-(4-(((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)methyl)piperazine-1-carbonyl)-3,3-dimethylpyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 3 using Intermediate 4. 1 H NMR (500 MHz, DMSO) δ 12.62 (s, 1H), 10.83 (s, 1H), 8.66 (s, 1H), 7.90 (s, 1H), 7.48-7.46 (m, 2H), 7.41 (s, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.14 (d, J = 12.4 Hz, 2H), 4.98 - 4.41 (m, 2H), 4.35 - 4.11 (m, 2H), 4.07 - 3.92 (m, 1H), 3.72 (s, 3H), 3.59 (s, 4H), 3.52 (s, 2H), 3.43 (s, 2H), 3.37 (s, 1H), 3.10 - 3.04 (m, 2H), 2.95 - 2.86 (m, 3H), 2.81 - 2.73 (m, 1H), 2.56 (s, 3H), 2.53 - 2.51 (m, 1H), 2.48 - 2.45 (m, 2H), 2.42 - 2.36 (m, 5H), 2.14 - 2.01 (m, 1H), 1.96 - 1.89 (m, 1H), 1.17 (s, 3H), 0.98 (s, 3H);[M+H] + =875.8.

[0222] Example 5: 3-(5-(4-(1-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperidin-4-yl)piperazin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 17. 1 H NMR (500 MHz, DMSO) δ 12.34 (s, 1H), 10.74 (s, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.59 - 4.49 (m, 1H), 4.20 - 4.10 (m, 2H), 3.86 - 3.82 (m, 1H), 3.77 - 3.71 (m, 1H), 3.65 (s, 3H), 3.24 - 3.22 (m, 4H), 2.89 - 2.78 (m, 5H), 2.65 (t, J = 11.4 Hz, 3H), 2.56 (d, J = 11.2 Hz, 1H), 2.54 - 2.48 (m, 5H), 2.46 - 2.39 (m, 5H), 2.20 (s, 3H), 2.14 - 2.10 (m, 1H), 2.07 - 2.01 (m, 1H), 1.96 - 1.83 (m, 2H), 1.59 - 1.53 (m, 2H), 1.23 - 1.12 (m, 1H);[M+H] + =798.1

[0223] Example 6: (R)-3-(4-(4-(4-(7 1 s,7 3 s,E)-11,26-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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-Butyl 4-((71 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazine-1-carboxylate [ka] To a stirred solution of Intermediate 1 (19.1 g, 102 mmol) in DMA (500 mL) was added tert-butyl piperazine-1-carboxylate (22.8 g, 122 mmol), t-BuONa (24.6 g, 256 mmol), Ruphos (19.6 g, 20 mmol), and Pd(dba) (9.3 g, 10 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (2000 mL) and washed with water (3 × 1000 mL) and brine (1000 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (0–7%) to give the product (25 g, 79.6%). [M+H] + =613.6.

[0224] Step 2: (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(piperazin-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)-cyclobutanacyclononaphan-3-one [ka] tert-Butyl 4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 To a solution of (-yl)piperazine-1-carboxylate (25 g, 40.8 mmol) was added TFA (50 mL). The reaction was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (1500 mL), washed with saturated aqueous NaHCO3 (3 x 500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH (3% NH3.H2O) / DCM (0-35%) to give the product (16 g, 76.5%). [M+H] + =513.5.

[0225] Step 3: (R)-3-(4-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6-yl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] (7 mL) in DCE (8 mL) 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(piperazin-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 To a solution of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphan-3-one (150 mg, 0.3 mmol) and Intermediate 6 (188 mg, 0.6 mmol) was added STAB (127 mg, 0.6 mmol). The mixture was then stirred at 50 °C for 16 h. Saturated aqueous NaHCO (70 mL) was added, and the resulting mixture was extracted with DCM (30 mL × 3). The combined organic phases were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (MeOH:DCM = 0-10%) to give the product (130 mg, 54.3%).

[0226] 1H NMR(500MHz,DMSO) δ 12.41 (s, 1H), 10.85 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.01 (s, 1H), 6.89 (d, J = 9.6 Hz, 1H), 6.64 (d, J = 13.0 Hz, 2H), 4.72 - 4.24 (m, 4H), 4.05 (d, J = 7.9 Hz, 1H), 3.81 (d, J = 11.9 Hz, 2H), 3.71 (s, 3H), 3.15 (s, 4H), 2.91 (s, 3H), 2.75 - 2.77 (m, 4H), 2.63 - 2.68 (m, 4H), 2.55 - 2.54 (m, 4H), 2.36 (s, 2H), 2.10 - 2.08 (m, 2H), 1.97 (s, 1H), 1.86 - 1.89 (m, 2H), 1.50 - 1.48 (m, 2H);[M+H] + =819.6.

[0227] Example 7: 3-(5-(4-((R)-4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 33.

[0228] 1H NMR(500MHz,DMSO) δ 12.34 (s, 1H), 10.71 (s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.28 (t, J = 8.3 Hz, 2H), 7.10 (d, J = 8.7 Hz, 1H), 6.94 (s, 1H), 6.81 (d, J = 7.7 Hz, 1H), 4.78 - 3.93 (m, 4H), 3.90 - 3.79 (m, 2H), 3.77 - 3.67 (m, 2H), 3.65 (s, 3H), 3.23 - 3.22 (m, 6H), 2.93 (s, 1H), 2.83 (s, 3H), 2.70 (t, J = 11.6 Hz, 2H), 2.61 (s, 1H), 2.58 - 2.55 (m, 1H), 2.53 - 2.47 (m, 6H), 2.14 - 2.08 (m, 1H), 2.05 - 2.01 (m, 1H), 1.84 (s, 2H), 1.50 (s, 2H), 0.90 (d, J = 5.9 Hz, 3H);[M+H] + =798.5

[0229] Example 9: (R)-3-(4-(2-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-oxopiperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 22 using Intermediate 5. 1H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 10.96 (s, 1H), 8.66 (s, 1H), 7.90 (s, 1H), 7.55 (d, J = 1.4 Hz, 1H), 7.50 (s, 1H), 7.48 (s, 1H), 7.18 (dd, J = 8.5, 1.7 Hz, 1H), 7.09 (d, J = 10.0 Hz, 2H), 4.62 (s, 2H), 4.40 - 3.94 (m, 3H), 3.72 (s, 3H), 3.69 (t, J = 5.2 Hz, 2H), 3.30 - 2.25 (m, 4H), 2.92 - 2.78 (m, 6H), 2.73 (t, J = 7.2 Hz, 2H), 2.60 - 2.51 (m, 7H), 2.14 (dt, J = 12.9, 10.9 Hz, 1H), 2.05 - 1.96 (m, 1H). [M+H] + =778.6.

[0230] Example 10: (R)-3-(4-(4-(4-(7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-oxopiperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 22 using Intermediate 6. 1H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 10.87 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.54 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.17 (dd, J = 8.5, 1.6 Hz, 1H), 6.66 (d, J = 12.8 Hz, 2H), 4.87 - 4.48 (m, 2H), 4.05 (dd, J = 12.7, 5.1 Hz, 3H), 3.81 (d, J = 12.5 Hz, 2H), 3.72 (s, 3H), 3.67 (s, 2H), 3.34 (s, 2H), 3.31 - 3.24 (m, 2H), 2.90 (s, 3H), 2.79 (t, J = 11.4 Hz, 4H), 2.59 - 2.53 (m, 7H), 2.13 - 2.05 (m, 1H), 2.01 - 1.94 (m, 1H), 1.91 (d, J = 10.1 Hz, 2H), 1.55 - 1.43 (m, 2H). [M+H] + =833.7.

[0231] Example 11: (R)-3-(4-(3-((4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-oxopiperazin-1-yl)methyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 22 using Intermediate 8. 1 H NMR (500 MHz, DMSO) δ 12.66 (s, 1H), 10.86 (s, 1H), 8.66 (s, 1H), 7.90 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 11.2 Hz, 2H), 4.67 (s, 2H), 4.06 (s, 2H), 4.03 (dd, J = 12.7, 4.9 Hz, 1H), 3.97 (s, 2H), 3.72 (s, 3H), 3.69 (s, 2H), 3.54 (s, 2H), 3.21 (s, 2H), 3.04 - 2.97 (m, 1H), 2.91 (s, 2H), 2.84 (s, 2H), 2.81 - 2.76 (m, 1H), 2.73 (d, J = 7.5 Hz, 2H), 2.60 - 2.51 (m, 8H), 2.11 - 2.04 (m, 1H), 1.99 - 1.92 (m, 1H). [M+H] + =819.7.

[0232] Example 12: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-oxopiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 22 using Intermediate 11.1 H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 10.78 (s, 1H), 8.66 (s, 1H), 8.23 ​​(d, J = 2.8 Hz, 1H), 7.90 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.35 (dd, J = 8.6, 2.8 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H), 4.55 (s, 2H), 4.21 (s, 2H), 3.89 (dd, J = 8.8, 5.3 Hz, 1H), 3.79 (d, J = 11.5 Hz, 2H), 3.72 (s, 3H), 3.68 (s, 2H), 3.35 (s, 2H), 2.92 (s, 4H), 2.76 (t, J = 11.4 Hz, 2H), 2.65 - 2.52 (m, 10H), 2.19 (dt, J = 18.4, 7.2 Hz, 1H), 2.10 (dd, J = 13.1, 6.0 Hz, 1H), 1.95 (d, J = 12.1 Hz, 2H), 1.57 (d, J = 10.2 Hz, 2H). [M+H] + =798.8.

[0233] Example 14: (R)-3-(4-((2-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)ethyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione [ka] (7 in MeCN (5 mL) and DMSO (1 mL) 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl 5 6 -(piperazin-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 A solution of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphan-3-one (80 mg, 0.16 mmol), Intermediate 13 (74 mg, 0.2 mmol), DIEA (61 mg, 0.47 mmol), and KI (52 mg, 0.31 mmol) was stirred at 80 °C for 16 h. HO (10 mL) was added, and the resulting mixture was extracted with DCM (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (DCM:CHOH=15:1) followed by SFC (column: CHIRALPAK IE-3, 4.6 × 50 mm, 3 mm; MtBE (0.1% FA):(MeOH:DCM=1:1)=35:65), and the title compound corresponded to peak A at 2.222 min / 254 nm (6.2 mg, 5.1%). 1H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.83 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.03 (s, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.29 (d, J = 12.1 Hz, 2H), 6.11 (s, 1H), 4.78 - 4.43 (m, 4H), 4.00 - 3.97 (m, 1H), 3.72 (s, 3H), 3.32 (s, 3H), 3.20 - 3.18 (m, 6H), 2.91 (s, 3H), 2.81 - 2.73 (m, 1H), 2.64 - 2.61 (m, 5H), 2.57 - 2.54 (m, 5H), 2.10 - 2.02 (m, 1H), 1.98 - 1.91 (m, 1H);[M+H] + =779.6.

[0234] Example 15: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 21 using Intermediate 11. 1H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 10.78 (s, 1H), 8.65 (s, 1H), 8.22 (d, J = 2.8 Hz, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.33 (dd, J = 11.6, 5.8 Hz, 2H), 7.16 (d, J = 8.6 Hz, 1H), 7.01 (s, 1H), 6.89 (dd, J = 8.8, 1.6 Hz, 1H), 4.94 - 4.39 (m, 2H), 4.36 - 3.93 (m, 2H), 3.9 - 3.87 (m, 1H), 3.8 - 3.77 (m, 2H), 3.72 (s, 3H), 3.16 (s, 5H), 2.93 - 2.98 (m, 3H), 2.77 - 2.59 (m, 7H), 2.59 - 2.51 (m, 6H), 2.44 - 2.40 (m, 1H), 2.22 - 2.15 (m, 1H), 2.13 - 2.07 (m, 1H), 1.91 (d, J = 11.5 Hz, 2H), 1.58 - 1.52 (m, 2H);[M+H] + =784.6.

[0235] Example 16: (R)-3-(4-(((1S,3S)-3-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-Butyl 4-(3-(((benzyloxy)carbonyl)amino)cyclobutyl)piperazine-1-carboxylate [ka] To a 250 mL round-bottom flask equipped with a magnetic stir bar was added benzyl (3-oxocyclobutyl)carbamate (2.2 g, 10.0 mmol), tert-butyl piperazine-1-carboxylate (2.2 g, 12.0 mmol), NaBH(OAc) (4.2 g, 20.0 mmol), and DCE (100 mL). After stirring at 50 °C for 6 h, the reaction mixture was diluted with saturated aqueous NaHCO (150 mL) and the layers were separated. The aqueous layer was extracted with DCM (3 × 70 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (0–7% MeOH in DCM) afforded the product (3.0 g, 77%). [M+H] + =390.0.

[0236] Step 2: tert-Butyl 4-(3-aminocyclobutyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(3-(((benzyloxy)carbonyl)amino)cyclobutyl)piperazine-1-carboxylate (3.8 g, 9.8 mmol) in 100 mL of MeOH was added Pd / C (4.0 g, 10 wt%, wet). The mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 3 h. The mixture was filtered directly through Celite and the solid was washed with MeOH (20 mL) and DCM (100 mL). The filtrate was concentrated in vacuo to give the crude product (2.8 g), which was used without further purification. [M+H] + =255.9.

[0237] Step 3: tert-butyl 4-((1s,3s)-3-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)cyclobutyl)piperazine-1-carboxylate [ka] A solution of intermediate 16 (3.5 g, 7.2 mmol), tert-butyl 4-(3-aminocyclobutyl)piperazine-1-carboxylate (2.8 g, 10.8 mmol), KPO (5.1 g, 24.0 mmol), CuI (306 mg, 1.6 mmol), and L-proline (522 mg, 3.2 mmol) in 100 mL of DMSO was stirred at 100 °C for 16 h under a nitrogen atmosphere. The mixture was diluted with EtOAc and filtered. The filtrate was washed with brine (300 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-7% MeOH in DCM) and SFC (Lux Cellulose-2 4.6 x 50 mm 3 μm, Hex:EtOH=95:5), and the title compound corresponded to peak A at 2.692 min / 254 nm (384 mg, 8%). [M+H] + =657.1.

[0238] Step 4: tert-butyl 4-((1s,3s)-3-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)cyclobutyl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-((1s,3s)-3-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)cyclobutyl)piperazine-1-carboxylate (1.0 g, 1.5 mmol) in 50 mL of DMF / iPrOH was added Pd / C (1.0 g, 10% wt). The mixture was stirred at 50 °C under an atmosphere of H for 16 h. The mixture was filtered directly through Celite and the solid was washed with MeOH (20 mL) and DCM (100 mL). The filtrate was concentrated in vacuo to give the crude product (604 mg), which was used without further purification. [M+H] + =478.9.

[0239] Step 5: 3-(2,6-difluoro-4-(((1s,3s)-3-(piperazin-1-yl)cyclobutyl)amino)phenyl)piperidine-2,6-dione [ka] To a 100 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl 4-((1s,3s)-3-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)cyclobutyl)piperazine-1-carboxylate (604 mg, 1.3 mmol), DCM (40 mL), and TFA (10 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure to give the product (720 mg) as the TFA salt, which was used without further purification. [M+H] + =378.9.

[0240] Step 6: (R)-3-(4-(((1S,3S)-3-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a stirred solution of Intermediate 1 (110 mg, 0.22 mmol) and 3-(2,6-difluoro-4-(((1s,3s)-3-(piperazin-1-yl)cyclobutyl)amino)phenyl)piperidine-2,6-dione (TFA salt) (150 mg, 0.33 mmol) in DMA (10 mL) was added t-BuONa (127 mg, 1.32 mmol), Ruphos (41 mg, 0.088 mmol), and Pd(dba) (40 mg, 0.044 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with DCM (40 mL) and washed with saturated aqueous NHCl (2×30 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 eluting with DCM / MeOH (10:1), followed by SFC (column: CHIRALPAK IA, 2 cm x 25 cm, 5 μm; flow rate: 20 mL / min), and the title compound corresponded to peak A at 2.227 min / 254 nm (4.32 mg, 2.5%). 1 H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.84 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.02 (s, 1H), 6.91 (d, J = 9.1 Hz, 1H), 6.50 (d, J = 7.4 Hz, 1H), 6.18 (d, J = 11.6 Hz, 2H), 3.99 - 3.96 (m, 2H), 3.72 (s, 4H), 3.19 - 3.14 (m, 3H), 2.95 - 2.88 (m, 5H), 2.67 - 2.62 (m, 5H), 2.59 - 2.52 (m, 6H), 2.46 - 2.43 (m, 3H), 2.37 (s, 2H), 2.09 - 2.01 (m, 1H), 1.98 - 1.91 (m, 1H), 1.72 - 1.65 (m, 2H), 1.24 (s, 1H);[M+H] + =805.4

[0241] Example 17: (R)-3-(4-(4-(1-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperidin-4-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(1,4-dioxa-8-azaspiro[4.5]decan-8-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)-cyclobutanacyclononaphan-3-one [ka] To a solution of intermediate 1 (3.0 g, 5.9 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (1.7 g, 11.8 mmol), and t-BuONa (1.2 g, 11.8 mmol) in 80 mL of DMA, Pd(dba) (540 mg, 0.59 mmol) and RuPhos (550 mg, 1.18 mmol) were added. The mixture was stirred at 100 °C under N for 3 h. After LCMS showed the reaction was complete, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (DCM:MeOH = 100:1 to 15:1) to give the product (2.5 g, 73.2%). [M+H] + =570.4.

[0242] Step 2: (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(4-oxopiperidin-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)-cyclobutanacyclononaphan-3-one [ka] (7 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(1,4-dioxa-8-azaspiro[4.5]decan-8-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)-cyclobutanacyclononaphan-3-one (300 mg, 0.53 mmol) was placed in a 25 mL round-bottom flask equipped with a magnetic stir bar. 4 mL of concentrated aqueous HCl was then added. The mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to saturated aqueous NaHCO3 solution to adjust the pH to 6-7. The liquid was extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, concentrated in vacuo, and purified by CombiFlash (DCM:MeOH = 20:1) to give the title compound (120 mg, 43.2% yield). [M+H] + =526.5.

[0243] Step 3: (R)-3-(4-(4-(1-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperidin-4-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] (7 mL) in DCE (8 mL) 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(4-oxopiperidin-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1To a solution of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphan-3-one (100 mg, 0.19 mmol), Intermediate 14 (86 mg, 0.25 mmol), and DIEA (50 mg, 0.38 mmol) was added STAB (121 mg, 0.57 mmol). The mixture was then stirred at 50 °C for 16 h. HO (10 mL) was added, and the resulting mixture was extracted with DCM (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH=10:1) followed by preparative HPLC chromatography to give the title product (30 mg, 14.7%). 1 H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.88 (s, 1H), 8.66 (s, 1H), 7.90 (s, 1H), 7.46 (s, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 12.6 Hz, 2H), 4.59 - 4.52 (m, 2H), 4.19 - 4.13 (m, 1H), 4.06 (dd, J = 12.5, 5.0 Hz, 1H), 3.75 (d, J = 8.8 Hz, 2H), 3.72 (s, 3H), 3.32-3.28 (m, 5H), 3.20 (s, 4H), 2.94 - 2.89 (m, 3H), 2.83 - 2.67 (m, 7H), 2.56 (s, 3H), 2.43 - 2.33 (m, 1H), 2.09 (dd, J = 13.0, 3.8 Hz, 1H), 2.02 - 1.91 (m, 3H), 1.64 - 1.59 (m, 2H);[M+H] + =819.6.

[0244] Example 18: (R)-3-(4-(4-((R)-4-((7 1 s,7 3 S,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 33 using Intermediate 6. 1 H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 10.87 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.00 (s, 1H), 6.87 (d, J = 9.0 Hz, 1H), 6.64 (d, J = 12.8 Hz, 2H), 5.11 - 4.12 (m, 4H), 4.07 - 4.03 (m, 1H), 3.90 (s, 1H), 3.81 - 3.79 (m, 2H), 3.72 (s, 3H), 3.29 (s, 1H), 3.23 - 3.22 (m, 1H), 3.00 - 2.97 (m, 5H), 2.82 - 2.77 (m, 3H), 2.71 - 2.53 (m, 9H), 2.44 (s, 1H), 2.09 (d, J = 16.5 Hz, 1H), 1.96 (d, J = 5.8 Hz, 1H), 1.85 (s, 2H), 1.52 - 1.49 (m, 2H), 0.96 (d, J = 6.3 Hz, 3H);[M+H] + =833.6.

[0245] Example 19: 3-(5-((3R,4S)-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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione Step 1: tert-Butyl (3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidine-1-carboxylate [ka] To 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)ethan-1-amine hydrochloride (3 g, 11.46 mmol), and NaHCO3 (3.85 g, 45.84 mmol) in 50 mL of EtOH was added, and the mixture was stirred at 80 °C for 16 h. LCMS showed the reaction was complete. The mixture was concentrated, washed with water, and extracted with DCM. The organic layer was separated and concentrated. The mixture was purified by silica column chromatography (MeOH:DCM = 0-4%) to give tert-butyl (3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidine-1-carboxylate (2 g, 5.3 mmol, 46.3%). [M+H] + =378.6.

[0246] Step 2: 1-benzyl-4-((3R,4S)-3-fluoropiperidin-4-yl)piperazine [ka] To a solution of tert-butyl (3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidine-1-carboxylate (2 g, 5.3 mmol) in 2 mL of DCM, 6 mL of TFA was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and saturated aqueous NaHCO3 was added. The aqueous layer was extracted with DCM and separated. The organic layer was dried over Na2SO4 and filtered. The liquid was concentrated to give 1-benzyl-4-((3R,4S)-3-fluoropiperidin-4-yl)piperazine (1.1 g, 3.97 mmol, 74.93%). [M+H] + =278.6.

[0247] Step 3: 2',6'-Bis(benzyloxy)-5-((3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidin-1-yl)-6-methyl-2,3'-bipyridine [ka] To a solution of 1-benzyl-4-((3R,4S)-3-fluoropiperidin-4-yl)piperazine (1.1 g, 3.97 mmol), 2',6'-bis(benzyloxy)-5-bromo-6-methyl-2,3'-bipyridine (1.84 g, 4 mmol), and CsCO (2.61 g, 8 mmol) in 15 mL of DMA, Pd(dba) (915 mg, 1 mmol) and Ruphos (466 mg, 1 mmol) were added. The mixture was stirred at 100 °C under N protection for 16 h. The mixture was concentrated in vacuo. The residue was washed with saturated aqueous NaCl and extracted with EtOAc. The organic layer was separated and concentrated. The residue was purified by silica column chromatography (EA:PE = 0-100%) to give 2',6'-bis(benzyloxy)-5-((3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidin-1-yl)-6-methyl-2,3'-bipyridine (1.2 g, 1.83 mmol, 46%). [M+H] + =658.7.

[0248] Step 4: tert-Butyl 4-((3R,4S)-1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)-3-fluoropiperidin-4-yl)piperazine-1-carboxylate [ka] To a solution of 2',6'-bis(benzyloxy)-5-((3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidin-1-yl)-6-methyl-2,3'-bipyridine (1.2 g, 1.83 mmol) in 40 mL of DMF and 40 mL of iPrOH was added 2 mL of BocO and Pd / C (1.2 g, 10% wt). The mixture was stirred under a H atmosphere at 55 °C for 16 h. The mixture was filtered through Celite. The liquid was concentrated and purified by silica column chromatography (MeOH:DCM=0-7%) to give tert-butyl 4-((3R,4S)-1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)-3-fluoropiperidin-4-yl)piperazine-1-carboxylate (450 mg, 0.92 mmol, 50.27%). [M+H] + =490.7.

[0249] Step 5: 3-(5-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate [ka] To a solution of tert-butyl 4-((3R,4S)-1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)-3-fluoropiperidin-4-yl)piperazine-1-carboxylate (150 mg, 0.31 mmol) in 1 mL of DCM was added 3 mL of TFA. The mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was complete. The mixture was concentrated to give 3-(5-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate (120 mg crude). [M+H] + =390.7.

[0250] Step 6: 3-(5-((3R,4S)-4-(4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to Step 4 of Example 26. 1H NMR (500 MHz, DMSO) δ 12.35 (s, 1H), 10.72 (s, 1H), 8.59 (s, 1H), 7.83 (s, 1H), 7.40 (s, 1H), 7.34 - 7.26 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.95 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H), 5.09 - 4.96 (m, 1H), 4.65 - 3.95 (m, 4H), 3.87 - 3.83 (m, 1H), 3.65 (s, 3H), 3.15 - 3.06 (m, 6H), 2.91 - 2.68 (m, 10H), 2.57 - 2.46 (m, 8H), 2.35 (s, 3H), 2.19 - 2.09 (m, 1H), 2.03 - 1.93 (m, 2H), 1.79 - 1.71 (m, 1H). [M+H] + =816.7.

[0251] Example 20: (R)-3-(4-(4-((S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 6. 1H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.87 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.97 (s, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.64 (d, J = 12.7 Hz, 2H), 4.82 - 4.13 (m, 4H), 4.07 - 4.03 (m, 2H), 3.83 (d, J = 11.7 Hz, 2H), 3.72 (s, 3H), 3.57 - 3.56 (m, 1H), 3.50 - 3.48 (m, 1H), 3.28 (d, J = 12.1 Hz, 5H), 3.21 (s, 1H), 3.02 (s, 2H), 2.98 - 2.86 (m, 4H), 2.83 - 2.70 (m, 5H), 2.65 - 2.64 (m, 2H), 2.55 (s, 4H), 2.1 - 2.08 (m, 1H), 1.96 (d, J = 5.3 Hz, 1H), 1.89 - 1.87 (m, 1H), 1.72 (s, 1H), 1.62 (d, J = 9.7 Hz, 1H), 1.45 - 1.43 (m, 1H);[M+H] + =863.7.

[0252] Example 21: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] in DCE (10 mL) 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(piperazin-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 To a solution of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphan-3-one (50 mg, 0.1 mmol) and Intermediate 12 (35 mg, 0.12 mmol) was added STAB (41 mg, 0.2 mmol). The mixture was then stirred at 50 °C for 6 h. HO (10 mL) was added, and the resulting mixture was extracted with DCM (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (DCM:CHOH = 20:1) to give the product (11.1 mg, 14.3%). 1 H NMR(500MHz, DMSO) δ 12.41 (s, 1H), 10.78 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.36 (dd, J = 12.4, 8.5 Hz, 2H), 7.11 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.91 (d, J = 10.8 Hz, 1H), 4.98 - 3.94 (m, 4H), 3.91 - 3.88 (m, 1H), 3.72 (s, 3H), 3.29 (s, 1H), 3.18 - 3.13 (m, 6H), 2.92 (s, 2H), 2.72 (s, 4H), 2.67 - 2.62 (m, 3H), 2.60 - 2.52 (m, 5H), 2.40 - 2.36 (m, 5H), 2.24 - 2.16 (m, 2H), 2.10 - 2.06 (m, 1H), 1.95 - 1.92 (m, 2H), 1.64 - 1.62 (m, 2H);[M+H] + =798.7.

[0253] Example 22: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-oxopiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione Step 1: tert-butyl 4-(3-((((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-4-nitrophenyl)-3-oxopiperazine-1-carboxylate [ka] To a stirred solution of methyl 2-(5-(((1s,3s)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (1.0 g, 1.83 mmol) and tert-butyl 3-oxopiperazine-1-carboxylate (1.1 g, 5.49 mmol) in DMSO (20 mL) was added N1,N2-dimethylethane-1,2-diamine (80 mg, 0.92 mmol), CuI (175 mg, 0.92 mmol), and K3PO4 (1.36 g, 6.4 mmol). The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction solution was diluted with water and extracted with EtOAc (50 mL × 2). The combined organic layer was washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 100 / 0 to 100 / 4) to give the product (520 mg, yield 43.3%). [M+H] + =664.5.

[0254] Step 2: tert-butyl 4-(4-amino-3-((((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)phenyl)-3-oxopiperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(3-((((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)-4-nitrophenyl)-3-oxopiperazine-1-carboxylate (500 mg, 0.75 mmol) and Raney nickel (500 mg) in THF (10 mL) was degassed and purged with H (40 Psi) three times at room temperature, and then the mixture was stirred under H atmosphere for 1.5 h, turning into a black suspension. The mixture was filtered and concentrated under reduced pressure. The product (410 mg, 86.3% yield) was used in the next step without purification. [M+H] + =634.5.

[0255] Step 3: tert-butyl 4-(2-amino-1-(((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)-1H-benzo[d]imidazol-6-yl)-3-oxopiperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-amino-3-((((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)amino)phenyl)-3-oxopiperazine-1-carboxylate (410 mg, 0.64 mmol) in DCM (8 mL) and t-BuOH (2 mL) was added CNBr (203 mg, 1.92 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was then quenched with saturated aqueous NaHCO3 (10 mL). The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 (10 mL × 2). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (270 mg, 64.1% yield), which was used in the next step without further purification. [M+H] + =659.7

[0256] Step 4: 2-(5-(((1s,3s)-3-((2-amino-6-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid [ka] To a solution of tert-butyl 4-(2-amino-1-(((1s,3s)-3-(((4-(4-(methoxycarbonyl)-6-methylpyridin-2-yl)-1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)methyl)-1H-benzo[d]imidazol-6-yl)-3-oxopiperazine-1-carboxylate (270 mg, 0.41 mmol) in THF (8 mL) was added NaOH (32.8 mg, 0.82 mmol) in HO (20 mL) at 25° C. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure to remove the solvent. The residue was acidified to pH=6 with 4 M aqueous HCl to form a slurry. The solid was filtered, washed with water (5 mL), and dried under reduced pressure to give the product. The product (220 mg, crude) was used in the next step without purification. [M+H] + =645.7.

[0257] Step 5: tert-Butyl 4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-oxopiperazine-1-carboxylate [ka] To a solution of 2-(5-(((1s,3s)-3-((2-amino-6-(4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinic acid (220 mg, 0.34 mmol) in DCM (10 mL) was added HATU (156 mg, 0.41 mmol) and DIEA (132 mg, 1.02 mmol) at 25 °C. The mixture was stirred at 25 °C for 1 h and turned into a black solution. The reaction mixture was washed with saturated aqueous NaHCO (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM:MeOH=100 / 1 to 10 / 1) to give the product (110 mg, yield 51.6%). [M+H] + =627.7.

[0258] Step 6: 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(2-oxopiperazin-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)-cyclobutanacyclononaphan-3-one [ka] tert-Butyl 4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 To a solution of (-yl)-3-oxopiperazine-1-carboxylate (110 mg, 0.175 mmol) was added TFA (2 mL). The reaction solution was stirred at room temperature for 1.5 hours and then concentrated in vacuo. The residue was dissolved in DCM and then washed with saturated aqueous NaHCO (5 mL) and brine (5 mL), dried over NaSO, filtered, and concentrated in vacuo to give the product (85 mg, 92.4%). [M+H] + =527.7.

[0259] Step 7: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-oxopiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 21 using Intermediate 12.

[0260] 1H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 10.78 (s, 1H), 8.67 (s, 1H), 7.90 (s, 1H), 7.49 (d, J = 4.1 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 9.9 Hz, 1H), 7.11 (d, J = 8.1 Hz, 2H), 4.19 - 4.13 (m, 2H), 3.91 - 3.88 (m, 1H), 3.76 - 3.71 (m, 4H), 3.69 - 3.66 (m, 2H), 3.36 (s, 3H), 3.18 - 3.12 (m, 2H), 2.99 - 2.89 (m, 5H), 2.68 - 2.62 (m, 3H), 2.60 - 2.58 (m, 1H), 2.56 (s, 3H), 2.44 - 2.40 (m, 3H), 2.27 - 2.20 (m, 2H), 2.13 - 2.06 (m, 2H), 1.97 - 1.93 (m, 3H), 1.67 - 1.61 (m, 3H);[M+H] + =812.7.

[0261] Example 23: 3-(5-(4-((R)-4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 30 using Intermediate 10. 1H NMR (500 MHz, DMSO) δ 12.35 (s, 1H), 10.73 (s, 1H), 8.59 (s, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.07 (s, 1H), 6.92 (s, 1H), 6.81 (d, J = 8.7 Hz, 1H), 4.87 - 3.91 (m, 4H), 3.86 - 3.80 (m, 1H), 3.65 (s, 3H), 3.54 - 3.46 (m, 1H), 3.45 - 3.40 (m, 1H), 3.23 - 3.07 (m, 6H), 3.03 - 2.93 (m, 2H), 2.92 - 2.78 (m, 5H), 2.75 - 2.68 (m, 1H), 2.67 - 2.61 (m, 2H), 2.55 - 2.45 (m, 10H), 2.19 (s, 3H), 2.18 - 2.10 (m, 1H), 2.09 - 2.00 (m, 1H), 1.90 - 1.84 (m, 1H), 1.75 - 1.67 (m, 2H), 1.54 - 1.46 (m, 1H). [M+H] + =842.7.

[0262] Example 24: 3-(5-(4-((R)-4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 30 using Intermediate 12.

[0263] 1 H NMR (500 MHz, DMSO) δ 12.34 (s, 1H), 10.72 (s, 1H), 8.59 (s, 1H), 7.83 (s, 1H), 7.39 (s, 1H), 7.30 (t, J = 8.5 Hz, 2H), 7.03 (d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 6.81 (d, J = 8.7 Hz, 1H), 4.92 - 3.90 (m, 4H), 3.82 (dd, J = 9.4, 5.3 Hz, 1H), 3.65 (s, 3H), 3.52 - 3.46 (m, 1H), 3.45 - 3.40 (m, 1H), 3.24 - 3.15 (m, 6H), 3.11 - 3.04 (m, 2H), 2.99 - 2.92 (m, 2H), 2.90 - 2.76 (m, 5H), 2.67 - 2.59 (m, 2H), 2.56 - 2.44 (m, 9H), 2.34 (s, 3H), 2.19 - 2.11 (m, 1H), 2.06 - 1.97 (m, 1H), 1.89 - 1.83 (m, 1H), 1.71 (s, 2H), 1.56 - 1.47 (m, 1H). [M+H] + =842.8.

[0264] Example 25: (R)-3-(4-(4-(4-(7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2-oxopiperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 26. 1 H NMR (500 MHz, DMSO) δ 12.43 (s, 1H), 10.88 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.07 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 12.7 Hz, 2H), 4.84 - 4.44 (m, 3H), 4.34 - 4.01 (m, 3H), 3.94 - 3.83 (m, 4H), 3.72 (s, 3H), 3.49 - 3.36 (m, 2H), 3.42 - 3.39 (m, 2H), 3.29 (s, 1H),2.99 - 2.75 (m, 6H), 2.58 - 2.52 (m, 7H), 2.13 - 2.05 (m, 1H), 1.97 - 1.96 (m, 1H), 1.80 - 1.78 (m, 2H), 1.64 - 1.62 (m, 1H);[M+H] + =833.7.

[0265] Example 26: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2-oxopiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione Step 1: tert-butyl 4-(1-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridin]-5-yl)piperidin-4-yl)-3-oxopiperazine-1-carboxylate [ka] To a stirred solution of 2',6'-bis(benzyloxy)-5-bromo-6-methyl-2,3'-bipyridine (1.5 g, 3.25 mmol) (compound obtained by a similar method to Step 1 of Intermediate 10) and tert-butyl 3-oxo-4-(piperidin-4-yl)piperazine-1-carboxylate (1.2 g, 4.23 mmol) in DMA (30 mL) was added CsCO (3.17 g, 9.75 mmol), Pd(dba) (300 mg, 0.325 mmol), and Ruphos (300 mg, 0.65 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL) and washed with water (3×100 mL) and brine (100 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (4:1) to give the product (350 mg, 16.7%). [M+H] + =664.7.

[0266] Step 2: tert-butyl 4-(1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)-3-oxopiperazine-1-carboxylate [ka] tert-Butyl 4-(1-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridin]-5-yl)piperidin-4-yl)-3-oxopiperazine-1-carboxylate (350 mg, 0.53 mmol) was dissolved in DMF (8 mL) and iPrOH (4 mL). Pd / C (350 mg, 10 wt%, wet) was added to the solution in one portion. The resulting mixture was stirred under a hydrogen atmosphere (1 atm) at 50°C overnight. The solids were filtered off, and the filtrate was concentrated to give the crude product. The crude was purified by silica gel column chromatography eluting with DMC / MeOH (20:1) to give the product (190 mg, 73.9%). [M+H] + =486.5.

[0267] Step 3: 3-(6-methyl-5-(4-(2-oxopiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] To a 100 mL round-bottom flask equipped with a magnetic stir bar was added tert-butyl 4-(1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)-3-oxopiperazine-1-carboxylate (190 mg, 0.39 mmol), DCM (6 mL), and TFA (2 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure to give the product (260 mg) as the TFA salt, which was used without further purification. [M+H] + =386.4.

[0268] Step 4: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2-oxopiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] To a stirred solution of Intermediate 1 (150 mg, 0.29 mmol) and 3-(6-methyl-5-(4-(2-oxopiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione (TFA salt) (209 mg, 0.44 mmol) in DMA (10 mL) was added t-BuONa (141 mg, 1.47 mmol), Ruphos (55 mg, 0.12 mmol), and Pd(dba) (54 mg, 0.06 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with water (3×50 mL) and brine (50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (10:1) to give the crude product, which was subsequently purified by preparative HPLC chromatography to give the title product (6.12 mg, 2.6%). 1H NMR (500 MHz, DMSO) δ 12.43 (s, 1H), 10.79 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.08 (s, 1H), 6.92 (d, J = 8.8 Hz, 1H), 4.49 - 4.41 (m, 1H), 3.93 - 3.88 (m, 2H), 3.87 (s, 2H), 3.72 (s, 4H), 3.55 - 3.46 (m, 6H), 3.16 (d, J = 9.6 Hz, 2H), 2.98 - 2.92 (m, 3H), 2.76 (t, J = 11.4 Hz, 3H), 2.59 - 2.51 (m, 7H), 2.43 (s, 3H), 2.29 - 2.21 (m, 1H), 2.11 - 2.07 (m, 1H), 1.97 - 1.92 (m, 2H), 1.72 - 1.65 (m, 2H);[M+H] + =812.7.

[0269] Example 27: (R)-3-(4-(4-((R)-4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 6.

[0270] 1 H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 10.87 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.97 (s, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.64 (d, J = 12.8 Hz, 2H), 4.96 - 4.08 (m, 4H), 4.08 - 4.02 (m, 1H), 3.83 (d, J = 12.4 Hz, 2H), 3.72 (s, 3H), 3.58 - 3.56 (m, 1H), 3.51 - 3.48 (m, 1H), 3.28 (d, J = 11.8 Hz, 4H), 3.20 (s, 1H), 3.02 (s, 2H), 2.99 - 2.85 (m, 5H), 2.82 - 2.64 (m, 6H), 2.55 - 2.52 (m, 6H), 2.15 - 2.04 (m, 1H), 1.96 (d, J = 5.1 Hz, 1H), 1.89 - 1.86 (m, 1H), 1.74 - 1.72 (m, 1H), 1.76 - 1.59 (m, 1H), 1.47 - 1.40 (m, 1H);[M+H] + =863.7.

[0271] Example 28: 3-(5-(4-(1-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperidin-4-yl)piperazin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] (7 mL) in DCE (8 mL) 1 s,7 3 s,E)-1 1 ,2 6 -Dimethyl-5 6 -(4-oxopiperidin-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 To a solution of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphan-3-one (80 mg, 0.15 mmol), Intermediate 15 (60 mg, 0.18 mmol), and DIEA (58 mg, 0.45 mmol) was added STAB (95 mg, 0.45 mmol). The mixture was then stirred at 50 °C for 16 h. HO (15 mL) was added, and the resulting mixture was extracted with DCM (15 mL × 3). The combined organic phase was washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH=10:1) followed by preparative HPLC chromatography to give the title product (35 mg, 28.9%). 1H NMR (500 MHz, DMSO) δ 12.31 (s, 1H), 10.78 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.40 - 7.31 (m, 2H), 7.11 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.91 (d, J = 8.9 Hz, 1H), 4.85 - 4.03 (m, 4H), 3.89 (dd, J = 9.4, 5.3 Hz, 1H), 3.77 - 3.70 (m, 5H), 3.61 - 3.50 (m, 1H), 3.00 - 2.81 (m, 7H), 2.75 - 2.63 (m, 6H), 2.62 - 2.52 (m, 6H), 2.45 - 2.35 (m, 4H), 2.28 - 2.15 (m, 2H), 2.08 (dd, J = 13.3, 5.5 Hz, 1H), 1.92 (d, J = 11.3 Hz, 2H), 1.65 - 1.55 (m, 2H). [M+H] + =798.6.

[0272] Example 29: (R)-3-(4-(3-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 7.

[0273] 1H NMR (500 MHz, DMSO) δ 12.34 (s, 1H), 10.79 (s, 1H), 8.59 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.28 (d, J = 8.7 Hz, 1H), 6.96 (s, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.08 (d, J = 11.2 Hz, 2H), 4.81 - 4.38 (m, 3H), 4.24 - 4.07 (m, 1H), 4.04 - 3.94 (m, 2H), 3.91 - 3.82 (m, 2H), 3.73 - 3.58 (m, 5H), 3.20 - 3.06 (m, 8H), 2.91 - 2.79 (m, 2H), 2.75 - 2.67 (m, 1H), 2.63 - 2.47 (m, 6H), 2.28 - 1.96 (m, 2H), 1.94 - 1.43 (m, 2H). [M+H] + =791.5.

[0274] Example 30: (R)-3-(4-(4-((S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-2-(hydroxymethyl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-Butyl (S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-2-(hydroxymethyl)piperazine-1-carboxylate [ka] A mixture of Intermediate 1 (506 mg, 1 mmol), tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate (325 mg, 1.5 mmol), Pd2dba3 (91 mg, 0.1 mmol), Ruphos (93 mg, 0.2 mmol), and t-BuONa (288 mg, 3 mmol) in DMA (10 mL) was stirred at 90 °C under N2 in a round-bottom flask for 2 h. Water (20 mL) was added, and the mixture was extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 80:20 gradient elution) to give the product (420 mg, 66%). [M+H] + =643.2.

[0275] Step 2: (7 1 s,7 3 R,E)-5 6 -((S)-3-(hydroxymethyl)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)-cyclobutanacyclononaphan-3-one [ka] tert-Butyl (S)-4-((7 1 s,7 3 R,E)-1 1 ,26 -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)-cyclobutanacyclononaphane-5 6 To a solution of (-yl)-2-(hydroxymethyl)piperazine-1-carboxylate (129 mg, 0.2 mmol), TFA (1 mL) was added at 25° C. The mixture was stirred at room temperature for 1 hour. Saturated aqueous NaHCO (20 mL) was added, and the mixture was extracted with DCM (50 mL×3). The combined organic layers were dried over NaSO. The solvent was concentrated under reduced pressure to give the product (90 mg, 85%). [M+H] + =543.2.

[0276] Step 3: (R)-3-(4-(4-((S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-2-(hydroxymethyl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] (7 in 1,2-dichloroethane (15 mL) 1 s,7 3 R,E)-5 6 -((S)-3-(hydroxymethyl)piperazin-1-yl)-1 1 ,2 6 -Dimethyl-5 2 ,5 3 -dihydro-11 H,5 1 A mixture of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphan-3-one (100 mg, 0.18 mmol) and Intermediate 6 (65 mg, 0.2 mmol) was stirred in a round-bottom flask at 70 °C for 2 h. NaBH(OAc) (80 mg, 0.37 mmol) was added to the mixture, and the reaction was stirred at 70 °C for 12 h. The mixture was evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 80:20 gradient elution) to give the product (15 mg, 10%). 1 H NMR (500 MHz, DMSO) δ 12.42 (s, 1H), 10.88 (s, 1H), 8.66 (s, 1H), 7.90 (s, 1H), 7.46 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 6.66 (d, J = 12.0 Hz, 2H), 4.63 - 4.61 (m, 2H), 4.32 - 4.15 (m, 1H), 4.05 - 4.01 (m, 2H), 3.85 - 3.81 (m, 2H), 3.72 - 3.69 (m, 3H), 3.70 - 3.65 (m, 1H), 3.30 - 3.18 (m, 9H), 3.10 -2.98 (m, 3H), 2.92 - 2.88 (m, 3H), 2.81 - 2.76 (m, 4H), 2.56 - 2.52 (m, 4H), 2.10 - 1.95 (m, 1H), 1.94 - 1.89 (m, 2H), 1.77 - 1.72 (m, 2H), 1.46 - 1.42 (m, 1H);[M+H] + =848.9.

[0277] Example 31: (R)-3-(4-(4-((R)-4-((7 1 s,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-52 ,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)-cyclobutanacyclononaphane-5 6 -yl)-2-(hydroxymethyl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to Example 30. 1 H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.87 (s, 1H), 8.65 (s, 1H), 7.91 (s, 1H), 7.45 (s, 1H), 7.36 (d, J = 8.6 Hz, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 6.66 (d, J = 12.0 Hz, 2H), 4.63 - 4.61 (m, 2H), 4.32 - 4.15 (m, 1H), 4.05 - 4.01 (m, 2H), 3.85 - 3.81 (m, 2H), 3.72 - 3.69 (m, 3H), 3.70 - 3.65 (m, 1H), 3.30 - 3.18 (m, 9H), 3.10 -2.98 (m, 3H), 2.92 - 2.88 (m, 3H), 2.81 - 2.76 (m, 4H), 2.56 - 2.52 (m, 4H), 2.10 - 1.95 (m, 1H), 1.94 - 1.90 (m, 2H), 1.77 - 1.73 (m, 2H), 1.46 - 1.41 (m, 1H);[M+H] + =848.9.

[0278] Example 32: 3-(5-(4-((S)-4-((7 1 s,7 3 R,E)-1 1 ,2 6 -dimethyl-3-oxo-52 ,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 33.

[0279] 1 H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 10.79 (s, 1H), 8.65 (s, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 7.36 (s, 1H), 7.13 (s, 1H), 7.01 (s, 1H), 6.87 (s, 1H), 4.83 - 4.07 (m, 4H), 3.95 - 3.83 (m, 2H), 3.70 (s, 3H), 3.28 - 3.13 (m, 6H), 3.06 - 2.86 (m, 6H), 2.79 - 2.60 (m, 7H), 2.43 - 2.32 (m, 2H), 2.29 - 2.03 (m, 6H), 1.95 - 1.85 (m, 2H), 1.69 - 1.52 (m, 2H), 1.05 - 0.90 (m, 3H). [M+H] + =812.4.

[0280] Example 33: 3-(5-(4-((S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione Step 1: tert-Butyl (S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazine-1-carboxylate [ka] To a stirred solution of Intermediate 1 (300 mg, 0.59 mmol) and tert-butyl (S)-3-methylpiperazine-1-carboxylate (237 mg, 1.18 mmol) in DMA (15 mL) was added t-BuONa (227 mg, 2.37 mmol), Ruphos (110 mg, 0.24 mmol), and Pd(dba) (108 mg, 0.12 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 2 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with water (3×50 mL) and brine (50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (15:1) to give the product (130 mg, 35.1%). [M+H] + =627.7.

[0281] Step 2: (71 s,7 3 R,E)-1 1 ,2 6 -Dimethyl-5 6 -((S)-2-Methylpiperazin-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)-cyclobutanacyclononaphan-3-one [ka] tert-Butyl (S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 To a solution of (-yl)-3-methylpiperazine-1-carboxylate (130 mg, 0.21 mmol) was added TFA (5 mL). The reaction was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (30 mL), washed with saturated aqueous NaHCO (20 mL) and brine (20 mL), dried over Na SO , filtered, and concentrated in vacuo to give the product (70 mg, 64.1%). [M+H] + =527.6.

[0282] Step 3: 3-(5-(4-((S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] in DCE (5 mL) 1 s,7 3 R,E)-1 1 ,2 6 -Dimethyl-5 6 -((S)-2-Methylpiperazin-1-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 To a solution of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphan-3-one (50 mg, 0.1 mmol) and Intermediate 12 (57 mg, 0.19 mmol) was added STAB (60 mg, 0.28 mmol). The mixture was then stirred at 50 °C for 6 h. HO (10 mL) was added, and the resulting mixture was extracted with DCM (10 mL × 3). The combined organic phases were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (DCM:CHOH = 20:1) to give the product (27.1 mg, 35.2%). 1H NMR(500MHz, DMSO) δ 12.34 (s, 1H), 10.72 (s, 1H), 8.59 (s, 1H), 7.82 (s, 1H), 7.40 (s, 1H), 7.30 (t, J = 8.0 Hz, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.95 (s, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.83 - 3.94 (m, 4H), 3.97 - 3.81 (m, 2H), 3.65 (s, 3H), 3.17 (s, 1H), 3.09 - 3.07 (m, 2H), 2.95 (s, 1H), 2.84 (s, 3H), 2.65 (s, 1H), 2.62 - 2.54 (m, 4H), 2.53 - 2.45 (m, 10H), 2.34 (s, 3H), 2.15 - 2.12 (m, 1H), 2.03 - 1.99 (m, 1H), 1.84 (s, 2H), 1.57 (s, 2H), 0.92 (d, J = 6.0 Hz, 3H);[M+H] + =812.6.

[0283] Example 34: 3-(5-(4-((R)-4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 33. 1H NMR(500MHz,DMSO) δ 12.34 (s, 1H), 10.71 (s, 1H), 8.59 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.30 (t, J = 8.2 Hz, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.95 (s, 1H), 6.82 (d, J = 8.5 Hz, 1H), 4.80 - 3.95 (m, 4H), 3.87 - 3.81 (m, 2H), 3.65 (s, 3H), 3.16 (s, 1H), 3.08 - 3.07 (m, 2H), 2.94 (s, 1H), 2.84 (s, 3H), 2.65 (s, 1H), 2.60 - 2.57 (m, 4H), 2.53 - 2.44 (m, 10H), 2.34 (s, 3H), 2.18 - 2.09 (m, 1H), 2.03 - 1.99 (m, 1H), 1.84 (s, 2H), 1.58 (s, 2H), 0.92 (d, J = 6.1 Hz, 3H);[M+H] + =812.6.

[0284] Example 35: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2-oxopiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 26. 1H NMR (500 MHz, DMSO) δ 12.38 (s, 1H), 10.75 (s, 1H), 8.61 (s, 1H), 8.19 (s, 1H), 7.85 (s, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.17 (s, 1H), 7.01 (s, 1H), 6.84 (d, J = 9.4 Hz, 1H), 4.43 - 4.38 (m, 2H), 3.84 - 3.81 (m, 3H), 3.79 - 3.76 (m, 3H), 3.65 (s, 4H), 2.93 - 2.83 (m, 3H), 2.80 - 2.73 (m, 5H), 2.57 (s, 2H), 2.52 - 2.48 (m, 4H), 2.29 (s, 1H), 2.17 - 2.10 (m, 2H), 2.07 - 1.95 (m, 2H), 1.85 - 1.75 (m, 3H), 1.65 - 1.58 (m, 2H);[M+H] + =798.6

[0285] Example 36: 3-(5-(4-((S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 33 using Intermediate 11.

[0286] 1H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.78 (s, 1H), 8.66 (s, 1H), 8.22 (d, J = 2.6 Hz, 1H), 7.90 (s, 1H), 7.46 (s, 1H), 7.40 - 7.31 (m, 2H), 7.17 (d, J = 8.7 Hz, 1H), 7.01 (s, 1H), 6.88 (d, J = 8.6 Hz, 1H), 4.81 - 4.02 (m, 4H), 3.92 - 3.86 (m, 2H), 3.80 - 3.69 (m, 5H), 3.32 - 3.20 (m, 5H), 3.02 - 2.96 (m, 1H), 2.95 - 2.86 (m, 2H), 2.79 - 2.72 (m, 2H), 2.71 - 2.52 (m, 10H), 2.23 - 2.16 (m, 1H), 2.14 - 2.06 (m, 1H), 1.94 - 1.86 (m, 2H), 1.62 - 1.49 (m, 2H), 0.97 (d, J = 6.2 Hz, 3H). [M+H] + =798.3.

[0287] Example 37: 3-(5-(3-(((S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)methyl)azetidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 33 using Intermediate 17.

[0288] 1 H NMR (500 MHz, DMSO) δ 12.39 (s, 1H), 10.74 (s, 1H), 8.64 (s, 1H), 7.88 (s, 1H), 7.62 (s, 1H), 7.45 (s, 1H), 7.34 (d, J = 8.6 Hz, 1H), 7.00 (s, 1H), 6.94 (s, 1H), 6.86 (d, J = 8.6 Hz, 1H), 4.98 - 4.15 (m, 4H), 4.13 - 4.06 (m, 2H), 3.90 - 3.85 (m, 1H), 3.84 - 3.79 (m, 1H), 3.70 (s, 3H), 3.64 - 3.58 (m, 2H), 3.24 - 3.15 (m, 2H), 3.04 - 2.87 (m, 5H), 2.64 - 2.52 (m, 10H), 2.48 - 2.43 (m, 2H), 2.31 - 2.25 (m, 1H), 2.20 - 2.12 (m, 4H), 2.11 - 2.03 (m, 1H), 0.95 (d, J = 6.1 Hz, 3H). [M+H] + =798.7.

[0289] Example 38: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-3-fluoropyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 9. The racemate was separated by preparative chiral HPLC using the following conditions: (Column: CHIRALPAK IF, 2 cm x 25 cm, 5 um; Flow rate: 20 mL / min) to give the title compound, which corresponded to Peak A at 254 nm (retention time: 2.186 min). 1 H NMR (500 MHz, DMSO) δ 12.42 (s, 1H), 10.86 (s, 1H), 8.67 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.47 (s, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.04 (s, 1H), 6.79 (d, J = 8.6 Hz, 1H), 4.15 - 4.08 (m, 1H), 3.91 - 3.85 (m, 2H), 3.73 - 3.70 (m, 4H), 3.52 (s, 2H), 3.34 - 3.30 (m, 5H), 3.20 - 3.14 (m, 3H), 2.98 - 2.89 (m, 3H), 2.85 - 2.80 (m, 3H), 2.75 - 2.69 (m, 4H), 2.65 (s, 2H), 2.57 (s, 3H), 2.37 (s, 1H), 2.26 - 2.22 (m, 1H), 2.09 - 2.05 (m, 1H), 1.94 - 1.90 (s, 2H), 1.59 - 1.55 (m, 1H);[M+H] + =802.5.

[0290] Example 40: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6-yl)piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 10. 1 H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 10.80 (s, 1H), 8.66 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.14 (s, 1H), 7.02 (s, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.81 - 4.01 (m, 4H), 3.89 (dd, J = 8.7, 5.3 Hz, 1H), 3.72 (s, 4H), 3.20 - 3.15 (m, 6H), 2.92 (d, J = 5.0 Hz, 2H), 2.76 - 2.66 (m, 6H), 2.64 - 2.52 (m, 7H), 2.40 (t, J = 11.2 Hz, 1H), 2.31 - 2.07 (m, 6H), 1.92 (d, J = 11.1 Hz, 2H), 1.67 - 1.56 (m, 2H). [M+H] + =798.6.

[0291] Example 102: 3-(5-(4-(1-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperidin-4-yl)piperazin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 28.

[0292] 1 H NMR (500 MHz, DMSO) δ 12.34 (s, 1H), 10.74 (s, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.62 - 4.51 (m, 1H), 4.22 - 4.11 (m, 2H), 3.86 - 3.82 (m, 1H), 3.71 (s, 1H), 3.65 (s, 3H), 3.24 - 3.22 (m, 4H), 2.89 - 2.83 (m, 5H), 2.65 (t, J = 11.4 Hz, 3H), 2.56 (d, J = 11.2 Hz, 1H), 2.52 - 2.49 (m, 5H), 2.46 - 2.44 (m, 5H), 2.20 (s, 3H), 2.14 - 2.10 (m, 1H), 2.06 - 2.03 (m, 1H), 1.92 - 1.83 (m, 2H), 1.60 - 1.56 (m, 2H), 1.23 - 1.16 (m, 1H). [M+H] + =798.6.

[0293] Example 70: (R)-3-(4-(4-(1-((7 1 s,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)-cyclobutanacyclononaphane-5 6-yl)piperidin-4-yl)-3-oxopiperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-Butyl 4-((2-(((benzyloxy)carbonyl)amino)ethyl)amino)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.1 g, 15.0 mmol), benzyl (2-aminoethyl)carbamate (3.0 g, 15.0 mmol), and AcOH (1.5 g, 22.5 mmol) in DCE (100 mL) was added STAB (6.3 g, 30.0 mmol). The mixture was then stirred at room temperature for 16 hours. The reaction was quenched with NaHCO / water (100 mL) and extracted with DCM (150 mL x 2). The combined organic phases were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (DCM:CHOH = 15:1) to give the title product (5.5 g, 93.3%). [M+H] + =378.5.

[0294] Step 2: tert-Butyl 4-(N-(2-(((benzyloxy)carbonyl)amino)ethyl)-2-chloroacetamido)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-((2-(((benzyloxy)carbonyl)amino)ethyl)amino)piperidine-1-carboxylate (5.5 g, 14.5 mmol) and DIEA (5.6 g, 43.5 mmol) in DCM (150 mL) was added 2-chloroacetyl chloride (2.0 g, 17.4 mmol) cooled to 0 °C. The mixture was then stirred at room temperature for 3 h. The reaction was quenched with water (100 mL) and extracted with DCM (150 mL × 2). The combined organic phases were washed with brine (100 mL × 1), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH = 20:1) to give the title product (6.0 g, 90.9%). [M+H] + =454.5.

[0295] Step 3: Benzyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-oxopiperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(N-(2-(((benzyloxy)carbonyl)amino)ethyl)-2-chloroacetamido)piperidine-1-carboxylate (6.0 g, 13.2 mmol) in DMF (80 mL) was added NaH (1.0 g, 26.4 mmol) at room temperature. The mixture was then stirred at room temperature for 0.5 h. The reaction was quenched with NH4Cl / water (100 mL) and extracted with EA (150 mL x 2). The combined organic phases were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH = 20:1) to give the title product (5.3 g, 96.3%). [M+H] + =418.5.

[0296] Step 4: tert-Butyl 4-(2-oxopiperazin-1-yl)piperidine-1-carboxylate [ka] To a solution of benzyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-oxopiperazine-1-carboxylate (5.3 g, 12.7 mmol) in THF (100 mL) was added Pd / C (1.5 g, 10 wt%, wet). The resulting mixture was stirred under a hydrogen atmosphere (balloon) at room temperature for 3 hours. The mixture was filtered through Celite and washed with DCM. The filtrate was concentrated in vacuo to give the desired product (3.4 g, 94.4%). [M+H] + =284.5.

[0297] Step 5: tert-Butyl 4-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-2-oxopiperazin-1-yl)piperidine-1-carboxylate [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (2.0 g, 4.1 mmol), tert-butyl 4-(2-oxopiperazin-1-yl)piperidine-1-carboxylate (1.8 g, 6.3 mmol), and CsCO (2.7 g, 8.2 mmol) in 100 mL of 1,4-dioxane was added G3 RuPhos Pd (690 mg, 0.82 mmol) and RuPhos (383 mg, 0.82 mmol). The mixture was stirred at 100 °C for 16 h. After LCMS showed the reaction was complete, the mixture was filtered through a Celite pad and washed with DCM. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by silica column chromatography (PE:EA=50:1 to 1:1) to give the product (2.6 g, 91.5%). [M+H] + =685.5.

[0298] Step 6: tert-Butyl 4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopiperazin-1-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-2-oxopiperazin-1-yl)piperidine-1-carboxylate (1.1 g, 1.6 mmol) in 15 mL of DMF and 15 mL of i-PrOH was added Pd / C (0.5 g, 10 wt %, wet). The mixture was stirred at 50° C. under a hydrogen atmosphere (balloon) for 24 h. The mixture was cooled to room temperature and filtered directly through Celite. The filtrate was concentrated in vacuo to give the desired product (780 mg, 95.8%). [M+H] + =507.5

[0299] Step 7: 3-(2,6-difluoro-4-(3-oxo-4-(piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione [ka] A solution of tert-butyl 4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopiperazin-1-yl)piperidine-1-carboxylate (780 mg, 1.5 mmol) in HCl / 1,4-dioxane (20 mL) was stirred at room temperature for 1 hour, and the reaction mixture was concentrated under reduced pressure to give the product (625 mg), which was used without further purification. [M+H] + =407.5

[0300] Step 8: (R)-3-(4-(4-(1-((7 1 s,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)-cyclobutanacyclononaphane-5 6-yl)piperidin-4-yl)-3-oxopiperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a stirred solution of Intermediate 1 (50 mg, 0.1 mmol) in DMA (5 mL) was added 3-(2,6-difluoro-4-(3-oxo-4-(piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione (80 mg, 0.2 mmol), t-BuONa (47 mg, 0.5 mmol), Ruphos (18 mg, 0.04 mmol), and Pd(dba) (18 mg, 0.04 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 1 hour. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with water (3×50 mL) and brine (50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (15:1) to give the crude product. Chiral separation by HPLC gave the title compound (4.49 mg, 5.5%). HPLC conditions: Column: CHIRALPAK IA, Column size: 2 cm × 25 cm, 5 μm, Mobile phase: HEX:DCM (0.1% FA):MeOH = 50:50, Flow rate: 20 mL / min, Retention time: 3.286 min.

[0301] 1H NMR (500 MHz, DMSO) δ 12.42 (s, 1H), 10.88 (s, 1H), 8.67 (s, 1H), 7.90 (s, 1H), 7.47 (s, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.07 (s, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.66 (s, 1H), 6.64 (s, 1H), 4.89 - 4.41 (m, 3H), 4.30 - 4.00 (m, 3H), 3.89 (s, 2H), 3.81 (d, J = 11.1 Hz, 2H), 3.72 (s, 3H), 3.54 - 3.46 (m, 3H), 3.00 - 2.87 (m, 3H), 2.84 - 2.74 (m, 4H), 2.69 - 2.62 (m, 2H), 2.16 - 2.04 (m, 1H), 2.01 - 1.85 (m, 3H), 1.73 - 1.62 (m, 2H), 1.32 - 1.14 (m, 4H), 0.91 - 0.77 (m, 1H). [M+H] + = 833.7.

[0302] Example 41: 3-(5-(4-(3-(((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)(methyl)amino)azetidin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6.

[0303] 1 H NMR (500 MHz, DMSO) δ 12.28 (s, 1H), 10.73 (s, 1H), 8.58 (s, 1H), 8.06 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.06 (s, 1H), 6.76 (s, 1H), 6.66 (d, J = 8.3 Hz, 1H), 4.95 - 3.87 (m, 6H), 3.81 (dd, J = 8.8, 5.3 Hz, 1H), 3.65 (s, 3H), 3.60 (t, J = 6.1 Hz, 2H), 3.07 - 2.99 (m, 2H), 2.88 - 2.82 (m, 4H), 2.76 (s, 3H), 2.66 - 2.60 (m, 2H), 2.53 - 2.46 (m, 5H), 2.21 - 2.08 (m, 6H), 2.06 - 2.00 (m, 1H), 1.81 (s, 1H), 1.75 - 1.68 (m, 3H), 1.35 - 1.25 (m, 2H). [M+H] + =798.30.

[0304] Example 82: 3-(5-(2-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)ethyl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] To a solution of the product of Step 2 of Example 6 (100 mg, 0.19 mmol), Intermediate 27 (96 mg, 0.29 mmol), and KI (65 mg, 0.38 mmol) in MeCN (5 mL) / DMSO (2 mL) was added DIEA (75 mg, 0.57 mmol). The resulting mixture was heated at 80 °C overnight under N. The mixture was quenched with water and extracted with DCM (3 × 20 mL). The combined organic phase was washed with brine (1 × 15 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by silica column chromatography (DCM:MeOH = 100:1 to 10:1) followed by preparative HPLC chromatography to give the title product (31 mg, 21.4%).

[0305] 1 H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.81 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.03 (s, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.88 - 3.99 (m, 4H), 3.92 (dd, J = 9.5, 5.3 Hz, 1H), 3.72 (s, 3H), 3.22 - 3.14 (m, 4H), 2.92 (s, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.68 - 2.51 (m, 14H), 2.46 (s, 3H), 2.23 (dd, J = 9.0, 4.6 Hz, 2H), 2.13 - 2.06 (m, 1H). [M+H] + =743.4.

[0306] Example 62: 3-(5-((3S,4R)-4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Step 4 of Example 26 using Intermediates 1 and 28. 1 H NMR (500 MHz, DMSO) δ 12.34 (s, 1H), 10.72 (s, 1H), 8.59 (s, 1H), 7.85 - 7.79 (m, 1H), 7.39 (s, 1H), 7.30 (dd, J = 16.3, 8.2 Hz, 2H), 7.05 (d, J = 7.7 Hz, 1H), 6.97 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 5.04 - 4.99 (m, 1H), 4.63 - 4.58 (m, 2H), 4.24 - 3.93 (m, 2H), 3.83 - 3.78 (m, 1H), 3.65 - 3.59 (m, 4H), 3.10 - 3.01 (m, 5H), 2.98 - 2.67 (m, 11H), 2.57 - 2.48 (m, 6H), 2.32 - 2.28 (m, 3H), 2.24 - 2.08 (m, 2H), 2.06 - 1.90 (m, 2H), 1.82 - 1.72 (m, 1H);[M+H] + =816.5.

[0307] Example 43: 3-(5-(4-((1R,4R)-5-((7 1 s,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,51 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphane-5 6 -yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 12. 1 H NMR (500 MHz, DMSO) δ 12.33 (s, 1H), 10.77 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.2 Hz, 1H), 6.65 (s, 1H), 6.55 (d, J = 8.7 Hz, 1H), 4.49 - 4.39 (m, 1H), 3.97 - 3.84 (m, 2H), 3.72 (s, 3H), 3.50 - 3.40 (m, 2H), 3.25 - 2.88 (m, 8H), 2.61 - 2.50 (m, 11H), 2.45 - 2.32 (m, 5H), 2.26 - 2.14 (m, 2H), 2.10 - 2.01 (m, 1H), 1.96 - 1.85 (m, 4H), 1.62 - 1.42 (m, 2H);[M+H] + =810.5.

[0308] Example 109: 3-(5-(4-((S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 30 using Intermediate 12. 1 H NMR (500 MHz, DMSO) δ 12.32 (s, 1H), 10.80 (s, 1H), 8.66 (s, 1H), 8.11 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.12 (s, 1H), 6.92 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 3.92 - 3.77 (m, 2H), 3.72 (s, 3H), 3.57 (s, 1H), 3.51 (s, 1H), 3.44 - 3.40 (m, 1H), 3.18 (s, 2H), 3.04 (s, 2H), 2.94 - 2.88 (m, 6H), 2.76 - 2.73 (m, 3H), 2.63 - 2.60 (m, 2H), 2.56 (s, 3H), 2.55 - 2.51(m, 6H), 2.36 (s, 1H), 2.28 (s, 1H), 2.26 (s, 3H), 2.24 - 2.16 (m, 2H), 2.10 (d, J = 12.6 Hz, 2H), 1.92 (s, 1H), 1.77 (s, 2H), 1.57 (d, J = 11.5 Hz, 1H). [M+H] + =842.6.

[0309] Example 110: 3-(5-((S)-4-(1-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)piperidin-4-yl)-3-methylpiperazin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 17 using Intermediate 22. 1 H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 10.80 (s, 1H), 8.66 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.46 (s, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.14 (s, 1H), 7.03 (s, 1H), 6.95 - 6.88 (m, 1H), 4.82 - 4.02 (m, 4H), 3.89 (dd, J = 8.8, 5.4 Hz, 1H), 3.78 - 3.70 (m, 5H), 3.02 - 2.82 (m, 9H), 2.78 - 2.53 (m, 11H), 2.27 (s, 3H), 2.19 (dd, J = 8.5, 4.7 Hz, 1H), 2.14 - 2.07 (m, 1H), 1.88 - 1.70 (m, 4H), 1.60 - 1.51 (m, 1H), 1.11 (d, J = 6.0Hz, 3H). [M+H] + =812.7.

[0310] Example 57: 3-(5-((3R,4R)-4-(4-((7 1 s,7 3 S,E)-11,26-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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Step 4 of Example 26 using Intermediates 1 and 29. 1 H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.79 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.48 - 7.40 (m, 2H), 7.35 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.03 (s, 1H), 6.92 (d, J = 9.1 Hz, 1H), 4.94 - 4.04 (m, 5H), 3.91 (dd, J = 9.4, 5.2 Hz, 1H), 3.72 (s, 3H), 3.44 - 3.36 (m, 2H), 3.17 (s, 4H), 3.09 - 3.05 (m, 1H), 2.95 - 2.83 (m, 5H), 2.79 - 2.72 (m, 2H), 2.68 - 2.53 (m, 8H), 2.43 - 2.36 (m, 4H), 2.25 - 2.17 (m, 1H), 2.12 - 2.05 (m, 1H), 1.94 - 1.88 (m, 1H), 1.76 - 1.70 (m, 1H). [M+H] + =816.60.

[0311] Example 112: 3-(5-(4-(6-(((7 1 s,7 3 s,E)-11,26-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)-cyclobutanacyclononaphane-5 6 -yl)(methyl)amino)-2-azaspiro[3.3]heptan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 12. 1 H NMR (500 MHz, DMSO) δ 12.38 (s, 1H), 10.78 (s, 1H), 8.65 (s, 1H), 7.90 (s, 1H), 7.46 (s, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 6.81 - 6.70 (m, 2H), 4.90 - 3.80 (m, 8H), 3.72 (s, 3H), 3.27 (s, 2H), 3.12 - 2.86 (m, 8H), 2.76 (s, 3H), 2.59 - 2.54 (m, 6H), 2.45 - 2.39 (m, 2H), 2.36 (s, 3H), 2.25 - 2.15 (m, 2H), 2.13 - 2.04 (m, 4H), 1.75 - 1.68 (m, 2H), 1.38 - 1.27 (m, 2H). [M+H] + =838.70.

[0312] Example 113: 3-(5-(4-(6-((7 1 s,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)-cyclobutanacyclononaphane-5 6-yl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 12. 1 H NMR (500 MHz, DMSO) δ 12.31 (s, 1H), 10.71 (s, 1H), 8.58 (s, 1H), 7.82 (s, 1H), 7.39 (s, 1H), 7.33 - 7.26 (m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 6.29 (d, J = 8.5 Hz, 1H), 4.82 - 3.79 (m, 11H), 3.65 (s, 3H), 3.06 - 2.79 (m, 8H), 2.56 - 2.47 (m, 10H), 2.31 (s, 3H), 2.19 - 2.09 (m, 2H), 2.05 - 1.98 (m, 1H), 1.84 (s, 1H), 1.78 - 1.68 (m, 1H), 1.36 - 1.26 (m, 1H). [M+H] + =810.7.

[0313] Example 114: 3-(5-(4-(3-((((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)(methyl)amino)methyl)azetidin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 12. 1 H NMR(500 MHz, DMSO) δ 12.33 (s, 1H), 10.77 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.44 (d, J = 12.1 Hz, 1H), 7.36 - 7.31 (m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.86 - 6.59 (m, 2H), 3.89 - 3.85 (m, 1H), 3.71 (s, 3H), 3.53 (s, 3H), 3.02 (s, 3H), 2.91 (s, 8H), 2.73 - 2.58 (m, 5H), 2.55 (s, 7H), 2.37 (s, 4H), 2.18 (s, 3H), 2.10 - 2.00 (m, 1H), 1.73 (s, 3H), 1.33 (d, J = 9.2 Hz, 2H);[M+H] + =812.4.

[0314] Example 47: 3-(5-((1S,4S)-5-(1-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 28 using Intermediate 23. 1H NMR (500 MHz, DMSO) δ 12.39 (s, 1H), 10.76 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.11 - 7.04 (m, 1H), 6.99 (d, J = 7.6 Hz, 2H), 6.88 (d, J = 9.0 Hz, 1H), 4.82 - 4.47 (m, 2H), 4.25 - 3.97 (m, 3H), 3.83 - 3.79 (m,1H), 3.76 (s, 1H), 3.61 - 3.53 (m, 2H), 2.98 - 2.83 (m, 3H), 2.81 - 2.71 (m, 2H), 2.64 - 2.54 (m, 7H), 2.41 - 2.24 (m, 9H), 2.24 - 2.03 (m, 4H), 1.92 - 1.66 (m, 5H), 1.52 - 1.38 (m, 2H);[M+H] + =810.5.

[0315] Example 117: 3-(5-(4-((1S,4S)-5-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 12. 1H NMR (500 MHz, DMSO) δ 12.32 (s, 1H), 10.77 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 7.9 Hz, 1H), 6.65 (s, 1H), 6.55 (d, J = 8.3 Hz, 1H), 4.46 - 4.39 (m, 2H), 3.87 (dd, J = 9.3, 5.3 Hz, 1H), 3.72 (s, 3H), 3.39 - 3.32 (m, 2H), 3.31 - 3.24 (m, 4H), 3.13 - 2.87 (m, 6H), 2.65 - 2.58 (m, 3H), 2.56 - 2.47 (m, 6H), 2.37 (s, 4H), 2.19 (d, J = 9.7 Hz, 2H), 2.06 (dd, J = 13.2, 5.7 Hz, 2H), 1.93 - 1.87 (m, 4H), 1.57 - 1.52 (m, 2H);[M+H] + =810.4.

[0316] Example 44: 3-(5-((S)-4-(1-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)piperidin-4-yl)-3-methylpiperazin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 17 using Intermediates 25 and 30. 1H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.79 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.04 (s, 1H), 6.92 (d, J = 9.1 Hz, 1H), 4.24 - 4.02 (m, 2H), 3.92 - 3.88 (m, 1H), 3.72 (s, 3H), 3.27 - 3.18 (m, 4H), 2.94 - 2.90 (m, 4H), 2.77 (m, 2H), 2.57 - 2.55 (m, 5H), 2.44 - 2.41 (m, 5H), 2.23 - 2.16 (m, 2H), 2.12 - 2.06 (m, 1H), 1.81 - 1.75 (m, 2H), 1.51 - 1.45 (m, 3H), 1.27 - 1.21 (m, 6H), 0.89 - 0.81 (m, 3H). [M+H] + =812.7.

[0317] Example 120: 3-(5-(4-((S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediates 1 and 10. 1H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.79 (s, 1H), 8.66 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.14 (s, 1H), 6.98 (s, 1H), 6.88 (d, J = 8.7 Hz, 1H), 3.92 - 3.77 (m, 2H), 3.72 (s, 3H), 3.57 (s, 1H), 3.51 (s, 1H), 3.44 - 3.40 (m, 1H), 3.18 (s, 2H), 3.04 (s, 2H), 2.94 - 2.88 (m, 6H), 2.76 - 2.73 (m, 3H), 2.63 - 2.60 (m, 2H), 2.56 (s, 3H), 2.55 - 2.51 (m, 6H), 2.36 (s, 1H), 2.28 (s, 1H), 2.26 (s, 3H), 2.24 - 2.16 (m, 2H), 2.10 (d, J = 12.6 Hz, 2H), 1.92 (s, 1H), 1.77 (s, 2H), 1.57 (d, J = 11.5 Hz, 1H). [M+H] + =842.0.

[0318] Example 121: 3-(5-(4-(3-(4-((7 1 s,7 3 s,E)-11,26-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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using intermediates 39 and 12. 1 H NMR (500 MHz, DMSO) δ 12.36 (s, 1H), 10.78 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (dd, J = 8.3, 3.5 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.62 - 4.51 (m, 2H), 4.29 - 4.18 (m, 2H), 3.88 (dd, J = 9.3, 5.3 Hz, 1H), 3.72 (s, 3H), 3.43 (s, 2H), 3.16 (s, 5H), 3.04 - 3.01 (m, 2H), 2.93 - 2.87 (m, 6H), 2.63 - 2.58 (m, 3H), 2.56 (s, 4H), 2.43 (s, 5H), 2.37 (s, 3H), 2.26 - 2.14 (m, 3H), 2.11 - 2.03 (m, 1H), 1.81 - 1.73 (m, 2H), 1.38 - 1.35 (m, 2H). [M+H] + =853.8.

[0319] Example 122: 3-(5-(4-((S)-1-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-3,3-difluoropiperidin-4-yl)piperazin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Step 4 of Example 26 using Intermediates 1 and 40. 1 H NMR (500 MHz, DMSO) δ 12.51 (s, 1H), 10.90 (s, 1H), 8.79 (s, 1H), 8.03 (s, 1H), 7.63 (s, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.33 (s, 1H), 7.15 (s, 1H), 6.98 (d, J = 8.6 Hz, 1H), 4.59 - 4.57 (m, 2H), 4.01 - 3.99 (m, 2H), 3.75 (s, 3H), 3.30 - 3.26 (m, 9H), 3.15 - 3.12 (m, 6H), 2.91- 2.88 (m, 5H), 2.65 (s, 3H), 2.48 (s, 3H), 2.26 (d, J = 8.4 Hz, 2H), 2.15 - 1.91 (m, 4H). [M+H] + =834.0.

[0320] Example 123: 3-(5-((R)-4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Step 4 of Example 26 using Intermediates 1 and 24. 1H NMR (500 MHz, DMSO) δ 12.54 (s, 1H), 10.87 (s, 1H), 8.81 (s, 1H), 8.05 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.28 (s, 1H), 7.12 (s, 1H), 6.97 (d, J = 8.9 Hz, 1H), 4.59 - 4.57 (m, 2H), 4.01 - 3.99 (m, 2H), 3.75 (s, 3H), 3.30 - 3.26 (m, 9H), 3.15 - 3.12 (m, 6H), 2.91- 2.88 (m, 5H), 2.65 (s, 3H), 2.48 (s, 3H), 2.26 (d, J = 8.4 Hz, 2H), 2.15 - 1.91 (m, 4H). [M+H] + =834.0.

[0321] Example 124: 3-(5-(4-(5-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 12. 1H NMR (500 MHz, DMSO) δ 12.50 (s, 1H), 10.78 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.47 (s, 1H), 7.42 - 7.33 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 7.03 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.83 - 4.47 (m, 4H), 4.44 - 4.03 (m, 5H), 3.92 - 3.85 (m, 1H), 3.72 (s, 3H), 3.24 - 3.19 (m, 3H), 3.13 - 3.09 (m, 3H), 3.06 - 2.99 (m, 3H), 2.97 - 2.84 (m, 4H), 2.64 - 2.59 (m, 6H), 2.20 - 2.16 (m, 3H), 2.07 - 2.01 (m, 2H), 1.88 - 1.81 (m, 3H), 1.72 - 1.59 (m, 3H). [M+H] + =840.5.

[0322] Example 125: 3-(5-((S)-4-(4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Step 4 of Example 26 using Intermediates 1 and 31. 1H NMR (500 MHz, DMSO) δ 12.54 (s, 1H), 10.87 (s, 1H), 8.81 (s, 1H), 8.05 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.28 (s, 1H), 7.12 (s, 1H), 6.97 (d, J = 8.9 Hz, 1H), 4.59 - 4.57 (m, 2H), 4.01 - 3.99(m, 2H), 3.75 (s, 3H), 3.30 - 3.26 (m, 9H), 3.15 - 3.12 (m, 6H), 2.91- 2.88 (m, 5H), 2.65 (s, 3H), 2.48 (s, 3H), 2.26 (d, J = 8.4 Hz, 2H), 2.15 - 1.91 (m, 4H). [M+H] + =834.0.

[0323] Example 126: 3-(5-(4-(5-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 12. 1H NMR (500 MHz, DMSO) δ 12.29 (s, 1H), 10.78 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.44 (d, J = 11.9 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.09 (d, J = 8.2 Hz, 1H), 6.68 (s, 1H), 6.60 - 6.58 (m, 1H), 4.13 - 4.08 (m, 3H), 3.91 - 3.86 (m, 1H), 3.71 (s, 3H), 3.63 - 3.59 (m, 1H), 3.26 - 3.17 (m, 4H), 3.10 - 3.02 (m, 2H), 3.00 - 2.86 (m, 5H), 2.66 - 2.62 (m, 2H), 2.60 - 2.53 (m, 6H), 2.37 - 2.32 (m, 4H), 2.25 - 2.19 (m, 2H), 2.13 - 1.90 (m, 5H), 1.88 - 1.83 (m, 1H), 1.81 - 1.74 (m, 1H), 1.64 - 1.55 (m, 1H), 1.52 - 1.47 (m, 2H). [M+H] + =824.5.

[0324] Example 127: 3-(5-(4-(8-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 12. 1 H NMR (500 MHz, DMSO) δ 12.33 (s, 1H), 10.77 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.32 (dd, J = 12.2, 8.5 Hz, 2H), 7.08 (d, J = 8.2 Hz, 1H), 6.92 (s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.87 - 4.44 (m, 2H), 4.32 (s, 2H), 4.26 - 3.95 (m, 2H), 3.87 (dd, J = 9.4, 5.2 Hz, 1H), 3.72 (s, 3H), 3.06 (d, J = 10.8 Hz, 2H), 2.91 (s, 3H), 2.67 - 2.53 (m, 13H), 2.37 (s, 3H), 2.26 - 2.13 (m, 3H), 2.10 - 2.01 (m, 1H), 1.93 - 1.78 (m, 6H), 1.60 - 1.48 (m, 2H). [M+H] + =824.5.

[0325] Example 128: (3R)-3-(4-(4-(8-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 6. 1 H NMR (500 MHz, DMSO) δ 12.32 (s, 1H), 10.86 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.28 (t, J = 15.4 Hz, 1H), 6.90 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.60 (d, J = 12.8 Hz, 2H), 4.88 - 4.39 (m, 2H), 4.30 (s, 2H), 4.23 - 4.08 (m, 1H), 4.03 (dd, J = 12.6, 4.9 Hz, 1H), 3.72 (s, 3H), 3.67 (d, J = 12.1 Hz, 2H), 2.93 - 2.89 (m, 3H), 2.77 - 2.74 (m, 3H), 2.65 - 2.51 (m, 12H), 2.26 (d, J = 3.3 Hz, 1H), 2.13 - 2.01 (m, 1H), 1.95 - 1.92 (m, 1H), 1.89 - 1.77 (m, 4H), 1.74 -1.71 (m, 2H), 1.42 - 1.39 (m, 2H). [M+H] + =845.5.

[0326] Example 129: (3R)-3-(4-(4-(7-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2,7-diazaspiro[4.4]nonane-2-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 6. 1 H NMR (500 MHz, DMSO) δ 12.31 (s, 1H), 10.87 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.45 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 10.6 Hz, 2H), 6.51 (s, 1H), 6.46 (d, J = 8.5 Hz, 1H), 4.62 - 4.51 (m, 2H), 4.25 - 4.15 (m, 1H), 4.05 (dd, J = 12.6, 4.8 Hz, 1H), 3.71 (s, 4H), 3.68 - 3.64 (m, 1H), 3.32 (s, 2H), 3.30 - 3.27 (m, 2H), 3.20 (s, 1H), 2.92 (s, 3H), 2.87 - 2.79 (m, 4H), 2.69 - 2.57 (m, 3H), 2.55 (m, 3H), 2.53 - 2.51(m, 3H), 2.22 (s, 1H), 2.13 - 2.02 (m, 2H), 2.01 - 1.92 (m, 3H), 1.87 - 1.81 (m, 4H), 1.44 (s, 2H). [M+H] + =859.7.

[0327] Example 130: 3-(5-(4-(8-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 10. 1 H NMR (500 MHz, DMSO) δ 12.32 (s, 1H), 10.80 (s, 1H), 8.66 (s, 1H), 8.11 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.12 (s, 1H), 6.92 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.58 (s, 1H), 4.33 (s, 2H), 3.87 (dd, J = 8.7, 5.4 Hz, 1H), 3.72 (s, 3H), 3.12 (d, J = 11.6 Hz, 2H), 2.91 (s, 3H), 2.67 - 2.64 (m, 5H), 2.58 (s, 2H), 2.57 - 2.54 (m, 8H), 2.36 (s, 1H), 2.24 - 2.20 (m, 6H), 2.10 - 2.07 (m, 1H), 1.90 (d, J = 6.8 Hz, 2H), 1.81 (d, J = 14.4 Hz, 4H), 1.52 (d, J = 11.2 Hz, 2H). [M+H] + =824.0.

[0328] Example 131: 3-(5-(4-(3-(4-((7 1 s,7 3 s,E)-11,26-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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using intermediates 39 and 10. 1 H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 10.79 (s, 1H), 8.65 (s, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.13 (s, 1H), 7.02 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.72 - 4.62 (m, 2H), 4.32 - 4.18 (m, 2H), 3.88 (dd, J = 8.7, 5.4 Hz, 1H), 3.72 (s, 3H), 3.43 (s, 3H), 3.17 (s, 4H), 3.12 - 3.06 (m, 2H), 2.92 (s, 5H), 2.71 - 2.67 (m, 2H), 2.59 - 2.53 (m, 5H), 2.52 - 2.51 (m, 1H), 2.44 (s, 5H), 2.23 (s, 4H), 2.20 - 2.06 (m, 3H), 1.79 - 1.76 (m, 2H), 1.37 - 1.31 (m, 2H). [M+H] + =853.8.

[0329] Example 132: 3-(5-(4-(5-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 10. 1 H NMR (500 MHz, DMSO) δ 12.30 (s, 1H), 10.79 (s, 1H), 8.65 (s, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 7.45 (s, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7.13 (s, 1H), 6.68 (s, 1H), 6.60 (d, J = 8.1 Hz, 1H), 4.84 - 4.44 (m, 2H), 4.38 - 4.06 (m, 2H), 4.02 (s, 1H), 3.88 (dd, J = 8.7, 5.3 Hz, 1H), 3.71 (s, 3H), 3.61 (d, J = 9.2 Hz, 1H), 3.30 - 3.20 (m, 4H), 3.13 (d, J = 6.3 Hz, 2H), 3.04 - 2.85 (m, 5H), 2.72 (t, J = 8.7 Hz, 2H), 2.64 - 2.53 (m, 6H), 2.28 (s, 1H), 2.24 (s, 3H), 2.21 - 2.14 (m, 1H), 2.09 (dd, J = 12.9, 6.3 Hz, 1H), 2.01 (d, J = 11.3 Hz, 1H), 1.99 - 1.91 (m, 2H), 1.87 (d, J = 10.6 Hz, 1H), 1.83 - 1.75 (m, 1H), 1.65 - 1.55 (m, 1H), 1.55 - 1.42 (m, 2H). [M+H] + =824.6.

[0330] Example 133: 3-(5-((3S,4R)-4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Step 4 of Example 26 using Intermediates 1 and 32. 1 H NMR (500 MHz, DMSO) δ 12.54 (s, 1H), 10.87 (s, 1H), 8.76 (s, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.28 (s, 1H), 7.18 (s, 1H), 7.00 (d, J = 8.9 Hz, 1H), 5.51 - 5.41 (m, 1H), 4.83 - 4.52 (m, 2H), 4.30 - 4.04 (m, 2H), 4.02 - 3.88 (m, 3H), 3.74 (s, 5H), 3.67 - 3.61 (m, 1H), 3.42 - 3.28 (m, 3H), 3.16 - 3.07 (m, 2H), 3.03 - 2.98 (m, 1H), 2.98 - 2.90 (m, 3H), 2.66 - 2.51 (m, 8H), 2.33 (s, 3H), 2.30 - 2.28 (m, 1H), 2.25 - 2.20 (m, 2H), 2.15 - 2.09 (m, 2H), 1.91 - 1.68 (m, 1H). [M+H] + =816.9.

[0331] Example 134: 3-(5-((3R,4S)-4-(4-((7 1 s,7 3 R,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-11 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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Step 4 of Example 26 using Intermediates 1 and 33. 1 H NMR (500 MHz, DMSO) δ 12.55 (s, 1H), 10.88 (s, 1H), 8.76 (s, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.28 (s, 1H), 7.18 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 5.51 - 5.42 (m, 1H), 4.87 - 4.49 (m, 2H), 4.42 - 4.06 (m, 2H), 4.03 - 3.87 (m, 3H), 3.78 - 3.68 (m, 5H), 3.64 (t, J = 11.3 Hz, 1H), 3.46 - 3.25 (m, 3H), 3.18 - 3.07 (m, 2H), 3.05 - 2.85 (m, 4H), 2.67 - 2.51 (m, 8H), 2.38 - 2.18 (m, 6H), 2.17 - 2.05 (m, 2H), 1.92 - 1.58 (m, 1H). [M+H] + =816.9.

[0332] Example 66: (R)-3-(4-((3S,4R)-4-(4-((7 1 s,7 3 S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,51 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazola-2(2,4)-pyridina-1(4,5)-pyrazola-7(1,3)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Step 4 of Example 26 using Intermediates 1 and 34 and purified by silica gel column (DCM:CHOH=15:1) to give the racemate, which was further purified by preparative chiral HPLC using the following conditions: (Column: CHIRALPAK IF, 2 cm × 25 cm, 5 μm, Flow rate: 20 mL / min, Gradient: 10% to 50% in 2.0 min, hold at 50% for 1.0 min, Injection volume: 5 μL) to give the title product. 1 H NMR (500 MHz, DMSO) δ 12.38 (s, 1H), 10.83 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.01 (s, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 13.0 Hz, 2H), 5.19 - 5.04 (m, 1H), 4.85 - 4.01 (m, 6H), 3.92 (d, J = 12.5 Hz, 1H), 3.71 (s, 3H), 3.21 - 3.12 (m, 4H), 3.05 - 2.73 (m, 10H), 2.70 - 2.52 (m, 8H), 2.14 - 2.04 (m, 1H), 2.00 - 1.85 (m, 2H), 1.79 (s, 1H). [M+H] + =837.7.

[0333] Example 136: (R)-3-(4-(4-(6-(((7 1 s,7 3 s,E)-11,26-dimethyl-3-oxo-52 ,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)-cyclobutanacyclononaphane-5 6 -yl)(methyl)amino)-2-azaspiro[3.3]heptan-2-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 6. 1 H NMR (500 MHz, DMSO) δ 12.37 (s, 1H), 10.87 (s, 1H), 8.65 (s, 1H), 7.90 (s, 1H), 7.46 (s, 1H), 7.33 (d, J = 8.6 Hz, 1H), 6.80 - 6.67 (m, 2H), 6.59 (d, J = 12.9 Hz, 2H), 4.86 - 3.96 (m, 6H), 3.82 - 3.75 (m, 1H), 3.71 (s, 3H), 3.63 - 3.51 (m, 3H), 3.21 (s, 2H), 3.04 (s, 2H), 2.93 - 2.87 (m, 2H), 2.81 - 2.73 (m, 6H), 2.57 - 2.52 (m, 4H), 2.44 - 2.35 (m, 3H), 2.13 - 2.03 (m, 4H), 1.96 - 1.89 (m, 2H), 1.67 - 1.59 (m, 2H), 1.18 - 1.13 (m, 2H). [M+H] + =859.70.

[0334] Example 137: (R)-3-(4-(4-(3-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using intermediates 39 and 6. 1 H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.88 (s, 1H), 8.65 (s, 1H), 7.90 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 6.99 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 12.9 Hz, 2H), 4.87 - 3.96 (m, 6H), 3.71 (s, 3H), 3.59 - 3.51 (m, 2H), 3.37 (s, 3H), 3.13 (s, 4H), 2.96 - 2.74 (m, 9H), 2.58 - 2.52 (m, 4H), 2.39 (s, 4H), 2.17 - 2.06 (m, 2H), 1.98 - 1.94 (m, 2H), 1.68 - 1.63 (m, 2H), 1.24 - 1.13 (m, 2H). [M+H] + =874.70.

[0335] Example 138: 3-(5-((3R,4R)-4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in analogy to Step 4 of Example 26 using Intermediate 35. 1 H NMR (500 MHz, DMSO) δ 12.57 (s, 1H), 10.90 (s, 1H), 8.81 (s, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.32 (s, 1H), 7.18 (s, 1H), 7.01 (d, J = 8.7 Hz, 1H), 5.53 - 5.21 (m, 1H), 4.78 - 4.57 (m, 2H), 4.29 - 4.24 (m, 2H), 4.01 (dd, J = 9.6, 5.2 Hz, 3H), 3.87 - 3.81 (m, 2H), 3.75 (s, 3H), 3.69 - 3.66 (m, 1H), 3.51 - 3.43 (m, 1H), 3.28 (d, J = 10.4 Hz, 2H), 3.06 - 2.76 (m, 6H), 2.72 - 2.51 (m, 8H), 2.37 - 2.21 (m, 6H), 2.16 - 2.08 (m, 1H), 2.04 - 1.90 (m, 1H), 1.89 - 1.61 (m, 1H). [M+H] + =816.7.

[0336] Example 139: 3-(5-(4-((2S,5S)-4-((7 1 s,7 3 R,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)-cyclobutanacyclononaphane-5 6 -yl)-2,5-dimethylpiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared similarly to Example 6 using Intermediates 1 and 12. 1 H NMR (500 MHz, DMSO) δ 12.51 (s, 1H), 10.84 (s, 1H), 8.73 (s, 1H), 7.97 (s, 1H), 7.55 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 7.00 - 6.93 (m, 1H), 3.81 - 3.71 (m, 6H), 3.69 - 3.62 (m, 3H), 3.29 - 3.24 (m, 5H), 3.18 - 3.00 (m, 3H), 3.00 - 2.80 (m, 5H), 2.77 - 2.71 (m, 1H), 2.60 (s, 6H), 2.41 (s, 2H), 2.36 - 2.32 (m, 1H), 2.27 - 2.20 (m, 2H), 2.15 - 2.04 (m, 3H), 1.93 - 1.71 (m, 2H), 1.55 - 1.48 (m, 3H), 1.12 (d, J = 6.8 Hz, 2H), 0.96 (d, J = 5.9 Hz, 1H). [M+H] + =826.7.

[0337] Example 140: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-6-ethylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 36. 1 H NMR(500MHz, DMSO) δ 12.41 (s, 1H), 10.79 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.91 (dd, J = 8.8, 1.7 Hz, 1H), 4.85 - 3.99 (m, 4H), 3.91 (dd, J = 7.7, 5.6 Hz, 1H), 3.72 (s, 3H), 3.20 - 3.14 (m, 4H), 3.08 (s, 2H), 2.96 - 2.88 (m, 2H), 2.84 - 2.52 (m, 16H), 2.38 (d, J = 12.0 Hz, 2H), 2.21 - 2.12 (m, 2H), 1.92 (d, J = 11.6 Hz, 2H), 1.63 (d, J = 11.5 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H). [M+H] + =812.6.

[0338] Example 141: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-4,6-dimethylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 37. 1 H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.78 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.03 - 6.88 (m, 3H), 4.85 - 3.99 (m, 4H), 3.84 (dd, J = 9.2, 5.4 Hz, 1H), 3.72 (s, 3H), 3.20 - 3.08 (m, 6H), 3.01 - 2.85 (m, 5H), 2.75 - 2.66 (m, 4H), 2.65 - 2.51 (m, 7H), 2.45 - 2.35 (m, 5H), 2.28 (s, 3H), 2.19 (dd, J = 8.9, 5.4 Hz, 1H), 2.08 (d, J = 6.1 Hz, 1H), 1.86 (d, J = 11.0 Hz, 2H), 1.58 (d, J = 8.1Hz, 2H). [M+H] + =812.6.

[0339] Example 142: 3-(5-(4-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-3-fluoro-6-methylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 38. 1 H NMR (500 MHz, DMSO) δ 12.39 (s, 1H), 10.84 (s, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.38 - 7.29 (m, 2H), 7.01 (s, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.90 - 4.08 (m, 6H), 3.72 (s, 3H), 3.17 (s, 6H), 2.96 - 2.86 (m, 2H), 2.75 - 2.63 (m, 9H), 2.59 - 2.53 (m, 6H), 2.38 (s, 3H), 2.28 - 2.23 (m, 1H), 2.07 - 2.02 (m, 1H), 1.97 - 1.90 (m, 2H), 1.67 - 1.58 (m, 2H).

[0340] [M+H] + =816.6.

[0341] Example 143: 3-(5-(4-(3-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6-yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using Intermediate 39. 1 H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.80 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.18 (s, 1H), 7.02 (s, 1H), 6.90 (d, J = 8.9 Hz, 1H), 4.85 - 4.47 (m, 2H), 4.32 - 4.01 (m, 2H), 3.94 - 3.91 (m, 1H), 3.72 (s, 3H), 3.42 - 3.40(m, 2H), 3.16 (s, 3H), 3.07 - 2.99 (m, 3H), 2.95 - 2.90 (m, 4H), 2.84 (t, J = 6.3 Hz, 2H), 2.73 - 2.68 (m, 3H), 2.65 - 2.58 (m, 4H), 2.56 (s, 4H), 2.43 (s, 4H), 2.25 - 2.06 (m, 4H), 1.77 - 1.75 (m, 2H), 1.34 - 1.32 (m, 2H), 1.20 (t, J = 7.5 Hz, 3H). [M+H] + =867.7.

[0342] Example 148: (R)-3-(4-(4-(3-((R)-4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6. 1 H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.86 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.01 (s, 1H), 6.88 (d, J = 9.1 Hz, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 4.93 - 4.44 (m, 2H), 4.39 - 4.09 (m, 2H), 4.04 (dd, J = 12.4, 4.8 Hz, 1H), 3.90 (d, J = 5.2 Hz, 1H), 3.72 (s, 3H), 3.60 (d, J = 12.4 Hz, 2H), 3.46 - 3.36 (m, 4H), 3.23 - 3.18 (m, 1H), 2.98 (t, J = 9.0 Hz, 1H), 2.95 - 2.82 (m, 7H), 2.82 - 2.74 (m, 2H), 2.67 - 2.61 (m, 1H), 2.59 - 2.51 (m, 5H), 2.44 (d, J = 8.8 Hz, 1H), 2.33 - 2.28 (m, 1H), 2.22 (ddd, J = 13.1, 8.4, 4.1 Hz, 1H), 2.17 - 2.11 (m, 1H), 2.10 - 2.03 (m, 1H), 1.99 - 1.91 (m, 1H), 1.70 (d, J = 10.0 Hz, 2H), 1.21 (d, J = 9.4 Hz, 2H), 0.96 (d, J = 6.3 Hz, 3H). [M+H]+ =888.7.

[0343] Example 149: 3-(5-(4-(3-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-6-ethylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 6 using intermediates 39 and 36. 1H NMR (500 MHz, DMSO) δ 12.41 (s, 1H), 10.78 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.87 - 3.99 (m, 4H), 3.90 (dd, J = 7.6, 5.7 Hz, 1H), 3.72 (s, 3H), 3.41 (t, J = 6.0 Hz, 3H), 3.18 - 3.13 (m, 4H), 3.01 - 2.82 (m, 8H), 2.80 - 2.53 (m, 11H), 2.46 - 2.39 (m, 4H), 2.15 (dd, J = 12.1, 6.3 Hz, 3H), 1.76 (d, J = 11.5 Hz, 2H), 1.35 (d, J = 9.0 Hz, 2H), 1.17 (t, J = 7.4 Hz, 3H). [M+H] + =867.6.

[0344] Example 150: 3-(5-(2-(3-(4-((7 1 s,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)-cyclobutanacyclononaphane-5 6 -yl)piperazin-1-yl)azetidin-1-yl)ethyl)-4,6-dimethylpyridin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a similar manner to Example 82 using intermediates 39 and 26.

[0345] 1 H NMR (500 MHz, DMSO) δ 12.42 (s, 1H), 10.80 (s, 1H), 8.65 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.34 (d, J = 8.7 Hz, 1H), 7.02 (s, 1H), 6.97 (s, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.80 - 3.82 (m, 6H), 3.72 (s, 3H), 3.51 - 3.45 (m, 2H), 3.16 (s, 4H), 2.98 - 2.83 (m, 6H), 2.65 - 2.52 (m, 10H), 2.46 - 2.39 (m, 7H), 2.29 (s, 3H), 2.21 - 2.19 (m, 1H), 2.09 - 2.04 (m, 1H), 1.84 - 1.61 (m, 1H). [M+H] + =812.6.

[0346] Generation of cell lines H1975-clone no. 28 (Del19 / T790M / C797S, or abbreviation: DTC), H1975-clone no. 23 (Del19 / C797S, or abbreviation: DC), H1975-clone no. 25 (L858R / T790M / C797S, or abbreviation: LTC), and H1975-clone no. 8 (L858R / C797S, or abbreviation: LC). EGFR-Del19 / T790M / C797S, EGFR-Del19 / C797S, EGFR-L858R / T790M / C797S, and EGFR-L858R / C797S were stably expressed in the H1975 cell line by lentivirus-mediated overexpression. EGFR-overexpressing cells were then knocked out using an EGFR-targeting sgRNA designed to target only the endogenous EGFR copy and preserve the exogenous EGFR copy. Following knockout, edited H1975 cells were seeded into 96-well plates at a density of 1 cell / well and cultured for approximately two weeks to allow for the formation of single clones. The resulting clones were screened for the desired editing process by DNA sequencing and full-exon sequence analysis. H1975-clone #28, H1975-clone #23, H1975-clone #25, and H1975-clone #8 were ultimately confirmed as homozygous Del19 / T790M / C797S EGFR, Del19 / C797S EGFR, L858R / T790M / C797S EGFR, and L858R / C797S EGFR clones, respectively.

[0347] cell degradation Cell treatment On day 1, H1975-clone number 28 (Del19 / T790M / C797S, or abbreviation: DTC), H1975-clone number 23 (Del19 / C797S, or abbreviation: DC), H1975-clone number 25 (L858R / T790M / C797S, or abbreviation: LTC), and H1975-clone number 8 (L858R / C797S, or abbreviation: LC) cells were cultured at 20,000 cells / well, 30,000 cells / well, 10,000 cells / well, or 5,000 cells / well, respectively, in a Corning 96-well plate (catalog number 3599) in cell culture medium [RPMI 1640 (Gibco, catalog number 72400-047), 10% heat-inactivated FBS, 1% PS (Gibco, Cat. No. 10378)].

[0348] H1975-#25, H1975-#28, H1975-#23, and H1975-#8 cells were treated with compounds diluted in 0.2% DMSO cell culture medium on day 2 and incubated for 16 hours at 37° C., 5% CO. The final compound concentration in all assays was 10 μM, starting with 5-fold dilutions, for a total of 8 doses.

[0349] HTRF assay To assess EGFR degradation, a total EGFR cell kit (64NG1PEH) was used.

[0350] After 16 hours of treatment, add HTRF lysis buffer to each well, seal the plate, and incubate on a plate shaker for 1 hour at room temperature. Once the cells are lysed, transfer 16 μL of cell lysate to a PE384-well HTRF detection plate and add 4 μL of premixed HTRF antibody to each well. Cover the plate with a plate sealer, spin at 1000 rpm for 1 minute, and incubate overnight at room temperature. Read on a BMG PheraStar using the HTRF protocol (337 nm-665 nm-620 nm).

[0351] The percentage of inhibition (degradation) of the compound was calculated by the following formula: Percentage of inhibition of compound = 100 - 100 x (signal - low control) / (high control - low control), where signal = each test compound group.

[0352] Low control = lysis buffer only with no cells, showing complete degradation of EGFR.

[0353] High control = DMSO added, compound-free cells, representing the microplate reading without EGFR degradation.

[0354] Imax (Dmax) is the maximum percentage of inhibition (degradation).

[0355] Compound IC 50 (DC 50 ) values ​​can be obtained by fitting the following formula

[0356] Y = bottom + (top - bottom) / (1 + ((IC 50 / X)^Hill gradient))

[0357] where X and Y are known values ​​and IC 50 , Hill slope, top, and bottom are parameters obtained by fitting with the software. Y is the inhibition rate (calculated from the formula), X is the compound concentration, and IC 50 is the concentration of the compound at which 50% inhibition is reached. 50 The smaller the value, the stronger the inhibitory ability of the compound. 50 The higher the value, the weaker the inhibitory ability of the compound. The Hill slope represents the slope of the fitted curve, which is generally about 1*. The bottom represents the minimum value of the curve obtained by data fitting, which is generally 0%±20%, and the top represents the maximum value of the curve obtained by data fitting, which is generally 100%±20%. The experimental data were fitted by calculation and analysis using Dotmatics data analysis software.

[0358] [Table 5-1] [Table 5-2]

[0359] cell line H1975-clone #8 (L858R / C797S): EGFR-L858R / C797S was stably expressed in the H1975 cell line via lentivirus-mediated overexpression. EGFR-overexpressing cells were then knocked out using an EGFR-targeting sgRNA designed to target only the endogenous EGFR copy and preserve the exogenous EGFR copy. Following knockout, edited H1975 cells were seeded into 96-well plates at a density of 1 cell / well and cultured for approximately two weeks to allow the formation of single clones. The resulting clones were screened for the desired editing process by DNA sequencing and full-exon sequence analysis. H1975-clone #8 was ultimately confirmed as a homozygous L858R / C797S EGFR clone.

[0360] BaF3-L858R (abbreviation L858R) cells were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.

[0361] cell degradation Cell treatment On day 1, H1975-clone number 8 (L858R / C797S) cells are seeded at 5000 cells / well in cell culture medium [RPMI1640 (Gibco, Catalog No. 72400-047), 10% heat-inactivated FBS, 1% PS (Gibco, Catalog No. 10378)] in Corning 96-well plates (Cat. No. 3599).

[0362] On day 2, BaF3-L858R cells are seeded at 50,000 cells / well in a volume of 54 μL / well in cell culture medium [RPMI1640 (Gibco, phenol red-free, catalog number 11835-030), 10% heat-inactivated FBS, 1% PS (Gibco, catalog number 10378)] in Corning 96-well plates (catalog number 3799).

[0363] H1975-#8 and BaF3-L858R cells are treated with compounds diluted in 0.1% DMSO cell culture medium on day 2 and incubated for 16 hours at 37°C, 5% CO. Final compound concentrations in all assays started at 10 uM, with 5-fold dilutions, for a total of 8 doses.

[0364] HTRF assay To assess EGFR degradation, a total EGFR cell kit (64NG1PEH) was used.

[0365] After 16 hours of treatment, for H1975-number 8 cells, add 100 μL of HTRF 1x lysis buffer to each well. For BaF3-L858R cells, add 20 μL of 4x lysis buffer to each well. Seal the plate and incubate for 1 hour at room temperature on a plate shaker. Once the cells are lysed, transfer 16 μL of cell lysate to a PE384-well HTRF detection plate and add 4 μL of premixed HTRF antibody to each well. Cover the plate with a plate sealer, spin at 1000 rpm for 1 minute, and incubate overnight at room temperature. Read on a BMG PheraStar using the HTRF protocol (337 nm-665 nm-620 nm).

[0366] The percentage of inhibition (degradation) of the compound was calculated by the following formula: Percentage of inhibition of compound = 100 - 100 x (signal - low control) / (high control - low control), where signal = each test compound group. Low control = lysis buffer only with no cells, showing complete degradation of EGFR. High control = DMSO added, compound-free cells, representing the microplate reading without EGFR degradation. Imax (Dmax) is the maximum percentage of inhibition (degradation). Compound IC 50 (DC 50 ) values ​​can be obtained by fitting the following formula Y = bottom + (top - bottom) / (1 + ((IC 50 / X)^Hill gradient)) where X and Y are known values ​​and IC 50 , Hill slope, top, and bottom are parameters obtained by fitting with the software. Y is the inhibition rate (calculated from the formula), X is the compound concentration, and IC 50 is the concentration of the compound at which 50% inhibition is reached. 50 The smaller the value, the stronger the inhibitory ability of the compound. 50 The higher the value, the weaker the inhibitory ability of the compound. The Hill slope represents the slope of the fitted curve, which is generally about 1*. The bottom represents the minimum value of the curve obtained by data fitting, which is generally 0%±20%, and the top represents the maximum value of the curve obtained by data fitting, which is generally 100%±20%. The experimental data were fitted by calculation and analysis using Dotmatics data analysis software.

[0367] [Table 6]

[0368] The foregoing examples and descriptions of certain specific embodiments should be construed as illustrative rather than limiting of the invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features described above can be utilized without departing from the invention as defined in the claims. All such variations are intended to be within the scope of the present invention. All references are incorporated herein by reference in their entirety.

[0369] It will be understood that where any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

Claims

1. A compound of formula (I), 【Chemistry 1】 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, During the ceremony, E １ But N or CR ５ and E ２ But N or CR ６ and R １ａ , R １ｂ , R ２ａ , and R ２ｂ each independently represents absence, 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 of the —C １－８ alkyl, the aforementioned -C ２－８ alkenyl, the aforementioned -C ２－８ alkynyl, the aforementioned —C １－８ Alkoxy, or the aforementioned —C ３－８ Cycloalkyl is optionally selected from hydrogen, halogen, —C １－８ Alkoxy, -C ３－８ substituted with at least one substituent selected from cycloalkyl, or —CN; R ３ and R ４ are each independently hydrogen, —C １－６ Alkyl, or -C ３－８ cycloalkyl, and each of the —C １－６ Alkyl or the aforementioned —C ３－８ Cycloalkyl is optionally selected from hydrogen, halogen, —C １－６ substituted with at least one substituent selected from alkoxy; R ５ and R ６ each independently represents absence, 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 of the —C １－８ alkyl, the aforementioned -C ２－８ alkenyl, the aforementioned -C ２－８ alkynyl, the aforementioned —C １－８ Alkoxy, or the aforementioned —C ３－８ Cycloalkyl is optionally selected from hydrogen, halogen, —C １－８ Alkoxy, -C ３－８ substituted with at least one substituent selected from -cycloalkyl, -CN, or -CN; R ５ and R ６ taken together with the carbon atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally containing at least one substituent halogen, hydroxy, or -C １ -C ８ is substituted with alkyl, R ７ each independently represents absence, 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 of the —C １－８ alkyl, the aforementioned -C ２－８ alkenyl, the aforementioned -C ２－８ alkynyl, the aforementioned —C １－８ Alkoxy, or the aforementioned —C ３－８ Cycloalkyl is optionally selected from hydrogen, halogen, —C １－８ Alkoxy, -C ３－８ substituted with at least one substituent selected from -cycloalkyl, -CN, or -CN; Two R's ７ are taken together with the carbon atom(s) to which they are attached to form a 3-12 membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said ring optionally containing at least one substituent halogen, hydroxy, or -C １ -C ８ is substituted with alkyl, R ８ and R ９ are each independently hydrogen, halogen, or —C １ -C ６ Alkyl, or C ３ -C ８ cycloalkyl, wherein said —C １ -C ６ Alkyl or the C ３ -C ８ Each cycloalkyl is optionally selected from hydrogen, halogen, —C １ -C ６ substituted with at least one substituent selected from alkoxy; R １０ are each independently hydrogen, halogen, or —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 Or -NR １０ａ SO ２ R １０ｂ or —CN, wherein said —C １ -C ８ alkyl, the aforementioned -C ２－８ alkenyl, the aforementioned -C ２－８ Alkynyl, the C ３ -C ８ cycloalkyl, the 3- to 8-membered heterocyclyl, the C ６ -C １２ aryl, or each of said 5- to 12-membered heteroaryl optionally contains at least one R １０ｃ is replaced by R １０ａ and R １０ｂ are each independently hydrogen, —C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; １ -C ８ alkyl, the aforementioned -C ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ Alkynyl, the C ３ -C ８ cycloalkyl, the 3- to 8-membered heterocyclyl, the C ６ -C １２ aryl, or each of said 5- to 12-membered heteroaryls optionally contains at least one substituent R １０ｄ is replaced by R １０ｃ and R １０ｄ are each independently a halogen, hydrogen, or —C １ -C ８ Alkyl, —C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ Aryl, 5- to 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 ８ｆ Or -NR １０ｅ SO ２ R １０ｆ or -CN; R １０ｅ and R １０ｆ are each independently hydrogen, —C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , and R １２ｄ each independently represents absent, oxo, hydrogen, halogen, —C １－８ Alkyl, —C ２－８ Alkenyl, -C ２－８ Alkynyl, —C １－８ Alkoxy, or -C ３－８ cycloalkyl, and the —C １－８ alkyl, the aforementioned -C ２－８ alkenyl, the aforementioned -C ２－８ alkynyl, the aforementioned —C １－８ Alkoxy, or the aforementioned —C ３－８ Each cycloalkyl is optionally selected from hydrogen, halogen, —C １－８ Alkyl, —C ２－８ Alkenyl, -C ２－８ Alkynyl, —C １－８ substituted with at least one substituent selected from alkoxy, or —CN; L １ are independently —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】 and 【Transformation 3】 The aforementioned 【Chemistry 4】 The aforementioned 【Transformation 5】 The aforementioned 【Transformation 6】 The aforementioned 【Transformation 7】 The aforementioned 【Transformation 8】 and the above 【Chemistry 9】 each optionally containing at least one R Ｌ１ｃ is replaced by During the ceremony, * Ｌ１ However, 【Chemistry 10】 refers to the position where the molecule is bonded to the ** moiety. Ｌ１ However, 【Chemistry 11】 refers to the position where the molecule is attached to the moiety, L ２ are independently —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 , 【Chemistry 12】 and 【Chemistry 13】 The aforementioned 【Chemistry 14】 The aforementioned 【Chemistry 15】 The aforementioned 【Chemistry 16】 The aforementioned 【Chemistry 17】 The aforementioned [Chemistry 18] and the above 【Chemistry 19】 each optionally containing at least one R Ｌ２ｃ is replaced by During the ceremony, * Ｌ２ However, 【Chemistry 20】 refers to the position where the molecule is bonded to the ** moiety. Ｌ２ However, 【Chemistry 21】 refers to the position where the molecule is attached to the moiety, L ３ are independently —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 22】 and 【Chemistry 23】 The aforementioned 【Chemistry 24】 The aforementioned 【Chemistry 25】 The aforementioned 【Chemistry 26】 The aforementioned 【Chemistry 27】 The aforementioned 【Chemistry 28】 and the above 【Chemistry 29】 each optionally containing at least one R Ｌ３ｃ is replaced by During the ceremony, * Ｌ３ However, 【Transformation 30】 refers to the position where the molecule is bonded to the ** moiety. Ｌ３ However, 【Chemistry 31】 refers to the position where the molecule is attached to the moiety, The R Ｌ１ｃ , the R Ｌ２ｃ , and the R Ｌ３ｃ each independently being absent, oxo (=O), halogen, hydroxy, -CN, -C １ -C ８ Alkyl, —C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, １ -C ８ alkyl, the aforementioned -C １ -C ８ Alkoxy, the above-C ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ Alkynyl, the C ３ -C ８ cycloalkyl, the 3- to 8-membered heterocyclyl, the C ６ -C １２ aryl, and each of said 5- to 12-membered heteroaryl optionally contains at least one R Ｌｃａ is replaced by R Ｌｃａ are independently absent, oxo (=O), halogen, hydroxy, -CN, -C １ -C ８ Alkyl, —C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; Two R's Ｌ１ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said ring optionally containing at least one substituent halogen, hydroxy, -C １ -C ８ is substituted with alkyl, Two R's Ｌ２ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said ring optionally containing at least one substituent halogen, hydroxy, -C １ -C ８ is substituted with alkyl, Two R's Ｌ３ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said ring optionally containing at least one substituent halogen, hydroxy, -C １ -C ８ is substituted with alkyl, Z １ and Z ２ are each independently N or CR ｚ and R ｚ is, in each occurrence, independently absent, hydrogen, halogen, —C １－８ Alkyl, —NR Ｚａ R Ｚｂ , -OR Ｚａ , -SR Ｚａ , C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, or CN; １－８ alkyl, the C ３ -C ８ cycloalkyl, each of said 3- to 8-membered heterocyclyl optionally contains at least one R Ｚｃ is replaced by R Ｚａ and R Ｚｂ each independently represents absence, hydrogen, or —C １ -C ８ Alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; １－８ alkyl, the C ３ -C ８ cycloalkyl, the 3- to 8-membered heterocyclyl, the C ６ -C １２ aryl, or each of said 5- to 12-membered heteroaryls optionally contains at least one substituent R Ｚｄ is replaced by R Ｚｃ and R Ｚｄ each independently represents halogen, hydroxy, —C １ -C ８ Alkyl, —C １－８ Alkoxy, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R １３ each independently represents absence, hydrogen, halogen, —C １－８ Alkyl, —C ２－８ Alkenyl, -C ２－８ Alkynyl, —C １－８ Alkoxy, -C ３ -C ８ cycloalkyl, 3- to 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, the aforementioned -C ２－８ alkenyl, the aforementioned -C ２－８ alkynyl, the aforementioned —C １－８ Alkoxy, the above-C ３ -C ８ cycloalkyl, the 3- to 8-membered heterocyclyl, the —C ６ -C １２ aryl, or each of said 5- to 12-membered heteroaryls is optionally selected from halogen, —C １－８ 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, 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 is replaced by In each occurrence, R １３ａ , R １３ｂ , R １３ｃ , and R １３ｄ each independently represents absence, hydrogen, or —C １－８ 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; In each occurrence, X １ , X ２ , and X ７ are each independently -CR ａ , or N; In each occurrence, X ３ , X ４ , and X ８ each independently represents -NR ａ -, -O-, -S-, and -CR ａ R ｂ - is selected from, In each occurrence, X ５ and X ６ each independently represents absence, a single bond, —C(O)—, or —NR ａ -, and -O-; In each occurrence, R ａ and R ｂ are each independently hydrogen, hydroxy, halogen, CN, -C １ -C ８ Alkyl, —C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, —C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; １ -C ８ alkyl, the aforementioned -C １ -C ８ Alkoxy, the above-C ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ alkynyl, the aforementioned —C ３ -C ８ cycloalkyl, the 3- to 8-membered heterocyclyl, the —C ６ -C １２ aryl, or each of said 5- to 12-membered heteroaryls, optionally contains at least one substituent halogen, hydroxy, halogen, —C １ -C ８ Alkyl, —C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, —C ６ -C １２ substituted with aryl, or 5- to 12-membered heteroaryl; R ａ and R ｂ are taken together with the carbon atoms to which they are attached to form a 3- to 12-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and said ring optionally containing at least one substituent halogen, hydroxy, -C １ -C ８ Alkyl, —C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, —C １ -C ８ Alkoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ Alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ substituted with aryl, or 5- to 12-membered heteroaryl; 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 are independently 0, 1, 2, 3, or 4 at each occurrence; s1 and s2 are each independently 0, 1, 2, or 3; s3 and s4 are each independently 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 １ If N, then X ５ is a single bond, absent, or —C(O)—, and / or X ２ If N, then X ６ is a single bond, absent, —C(O)—, L １ but 【Chemistry 32】 If X １ If N, then X ５ is a single bond, absent, or —C(O)—, and / or X ３ But, -CR ａ R ｂ - and X ２ If N, then X ６ is a single bond, absent, or —C(O)—, and / or X ４ But, -CR ａ R ｂ - and L ２ but 【Transformation 33】 If X １ If N, then X ５ is a single bond, absent, or —C(O)—, and / or X ３ But, -CR ａ R ｂ - and X ２ If N, then X ６ is a single bond, absent, or —C(O)—, and / or X ４ But, -CR ａ R ｂ - and L ３ but 【Transformation 34】 If X １ If N, then X ５ is a single bond, absent, or —C(O)—, and / or X ３ But, -CR ａ R ｂ - and X ２ If N, then X ６ is a single bond, absent, or —C(O)—, and / or X ４ But, -CR ａ R ｂ or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, provided that:

2. The compound is selected from formula (IIa) or (IIb): 【Chemistry 35】 【Transformation 36】 In the formula, 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 , R １３ , L １ , L ２ , L ３ , Z １ , s1, s2, s3, s4, s5, s6, s7, m1, m2, m3, m4, m5, m6, and m7 are as defined in any one of the preceding claims; More preferably, the compound is selected from formula (IIIa) or (IIIb): 【Chemistry 37】 【Transformation 38】 In the formula, 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 , R １３ , L １ , L ２ , L ３ , s1, s2, s3, s4, s5, s6, s7, m1, m2, m3, m4, m5, m6, and m7 are as defined in any one of the preceding claims; Even more preferably, the compound is selected from formula (IVa) or (IVb): 【Chemistry 39】 【Chemistry 40】 In the formula, 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 １３ , L １ , L ２ , L ３ , s1, s2, s3, s4, s5, s6, s7, m1, m2, m3, m4, m5, m6, and m7 are as defined in any one of the preceding claims; Even more preferably, the compound is selected from formula (Va) or (Vb): 【Chemistry 41】 【Chemistry 42】 In the formula, R １０ , R １３ , L １ , L ２ , L ３ , s7, m1, m2, m3, m4, m5, m6, and m7 are as defined in any one of the preceding claims.

3. The compound is selected from formula (VIa): 【Chemistry 43】 Preferably, the compound is selected from formula (VIb), (VIc) or (VIc'): 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 More preferably, the compound is selected from formula (VId) or (VIe): 【Chemistry 47】 【Chemistry 48】 More preferably, said compound is selected from formula (VIf) or (VIg): 【Chemistry 49】 [Transformation 50] Even more preferably, said compound is selected from formula (VIh) or (VIi): 【Chemistry 51】 【Chemistry 52】 Even more preferably, the compound is selected from formula (VIj), (VIk), (VIl), or (VIm), 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 Even more preferably, the compound is selected from formula (VIn), (VIo), (VIp), or (VIq), 【Chemistry 57】 【Chemical Formula 58】 【Chemistry 59】 【Transformation 60】 In the formula, 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 , R １３ , L １ , L ２ , L ３ , s1, s2, s3, s4, s5, s6, s7, m1, m2, m3, m4, m5, m6, m7, n6, Z １ , Z ２ , X ７ , and X ８ 10. A compound according to any one of the preceding claims, wherein:

4. 10. A compound according to any one of the preceding claims, wherein m1 + m2 + m3 + m4 ≦ 3.

5. 10. A compound according to any one of the preceding claims, wherein m1+m2+m3+m4=0, 1, 2 or 3, preferably m1+m2+m3+m4=0, 1 or 2. 【Request Item 6】 【Chemistry 61】 -CH in the moiety ２ 10. A compound according to any one of the preceding claims, wherein the number of - is 4 or less, preferably 3 or less, even more preferably 2 or less.

7. R ３ and R ４ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, or said cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy; Preferably, R ３ and R ４ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and preferably R ３ are independently methyl, and R ４ 10. A compound according to any one of the preceding claims, wherein is hydrogen.

8. R １ａ , R １ｂ , R ２ａ , and R ２ｂ are each independently 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, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or —CN, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —C ２－８ alkenyl, the aforementioned -C ２－８ 10. The compound of any one of the preceding claims, wherein alkynyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, and the 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.

9. R １ａ , R １ｂ , R ２ａ , and R ２ｂ are 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 , -CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ and Preferably, R １ａ , R １ｂ , R ２ａ , and R ２ｂ are each independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF ３ , or -CHF ２ , -CH ２ OCH ３ 10. A compound according to any one of the preceding claims, wherein

10. R ５ and R ６ are 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 , -CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ and Preferably, R ５ and R ６ are each independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF ３ , or -CHF ２ , -CH ２ OCH ３ 10. A compound according to any one of the preceding claims, wherein

11. R ５ and R ６ together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; Preferably, R ５ and R ６ are taken together with the carbon atoms to which they are attached to form a 3-, 4-, 5-, or 6-membered ring, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl.

12. R ７ are 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 , -CH ２ OCH ２ CH ３ , -CH ２ CH ２ OCH ３ , -CH ２ CH ２ OCH ２ CH ３ and Preferably, R ７ are each independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF ３ , or -CHF ２ , -CH ２ OCH ３ 10. A compound according to any one of the preceding claims, wherein

13. Two R's ７ together with the carbon atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; Preferably, two R ７ together with the carbon atom(s) to which they are attached form a 3-, 4-, 5-, or 6-membered ring, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl.

14. R ８ and R ９ are each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, wherein said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, or said cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy; Preferably, R ８ and R ９ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, preferably R ８ are independently hydrogen, and R ９ 10. A compound according to any one of the preceding claims, wherein is F or methyl.

15. R １０ are 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 , -CO ２ R １０ａ , —C(O)NR １０ａ R １０ｂ , -NR １０ａ COR １０ｂ , -NR １０ａ CO ２ R １０ｂ Or -NR １０ａ SO ２ R １０ｂ or —CN, wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the —C ２－８ alkenyl, the aforementioned -C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, or the phenyl optionally comprises at least one R １０ｃ is replaced by R １０ａ and R １０ｂ each independently represents hydrogen, 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, or phenyl; and ２－８ alkenyl, the aforementioned -C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, or the phenyl optionally contains at least one substituent R １０ｄ is replaced by R １０ｃ and R １０ｄ are 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 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 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 Or -NR １０ｅ SO ２ R １０ｆ or -CN; R １０ｅ and R １０ｆ each independently represents 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- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, R １０ each independently represents hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 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 Or -NR １０ａ SO ２ R １０ｂ or —CN, wherein the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the —C ２－８ alkenyl, the aforementioned -C ２－８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, or the phenyl optionally comprises at least one R １０ｃ is replaced by R １０ａ and R １０ｂ each independently represents 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- to 8-membered heterocyclyl, or phenyl; R １０ｃ are 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, oxo (=O), -NR １０ｅ R １０ｆ , -OR １０ｅ or -CN; R １０ｅ and R １０ｆ are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; More preferably, R １０ each independently represents hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclyl, —NR １０ａ R １０ｂ , -OR １０ａ , -CO ２ R １０ａ or —C(O)NR １０ａ R １０ｂ wherein each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, or said 3- to 8-membered heterocyclyl optionally comprises at least one R １０ｃ is replaced by R １０ａ and R １０ｂ are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, or 6-membered heterocyclyl; R １０ｃ each independently represents hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxo (═O), —NR １０ｅ R １０ｆ , -OR １０ｅ or -CN; R １０ｅ and R １０ｆ are each independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and cyclopentyl; Even more preferably, R １０ are each independently H, F, Cl, Br, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 【Transformation 62】 -COOH, -CONH ２ , -CH ２ OCH ３ , or -CH ２ 10. A compound according to any one of the preceding claims, selected from: OH.

16. The aforementioned 【Transformation 63】 The part is, 【Chemistry 64】 10. A compound according to any one of the preceding claims, selected from:

17. The aforementioned 【Transformation 65】 The part is, 【Chemical Formula 66】 10. A compound according to any one of the preceding claims, selected from:

18. R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , and R １２ｄ are each independently oxo, 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, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and ２－８ alkenyl, the aforementioned -C ２－８ Each of alkynyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, or the cyclooctyl is optionally selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ substituted with at least one substituent selected from alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, or —CN; Preferably, R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , and R １２ｄ are each 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, and preferably R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , and R １２ｄ are each independently oxo, hydrogen, F, Cl, Br, I, methyl, ethyl, or propyl, more preferably R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , and R １２ｄ 5. A compound according to any one of the preceding claims, wherein each is independently hydrogen or methyl.

19. 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 67-1】 【Chemistry 67-2】 is selected from The aforementioned 【Transformation 68】 The aforementioned 【Transformation 69】 The aforementioned 【Transformation 70】 The aforementioned 【Chemistry 71】 The aforementioned 【Chemistry 72】 The aforementioned 【Transformation 73】 The aforementioned 【Chemistry 74】 The aforementioned 【Chemistry 75】 The aforementioned 【Transformation 76】 The aforementioned 【Chemical 77】 The aforementioned 【Transformation 78】 The aforementioned 【Chemistry 79】 The aforementioned 【Chemistry 80】 The aforementioned 【Chemistry 81】 The aforementioned 【Chemistry 82】 The aforementioned 【Chemistry 83】 The aforementioned 【Chemical 84】 The aforementioned 【Chemical 85】 The aforementioned 【Chemical 86】 The aforementioned 【Chemistry 87】 The aforementioned 【Chemical 88】 The aforementioned 【Chemical 89】 The aforementioned 【Chemistry 90】 The aforementioned 【Chemistry 91】 The aforementioned 【Chemistry 92】 The aforementioned 【Chemistry 93】 The aforementioned 【Chemical 94】 The aforementioned 【Chemical 95】 The aforementioned 【Chemistry 96】 The aforementioned 【Chemistry 97】 The aforementioned 【Chem.98】 The aforementioned 【Chem.99】 The aforementioned 【Chemistry 100】 The aforementioned 【Chemistry 101】 The aforementioned 【Chemical Engineering 102】 The aforementioned 【Chemistry 103】 The aforementioned 【Chemical 104】 The aforementioned 【Chemistry 105】 The aforementioned 【Chemistry 106】 The aforementioned 【Chemistry 107】 The aforementioned 【Chemistry 108】 The aforementioned 【Chemistry 109】 The aforementioned 【Chemical 110】 The aforementioned 【Chemistry 111】 The aforementioned 【Chemistry 112】 The aforementioned 【Chemistry 113】 The aforementioned 【Chemistry 114】 The aforementioned 【Chemical 115】 The aforementioned 【Chemistry 116】 The aforementioned 【Chemistry 117】 The aforementioned 【Chemistry 118】 The aforementioned 【Chemical 119】 The aforementioned 【Chemical 120】 The aforementioned 【Chemistry 121】 The aforementioned 【Chemistry 122】 The aforementioned 【Chemical 123】 The aforementioned 【Chemistry 124】 and the above 【Chemistry 125】 each optionally containing at least one R Ｌ１ｃ is replaced by The R Ｌ１ｃ each 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 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the -C ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, and the 5- to 12-membered heteroaryl may each optionally be selected from the group consisting of at least one R Ｌｃａ is replaced by R Ｌｃａ are independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Two R's Ｌ１ｃ together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring being optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; R ａ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, and the cyclooctyl may optionally contain at least one substituent selected from the group consisting of halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ 10. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

20. L １ が、-O-、-N(CH ３ )-、-C(O)-、-NH-、 ＊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 126-1】 【Chemistry 126-2】 【Chemistry 126-3】 【Chemistry 126-4】 【Chemistry 126-5】 【Chemistry 126-6】 【Chemistry 126-7】 10. A compound according to any one of the preceding claims, selected from:

21. 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 127-1】 【Chemistry 127-2】 is selected from The aforementioned 【Chemistry 128】 The aforementioned 【Chemistry 129】 The aforementioned 【Chemistry 130】 The aforementioned 【Chemistry 131】 The aforementioned 【Chemistry 132】 The aforementioned 【Chemistry 133】 The aforementioned 【Chemistry 134】 The aforementioned 【Chemistry 135】 The aforementioned 【Transformation 136】 The aforementioned 【Chemistry 137】 The aforementioned 【Chemistry 138】 The aforementioned 【Chemistry 139】 The aforementioned [Chemistry 140] The aforementioned 【Chemistry 141】 The aforementioned 【Chemistry 142】 The aforementioned 【Chemistry 143】 The aforementioned 【Chemistry 144】 The aforementioned 【Chemistry 145】 The aforementioned 【Chemistry 146】 The aforementioned 【Chemistry 147】 The aforementioned 【Chemistry 148】 The aforementioned 【Chemistry 149】 The aforementioned [Chemical 150] The aforementioned 【Chemistry 151】 The aforementioned 【Chemistry 152】 The aforementioned 【Chemistry 153】 The aforementioned 【Chemistry 154】 The aforementioned 【Chemistry 155】 The aforementioned 【Chemistry 156】 The aforementioned 【Chemistry 157】 The aforementioned 【Chemistry 158】 The aforementioned 【Chemistry 159】 The aforementioned [Chemical 160] The aforementioned 【Chemistry 161】 The aforementioned 【Chemistry 162】 The aforementioned 【Chemistry 163】 The aforementioned 【Chemistry 164】 The aforementioned 【Chemistry 165】 The aforementioned 【Chemistry 166】 The aforementioned 【Chemistry 167】 The aforementioned 【Chemical 168】 The aforementioned 【Chemistry 169】 The aforementioned 【Chemistry 170】 The aforementioned 【Chemistry 171】 The aforementioned 【Chemistry 172】 The aforementioned 【Chemistry 173】 The aforementioned 【Chemistry 174】 The aforementioned 【Chemistry 175】 The aforementioned 【Chemistry 176】 The aforementioned 【Chemistry 177】 The aforementioned 【Chemistry 178】 The aforementioned 【Chemistry 179】 The aforementioned 【Chemistry 180】 The aforementioned 【Chemistry 181】 The aforementioned 【Chemistry 182】 The aforementioned 【Chemistry 183】 and the above 【Chemistry 184】 each optionally containing at least one R Ｌ２ｃ is replaced by The R Ｌ２ｃ each 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 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the -C ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, and the 5- to 12-membered heteroaryl may each optionally be selected from the group consisting of at least one R Ｌｃａ is replaced by R Ｌｃａ are independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Two R's Ｌ２ｃ together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; R ａ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, and the cyclooctyl may optionally contain at least one substituent selected from the group consisting of halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ 10. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

22. L ２ が、-O-、-N(CH ３ )-、-C(O)-、-NH-、 ＊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 185-1】 【Chemistry 185-2】 【Chemistry 185-3】 【Chemistry 185-4】 【Chemistry 185-5】 【Chemistry 185-6】 【Chemistry 185-7】 10. A compound according to any one of the preceding claims, selected from:

23. 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 186-1】 【Chemistry 186-2】 is selected from The aforementioned 【Chemistry 187】 The aforementioned 【Chemical 188】 The aforementioned 【Chemical 189】 The aforementioned 【Chemistry 190】 The aforementioned 【Chemistry 191】 The aforementioned 【Chemistry 192】 The aforementioned 【Chemistry 193】 The aforementioned 【Chemistry 194】 The aforementioned 【Chemistry 195】 The aforementioned 【Chemistry 196】 The aforementioned 【Chemistry 197】 The aforementioned 【Chemistry 198】 The aforementioned 【Chemistry 199】 The aforementioned 【Chemistry 200】 The aforementioned 【Chemical Engineering 201】 The aforementioned 【Chemical Engineering 202】 The aforementioned 【Chemical 203】 The aforementioned 【Chemical 204】 The aforementioned 【Chemical 205】 The aforementioned 【Chemical 206】 The aforementioned 【Chemical 207】 The aforementioned 【Chemical 208】 The aforementioned 【Chemical Engineering 209】 The aforementioned 【Chemical 210】 The aforementioned 【Chemistry 211】 The aforementioned 【Chemical Engineering 212】 The aforementioned 【Chemistry 213】 The aforementioned 【Chemical 214】 The aforementioned 【Chemical 215】 The aforementioned 【Chemical 216】 The aforementioned 【Chemical 217】 The aforementioned 【Chemistry 218】 The aforementioned 【Chemical 219】 The aforementioned 【Chemical 220】 The aforementioned 【Chemistry 221】 The aforementioned 【Chemistry 222】 The aforementioned 【Chemical 223】 The aforementioned 【Chemistry 224】 The aforementioned 【Chemical 225】 The aforementioned 【Chemistry 226】 The aforementioned 【Chemistry 227】 The aforementioned 【Chemistry 228】 The aforementioned 【Chemistry 229】 The aforementioned 【Chemistry 230】 The aforementioned 【Chemistry 231】 The aforementioned 【Chemistry 232】 The aforementioned 【Chemical 233】 The aforementioned 【Chemistry 234】 The aforementioned 【Chemical 235】 The aforementioned 【Chemistry 236】 The aforementioned 【Chemistry 237】 The aforementioned 【Chemical 238】 The aforementioned 【Chemistry 239】 The aforementioned 【Chemistry 240】 The aforementioned 【Chemistry 241】 The aforementioned 【Chemistry 242】 The aforementioned 【Chemistry 243】 The aforementioned 【Chemistry 244】 and the above 【Chemistry 245】 each optionally containing at least one R Ｌ３ｃ is replaced by The R Ｌ３ｃ each 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 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptyloxy, the octyloxy, the -C ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, and the 5- to 12-membered heteroaryl may each optionally be selected from the group consisting of at least one R Ｌｃａ is replaced by R Ｌｃａ are independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Two R's Ｌ３ｃ together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, said ring optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; R ａ is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, and the cyclooctyl may optionally contain at least one substituent selected from the group consisting of halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, -C ２ -C ８ Alkenyl, -C ２ -C ８ 10. A compound according to any one of the preceding claims substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

24. L ３ が、-O-、-N(CH ３ )-、-C(O)-、-NH-、 ＊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 246-1】 【Chemistry 246-2】 【Chemistry 246-3】 【Chemistry 246-4】 【Chemistry 246-5】 【Chemistry 246-6】 【Chemistry 246-7】 10. A compound according to any one of the preceding claims, selected from:

25. 【Chemistry 247】 The part is, 【Chemistry 248-1】 【Chemistry 248-2】 10. A compound according to any one of the preceding claims, selected from:

26. The aforementioned 【Chemistry 249】 The part is, [Chemical 250] 10. A compound according to any one of the preceding claims, selected from:

27. X ７ But independently, -CR ａ or N, R ａ are 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 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, or the 5- to 12-membered heteroaryl optionally 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, -C ２ -C ８ Alkenyl, -C ２ -C ８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, X ７ are independently —CH, —C(CH ３ ), or N, preferably X ７ 4. A compound according to any one of the preceding claims, wherein is independently selected from -CH.

28. X ８ are independently -NR ａ -, -O-, -S-, and -CR ａ R ｂ - is selected from, In each occurrence, R ａ and R ｂ are 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 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and ２ -C ８ alkenyl, the aforementioned -C ２ -C ８ Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the 3- to 8-membered heterocyclyl, the phenyl, or the 5- to 12-membered heteroaryl optionally 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, -C ２ -C ８ Alkenyl, -C ２ -C ８ substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, X ８ are independently —NH— and —CH ２ -, preferably X ８ are independently -CH ２ 10. A compound according to any one of the preceding claims, selected from: 【Request Item 29】 【Chemistry 251】 but, 【Chemistry 252】 is selected from, preferably 【Chemistry 253】 but, 【Chemistry 254】 10. A compound according to any one of the preceding claims, selected from:

30. Z １ and Z ２ At most one of Z is N, and preferably １ and Z ２ However, each independently, CR ｚ 10. A compound according to any one of the preceding claims, wherein

31. R Ｚ is, in each occurrence, independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —NR Ｚａ R Ｚｂ , -OR Ｚａ , -SR Ｚａ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, or CN, wherein each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, or said 3- to 8-membered heterocyclyl optionally comprises at least one R Ｚｃ is replaced by R Ｚａ and R Ｚｂ are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of said hydrogen, said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said 3- to 8-membered heterocyclyl, said phenyl, or said 5- to 12-membered heteroaryl optionally contains at least one substituent R Ｚｄ is replaced by R Ｚｃ and R Ｚｄ are each 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- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, R ｚ is H, -CH ３ , -C ２ H ５ , F, -CH ２ F, -CHF ２ , -CF ３ , -OCH ３ , -OC ２ H ５ , -C ３ H ７ , -OCH ２ F, -OCHF ２ , -OCH ２ CF ３ , -OCF ３ , -SCF ３ , -CF ３ , or -CH(OH)CH ３ 10. A compound according to any one of the preceding claims, selected from:

32. R １３ are 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 alkynyl, 3- to 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 is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ alkenyl, the aforementioned -C ２－８ alkynyl, the 3- to 8-membered heterocyclyl, the —C ６ -C １２ aryl, each of said 5- to 12-membered heteroaryl is optionally selected from 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 alkynyl, 3- to 8-membered heterocyclyl, —C ６ -C １２ Aryl, 5- to 12-membered 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 is replaced by R １３ａ , R １３ｂ , R １３ｃ , and R １３ｄ each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ Alkenyl, -C ２－８ alkynyl, 3- to 8-membered heterocyclyl, —C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; Preferably, R １３ are 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 2. A compound according to any one of the preceding claims, wherein the compound is selected from:

33. 【Chemistry 255】 but, 【Chemistry 256】 10. A compound according to any one of the preceding claims, wherein 【Request Item 34】 【Chemistry 257】 but, 【Chemistry 258】 10. A compound according to any one of the preceding claims, wherein

35. below: 【Chemistry 259-1】 【Chemistry 259-2】 【Chemistry 259-3】 【Chemistry 259-4】 【Chemistry 259-5】 【Chemistry 259-6】 【Chemistry 259-7】 【Chemistry 259-8】 【Chemistry 259-9】 【Chemistry 259-10】 【Chemistry 259-11】 【Chemistry 259-12】 【Chemistry 259-13】 【Chemistry 259-14】 【Chemistry 259-15】 【Chemistry 259-16】 10. A compound according to any one of the preceding claims, selected from:

36. 33. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, together with a pharmaceutically acceptable excipient.

37. 34. A method of treating a disease that can be affected by EGFR modulation, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

38. 35. The method of claim 34, wherein the disease is selected from cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

39. 33. Use of a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in the preparation of a medicament for treating a disease that can be affected by EGFR modulation.

40. 37. The use according to claim 36, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

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