Compounds for degrading EGFR kinase

Abstract

Disclosed herein are novel bifunctional compounds having formula (I) formed by conjugating an EGFR inhibitor moiety to an E3 ligase ligand moiety, and methods of making and uses thereof, the function of these bifunctional compounds being recruited to the E3 ubiquitin ligase for degradation. # imgabs0 #

Description

Technical Field

[0001] The present disclosure provides novel bifunctional compounds formed by conjugating an EGFR inhibitor moiety with an E3 ligase ligand moiety, methods for preparing the same, and uses thereof. These bifunctional compounds function to recruit target proteins to E3 ubiquitin ligases for degradation. Background Art

[0002] Proteolysis-targeting chimeras (PROTACs) consist of two covalently linked protein-binding molecules: one that is capable of engaging an E3 ubiquitin ligase and another that binds to the protein of interest (POI) as the target for degradation (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98:8554-9.; Sakamoto K.M. et al., Methods Enzymol. 2005; 399:833-847.). The E3 ligase does not inhibit the enzymatic activity of the target protein but recruits the target protein to a specific unwanted protein, which leads to ubiquitination and subsequent degradation of the target protein by the proteasome. The entire process of ubiquitination and proteasomal degradation is referred to 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.L. et al., Cell Rep. 2015, 12, 545-553; Swatek K.N. et al., Cell Res. 2016, 26, 399-422). The proteasome is a protein complex that degrades unwanted, misfolded, or abnormal proteins into small peptides to maintain cell health and proliferative capacity. The ubiquitin ligase, also known as the E3 ubiquitin ligase, directly catalyzes the transfer of ubiquitin from E2 to the target protein for degradation. Although the human genome encodes more than 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), murine double minute 2 homolog (MDM2), and cellular inhibitor of apoptosis (cIAP) (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578), recombinant human ring finger protein 114 (RNF114) (Spradlin, J.N. et 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 some 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, act by binding to CRL4A. CRBNThe cerebellin (CRBN) subunit of the E3 ligase complex binds and recruits new substrate proteins, acting as a monovalent facilitator of PPI. (Matyskiela, M. E. et al., Nat Chem Biol 2018, 14, 981 - 987.) Therefore, the ability of thalidomide and its derivatives to recruit CRBN has been widely applied in proteolysis-targeting chimera (PROTAC)-related research (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 in eliminating protein targets that are "inaccessible" to traditional inhibitors or protein targets that are non-enzymatic proteins (Chu TT. et al., Cell Chem Biol. 2016; 23:453 - 461; Qin C. et al., J Med Chem 2018; 61:6685 - 6704; Winter GE. et al., Science 2015; 348:1376 - 1381).In recent years, PROTACs have been reported in anti-tumor research as useful modulators for promoting the selective degradation of various 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 C.M. et al., J Med Chem. 2018; 61(2): 403-404; Neklesa T.K. et al., Pharmacol Ther. 2017, 174: 138-144.; Cermakova K. et al., Molecules 2018. 23(8).; An S. et al., EBioMedicine 2018.; Lebraud H. et al., Essays Biochem. 2017; 61(5): 517-527.; Sun Y.H. et 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, Vol. 33, pp. 2105-2110 (2019); Shaodong Liu et al., Medicinal Chemistry Research, Vol. 29, pp. 802-808 (2020)); and have been disclosed or discussed in patent publications such as US20160045607, US20170008904, US20180050021, US 20180072711, WO2002020740, WO 2014108452, WO 2016146985, WO 2016149668, WO 2016197032, WO2016197114, WO 2017011590, WO 2017030814, WO 2017079267, WO 2017182418, WO2017197036, WO 2017197046, WO 2017197051, WO 2017197056, WO 2017201449, WO2018071606, WO 2021178920, WO 2021127283, WO 2021127190, WO 202111871 and WO202111913.

[0003] The epidermal growth factor receptor (EGFR), which belongs to the ErbB family, is a transmembrane receptor tyrosine kinase (RTK) that plays a fundamental and crucial role in cell proliferation, differentiation, and motility (Y. Yarden, et al., Nat. Rev. Mol. Cell Biol. [Nature Reviews: Molecular Cell Biology] 2001; 2: 127 - 137.). Homodimerization or heterodimerization of EGFR and other ErbB family members activates the cytoplasmic tyrosine kinase domain, thereby initiating intracellular signal transduction. Overexpression or activating mutations of EGFR are associated with the development of many types of cancers, such as pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, and non - small cell lung cancer (Yewale C., et al., Biomaterials. [Biomaterials] 2013, 34(34): 8690 - 8707.). Activating mutations (L858R mutation and exon 19 deletion) in the tyrosine kinase domain of EGFR have been identified as oncogenic drivers of NSCLC (Konduri, K., et al., Cancer Discovery [Cancer Discovery] 2016, 6(6), 601 - 611.). The first - generation EGFR tyrosine kinase inhibitors (EGFR - TKIs), gefitinib and erlotinib, have been approved for NSCLC patients with EGFR - activating mutations (M. Maemondo, N. Engl. J. Med. [New England Journal of Medicine] 362(2010) 2380 - 2388.). Although most patients with EGFR - mutant NSCLC respond to these therapies, patients usually develop drug resistance after an average of one year of treatment. There are several mechanisms of acquired resistance to gefitinib and erlotinib, including the secondary mutation of threonine 790 to methionine 790 (T790M), also known as the “gatekeeper” T790M mutation (Xu Y., et al., Cancer Biol Ther. [Cancer Biology & Therapeutics] 2010, 9(8): 572 - 582.). Therefore, the second - generation EGFR - TKI afatinib and the third - generation EGFR - TKI osimertinib (AZD9291) have been developed as irreversible EGFR inhibitors that bind to Cys797 for the treatment of patients with the T790M mutation. In particular, osimertinib largely spares WT EGFR and has achieved greater clinical responses in NSCLC patients with EGFR T790M. However, some recent studies have reported the emergence of a third Cys797 to Ser797 (C797S) point mutation during osimertinib clinical treatment (Thress KS, et al., Nat. Med. [Nature Medicine] 2015, 21(6): 560 - 562.). Drugs that can overcome the EGFR (C797S) drug - resistance barrier in non - small cell lung cancer (NSCLC) are needed.Targeted EGFR PROTACs as a potential strategy to overcome these mutant-mediated drug resistances have been disclosed or discussed in patent publications such as WO 2018119441, WO 2019149922, WO2019183523, WO 2019121562, US20190106417, WO 202157882, WO 2021123087, WO2021133809, WO 2021168074, WO 2021208918 and WO 2021216440.

[0004] Nonetheless, many targeted EGFR PROTACs designed to degrade EGFR mutant proteins have been published (Zhang X., et al. Eur. J. Med. Chem. [European Journal of Medicinal Chemistry] 2020, 192, 112199.; Zhang H, et al. Eur. J. Med. Chem. [European Journal of Medicinal Chemistry] 2020, 189, 112061.; Lu X, Med. Res. Rev. [Medical Research Reviews] 2018, 38(5):1550 - 1581.; He K., et al. Bioorg. Med. Chem. Lett. [Bioorganic & Medicinal Chemistry Letters] 2020, 15, 127167.). Most of the published molecules are based on first-generation, second-generation, and third-generation EGFR inhibitors (WO 2021023233, WO 2019121562 and WO 2018119441) or allosteric EGFR inhibitors (WO2021127561). However, there is no data showing that these targeted EGFR PROTACs can degrade all major EGFR mutations such as Del19, L858R, Del19 / T790M, L858R / T790M, Del19 / T790M / C797S, L858R / T790M / C797S.

[0005] This application provides novel bifunctional compounds and compositions for treating major diseases. Summary of the Invention

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

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

[0008] Aspect 1. A compound having the formula (I):

[0009]

[0010] or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, or its prodrug,

[0011] wherein:

[0012] E 1 is N or CR 5 ;

[0013] E 2 is N or CR 6 ;

[0014] R 1a 、R 1b 、R 2a and R 2b are each independently absent, hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -C 3-8 cycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN;

[0015] R 3 and R 4 are each independently hydrogen, -C 1-6 alkyl or -C 3-8 cycloalkyl; each of said -C 1-6 alkyl or -C 3-8The cycloalkyl group is optionally substituted by at least one substituent selected from hydrogen, halogen, -C 1-6 alkoxy;

[0016] R 5 and R 6 are each independently absent, hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -C 3-8 cycloalkyl is optionally substituted by at least one substituent selected from hydrogen, halogen, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; or

[0017] R 5 and R 6 together with the carbon atom 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 is optionally substituted by at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0018] R 7 are each independently absent, hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -C 3-8 cycloalkyl is optionally substituted by at least one substituent selected from hydrogen, halogen, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; or

[0019] Two R 7 together with the carbon atom 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 is optionally substituted by at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0020] R 8 and R 9Each of -C1-C6 alkyl or C3-C8 cycloalkyl is independently selected from hydrogen, halogen, -C1-C6 alkyl or C3-C8 cycloalkyl; each of -C1-C6 alkyl or C3-C8 cycloalkyl is optionally substituted by at least one selected from hydrogen, halogen, -C 1-6 Substitution of alkoxy groups;

[0021] R 10 are independently selected from hydrogen, halogen, -C1-C8 alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, -NR 10a R 10b 、-OR 10a 、-SR 10a 、-C(O)R 10a 、-CO2R 10a 、-C(O)NR 10a R 10b 、-NR 10a COR 10b 、-NR 10a CO2R 10b or -NR 10a S02R 10b or -CN; -C1-C8 alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted by at least one R 10c replace;

[0022] R 10a and R 10b Each is independently selected from 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, the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl group or the 5- to 12-membered heteroaryl group is optionally substituted with at least one substituent R 10d replace;

[0023] R 10c and R 10d Each is independently selected from halogen, hydrogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12Aryl, 5- to 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 8f or -NR 10e S02R 10f or -CN;

[0024] R 10e and R 10f Each is independently selected from 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;

[0025] R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d are each independently 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; the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituent substitution;

[0026] L 1 Independently selected from -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 、

[0027] wherein each of the

[0028]

[0029] is optionally substituted with at least one R L1c ;

[0030] where * L1 refers to the position attached to the portion, and ** L1 refers to the position attached to the portion;

[0031] L 2 is independently selected from -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 、

[0032] wherein each of the

[0033]

[0034] is optionally substituted with at least one R L2c ;

[0035] where * L2 refers to the position attached to the position of the moiety, and ** L2 refers to attached to the position of the moiety;

[0036] L 3 is independently selected from -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 ,

[0037] wherein each of the

[0038]

[0039] is optionally substituted by at least one R L3c ;

[0040] wherein * L3 refers to attached to the position of the moiety, and ** L3 refers to attached to the position of the moiety;

[0041] said R L1c , R L2c and R L3c each is 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 heterocyclic group, C6-C 12 aryl or 5- to 12-membered heteroaryl; each of said -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl and 5- to 12-membered heteroaryl is optionally substituted by at least one R Lca ;

[0042] R LcaIndependently, it is 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 heterocyclic group, C6-C 12 aryl or 5- to 12-membered heteroaryl; or

[0043] Two Rs L1c together with the atoms to which they are attached form a 3- to 12-membered ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted by at least one substituent halogen, hydroxy, -C1-C8 alkyl;

[0044] Two Rs L2c together with the atoms to which they are attached form a 3- to 12-membered ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted by at least one substituent halogen, hydroxy, -C1-C8 alkyl;

[0045] Two Rs L3c together with the atoms to which they are attached form a 3- to 12-membered ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted by at least one substituent halogen, hydroxy, -C1-C8 alkyl;

[0046] Z 1 and Z 2 each independently is N or CR z ;

[0047] R z , each time it appears, independently selected from absent, hydrogen, halogen, -C 1-8 alkyl, -NR Za R Zb , -OR Za , -SR Za , C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group or CN; -C 1-8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group each is optionally substituted by at least one R Zc ;

[0048] R Za and R Zb each independently selected from absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl, the -C 1-8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl each is optionally substituted by at least one substituent R ZdSubstituted;

[0049] R Zc and R Zd each independently is halogen, hydroxy, -C1-C8 alkyl, -C 1-8 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0050] R 13 each independently is selected from absent, hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl, 5- to 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 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl is each optionally substituted by halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d, -NR 13c COR 13d , -NR 13c CO2R 13d or -NR 13c SO2R 13d is substituted;

[0051] At 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 - to 8 - membered heterocyclic group, C6 - C 12 aryl, or 5 - to 12 - membered heteroaryl;

[0052] At each occurrence, X 1 , X 2 and X 7 are each independently selected from -CR a or N;

[0053] At each occurrence, X 3 , X 4 and X 8 are each independently selected from -NR a -, -O -, -S - and -CR a R b -;

[0054] At each occurrence, X 5 and X 6 are each independently selected from absent, single bond, -C(O)-, -NR a - and -O -;

[0055] At each occurrence, R a and R b are each independently selected from hydrogen, hydroxy, halogen, CN, -C1 - C8 alkyl, -C1 - C8 alkoxy, -C2 - C8 alkenyl, -C2 - C8 alkynyl, -C3 - C8 cycloalkyl, 3 - to 8 - membered heterocyclic group, -C6 - C 12 aryl or 5 - to 12 - membered heteroaryl, wherein the -C1 - C8 alkyl, -C1 - C8 alkoxy, -C2 - C8 alkenyl, -C2 - C8 alkynyl, -C3 - C8 cycloalkyl, 3 - to 8 - membered heterocyclic group, -C6 - C 12Each of the aryl or 5- to 12-membered heteroaryl is optionally substituted by at least one substituent selected from halogen, hydroxy, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 substituted by aryl or 5- to 12-membered heteroaryl; or

[0056] R a and R b together with the carbon atom to which they are attached form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted by at least one substituent selected from 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 heterocyclic group, C6-C 12 substituted by aryl or 5- to 12-membered heteroaryl;

[0057] m1, m2, m3 and m4 are each independently 0, 1 or 2; provided that m1 + m2 + m3 + m4 ≤ 4;

[0058] m5, m6 and m7 are each independently 0, 1 or 2; provided that m5 + m6 + m7 ≥ 1;

[0059] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0060] n6 is each independently 0, 1, 2, 3 or 4;

[0061] s1 and s2 are each independently 0, 1, 2 or 3;

[0062] s3 and s4 are each independently 1, 2 or 3;

[0063] s5, s6 and s7 are each independently 0, 1, 2 or 3;

[0064] Provided that:

[0065] For any one of L 1 , L 2 or L 3 , when X 1 is N, X 5 is a single bond, absent, -C(O)-; and / or when X 2 is N, X 6 is a single bond, absent, -C(O)-;

[0066] When L 1 is , when X 1 is N, X5 is a single bond, absent, -C(O)-; and / or X 3 is –CR a R b -; when X 2 is N, X 6 is a single bond, absent, -C(O)-, and / or X 4 is –CR a R b -;

[0067] When L 2 is then, when X 1 is N, X 5 is a single bond, absent, -C(O)-; and / or X 3 is –CR a R b -; when X 2 is N, X 6 is a single bond, absent, -C(O)-, and / or X 4 is –CR a R b -;

[0068] When L 3 is then, when X 1 is N, X 5 is a single bond, absent, -C(O)-; and / or X 3 is –CR a R b -; when X 2 is N, X 6 is a single bond, absent, -C(O)-, and / or X 4 is –CR a R b -.

[0069] Aspect 2. The compound according to aspect 1, wherein the compound is selected from formula (IIa) or (IIb),

[0070]

[0071] wherein, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R11a , 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 foregoing aspects;

[0072] More preferably, the compound is selected from formula (IIIa) or (IIIb),

[0073]

[0074] wherein, 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 foregoing aspects;

[0075] Even more preferably, the compound is selected from formula (IVa) or (IVb),

[0076]

[0077] wherein, R 1a , R 1b , R 2a , R 2b , R 3 , R 4 , R5 , 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 defined as in any of the foregoing aspects;

[0078] Even more preferably, the compound is selected from formula (Va) or (Vb),

[0079]

[0080] wherein, R 10 , R 13 , L 1 , L 2 , L 3 , s7, m1, m2, m3, m4, m5, m6 and m7 are defined as in any of the foregoing aspects.

[0081] Aspect 3. The compound according to any of the foregoing aspects, wherein the compound is selected from formula (VIa),

[0082]

[0083] Preferably, the compound is selected from formula (VIb), (VIc) or (VIc’)

[0084]

[0085]

[0086] More preferably, the compound is selected from formula (VId) or (VIe)

[0087]

[0088] More preferably, the compound is selected from formula (VIf) or (VIg)

[0089]

[0090]

[0091] Even more preferably, the compound is selected from formula (VIh) or (VIi)

[0092]

[0093] Even more preferably, the compound is selected from formula (VIj), (VIk), (VIl) or (VIm)

[0094]

[0095]

[0096] Even more preferably, the compound is selected from formula (VIn), (VIo), (VIp) or (VIq)

[0097]

[0098]

[0099] wherein, 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 are as defined in any one of the foregoing aspects.

[0100] Aspect 4. The compound according to any one of the foregoing aspects, wherein m1 + m2 + m3 + m4 ≤ 3.

[0101] Aspect 5. The compound according to any one of the foregoing aspects, wherein m1 + m2 + m3 + m4 = 0, 1, 2 or 3; preferably, m1 + m2 + m3 + m4 = 0, 1 or 2.

[0102] Aspect 6. The compound according to any one of the foregoing aspects, wherein The number of –CH2- in the moiety does not exceed 4, preferably does not exceed 3, and even more preferably does not exceed 2.

[0103] Aspect 7. A compound as described in any one of the foregoing aspects, wherein R 3 and R 4 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy;

[0104] Preferably, R 3 and R 4 are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; preferably, R 3 is independently methyl, and R 4 is hydrogen.

[0105] Aspect 8. A compound as described in any one of the foregoing aspects, wherein 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, pentyloxy, hexyloxy, 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, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or -CN.

[0106] Aspect 9. A compound as described in any one of the foregoing aspects, wherein R 1a , R 1b , R 2a and R 2bEach independently is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CF3, -CHF2, -CN, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3;

[0107] Preferably, R 1a , R 1b , R 2a and R 2b Each independently is hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3 or -CHF2, -CH2OCH3.

[0108] Aspect 10. A compound as described in any one of the foregoing aspects, wherein R 5 and R 6 Each independently is hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CF3, -CHF2, -CN, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3;

[0109] Preferably, R 5 and R 6 Each independently is hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3 or -CHF2, -CH2OCH3.

[0110] Aspect 11. A compound as described in any one of the foregoing aspects, wherein R 5 and R 6 Together with the carbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted by at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl;

[0111] Preferably, R 5 and R 6 Together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered ring, the ring optionally substituted by at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl.

[0112] Aspect 12. The compound according to any one of the preceding aspects, wherein R 7 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CF3, -CHF2, -CN, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3;

[0113] Preferably, R 7 are each independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3 or -CHF2, -CH2OCH3.

[0114] Aspect 13. The compound according to any one of the preceding aspects, wherein two Rs 7 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, the ring containing 0 - 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted by at least one substituent selected from F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl;

[0115] Preferably, two Rs 7 together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered ring, the ring being optionally substituted by at least one substituent selected from F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl.

[0116] Aspect 14. The compound according to any one of the preceding aspects, wherein 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; the methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted by at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy;

[0117] 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 is independently hydrogen, and R 9 is F or methyl.

[0118] Aspect 15. A compound as described in any of the preceding aspects, wherein R 10 are each independently selected from 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 heterocyclic group, phenyl, 5- to 12-membered heteroaryl, -NR 10a R 10b , -OR 10a , -SR 10a , -C(O)R 10a , -CO2R 10a , -C(O)NR 10a R 10b , -NR 10a COR 10b , -NR 10a CO2R 10b or -NR 10a SO2R 10b or -CN; each of 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 heterocyclic group or phenyl is optionally substituted with at least one R 10c ;

[0119] R 10a and R 10b are each independently selected from 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 heterocyclic group or phenyl, and each of the 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 heterocyclic group or phenyl is optionally substituted with at least one substituent R 10d ;

[0120] R 10c and R 10d are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, 5- to 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;

[0121] R 10e and R 10f each independently selected from 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 heterocyclic group, phenyl or 5- to 12-membered heteroaryl;

[0122] Preferably, R 10 each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, -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; 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 heterocyclic group or phenyl each optionally substituted with at least one R10c Substituted;

[0123] R 10a and R 10b each independently selected from 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 heterocyclic group or phenyl;

[0124] R 10c each independently selected from 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 heterocyclic group, phenyl, 5- to 12-membered heteroaryl, oxo(=O), -NR 10e R 10f , -OR 10e or -CN;

[0125] R 10e and R 10f each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl;

[0126] More preferably, R 10 each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3- to 8-membered heterocyclic group, -NR 10a R 10b , -OR 10a , -CO2R 10a or -C(O)NR 10a R 10b ; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3- to 8-membered heterocyclic group is optionally substituted with at least one R 10c substituted;

[0127] R 10a and R 10b each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group or 6-membered heterocyclic group;

[0128] R 10cEach independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxo(=O), -NR 10e R 10f , -OR 10e or -CN;

[0129] R 10e and R 10f Each independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl;

[0130] Even more preferably, R 10 Each independently selected from H, F, Cl, Br, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -COOH, -CONH2, -CH2OCH3 or -CH2OH.

[0131] Aspect 16. The compound according to any one of the foregoing aspects, wherein the moiety is selected from

[0132] Aspect 17. The compound according to any one of the foregoing aspects, wherein the moiety is selected from

[0133] Aspect 18. The compound according to any one of the foregoing aspects, wherein R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d Each independently is 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted by at least one substituent selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or -CN;

[0134] 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; preferably, R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d 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 are each independently hydrogen or methyl.

[0135] Aspect 19. A compound according to any one of the preceding aspects, wherein L 1 is selected from -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 ,

[0136]

[0137] wherein each of

[0138]

[0139] is optionally substituted by at least one R L1c ;

[0140] each of said R L1c is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group, phenyl or a 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group, phenyl and a 5- to 12-membered heteroaryl is optionally substituted by at least one R Lca ;

[0141] R Lca is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group, phenyl or a 5- to 12-membered heteroaryl; or

[0142] two R L1c together with the carbon atom 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 is optionally substituted by at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl;

[0143] R aSelected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted by at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl.

[0144] Aspect 20. The compound according to any one of the preceding aspects, wherein L 1 is selected from -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 ,

[0145]

[0146]

[0147]

[0148]

[0149] Aspect 21. The compound according to any one of the foregoing aspects, wherein L 2 is selected from -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 ,

[0150]

[0151] wherein each of said

[0152] is optionally substituted by at least one R L2c ;

[0153] each of said R L2c is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl and 5- to 12-membered heteroaryl is optionally substituted by at least one R Lca ;

[0154] R Lca is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; or

[0155] two RL2c 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 is optionally substituted by at least one substituent selected from F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl;

[0156] R a Selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted by at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl.

[0157] Aspect 22. The compound according to any one of the preceding aspects, wherein L 2 Selected from -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 、

[0158]

[0159]

[0160]

[0161]

[0162] Aspect 23. A compound according to any one of the preceding aspects, wherein L 3 is selected from -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 ,

[0163]

[0164] wherein each of the

[0165]

[0166] is optionally substituted by at least one R L3c ;

[0167] Each of said R L3c is independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl and 5- to 12-membered heteroaryl is optionally substituted by at least one RLca is substituted with

[0168] R Lca is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; or

[0169] two Rs L3c together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, the ring containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl;

[0170] 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, cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted with at least one substituent halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl.

[0171] Aspect 24. The compound according to any one of the preceding aspects, wherein L 3 is selected from -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 ,

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178] Aspect 25. The compound according to any one of the preceding aspects, wherein the moiety is selected from

[0179]

[0180] Aspect 26. The compound according to any one of the preceding aspects, wherein the moiety is selected from

[0181]

[0182] Aspect 27. The compound according to any one of the preceding aspects, wherein X 7 is independently selected from -CR a or N;

[0183] R aIndependently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl is optionally substituted by at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl;

[0184] Preferably, X 7 is independently selected from -CH, -C(CH3) or N; preferably, X 7 is independently selected from -CH.

[0185] Aspect 28. A compound according to any one of the preceding aspects, wherein X 8 is independently selected from -NR a -, -O-, -S- and -CR a R b -;

[0186] In each occurrence, R a and R bEach independently selected from hydrogen, hydroxyl, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl is optionally substituted by at least one substituent selected from halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl;

[0187] Preferably, X 8 is independently selected from -NH- and -CH2-; preferably, X 8 is independently selected from -CH2-.

[0188] Aspect 29. A compound according to any one of the preceding aspects, wherein selected from

[0189] Preferably, selected from

[0190] Aspect 30. A compound according to any one of the preceding aspects, wherein at most one of Z 1 and Z 2 is N; preferably, Z 1 and Z 2 are each independently CR z .

[0191] Aspect 31. A compound according to any one of the preceding aspects, wherein R Z , each time it appears, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR Za RZb 、 -OR Za 、 -SR Za 、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 - to 8 - membered heterocyclic group or CN; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3 - to 8 - membered heterocyclic group is optionally substituted by at least one R Zc substituted;

[0192] 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 heterocyclic group, 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 heterocyclic group, phenyl or 5 - to 12 - membered heteroaryl is optionally substituted by at least one substituent R Zd substituted;

[0193] 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 - to 8 - membered heterocyclic group, phenyl or 5 - to 12 - membered heteroaryl;

[0194] 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.

[0195] Aspect 32. The compound according to any one of the preceding aspects, wherein R 13 are each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3 - to 8 - membered heterocyclic group, -C6 - C 12 aryl, 5 - to 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 ; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl, 5- to 12-membered heteroaryl is optionally substituted by F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c , -SO2R 13c , -SO2NR 13c R 13d , -COR 13c , -CO2R 13c , -CONR 13c R 13d , -NR 13c R 13d , -NR 13c COR 13d , -NR 13c CO2R 13d or –NR 13c SO2R 13d substituted;

[0196] R 13a , R 13b , R 13c and R 13d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C2-8 alkenyl, -C 2-8 alkynyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl;

[0197] 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3 or phenyl.

[0198] Aspect 33. The compound according to any one of the foregoing aspects, wherein is

[0199] Aspect 34. The compound according to any one of the foregoing aspects, wherein is

[0200] Aspect 35. The compound according to any one of the foregoing aspects, the compound is selected from

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217] Aspect 36. A pharmaceutical composition comprising a compound as described in any one of Aspects 1 - 32 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

[0218] Aspect 37. A method of treating a disease that can be affected by EGFR modulation, the method comprising administering to a subject in need thereof an effective amount of a compound as described in any one of Aspects 1 - 32 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof.

[0219] Aspect 38. The method as described in Aspect 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.

[0220] Aspect 39. Use of a compound as described in any one of Aspects 1 - 32 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof in the manufacture of a medicament for treating a disease that can be affected by EGFR modulation.

[0221] Aspect 40. The use as described in 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

[0222] The following terms have the indicated meanings throughout the specification:

[0223] Unless otherwise specifically defined elsewhere in this document, all other technical and scientific terms used in this invention have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0224] The following terms have the indicated meanings throughout the specification:

[0225] As used herein, including in the appended claims, unless the context clearly indicates otherwise, singular forms of words such as "a / an" and "the" include their corresponding plural referents.

[0226] Unless the context clearly indicates otherwise, the term "or" means the term "and / or" and may be used interchangeably with the term "and / or".

[0227] The term "alkyl" includes hydrocarbon groups selected from saturated hydrocarbon groups that are linear or branched, the hydrocarbon groups containing from 1 to 18, such as from 1 to 12, further such as from 1 to 10, still further such as from 1 to 8, or from 1 to 6, or from 1 to 4 carbon atoms. Examples of alkyl groups containing from 1 to 6 carbon atoms (i.e., C 1-6 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 sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-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.

[0228] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0229] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu").

[0230] 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.

[0231] 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.

[0232] The term "alkylene" refers to a divalent alkyl group obtained by removing two hydrogens from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, etc.

[0233] The term "halogen" includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0234] The term "alkenyl" includes hydrocarbon groups selected from straight-chain and branched-chain hydrocarbon groups, which contain at least one C═C double bond and from 2 to 18, for example from 2 to 8, further for example from 2 to 6 carbon atoms. Examples of alkenyl groups (such as C 2-6 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-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups.

[0235] The term "alkenylene" refers to a divalent alkenyl group formed by removing two hydrogens from an alkene. Alkenylene includes but is not limited to vinylene, butenylene, etc.

[0236] The term "alkynyl" includes hydrocarbon groups selected from straight-chain and branched-chain hydrocarbon groups, which contain at least one C≡C triple bond and from 2 to 18, for example from 2 to 8, further for example from 2 to 6 carbon atoms. Examples of alkynyl groups (such as C 2-6 alkynyl) include but are not limited to ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0237] 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, etc.

[0238] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, which contain monocyclic and polycyclic (such as bicyclic and tricyclic) groups (including fused, bridged, or spirocycloalkyl).

[0239] For example, cycloalkyl groups can contain from 3 to 12, for example from 3 to 10, further for example 3 to 8, further for example 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, cycloalkyl groups can be selected from monocyclic groups containing from 3 to 12, for example from 3 to 10, further for example 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. In particular, examples of saturated monocyclic cycloalkyl groups (such as C 3-8 cycloalkyl) include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, cycloalkyl is a monocyclic group containing 3 to 6 carbon atoms (abbreviated as C 3-6cycloalkyl), including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms, having a fused bicyclic arrangement (selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems) or having a bridged bicyclic arrangement (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 having a bicyclic arrangement (selected from [5,6] and [6,6] ring systems).

[0240] The term "spirocycloalkyl" includes a cyclic structure containing carbon atoms and formed by at least two rings sharing one atom.

[0241] The term "fused cycloalkyl" includes bicyclic cycloalkyl groups as defined herein, which are saturated and formed by two or more rings sharing two adjacent atoms.

[0242] The term "bridged cycloalkyl" includes a cyclic structure containing carbon atoms and formed by two rings sharing two non-adjacent atoms with each other. The term "7- to 10-membered bridged cycloalkyl" includes a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two non-adjacent atoms with each other.

[0243] Examples of fused cycloalkyl, fused cycloalkenyl or fused cycloalkynyl include but are not limited to bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin and benzo 3- to 8-membered cycloalkyl, benzoC 4-6 cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,4-dihydronaphthalenyl, etc. A preferred embodiment is an 8- to 9-membered fused ring, which refers to a cyclic structure containing 8 to 9 ring atoms in the above examples.

[0244] The term "aryl", used alone or in combination with other terms, includes groups selected from:

[0245] 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0246] bicyclic systems (such as 7- to 12-membered bicyclic systems), where at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0247] tricyclic systems (such as 10- to 15-membered tricyclic systems), where at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0248] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, a 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, naphthalen-1-yl, naphthalen-2-yl, anthryl, phenanthryl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalen-1-yl or naphthalen-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0249] Specifically, the term "bicyclic fused heteroaryl" includes a bicyclic heteroaryl ring as defined herein. A typical bicyclic fused heteroaryl is naphthalene.

[0250] The term "heteroaryl" includes groups selected from:

[0251] 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., from 1 to 4, or in some embodiments from 1 to 3, or in some embodiments from 1 to 2 heteroatoms), wherein the remaining ring atoms are carbon;

[0252] a 7- to 12-membered bicyclic ring containing at least one heteroatom selected from N, O, and S (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms), wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0253] an 11- to 14-membered tricyclic ring containing at least one heteroatom selected from N, O, and S (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms), wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0254] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in an aromatic heterocyclic ring does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, these heteroatoms can be the same or different. One or more nitrogen atoms in a heteroaryl group can be oxidized to form an N-oxide.

[0255] Specifically, the term "bicyclic fused heteroaryl" includes a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl ring as defined herein. Typically, the bicyclic fused heteroaryl is a 5 / 5, 5 / 6, 6 / 6, or 6 / 7 bicyclic ring. The group can be attached to the remainder of the molecule through either ring.

[0256] The terms "heterocyclic group", "heterocycle", or "heterocyclic" are interchangeable and include non-aromatic heterocyclic groups (which contain one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, where the remaining ring members are carbon), including monocyclic, fused, bridged, and spiro rings, i.e., containing monocyclic heterocyclic groups, bridged heterocyclic groups, spiro heterocyclic groups, and fused heterocyclic groups.

[0257] The term "H" or "hydrogen" as disclosed herein includes hydrogen and the non-radioactive isotope deuterium.

[0258] The term "at least one substituent" as disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, and further such as 1 or 2 substituents, provided that the valence theory is satisfied. For example, "at least one substituent F" as disclosed herein includes from 1 to 4, such as from 1 to 3, and further such as 1 or 2 substituents F.

[0259] The term "divalent" refers to a linking group capable of forming covalent bonds 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 a linking group. The terms "divalent aryl group", "divalent heterocyclic group", or "divalent heteroaryl group" should be understood in a similar manner.

[0260] The compounds disclosed herein may contain asymmetric centers and can thus exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they can additionally exist as diastereomers. Enantiomers and diastereomers belong to the broader category of stereoisomers. It is intended to include all possible stereoisomers, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds and / or their pharmaceutically acceptable salts disclosed herein. Unless otherwise specifically stated, a reference to an isomer applies to any possible isomer. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0261] When the compounds disclosed herein contain an olefinic double bond, such double bonds are intended to include E and Z geometric isomers unless otherwise stated.

[0262] When the compounds disclosed herein contain a disubstituted ring system, the substituents found on such a ring system can adopt cis and trans forms. The cis form means that both substituents are on the upper side of the 2 substituent positions on carbon, while the trans means that they are on opposite sides. For example, the disubstituted ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0263] It may be advantageous to separate the reaction products from each other and / or from the starting materials. By ordinary skill in the art, the desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) to the desired degree of homogeneity. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reverse and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving bed (“SMB”) and preparative thin or thick layer chromatography, and techniques of small-scale thin layer and flash chromatography. One of ordinary skill in the art can select and apply the technique most likely to achieve the desired separation.

[0264] “Diastereomers” refer to stereoisomers of a compound having two or more chiral centers that are not mirror images of each other. A mixture of diastereomers can be separated into its individual diastereomers according to their physicochemical differences by methods known to those of ordinary skill in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated as follows: the enantiomer mixture is converted into a mixture of diastereomers by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), the diastereomers are separated, and the individual diastereomers are converted (e.g., hydrolyzed) into the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0265] A single stereoisomer (e.g., a substantially pure enantiomer) can be obtained by resolving a racemic mixture using methods such as forming diastereomers with an optically active resolving agent (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). The racemic mixtures of the chiral compounds of the present invention can be separated and resolved by any suitable method, including: (1) forming an ionic diastereomeric salt with the chiral compound and separating by fractional crystallization or other methods; (2) forming diastereomeric compounds with a chiral derivatizing reagent, separating the diastereomers and converting to the pure stereoisomers; and (3) directly separating 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.

[0266] Some of the compounds disclosed herein can have different attachment points for hydrogen, known as tautomers. For example, a compound including a carbonyl - CH2C(O)- group (keto form) can undergo tautomerization to form a hydroxy - CH = C(OH)- group (enol form). Where applicable, it is also intended to include both the individual keto and enol forms and mixtures thereof. For another example, compounds such as pyrazolyl may undergo tautomerization to form different rings as shown below:

[0267]

[0268] For another example, compounds such as guanidyl in a ring may undergo tautomerization to form different rings as shown below:

[0269]

[0270] "Prodrug" refers to a derivative of an active agent that needs to be converted in vivo to release the active agent. In some embodiments, the conversion is an enzymatic conversion. Prodrugs are often (although not necessarily) pharmacologically inactive until converted to the active agent.

[0271] "Deuterated analog" refers to a derivative of an active agent in which any hydrogen has been replaced by deuterium. In some embodiments, the deuterated site is in the warhead moiety. In some embodiments, the deuterated site is in the linker moiety. In some embodiments, the deuterated site is in the degron moiety.

[0272] "Pharmaceutically acceptable salt" refers to those salts that are suitable, within the scope of sound medical judgment, for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with 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 separately by reacting the free base functional group with a suitable organic acid, or by reacting the acidic group with a suitable base. The term also includes salts of stereoisomers (e.g., enantiomers and / or diastereoisomers), tautomers, and prodrugs of the compounds of the invention.

[0273] Furthermore, 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, in accordance with conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0274] As used herein, the terms "administration" and "treating" when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with the cell and contact of a reagent with a fluid that is in contact with the cell. The terms "administration" and "treating" also mean in vitro and ex vivo treatment of a cell, for example, by a reagent, diagnostic agent, binding compound, or another cell. As used herein, the term "subject" includes any living organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0275] As used herein, the term "treated, treating or treatment" generally also refers to obtaining the desired pharmacological and / or physiological effect. Depending on the full or partial prevention of a disease or its symptoms, the effect may be prophylactic; and / or depending on the partial or complete stabilization or cure of a disease and / or side effects caused by the disease, the effect may be therapeutic. As used herein, "treated, treating or treatment" includes any treatment of a patient's disease, including: (a) preventing a disease or disorder in a patient who may be predisposed to the disease or disorder but has not yet been diagnosed; (b) inhibiting the symptoms of a disease, i.e., preventing its development; or (c) alleviating the symptoms of a disease, i.e., causing a remission of the disease or symptoms, in whole or in part.

[0276] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a compound) sufficient to affect the treatment of a disease, or at least one clinical symptom of a disease or disorder, when administered to a subject to treat the disease, disorder or symptom. The term "therapeutically effective amount" can vary with the compound, the disease, the disorder, and / or the symptom of the disease or disorder, the severity of the disease, disorder, and / or the symptom of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is the amount of at least one compound and / or at least one of its stereoisomers, tautomers or prodrugs, and / or at least one of its pharmaceutically acceptable salts as defined herein that effectively "treats" the disease or disorder of a subject. In the case of combination therapy, the term "therapeutically effective amount" refers to the total amount of the combination of agents effective to treat a disease, disorder or condition.

[0277] The term "disease" refers to any disease, discomfort, illness, symptom or indication and may be used interchangeably with the term "disorder" or "condition".

[0278] Throughout this specification and the appended claims, unless the context otherwise requires, the term "comprise" and variations such as "comprises" and "comprising" are intended to specify the presence of the recited features, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced with the term "containing" or "including", or sometimes with "having".

[0279] Throughout this specification and the appended claims, the term "C n-m " or "C n -Cm ”Indicates a range including 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.

[0280] Unless otherwise indicated, the percentages, ratios, rates or parts used in this application are calculated by weight or volume. The amounts used in this application are amounts by weight or volume. These can be readily determined by those skilled in the art.

[0281] Hereinafter, this application will illustrate the beneficial effects of this application by way of examples. Those skilled in the art will recognize that these examples are illustrative and not restrictive. These examples will not limit the scope of this application in any way. Unless otherwise indicated, the experimental methods described in the following examples are all conventional methods; unless otherwise indicated, the reagents and materials are commercially available.

[0282] Unless specifically defined elsewhere in this document, all other technical and scientific terms used in this invention have the meanings commonly understood by those of ordinary skill in the art to which this invention pertains.

[0283] Examples

[0284] The following examples are intended to be purely exemplary and should not be regarded as limiting in any way. Although efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), some experimental errors and deviations should be considered. Unless otherwise indicated, the temperatures are in degrees Celsius. The 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, the reactions described below were carried out under a positive pressure of nitrogen or argon or in an anhydrous solvent with a drying tube; the reaction flasks were equipped with rubber septa for introducing substrates and reagents via syringes; and the glassware was oven-dried and / or heat-dried.

[0285] Recorded on an Agilent instrument operating at 400 MHz 1 1H NMR spectra. 1 1HNMR

[0286] Spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone or (CD3)2CO as solvents and tetramethylsilane (0.00 ppm) or residual solvents (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05) as reference standards. When reporting the number of multiplets, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). If coupling constants are given, they are reported in Hertz (Hz).

[0287] 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 (%)

[0288] Time (min) A(％) B(％) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0289] 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 (%)

[0290] Time (min) A(％) B(％) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0291] 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 (%)

[0292] Time (min) A(％) B(％) 0.00 90 10 1.5 5 95 2.0 5 95 2.1 90 10 3.0 90 10

[0293] Preparative HPLC was performed on a column (150 x 21.2 mm ID, 5 µm, Gemini NXC 18) at a flow rate of 20 ml / min, an injection volume of 2 ml, at room temperature and with UV detection at 214 nm and 254 nm.

[0294] In the following examples, the following abbreviations are used:

[0295]

[0296]

[0297]

[0298]

[0299] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one

[0300] Step 1: Methyl (1S,3S)-3-formylcyclobutane-1-carboxylate

[0301]

[0302] At room temperature, Dess-Martin periodinane (353 g, 832 mmol) was added to a stirred solution of methyl 3-(hydroxymethyl)cyclobutane-1-carboxylate (100 g, 693 mmol) in DCM (1000 mL). The resulting mixture was stirred at room temperature for 2 h. Then the mixture was diluted with DCM (1000 mL) and washed with saturated aqueous NaHCO3 (3 x 1000 mL) and brine (1000 mL). The organic layer was dried over anhydrous Na2SO4, 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 product (cis) (45 g, 45.6%) and the trans product (30 g, 30.4%); 11H NMR (500 MHz, 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).

[0303] Step 2: Methyl (1S,3S)-3-(((tert-butylsulfinyl)amino)methyl)cyclobutane-1-carboxylate

[0304]

[0305] At room temperature, 2-methylpropane-2-sulfinamide (42.2 g, 348 mmol) and 5 mL of AcOH were added to a stirred solution of (1S,3S)-methyl 3-formylcyclobutane-1-carboxylate (45 g, 318 mmol) in DCM (200 mL). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated and diluted with MeOH (200 mL). Then, NaBH4 (24 g, 633 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was concentrated and diluted with DCM (1000 mL) and washed with brine (500 mL x 2). 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 PE / EtOAc (4:1) to afford the product (48 g, 61.3%); [M+H] + = 248.2.

[0306] Step 3: Methyl (1S,3S)-3-(aminomethyl)cyclobutane-1-carboxylate hydrochloride

[0307]

[0308] A solution of (1S,3S)-methyl 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 h. The resulting mixture was concentrated to afford the product (38 g) as the hydrochloride salt; [M+H] + = 144.1.

[0309] Step 4: Methyl (1S,3S)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutane-1-carboxylate

[0310]

[0311] A solution of (1s,3s)-3-(aminomethyl)cyclobutane-1-carboxylic acid methyl ester 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 and diluted with DCM (1000 mL), and then washed with saturated aqueous NH4Cl (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 EtOAc / PE (0 - 20%), to give the product (45 g, 49.4%); [M+H] + = 343.2.

[0312] Step 5: ((1S,3S)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutyl)methanol

[0313]

[0314] A solution of (1s,3s)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutane-1-carboxylic acid methyl ester (45 g, 131 mmol) in 600 mL of THF was cooled to -20 °C. At -20 °C, LiAlH4 (2.4 M in THF, 60 mL) was added over 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 NH4Cl (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 EtOAc / PE (0 - 60%), to give the product (37 g, 89.5%); [M+H] + = 315.1.

[0315] Step 6: Methyl 2-(5-(((1S,3S)-3-(((5-bromo-2-nitrophenyl)amino)methyl)cyclobutyl)methoxy)-1- methyl-1H-pyrazol-4-yl)-6-methylisonicotinate

[0316]

[0317] 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 afford the product (72 g) admixed with PPh3O; [M+H] + = 544.3.

[0318] Step 7: Methyl 2-(5-(((1S,3S)-3-(((2-amino-5-bromophenyl)amino)methyl)cyclobutyl)methoxy)-1- methyl-1H-pyrazol-4-yl)-6-methylisonicotinate

[0319]

[0320] 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 h under a hydrogen atmosphere (1 atm). The mixture was then filtered and the filtrate concentrated. The resulting mixture (66 g) was used in the next step without purification; [M+H] + = 514.3.

[0321] 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 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

[0322]

[0323] 2-(5-(((1s,3s)-3-(((2-amino-5-bromophenyl)amino)methyl)

[0324] Methyl (2-(5-(((1S,3S)-3-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]pyridin-1-yl)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (66 g, 128 mmol) and BrCN (41 g, 384 mmol) in MeOH (200 mL) were stirred at room temperature for 4 h. The mixture was then concentrated and 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.

[0325] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one

[0326]

[0327] At room temperature, LiHMDS (1 N in THF, 137 mL) was added to a stirred solution of methyl (2-(5-(((1S,3S)-3-((6-bromo-2-imino-2,3-dihydro-1H-benzo[d]imidazo[1,2-a]pyridin-1-yl)methyl)cyclobutyl)methoxy)-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (37 g, 69.6 mmol) in 600 mL of THF over 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.

[0328] 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]imidazo[2,4-b]pyridin-1(4,5)-pyrazolo[1,3-c]cyclobutane-3-one

[0329]

[0330] The title compound was prepared in a similar manner to Intermediate 1. [M+H] + = 507.2.

[0331] Intermediate 3: (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid

[0332] Step 1: Methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate Step 1: Methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate

[0333]

[0334] A mixture of Intermediate 16 (3.00 g, 6.22 mmol), azetidine-3-carboxylic acid methyl ester hydrochloride (1.41 g, 9.33 mmol), Cs2CO3 (6.06 g, 18.66 mmol) and RuPhos Pd G3 (520.7 mg, 0.62 mmol) in toluene (50 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was diluted with brine (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. 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.

[0335] Step 2: 1-(4-(2,6-Bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid

[0336]

[0337] At room temperature, LiOH·H2O (168 mg, 4 mmol) in 10 mL of water was added dropwise to a stirred mixture of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid methyl ester (1.7 g, 3.29 mmol) in THF (20 mL). The mixture was then stirred for 2 h. The resulting mixture was concentrated in vacuo. The aqueous layer was adjusted to pH < 5 with 1N HCl and then extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. 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.

[0338] Step 3: (R)-1-(4-(2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid

[0339]

[0340] 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 at room temperature under a hydrogen atmosphere 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)), and the title compound corresponded to peak A @ 1.849 min / 254 nm (190 mg, 22%). [M+1] + = 325.3.

[0341] Intermediate 4: (S)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylic acid

[0342] Step 1: Methyl (S)-4,4-dimethylpyrrolidine-3-carboxylate

[0343]

[0344] At 0 °C under a nitrogen atmosphere, SOCl2 (1.66 g, 13.96 mmol) was added dropwise to a stirred solution of (S)-4,4-dimethylpyrrolidine-3-carboxylic acid (2 g, 13.96 mmol) in MeOH (30 mL). The resulting mixture was stirred at 60 °C for 2 h. 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

[0345] Steps 2 - 4: (S)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylic acid Steps 2 - 4: (S)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carboxylic acid

[0346]

[0347] The title compound was prepared in a similar manner to the synthesis of Intermediate 3 (Steps 1-3). [M+H] + = 367.4.

[0348] Intermediate 5: (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde

[0349] Step 1: Ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyrate

[0350]

[0351] Within 20 min, at -65 °C, LDA (2 M in THF, 24 mL, 48 mmol) was added dropwise to a solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (10 g, 43.1 mmol) in THF (150 mL). The reaction solution was stirred at this temperature for 1 h, and then ethyl 3-bromopropionate (9.4 g, 51.7 mmol) in THF (30 mL) was added dropwise thereto within 10 min. The resulting solution was stirred at -65 °C for 30 min and then allowed to warm to room temperature naturally. The reaction was quenched by adding saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (13.8 g, 96.5%). [M+H] + = 332.0.

[0352] Step 2: 4-(4-Bromo-2,6-difluorophenyl)-4-cyanobutyric acid

[0353]

[0354] To a solution of ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyrate (13.5 g, 40.7 mmol) in THF / H2O (90 mL / 30 mL) was added LiOH (2.9 g, 0.122 mol). The reaction mixture was stirred at room temperature for 12 h. 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 1 N 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (10.2 g, 82.5%). [M+H] + = 304.2.

[0355] Step 3: 3-(4-Bromo-2,6-difluorophenyl)piperidine-2,6-dione

[0356]

[0357] To a stirred solution of 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutyric 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 under vacuum, and then the mixture was poured into water. The pH was adjusted to 7 - 8 with 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.

[0358] Step 4: (R,E)-3-(4-(2-Ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione

[0359]

[0360] 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 / H2O (100 mL / 20 mL) was added Pd(dtbpf)Cl2 (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 h. The reaction solution was diluted with water and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SFC (IH(3*25 cm, 5um), 13% EtOH / 87% CO2, 100 bar, 100 ml / min), and the title compound corresponded to peak A @ 1.679 min / 254 nm. (3.1 g, 39.0%). [M+H] + = 296.1.

[0361] Step 5: (R)-2-(4-(2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde

[0362]

[0363] (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 h. The reaction solution was evaporated to dryness to give the product (2.6 g, 91.8%). [M+H] + = 268.1.

[0364] Intermediate 6: (R)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione

[0365] Step 1: 8-(4-(2,6-Bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane Step 1: 8-(4-(2,6-Bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane

[0366]

[0367] Under N2 atmosphere, Pd2(dba)3 (2.85 g, 3.11 mmol) and Xantphos (3.6 g, 6.22 mmol) were added to a solution of Intermediate 16 (30 g, 62.24 mmol), 1,4-dioxo-8-azaspiro[4.5]decane (10.68 g, 74.69 mmol) and Cs2CO3 (40.58 g, 124.48 mmol) in 500 mL of dioxane. The mixture was stirred at 80 °C under N2 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 obtain the crude product. The crude product was recrystallized with MeOH and filtered. The filter cake was dried to obtain the title compound (26.8 g, 79% yield); [M+H] + = 544.9.

[0368] Step 2: 3-(2,6-difluoro-4-(1,4-dioxo-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6- dione

[0369]

[0370] Pd / C (27 g, 10 wt.%, wet) was added to a solution of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-1,4-dioxo-8-azaspiro[4.5]decane (26.8 g, 49.26 mmol) in 400 mL of DMF and 80 mL of iPrOH. The mixture was stirred at 45 °C under H2 atmosphere (4 bar) for 16 h. The mixture was filtered and the filter cake was washed with DMF. The combined liquids were concentrated in vacuo to obtain the title compound (15 g, 83.2% yield); [M+H] + = 367.1.

[0371] Step 3: (R)-3-(2,6-difluoro-4-(1,4-dioxo-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine- 2,6-dione

[0372]

[0373] The title compound was purified by chiral-HPLC (CHIRALPAK IF (2 * 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 the racemate); [M+H] + = 367.1.

[0374] The title compound can 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 corresponds to peak A @ 0.990 min / 254 nm.

[0375] Step 4: (R)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione

[0376]

[0377] (R)-3-(2,6-Difluoro-4-(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)phenyl)piperidine-2,6-dione (1 g, 2.73 mmol) was placed in a 100 mL round-bottom flask with a magnetic stir bar. Then, 10 mL of 12N HCl (aqueous) was added. The mixture was stirred at room temperature for 30 minutes. The mixture was added dropwise to saturated aqueous NaHCO3 solution until the final pH = 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.

[0378] Intermediate 7: (R)-3-(2,6-Difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione

[0379] Step 1: 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidin-1-yl)-2,6-difluorophenyl)pyridine

[0380]

[0381] Under a nitrogen atmosphere, a solution of intermediate 16 (20 g, 41.49 mmol), 3-(benzyloxy)azetidine hydrochloride (9.96 g, 49.79 mmol), Pd2(dba)3 (3.79 g, 4.15 mmol), RuPhos (3.88 g, 8.3 mmol) and Cs2CO3 (40.58 g, 124.47 mmol) in dioxane (400 mL) was stirred at 100 °C for 3 h. 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 PE / EtOAc (10:1) to afford 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidin-1-yl)-2,6-difluorophenyl)pyridine (17 g, 72.6%). [M+H] + = 565.6.

[0382] Step 2: 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione

[0383]

[0384] 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 at 65 °C under a hydrogen atmosphere 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 afford 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (8 g, 89.9%). [M+H] + = 297.1

[0385] Step 3: 3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2,6-difluorobenz yl)piperidine-2,6-dione

[0386]

[0387] 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 rt for 2 h. The resulting mixture was quenched with saturated aqueous NaHCO3 (500 mL) and extracted with EA (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. 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 afford 3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (11 g, 72.4%). [M+H] + = 411.2

[0388] Step 4: (R)-3-(4-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2,6-di fluorophenyl)piperidine-2,6-dione

[0389]

[0390] The crude product (11 g) was purified by preparative HPLC (CHIRALPAK IF-3, 4.6*50 mm, 3 μm, MtBE (0.1% DEA):(MeOH:DCM = 1:1) = 80:20, flow rate 1.0 mL / min), and the title compound corresponded to peak A at 1.084 min. (4 g, 36%, ee = 100%). [M+H] + = 411.2

[0391] Step 5: (R)-3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione

[0392]

[0393] (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 stir bar. Then, 60 mL of THF and 60 mL of 1M 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 and the pH was adjusted to 6 - 7. The liquid was extracted with DCM (50 mL x 3) and separated. The combined organic phases were concentrated in vacuo and purified by combiflash (DCM:MeOH = 20:1) to afford the title compound (1.8 g, 95% yield). [M+H] + = 297.2

[0394] Step 6: (R)-3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione

[0395]

[0396] At room temperature, Dess-Martin periodinane (3.8 g, 9.0 mmol) was added 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). The resulting mixture was stirred at room temperature for 2 h. Then the mixture was diluted with DCM (100 mL) and washed with saturated aqueous Na2S2O3 (100 mL), 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 (2.0 g), which was used without further purification. [M+H] + = 295.2.

[0397] Intermediate 8: (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbaldehyde

[0398] Step 1: (R)-3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)piperidine-2,6-di one

[0399]

[0400] At 0 °C, BH3.THF (30 mL, 1 M in THF) was added dropwise to a solution of Intermediate 3 (6.5 g, 20 mmol) in THF. The reaction mixture was stirred at room temperature overnight. Then the mixture was quenched with MeOH (20 mL) and 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.

[0401] Step 2: (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbaldehyde

[0402]

[0403] 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 overnight in a flask at room temperature. The reaction was quenched with water and the mixture was extracted with DCM (60 mL x 3). The combined organic layers were washed with saturated aqueous Na2S2O3 (100 mL), saturated aqueous NaHCO3 (100 mL x 2), saturated aqueous NaCl (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the product (2.3 g, 70.1%), which was used without further purification. [M+H] + = 309.1.

[0404] Intermediate 9: 3-(3-fluoro-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0405] Step 1: 8-(6-chloro-5-fluoropyridin-3-yl)-1,4-dioxo-8-azaspiro[4.5]decane

[0406]

[0407] To a solution of 5-bromo-2-chloro-3-fluoropyridine (2.0 g, 9.5 mmol), 1,4-dioxane-8-azaspiro[4.5]decane (2.0 g, 14.25 mmol) and Cs2CO3 (9.26 g, 28.5 mmol) in 80 mL of 1,4-dioxane was added Pd2(dba)3 (871 mg, 0.95 mmol) and XantPhos (880 mg, 1.9 mmol). The mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. After LCMS showed the reaction was complete, the mixture was filtered through a pad of Celite 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 - 2:1) to give the product (1.7 g, 65.8%). [M+H] + = 273.5.

[0408] Step 2: 8-(2',6'-bis(benzyloxy)-3-fluoro-[2,3'-bipyridin]-5-yl)-1,4-dioxo-8-aza spiro[4.5]decane

[0409]

[0410] 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 K2CO3 (2.43 g, 17.61 mmol) in 40 mL of 1,4-dioxane and 8 mL of H2O was added Pd(dppf)Cl2 (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 - 2:1) to give the product (2.7 g, 90.1%); [M+H] + = 528.5.

[0411] Step 3: 3-(3-fluoro-5-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)pyridin-2-yl)piperidine-2, 6-dione

[0412]

[0413] 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 solid was filtered off and the filtrate was concentrated to give the crude product. The crude was purified by silica column chromatography, eluting with DCM / MeOH (20:1) to give the product (1.6 g, 89.8%); [M+H] + = 350.5.

[0414] Step 4: 3-(3-fluoro-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0415]

[0416] 3-(3-Fluoro-5-(1,4-dioxo-8-azaspiro[4.5]dec-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 stir bar. Then, 5 mL of concentrated HCl (aqueous) was added. The mixture was stirred at room temperature for 2 h. The mixture was added dropwise to saturated aqueous NaHCO3 and the pH was adjusted to 6 - 7. The liquid was extracted with DCM (20 mL x 3) and separated. The combined organic phases were concentrated in vacuo and purified by combiflash (DCM:MeOH = 20:1) to afford the title compound (350 mg, 80.2% yield). [M+H] + = 306.5.

[0417] Intermediate 10: 3-(4-Methyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0418] Step 1: 2',6'-bis(benzyloxy)-5-bromo-4-methyl-2,3'-bipyridine

[0419]

[0420] 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 K2CO3 (4.5 g, 32.2 mmol) in 100 mL of 1,4-dioxane and 20 mL of H2O was added Pd(dppf)Cl2 (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 - 5:1) to afford the product (6.7 g, 90.5%). [M+H] + = 461.5.

[0421] Step 2: 8-(2',6'-bis(benzyloxy)-4-methyl-[2,3'-bipyridin]-5-yl)-1,4-dioxo-8-aza spiro[4.5]dec

[0422]

[0423] To a solution of 2',6'-bis(benzyloxy)-5-bromo-4-methyl-2,3'-bipyridine (6.7 g, 14.5 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (5.2 g, 36.3 mmol) and Cs2CO3 (9.4 g, 29.0 mmol) in 80 mL of DMA was added Pd2(dba)3 (2.6 g, 2.9 mmol) and RuPhos (2.7 g, 5.8 mmol). The mixture was stirred at 100 °C for 16 h 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 - 2:1) to afford the product (5.3 g, 69.7%). [M+H] + = 524.5.

[0424] Step 3: 3-(4-methyl-5-(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)pyridin-2-yl)piperidine- 2,6-dione

[0425]

[0426] 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 for 20 h under a hydrogen atmosphere (balloon). The mixture was cooled to room temperature and filtered directly through Celite. The filtrate was concentrated in vacuo to afford the desired product (2.7 g, 77.1%). [M+H] + = 346.6.

[0427] Step 4: 3-(4-methyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0428]

[0429] 3-(4-Methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-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 stir bar. Then 45 mL of 8N HCl (aqueous) was added. The mixture was stirred at room temperature for 2 h. The mixture was added dropwise to saturated aqueous NaHCO3 and the pH was adjusted to 6 - 7. The liquid was extracted with DCM (40 mL x 3) and separated. The combined organic phases were concentrated in vacuo and purified by combiflash (DCM:MeOH = 25:1) to afford the title compound (2.2 g, 93.6% yield). [M+H] += 302.5。

[0430] Intermediate 11: 3-(5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0431]

[0432] The title compound was prepared by a procedure similar to that in Intermediate 10. [M+H] + = 288.2。

[0433] Intermediate 12: 3-(6-methyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0434]

[0435] The title compound was prepared by a procedure similar to that in Intermediate 10. [M+H] + = 302.5。

[0436] Intermediate 13: Ethyl 2-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)methanesulfonate

[0437] Step 1: 2-((4-(2,6-Bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)ethan-1-ol

[0438]

[0439] Under N2 protection, CuI (7.1 g, 37.4 mmol) and L-proline (4.3 g, 37.4 mmol) were added to a solution of Intermediate 16 (180 g, 374 mmol), 2-aminoethan-1-ol (45.6 g, 748 mmol) and K3PO4 (158.6 g, 748 mmol) in 1 L of DMSO. The mixture was stirred at 90 °C for 16 h. The mixture was diluted with EtOAc and filtered. The filtrate was washed with saturated NaCl (aqueous) and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EA:PE = 0-70%) to give the title compound (109 g, 63% yield). [M+H] + = 463.6。

[0440] Step 2: 3-(2,6-Difluoro-4-((2-hydroxyethyl)amino)phenyl)piperidine-2,6-dione

[0441]

[0442] 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% w.t.). The mixture was stirred at 45 °C under a H2 atmosphere for 16 h. The mixture was filtered through Celite. The cake was washed twice with DMF and the filtrates were combined and concentrated in vacuo to afford the title compound (45.6 g, 68% yield). [M+H] + = 285.6.

[0443] Step 3: Ethyl 2-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)methanesulfonate

[0444]

[0445] To a solution of 3-(2,6-difluoro-4-((2-hydroxyethyl)amino)phenyl)piperidine-2,6-dione (5.1 g, 18 mmol) and Et3N (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 h. After LCMS showed the reaction was complete, the mixture was concentrated in vacuo and purified by silica column chromatography (MeOH:DCM = 0 - 3%) to afford the title compound (4.2 g, 64% yield). [M+H] + = 363.6.

[0446] Intermediate 14: (R)-3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione

[0447]

[0448] Step 1: Benzyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperazine-1-carboxylate

[0449]

[0450] To a solution of Intermediate 16 (4.8 g, 10 mmol), benzyl piperazine-1-carboxylate (2.4 g, 11 mmol) and Cs2CO3 (6.5 g, 20 mmol) in 100 mL of dioxane were added Pd2(dba)3 (457 mg, 0.5 mmol) and Xantphos (578 mg, 1 mmol). The mixture was stirred at 90 °C under a N2 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 afford the desired product (5.9 g, 95%). [M+H] + = 622.7.

[0451] Step 2: (R)-3-(2,6-Difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione

[0452]

[0453] 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% w.t.). The mixture was stirred at 45 °C under a H2 atmosphere for 18 h. After completion of the reaction was shown by LCMS, 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 um), 60% MtBE / 40% MeOH:DCM = 1:1, 80 bar, 20 ml / min) (2.5 g, 85%). [M+H] + = 310.7.

[0454] The title compound can also be purified by chiral SFC (column: Chiral ND(2) 3.0*100 mm, 3 um; 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).

[0455] Intermediate 15: Step 3: 3-(6-Methyl-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0456] Step 1: tert-Butyl 4-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridin]-5-yl)piperazine-1-carboxylate Ester

[0457]

[0458] To a solution of 2',6'-bis(benzyloxy)-5-bromo-6-methyl-2,3'-bipyridine (4.0 g, 8.7 mmol) (this compound was obtained in a similar manner to that of step 1 of intermediate 10), tert-butyl piperazine-1-carboxylate (4.0 g, 17.4 mmol) and Cs2CO3 (5.7 g, 17.4 mmol) in 80 mL of DMA were added Pd2(dba)3 (1.6 g, 1.74 mmol) and RuPhos (1.6 g, 3.48 mmol). The mixture was stirred at 100 °C for 16 h 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 - 2:1) to give the product (1.9 g, 38.8%). [M+H] + = 567.5.

[0459] Step 2: tert-Butyl 4-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperazine-1-carboxylate

[0460]

[0461] 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 for 16 h under a hydrogen atmosphere (balloon). 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.

[0462] Step 3: 3-(6-Methyl-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0463]

[0464] 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.

[0465] Intermediate 16: 2,6-Bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine

[0466] Step 1: 2,6-Bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0467]

[0468] Four reactions were carried out in parallel.

[0469] To a solution of 2,6-dibenzyloxy-3-bromo-pyridine (2.00 kg, 5.40 mol, 1.00 eq) 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 eq) and TEA (1.09 kg, 10.8 mol, 1.50 L, 2.00 eq). The mixture was degassed and purged with N2, and then Pd(PPh3)2Cl2 (189 g, 270 mmol, 0.05 eq) 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 (product) = 0.55) showed that the starting material was completely consumed. 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

[0470] Step 2: 5-Bromo-1,3-difluoro-2-iodobenzene

[0471]

[0472] Five reactions were carried out in parallel.

[0473] At -70 °C, LDA (2 M, 2.59 L) was added to a solution of 1-bromo-3,5-difluoro-benzene (1.00 kg, 5.18 mol, 595 mL) in THF (4.00 L). The mixture was stirred at -70 °C for 1 h. Then, at -70 °C, a solution of I2 (1.33 kg, 5.23 mol, 1.05 L) in THF (1.00 L) was added to the mixture. The mixture was stirred at -70 °C for 1 h. TLC (petroleum ether:ethyl acetate = 1:0, R f (starting material) = 0.86, R f(Product) = 0.80) indicates that the starting material is completely consumed. The reaction mixture was poured into H2O (5.00 L), extracted with EtOAc (3.00 L x 2), the 5 reactions were combined, the combined organic layers were washed with brine (5.00 L), dried over Na2SO4, filtered and concentrated in vacuo at 40 °C to give a residue. The crude product was triturated with petroleum ether (6.00 L). Compound 5-bromo-1,3-difluoro-2-iodo-benzene (4.50 kg, 14.1 mol, 54.4% yield) was obtained. [M+H] + = 318.8

[0474] Step 3: 2,6-Bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine

[0475]

[0476] 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 H2O (4.50 L) was added Pd(PPh3)4 (1.63 kg, 1.41 mol), K3PO4 (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 (product) = 0.66) indicates that the starting material is completely consumed. 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). Compound 2,6-dibenzyloxy-3-(4-bromo-2,6-difluoro-phenyl)pyridine (3.00 kg, 6.01 mol, 42.5% yield, 96.5% purity) was obtained. 1 1H NMR (400 MHz, chloroform-d) 7.47 - 7.40 (m, 1H), 7.39 - 7.34 (m, 2H), 7.34 - 7.29 (m, 2H), 7.29 - 7.25 (m, 4H), 7.25 - 7.17 (m, 2H), 7.12 - 7.05 (m, 2H), 6.42 (d, J = 8.0 Hz, 1H), 5.32 (s, 2H), 5.28 (s, 2H); [M+H] + = 482.1.

[0477] Intermediate 17: 1-(6-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-3-yl)azetidine-3-carbaldehyde

[0478]

[0479] The title compound was prepared by analogy with the procedures in Intermediates 8 and 10. [M+H] + =288.3.

[0480] Intermediate 18: 2',6'-bis(benzyloxy)-3-fluoro-5-iodo-6-methyl-2,3'-bipyridine

[0481] Step 1: 5-Fluoro-2-methylpyridin-3-amine

[0482]

[0483] 2-bromo-5-fluoropyridine-3-amine (20g, 105.26mmol) in dioxane / HO (200 / 40mL) solution was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxa triborane (15.91g, 126.32mmol), Pd (dppf) Cl (8.59g, 10.53mmol) and KCO (43.57g, 315.79mmol). The resulting solution was stirred overnight at 120 ° C under N atmosphere. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc. 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 MeOH / DCM (0-10%) to give 5-fluoro-2-methylpyridin-3-amine (12 g, 90.1%). [M+H] + =127.1.

[0484] Step 2: 6-Chloro-5-fluoro-2-methylpyridin-3-amine

[0485]

[0486] At 0 ° C, NCS (8.43 g, 47.62 mmol) was added to a stirred mixture of 5-fluoro-2-methylpyridine-3-amine (6 g, 47.62 mmol) in DMF (120 mL). 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 layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with EA / PE (0-50%)) to obtain 6-chloro-5-fluoro-2-methylpyridine-3-amine (3 g, 39.5%). [M+H]+ = 161.3。

[0487] Step 3: 2',6'-Bis(benzyloxy)-3-fluoro-6-methyl-[2,3'-bipyridin]-5-amine

[0488]

[0489] To a solution of 6-chloro-5-fluoro-2-methylpyridin-3-amine (3 g, 18.63 mmol) in dioxane / H2O (30 / 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)Cl2 (1.52 g, 1.86 mmol), and K2CO3 (7.71 g, 55.89 mmol). The resulting solution was stirred overnight at 100 °C under a N2 atmosphere. After cooling to rt, it was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0 - 50%) to give 2',6'-bis(benzyloxy)-3-fluoro-6-methyl-[2,3'-bipyridine]-5-amine (5 g, 64.3%). [M+H] + = 416.2。

[0490] Step 4: 2',6'-Bis(benzyloxy)-3-fluoro-5-iodo-6-methyl-2,3'-bipyridine

[0491]

[0492] 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 N2 atmosphere. After cooling to rt, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0 - 15%) to give 2',6'-bis(benzyloxy)-3-fluoro-5-iodo-6-methyl-2,3'-bipyridine (2.5 g, 65.79%). [M+H] + = 527.1。

[0493] 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

[0494] Step 1: tert-Butyl (3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidine-1-carboxylate

[0495]

[0496] 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 completion of the reaction as shown by LCMS, 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.

[0497] Step 2: 1-Benzyl-4-((3R,4S)-3-fluoropiperidin-4-yl)piperazine

[0498]

[0499] TFA (10 mL) was added 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). The reaction was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in DCM (200 mL), washed with saturated NaHCO3 solution (3 x 100 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (3 g, 81.7%); [M+H] + = 278.4.

[0500] 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

[0501]

[0502] At room temperature under a nitrogen atmosphere, Cs2CO3 (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-G3 (0.3 g, 0.4 mmol) were added to a stirred solution of Intermediate 18 (0.95 g, 1.8 mmol) in dioxane (20 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 12 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with water (3 x 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 (0.95 g, 78%). [M+H] + = 676.7.

[0503] 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

[0504]

[0505] 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) and 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 at room temperature under a hydrogen atmosphere (1 atm) for 24 h. The mixture was then filtered and the filtrate 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.

[0506] 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

[0507]

[0508] 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 NaHCO3 solution (3 x 20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the product (260 mg, 70.4%). [M+H] + = 408.5.

[0509] Intermediate 20: 3-(5-((3R,4S)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0510]

[0511] The compound was prepared in a similar manner to Intermediate 19.

[0512] Intermediate 21: 3-(4-methyl-5-(piperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0513]

[0514] The compound was prepared in a similar manner to Intermediate 15.

[0515] Intermediate 22: 3-(4-methyl-5-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0516]

[0517] The compound was prepared in a similar manner to Intermediate 15.

[0518] Intermediate 23: 3-(5-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0519]

[0520] The compound was prepared in a similar manner to Intermediate 15.

[0521] Intermediate 24: 3-(5-((R)-3,3-difluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0522]

[0523] This compound was prepared in a similar manner to Intermediate 19.

[0524] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one

[0525] Step 1: (7 1 s,7 3 s,E)-1 1 ,2 6 -dimethyl-5 6 -(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)- 5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7 (1,3)-Cyclobutane ring nonapeptide-3-one

[0526]

[0527] To a solution of Intermediate 1 (3.0 g, 5.9 mmol), 1,4-dioxo-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 was added Pd2(dba)3 (540 mg, 0.59 mmol) and RuPhos (550 mg, 1.18 mmol). The mixture was stirred at 100 °C under N2 for 3 hours. After completion of the reaction was shown by LCMS, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (DCM:MeOH = 100:1 - 15:1) to afford the product (2.5 g, 73.2%). [M+H] + = 570.4.

[0528] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonapeptide- 3-one

[0529]

[0530] The (7 1 s,7 3 s,E)-1 1 ,2 6 -dimethyl-5 6-(1,4-Dioxo-8-azaspiro[4.5]dec-8-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one (300 mg, 0.53 mmol) was placed in a 25 mL round bottom flask equipped with a magnetic stir bar. Then, 4 mL of concentrated HCl (aqueous) was added. The mixture was stirred at room temperature for 2 h. Saturated aqueous NaHCO3 solution was added dropwise to the mixture and the pH was adjusted 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 afford the title compound (120 mg, 43.2% yield). [M+H] + = 526.5.

[0531] Intermediate 26: Ethyl 2-(6-(2,6-dioxopiperidin-3-yl)-2,4-dimethylpyridin-3-yl)methanesulfonate

[0532] Step 1: 2',6'-Bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine

[0533]

[0534] To a solution of 3-bromo-6-chloro-2,4-dimethylpyridine (9 g, 40.9 mmol) in dioxane / H2O (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(PPh3)4 (4.64 g, 4.10 mmol) and K2CO3 (16.94 g, 122.73 mmol). The resulting solution was stirred at 100 °C under N2 atmosphere for 5 h. After cooling to rt, it was diluted with H2O and extracted with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0 - 50%) to afford 2',6'-bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine (12 g, 62.2%). [M+H] + = 475.1.

[0535] Step 2: 2',6'-Bis(benzyloxy)-4,6-dimethyl-5-vinyl-2,3'-bipyridine

[0536]

[0537] To a stirred mixture of 2',6'-bis(benzyloxy)-5-bromo-4,6-dimethyl-2,3'-bipyridine (3 g, 6.31 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.17 g, 7.58 mmol) and K2CO3 (2.61 g, 18.93 mmol) in 1,4-dioxane (30 mL) and H2O (6 mL) was added Pd(dpppf)Cl2 (514.1 mg, 0.63 mmol). The resulting solution was stirred at 100 °C under N2 atmosphere for 5 h. After cooling to rt, it was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The filtrate was concentrated under reduced pressure. The crude product was purified by silica column chromatography (EA / PE = 0 - 20%) to afford 2',6'-bis(benzyloxy)-4,6-dimethyl-5-vinyl-2,3'-bipyridine (1.7 g, 63.9%). [M+H] + = 423.0.

[0538] Step 3: 2-(2',6'-Bis(benzyloxy)-4,6-dimethyl-[2,3'-bipyridin]-5-yl)ethan-1-ol

[0539]

[0540] At 0 °C, 9-BBN (0.5 M in THF, 40 mL, 20.0 mmol) was added dropwise 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). The reaction mixture was stirred at rt overnight, then at 0 °C, NaOH (2 M in water, 4 mL, 8.03 mmol) and H2O2 (30%, 40.2 mL, 12.1 mmol) were added. The reaction mixture was stirred at rt for 2 h, the mixture was diluted with H2O, and extracted with EA, and the residue was purified by column chromatography (EA / PE = 0 - 35%) to afford 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.

[0541] Step 4: 3-(5-(2-Hydroxyethyl)-4,6-dimethylpyridin-2-yl)piperidine-2,6-dione

[0542]

[0543] 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 and purged with H2 five times, then stirred at 50 °C overnight. The resulting mixture was filtered and the 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. 1 H NMR (300 MHz, DMSO) δ 10.80 (s, 1H), 6.96 (s, 1H), 4.83–4.74 (m, 1H), 3.83 (m, 1H), 3.52 (m, 2H), 2.78 (t, J = 9 Hz, 2H), 2.64–2.54 (m, 3H), 2.44 (s, 3H), 2.29 (s, 3H), 2.26–2.02 (m, 1H).

[0544] Step 5: Ethyl 2-(6-(2,6-dioxopiperidin-3-yl)-2,4-dimethylpyridin-3-yl)methanesulfonate

[0545]

[0546] At 0 °C, MsCl (172 mg, 1.49 mmol) was slowly added to a solution of 3-(5-(2-hydroxyethyl)-4,6-dimethylpyridin-2-yl)piperidine-2,6-dione (300 mg, 1.15 mmol) and Et3N (347 mg, 3.44 mmol) in DCM (6 mL) and THF (6 mL). The mixture was stirred at 25 °C for 2 h. After LCMS indicated completion of the reaction, 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.

[0547] Intermediate 27: Ethyl 2-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)methanesulfonate

[0548]

[0549] This compound was prepared in a similar manner to Intermediate 26.

[0550] Intermediate 28: 3-(5-((3S,4R)-3-Fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0551]

[0552] This compound was prepared in a similar manner to Intermediate 19.

[0553] Intermediate 29: 3-(5-((3R,4R)-3-Fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0554]

[0555] This compound was prepared in a similar manner to Intermediate 19.

[0556] Intermediate 30: 3-(6-Methyl-5-((S)-3-methylpiperazin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0557]

[0558] This compound was prepared in a similar manner to Intermediate 15.

[0559] Intermediate 31: 3-(5-((S)-3,3-Difluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0560]

[0561] This compound was prepared in a similar manner to Intermediate 19.

[0562] Intermediate 32: 3-(5-((3S,4R)-3-Fluoro-4-(piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0563]

[0564] This compound was prepared in a similar manner to Intermediate 19.

[0565] Intermediate 33: 3-(5-((3R,4S)-3-Fluoro-4-(piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0566]

[0567] This compound was prepared in a similar manner to Intermediate 19.

[0568] Intermediate 34: 3-(2,6-difluoro-4-((3S,4R)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)phenyl)piperidine-2,6-dione

[0569]

[0570] This compound is prepared in a similar manner to Intermediate 19.

[0571] Intermediate 35: 3-(5-((3R,4R)-3-fluoro-4-(piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0572]

[0573] This compound is prepared in a similar manner to Intermediate 19.

[0574] Intermediate 36: 3-(6-ethyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0575]

[0576] This compound is prepared in a similar manner to Intermediate 10.

[0577] Intermediate 37: 3-(4,6-dimethyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0578]

[0579] This compound is prepared in a similar manner to Intermediate 10.

[0580] Intermediate 38: 3-(3-fluoro-6-methyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0581]

[0582] This compound is prepared in a similar manner to Intermediate 10.

[0583] 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 1H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutanacyclonon-3-one

[0584] Step 1: 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring nonadeca-5 6 -yl)piper tert-Butyl 1-((2S,4S)-4-(4-methoxyphenyl)-2-(piperazin-1-ylmethyl)pyrrolidine-1-carboxylate

[0585]

[0586] To (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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutanacyclonon-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) were added to a solution of Pd2(dba)3 (183 mg, 0.2 mmol) and RuPhos (186 mg, 0.4 mmol) in 10 mL of DMA. The mixture was stirred at 90 °C under N2 for 1.5 h. The mixture was diluted with aqueous NH4Cl (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 - 90:10) to give the product (450 mg, 67.5%). [M+H] + = 668.7.

[0587] 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]imidazol-2(2,4)-pyridine-1(4,5)-pyrazole-7(1,3)- Cyclobutanecyclonon-3-one

[0588]

[0589] To 3-(4-((7 1 s,7 3 s,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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring nonadeca-5 6 To a solution of tert-butyl (4-((R)-3,3-difluoropiperidin-4-yl)piperazin-1-yl)azetidine-1-carboxylate (400 mg, 0.599 mmol) in DCM (6 mL) was added TFA (2 mL). The reaction solution was stirred at rt for 1.5 h 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

[0590] Intermediate 40: 3-(5-(4-((R)-3,3-difluoropiperidin-4-yl)piperazin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0591] Step 1: (S)-tert-Butyl 4-(4-benzylpiperazin-1-yl)-3,3-difluoropiperidine-1-carboxylate

[0592]

[0593] 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 EtOH was stirred at 80 °C for 16 h. After completion of the reaction as shown by LCMS, 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

[0594] Step 2: (S)-tert-Butyl 3,3-difluoro-4-(piperazin-1-yl)piperidine-1-carboxylate

[0595]

[0596] To a solution of (S)-tert-butyl 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 h. The reaction was filtered and the filtrate was concentrated to give the product (S)-tert-butyl 3,3-difluoro-4-(piperazin-1-yl)piperidine-1-carboxylate (1.2 g, 77.5%). [M+H] + = 306.4.

[0597] Step 3: (S)-tert-Butyl 4-(4-(2',6'-bis(benzyloxy)-6-methyl-[2,3'-bipyridin]-5-yl)piperazin-1- yl)-3,3-difluoropiperidine-1-carboxylate

[0598]

[0599] 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) were added Cs2CO3 (1.4 g, 4.34 mmol), (S)-tert-butyl 3,3-difluoro-4-(piperazin-1-yl)piperidine-1-carboxylate (997 mg, 3.26 mmol), Pd2(dba)3 (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 cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with water (3 x 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 (S)-tert-butyl 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.

[0600] Step 4: (4S)-tert-Butyl 4-(4-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperazin-1-yl)- 3,3-difluoropiperidine-1-carboxylate

[0601]

[0602] 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 for 24 h under a hydrogen atmosphere (1 atm). 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 afford the product (400 mg, 67.4%). [M+H] + = 508.6.

[0603] Step 5: 3-(5-(4-((S)-3,3-Difluoropiperidin-4-yl)piperazin-1-yl)-6-methylpyridin-2-yl)piperidine- 2,6-dione

[0604] 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 h and then concentrated in vacuo to afford the product (260 mg, 80.8%). [M+H] + = 408.5.

[0605] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0606]

[0607] The title compound was prepared in a similar manner to Example 33.

[0608] 11H 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.

[0609] 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 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)methyl)piperazine-1-carbonyl)-3,3-dimethylpyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0610]

[0611] The title compound was prepared from Intermediate 4 in a similar manner to Example 3.

[0612] 11H 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, 2H), 2.40–2.35 (m, 2H), 2.20–1.99 (m, 4H), 1.98–1.62 (m, 3H), 1.17 (s, 3H), 0.98 (s, 3H); [M+H] + = 875.8。

[0613] 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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonaene-5 6 -yl)methyl)piperazine-1-carbonyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0614] Step 1: tert-Butyl 4-(3-fluoro-4-nitrobenzyl)piperazine-1-carboxylate

[0615]

[0616] 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 rt for 6 h. The reaction was quenched with saturated aqueous NaHCO3 (60 mL) and the resulting mixture was extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (130 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (PE:EA = 1:1) to afford tert-butyl 4-(3-fluoro-4-nitrobenzyl)piperazine-1-carboxylate (8.6 g, 86%). [M+H] + = 340.2.

[0617] Step 2: tert-Butyl 4-(3-((((1s,3s)-3-(methoxycarbonyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piper- azine-1-carboxylate

[0618]

[0619] To a mixture of tert-butyl 4-(3-fluoro-4-nitrobenzyl)piperazine-1-carboxylate (4 g, 11.8 mmol) and (1s,3s)-methyl 3-(aminomethyl)cyclobutane-1-carboxylate hydrochloride (2.0 g, 14.1 mmol) in CH3CN (80 mL) was added DIEA (6.1 g, 47.0 mmol). The reaction was stirred at 70 °C for 16 h. After cooling to rt, the reaction was concentrated in vacuo. The residue was purified by silica gel column (PE:EA = 1:2) to afford 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.

[0620] Step 3: tert-Butyl 4-(3-((((1s,3s)-3-(hydroxymethyl)cyclobutyl)methyl)amino)-4-nitrobenzyl)piperazine- 1-carboxylate

[0621]

[0622] 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 LiAlH4 (246 mg, 6.5 mmol) was added. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and the resulting mixture was extracted with DCM (40 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (PE:EA = 1:2) to afford 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.

[0623] 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

[0624]

[0625] 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 rt for 2 h. The reaction was concentrated in vacuo and the residue was purified by silica gel column (DCM:CH3OH = 20:1) to afford 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.

[0626] 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

[0627]

[0628] 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 at rt under H2 atmosphere for 2 h. The catalyst was filtered out and the filtrate was concentrated in vacuo to afford 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.

[0629] 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

[0630]

[0631] 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 CH3OH (2 mL) was added BrCN (166 mg, 1.58 mmol). The reaction was stirred at rt for 16 h. The reaction was concentrated in vacuo and the residue was purified by silica gel column (DCM:MeOH = 8:1) to afford 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.

[0632] 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

[0633]

[0634] 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 H2O (5 mL) was added LiOH monohydrate (156 mg, 3.72 mmol). The reaction was stirred at rt for 5 h. The pH of the reaction mixture was adjusted to 5 - 6 with 1N HCl solution and then extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 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.

[0635] Step 8: 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 Hetero-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring nonadeca-5 6 -yl)methyl) tert-Butyl piperazine-1-carboxylate

[0636]

[0637] 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 rt for 30 min. The reaction was quenched with water (10 mL) and the resulting mixture was extracted with EA (15 mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH = 15:1) to afford 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane cyclononaphane-5 6 -yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (220 mg, 50.1%). [M+H] + = 627.5.

[0638] 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- 9-Oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3- one

[0639]

[0640] To a solution of 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane cyclononaphane-5 6 -yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (220 mg, 0.35 mmol) in DCM (8 mL) was added TFA (2 mL). The reaction was stirred at rt for 1 h. The reaction was concentrated in vacuo. The residue was dissolved in DCM (15 mL), washed with saturated aqueous NaHCO3 solution (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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane cyclononaphane-3-one (170 mg, 92%). [M+H] + = 527.4.

[0641] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring Jiufan-5 6 -((((9H-fluoren-9-yl)methyl)piperazin-1-yl)carbonyl)azetidin-1-yl)(2,6-difluorophenyl)piperidine-2,6-dione

[0642]

[0643] To (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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one (50 mg, 0.10 mmol) and Intermediate 3 (36.9 mg, 0.11 mmol) in DCM (5 mL) was added T3P (90 mg, 0.14 mmol, 50% in EA) and DIEA (24.5 mg, 0.19 mmol). The reaction was stirred at rt for 1 h. The reaction was quenched with water (5 mL) and the resulting mixture was extracted with DCM (10 mL x 3), the combined organic phases were washed with brine (10 mL x 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)methyl)piperazine-1-carbonyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (24 mg, 30.4%). 11H 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。

[0644] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)methyl)piperazine-1-carbonyl)-3,3-dimethylpyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0645]

[0646] The title compound was prepared from Intermediate 4 in a similar manner to Example 3. 1¹H 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。

[0647] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)piperidin-4-yl)piperazin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0648]

[0649] The title compound was prepared in a similar manner to Example 17. 11H 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

[0650] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonadeca-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0651] Step 1: 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 Hetero-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutanacyclononaphane-5 6 -yl)piperazine- 1-tert-Butyl ester

[0652]

[0653] At room temperature under a nitrogen atmosphere, piperazine-1-carboxylic acid tert-butyl ester (22.8 g, 122 mmol), t-BuONa (24.6 g, 256 mmol), Ruphos (19.6 g, 20 mmol), and Pd2(dba)3 (9.3 g, 10 mmol) were added to a stirred solution of intermediate 1 (19.1 g, 102 mmol) in DMA (500 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (2000 mL) and washed with water (3 x 1000 mL) and brine (1000 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 - 7%), to give the product (25 g, 79.6%); [M+H] + = 613.6.

[0654] 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 1 H-9-oxa- 4-Aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one

[0655]

[0656] To a solution of 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperazine-1-carboxylic acid tert-butyl ester (25 g, 40.8 mmol) in DCM (100 mL) was added TFA (50 mL). The reaction was stirred at room temperature for 2 h 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 (containing 3% NH3.H2O) / DCM (0 - 35%), to give the product (16 g, 76.5%); [M+H] + = 513.5.

[0657] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring Jiufan-5 6 piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione)-piperazin-1-yl

[0658]

[0659] To (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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one (150 mg, 0.3 mmol) and Intermediate 6 (188 mg, 0.6 mmol) were added to a solution in DCE (8 mL) of STAB (127 mg, 0.6 mmol). The mixture was then stirred at 50 °C for 16 h. Saturated aqueous NaHCO3 (70 mL) was added and the resulting mixture was extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, 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%).

[0660] 1 H NMR (500 MHz, 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.

[0661] Example 7: 3-(5-(4-((R)-4-((7 1 s,7 3 S,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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutacyclononaphthalen-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0662]

[0663] The title compound was prepared in a similar manner to Example 33.

[0664] 1 H NMR (500 MHz, 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

[0665] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutacyclononaphthalen-5 6-yl)-3-oxopiperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione

[0666]

[0667] The title compound was prepared from Intermediate 5 in a similar manner to Example 22. 1 H NMR(500MHz,DMSO)δ12.67(s,1H),10.96(s,1H),8.66(s,1H),7.90(s,1H),7.55(d,J=1.4Hz,1H),7.50(s,1H),7.48(s,1H),7.18(dd,J=8.5,1.7Hz,1H),7.09(d,J=10.0Hz,2H),4.62(s,2H),4.40–3.94(m,3H),3.72(s,3H),3.69(t,J=5.2Hz,2H),3.30–2.25(m,4H),2.92–2.78(m,6H),2.73(t,J=7.2Hz,2H),2.60–2.51(m,7H),2.14(dt,J=12.9,10.9Hz,1H),2.05–1.96(m,1H).[M+H] + =778.6。

[0668] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)-3-oxopiperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0669]

[0670] The title compound was prepared from Intermediate 6 in a similar manner to Example 22. 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.

[0671] 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]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)-3-oxopiperazin-1-yl)methyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0672]

[0673] The title compound was prepared from Intermediate 8 in a similar manner to Example 22. 11H 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.

[0674] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)-3-oxopiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0675]

[0676] The title compound was prepared from Intermediate 11 in a similar manner to Example 22. 11H 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。

[0677] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)piperazin-1-yl)ethyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0678]

[0679] Dissolve (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 1(80 mg, 0.16 mmol) of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one, intermediate 13 (74 mg, 0.2 mmol), DIEA (61 mg, 0.47 mmol) and KI (52 mg, 0.31 mmol) in a solution of MeCN (5 mL) and DMSO (1 mL) were stirred at 80 °C for 16 h. H2O (10 mL) was added and the resulting mixture was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH = 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%). 1 H 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.

[0680] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6(-yl)piperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0681]

[0682] The title compound was prepared from Intermediate 11 in a manner similar to that in Example 21. 1 H 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.

[0683] 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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperazin-1-yl)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0684] Step 1: tert-Butyl 4-(3-(((benzyloxy)carbonyl)amino)cyclobutyl)piperazine-1-carboxylate

[0685]

[0686] 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)3 (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 NaHCO3 (150 mL) and the layers were separated. The aqueous layer was extracted with DCM (3 x 70 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, 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.

[0687] Step 2: tert-Butyl 4-(3-aminocyclobutyl)piperazine-1-carboxylate

[0688]

[0689] 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 at room temperature under a hydrogen atmosphere (balloon) 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 afford the crude product (2.8 g), which was used without further purification. [M+H] + = 255.9.

[0690] Step 3: tert-Butyl 4-((1S,3S)-3-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)cyclo butyl)piperazine-1-carboxylate

[0691]

[0692] 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), K3PO4 (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 under a nitrogen atmosphere for 16 h. The mixture was diluted with EtOAc and filtered. The filtrate was washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (0-7% MeOH in DCM) and SFC (Lux Cellulose-2 4.6*50 mm 3um, Hex:EtOH = 95:5), and the title compound corresponded to peak A @ 2.692 min / 254 nm (384 mg, 8%). [M+H] + = 657.1.

[0693] Step 4: tert-Butyl 4-((1S,3S)-3-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)cyclobut yl)piperazine-1-carboxylate

[0694]

[0695] 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% w.t.). The mixture was stirred at 50 °C under a H2 atmosphere 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 afford the crude product (604 mg), which was used without further purification. [M+H] + = 478.9.

[0696] Step 5: 3-(2,6-Difluoro-4-(((1S,3S)-3-(piperazin-1-yl)cyclobutyl)amino)phenyl)piperidine-2,6- dione

[0697]

[0698] 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 for 1 h at room temperature, the reaction mixture was concentrated under reduced pressure to give the product as the TFA salt (720 mg), which was used without further purification. [M+H] + = 378.9.

[0699] 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 -di Hydrogen-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cycle Butane cyclonona-5 6 -yl)piperazin-1-yl)cyclobutyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione

[0700]

[0701] Under a nitrogen atmosphere at room temperature, t-BuONa (127 mg, 1.32 mmol), Ruphos (41 mg, 0.088 mmol), and Pd2(dba)3 (40 mg, 0.044 mmol) were added 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). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with DCM (40 mL) and washed with saturated aqueous NH4Cl (2 x 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 um; flow rate: 20 mL / min), and the title compound corresponded to peak A at 2.227 min / 254 nm (4.32 mg, 2.5%). 11H 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

[0702] 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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonacosane-5 6 -yl)piperidin-4-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0703] Step 1: (7 1 s,7 3 s,E)-1 1 ,2 6 -dimethyl-5 6 -(1,4-dioxo-8-azaspiro[4.5]dec-8-yl)- 5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7 (1,3)-Cyclobutanacyclonon-3-one

[0704]

[0705] To a solution of Intermediate 1 (3.0 g, 5.9 mmol), 1,4-dioxo-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 was added Pd2(dba)3 (540 mg, 0.59 mmol) and RuPhos (550 mg, 1.18 mmol). The mixture was stirred at 100 °C under N2 for 3 h. After completion of the reaction was shown by LCMS, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by silica column chromatography (DCM:MeOH = 100:1 - 15:1) to afford the product (2.5 g, 73.2%). [M+H] + = 570.4.

[0706] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclon- 3-one

[0707]

[0708] (7 1 s,7 3 s,E)-1 1 ,2 6 -dimethyl-5 6 -(1,4-dioxo-8-azaspiro[4.5]decane-8-yl)-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-3-one (300 mg, 0.53 mmol) was placed into a 25 mL round-bottom flask equipped with a magnetic stir bar. Then, 4 mL of concentrated HCl (aqueous) was added. The mixture was stirred at room temperature for 2 h. The mixture was added dropwise to saturated aqueous NaHCO3 solution and the pH was adjusted 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 afford the title compound (120 mg, 43.2% yield). [M+H] + = 526.5.

[0709] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring Jiufan-5 6 -((1-(4-(4-(2,6-difluorophenyl)piperidin-1-yl)piperidin-4-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0710]

[0711] To (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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one (100 mg, 0.19 mmol), Intermediate 14 (86 mg, 0.25 mmol) and DIEA (50 mg, 0.38 mmol) were added to a solution of STAB (121 mg, 0.57 mmol) in DCE (8 mL). The mixture was then stirred at 50 °C for 16 h. H2O (10 mL) was added and the resulting mixture was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, 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。

[0712] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutacyclonon-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0713]

[0714] The title compound was prepared from Intermediate 6 in a similar manner to Example 33. 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.

[0715] Example 19: 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutacyclonon-5 6-yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0716] Step 1: (3R,4S)-tert-Butyl 4-(4-benzylpiperazin-1-yl)-3-fluoropiperidine-1-carboxylate

[0717]

[0718] To a solution of (3R,4S)-tert-butyl 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, the mixture was stirred at 80 °C for 16 h. After completion of the reaction was shown by LCMS, 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 (3R,4S)-tert-butyl 4-(4-benzylpiperazin-1-yl)-3-fluoropiperidine-1-carboxylate (2 g, 5.3 mmol, 46.3%). [M+H] + = 378.6.

[0719] Step 2: 1-Benzyl-4-((3R,4S)-3-fluoropiperidin-4-yl)piperazine

[0720]

[0721] To a solution of (3R,4S)-tert-butyl 4-(4-benzylpiperazin-1-yl)-3-fluoropiperidine-1-carboxylate (2 g, 5.3 mmol) in 2 mL of DCM was added 6 mL of TFA. The mixture was stirred at room temperature for 1 h. 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, 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.

[0722] Step 3: 2',6'-Bis(benzyloxy)-5-((3R,4S)-4-(4-benzylpiperazin-1-yl)-3-fluoropiperidin-1-yl)- 6-methyl-2,3'-bipyridine

[0723]

[0724] 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 Cs2CO3 (2.61 g, 8 mmol) in 15 mL of DMA was added Pd2(dba)3 (915 mg, 1 mmol) and Ruphos (466 mg, 1 mmol). The mixture was stirred at 100 °C under N2 protection for 16 h. The mixture was concentrated in vacuo. The residue was washed with saturated NaCl (aqueous) 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.

[0725] Step 4: 4-((3R,4S)-1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)-3-fluoropip idin-4-yl)piperazine-1-carboxylate

[0726]

[0727] 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 Boc2O and Pd / C (1.2 g, 10% w.t.). The mixture was stirred at 55 °C under H2 atmosphere 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.

[0728] Step 5: 3-(5-((3R,4S)-3-Fluoro-4-(piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)pi peridine-2,6-dione 2,2,2-trifluoroacetate

[0729]

[0730] 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. After LCMS showed the reaction was complete, the mixture was concentrated to afford 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.

[0731] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane Cyclonine-5 6 -piperazin-1-yl)-3-fluoro-1-piperidinyl)-6-methyl-2-pyridinyl)piperidine-2,6-dione

[0732]

[0733] The title compound was prepared in a similar manner to Step 4 of Example 26. 1 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.

[0734] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonadeca-56 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0735]

[0736] The title compound was prepared from Intermediate 6 in a similar manner to Example 6. 1 H 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.

[0737] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0738]

[0739] To (7 1 s,73 (s,E)-1 1 ,2 6 -Dimethyl-5 6 -(piperazin-1-yl)-5 2 ,5 3 -Dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one (50 mg, 0.1 mmol) and Intermediate 12 (35 mg, 0.12 mmol) were added to a solution of STAB (41 mg, 0.2 mmol) in DCE (10 mL). The mixture was then stirred at 50 °C for 6 h. H2O (10 mL) was added and the resulting mixture was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH = 20:1) to afford the product (11.1 mg, 14.3%). 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), 7.36 (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.

[0740] 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 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring nonadeca-5 6 -yl)-3-oxopiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0741] Step 1: 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-tert-butyl ester

[0742]

[0743] 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 under a nitrogen atmosphere for 2 h. The reaction solution was diluted with water and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 100 / 0 to 100 / 4) to give the product (520 mg, 43.3% yield). [M+H] + = 664.5.

[0744] Step 2: 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-carboxylic acid tert-butyl ester Ester

[0745]

[0746] 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 H2 (40 Psi) three times at room temperature, and then the mixture was stirred under a H2 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.

[0747] Step 3: 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-oxopiper azine-1-carboxylic acid tert-butyl ester

[0748]

[0749] At 25 °C, CNBr (203 mg, 1.92 mmol) was added 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). The mixture was stirred at 25 °C for 16 h. Then the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHCO3 (10 mL x 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

[0750] 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

[0751]

[0752] At 25 °C, 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 H2O (20 mL). The mixture was stirred at 25 °C for 2 h. Then the reaction mixture was 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.

[0753] Step 5: 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 Hetero-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring nonaene-5 6 -yl)-3-oxo acid tert-butyl ester

[0754]

[0755] At 25 °C, 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). The mixture was stirred at 25 °C for 1 h to become a black solution. The reaction mixture was washed with saturated aqueous NaHCO3 (10 mL x 3), dried over Na2SO4, 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, 51.6% yield). [M+H] + = 627.7.

[0756] Step 6: (7 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon- 3-one

[0757]

[0758] To 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]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphane-5 6 -yl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.175 mmol) in DCM (6 mL) was added TFA (2 mL). The reaction solution was stirred at rt for 1.5 h and then concentrated in vacuo. The residue was dissolved in DCM and then washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the product (85 mg, 92.4%). [M+H] + = 527.7.

[0759] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon- 5 6 -yl)-3-oxopiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0760]

[0761] The title compound was prepared from Intermediate 12 in a similar manner to Example 21.

[0762] 1 H 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.

[0763] Example 23: 3-(5-(4-((R)-4-((7 1 s,73 (S,E)-1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphane-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0764]

[0765] The title compound was prepared from Intermediate 10 in a similar manner to Example 30. 1 H 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.

[0766] 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 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclononaphane-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0767]

[0768] The title compound was prepared from Intermediate 12 in a manner similar to that in Example 30.

[0769] 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.

[0770] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclononaphane-5 6 -yl)-2-oxopiperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0771]

[0772] 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.

[0773] 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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)-2-oxopiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0774] Step 1: 4-(1-(2',6'-Bis(benzyloxy)-6-methyl-[2,3'-bipyridin]-5-yl)piperidin-4-yl)-3- oxopiperazine-1-carboxylic acid tert-butyl ester

[0775]

[0776] At room temperature under a nitrogen atmosphere, Cs2CO3 (3.17 g, 9.75 mmol), Pd2(dba)3 (300 mg, 0.325 mmol), and Ruphos (300 mg, 0.65 mmol) were added to a stirred solution of 2',6'-bis(benzyloxy)-5-bromo-6-methyl-2,3'-bipyridine (1.5 g, 3.25 mmol) (this compound was obtained in a similar manner 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). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL) and washed with water (3 x 100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (4:1), to give the product (350 mg, 16.7%); [M+H] + = 664.7.

[0777] Step 2: 4-(1-(6-(2,6-Dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)-3-oxo piperazine-1-carboxylic acid tert-butyl ester

[0778]

[0779] 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 at 50 °C overnight under a hydrogen atmosphere (1 atm). The solid was filtered off and the filtrate was concentrated to give the crude product. The crude product 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.

[0780] Step 3: 3-(6-Methyl-5-(4-(2-oxopiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-di one

[0781]

[0782] 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 for 1 h at room temperature, the reaction mixture was concentrated under reduced pressure to afford the product as the TFA salt (260 mg), which was used without further purification. [M+H] + = 386.4.

[0783] 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 1 H-9- Oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon- 5 6 -yl)-2-oxopiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0784]

[0785] Under a nitrogen atmosphere at room temperature, t-BuONa (141 mg, 1.47 mmol), Ruphos (55 mg, 0.12 mmol), and Pd2(dba)3 (54 mg, 0.06 mmol) were added 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). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with water (3 x 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 DCM / MeOH (10:1) to afford the crude product, which was subsequently purified by preparative HPLC chromatography to afford the title product (6.12 mg, 2.6%). 11H 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。

[0786] 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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0787]

[0788] The title compound was prepared from Intermediate 6 in a similar manner to Example 6.

[0789] 11H 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。

[0790] 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]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)piperidin-4-yl)piperazin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0791]

[0792] To (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 1A solution of H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclononane-3-one (80 mg, 0.15 mmol), Intermediate 15 (60 mg, 0.18 mmol) and DIEA (58 mg, 0.45 mmol) in DCE (8 mL) was added to STAB (95 mg, 0.45 mmol). The mixture was then stirred at 50 °C for 16 h. H2O (15 mL) was added and the resulting mixture was extracted with DCM (15 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, 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%). 1 H 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.

[0793] 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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclononane-5 6 -yl)piperazin-1-yl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0794]

[0795] The title compound was prepared from Intermediate 7 in a similar manner to Example 6.

[0796] 1 H 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.

[0797] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonaene-5 6 -yl)-2-(hydroxymethyl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0798] Step 1: (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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutacyclononaphane-5 6 -yl)- 2-(Hydroxymethyl)

[0799] piperazine-1-carboxylic acid tert-butyl ester

[0800]

[0801] A mixture of intermediate 1 (506 mg, 1 mmol), (R)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (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 in a round-bottom flask at 90 °C under N2 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 (gradient elution with DCM:MeOH = 100:0 - 80:20) to give the product (420 mg, 66%). [M+H] + = 643.2.

[0802] 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 -di Hydrogen-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cycle Butanacyclonon-3-one

[0803]

[0804] At 25 °C, to a solution of (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]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)-2-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (129 mg, 0.2 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at rt for 1 h. Saturated aqueous NaHCO3 (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 concentrated under reduced pressure to give the product (90 mg, 85%). [M+H] + = 543.2.

[0805] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane Cyclonine-5 6 -yl)-2-(hydroxymethyl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0806]

[0807] The (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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-3-one (100 mg, 0.18 mmol) and Intermediate 6 (65 mg, 0.2 mmol) in a mixture of 1,2-dichloroethane (15 mL) in a round-bottom flask was stirred at 70 °C for 2 h. NaBH(OAc)3 (80 mg, 0.37 mmol) was added to the mixture and the reaction was stirred at 70 °C for 12 h. The mixture was then evaporated in vacuo to give the crude product, which was purified by silica gel column chromatography (gradient elution with DCM:MeOH = 100:0 - 80:20) 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。

[0808] Example 31: (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 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclononaphane-5 6 -yl)-2-(hydroxymethyl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0809]

[0810] The title compound was prepared in a similar manner 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.

[0811] Example 32: 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclononaphane-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0812]

[0813] The title compound was prepared in a similar manner to Example 33.

[0814] 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.

[0815] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane cyclononaphthalen-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0816] Step 1: (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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutanacyclononaphane-5 6 -yl)- tert-Butyl 3-methylpiperazine-1-carboxylate

[0817]

[0818] At room temperature under a nitrogen atmosphere, t-BuONa (227 mg, 2.37 mmol), Ruphos (110 mg, 0.24 mmol), and Pd2(dba)3 (108 mg, 0.12 mmol) were added to a stirred solution of Intermediate 1 (300 mg, 0.59 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (237 mg, 1.18 mmol) in DMA (15 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with water (3 x 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 DCM / MeOH (15:1), to afford the product (130 mg, 35.1%); [M+H] + = 627.7.

[0819] Step 2: (7 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 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring Cyclonon-3-one

[0820]

[0821] To a solution of (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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (130 mg, 0.21 mmol) in DCM (10 mL) was added TFA (5 mL). The reaction was stirred at rt for 2 h and then concentrated in vacuo. The residue was dissolved in DCM (30 mL), and then washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the product (70 mg, 64.1%). [M+H] + = 527.6.

[0822] 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 1 H, 5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring Jiufan-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0823]

[0824] To (7 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 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-3-one (50 mg, 0.1 mmol), intermediate 12 (57 mg, 0.19 mmol) was added to a solution in DCE (5 mL) of STAB (60 mg, 0.28 mmol). The mixture was then stirred at 50 °C for 6 h. H2O (10 mL) was added and the resulting mixture was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH = 20:1) to give the product (27.1 mg, 35.2%). 1 H NMR (500 MHz, 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.

[0825] Example 34: 3-(5-(4-((R)-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]imidazo[2,4]pyrido[1,4,5-pq]pyrazolo[7,1,3-cd]cyclonon-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0826]

[0827] The title compound was prepared in a similar manner to Example 33. 1 H NMR (500 MHz, 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.

[0828] 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]imidazo[2,4]pyrido[1,4,5-pq]pyrazolo[7,1,3-cd]cyclonon-5 6 -yl)-2-oxopiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0829]

[0830] The title compound was prepared in a similar manner to that in Example 26. 1 H NMR(500MHz,DMSO)δ12.38(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=8.6Hz,1H),7.17(s,1H),7.01(s,1H),6.84(d,J=9.4Hz,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

[0831] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring Jiufan-5 6 -yl)-3-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)piperidine-2,6-dione

[0832]

[0833] The title compound was prepared from Intermediate 11 in a similar manner to that in Example 33.

[0834] 1 H NMR(500MHz,DMSO)δ12.41(s,1H),10.78(s,1H),8.66(s,1H),8.22(d,J=2.6Hz,1H),7.90(s,1H),7.46(s,1H),7.40–7.31(m,2H),7.17(d,J=8.7Hz,1H),7.01(s,1H),6.88(d,J=8.6Hz,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=6.2Hz,3H). [M+H]+ = 798.3。

[0835] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonadeca-5 6 -yl)-3-methylpiperazin-1-yl)methyl)azetidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0836]

[0837] The title compound was prepared from Intermediate 17 in a manner similar to that in Example 33.

[0838] 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。

[0839] 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]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonadeca-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-3-fluoropyridin-2-yl)piperidine-2,6-dione

[0840]

[0841] The title compound was prepared from Intermediate 9 in a similar manner to Example 6. The racemate was separated by preparative chiral HPLC under the following conditions: (Column: CHIRALPAK IF, 2 cm × 25 cm, 5 μm; Flow rate: 20 mL / min), to afford 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.

[0842] 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 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclononaphane-5 6 ((piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0843]

[0844] The title compound was prepared from Intermediate 10 using a procedure similar to that in Example 6. 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.

[0845] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclononaphane-5 6 ((piperidin-4-yl)piperazin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0846]

[0847] The title compound was prepared in a manner similar to that in Example 28.

[0848] 11H 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.

[0849] 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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)piperidin-4-yl)-3-oxopiperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0850] Step 1: tert-Butyl 4-((2-(((benzyloxy)carbonyl)amino)ethyl)amino)piperidine-1-carboxylate

[0851]

[0852] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.1 g, 15.0 mmol), (2-aminoethyl)carbamic acid benzyl ester (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 RT for 16 h. The reaction was quenched with NaHCO3 / water (100 mL) and extracted with DCM (150 mL x 2). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH = 15:1) to afford the title product (5.5 g, 93.3%). [M+H] + = 378.5.

[0853] Step 2: tert-Butyl 4-(N-(2-(((benzyloxy)carbonyl)amino)ethyl)-2-chloroacetamido)piperidine-1-carboxylate Ester

[0854]

[0855] 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 RT for 3 h. The reaction was quenched with water (100 mL) and extracted with DCM (150 mL x 2). The combined organic phases were washed with brine (100 mL x 1), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (DCM:CH3OH = 20:1) to afford the title product (6.0 g, 90.9%). [M+H] + = 454.5.

[0856] Benzyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-oxopiperazine-1-carboxylate

[0857]

[0858] Under RT, NaH (1.0 g, 26.4 mmol) was added 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). The mixture was then stirred at RT 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 afford the title product (5.3 g, 96.3%). [M+H] + = 418.5.

[0859] tert-Butyl 4-(2-oxopiperazin-1-yl)piperidine-1-carboxylate

[0860]

[0861] 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 at RT under a hydrogen atmosphere (balloon) for 3 h. The mixture was filtered through Celite and washed with DCM. The filtrate was concentrated in vacuo to afford the desired product (3.4 g, 94.4%). [M+H] + = 284.5.

[0862] Step 5: tert-Butyl 4-(4-(4-(2,6-Bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-2-oxopiperazin-1- yl)piperidine-1-carboxylate

[0863]

[0864] 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 Cs2CO3 (2.7 g, 8.2 mmol) in 100 mL of 1,4-dioxane were 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 indicated the reaction was complete, the mixture was filtered through a Celite pad and washed with DCM. The filtrate was concentrated under reduced pressure to afford a crude residue, which was purified by silica gel column chromatography (PE:EA = 50:1 - 1:1) to afford the product (2.6 g, 91.5%). [M+H] + = 685.5.

[0865] Step 6: tert-Butyl 4-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2-oxopiperazin-1-yl)piperidine-1-carboxylate Step 7: 3-(2,6-Difluoro-4-(3-oxo-4-(piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0866]

[0867] 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 afford the desired product (780 mg, 95.8%). [M+H] + = 507.5

[0868] 3-(2,6-Difluoro-4-(3-oxo-4-(piperidin-4-yl)piperazin-1-yl)phenyl)piperidine-2,6-dione

[0869]

[0870] 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 h. The reaction mixture was concentrated under reduced pressure to afford the product (625 mg), which was used without further purification. [M+H] + = 407.5

[0871] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazol-7(1,3)-cyclobutane ring Jiufan-5 6 -((4-(4-(2,6-difluorophenyl)piperidin-2-yl)-3-oxopiperazin-1-yl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0872]

[0873] At room temperature under a nitrogen atmosphere, to a stirred solution of Intermediate 1 (50 mg, 0.1 mmol) in DMA (5 mL) was added ​(80 mg, 0.2 mmol), t-BuONa (47 mg, 0.5 mmol), Ruphos (18 mg, 0.04 mmol) and Pd2(dba)3 (18 mg, 0.04 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with water (3 x 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 DCM / MeOH (15:1) to give the crude product. Chiral separation by HPLC provided the title compound (4.49 mg, 5.5%). HPLC conditions: column: CHIRALPAK IA; column size: 2 cm x 25 cm, 5 um; mobile phase: HEX:DCM(0.1% FA):MeOH = 50:50; flow rate: 20 mL / min; retention time: 3.286 min.

[0874] 1 H 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.

[0875] 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 1H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclononaphane-5 6 ((7-((7-((methyl)(azetidin-1-yl)amino)azetidin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0876]

[0877] The title compound was prepared in a similar manner to Example 6.

[0878] 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.

[0879] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclononaphane-5 6 -yl)piperazin-1-yl)ethyl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0880]

[0881] To a solution of the product from 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 under N2 overnight. The mixture was quenched with water and extracted with DCM (3 x 20 mL). The combined organic phases were washed with brine (1 x 15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by silica column chromatography (DCM:MeOH = 100:1 - 10:1), followed by preparative HPLC chromatography to give the title product (31 mg, 21.4%).

[0882] 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.

[0883] Example 62: 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0884]

[0885] The title compound was prepared from Intermediates 1 and 28 in a manner similar to that in Step 4 of Example 26. 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.

[0886] 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,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0887]

[0888] The title compound was prepared from Intermediate 12 in a manner similar to that in Example 6. 11H 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.

[0889] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0890]

[0891] The title compound was prepared from Intermediate 12 in a similar manner to Example 30. 11H 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。

[0892] Example 110: 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonadeca-5 6 -yl)piperidin-4-yl)-3-methylpiperazin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0893]

[0894] The title compound was prepared from Intermediate 22 in a manner similar to that in Example 17. 11H 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 = 6.0 Hz, 3H). [M+H] + = 812.7。

[0895] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonacos-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0896]

[0897] The title compound was prepared from Intermediate 1 and 29 in a similar manner to Step 4 of Example 26. 11H 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.

[0898] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonona-5 6 -yl)(methyl)amino)-2-azaspiro[3.3]heptan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0899]

[0900] The title compound was prepared from Intermediate 12 in a manner similar to that in Example 6. 11H 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.

[0901] 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]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0902]

[0903] The title compound was prepared from Intermediate 12 in a similar manner to Example 6. 11H 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.

[0904] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonadeca-5 6 -yl)(methyl)amino)methyl)azetidin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0905]

[0906] The title compound was prepared from Intermediate 12 in a similar manner to Example 6. 11H 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。

[0907] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0908]

[0909] The title compound was prepared from Intermediate 23 in a similar manner to Example 28. 11H 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。

[0910] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonaene-5 6 -yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0911]

[0912] The title compound was prepared from Intermediate 12 in a similar manner to Example 6. 11H 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

[0913] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperidin-4-yl)-3-methylpiperazin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0914]

[0915] The title compound was prepared from Intermediate 25 and 30 in a similar manner to Example 17. 11H 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。

[0916] 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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)-2-(methoxymethyl)piperazin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0917]

[0918] The title compound was prepared from Intermediate 1 and 10 in a similar manner to Example 6. 11H 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。

[0919] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonaene-5 6 -yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0920]

[0921] The title compound was prepared from intermediate 39 and 12 in a similar manner to Example 6. 11H 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.

[0922] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)-3,3-difluoropiperidin-4-yl)piperazin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0923]

[0924] The title compound was prepared from Intermediate 1 and 40 in a similar manner to Step 4 of Example 26. 11H 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

[0925] 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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0926]

[0927] The title compound was prepared from Intermediate 1 and 24 in a similar manner to Step 4 of Example 26. 11H 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。

[0928] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonadeca-5 6 -yl)-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0929]

[0930] The title compound was prepared from Intermediate 12 in a manner similar to Example 6. 11H 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。

[0931] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonaene-5 6 -yl)piperazin-1-yl)-3,3-difluoropiperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0932]

[0933] The title compound was prepared from Intermediate 1 and 31 in a similar manner to Step 4 of Example 26. 11H 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。

[0934] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonaene-5 6 -yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0935]

[0936] The title compound was prepared from Intermediate 12 in a similar manner to Example 6. 11H 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.

[0937] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0938]

[0939] The title compound was prepared from Intermediate 12 in a similar manner to Example 6. 11H 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。

[0940] 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]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0941]

[0942] The title compound was prepared from Intermediate 6 in a similar manner to Example 6. 11H 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。

[0943] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)-2,7-diazaspiro[4.4]nonan-2-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0944]

[0945] The title compound was prepared from Intermediate 6 in a similar manner to Example 6. 11H 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.

[0946] 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]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonaene-5 6 -yl)-3,8-diazabicyclo[3.2.1]octan-3-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0947]

[0948] The title compound was prepared from Intermediate 10 in a similar manner to Example 6. 11H 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。

[0949] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0950]

[0951] The title compound was prepared from Intermediate 39 and 10 in a similar manner to Example 6. 11H 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.

[0952] 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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonacontan-5 6 -yl)-2,5-diazabicyclo[2.2.2]octan-2-yl)piperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0953]

[0954] The title compound was prepared from Intermediate 10 in a manner similar to that in Example 6. 11H 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.

[0955] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0956]

[0957] The title compound was prepared from Intermediate 1 and 32 in a similar manner to Step 4 of Example 26. 11H 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.

[0958] 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-1 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0959]

[0960] The title compound was prepared from Intermediate 1 and 33 in a similar manner to Step 4 of Example 26. 11H 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。

[0961] 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,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0962]

[0963] The title compound was prepared in a similar manner to that in Step 4 of Example 26 using Intermediates 1 and 34 and purified by silica gel column (DCM:CH3OH = 15:1) to obtain the racemate, which was further purified by preparative chiral HPLC under 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, held at 50% for 1.0 min; injection volume: 5 μL), to obtain the title product. 11H 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。

[0964] Example 136: (R)-3-(4-(4-(6-(((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]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)(methyl)amino)-2-azaspiro[3.3]heptan-2-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0965]

[0966] The title compound was prepared from Intermediate 6 in a similar manner to Example 6. 11H 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.

[0967] 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 1 H, 5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0968]

[0969] The title compound was prepared from Intermediate 39 and 6 in a similar manner to Example 6. 11H 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.

[0970] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperazin-1-yl)-3-fluoropiperidin-1-yl)-4-methylpyridin-2-yl)piperidine-2,6-dione

[0971]

[0972] The title compound was prepared from Intermediate 35 in a manner similar to that in Step 4 of Example 26. 11H 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.

[0973] 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 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclonon-5 6 -yl)-2,5-dimethylpiperazin-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)piperidine-2,6-dione

[0974]

[0975] The title compound was prepared from Intermediates 1 and 12 in a manner similar to Example 6. 11H 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。

[0976] 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 1 H,5 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutanacyclononaphthalen-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-6-ethylpyridin-2-yl)piperidine-2,6-dione

[0977]

[0978] The title compound was prepared from Intermediate 36 in a similar manner to Example 6. 11H 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), 7.41 (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。

[0979] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridin-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonadeca-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-4,6-dimethylpyridin-2-yl)piperidine-2,6-dione

[0980]

[0981] The title compound was prepared from Intermediate 37 in a similar manner to Example 6. 11H 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 = 8.1 Hz, 2H). [M+H] + = 812.6

[0982] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonaene-5 6 -yl)piperazin-1-yl)piperidin-1-yl)-3-fluoro-6-methylpyridin-2-yl)piperidine-2,6-dione

[0983]

[0984] The title compound was prepared from Intermediate 38 in a manner similar to that in Example 6. 11H 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).

[0985] [M+H] + = 816.6.

[0986] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonacosane-5 6 -yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)piperidine-2,6-dione

[0987]

[0988] The title compound was prepared from Intermediate 39 in a similar manner to Example 6. 11H 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.

[0989] 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 1 H-9-oxa-4-aza-5(2,1)-benzo[d]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonaene-5 6 -yl)-3-methylpiperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione

[0990]

[0991] The title compound was prepared in a similar manner to Example 6. 11H 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.

[0992] 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]imidazo-2(2,4)-pyridine-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonacos-5 6 -yl)piperazin-1-yl)azetidin-1-yl)piperidin-1-yl)-6-ethylpyridin-2-yl)piperidine-2,6-dione

[0993]

[0994] The title compound was prepared from intermediates 39 and 36 in a similar manner to Example 6. 11H 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.

[0995] 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]imidazo-2(2,4)-pyrido-1(4,5)-pyrazolo-7(1,3)-cyclobutane ring nonaene-5 6 -yl)piperazin-1-yl)azetidin-1-yl)ethyl)-4,6-dimethylpyridin-2-yl)piperidine-2,6-dione

[0996]

[0997] The title compound was prepared from intermediates 39 and 26 in a similar manner to Example 82.

[0998] 11H 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.

[0999] Cell line generation

[1000] 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). Through lentivirus - mediated overexpression, EGFR - Del19 / T790M / C797S, EGFR - Del19 / C797S, EGFR - L858R / T790M / C797S, and EGFR - L858R / C797S were stably expressed in the H1975 cell line respectively. Then, the cells with overexpressed EGFR were knocked out, where the sgRNA targeting EGFR was designed to target only the endogenous EGFR copy and retain the exogenous EGFR copy. After knockout, the edited H1975 cells were seeded into 96 - well plates at a concentration of 1 cell / well and cultured for about 2 weeks to form single clones. The formed clones were screened for the required version by DNA sequencing and whole - exome sequencing analysis. H1975 - Clone No. 28, H1975 - Clone No. 23, H1975 - Clone No. 25, and H1975 - Clone No. 8 were finally identified as homozygous Del19 / T790M / C797S EGFR, Del19 / C797S EGFR, L858R / T790M / C797S EGFR, and L858R / C797S EGFR clones respectively.

[1001] Cell degradation

[1002] Cell treatment

[1003] On day 1, H1975-clone 28 (Del19 / T790M / C797S, or abbreviation: DTC), H1975-clone 23 (Del19 / C797S, or abbreviation: DC), H1975-clone 25 (L858R / T790M / C797S, or abbreviation: LTC), and H1975-clone 8 (L858R / C797S, or abbreviation: LC) cells were seeded at 20,000 cells / well, 30,000 cells / well, 10,000 cells / well, or 5,000 cells / well, respectively, in cell culture medium [RPMI1640 (Gibco, catalog number 72400-047), 10% heat-inactivated FBS, 1% PS (Gibco, catalog number 10378)] in a Corning 96-well plate (catalog number 3599).

[1004] On day 2, H1975-#25, H1975-#28, H1975-#23, and H1975-#8 cells were treated with compounds diluted in 0.2% DMSO cell culture medium and incubated at 37 °C and 5% CO2 for 16 h. The final concentration of the compounds in all assays started at 10 μM and was diluted 5-fold, including a total of 8 doses.

[1005] HTRF assay

[1006] The Total-EGFR cell kit (64NG1PEH) was used to evaluate EGFR degradation.

[1007] After 16 h of treatment, HTRF lysis buffer was added to each well; the plate was sealed and incubated on a plate shaker at room temperature for 1 h; after cell lysis, 16 μL of cell lysate was transferred to a PE 384-well HTRF detection plate; 4 μL of premixed HTRF antibody was added to each well; the plate was covered with a plate sealer, rotated at 1000 rpm for 1 min, and incubated overnight at room temperature; readings were taken on a BMG PheraStar with an HTRF protocol (337 nm - 665 nm - 620 nm).

[1008] The inhibition (degradation) percentage of the compound was calculated by the following formula: Inhibition percentage of the compound = 100 - 100 × (low signal control) / (high control - low control), where signal = each test compound group

[1009] Low control = lysis buffer only (without cells), indicating complete degradation of EGFR.

[1010] High control = cell group with DMSO added and without compound, indicating the microplate reading without EGFR degradation.

[1011] Imax (Dmax) is the maximum percentage of inhibition (degradation).

[1012] The IC 50 (DC 50 ) value of the compound can be obtained by fitting the following formula

[1013] Y = lower + (upper - lower) / (1 + ((IC 50 / X)^slope))

[1014] where X and Y are known values, and IC 50 , slope, upper, and lower are parameters obtained by software fitting. Y is the percentage of inhibition (calculated by the formula), X is the concentration of the compound; IC 50 is the concentration of the compound when 50% inhibition is achieved. The smaller the IC 50 value, the stronger the inhibitory ability of the compound. Vice versa, the higher the IC 50 value, the weaker the inhibitory ability of the compound; the slope represents the slope of the fitting curve, usually about 1*; the lower represents the minimum value of the curve obtained by data fitting, usually 0% ± 20%; the upper represents the maximum value of the curve obtained by data fitting, usually 100% ± 20%. The experimental data is fitted by calculation and analysis using Dotmatics data analysis software.

[1015] Table 1. Degradation (H1975#28DTC and H1975#25-LTC) results of each example

[1016]

[1017]

[1018]

[1019]

[1020] Cell line

[1021] H1975 - Clone No. 8 (L858R / C797S): EGFR - L858R / C797S was stably expressed in the H1975 cell line by lentivirus - mediated overexpression respectively. Then the cells with overexpressed EGFR were knocked out, in which the sgRNA targeting EGFR was designed to target only the endogenous EGFR copy and retain the exogenous EGFR copy. After knockout, the edited H1975 cells were seeded in 96 - well plates at a concentration of 1 cell / well and cultured for about 2 weeks to form single clones. The formed clones were screened for the required version by DNA sequencing and whole - exome sequencing analysis. H1975 - Clone No. 8 was finally confirmed as a homozygous L858R / C797S EGFR clone.

[1022] The BaF3-L858R (abbreviation: L858R) cells were purchased from Kangyuan Botech (Beijing) Co., Ltd.

[1023] Cell degradation

[1024] Cell treatment

[1025] On day 1, the H1975-clone 8 (L858R / C797S) cells were seeded at 5000 cells / well in cell culture medium [RPMI1640 (Gibco, catalog number 72400-047), 10% heat-inactivated FBS, 1% PS (Gibco, catalog number 10378)] in a Corning 96-well plate (catalog number 3599).

[1026] On day 2, the BaF3-L858R cells were seeded at 50000 cells / well in a volume of 54 μL / well in cell culture medium [RPMI1640 (Gibco, without phenol red, catalog number 11835-030), 10% heat-inactivated FBS, 1% PS (Gibco, catalog number 10378)] in a Corning 96-well plate (catalog number 3799).

[1027] On day 2, the H1975-#8 and BaF3-L858R cells were treated with compounds diluted in 0.1% DMSO cell culture medium, incubated for 16 h at 37 °C with 5% CO2. The final concentration of the compounds in all assays started from 10 μM and was diluted 5-fold, including a total of 8 doses.

[1028] HTRF assay

[1029] The Total-EGFR cell kit (64NG1PEH) was used to evaluate EGFR degradation.

[1030] After 16 h of treatment, for H1975-#8 cells, 100 μL of HTRF 1X lysis buffer was added to each well; for BaF3-L858R cells, 20 μL of 4X lysis buffer was added to each well; the plate was sealed and incubated on a plate shaker at room temperature for 1 hour; after cell lysis, 16 μL of cell lysate was transferred to a PE 384-well HTRF detection plate; 4 μL of pre-mixed HTRF antibody was added to each well; the plate was covered with a plate sealer, rotated at 1000 rpm for 1 min, and incubated overnight at room temperature; readings were taken on a BMG PheraStar with an HTRF protocol (337 nm - 665 nm - 620 nm).

[1031] The inhibition (degradation) percentage of the compound is calculated by the following formula: Inhibition percentage of the compound = 100 - 100×(low signal control) / (high control - low control), where the signal = each test compound group

[1032] Low control = lysis buffer only (without cells), indicating that EGFR has been completely degraded.

[1033] High control = cell group with DMSO added and without the compound, indicating the microplate reading without EGFR degradation.

[1034] Imax (Dmax) is the maximum percentage of inhibition (degradation).

[1035] The IC 50 (DC 50 ) value can be obtained by fitting the following formula

[1036] Y = lower + (upper - lower) / (1 + ((IC 50 / X)^slope))

[1037] where X and Y are known values, and IC 50 , slope, upper, and lower are parameters obtained by software fitting. Y is the inhibition percentage (calculated by the formula), X is the concentration of the compound; IC 50 is the concentration of the compound when 50% inhibition is achieved. The smaller the IC 50 value, the stronger the inhibitory ability of the compound. Conversely, the higher the IC 50 value, the weaker the inhibitory ability of the compound; the slope represents the slope of the fitting curve, usually about 1*; the lower represents the minimum value of the curve obtained by data fitting, usually 0% ± 20%; the upper represents the maximum value of the curve obtained by data fitting, usually 100% ± 20%. The experimental data is fitted by calculation and analysis using Dotmatics data analysis software.

[1038] Table 2. Degradation results of each example

[1039]

[1040] The description of the foregoing examples and certain embodiments should be regarded as illustrative rather than limiting the invention as defined by the claims. As will be readily understood, many variations and combinations of the features set forth above can be used without departing from the invention as set forth in the claims. All such variations are intended to be included within the scope of the invention. All references cited are incorporated herein by reference in their entirety.

[1041] It should be understood that even if any prior art publication is mentioned herein, such mention 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 having the formula (I): or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, or its prodrug, wherein: E 1 is N or CR 5 ; E 2 is N or CR 6 ; R 1a 、R 1b 、R 2a and R 2b each independently is absent, hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; each said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -C 3-8 cycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; R 3 and R 4 each independently is hydrogen, -C 1-6 alkyl or -C 3-8 cycloalkyl; each said -C 1-6 alkyl or -C 3-8 cycloalkyl is optionally substituted by at least one substituent selected from hydrogen, halogen, -C 1-6 alkoxy; R 5 and R 6 each independently is absent, hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; each said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -C 3-8 cycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; or R 5 and R 6 together with the carbon atom 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 is optionally substituted by at least one substituent selected from halogen, hydroxy, or -C1-C8 alkyl; R 7 each independently is absent, hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; each said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -C 3-8 cycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -C 1-8 alkoxy, -C 3-8 cycloalkyl or -CN; or Two Rs 7 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 is optionally substituted by at least one substituent halogen, hydroxy, or -C1-C8 alkyl; R 8 and R 9 each independently selected from hydrogen, halogen, -C1-C6 alkyl or C3-C8 cycloalkyl; each of the -C1-C6 alkyl or C3-C8 cycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -C 1-6 alkoxy; R 10 Each independently selected from hydrogen, halogen, -C1-C8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, 5- to 12-membered heteroaryl, -NR 10a R 10b 、-OR 10a 、-SR 10a 、-C(O)R 10a 、-CO2R 10a 、-C(O)NR 10a R 10b 、-NR 10a COR 10b 、-NR 10a CO2R 10b or -NR 10a SO2R 10b or -CN; each of -C1-C8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl or 5- to 12-membered heteroaryl is optionally substituted by at least one R 10c ; R 10a and R 10b are each independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl, and each of the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R 10d ; R 10c and R 10d are each independently selected from halogen, hydrogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, 5- to 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 8f or -NR 10e SO2R 10f or -CN; R 10e and R 10f each independently selected from hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, 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 is 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; each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy or -C 3-8 cycloalkyl is optionally substituted by at least one substituent selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy or CN; L 1 independently selected from -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 、 wherein each of said is optionally substituted by at least one R L1c substituent; Among them, * L1 refers to the position attached to part, and ** L1 refers to the position attached to part; L 2 independently selected from -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 、 wherein each of said is optionally substituted by at least one R L2c ; wherein * L2 refers to the position attached to part, and ** L2 refers to the position attached to part; L 3 independently selected from -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 、 wherein each of said is optionally substituted by at least one R L3c substituent; wherein * L3 refers to the position attached to part, and ** L3 refers to the position attached to part; The R L1c , R L2c and R L3c each independently is 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 heterocyclic group, C6-C 12 aryl or 5- to 12-membered heteroaryl; each of the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl and 5- to 12-membered heteroaryl is optionally substituted by at least one R Lca substituent, R Lca independently is 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 heterocyclic group, C6-C 12 aryl or 5- to 12-membered heteroaryl; or Two Rs 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; said ring is optionally substituted by at least one substituent halogen, hydroxy, -C1-C8 alkyl; Two Rs 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; said ring is optionally substituted by at least one substituent halogen, hydroxy, -C1-C8 alkyl; Two Rs 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; said ring is optionally substituted by at least one substituent halogen, hydroxy, -C1-C8 alkyl; Z 1 and Z 2 each independently is N or CR z ; R z , at each occurrence, is independently selected from absent, hydrogen, halogen, -C 1-8 alkyl, -NR Za R Zb , -OR Za , -SR Za , C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group or CN; -C 1-8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group is each optionally substituted by at least one R Zc ; R Za and R Zb each independently selected from absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl, wherein each of said -C 1-8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Zd ; R Zc and R Zd each independently is halogen, hydroxy, -C1-C8 alkyl, -C 1-8 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl; R 13 Each independently selected from absent, hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl, 5- to 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 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl is each optionally substituted by halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c , -SO2R 13c , -SO2NR 13c R 13d , -COR 13c , -CO2R 13c , -CONR 13c R 13d , -NR 13c R 13d , -NR 13c COR 13d , -NR 13c CO2R 13d or -NR 13c SO2R 13d substituted; At 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- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl; At each occurrence, X 1 、X 2 and X 7 are each independently selected from -CR a or N; At each occurrence, X 3 、X 4 and X 8 are each independently selected from -NR a -, -O-, -S- and -CR a R b -; At each occurrence, X 5 and X 6 are each independently selected from absent, single bond, -C(O)-, -NR a -, and -O-; At each occurrence, R a and R b are each independently selected from hydrogen, hydroxy, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl, and each of the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl is optionally substituted by at least one substituent selected from halogen, hydroxy, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 aryl or 5- to 12-membered heteroaryl; or R a and R b together with the carbon atom 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 is optionally substituted by at least one substituent halogen, hydroxy, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyloxy, -C2-C8 alkynyloxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 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 is each independently 0, 1, 2, 3 or 4; 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; provided that: For L 1 、L 2 or L 3 in any one of them, when X 1 is N, X 5 is a single bond, absent, -C(O)-; and / or when X 2 is N, X 6 is a single bond, absent, -C(O)-; When L 1 is , when X 1 is N, X 5 is a single bond, absent, -C(O)-; and / or X 3 is –CR a R b -; when X 2 is N, X 6 is a single bond, absent, -C(O)-, and / or X 4 is –CR a R b -; When L 2 is , when X 1 is N, X 5 is a single bond, absent, -C(O)-; and / or X 3 is –CR a R b -; when X 2 is N, X 6 is a single bond, absent, -C(O)-, and / or X 4 is –CR a R b -; When L 3 is , when X 1 is N, X 5 is a single bond, absent, -C(O)-; and / or X 3 is –CR a R b -; when X 2 is N, X 6 is a single bond, absent, -C(O)-, and / or X 4 is –CR a R b -.

2. The compound according to claim 1, wherein the compound is selected from formula (IIa) or (IIb), Among them, 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 defined as in any one of the preceding claims; more preferably, the compound is selected from formula (IIIa) or (IIIb), wherein, 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), wherein, 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 defined as in any one of the preceding claims; even more preferably, the compound is selected from formula (Va) or (Vb), wherein, 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 according to any one of the preceding claims, wherein the compound is selected from formula (VIa), preferably, the compound is selected from formula (VIb), (VIc) or (VIc’) more preferably, the compound is selected from formula (VId) or (VIe) more preferably, the compound is selected from formula (VIf) or (VIg) even more preferably, the compound is selected from formula (VIh) or (VIi) even more preferably, the compound is selected from formula (VIj), (VIk), (VIl) or (VIm) even more preferably, the compound is selected from formula (VIn), (VIo), (VIp) or (VIq) Among them, 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 as defined in any of the preceding claims.

4. The compound according to any one of the preceding claims, wherein m1 + m2 + m3 + m4 ≤ 3.

5. The 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.

6. The compound according to any one of the preceding claims, wherein the number of –CH2- in the moiety does not exceed 4, preferably does not exceed 3, and even more preferably does not exceed 2.

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

8. A compound according to any one of the preceding claims, wherein 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 enyl, -C 2-8 ynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or -CN; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or -CN.

9. The compound according to any one of the preceding claims, wherein 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CF3, -CHF2, -CN, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3; Preferably, R 1a , R 1b , R 2a and R 2b are each independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3 or -CHF2, -CH2OCH3.

10. The compound according to any one of the preceding claims, wherein 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CF3, -CHF2, -CN, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3; Preferably, R 5 and R 6 are each independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3 or -CHF2, -CH2OCH3.

11. A compound according to any one of the preceding claims, wherein R 5 and R 6 together with the carbon atom 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 is optionally substituted by at least one substituent selected from F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl; Preferably, R 5 and R 6 together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered ring, which ring is optionally substituted by at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl.

12. The compound according to any one of the preceding claims, wherein R 7 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CF3, -CHF2, -CN, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3; Preferably, R 7 is independently hydrogen, F, Cl, methyl, methoxy, cyclopropyl, -CF3 or -CHF2, -CH2OCH3.

13. The compound according to any one of the preceding claims, wherein the two Rs 7 together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, the ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted by at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl; Preferably, the two Rs 7 together with the carbon atom to which they are attached form a 3-, 4-, 5- or 6-membered ring, which ring is optionally substituted by at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl.

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

15. The compound according to any one of the preceding claims, wherein R 10 is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group, phenyl, a 5- to 12-membered heteroaryl, -NR 10a R 10b , -OR 10a , -SR 10a , -C(O)R 10a , -CO2R 10a , -C(O)NR 10a R 10b , -NR 10a COR 10b , -NR 10a CO2R 10b or -NR 10a SO2R 10b or -CN; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group or phenyl is optionally substituted with at least one R 10c ; R 10a and R 10b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group or phenyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group or phenyl is optionally substituted by at least one substituent R 10d ; R 10c and R 10d are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, 5- to 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 selected from 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 heterocyclic group, phenyl or 5- to 12-membered heteroaryl; Preferably, R 10 is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group, -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; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group or phenyl is optionally substituted by at least one R 10c ; R 10a and R 10b each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group or phenyl; R 10c Each independently selected from 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 heterocyclic group, phenyl, 5- to 12-membered heteroaryl, oxo(=O), -NR 10e R 10f , -OR 10e or -CN; R 10e and R 10f each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group, phenyl or a 5- to 12-membered heteroaryl group; More preferably, R 10 is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a 3- to 8-membered heterocyclic group, -NR 10a R 10b , -OR 10a , -CO2R 10a or -C(O)NR 10a R 10b ; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a 3- to 8-membered heterocyclic group is optionally substituted with at least one R 10c ; R 10a and R 10b each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group; R 10c Each independently selected from 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 each independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl; Even more preferably, R 10 is independently selected from H, F, Cl, Br, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -COOH, -CONH2, -CH2OCH3 or -CH2OH.

16. The compound according to any one of the preceding claims, wherein the 17. The compound according to any one of the preceding claims, wherein the moiety is selected from 18. A compound according to any one of the preceding claims, wherein 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 enyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted by at least one substituent selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; preferably, R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d 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 are each independently hydrogen or methyl.

19. A compound according to any one of the preceding claims, wherein L 1 is selected from -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 , wherein the Each of which is optionally substituted by at least one R L1c substituted; Each of said R L1c is independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl and 5- to 12-membered heteroaryl is optionally substituted with at least one R Lca substituent; R Lca independently is oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; or Two Rs 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 is optionally substituted by at least one substituent F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; R a selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl.

20. The compound according to any one of the preceding claims, wherein L 1 is selected from -O-, -N(CH3)-, -C(O)-, -NH-, *L1 -C(O)N(CH3)- **L1 and *L1 -C(O)NH- **L1 and *L1 -C(O)O- **L1 and *L1 -C(O)N(C2H5)- **L1 and *L1 -C(O)N(C3H7)- **L1 and *L1 -N(CH3)C(O)- **L1 and *L1 -NHC(O)- **L1 and *L1 -OC(O)- **L1 and *L1 -N(C2H5)C(O)- **L1 and *L1 -N(C3H7)C(O)- **L1 and 21. The compound according to any one of the preceding claims, wherein L 2 is selected from -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 , wherein said Each of which is optionally substituted by at least one R L2c substituted; Each of said R L2c is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl and 5- to 12-membered heteroaryl is optionally substituted with at least one R Lca substituent; R Lca independently is oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; or Two Rs 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 is optionally substituted by at least one substituent selected from F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; R a selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted by at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl.

22. The compound according to any one of the preceding claims, wherein L 2 is selected from -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 , 23. A compound according to any one of the preceding claims, wherein L 3 is selected from -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 , wherein the Each of which is optionally substituted by at least one R L3c substituted; Each of said R L3c is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl and 5- to 12-membered heteroaryl is optionally substituted with at least one R Lca substituent; R Lca independently is oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; or Two Rs 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 is optionally substituted by at least one substituent selected from F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; R a Selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted by at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl.

24. A compound according to any one of the preceding claims, wherein L 3 is selected from -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 , 25. The compound according to any one of the preceding claims, wherein Partially selected from 26. The compound according to any one of the preceding claims, wherein Selected in part from 27. The compound according to any one of the preceding claims, wherein X 7 is independently selected from -CR a or N; R a independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl being optionally substituted by at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl; Preferably, X 7 is independently selected from -CH, -C(CH3) or N; preferably, X 7 is independently selected from -CH.

28. A compound according to any one of the preceding claims, wherein X 8 is independently selected from -NR a -, -O-, -S- and -CR a R b -; At each occurrence, R a and R b each independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, 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-.

29. The compound according to any one of the preceding claims, wherein selected from Preferably, selected from 30. A compound according to any one of the preceding claims, wherein Z 1 and Z 2 at most one of which is N; preferably, Z 1 and Z 2 are each independently CR z .

31. A compound according to any one of the preceding claims, wherein R Z , in each occurrence, is 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, a 3- to 8-membered heterocyclic group or CN; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or a 3- to 8-membered heterocyclic group is optionally substituted by at least one R Zc ; R Za and R Zb each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group, phenyl or a 5- to 12-membered heteroaryl, each of the hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 12-membered heteroaryl being optionally substituted by at least one substituent R Zd substituted; R Zc and R Zd each independently is -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclic group, phenyl or a 5- to 12-membered heteroaryl; Preferably, R z is selected from H, -CH3, -C2H5, F, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -C3H7, -OCH2F, -OCHF2, -OCH2CF3, -OCF 3、 -SCF3, -CF3 or -CH(OH)CH3.

32. A compound according to any one of the preceding claims, wherein R 13 is independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, a 3- to 8-membered heterocyclic group, -C6-C 12 aryl, a 5- to 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 ; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, a 3- to 8-membered heterocyclic group, -C6-C 12 aryl, a 5- to 12-membered heteroaryl is optionally substituted by F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, a 3- to 8-membered heterocyclic group, -C6-C 12 aryl, a 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c , -SO2R 13c , -SO2NR 13c R 13d , -COR 13c , -CO2R 13c , -CONR 13c R 13d , -NR 13c R 13d , -NR 13c COR 13d , -NR 13c CO2R 13d or –NR 13c SO2R 13d is substituted; R 13a 、R 13b 、R 13c and R 13d each independently is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 enyl, -C 2-8 ynyl, a 3- to 8-membered heterocyclic group, -C6-C 12 aryl or a 5- to 12-membered heteroaryl; Preferably, R 13 is independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF 3、 -SCF3 or phenyl.

33. The compound according to any one of the preceding claims, wherein is 34. The compound according to any one of the preceding claims, wherein is 35. The compound according to any one of the preceding claims, the compound is selected from 36. A pharmaceutical composition comprising the compound according to any one of claims 1 - 32 or its pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug, and a pharmaceutically acceptable excipient.

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

38. The method according to 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. Use of a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof according to any one of claims 1 - 32 in the manufacture of a medicament for the treatment of a disease which can be affected by modulation of EGFR.

40. 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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