Degradation of (EGFR) by binding of E3 ligase ligands to EGFR inhibitors and methods of use

Abstract

Disclosed herein are novel bifunctional compounds formed by combining an EGFR inhibitor moiety and an E3 ligase ligand moiety that function to recruit target proteins to E3 ubiquitin ligase for degradation, and methods for their preparation and use.

Description

[Technical field]

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

[0002] The proteolysis-inducing chimeric molecule is composed of two protein-binding molecules covalently linked together, one capable of binding to an E3 ubiquitin ligase and the other capable of binding to a target protein (POI) for degradation (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98:8554-9 and Sakamoto KMet al., Methods Enzymol. 2005;399:833-847). Rather than inhibiting the enzymatic activity of the target protein, the recruitment of E3 ligase to a specific unwanted protein leads to ubiquitination and subsequent degradation of the target protein by the proteasome. The entire process of ubiquitination and proteasomal degradation is known as the ubiquitin-proteasome pathway (UPP) (Ardley H. et al., Essays Biochem. 2005, 41, 15-30; Komander D. et al., Biochem. 2012, 81, 203-229; Grice GL et al., Cell Rep. 2015, 12, 545-553; and Swatek KNet al., Cell Res. 2016, 26, 399-422). The proteasome is a protein complex that degrades unnecessary, misfolded, or abnormal proteins into small peptides to maintain cellular health and productivity. Ubiquitin ligases, also called E3 ubiquitin ligases, directly catalyze the transfer of ubiquitin from E2s to target proteins for degradation.Although it is estimated that there are more than 600 E3 ligases encoded in the human genome, only a limited number of E3 ubiquitin ligases have been widely applied in small molecule PROTAC technology: cereblon (CRBN), Von Hippel-Lindau (VHL), mouse double minute 2 homologue (MDM2), and cellular inhibitor of apoptosis protein (cIAP) (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578), recombinant Human Ring Finger Protein114 (RNF114) (Spradlin, JNet al. Nat. Chem. Biol. 2019, 15, 747-755), and DDB1 and CUL4 Associated Factor 16 (DCAF16) (Zhang, X. et al. Nat. Chem. Biol. 2019, 15, 737-746). For example, cereblon (CRBN) forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and cullin 4A (CUL4A) to ubiquitinate several other proteins, which are then degraded via the proteasome. (Yi-An Chen, et al., Scientific Reports 2015, 5, 1-13) Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, inhibit CRL4A. CRBNIt functions as a monovalent promoter of PPIs by binding to the cereblon (CRBN) subunit of the E3 ligase complex and recruiting neo-substrate proteins. (Matyskiela, ME et al., Nat Chem Biol 2018, 14, 981-987). As a result, the ability of thalidomide and its derivatives to recruit CRBN has been widely applied in targeted proteolysis-inducing chimeric molecules (PROTAC) related research (Christopher T. et al. ACS Chem.Biol. 2019, 14, 342-347. and Honorine L. et al, ACS Cent. Sci. 2016, 2, 927-934). PROTACs have great potential to remove protein targets that are "undruggable" by traditional inhibitors or that are non-enzymatic proteins. (Chu TT.et al.,Cell Chem Biol.2016;23:453-461, Qin C.et al.,J Med Chem2018;61:6685-6704, Winter GE.et al.,Science 2015;348:1376-1381).In recent years, in antitumor research, PROTACs have been reported as useful regulators that promote the selective degradation of a wide range of target proteins (Lu J.et al.,Chem Biol.2015;22(6):755-763; Ottis P.et al.,Chem Biol.2017;12(4):892-898.; Crews CMet al.,J Med Chem.2018;61(2):403-404; Neklesa TKet al.,Pharmacol Ther.2017,174:138-144.; Cermakova K.et al.,Molecules,2018.23(8).; An S.et al.,EBioMedicine,2018.; Lebraud H.et al.,Essays Biochem.2017;61(5):517-527.; Sun YHet al.,Cell Res.2018;28:779-81, Toure M.et al.,Angew Chem Int Ed Engl.2016;55(6):1966-1973, Yonghui Sun et al.,Leukemia,volume 33,pages2105-2110(2019),Shaodong Liu et al.,Medicinal Chemistry Research, volume 29, pages 802-808 (2020)), and for example, patent publications US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO20161 97032, WO2016197114, WO2017011590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449, and WO2018071606.

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

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

[0005] The present application provides novel bifunctional compounds and compositions for the treatment of serious diseases. One object of the present invention is to The present invention provides compounds and derivatives formed by combining an EGFR inhibitor moiety with an E3 ligase ligand moiety, which function to recruit target proteins to E3 ubiquitin ligase for degradation, as well as methods for their preparation and use.

[0006] Aspect 1. A compound of formula (I): [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analogue thereof, or a prodrug thereof, During the ceremony, Z is N or CR z and; R z is H, -C1-C8 alkyl, C3-C8 cycloalkyl, or halogen; R 1 and R 2 are each independently -C 1-8 Alkyl or -C 3-8 cycloalkyl, each of said -C1-C8 alkyl or C3-C8 cycloalkyl optionally substituted with at least one halogen; R 3 is hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, halogen, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, -OR 3a , -SR 3a , -CN, -C(O)R 3a , -CO2R 3a , -C(O)NR 3a R 3b , -NR 3a R 3b , -NR 3a COR 3b and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12Each aryl or 5-12 membered heteroaryl is optionally selected from 0-2 R 3c Replaced with; R 3a and R 3b are each independently hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; R 3c is, for each occurrence, independently selected from halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; R 4 is halogen, methyl, or methoxy; R 5 is hydrogen, halogen, -C1-C8 alkyl, -NR 5a R 5b , -OR 5a , -SR 5a , C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, 5-12 membered heteroaryl, or CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, aryl, or 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one R 5c Replaced with; R 5a and R 5b are each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12aryl, or 5-12 membered heteroaryl, and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 5d Replaced with; R 5c and R 5d are each independently halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; R 6 is hydrogen, halogen, -C1-C8 alkyl, -NR 6a R 6b , -OR 6a , -SR 6a , C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, 5-12 membered heteroaryl, or CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, aryl, or 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one R 6c Replaced with; R 6a and R 6b are each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl, and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 6d Replaced with; R 6c and R6d are each independently halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; R 7 and R 8 are each independently hydrogen, halogen, -C1-C8 alkyl, -NR 7a R 7b , -OR 7a , -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, 5-12 membered heteroaryl, or -CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 7c is replaced by; or R 7a and R 7b are each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl, and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 7d Replaced with; R 7c and R 7d are each independently halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; [ka] teeth, [ka] and; L 1 teeth, [ka] where *L1 teeth, [ka] indicates the position at which the moiety is attached, and **L1 teeth, [ka] refers to the position at which the moiety is attached; L 2 teeth, [ka] or *L2 -(CH2) 1-3 - **L2 where: *L2 teeth, [ka] indicates the position at which the moiety is attached, and **L2 teeth, [ka] refers to the position at which the moiety is attached; L 3 teeth, [ka] where *L3 teeth, [ka] indicates the position at which the moiety is attached, and **L3 teeth, [ka] refers to the position at which the moiety is attached; The above [ka] , *L2- (CH2) 1-3 - **L2 , [ka] , -N(CH3)-, -NH-, [ka] Each of the is optionally 0 to 2 R La Replaced with; R La is, for each occurrence, independently selected from halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; n is 0 or 1; However, the compound is [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analogue thereof, or a prodrug thereof, which is not

[0007] In other embodiments, the compound has formula (Ia): [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analogue thereof, or a prodrug thereof; During the ceremony, Z is N or CR z and; Rz is H, -C1-C8 alkyl, C3-C8 cycloalkyl, or halogen; R 1 and R 2 are each independently -C 1-8 Alkyl or -C 3-8 cycloalkyl, each of said -C1-C8 alkyl or C3-C8 cycloalkyl optionally substituted with at least one halogen; R 3 is hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, halogen, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, -OR 3a , -SR 3a , -CN, -C(O)R 3a , -CO2R 3a , -C(O)NR 3a R 3b , -NR 3a R 3b , -NR 3a COR 3b and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each aryl or 5-12 membered heteroaryl is optionally selected from 0-2 R 3c Replaced with; R 3a and R 3b are each independently hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; R 3c is, for each occurrence, independently selected from halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12aryl, or 5-12 membered heteroaryl; R 4 is halogen, methyl, or methoxy; R 5 is hydrogen, halogen, -C1-C8 alkyl, -NR 5a R 5b , -OR 5a , -SR 5a , C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, 5-12 membered heteroaryl, or CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, aryl, or 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one R 5c Replaced with; R 5a and R 5b are each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl, and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 5d Replaced with; R 5c and R 5d are each independently halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; R 6 is hydrogen, halogen, -C1-C8 alkyl, -NR 6a R 6b , -OR 6a , -SR 6a, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, 5-12 membered heteroaryl, or CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, aryl, or 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one R 6c Replaced with; R 6a and R 6b are each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl, and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 6d Replaced with; R 6c and R 6d are each independently halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; R 7 and R 8 are each independently hydrogen, halogen, -C1-C8 alkyl, -NR 7a R 7b , -OR 7a , -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, 5-12 membered heteroaryl, or -CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 7c is replaced by; or R 7a and R 7b are each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl, and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 7d Replaced with; R 7c and R 7d are each independently halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; [ka] teeth, [ka] Selected from; L 1 teeth, [ka] where *L1 teeth, [ka] indicates the position at which the moiety is attached, and **L1 teeth, [ka] refers to the position at which the moiety is attached; L 2 teeth, [ka] or *L2 -(CH2) 1-3 - **L2 where: *L2 teeth, [ka] indicates the position at which the moiety is attached, and **L2 teeth, [ka] refers to the position at which the moiety is attached; L 3 teeth, [ka] -N(CH3)-, -NH-, or [ka] where *L3 teeth, [ka] indicates the position at which the moiety is attached, and **L3 teeth, [ka] refers to the position at which the [ka] *L2- (CH2) 1-3 - **L2 , [ka] -N(CH3)-, -NH-, [ka] Each of the is optionally 0 to 2 R La Replaced with; RLa is, for each occurrence, independently selected from halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; The compound, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analogue thereof, or a prodrug thereof, wherein n is 0 or 1.

[0008] In other embodiments, the compound has the formula (Ib): [ka] or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analogue thereof, or a prodrug thereof; During the ceremony, Z is N or CR z and; R z is H, -C1-C8 alkyl, C3-C8 cycloalkyl, or halogen; R 1 and R 2 are each independently -C 1-8 Alkyl or -C 3-8 cycloalkyl, each of said -C1-C8 alkyl or C3-C8 cycloalkyl optionally substituted with at least one halogen; R 3 is hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, halogen, 3-8 membered heterocyclyl, C6-C 12 Aryl, 5-12 membered heteroaryl, -OR 3a , -SR 3a , -CN, -C(O)R 3a , -CO2R 3a , -C(O)NR 3a R 3b , -NR 3a R 3b, -NR 3a COR 3b and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each aryl or 5-12 membered heteroaryl is optionally selected from 0-2 R 3c Replaced with; R 3a and R 3b are each independently hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; R 3c is, for each occurrence, independently selected from halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; R 4 is halogen, methyl, or methoxy; R 5 is hydrogen, halogen, -C1-C8 alkyl, -NR 5a R 5b , -OR 5a , -SR 5a , C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, 5-12 membered heteroaryl, or CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, aryl, or 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one R 5c Replaced with; R 5a and R 5bare each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl, and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 5d Replaced with; R 5c and R 5d are each independently halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; R 6 is hydrogen, halogen, -C1-C8 alkyl, -NR 6a R 6b , -OR 6a , -SR 6a , C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 aryl, 5-12 membered heteroaryl, or CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, aryl, or 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one R 6c Replaced with; R 6a and R 6b are each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl, and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 6d Replaced with; R 6c and R 6d are each independently halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5-12 membered heteroaryl; R 7 and R 8 are each independently hydrogen, halogen, -C1-C8 alkyl, -NR 7a R 7b , -OR 7a , -C3-C8 cycloalkyl, 3-8 membered heterocyclyl, -C6-C 12 aryl, 5-12 membered heteroaryl, or -CN; -C1-C8 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 7c is replaced by; or R 7a and R 7b are each independently hydrogen, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl, and the -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, C6-C 12 Each of the aryl, or 5- to 12-membered heteroaryl, optionally contains at least one substituent R 7d Replaced with; R 7c and R 7dare each independently halogen, hydroxy, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; [ka] [ka] Selected from; L 1 teeth, [ka] where *L1 teeth, [ka] indicates the position at which the moiety is attached, and **L1 teeth, [ka] refers to the position at which the moiety is attached; L 2 teeth, [ka] or *L2 -(CH2) 1-3 - **L2 where: *L2 teeth, [ka] indicates the position at which the moiety is attached, and **L2 teeth, [ka] refers to the position at which the moiety is attached; The above [ka] ,*L2 -(CH2) 1-3 - **L2 Each of the is optionally 0 to 2 R La Replaced with; R La is, for each occurrence, independently selected from halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5-12 membered heteroaryl; The compound, or an N-oxide thereof, or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analogue thereof, or a prodrug thereof, wherein n is 0 or 1.

[0009] Aspect 2. The compound is of formula (IIa) or (IIb): [ka] During the ceremony, R z , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , [ka] , L 1 , L 2 , L 3 and n are each defined as in embodiment 1.

[0010] Aspect 3. The compound is represented by formula (IIIa)-(IIIu): [ka] [ka] [ka] [ka] [ka] [ka] [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, L 1 , L 2 , L 3 and n are each defined as in embodiment 1.

[0011] Aspect 4. The compound is represented by formula (IVa)-(IVh): [ka] [ka] [ka] During the ceremony, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and [ka] and R are each defined as in embodiment 1,

[0012] 5. Z is N or CRz and R z is H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -F, -Cl, -Br, or -I.

[0013] 6. Z is N or CR z and R z is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -F, -Cl, -Br, or -I.

[0014] Aspect 7.R 1 and R 2 is each independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0015] Aspect 8.R 1 and R 2 is each independently methyl.

[0016] Aspect 9.R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -F, -Cl, -Br, -I, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -OR 3a , -SR 3a , -CN, -C(O)R 3a , -CO2R 3a , -C(O)NR 3aR 3b , -NR 3a R 3b , -NR 3a COR 3b each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -F, -Cl, -Br, -I, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally comprises 0, 1, or 2 R 3c Replaced with; R 3a and R 3b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; R 3c is, for each occurrence, independently, -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0017] Aspect 10.R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -F, -Cl, -Br, -I, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl; Preferably, R3 is methyl, ethyl, propyl (n-propyl, iso-propyl), butyl (n-butyl, iso-butyl, sec-butyl, tert-butyl), pentyl, hexyl, heptyl, octyl.

[0018] Aspect 11.R 4 is -F, -Cl, -Br, -I, Me, OMe.

[0019] Aspect 12.R 4 The compound of any of the preceding embodiments, wherein is -Cl or -Br.

[0020] Aspect 13.R 5 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, 5-12 membered heteroaryl, -NR 5a R 5b , -OR 5a , -SR 5a or CN; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally comprises at least one R 5c Replaced with; R 5a and R 5bare each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, each of which may optionally be selected from at least one R 5d Replaced with; R 5c and R 5d are each independently selected from -F, -Cl, -Br, -I, hydroxy, 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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0021] Aspect 14.R 5 -OR 5a and R 5ais selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, optionally selected from at least one R 5d Replaced with; R 5d is independently selected from -F, -Cl, -Br, -I, hydroxy, 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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; Preferably, R 5 is methoxy, ethoxy, propoxy (n-propoxy, isopropoxy), butoxy (n-butoxy, isobutoxy, sec-butoxy, tert-butoxy), pentoxy, hexoxy, heptoxy, or octoxy.

[0022] Aspect 15.R 6 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR 6a R 6b , -OR 6a , -SR 6a, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one R 6c Replaced with; R 6a and R 6b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, each of which may optionally be selected from at least one R 6d Replaced with; R 6c and R 6d are each independently selected from -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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0023] Aspect 16.R 6is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may optionally be selected from the group consisting of at least one R 6c Replaced with; R 6c is independently selected from -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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; Preferably, R 6 is hydrogen, methyl, ethyl, propyl (n-propyl, iso-propyl), butyl (n-butyl, sec-butyl, iso-butyl, tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0024] Aspect 17.R 7 and R 8 are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR 7a R 7b , -OR 7a, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl may optionally be selected from at least one R 7c is replaced by; or R 7a and R 7b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, each of which may optionally be selected from at least one R 7d is replaced by; or R 7c and R 7d are each independently -F, -Cl, -Br, -I, hydroxy, 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, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

[0025] Aspect 18.R 7 and R8 are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; Preferably, R 7 and R 8 is independently hydrogen, -F, -Cl, -Br, or -I.

[0026] Aspect 19. [ka] The part is [ka] The compound according to any of the preceding aspects, selected from:

[0027] Aspect 20. [ka] The part is [ka] The compound according to any of the preceding aspects, selected from:

[0028] Aspect 21. [ka] The part is [ka] The compound according to any of the preceding aspects, selected from:

[0029] Aspect 22. [ka] The part is [ka] [ka] The compound according to any of the preceding aspects, selected from:

[0030] Aspect 23. The compound of any of the preceding aspects, wherein the compound is selected from: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] In some embodiments, a compound disclosed herein, including general compounds and specific compounds, is not any one of the compounds of Examples 1-756 of PCT / CN2021 / 106482.

[0031] Aspect 24. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 23, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in combination with a pharma- ceutically acceptable excipient.

[0032] Aspect 25. A method for treating a disease in which EGFR modulation may be affected, comprising administering to a subject in need thereof an effective amount of a compound according to any one of aspects 1 to 23, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

[0033] Aspect 26. The method of aspect 25, wherein said disease is selected from cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0034] Aspect 27. Use of a compound according to any one of aspects 1 to 23, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in the preparation of a medicament for treating a disease in which EGFR modulation may be affected.

[0035] Embodiment 28. The use according to embodiment 27, wherein said disease is selected from cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] The following terms have the meanings indicated throughout this specification. Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0037] The following terms have the meanings indicated throughout this specification.

[0038] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" are intended to include the corresponding plural forms unless the context clearly indicates otherwise.

[0039] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0040] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms, such as 1 to 12 carbon atoms, further such as 1 to 10 carbon atoms, even further such as 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0041] The term "propyl" includes 1-propyl or n-propyl or n-Pr, 2-propyl or isopropyl or i-Pr.

[0042] The term "butyl" includes 1-butyl or n-butyl or n-Bu, 2-methyl-1-propyl or isobutyl or i-Bu, 1-methylpropyl or s-butyl or s-Bu, 1,1-dimethylethyl or t-butyl or t-Bu.

[0043] 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.

[0044] 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.

[0045] The term "alkylene" refers to a divalent alkyl group formed by removing two hydrogens from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, and the like.

[0046] The term "halogen" includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0047] The term "alkenyl" includes hydrocarbon groups selected from linear and branched chain hydrocarbon groups containing at least one C=C double bond and 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms. Alkenyl groups, such as C 2-6 Examples of alkenyl include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups.

[0048] The term "alkenylene" refers to a divalent alkenyl group formed by removing two hydrogens from an alkene. Alkenylene includes, but is not limited to, vinylidene, butenylene, and the like.

[0049] The term "alkynyl" includes hydrocarbon groups selected from linear and branched chain hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms. Alkynyl groups, such as C 2-6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0050] The term "alkynylene" refers to a divalent alkynyl group obtained by removing two hydrogens from an alkyne. Alkynylene includes, but is not limited to, ethynylene, and the like.

[0051] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0052] For example, the cycloalkyl group may contain 3 to 12 carbon atoms, such as 3 to 10 carbon atoms, further such as 3 to 8 carbon atoms, further such as 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Further for example, the cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms, such as 3 to 10 carbon atoms, further such as 3 to 8 carbon atoms, 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, saturated monocyclic cycloalkyl groups such as C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (C 3-6 Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0053] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings which share one atom.

[0054] The term "fused cycloalkyl" includes bicyclic cycloalkyl groups, as defined herein, that are saturated and formed by two or more rings sharing two adjacent atoms.

[0055] The term "bridged cycloalkyl" includes cyclic structures containing carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other. The term "7-10 membered bridged cycloalkyl" includes cyclic structures containing 7-12 carbon atoms and formed by two rings sharing two atoms that are not adjacent to each other.

[0056] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo 3-8 membered cycloalkyl, benzo C 4-6 Examples include, but are not limited to, cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused rings, which refers to ring structures containing 8-9 ring atoms within the scope of the preceding examples.

[0057] The term "aryl" when used alone or in combination with other terms, - 5 and 6 membered carbocyclic aromatic rings, for example phenyl; - bicyclic ring systems, for example 7-12 membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl; and - Tricyclic ring systems, such as 10-15 membered tricyclic ring systems, including groups selected from tricyclic ring systems in which at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0058] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0059] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0060] The term "heteroaryl" means - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1-4 heteroatoms, or in some embodiments 1-3 heteroatoms, and in some embodiments 1-2 heteroatoms, with the remaining ring atoms being carbon; - a 7-12 membered bicyclic ring containing at least one heteroatom selected from N, O, and S, e.g., 1-4 heteroatoms, or in some embodiments 1-3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, with the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring; and - includes a group selected from 11-14 membered tricyclic rings containing at least one heteroatom selected from N, O, and S, for example, 1-4 heteroatoms, or in some embodiments 1-3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being in the aromatic ring.

[0061] When the total number of S and O atoms in a heteroaryl group is more than 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is 1 or less. When a heteroaryl group contains two or more heteroatom ring members, the heteroatoms may be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group may be oxidized to form an N-oxide.

[0062] In particular, the term "bicyclic fused heteroaryl" includes 7-12 membered, preferably 7-10 membered, more preferably 9 or 10 membered fused bicyclic heteroaryl rings as defined herein. Typically, bicyclic fused heteroaryls are 5 / 5 membered, 5 / 6 membered, 6 / 6 membered, or 6 / 7 membered bicyclic. Groups can be attached to the remainder of the molecule via either ring.

[0063] "Heterocyclyl", "heterocycle", or "heterocyclic" are used interchangeably and include non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spirocyclic, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.

[0064] The term "H" or "hydrogen" as disclosed herein includes hydrogen and non-radioactive deuterium isotopes.

[0065] The term "at least one substituent" disclosed herein includes, for example, 1 to 4 substituents, for example, 1 to 3 substituents, further for example, 1 or 2 substituents, so long as valence theory is satisfied. For example, "at least one substituent F" disclosed herein includes, for example, 1 to 4 substituents F, for example, 1 to 3 substituents F, further for example, 1 or 2 substituents F.

[0066] The term "divalent" refers to a linking group that can form a covalent bond with two other moieties. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkene to form the linking group. The terms "divalent aryl group," "divalent heterocyclyl group," or "divalent heteroaryl group" should be understood similarly.

[0067] The compounds disclosed herein may have asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they may further exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, such as substantially purely resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharma-ceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0068] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, such double bond is intended to include both E and Z geometric isomers.

[0069] When the compounds disclosed herein comprise a disubstituted cyclic ring system, the substituents found in such ring system can adopt cis and trans configuration.Cis configuration means that both substituents are found on the top side of the arrangement of two substituents on carbon, while trans means that they are on opposite sides.For example, disubstituted cyclic ring system can be cyclohexyl or cyclobutyl ring.

[0070] It may be advantageous to separate reaction products from each other and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter, separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse and normal phase, size exclusion, ion exchange, high, medium, and low pressure liquid chromatography methods and apparatus, small scale analytical, simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques. One skilled in the art will be able to select and apply the technique most likely to achieve the desired separation.

[0071] "Diastereomers" refers to stereoisomers of a compound that have two or more chiral centers, but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional recrystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of chiral HPLC columns.

[0072] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3)(1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0073] Some of the compounds disclosed herein may exist as so-called tautomers, which have different points of hydrogen attachment. For example, compounds containing a carbonyl -CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both keto and enol forms are intended to be included, both individually and in mixtures thereof.

[0074] "Prodrug" refers to a derivative of an active drug that requires a transformation within the body to release the active drug. In some embodiments, the transformation is enzymatic. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to an active drug.

[0075] "Deuterated analog" refers to a derivative of an active agent in which any hydrogen has been replaced with deuterium. In some embodiments, the deuteration site is in the Warhead portion. In some embodiments, the deuteration site is in the Linker portion. In some embodiments, the deuteration site is in the Degron portion.

[0076] "Pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, within the scope of sound medical judgment, and that correspond to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately, by reacting a free base functional group with a suitable organic acid, or by reacting an acidic group with a suitable base. The term also includes salts of stereoisomers (such as enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the invention.

[0077] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, an addition salt, such as a pharma- ceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used without undue experimentation to prepare non-toxic pharma-ceutically acceptable addition salts.

[0078] The terms "administration," "administering," "treating," and "treatment," as used herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with the cell as well as contact of a reagent with a fluid, which will contact the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell with a reagent, diagnostic, binding compound, or with another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0079] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. The term "therapeutically effective amount" can vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case may be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug thereof, and / or at least one pharma- ceutically acceptable salt thereof, which is effective in "treating" a disease or disorder in a subject, as defined herein. In the case of a combination therapy, the term "therapeutically effective amount" refers to the total amount of the combination objects for effective treatment of a disease, disorder, or condition.

[0080] The term "disease" refers to any disease, ailment, illness, symptom or sign, and may be interchangeable with the term "disorder" or "medical condition."

[0081] Throughout this specification and the claims that follow, unless the context otherwise requires, the term "comprise," as well as variations such as "comprise" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the term "comprising" can be substituted with the terms "containing," "including," or, in some cases, "having."

[0082] Throughout this specification and the following claims, "C n-m " or "C n -C m " denotes an inclusive range, where n and m are integers and indicate the number of carbons. Examples include 1-8 , C 1-6 , C1-C8, C1-C6, etc.

[0083] Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. EXAMPLES

[0084] The following examples are intended to be merely illustrative and should not be considered as limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and used without further purification unless otherwise indicated. Unless otherwise indicated, reactions described below were carried out in anhydrous solvents under a positive pressure of nitrogen or argon, or with drying tubes, reaction flasks were fitted with rubber septa for the introduction of substrates and reagents by syringe, and glassware was oven-dried and / or heat-dried.

[0085] 1 1 H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. 1 H NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone, or (CD3)2CO as solvents and tetramethylsilane (0.00 ppm) or residual solvent as reference standards (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; DO: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05). When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sexlet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). When given, coupling constants are reported in Hertz (Hz).

[0086] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity), detector: MWD (190-400 nm), mass detector: 6120SQ, mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid acetonitrile solution, column: Poroshell 120EC-C18, 4.6 x 50 mm, 2.7 pm Gradient method: flow rate: 1.8 mL / min time (min) A (%) B (%) [Table 2] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: 0.1% formic acid aqueous solution, B: 0.1% formic acid acetonitrile solution, column: Poroshell 120EC-C18, 4.6 x 50 mm, 2.7 pm Gradient method: flow rate: 1.8 mL / min time (min) A (%) B (%) [Table 3] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: 0.1% formic acid in water, B: 0.1% formic acid in acetonitrile, column: Poroshell 120EC-C18, 4.6 x 50 mm, 2.7 pm Gradient method: flow rate: 1.2 mL / min time (min) A (%) B (%) [Table 4] Preparative HPLC was performed on a column (150×21.2 mm ID, 5 pm, Gemini NXC18) with a flow rate of 20 ml / min, injection volume of 2 ml, room temperature, and UV detection at 214 nm and 254 nm.

[0087] In the examples below, the following abbreviations are used: [Table 5-1] [Table 5-2] [Table 5-3]

[0088] Example 1: (R)-3-(4-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (30 g, 62.24 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (10.68 g, 74.69 mmol), and Cs2CO3 (40.58 g, 124.48 mmol) in 500 mL of dioxane was added Pd2(dba)3 (2.85 g, 3.11 mmol) and Xantphos (3.6 g, 6.22 mmol) under N2 atmosphere. 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 vacuum and purified by silica column chromatography (EA:PE=0-80%) to give the crude product. The crude material was recrystallized with MeOH and filtered. The filter cake was dried to give the title compound (26.8 g, 79% yield). [M+H] + =544.9.

[0089] Step 2: 3-(2,6-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione [ka] To a solution of 8-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (26.8 g, 49.26 mmol) in 400 mL of DMF and 80 mL of iPrOH was added Pd / C (27 g, 10 wt%, wet). The mixture was stirred at 45° C. under H2 atmosphere (4 bar) for 16 h. The mixture was filtered and the filter cake was washed with DMF. The combined liquid was concentrated in vacuo to give the title compound (15 g, 83.2% yield); [M+H] + =367.1.

[0090] Step 3: (R)-3-(2,6-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione [ka] The title compound was purified by SFC (IF (2×25 cm, 5 um), MtBE (0.1% DEA):(MeOH:DCM=1:1)=50:50, 100 bar, 20 ml / min) which corresponded to the title compound in peak A (4.47 g, 37% yield from 12 g racemate) at 0.990 min / 254 nm; [M+H] + =367.1.

[0091] Step 4: (R)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione [ka] (R)-3-(2,6-difluoro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)piperidine-2,6-dione (1 g, 2.73 mmol) was placed in a 100 mL round-bottom flask with a magnetic stir bar. Then, 10 mL of 12 N HCl aqueous solution was added. The mixture was stirred at room temperature for 30 min. The mixture was added dropwise to saturated NaHCO3 aqueous solution to a final pH=6-7. The liquid was extracted with DCM and separated. The organic phase was concentrated in vacuum and purified by CombiFlash (MeOH:DCM=0-5%) to give the title compound (850 mg, 96.7% yield); [M+H] + =323.1.

[0092] Step 5: 1-Fluoro-5-methoxy-4-nitro-2-vinylbenzene [ka] A 2L round bottom flask was charged with 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (40 g, 160.64 mmol), potassium vinyltrifluoroborate (43.1 g, 321.28 mmol), Pd(dppf)Cl2 (11.6 g, 16.06 mmol), and K2CO3 (66.5 g, 481.92 mmol) in 1,4-dioxane (400 mL) and H2O (80 mL). The mixture was stirred at 100 °C under N2 protection for 1.5 h. The mixture was concentrated in vacuum and purified by silica column chromatography (EA:PE=0-10%) to give 1-fluoro-5-methoxy-4-nitro-2-vinylbenzene (25 g, 80.64%). [M+H] + =198.2.

[0093] Step 6: tert-Butyl 9-(5-methoxy-4-nitro-2-vinylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate [ka] A 1-L round-bottom flask was charged with a solution of 1-fluoro-5-methoxy-4-nitro-2-vinylbenzene (20 g, 101.52 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (25.7 g, 101.52 mmol), and DIEA (35.3 mL, 203.04 mmol) in DMSO (200 mL). The mixture was stirred at 90° C. under nitrogen atmosphere for 5 h. The mixture was extracted with EA for separation. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EA (0-50%) to give tert-butyl 9-(5-methoxy-4-nitro-2-vinylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (14 g, 32.1%). [M+H] + =432.2.

[0094] Step 7: tert-Butyl 9-(4-amino-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate [ka] To a solution of tert-butyl 9-(5-methoxy-4-nitro-2-vinylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (28 g, 64.95 mmol) in MeOH (400 mL) was added wet Pd / C (28 g, 10 wt%). H2(g) was introduced to the above. The resulting solution was stirred overnight at room temperature under H2 atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure and recrystallized from PE / EA (10:1) to give tert-butyl 9-(4-amino-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (19.4 g, 74.61%). [M+H]+=404.1.

[0095] Step 8: 3-Fluoroquinolin-2(1H)-one [ka] To a solution of quinolin-2(1H)-one (25.0 g, 0.17 mol) in MeCN (30 mL) was added Selectfluor (64.0 g, 0.18 mol) at room temperature. The resulting mixture was stirred at 80° C. overnight. The reaction was concentrated to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 20:1 gradient elution) to give a mixture containing the desired product (10.4 g, 37%). [M+H] + =164.2.

[0096] Step 9: 3-Fluoro-6-nitroquinolin-2(1H)-one [ka] To the mixture from the above step (10.4 g, 63.4 mmol) dissolved in concentrated H2SO4 (98%, 80 mL) was added concentrated HNO3 (65%, 7.4 g, 76.1 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was poured into ice water (200 mL) and stirred for 10 min. The mixture was filtered and the solid was washed with water (50 mL x 2) and dried under reduced pressure to give the crude product (7.5 g, 56.8%).

[0097] 1 H NMR(500 MHz, DMSO) δ12.84(s, 1H), 8.68(d, J=2.5 Hz, 1H), 8.31(dd, J=9.1, 2.5 Hz, 1H), 8.09(d, J=10.7 Hz, 1H), 7.47(d, J=9.1 Hz, 1H). [M+H] + =209.2.

[0098] Step 10: 2-Chloro-3-fluoro-6-nitroquinoline [ka] A solution of 3-fluoro-6-nitroquinolin-2(1H)-one (7.5 g, 35.9 mmol) in POCl3 (60 mL) was heated at 100 °C overnight. The reaction was concentrated, basified with saturated aqueous NaHCO3, and then extracted with DCM (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 10:1 gradient elution) to give the desired product (3.7 g, 32%). [M+H] + =227.0.

[0099] Step 11: 3-Fluoro-2-methyl-6-nitroquinoline [ka] A mixture of 2-chloro-3-fluoro-6-nitroquinoline (3.7 g, 16.3 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (14.0 mL, 48.9 mmol), Pd(dppf)Cl2 (1.2 g, 1.63 mmol), and K3PO4 (6.9 g, 32.6 mmol) in DME (100 mL) and H2O (20 mL) was stirred overnight at 80 °C in a round-bottom flask under nitrogen atmosphere. The mixture was evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 20:1 gradient elution) to give the title product (2.6 g, 77%). [M+H] + =207.1.

[0100] Step 12: 3-Fluoro-2-methylquinolin-6-amine [ka] To a solution of 3-fluoro-2-methyl-6-nitroquinoline (2.6 g, 12.5 mmol) in MeOH (50 mL) / DCM (25 mL) was added Pd / C (10 wt%, wet, 800 mg) under nitrogen atmosphere at 25° C. The flask was evacuated / backfilled with hydrogen three times. After stirring under hydrogen atmosphere at 25° C. for 5 h, the mixture was filtered through a Celite pad and the solid was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to give the desired product (2.2 g, 99%). [M+H] + =177.1.

[0101] Step 13: 3-Fluoro-5-iodo-2-methylquinolin-6-amine [ka] To a solution of 3-fluoro-2-methylquinolin-6-amine (2.2 g, 12.4 mmol) in AcOH (60 mL) was added ICl (16.1 mL, 16.1 mmol) at 20° C. The mixture was then stirred at 20° C. for 1 h. The mixture was then adjusted to pH=8 with saturated aqueous NaHCO3. The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the desired product (3.3 g, 88%). [M+H] + =303.0.

[0102] Step 14: (6-amino-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide [ka] To a solution of 3-fluoro-5-iodo-2-methylquinolin-6-amine (3.3 g, 10.9 mmol) and dimethylphosphine oxide (1.3 g, 16.3 mmol) in dioxane (120 mL) was added K3PO4 (6.9 g, 32.7 mmol) at 20°C. Then, Pd(OAc)2 (244 mg, 1.09 mmol) and Xantphos (1.2 g, 2.18 mmol) were added to the mixture at the same temperature. After the flask was evacuated and backfilled with nitrogen three times, the mixture was stirred at 100°C overnight. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH=100:0 to 10:1 gradient elution) to give the desired product (2.5 g, 91%). [M+H] + =253.1.

[0103] Step 15: (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide [ka] To a solution of (6-amino-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (2.5 g, 9.9 mmol) and 5-bromo-2,4-dichloropyrimidine (6.7 g, 29.7 mmol) in BuOH (100 mL) was added DIEA (3.8 g, 29.7 mmol) at room temperature. The resulting mixture was stirred at 120° C. overnight. The reaction was concentrated to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 15:1 gradient elution) to give the desired product (2.9 g, 66%). [M+H] + =443.1.

[0104] Step 16: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide [ka] To a solution of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (4.9 g, 11 mmol), tert-butyl 9-(4-amino-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (4.8 g, 12 mmol), and TsOH (4.8 g, 28 mmol) in 70 mL of n-BuOH and 10 mL of CF3CH2OH. The mixture was stirred at 100 °C for 16 h. The mixture was concentrated in vacuo. The solid was diluted with DCM and water and separated. The aqueous solution was adjusted to pH = 6-7 with 1N NaOH aqueous solution and filtered. The solid was purified by Combiflash (MeOH:DCM=0-20% containing 1% NH3·H2O) to give the title compound (5.7 g, 73% yield); [M+H] + =710.9.

[0105] Step 9: (R)-3-(4-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (1.42 g, 2 mmol) and (R)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione (805 mg, 2.5 mmol) in 30 mL of DCE and 5 mL of DMSO was added 3 mL of Ti(OiPr)4. The mixture was stirred at 40° C. for 2 h. NaBH(OAc)3 (1.27 g, 6 mmol) was then added. The mixture was stirred at 40° C. for 1 h. The mixture was quenched with aqueous NaHCO3 and filtered. The organic layer was separated and concentrated in vacuo. The crude product was purified by Combiflash (MeOH:DCM=0-8%) to give the title compound (1.2 g, 59% yield).

[0106] 1 H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 10.87(s, 1H), 8.60(d, J=11.6 Hz, 1H), 8.27 - 8.15(m, 2H), 8.01 - 7.89(m, 2H), 7.30(s, 1H), 6.78(s, 1H), 6.63(d, J=13.0 Hz, 2H), 4.04(dd, J=11.8, 4.8 Hz, 1H), 3.86 - 3.72(m, 5H), 3.31 - 3.24(m, 2H), 2.87 - 2.67(m, 8H), 2.67 - 2.57(m, 4H), 2.39 - 2.49(m, 2H), 2.26 - 2.15(m, 2H), 2.12 - 2.03(m, 1H), 1.99 - 1.88(m, 7H), 1.87 - 1.73(m, 2H), 1.65 - 1.39(m, 10H), 0.72(s, 3H);[M+H] + =1016.7.

[0107] Example 2: (R)-3-(4-(4-(9-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 1. 1 H NMR(500 MHz, DMSO) δ 11.67(s, 1H), 10.87(s, 1H), 8.54(d, J=9.5 Hz, 1H), 8.36(s, 1H), 8.15(s, 1H), 8.00(s, 1H), 7.94(d, J=9.4 Hz, 1H), 7.33(s, 1H), 6.80(s, 1H), 6.65(s, 2H), 4.05(dd, J=12.3, 4.5 Hz, 1H), 3.85 - 3.73(m, 5H), 2.83 - 2.67(m, 8H), 2.64(s, 3H), 2.51(s, 2H), 2.47 - 2.38(m, 1H), 2.25(d, J=6.3 Hz, 2H), 2.13 - 2.04(m, 2H), 2.00 - 1.93(m, 8H), 1.82(s, 2H), 1.70 - 1.43(m, 10H), 0.77(s, 3H). [M+H] + =972.7.

[0108] Example 3: (R)-3-(4-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: 2-Ethyl-6-nitroquinazoline [ka] To a solution of 2-fluoro-5-nitrobenzaldehyde (10.0 g, 59.17 mmol) in MeCN (150 mL) was added propionimidamide hydrochloride (9.59 g, 88.75 mmol) and K2CO3 (20.4 g, 147.93 mmol) at room temperature. The resulting mixture was stirred at 80 °C overnight. The reaction was concentrated to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 98:2 gradient elution) to give a mixture containing the desired product (3.6 g, 30%). [M+H]+ = 204.2.

[0109] Step 2: 2-Ethylquinazolin-6-amine [ka] To a solution of 2-ethyl-6-nitroquinazoline (3.6 g, 17.73 mmol) in THF (100 mL) / HO (20 mL) was added Fe (4.96 g, 88.67 mmol) and NHCl (4.7 g, 88.67 mmol) at 25 °C. The mixture was then stirred at 25 °C overnight. The mixture was filtered through a Celite pad and washed with EA (150 mL) and HO (60 mL). The filtrate was separated and the organic layer was concentrated to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 20:1 gradient elution) to give a mixture containing the desired product (1.8 g, 58%). [M+H]+ = 174.2.

[0110] Step 3: 2-Ethyl-5-iodoquinazolin-6-amine [ka] To a solution of 2-ethylquinazolin-6-amine (1.8 g, 10.4 mmol) in AcOH (30 mL) was added ICl (15.6 mL, 15.6 mmol) at 20° C. The mixture was then stirred at 20° C. for 3 min. The mixture was then adjusted to pH=8 with saturated aqueous NaHCO3 and extracted with DCM (2×100 mL). The organic layer was washed with brine (80 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the desired product (2.6 g, 84%). [M+H]+=300.1.

[0111] Step 4: (6-amino-2-ethylquinazolin-5-yl)dimethylphosphine oxide [ka] To a solution of 2-ethyl-5-iodoquinazolin-6-amine (2.6 g, 8.69 mmol) and dimethylphosphine oxide (1.36 g, 17.39 mmol) in dioxane (100 mL) was added K3PO4 (4.6 g, 21.73 mmol) at 20 °C. To the mixture was added Pd(OAc)2 (390 mg, 1.74 mmol) and Xantphos (1.0 g, 1.74 mmol) at 20 °C. The suspension was degassed under vacuum and purged with N2 three times. The mixture was then stirred at 100 °C overnight. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:0 to 10:1 gradient elution) to give the desired product (2.1 g, 97%). [M+H]+ = 250.1.

[0112] Step 5: (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide [ka] To a solution of (6-amino-2-ethylquinazolin-5-yl)dimethylphosphine oxide (2.1 g, 8.4 mmol) and 5-bromo-2,4-dichloropyrimidine (5.7 g, 25.2 mmol) in n-BuOH (90 mL) was added DIEA (3.3 g, 25.2 mmol) at room temperature. The resulting mixture was stirred at 120° C. overnight. The reaction was concentrated to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 15:1 gradient elution) to give the desired product (2.3 g, 62%). 1 H NMR(500 MHz, DMSO) δ 12.44(s, 1H), 9.83(s, 1H), 8.59(s, 1H), 8.56(dd, J=9.3, 3.8 Hz, 1H), 8.12(d, J=9.3 Hz, 1H), 3.07(q, J=7.6 Hz, 2H), 2.12 - 2.08(m, 6H), 1.38(t, J=7.6 Hz, 3H). [M+H] + =440.1.

[0113] Step 6: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide [ka] In a similar manner as described in step 8 of Example 1, the title compound (410 mg, 62%) was prepared from (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide and tert-butyl 9-(4-amino-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0114] Step 7: (R)-3-(4-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (70 mg, 0.1 mmol) and (R)-3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione (40 mg, 0.13 mmol) in 3 mL of DCE was added one drop of Ti(OiPr)4. The mixture was stirred at 40° C. for 2 h. Then NaBH(OAc)3 (40 mg, 0.2 mmol) was added. The mixture was stirred at 40° C. for 1 h. The mixture was quenched with aqueous NaHCO3 and filtered. The organic layer was separated and concentrated in vacuo. The crude product was purified by preparative TLC (DCM:MeOH=11:1) to give the title compound (8 mg, yield 8%). 1H NMR(500 MHz, DMSO) δ 11.57(s, 1H), 10.88(s, 1H), 9.89(s, 1H), 8.48(s, 1H), 8.24(s, 1H), 8.03(s, 1H), 7.86(d, J=9.1 Hz, 1H), 7.30(s, 1H), 6.82(s, 1H), 6.72(d, J=12.9 Hz, 2H), 4.10 - 4.04(m, 1H), 4.01 - 3.95(m, 2H), 3.77(s, 3H), 3.48 - 3.33(m, 4H), 3.17 - 3.01(m, 4H), 2.85 - 2.71(m, 7H), 2.30 - 2.21(m, 2H), 2.17 - 2.07(m, 4H), 2.06 - 2.01(m, 7H), 1.99 - 1.91(m, 3H), 1.73 - 1.62(m, 4H), 1.54 - 1.47(m, 2H), 1.38(t, J=7.5 Hz, 3H), 0.73(s, 3H);[M+H] + =1013.7.

[0115] Example 4: (R)-3-(4-(9-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (2 g, 4.15 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1.27 g, 5 mmol), and Cs2CO3 (2.6 g, 8 mmol) in 20 mL of dioxane, Pd2(dba)3 (183 mg, 0.2 mmol) and Xantphos (231 mg, 0.4 mmol) were added under N2 protection. The mixture was stirred at 80 °C under N2 atmosphere for 16 h. The mixture was filtered and concentrated in vacuum. The mixture was purified by CombiFlash (EA:PE=0-20%) to give the title compound (1.6 g, 59% yield); [M+H] + =655.9.

[0116] Step 2: tert-butyl 9-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate [ka] To a solution of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.6 g, 2.44 mmol) in 10 mL of DCM and 60 mL of iPrOH was added Pd / C (1.6 g, 10 wt%, wet). The mixture was stirred at 45° C. under H2 atmosphere for 16 h. The mixture was directly filtered and concentrated to give the title compound (860 mg, 74% yield); [M+H] + =477.9.

[0117] Step 3: 3-(2,6-difluoro-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione hydrochloride [ka] To a solution of tert-butyl 9-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (60 mg, 0.12 mmol) in 0.5 mL of DCM was added 5 mL of 4N HCl / dioxane. The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give the title compound (40 mg, 88% yield); [M+H] + =377.9.

[0118] Step 4: (R)-3-(4-(9-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (60 mg, 0.1 mmol), 3-(2,6-difluoro-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2,6-dione hydrochloride (40 mg, 0.1 mmol), and DIEA (129 mg, 1 mmol) in 1.5 mL of DMSO. The mixture was stirred at 70° C. for 16 h. Then, NaBH(OAc)3 (60 mg, 0.3 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM and washed with saturated brine. The organic layer was concentrated in vacuo and purified by preparative TLC (DCM:MeOH=11:1). The crude product was purified by SFC (IF (2cm×25cm, 5um), MtBE (0.1% DEA):(MeOH:DCM=1:1)=50:50, 100 bar, 20 ml / min) to give the title compound (28 mg, 27% yield) corresponding to peak A at 1.402 min / 254 nm. 1H NMR(500 MHz, DMSO) δ 11.62(s, 1H), 10.86(s, 1H), 9.86(s, 1H), 8.46(s, 1H), 8.23(s, 1H), 8.05(s, 1H), 7.85(d, J=8.9 Hz, 1H), 7.28(s, 1H), 6.74(s, 1H), 6.61(d, J=13.0 Hz, 2H), 4.04(dd, J=12.0, 4.1 Hz, 1H), 3.75(s, 3H), 3.31 - 3.26(m, 1H), 3.20(s, 4H), 3.09 - 3.01(m, 2H), 2.98 - 2.90(m, 2H), 2.84 - 2.73(m, 1H), 2.71 - 2.62(m, 2H), 2.44 - 2.35(m, 4H), 2.30 - 2.23(m, 2H), 2.14 - 1.90(m, 9H), 1.88 - 1.78(m, 2H), 1.66 - 1.56(m, 2H), 1.55 - 1.43(m, 8H), 1.42 - 1.35(m, 3H), 0.76(s, 3H);[M+H] + =1013.5.

[0119] Example 5: (R)-3-(4-(3-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)cyclobutyl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: 2,6-Bis(benzyloxy)-3-(2,6-difluoro-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)pyridine [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (1 g, 1.94 mmol), 2-bromo-5,8-dioxaspiro[3.4]octane (598.8 mg, 2.91 mmol) in DMA (10 mL) was added NiI2 (121.7 mg, 0.39 mmol), picolinimidamide (61.2 mg, 0.39 mmol), NaI (144.53 mg, 0.97 mmol), Mn (320.1 mg, 5.82 mmol). After protection with nitrogen gas, a solution of TFA (29 mL, 0.39 mmol) in DMA (1 mL) was added. The mixture was stirred at 100 °C under nitrogen atmosphere for 3 h. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 column chromatography (0.05% TFA in ACN / H2O, 75%-80% for 40 min) to give 2,6-bis(benzyloxy)-3-(2,6-difluoro-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)pyridine (400 mg, 37.3%). [M+H] + =516.2.

[0120] Step 2: 3-(2,6-difluoro-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)piperidine-2,6-dione [ka] To a solution of 2,6-bis(benzyloxy)-3-(2,6-difluoro-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)pyridine (400 mg, 0.78 mmol) in THF (10 mL) was added Pd / C (1 g, 10 wt%, wet). The mixture was stirred overnight at 50° C. under hydrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure and recrystallized from PE / EA (10:1) to give 3-(2,6-difluoro-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)piperidine-2,6-dione (99.1 mg, 37.9%). [M+H]+ =338.3.

[0121] Step 3: 3-(2,6-difluoro-4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione [ka] To a stirred solution of 3-(2,6-difluoro-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)piperidine-2,6-dione (200 mg, 0.592 mmol) in 2 mL of dioxane:HO was added 1 M HCl in dioxane (2 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to give the product (165 mg, 94.8%) [M+H]. + =294.2.

[0122] Step 4: (R)-3-(4-(3-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)cyclobutyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (100 mg, 0.14 mmol) and 3-(2,6-difluoro-4-(3-oxocyclobutyl)phenyl)piperidine-2,6-dione (49.24 mg, 0.168 mmol) in DCE (3 mL) was added NaBH(OAc)3 (89.01 mg, 0.42 mmol) at 20° C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 10:1 gradient elution) to give an impure product, which was separated by chiral-HPLC (CHIRALPAK IF-3 (4.6×50 mm, 3 μm), MtBE (0.1% DEA):(MeOH:DCM=1:1)=80:20, 1 ml / min) to give the title compound (8 mg, 8.1%) corresponding to peak A at 2.951 min / 254 nm. 1 H NMR(500 MHz, DMSO) δ 11.35(s, 1H), 10.95(s, 1H), 8.61(s, 1H), 8.22(s, 2H), 7.97(s, 2H), 7.30(s, 1H), 6.98(s, 2H), 6.78(s, 1H), 4.21(s, 1H), 3.72-3.76(m, 3H), 3.15-3.17(m, 1H), 2.72(s, 6H), 2.29-2.31(m, 4H), 2.20-2.22(m, 2H), 1.96-1.98(m, 8H), 1.86(s, 2H), 1.54(s, 8H), 1.21-1.24(m, 4H), 0.86(s, 2H), 0.73(s, 3H). [M+H] + =987.5.

[0123] Example 6: (R)-3-(4-(2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: Ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate [ka] To a solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (10 g, 43.1 mmol) in THF (150 mL) was added LDA (2M, 24 mL, 48 mmol) dropwise at -65°C for 20 min, the reaction solution was stirred at the same temperature for 1 h, and then to this was added a solution of ethyl 3-bromopropanoate (9.4 g, 51.7 mmol) in THF (30 mL) dropwise for 10 min. The resulting solution was stirred at -65°C for 30 min, and then the temperature was allowed to rise to room temperature. The reaction was quenched by adding saturated aqueous NH4Cl (50 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL x 3), and 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.

[0124] Step 2: 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoic acid [ka] To a solution of ethyl 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoate (13.5 g, 40.7 mmol) in THF / H2O (90 mL / 30 mL) 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 the layers were separated. The pH value of the aqueous layer was adjusted to 4-5 using 1M HCl and then extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL) 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.

[0125] Step 3: 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a stirred solution of 4-(4-bromo-2,6-difluorophenyl)-4-cyanobutanoic acid (10.2 g, 33.5 mmol) in toluene (100 mL) was added concentrated H2SO4 (2 mL, 36.9 mmol). The resulting solution was stirred at 100 °C for 3 h. The reaction mixture was concentrated under vacuum and then the mixture was poured into water. The pH value was adjusted to 7-8 using saturated aqueous NaHCO3 solution and then the mixture was extracted with EtOAc (50 m × 3). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the product (8.2 g, 80.4%). [M+H] + =304.3.

[0126] Step 4: (R)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a stirred solution of 3-(4-bromo-2,6-difluorophenyl)piperidine-2,6-dione (8.2 g, 27.0 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.4 g, 32.4 mmol) in DMF / 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 nitrogen atmosphere for 2 h. The reaction solution was diluted with water (400 ml) and extracted with EtOAc (100 ml×2). The combined organic layer was washed with water (100 ml) and brine (100 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SFC (IH (3×25 cm, 5 um), 13% EtOH / 87% CO2, 100 bar, 100 ml / min) to give (S,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione (3.1 g, 39.0%) corresponding to peak B at 2.049 min / 254 nm and peak A at 1.679 min / 254 nm. The (R)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione was obtained (2.9 g, 36.5%). (S)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione and (R,E)-3-(4-(2-ethoxyvinyl)-2,6-difluorophenyl)piperidine-2,6-dione were the same. 1 H NMR and LCMS data were obtained. 1 H NMR(500 MHz, DMSO) δ 10.92(s, 1H), 7.41(d, J=12.9 Hz, 1H), 7.06(d, J=10.7 Hz, 2H), 5.82(d, J=12.9 Hz, 1H), 4.17-4.13(m, 1H), 3.92- 3.88(m, 2H), 3.45-3.39(m, 1H), 2.82 - 2.76(m, 1H), 2.12-2.07(m, 1H), 2.00-1.96(m, 1H), 1.26(t, J=7.0 Hz, 3H). [M+H] + =295.9.

[0127] Step 5: (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde [ka] (R)-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.

[0128] Step 6: (R)-3-(4-(2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (1.4 g, 2 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (667 mg, 2.5 mmol) in 20 mL of DCM was added and the mixture was stirred at room temperature for 30 min. Then NaBH(OAc)3 (1.27 g, 6 mmol) was added. The mixture was stirred at room temperature for 30 min. The mixture was diluted with DCM and washed with water. The organic layer was separated and concentrated in vacuo. The crude product was purified by Combiflash (MeOH:DCM=0-8%) to give the title compound (1.3 g, yield 67%). 1H NMR(500 MHz, DMSO) δ 11.33(s, 1H), 10.95(s, 1H), 8.61(d, J=12.4 Hz, 1H), 8.24 - 8.16(m, 2H), 7.99 - 7.92(m, 2H), 7.30(s, 1H), 7.03(d, J=9.7 Hz, 2H), 6.79(s, 1H), 4.24 - 4.18(m, 1H), 3.76(s, 3H), 3.32(s, 2H), 2.88 - 2.76(m, 3H), 2.72(s, 4H), 2.64(d, J=2.4 Hz, 3H), 2.59 - 2.52(m, 2H), 2.48 - 2.34(m, 3H), 2.24 - 2.07(m, 3H), 2.03 - 1.92(m, 7H), 1.72 - 1.39(m, 8H), 0.72(s, 3H);[M+H] + =961.6.

[0129] Example 7: (R)-3-(4-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidin-3-ol [ka] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (2 g, 4.16 mmol), azetidin-3-ol hydrochloride (1.36 g, 12.47 mmol), Pd2(dba)3 (380 mg, 0.42 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (486 mg, 0.84 mmol), Cs2CO3 (4.07 g, 12.47 mmol) in 1,4-dioxane (40 mL) was stirred at 100 °C for 16 h under N2 atmosphere in a 100 ml flask. After cooling to room temperature, the mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified on a silica gel column eluting with PE / EA (2:1) to give the target product (1.8 g, 91%). [M+H] + =475.3.

[0130] Step 2: 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione [ka] To a mixture of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidin-3-ol (1.8 g, 3.79 mmol) in iPrOH (30 mL) and DMF (30 mL) was added Pd / C (10%, w / w, 1 g) under N2(g). The resulting mixture was stirred overnight under H2 atmosphere until LC-MS showed all starting material had disappeared. The resulting solution was filtered and the filtrate was concentrated to give the desired product (0.9 g, 80%). [M+H] + =297.2.

[0131] Step 3: 3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione [ka] A mixture of 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (900 mg, 3.03 mmol) and DMP (1.93 g, 4.55 mmol) in DCM (10 mL) was stirred in a flask at room temperature for 2 h. The reaction was quenched with concentrated aqueous Na2S2O3, and the mixture was extracted with DCM, washed three times with saturated aqueous NaCl and twice with saturated aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuum to give the crude product (1.1 g). [M+H] + =295.2.

[0132] Step 4: tert-Butyl 4-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] A mixture of 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene (4 g, 16 mmol), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (6.4 g, 24 mmol), K2CO3 (4.4 g, 32 mmol) in DMF (50 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (500 mL) 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 (1:1) to give the product (7 g, 90%). [M+H] + =499.0.

[0133] Step 5: tert-Butyl 4-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(1-(2-bromo-5-methoxy-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (7 g, 14 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.3 g, 28 mmol), Pd(dppf)Cl2 (1.1 g, 1.4 mmol), and K3PO4 (8.9 g, 42 mmol) in DMF (160 mL) and water (20 mL) was stirred at 90 °C in a flask under nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3 x 1000 mL). The combined organic layers were washed with brine (500 mL) 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 (1:1) to give the product (5 g, 80%). [M+H] + =447.0.

[0134] Step 6: tert-Butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-(1-(5-methoxy-4-nitro-2-vinylphenyl)piperidin-4-yl)piperazine-1-carboxylate (5 g, 11.2 mmol) in MeOH (100 mL) and DCM (20.00 mL) was added Pd / C (wet, 10%) (1 g) under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. The resulting mixture was filtered and the filter cake was washed with DCM / CH3OH (10:1, 200 mL). The filtrate was concentrated under reduced pressure to give the product (4.0 g, 85.3%). [M+H] + =419.1.

[0135] Step 7: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide [ka] The title compound (210 mg, 45%) was prepared from (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide and tert-butyl 4-(1-(4-amino-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate in a similar manner as described in Step 8 of Example 1.

[0136] Step 8: (R)-3-(4-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (117 mg, 0.16 mmol), 3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione (95 mg, 0.32 mmol), and NaBH(OAc)3 (103 mg, 0.49 mmol) and one drop of AcOH was stirred at 70° C. in an 8 ml vial for 2 hours. The mixture was then evaporated in vacuum to give the crude product, which was purified by HPLC chromatography (0.1% FA aqueous solution:acetonitrile=90:10 to 50:50 gradient elution) to give the racemic product (15 mg, 27%). The racemic mixture was purified by SFC (IF (2×25 cm, 5 μm), MtBE (0.1% DEA):(MeOH:DCM=1:1)=60:40, 20 ml / min), and the title compound corresponded to peak A (4.2 mg, 56%). 1H NMR(500 MHz, DMSO) δ 11.60(s, 1H), 10.86(s, 1H), 9.86(s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8.05(s, 1H), 7.85(d, J=9.0 Hz, 1H), 7.27(s, 1H), 6.74(s, 1H), 6.12(d, J=11.1 Hz, 2H), 4.03(dd, J=12.5, 4.9 Hz, 1H), 3.91(t, J=7.2 Hz, 2H), 3.75(s, 3H), 3.64(s, 2H), 3.25(d, J=5.3 Hz, 2H), 3.05(q, J=7.5 Hz, 2H), 2.93(d, J=10.1 Hz, 2H), 2.77(dd, J=21.5, 9.1 Hz, 1H), 2.71 - 2.62(m, 3H), 2.54(s, 3H), 2.31(d, J=50.2 Hz, 7H), 2.03(d, J=13.4 Hz, 7H), 1.95(d, J=4.8 Hz, 1H), 1.84(d, J=10.7 Hz, 2H), 1.54(d, J=10.3 Hz, 2H), 1.37(t, J=7.6 Hz, 3H), 0.75(s, 3H). [M+H] + =1000.4.

[0137] Example 8: (R)-3-(4-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was synthesized in the same manner as in Example 1. 1H NMR(500 MHz, DMSO) δ 11.61(s, 1H), 10.86(s, 1H), 9.85(s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8.05(s, 1H), 7.85(d, J=9.2 Hz, 1H), 7.27(s, 1H), 6.74(s, 1H), 6.12(d, J=11.1 Hz, 2H), 4.03(dd, J=12.5, 4.9 Hz, 1H), 3.91(t, J=7.2 Hz, 2H), 3.75(s, 3H), 3.64(s, 2H), 3.10 - 3.03(m, 2H), 3.03 - 2.82(m, 3H), 2.82 - 2.73(m, 1H), 2.66(t, J=11.6 Hz, 3H), 2.36(s, 3H), 2.28 - 2.06(m, 4H), 2.03(d, J=13.4 Hz, 7H), 1.95(d, J=5.6 Hz, 1H), 1.89(d, J=43.9 Hz, 2H), 1.83 - 1.27(m, 7H), 0.81(d, J=52.4 Hz, 3H). [M+H] + =1003.4.

[0138] Example 9: (R)-3-(4-((S)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-ol [ka] To a mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (5.0 g, 10.39 mmol) in DMA (500 mL) was added (R)-pyrrolidin-3-ol hydrochloride (1.53 g, 12.44 mmol), Pd2(dba)3 (0.95 g, 1.03 mmol), BINAP (1.29 g, 2.07 mmol), and Cs2CO3 (10.2 g, 31.29 mmol). The mixture was stirred at 100° C. under nitrogen for 16 hours. After LCMS, the reaction was shown to be complete. The mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0-70% ethyl acetate in petroleum ether to give (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-ol (4.5 g, 90%). [M+H] + =489.2.

[0139] Step 2: (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl methanesulfonic acid [ka] To a mixture of (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-ol (1.0 g, 2.05 mmol) and TEA (0.62 g, 6.15 mmol) in DCM (10 mL) was added MsCl (0.35 g, 3.07 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. After LCMS, the reaction was shown to be complete. The mixture was diluted with DCM, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography using 0-80% ethyl acetate in petroleum ether to give (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl methanesulfonic acid (1.0 g, 86%). [M+H]+ =567.2.

[0140] Step 3: (S)-benzyl 4-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)piperazine-1-carboxylate [ka] To a mixture of (R)-1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl methanesulfonic acid (0.90 g, 1.59 mmol) and DIEA (0.61 g, 4.77 mmol) in ACN (10 mL) was added benzyl piperazine-1-carboxylate (1.1 g, 4.77 mmol). The mixture was stirred at 100° C. for 16 hours. After LCMS, the reaction was shown to be complete. The mixture was diluted with DCM, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography using 0-80% ethyl acetate in petroleum ether to give (S)-benzyl 4-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)piperazine-1-carboxylate (0.72 g, 59%). [M+H] + =691.3.

[0141] Step 4: 3-(2,6-difluoro-4-((S)-3-(piperazin-1-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione [ka] To a solution of (S)-benzyl 4-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-yl)piperazine-1-carboxylate (0.72 g, 1.04 mmol) in AcOH (20 mL) was added Pd / C (0.72 g, 10 wt%, wet). The mixture was stirred at 50° C. under a hydrogen atmosphere (balloon) for 16 h. After LCMS showed the reaction was complete, the mixture was cooled to room temperature and filtered directly through celite. The filtrate was concentrated in vacuo to give the crude product (377 mg). [M+H] + =379.2.

[0142] Step 5: 8-(5-methoxy-4-nitro-2-vinylphenyl)-1,4-dioxa-8-azaspiro[4.5]decane [ka] To a mixture of 1-fluoro-5-methoxy-4-nitro-2-vinylbenzene (10 g, 50.8 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (8.7 g, 60.9 mmol) in CH3CN (100 mL) was added K2CO3 (14 g, 101.6 mmol). The mixture was then stirred at 70 °C for 18 h. With ice cooling, the reaction was quenched with water (100 mL) and the resulting mixture was extracted with EtOAc (100 mL). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (PE:EA=2:1). 8-(5-Methoxy-4-nitro-2-vinylphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (14.8 g, 90.8%) was obtained. [M+H] + =321.2.

[0143] Step 6: 5-Ethyl-2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline [ka] To a solution of 8-(5-methoxy-4-nitro-2-vinylphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (13 g, 40.6 mmol) in iPrOH (15 mL) and DCM (80 mL) was added Pd / C (2.3 g, 10%) and the resulting mixture was stirred at room temperature under a H2 balloon for 5 h. The solid was filtered and the filtrate was concentrated in vacuum. The residue was purified by silica gel column (PE:EA=1:1). 5-Ethyl-2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline (10.2 g, 85.7%) was obtained. [M+H] + =293.3.

[0144] Step 7: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide [ka] To a mixture of (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (5.2 g, 11.4 mmol) and 5-ethyl-2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline (4.3 g, 14.9 mmol) in ethylene glycol (52 mL) was added TsOH (2.94 g, 17.1 mmol). The mixture was stirred at 80° C. for 18 h. With ice cooling, the reaction was quenched with saturated NaHCO3 solution (40 mL) and the resulting mixture was extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on a silica gel column (DCM:CH3OH=15:1). (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (4.6 g, 58.2%) was obtained. [M+H]+ =696.2.

[0145] Step 8: 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one [ka] To a mixture of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (4 g, 5.75 mmol) in THF (30 mL) and HO (30 mL) was added TsOH (1.98 g, 11.5 mmol). The mixture was stirred at 70 °C for 18 h. With ice cooling, the reaction was quenched with saturated NaHCO3 solution (20 mL) and the resulting mixture was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo. 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (3.4 g, 90.7%) was obtained. [M+H] + =652.1.

[0146] Step 9: (R)-3-(4-((S)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (86 mg, 0.13 mmol) in DCE (2 mL) was added 3-(2,6-difluoro-4-((S)-3-(piperazin-1-yl)pyrrolidin-1-yl)phenyl)piperidine-2,6-dione (50 mg, 0.13 mmol), DIEA (119 mg, 0.92 mmol), and NaBH(OAc)3 (112 mg, 0.53 mmol). The mixture was stirred at 70° C. for 16 hours. After LCMS, the reaction was shown to be complete. The mixture was diluted with DCM, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0 to 25% MeOH in DCM and preparative HPLC chromatography (0.1% FA aqueous solution:acetonitrile=90:10 to 50:50 gradient elution) to give 3-(4-((S)-3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl to give (phenyl)piperidin-4-yl)piperazin-1-yl)pyrrolidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione which was further purified by SFC (IF (2×25 cm, 5 um), 60% MtBE (0.1% DEA) / 40% MeOH:DCM (1:1), 100 bar, 20 ml / min) which corresponded to the title compound as peak A at 1.711 min / 254 nm (14 mg, 28%). 1H NMR(500 MHz, DMSO) δ 11.62(s, 1H), 10.84(s, 1H), 9.85(s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8.05(s, 1H), 7.85(d, J=9.0 Hz, 1H), 7.27(s, 1H), 6.75(s, 1H), 6.23(d, J=12.5 Hz, 2H), 4.05 - 3.98(m, 1H), 3.75(s, 3H), 3.50 - 3.42(m, 1H), 3.39 - 3.34(m, 1H), 3.30 - 3.26(m, 1H), 3.25 - 3.16(m, 1H), 3.10 - 2.99(m, 3H), 2.99 - 2.51(m, 13H), 2.34 - 1.70(m, 16H), 1.62 - 1.46(m, 2H), 1.38(t, J=7.5 Hz, 3H), 0.76(s, 3H);[M+H] + =1014.5.

[0147] Example 10: (R)-3-(4-(4-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide (intermediate obtained in a similar manner to step 7 of example 7) (70 mg, 0.1 mmol) and 3-(2,6-difluoro-4-(4-oxopiperidin-1-yl)phenyl)piperidine-2,6-dione (40 mg, 0.13 mmol) in 3 mL of DCE was added one drop of Ti(OiPr)4. The mixture was stirred at 40° C. for 2 h. Then NaBH(OAc)3 (40 mg, 0.2 mmol) was added. The mixture was stirred at 40° C. for 1 h. The mixture was quenched with aqueous NaHCO3 and filtered. The organic layer was concentrated in vacuo and purified by preparative TLC (DCM:MeOH=11:1). The crude product was purified by SFC (IF (2cm×25cm, 5um), MtBE (0.1%DEA):(MeOH:DCM=1:1)=40:60, 100 bar, 20 ml / min) to give the title compound (12 mg, 12% yield) corresponding to peak A at 1.342 min / 254 nm. 1 H NMR(500 MHz, DMSO) δ 11.79(s, 1H), 10.87(s, 1H), 8.56(d, J=9.2 Hz, 1H), 8.28(s, 1H), 8.21(s, 1H), 8.00(s, 1H), 7.87(d, J=9.0 Hz, 1H), 7.44(d, J=9.0 Hz, 1H), 7.33(s, 1H), 6.75(s, 1H), 6.63(d, J=13.4 Hz, 2H), 4.04(dd, J=13.1, 5.3 Hz, 1H), 3.82 - 3.74(m, 5H), 3.31 - 3.27(m, 2H), 2.96 - 2.89(m, 4H), 2.83 - 2.62(m, 7H), 2.60 - 2.54(m, 6H), 2.41 - 2.23(m, 4H), 2.14 - 2.04(m, 1H), 2.03 - 1.93(m, 7H), 1.89 - 1.79(m, 3H), 1.59 - 1.38(m, 4H), 1.32(t, J=7.6 Hz, 3H), 0.77(s, 3H);[M+H]+ =1027.7.

[0148] Example 11: (R)-3-(4-(4-(1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidine]-4-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A mixture of 1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidin]-4-one (intermediate obtained in a manner similar to step 7 of Example 7) (70 mg, 0.1 mmol), (R)-3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (intermediate obtained in a manner similar to step 4 of Example 9) (29 mg, 0.1 mmol), STAB (40 mg, 0.2 mmol), and Ti(i-PrOH)4 (27 mg, 0.1 mmol) in DMSO (10 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with DCM (100 mL), washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MEOH=0-10%) to give the crude product, which was purified by SFC (IH (3×25 cm, 5 um), 13% EtOH / 87% CO2, 100 bar, 100 ml / min) to give the title compound (8.9 mg, 9%) corresponding to peak A at 1.24 min / 254 nm. 1H NMR(500 MHz, DMSO) δ 11.80(s, 1H), 10.87(s, 1H), 8.55(d, J=8.4 Hz, 1H), 8.27(s, 2H), 8.00(s, 1H), 7.87(d, J=9.0 Hz, 1H), 7.44(d, J=8.9 Hz, 1H), 7.33(s, 1H), 6.75(s, 1H), 6.63(d, J=12.9 Hz, 2H), 4.05(d, J=8.2 Hz, 1H), 3.76(s, 3H), 3.17(s, 4H), 3.06 - 2.87(m, 6H), 2.77(d, J=11.9 Hz, 1H), 2.67(t, J=11.8 Hz, 2H), 2.59(s, 4H), 2.28(s, 3H), 2.17(s, 1H), 1.98(d, J=13.2 Hz, 6H), 1.79(s, 5H), 1.57(d, J=10.8 Hz, 4H), 1.40(d, J=9.5 Hz, 2H), 1.32(t, J=7.5 Hz, 4H), 0.77(s, 4H). [M+H] + =1027.8.

[0149] Example 12: (R)-3-(4-(4-(1'-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidine]-4-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: (6-((5-chloro-2-((5-ethyl-2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide [ka] To a solution of (6-((2,5-dichloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (1.35 g, 3.4 mmol) and 5-ethyl-2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline (1.2 g, 4.1 mmol) in ethylene glycol (50 mL) and CF3CH2OH (25 mL) was added TsOH (1.0 g, 5.9 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 48 h. The reaction was concentrated, basified with aqueous NaHCO3, and extracted with DCM (2 x 60 mL). The combined organic layers were washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 20:1 gradient elution) to give the desired product (1.87 g, 84%). [M+H] + =655.3.

[0150] Step 2: 1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one [ka] To a solution of (6-((5-chloro-2-((5-ethyl-2-methoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (1.9 g, 2.9 mmol) in THF (45 mL) and HO (40 mL) was added TsOH (1.0 g, 5.8 mmol) at room temperature. The resulting mixture was heated at 70° C. overnight. The reaction was concentrated, basified with aqueous NaHCO3, and extracted with DCM (2×80 mL). The combined organic layers were washed with brine (1×60 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the desired product (1.7 g, 96%). [M+H] + =611.1.

[0151] Step 3: (6-((2-((4-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide [ka] To a solution of 1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (465 mg, 0.76 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (328 mg, 2.28 mmol) in DMSO (50 mL) was added NaBH(OAc)3 (486 mg, 2.28 mmol) at room temperature. The resulting mixture was heated at 80° C. for 4 h. The reaction was quenched with water and extracted with DCM (2×60 mL). The combined organic layers were washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 15:1 gradient elution) to give the desired product (448 mg, 80%). [M+H] + =738.4.

[0152] Step 4: 1'-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidin]-4-one [ka] A solution of (6-((2-((4-(4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)piperidin-1-yl)-5-ethyl-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (450 mg, 0.61 mmol) in 8N HCl (12 mL) was stirred at room temperature overnight. The reaction was basified with aqueous Na2CO3 and extracted with DCM (2 x 80 mL). The combined organic layers were washed with brine (1 x 60 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the desired product (393 mg, 93%). [M+H] + =694.2.

[0153] Step 5: (R)-3-(4-(4-(1'-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidine]-4-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of 1'-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidin]-4-one (69 mg, 0.1 mmol) and (R)-3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (38 mg, 0.12 mmol) in DCE (5 mL) was added STAB (43 mg, 0.2 mmol) at 60°C. The mixture was stirred at 60°C for 1 h. Water (10 mL) was poured into the mixture. The mixture was then extracted with DCM (20 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography (0.1% FA aqueous solution:acetonitrile = 90:10 to 60:40 gradient elution) to give the product (21.2 mg, 21.5%). 1 H NMR(500 MHz, DMSO) δ 11.65(s, 1H), 10.87(s, 1H), 8.56(d, J=12.1 Hz, 1H), 8.35(s, 1H), 8.15(s, 1H), 7.98(s, 1H), 7.94(d, J=9.1 Hz, 1H), 7.35(s, 1H), 6.73(s, 1H), 6.64(s, 1H), 6.61(s, 1H), 4.05(dd, J=12.5, 4.7 Hz, 1H), 3.75(s, 3H), 3.31 - 3.27(m, 2H), 3.17(s, 4H), 3.05 - 2.89(m, 4H), 2.78(t, J=12.6 Hz, 1H), 2.69 - 2.55(m, 10H), 2.29 - 2.04(m, 6H), 1.98(s, 3H), 1.95(s, 3H), 1.87 - 1.74(m, 4H), 1.66 - 1.53(m, 2H), 1.41(d, J=9.5 Hz, 2H), 0.77(s, 3H). [M+H] + =987.7.

[0154] Example 13: (R)-3-(4-(1-(1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate [ka] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (4.81 g, 10.0 mmol), Pd(dppf)Cl2 (731 mg, 1 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.42 g, 11.0 mmol), and K2CO3 (2.76 g, 20.0 mmol) in dioxane (80 mL) and H2O (20 mL) was stirred at 100 °C for 2 h in a flask under N2. Water (160 mL) was poured into the mixture and extracted with EA (200 mL). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (5.5 g, 94.0%). [M+H] + =585.2.

[0155] Step 2: 2,6-Bis(benzyloxy)-3-(2,6-difluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyridine [ka] A mixture of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.34 g, 4.0 mmol) in HCl (10 mL, 4N) was stirred in a flask at room temperature for 2 h. The mixture was concentrated in vacuo, extracted with EA (200 mL), washed with NaHCO3 (aq, 100 ml), dried over Na2SO4, filtered and concentrated in vacuo. 2,6-Bis(benzyloxy)-3-(2,6-difluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyridine (1.9 g, 98.1%) was obtained. [M+H] + =485.2.

[0156] Step 3: tert-butyl 3-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)azetidine-1-carboxylate [ka] To a solution of 2,6-bis(benzyloxy)-3-(2,6-difluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyridine (1.45 g, 3.0 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (564 mg, 3.3 mmol) in DCE (30 mL) was added STAB (1.27 g, 6.0 mmol) at 60° C. The mixture was stirred at 20° C. for 1 h. Water (50 mL) was poured into the mixture. The mixture was then extracted with DCM (100 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography. 3-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)azetidine-1-carboxylate tert-butyl ester (1.4 g, 72.9%) was obtained. [M+H] + =640.3.

[0157] Step 4: tert-Butyl 3-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-1-yl)azetidine-1-carboxylate [ka] To a mixture of tert-butyl 3-(4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-3,6-dihydropyridin-1(2H)-yl)azetidine-1-carboxylate (1.4 g, 2.2 mmol) in DMF (20 mL) and i-PrOH (5 mL) was added Pd / C (700 mg, 10%). The resulting mixture was stirred at 50° C. under H2 for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl 3-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-1-yl)azetidine-1-carboxylate (0.91 g, 89.0%). [M+H] + =464.3.

[0158] Step 5: (R)-3-(4-(1-(azetidin-3-yl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A mixture of tert-butyl 3-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-1-yl)azetidine-1-carboxylate (0.91 g, 1.9 mmol) in HCl (10 mL, 4N) was stirred in a flask at room temperature for 2 hours. The mixture was concentrated in vacuo to give the crude product which was purified by SFC (IH (3×25 cm, 5 um), 13% EtOH / 87% CO2, 100 bar, 100 ml / min) which corresponded to the title compound as peak A at 0.655 min / 254 nm (200 mg, 34%). [M+H] + =364.2.

[0159] Step 6: (R)-3-(4-(1-(1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound (19 mg, 30%) was prepared from 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one and (R)-3-(4-(1-(azetidin-3-yl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione in a manner similar to step 9 of example 9. 1 H NMR(500 MHz, DMSO) δ 11.60(s, 1H), 10.95(s, 1H), 9.86(s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8.04(s, 1H), 7.85(d, J=9.0 Hz, 1H), 7.27(s, 1H), 7.05(s, 1H), 7.02(s, 1H), 6.73(s, 1H), 4.19(dd, J=12.6, 4.6 Hz, 1H), 3.76(s, 3H), 3.47 - 3.39(m, 3H), 2.93 - 2.73(m, 8H), 2.61(t, J=10.2 Hz, 2H), 2.54(s, 2H), 2.24 - 1.99(m, 11H), 1.84(t, J=11.2 Hz, 2H), 1.75(t, J=12.7 Hz, 4H), 1.62(dd, J=23.2, 11.3 Hz, 2H), 1.42 - 1.22(m, 6H), 0.74(s, 3H). [M+H] + =999.7

[0160] Example 14: (R)-3-(4-(1-(1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound (17 mg, 28%) was prepared in a similar manner to step 9 of example 9 from 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (intermediate obtained in a similar manner to step 2 of example 12) and (R)-3-(4-(1-(azetidin-3-yl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione. 1 H NMR(500 MHz, DMSO) δ 11.78(s, 1H), 10.95(s, 1H), 8.56(d, J=8.8 Hz, 1H), 8.27(s, 1H), 8.21(s, 1H), 7.99(s, 1H), 7.87(d, J=9.3 Hz, 1H), 7.44(d, J=8.9 Hz, 1H), 7.32(s, 1H), 7.05(s, 1H), 7.02(s, 1H), 6.73(s, 1H), 4.19(dd, J=12.4, 5.0 Hz, 1H), 3.76(s, 3H), 3.41(s, 2H), 2.97 - 2.72(m, 10H), 2.62(t, J=9.3 Hz, 2H), 2.54(s, 2H), 2.26(d, J=7.5 Hz, 2H), 2.18 - 2.06(m, 2H), 2.00(s, 1H), 2.00(s, 3H), 1.97(s, 3H), 1.84(t, J=11.1 Hz, 2H), 1.75(s, 4H), 1.67 - 1.57(m, 2H), 1.32(t, J=7.6 Hz, 5H), 0.76(s, 3H). [M+H] +=998.7

[0161] Example 15: (R)-3-(4-(1-(1-(1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)azetidin-3-yl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound (22 mg, 31%) was prepared from 1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-one (intermediate obtained in a similar manner to step 2 of example 12) and (R)-3-(4-(1-(azetidin-3-yl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione in a manner similar to step 9 of example 9. 1H NMR(500 MHz, DMSO) δ 11.55(s, 1H), 10.95(s, 1H), 8.61(d, J=12.1 Hz, 1H), 8.32(s, 1H), 8.16(s, 1H), 7.95(d, J=9.2 Hz, 1H), 7.89(s, 1H), 7.38(s, 1H), 7.04(s, 1H), 7.02(s, 1H), 6.69(s, 1H), 4.19(dd, J=12.6, 4.9 Hz, 1H), 4.01(q, J=6.9 Hz, 2H), 3.41(s, 2H), 2.92 - 2.72(m, 8H), 2.64(d, J=2.1 Hz, 3H), 2.61 - 2.52(m, 4H), 2.26 - 2.06(m, 4H), 2.00(d, J=5.6 Hz, 1H), 1.98(s, 3H), 1.95(s, 3H), 1.84(t, J=11.2 Hz, 2H), 1.74(t, J=14.7 Hz, 4H), 1.61(dd, J=22.4, 11.6 Hz, 2H), 1.34 - 1.23(m, 5H), 0.71(s, 3H). [M+H] + =972.7

[0162] Example 16: (R)-3-(4-(4-(1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidin-3-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-butyl 3-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)azetidine-1-carboxylate [ka] To a solution of 3-(2,6-difluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione (100 mg, 0.324 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (221.36 mg, 1.29 mmol) in DCM (3 mL) was added AcOH (77 mg, 1.29 mmol) at 20° C. The mixture was stirred at 70° C. for 1 h. The mixture was diluted with water (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and evaporated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 10:1 gradient elution) to give the desired product (100 mg, 84.8%). [M+H] + =465.5

[0163] Step 2: 3-(4-(4-(azetidin-3-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A solution of tert-butyl 3-(4-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)azetidine-1-carboxylate (100 mg, 0.215 mmol) in 4N HCl / 1,4-dioxane (2 mL) was stirred overnight at room temperature in a round-bottom flask. The mixture was concentrated under reduced pressure to give the crude product (70 mg, 89.2%), which was used in the next step without further purification. [M+H] + =365.5

[0164] Step 3: (R)-3-(4-(4-(1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidin-3-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (intermediate obtained in a similar manner to step 2 of example 12) (125.8 mg, 0.19 mmol) and 3-(4-(4-(azetidin-3-yl)piperazin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione (70 mg, 0.19 mmol) in DCE (10 mL) was added NaBH(OAc)3 (120.8 mg, 0.57 mmol) at 20°C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 10:1 gradient elution) to give an impure product, which was separated by chiral-HPLC (CHIRALPAK IF-3 (4.6×50 mm, 3 μm), MtBE (0.1% DEA):(MeOH:DCM=1:1)=70:30, 1 ml / min) to give the title compound (32 mg, 16.8%) corresponding to peak A at 1.751 min / 254 nm. 1 H NMR(500 MHz, DMSO) δ 11.29(s, 1H), 10.87(s, 1H), 8.63(d, J=12.1 Hz ,1H), 8.22(s, 2H), 7.94(d, J=9.9 Hz, 2H), 7.32(s, 1H), 6.70(s, 1H), 6.64(d, J=12.8 Hz, 2H), 4.06(d, J=7.7 Hz,1H), 3.75(s, 3H), 3.40(s, 8H), 3.20(s, 4H), 2.81-2.84(m, 6H), 2.64(s, 5H), 2.09(d, J=13.7Hz,2H), 1.95(d, J=13.3 Hz, 8H), 1.72(s, 2H), 1.32 - 1.25(m, 2H), 0.71(s, 3H). [M+H]+ =1003.5.

[0165] Example 17: (3R)-3-(4-(7-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate [ka] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (960 mg, 2.0 mmol), tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (680 mg, 3.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (180 mg, 0.2 mmol), and RuPhos (0.10 g, 0.22 mmol) in 1,4-dioxane (40 mL) was stirred at 100° C. for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was 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 / EA (2:1) to give tert-butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (700 mg, 55.8%). [M+H] + =628.2.

[0166] Step 2: tert-butyl 7-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate [ka] A mixture of tert-butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (700 mg, 1.12 mmol) and Pd / C (10 wt%, 600 mg) in THF (10 mL) was stirred at 50° C. for 5 h under hydrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. The resulting solid was dried under vacuum. This gave tert-butyl 7-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (400 mg, 81.2%). [M+H] + =450.3.

[0167] Step 3: (3R)-3-(2,6-difluoro-4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione [ka] A mixture of tert-butyl 7-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (400 mg, 0.91 mmol) in HCl (10 mL, 4N) was stirred in a flask at room temperature for 2 hours. The mixture was concentrated in vacuo to give the crude product which was purified by SFC (IH (3×25 cm, 5 um), 13% EtOH / 87% CO2, 100 bar, 100 ml / min) to give the title compound (50 mg, 34%) corresponding to peak A at 0.655 min / 254 nm. [M+H] + =350.2.

[0168] Step 4: (3R)-3-(4-(7-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] In a similar manner to step 9 of Example 9, the title compound (22 mg, 24.3%) was obtained from 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one and (3R)-3-(2,6-difluoro-4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)piperidine-2,6-dione. 1 H NMR(500 MHz, DMSO) δ 11.29(s, 1H), 10.84(s, 1H), 8.63(d, J =11.7 Hz, 1H), 8.22(s, 1H), 8.18(s, 1H), 7.96(s, 1H), 7.94(s, 1H), 7.32(s, 1H), 6.71(s, 1H), 6.20(s, 1H), 6.17(s, 1H), 4.01(dd, J =12.8, 4.7 Hz, 1H), 3.75(s, 3H), 3.31 - 3.13(m, 6H), 2.92 - 2.86(m, 2H), 2.82 - 2.72(m, 2H), 2.67 - 2.58(m, 8H), 2.19(ddd, J =12.3, 9.3, 3.6 Hz, 2H), 2.14 - 2.03(m, 2H), 2.01 - 1.97(m, 1H), 1.96(s, 3H), 1.94(s, 3H), 1.93 - 1.86(m, 3H), 1.77(s, 2H), 1.52(s, 2H), 0.71(s, 3H). [M+H] + =988.7

[0169] Example 18: (R)-3-(4-(2-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate [ka] A stirred mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (1 g, 2 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (0.47 g, 2 mmol), Pd2(dba)3 (0.19 g, 0.2 mmol), BINAP (0.26 g, 0.4 mmol), and Cs2CO3 (1.4 g, 4 mmol) in dioxane (50 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE=0-50%) to give the product (1.1 g, 84% yield). [M+H] + =628.7.

[0170] Step 2: tert-butyl 7-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate [ka] To a solution of tert-butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.1 g, 1.8 mmol) in 20 mL of DMF and 20 mL of iPrOH was added Pd / C (1 g, 10%). The mixture was stirred at 40° C. under H2 atmosphere (balloon) for 16 h. The mixture was cooled to room temperature and filtered directly through celite. The filtrate was concentrated under reduced pressure to give the product (760 mg, 96% yield). [M+H] + =450.5.

[0171] Step 3: 3-(2,6-difluoro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione [ka] To a stirred mixture of tert-butyl 7-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.76 g, 1.7 mmol) in DCM (2 mL) was added TFA (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with DCM (100 mL). The DCM was washed with NaHCO3 (aq., 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (0.45 g, 78% yield). [M+H] + =350.4.

[0172] Step 4: (R)-3-(4-(2-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A mixture of 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (70 mg, 0.1 mmol), 3-(2,6-difluoro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione (37 mg, 0.1 mmol), STAB (45 mg, 0.2 mmol), and AOH (13 mg, 0.2 mmol) in DCE (10 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with DCM (100 mL), washed with brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MEOH=0-10%) to give a crude product, which was purified by SFC (IH (3×25 cm, 5 um), 13% EtOH / 87% CO2, 100 bar, 100 ml / min) to give the title compound (4.6 mg, 4.4%) corresponding to peak A at 1.77 min / 254 nm. 1 H NMR(500 MHz, DMSO) δ 11.30(s, 1H), 10.89(s, 1H), 8.64(d, J =12.2 Hz, 1H), 8.21(d, J =20.2 Hz, 2H), 7.95(d, J =9.5 Hz, 2H), 7.31(s, 1H), 6.70(s, 1H), 6.64(d, J =13.2 Hz, 2H), 4.04(dd, J =12.2, 4.0 Hz, 1H), 3.75(s, 3H), 3.20(s, 4H), 3.02 - 2.73(m, 7H), 2.66 - 2.57(m, 5H), 2.24 - 2.05(m, 4H), 1.95(d, J =13.4 Hz, 8H), 1.72(s, 6H), 1.29(d, J =10.3 Hz, 2H), 0.70(s, 3H). [M+H] + =988.2.

[0173] Example 19: (R)-3-(4-(7-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-butyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [ka] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (200 mg, 0.415 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (103.5 mg, 0.457 mmol), Pd2(dba)3 (37.9 mg, 0.0415 mmol), Xantphos (48.02 g, 0.083 mmol), Cs2CO3 (405.6 mg, 1.245 mmol) in dioxane (5 mL) was stirred at 100° C. for 15 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuum. The residue was purified by silica gel column (PE:EA=1:1) to give the product (200 mg, 76.8%). [M+H] + =628.3.

[0174] Step 2: tert-butyl 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [ka] To a solution of tert-butyl 2-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (200 mg, 0.319 mmol) in 5 mL of DCM and 5 mL of i-PrOH was added Pd / C (20 mg, 10%). The mixture was stirred at 45° C. under a hydrogen atmosphere (balloon) for 16 h. After LCMS showed the reaction was complete, the mixture was cooled to room temperature and filtered directly through celite. The solid was partitioned between DCM (5 mL) and MeOH (50 mL), which was sonicated for 5 min. The mixture was then filtered through celite and the combined filtrate was concentrated in vacuo to give the product (140 mg, 98.03% yield). [M+H] + =450.2.

[0175] Step 3: 3-(2,6-difluoro-4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)piperidine-2,6-dione [ka] A solution of tert-butyl 2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (140 mg, 0.311 mmol) in 4N HCl / 1,4-dioxane (4 mL) was stirred overnight at room temperature in a round-bottom flask. The mixture was concentrated under reduced pressure to give the crude product (100 mg, 91.9%), which was used in the next step without further purification. [M+H] + =350.2.

[0176] Step 4: (R)-3-(4-(7-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-one (intermediate obtained in a similar manner to step 2 of example 12) (100 mg, 0.15 mmol) and 3-(2,6-difluoro-4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)piperidine-2,6-dione (62.9 mg, 0.18 mmol) in DCE (10 mL) was added NaBH(OAc)3 (95.37 mg, 0.45 mmol) at 20° C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 10:1 gradient elution) to give an impure product, which was separated by chiral-HPLC (CHIRALPAK IF-3 (4.6×50 mm, 3 μm), MtBE (0.1% DEA):(MeOH:DCM=1:1)=70:30, 1 ml / min) to give the title compound (38 mg, 25.4%) corresponding to peak A at 1.723 min / 254 nm. 1H NMR(500 MHz, DMSO) δ 11.53(s, 1H), 10.85(s, 1H), 9.90(s, 1H), 8.44(s, 1H), 8.25(s, 1H), 7.95(s, 1H), 7.85(d, J =9.4 Hz, 1H), 7.32(s, 1H), 6.70(s, 1H), 6.11(d, J =11.8 Hz, 2H), 4.00(s, 2H), 3.55(s, 5H), 3.06(d, J =7.2 Hz,2H), 2.92(d, J =9.6 Hz,3H), 2.76(d, J =11.6 Hz,2H), 2.62(s, 4H), 2.36(s, 1H), 2.22(s, 2H), 2.03(d, J =13.2 Hz, 8H), 1.95(s, 1H), 1.74(s, 6H), 1.57(d, J =10.6 Hz, 2H), 1.39(d, J =7.4 Hz, 3H), 1.23-1.26(m, 3H), 0.69(s, 3H). [M+H] + =999.4.

[0177] Example 20: (R)-3-(4-(2-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A mixture of 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (70 mg, 0.11 mmol), 3-(2,6-difluoro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6-dione (38 mg, 0.11 mmol), STAB (45 mg, 0.21 mmol), and AOH (13 mg, 0.21 mmol) in DCE (10 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with DCM (100 mL), washed with brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MEOH=0-10%) to give a crude product, which was purified by SFC (IH (3×25 cm, 5 um), 13% EtOH / 87% CO2, 100 bar, 100 ml / min) to give the title compound (6.1 mg, 5.8%) corresponding to peak A at 1.29 min / 254 nm. 1 H NMR(500 MHz, DMSO) δ 11.56(s, 1H), 10.87(s, 1H), 9.88(s, 1H), 8.45(s, 1H), 8.24(s, 1H), 8.03(s, 1H), 7.86(d, J =9.9 Hz, 1H), 7.28(s, 1H), 6.73(s, 1H), 6.65(d, J =13.5 Hz, 2H), 4.04(dd, J =12.9, 4.9 Hz, 1H), 3.76(s, 3H), 3.29(s, 1H), 3.21(s, 4H), 3.08 - 3.03(m, 2H), 2.91(s, 4H), 2.77(dd, J =21.4, 9.3 Hz, 1H), 2.63(t, J =10.3 Hz, 2H), 2.51(s, 1H), 2.22(s, 2H), 2.08(d, J =10.1 Hz, 1H), 2.03(d, J =13.4 Hz, 6H), 1.96(d, J =5.6 Hz, 2H), 1.75(s, 5H), 1.41 - 1.22(m, 7H), 0.74(s, 3H). [M+H]+ =985.2.

[0178] Example 21: 3-(4-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)azetidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] Step 1: 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-(3-hydroxyazetidin-1-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] A mixture of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.03 g, 2.0 mmol), azetidin-3-ol (220 mg, 3.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (180 mg, 0.2 mmol), and RuPhos (0.10 g, 0.22 mmol) in 1,4-dioxane (40 mL) was stirred at 100° C. for 2 h under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was 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 / EA (1:1) to give 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-(3-hydroxyazetidin-1-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (800 mg, 78.7%). [M+H] + =509.2.

[0179] Step 2: 3-(4-(3-hydroxyazetidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] A mixture of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-(3-hydroxyazetidin-1-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (800 mg, 1.57 mmol) and Pd / C (10 wt%, 600 mg) in THF (10 mL) was stirred at 50° C. for 5 h under hydrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure. After drying in vacuum, 3-(4-(3-hydroxyazetidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (380 mg, 73.1%) was obtained. [M+H] + =331.2.

[0180] Step 3: 3-(3-methyl-2-oxo-4-(3-oxoazetidin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] A mixture of 3-(4-(3-hydroxyazetidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (380 mg, 1.15 mmol) and IBX (480 mg, 1.72 mmol) in DMSO (10 mL) was stirred in a flask at room temperature overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc and washed three times with saturated aqueous NaCl and twice with saturated aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuum to give the product (310 mg, 81.2%). [M+H]+=329.2.

[0181] Step 4: 3-(4-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)azetidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] The title compound (22 mg, 27%) was prepared in a similar manner to Step 9 of Example 1 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinolin-5-yl)dimethylphosphine oxide and 3-(3-methyl-2-oxo-4-(3-oxoazetidin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. 1H NMR(500 MHz, DMSO) δ 11.80(s, 1H), 11.08(s, 1H), 8.55(d, J =8.9 Hz, 1H), 8.27(s, 1H), 8.21(s, 1H), 8.00(s, 1H), 7.87(d, J =9.5 Hz, 1H), 7.44(d, J =8.9 Hz, 1H), 7.33(s, 1H), 6.96(t, J =8.0 Hz, 1H), 6.75(s, 1H), 6.74(s, 1H), 6.68(d, J =8.1 Hz, 1H), 5.32(dd, J =12.6, 5.1 Hz, 1H), 3.90(d, J =4.4 Hz, 2H), 3.76(s, 3H), 3.64(s, 2H), 3.57(s, 3H), 3.29(s, 2H), 3.24 - 3.16(m, 1H), 2.96 - 2.84(m, 5H), 2.73 - 2.53(m, 8H), 2.43 - 2.26(m, 6H), 2.00(s, 3H), 1.97(s, 3H), 1.84(d, J =10.5 Hz, 2H), 1.55(d, J =9.6 Hz, 2H), 1.32(t, J =7.6 Hz, 3H), 0.77(s, 3H). [M+H] + =1033.7

[0182] Example 22: 3-(4-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)azetidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] The title compound (19 mg, 26%) was prepared in a similar manner to step 9 of example 1 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (intermediate obtained in a similar manner to step 7 of example 7) and 3-(3-methyl-2-oxo-4-(3-oxoazetidin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. 1 H NMR(500 MHz, DMSO) δ 11.29(s, 1H), 11.08(s, 1H), 8.64(d, J =9.4 Hz, 1H), 8.22(s, 1H), 8.18(s, 1H), 7.95(s, 1H), 7.93(s, 1H), 7.34(s, 1H), 6.96(t, J =8.0 Hz, 1H), 6.75(d, J =7.9 Hz, 1H), 6.71(s, 1H), 6.67(d, J =8.2 Hz, 1H), 5.32(dd, J =12.4, 5.1 Hz, 1H), 3.89(d, J =4.3 Hz, 2H), 3.75(s, 3H), 3.63(s, 2H), 3.57(s, 3H), 3.46 - 3.41(m, 2H), 3.21 - 3.17(m, 1H), 2.88(dd, J =21.8, 8.3 Hz, 3H), 2.62(d, J =18.8 Hz, 9H), 2.39 - 2.25(m, 5H), 2.18(s, 2H), 1.99(d, J =5.6 Hz, 1H), 1.96(s, 3H), 1.94(s, 3H), 1.82(d, J =10.5 Hz, 2H), 1.53(d, J =10.0 Hz, 2H), 0.70(s, 3H). [M+H] + =1037.7

[0183] Example 23: 3-(4-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)azetidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] The title compound (21 mg, 27%) was prepared in a similar manner to Step 9 of Example 1 from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide and 3-(3-methyl-2-oxo-4-(3-oxoazetidin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. 1H NMR(500 MHz, DMSO) δ 11.61(s, 1H), 11.08(s, 1H), 9.85(s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8.05(s, 1H), 7.85(d, J =9.0 Hz, 1H), 7.27(s, 1H), 6.96(t, J =8.0 Hz, 1H), 6.74(s, 2H), 6.68(d, J =8.0 Hz, 1H), 5.32(dd, J =12.6, 5.3 Hz, 1H), 3.90(d, J =4.2 Hz, 2H), 3.75(s, 3H), 3.64(s, 2H), 3.57(s, 3H), 3.23 - 3.17(m, 1H), 3.05(q, J =7.6 Hz, 2H), 2.93(d, J =10.3 Hz, 2H), 2.90 - 2.82(m, 1H), 2.74 - 2.53(m, 9H), 2.43 - 2.24(m, 6H), 2.04(s, 3H), 2.02(s, 3H), 2.01 - 1.95(m, 1H), 1.84(d, J =11.7 Hz, 2H), 1.54(d, J =9.5 Hz, 2H), 1.37(t, J =7.6 Hz, 3H), 0.76(s, 3H). [M+H] + =1034.7

[0184] Example 24: (S)-3-(4-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)azetidin-1-yl)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione Step 1: 2-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-6-bromo-3-fluorobenzoic acid [ka] To a solution of 2,6-bis(benzyloxy)pyridin-3-amine (15 g, 49.0 mmol) in THF (300 mL), LiHMDS (1 M in THF, 80 mL) was added dropwise at 0°C for 30 min, the reaction solution was stirred at the same temperature for 60 min, and then 6-bromo-2,3-difluorobenzoic acid (10 g, 42.4 mmol) dissolved in THF (50 mL) was added dropwise thereto for 20 min. The resulting solution was stirred at 10°C-20°C for 12 h. The reaction was quenched by adding saturated aqueous NH4Cl solution. The residue was purified by silica gel column eluting with DCM / MeOH (5:1) to give the product (20 g, 90.4%). [M+H] + =523.2.

[0185] Step 2: 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] To a solution of 2-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-6-bromo-3-fluorobenzoic acid (20 g, 38.3 mmol) in DMA (400 mL) was added TEA (11.6 g, 114.8 mmol) and DPPA (15.8 g, 57.4 mmol). The mixture was stirred at 80° C. under nitrogen atmosphere for 12 h. The mixture was quenched with water at 30° C. and extracted with EtOAc. The combined organic phase was concentrated under reduced pressure. The residue was purified on a silica gel column eluting with DCM / EtOAc (1:1) to give the product (18 g, 90.9%). [M+H] + =520.1.

[0186] Step 3: 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-7-fluoro-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] To a solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-7-fluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one (10 g, 19.2 mmol) in DMF (100 mL) was added Cs2CO3 (18.7 g, 57.5 mmol) at 0° C. for 10 min. To this was then added CHI (8.2 g, 57.7 mmol). The resulting solution was stirred at 10° C.-20° C. for 12 h. The mixture was quenched with water at 30° C. and extracted with EtOAc. The combined organic phase was concentrated under reduced pressure. The residue was purified on a silica gel column eluting with DCM / EtOAc (1:1) to give the product (8 g, 77.9%). [M+H] + =534.3.

[0187] Step 4: Benzyl 1-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azetidine-3-carboxylate [ka] To a solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-7-fluoro-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4 g, 7.4 mmol) in dioxane (40 mL) was added azetidine-3-carboxylate benzyl TFA salt (3.0 g, 10.4 mmol), Ruphos (0.6 g, 1.2 mmol), Pd2(dba)3 (0.6 g, 0.6 mmol), and Cs2CO3 (9.6 g, 29.6 mmol). The resulting solution was stirred at 90° C. under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with DCM / EtOAc (1:1) to give the product (2.36 g, 49.5%). [M+H] + =645.2.

[0188] Step 5: 1-(1-(2,6-dioxopiperidin-3-yl)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azetidine-3-carboxylic acid [ka] To a solution of benzyl 1-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azetidine-3-carboxylate (1.4 g, 2.2 mmol) in THF (30 mL) was added Pd / C (1.4 g, 10 wt %) and CHCOOH (0.3 mL). The resulting solution was diluted with H 2 The mixture was stirred at 30° C. for 8 hours under atmospheric pressure. After filtration, the filtrate was concentrated under reduced pressure to give 1-(1-(2,6-dioxopiperidin-3-yl)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azetidine-3-carboxylic acid (0.5 g, 65.6%). 1 H NMR(500 MHz, DMSO) δ 12.48(s, 1H), 11.10(d, J=8.4 Hz, 1H), 7.30 - 7.05(m, 1H), 6.98 - 6.79(m, 1H), 5.49(s, 1H), 4.08 - 3.91(m, 1H), 3.85(td, J=6.6, 2.7 Hz, 1H), 3.53(s, 2H), 3.50 - 3.35(m, 3H), 2.97(d, J=14.8 Hz, 1H), 2.61(d, J=18.1 Hz, 1H), 2.38 - 2.02(m, 2H), 1.95(d, J=23.9 Hz, 1H). [M+H] + =377.1.

[0189] Step 6: (S)-3-(4-(3-(4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)azetidin-1-yl)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (80 mg, 0.11 mmol), 1-(1-(2,6-dioxopiperidin-3-yl)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azetidine-3-carboxylic acid (41.4 mg, 0.11 mmol), and DIEA (42.63 mg, 0.33 mmol) in DCM (3 mL) was added T3P (139.99 mg, 0.44 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 10:1 gradient elution) to give an impure product, which was separated by chiral-HPLC (CHIRALPAK IF-3 (4.6×50 mm, 3 μm), MtBE (0.1% DEA):(MeOH:DCM=1:1)=50:50, 1 ml / min) to give the title compound (20 mg, 16.8%) corresponding to peak A at 1.719 min / 254 nm. 1H NMR(500 MHz, DMSO) δ 11.30(s, 1H), 11.12(s, 1H), 8.64(d, J=11.4 Hz, 1H), 8.23(s, 2H), 7.96(s, 2H), 7.33(s, 1H), 6.88(t, 1H), 6.79(d, J=4.8 Hz, 1H), 6.72(s, 1H), 5.54 - 5.45(m, 1H), 3.94(d, J=34.1 Hz, 4H), 3.75(s, 4H), 3.68(s, 3H), 3.60(s, 1H), 3.49(s, 2H), 3.05 - 2.86(m, 3H), 2.64(s, 6H), 2.52(d, J=18.1 Hz, 5H), 2.36(s, 1H), 2.18(s, 3H), 2.09(s, 1H), 1.95(d, J=13.4 Hz,6H), 1.81(s, 2H), 1.56(s, 2H), 0.70(s, 3H). [M+H] + =1083.3.

[0190] Example 25: 3-(4-(6-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione Step 1: tert-butyl 6-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] A stirred mixture of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 g, 1.9 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.38 g, 1.9 mmol), Pd2(dba)3 (0.17 g, 0.2 mmol), Xantphos (0.23 g, 0.4 mmol), and Cs2CO3 (1.3 g, 3.8 mmol) in dioxane (50 mL) was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:PE=0-50%) to give the product (1.1 g, 89% yield). [M+H] + =634.5.

[0191] Step 2: tert-butyl 6-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.1 g, 1.7 mmol) in 20 mL of DMF and 20 mL of iPrOH was added Pd / C (1 g, 10%). The mixture was stirred at 40° C. under H2 atmosphere (balloon) for 16 h. The mixture was cooled to room temperature and filtered directly through celite. The filtrate was concentrated under reduced pressure to give the product (670 mg, 82% yield). [M+H] + =456.3.

[0192] Step 3: 3-(3-methyl-2-oxo-4-(2,6-diazaspiro[3.3]heptan-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] To a stirred mixture of tert-butyl 6-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.65 g, 1.4 mmol) in DCM (2 mL) was added TFA (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with DCM (100 mL). The DCM was washed with NaHCO3 (aq., 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the product (0.12 g, 24% yield). [M+H] + =356.2.

[0193] Step 4: 3-(4-(6-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] A mixture of 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (50 mg, 0.07 mmol), 3-(3-methyl-2-oxo-4-(2,6-diazaspiro[3.3]heptan-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (27 mg, 0.07 mmol), STAB (32 mg, 0.15 mmol), and AOH (9 mg, 0.15 mmol) in DCE (10 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with DCM (100 mL), washed with brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (0-10% MeOH in DCM) followed by preparative HPLC chromatography (0.1% aqueous FA:acetonitrile = 90:10-50:50 gradient elution) afforded the title compound (10.8 mg, 14.2%). 1 H NMR(500 MHz, DMSO) δ 11.59(s, 1H), 11.08(s, 1H), 9.87(s, 1H), 8.46(s, 1H), 8.24(s, 1H), 8.04(s, 1H), 7.86(d, J=9.3 Hz, 1H), 7.27(s, 1H), 6.95(t, J=8.3 Hz, 1H), 6.73(s, 2H), 6.64(d, J=8.4 Hz, 1H), 5.36 - 5.29(m, 1H), 3.91(s, 3H), 3.76(s, 3H), 3.58(s, 3H), 3.08 - 3.03(m, 2H), 2.88(s, 4H), 2.66(d, J=26.1 Hz, 6H), 2.23(s, 1H), 2.03(d, J=13.4 Hz, 7H), 1.98(s, 1H), 1.74(d, J=9.6 Hz, 2H), 1.37(q, J=7.5 Hz, 4H), 1.30(s, 2H), 1.24(s, 2H), 0.74(s, 3H). [M+H] + =991.4.

[0194] Example 26: 3-(4-(6-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] A mixture of 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (50 mg, 0.07 mmol), 3-(3-methyl-2-oxo-4-(2,6-diazaspiro[3.3]heptan-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (27 mg, 0.07 mmol), STAB (32 mg, 0.15 mmol), and AOH (9 mg, 0.15 mmol) in DCE (10 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with DCM (100 mL), washed with brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (0-10% MeOH in DCM) followed by preparative HPLC chromatography (0.1% aqueous FA:acetonitrile = 90:10-50:50 gradient elution) afforded the title compound (7.8 mg, 10.3%). 1H NMR(500 MHz, DMSO) δ 11.29(s, 1H), 11.08(s, 1H), 8.62(s, 1H), 8.21(d, J=19.3 Hz, 2H), 7.95(d, J=10.3 Hz, 2H), 7.32(s, 1H), 6.95(t, J=8.0 Hz, 1H), 6.72(d, J=18.4 Hz, 2H), 6.64(d, J=7.1 Hz, 1H), 5.35 - 5.29(m, 1H), 3.91(s, 3H), 3.76(s, 3H), 3.58(s, 3H), 2.87(d, J=11.2 Hz, 3H), 2.63(dd, J=14.8, 11.2 Hz, 6H), 2.16(s, 4H), 1.95(d, J=13.4 Hz, 9H), 1.73(d, J=19.2 Hz, 3H), 1.27(d, J=32.2 Hz, 4H), 0.71(s, 3H). [M+H] + =994.5

[0195] Example 27: (R)-3-(4-(6-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] A mixture of 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (100 mg, 0.15 mmol), (R)-3-(2,6-difluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)piperidine-2,6-dione (intermediate obtained in a similar manner to step 4 of example 9) (49 mg, 0.15 mmol), STAB (65 mg, 0.3 mmol), and AOH (18 mg, 0.3 mmol) in DCE (10 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with DCM (100 mL), washed with brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MEOH=0-10%) to give the crude product, which was purified by SFC (IH (3×25 cm, 5 um), 13% EtOH / 87% CO2, 100 bar, 100 ml / min) to give the title compound (22.9 mg, 15.6%) corresponding to peak A at 1.36 min / 254 nm. 1H NMR(500 MHz, DMSO) δ 11.77(s, 1H), 10.86(s, 1H), 8.58(d, J=8.6 Hz, 1H), 8.27(s, 1H), 8.21(s, 1H), 7.99(s, 1H), 7.88(d, J=9.2 Hz, 1H), 7.44(d, J=8.9 Hz, 1H), 7.34(s, 1H), 6.74(s, 1H), 6.16(s, 2H), 4.04(dd, J=12.5, 4.9 Hz, 1H), 3.92(s, 3H), 3.77(s, 3H), 3.32 - 3.21(m, 8H), 2.93(dd, J=15.1, 7.5 Hz, 4H), 2.77(dd, J=21.4, 9.2 Hz, 1H), 2.63(t, J=9.9 Hz, 2H), 2.26(d, J=7.1 Hz, 2H), 2.08(d, J=12.9 Hz, 2H), 1.97(t, J=14.6 Hz, 7H), 1.72(s, 1H), 1.32(t, J=7.6 Hz, 4H), 0.75(s, 3H). [M+H] + =956.3.

[0196] Example 28: 3-(4-(3-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione Step 1: 4-(3-(benzyloxy)propyl)-1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] To a solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.04 g, 1.89 mmol), ((3-bromopropoxy)methyl)benzene (520 mg, 2.29 mmol) and benzamidine (60 mg, 0.38 mmol) in DMA (10 mL) was added Mn (310 mg, 5.64 mmol), nickel(II) iodide (120 mg, 0.38 mmol), NaI (140 mg, 0.93 mmol) and TFA (110 m, 0.97 mmol) at 0° C. The mixture was stirred at room temperature for 15 min and then at 100° C. for 2 h under N2 atmosphere. The reaction was quenched with HO at room temperature. The resulting mixture was filtered and the filter cake was washed with EA. The filtrate was extracted with EA. The combined organic layers were washed with brine and concentrated under reduced pressure. The residue was loaded onto a silica gel column with PE:EA (100:0 to 75:25). This afforded 4-(3-(benzyloxy)propyl)-1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (700 mg, 63.2%). [M+1]=586.3.

[0197] Step 2: 3-(4-(3-hydroxypropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] A 50 mL round bottom flask was charged with 4-(3-(benzyloxy)propyl)-1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (700 mg, 1.19 mmol), THF (20 mL), and Pd / C (500 mg, 10 wt%). To the flask was introduced H2(g). The resulting solution was stirred at 25° C. overnight. The solids were filtered. The resulting mixture was concentrated under vacuum. This afforded 270 mg (71.3%) of 3-(4-(3-hydroxypropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. [M+1]=318.2.

[0198] Step 3: 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propanal [ka] The title compound (130 mg, 89.2%) was prepared from 3-(4-(3-hydroxypropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione and DMP in a similar manner to step 9 of example 1. [M+H] + =316.1.

[0199] Step 4: 3-(4-(3-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (71 mg, 0.1 mmol) and 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propanal (38 mg, 0.12 mmol) in DCE (5 mL) was added STAB (43 mg, 0.2 mmol) at 60° C. The mixture was stirred at 60° C. for 1 h. Water (10 mL) was poured into the mixture. The mixture was then extracted with DCM (20 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography (0.1% FA aqueous solution:acetonitrile = 90:10 to 60:40 gradient elution) to give the product (21.4 mg, 21.2%). 1 H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 11.09(s, 1H), 8.60(d, J=12.2 Hz, 1H), 8.22(s, 1H), 8.19(s, 1H), 7.96(s, 1H), 7.94(d, J=9.9 Hz, 1H), 7.30(s, 1H), 6.97(s, 1H), 6.96(s, 1H), 6.92 - 6.87(m, 1H), 6.79(s, 1H), 5.37(dd, J=12.6, 5.3 Hz, 1H), 3.75(s, 3H), 3.58(s, 3H), 2.94 - 2.85(m, 3H), 2.73 - 2.68(m, 5H), 2.63(d, J=1.7 Hz, 4H), 2.41 - 2.36(m, 5H), 2.20(d, J=3.8 Hz, 2H), 2.00(d, J=6.0 Hz, 2H), 1.97(s, 3H), 1.94(s, 3H), 1.82 - 1.74(m, 2H), 1.56 - 1.49(m, 8H), 0.72(s, 3H). [M+H] + =1009.7

[0200] Example 29: 3-((4-(1-(2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethyl)piperidin-4-yl)phenyl)amino)piperidine-2,6-dione [ka] To a mixture of 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-yl)acetic acid (this intermediate was prepared in a similar manner as described in WO2021178920A1) (48 mg, 0.139 mmol) and HATU (58.1 mg, 0.153 mmol) in DMF (3 mL) was added DIEA (25 mg, 0.190 mmol). The mixture was stirred at room temperature for 15 min. (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (90 mg, 0.127 mmol) was added and the mixture was stirred for 2 h. The mixture was concentrated in vacuo and purified by preparative HPLC chromatography (0.1% FA in water:acetonitrile = 90:10 to 50:50 gradient elution) to give the racemate, which was purified by SFC (IF (2 x 25 cm, 5 um), Phase A: METB, Phase B: MeOH / DCM, 20 ml / min, UV 220 nm) to give the title compound (24.09 mg, 17.84%) as peak A at 1.547 min / 254 nm. 1H NMR(500 MHz, DMSO) δ 11.33(s, 1H), 10.76(s, 1H), 8.61(d, J=12.5 Hz, 1H), 8.22(s, 2H), 7.95(d, J=14.2 Hz, 2H), 7.31(s, 1H), 6.96(d, J=8.1 Hz, 2H), 6.81(s, 1H), 6.61(d, J=8.2 Hz, 2H), 5.68(s, 1H), 4.26(s, 1H), 3.76(s, 3H), 3.50(s, 4H), 2.81 - 2.71(m, 6H),2.68 - 2.52(m, 6H), 2.42 - 2.35(m, 2H), 2.26 - 2.15(m, 2H), 2.15 - 2.08(m, 2H), 1.95(d, J=13.3 Hz, 6H), 1.90 - 1.82(m, 2H), 1.81 - 1.71(m, 2H), 1.65 - 1.52(m, 8H), 1.47(s, 2H), 0.72(s, 3H). ;[M+H] + =1037.5.

[0201] Example 30: (R)-3-(4-(1-(1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidine]-4-yl)azetidin-3-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: tert-butyl 3-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-1-carboxylate [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (7.0 g, 14.5 mmol) in DMA (70 mL) was added tert-butyl 3-iodoazetidine-1-carboxylate (4.9 g, 17.3 mmol), pyridine-2-carboximidamide hydrochloride (0.5 g, 3.2 mmol), NiI2 (0.9 g, 2.9 mmol), NaI (1.1 g, 7.3 mmol), and Mn (2.4 g, 43.7 mmol). To this was then added a solution of TFA (0.8 g, 7.0 mmol) in DMA (1 mL) dropwise over 5 min under nitrogen atmosphere. The resulting solution was stirred at 25° C. for 5 min under nitrogen atmosphere. The reaction was then stirred at 100° C. for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE / EtOAc (2:1) to give the product (2.2 g, 27.2%). [M+H] + =559.2.

[0202] Step 2: tert-Butyl 3-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-1-carboxylate [ka] To a solution of tert-butyl 3-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-1-carboxylate (2.2 g, 3.9 mmol) in EtOH (30 mL) and DCM (6 mL) was added Pd / C (2.2 g, 10 wt%). The resulting solution was stirred at 40° C. under H2 atmosphere for 8 h. After filtration, the filtrate was concentrated under reduced pressure. This gave tert-butyl 3-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-1-carboxylate (1.4 g, 93.6%). 1H NMR(500 MHz, DMSO) δ 10.95(s, 1H), 7.16 - 7.11(m, 2H), 4.25 - 4.19(m, 3H), 3.87 - 3.85(m, 3H), 3.46 - 3.42(m, 1H), 2.87 - 2.76(m, 1H), 2.22 - 1.95(m, 2H), 1.40(s, 9H). [M+H] + =381.2.

[0203] Step 3: 3-(4-(azetidin-3-yl)-2,6-difluorophenyl)piperidine-2,6-dione hydrochloride [ka] To a solution of tert-butyl 3-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-1-carboxylate (50 mg, 0.131 mmol) in dioxane (1 mL) was added 4M hydrochloride in dioxane (3 mL) and stirred at room temperature for 2 hours. The resulting mixture was concentrated and dried in vacuo to give 3-(4-(azetidin-3-yl)-2,6-difluorophenyl)piperidine-2,6-dione hydrochloride (41 mg, crude). [M+H] + =281.1.

[0204] Step 4: (R)-3-(4-(1-(1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidine]-4-yl)azetidin-3-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a suspension of 1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidin]-4-one (80 mg, 0.109 mmol) and 3-(4-(azetidin-3-yl)-2,6-difluorophenyl)piperidine-2,6-dione hydrochloride (41 mg, 0.131 mmol) in dichloromethane / methanol (8 mL / 4 mL) was added N,N-diethylpropylethylamine (40 mg, 0.31 mmol) and stirred for 20 minutes, acetic acid (24 mg, 0.4 mmol) was added and stirred for 20 minutes, followed by NaBH3CN (20 mg, 0.32 mmol) and stirring at room temperature for an additional 2 hours. After LCMS, the reaction was shown to be complete. The mixture was diluted with DCM, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography using 0-25% MeOH in DCM and preparative HPLC chromatography (0.1% FA in water:acetonitrile=90:10-50:50 gradient elution) to give the product, which was further purified by SFC using chiral-HPLC (CHIRALPAK IF-3 (4.6×50 mm, 3 μm), MtBE (0.1% DEA):(MeOH:DCM=1:1)=50:50, 1.5 ml / min) to give the title compound corresponding to peak A at 1.65 min / 254 nm, as the desired enantiomer (20 mg, 18%). 1H NMR(500 MHz, DMSO) δ=11.80(s, 1H), 10.96(s, 1H), 8.55(d, J=9.0, 1H), 8.27(s, 1H), 8.21(s, 1H), 8.00(s, 1H), 7.87(d, J=9.3, 1H), 7.44(d, J=8.9, 1H), 7.33(s, 1H), 7.12(d, J=10.1, 2H), 6.75(s, 1H), 4.21(dd, J=12.6, 4.9, 1H), 3.76(s, 3H), 3.61 - 3.51(m, 3H), 3.06(m, 2H), 2.93(m, 4H), 2.88 - 2.75(m, 3H), 2.66(t, J=11.4, 2H), 2.55(m, 1H), 2.41 - 2.07(m, 6H), 1.98(d, J=13.3, 7H), 1.80(d, J=10.8, 2H), 1.69 - 1.52(m, 4H), 1.32(t, J=7.6, 3H), 1.20(m, 3H), 0.77(s, 3H). [M+H] + =998.7.

[0205] Example 31: 3-(4-(2-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] A mixture of 1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-one (50 mg, 0.08 mmol), 3-(3-methyl-2-oxo-4-(2,7-diazaspiro[3.5]nonan-7-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (intermediate obtained in a similar manner to step 3 of example 25) (29 mg, 0.08 mmol), STAB (32 mg, 0.15 mmol), and AOH (9 mg, 0.15 mmol) in DCE (10 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with DCM (100 mL), washed with brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (0-10% MeOH in DCM) followed by preparative HPLC chromatography (0.1% aqueous FA:acetonitrile = 90:10-50:50 gradient elution) afforded the title compound (28 mg, 35.8%). 1 H NMR(500 MHz, DMSO) δ 11.60(s, 1H), 11.08(s, 1H), 9.86(s, 1H), 8.45(s, 1H), 8.24(s, 1H), 8.05(s, 1H), 7.86(d, J=9.3 Hz, 1H), 7.27(s, 1H), 6.97(t, J=8.0 Hz, 1H), 6.88(dd, J=13.3, 7.9 Hz, 2H), 6.74(s, 1H), 5.35(dd, J=12.7, 5.3 Hz, 1H), 3.76(s, 3H), 3.63(s, 3H), 3.12 - 2.85(m, 11H), 2.75 - 2.58(m, 6H), 2.23(s, 3H), 2.01(dd, J=21.5, 9.3 Hz, 7H), 1.87(d, J=20.5 Hz, 4H), 1.75(d, J=9.4 Hz, 2H), 1.38(t, J=7.6 Hz, 3H), 1.32(d, J=10.2 Hz, 2H), 0.75(s, 3H). [M+H] +=1019.5

[0206] Example 32: 3-(4-(2-(1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] A mixture of 1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-one (50 mg, 0.08 mmol), 3-(3-methyl-2-oxo-4-(2,7-diazaspiro[3.5]nonan-7-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (31 mg, 0.08 mmol), STAB (34 mg, 0.16 mmol), and AOH (10 mg, 0.16 mmol) in DCE (10 mL) was stirred in a flask at 80° C. overnight. The reaction mixture was cooled to room temperature. The resulting mixture was diluted with DCM (100 mL), washed with brine (100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (0-10% MeOH in DCM) followed by preparative HPLC chromatography (0.1% aqueous FA:acetonitrile = 90:10-50:50 gradient elution) afforded the title compound (48 mg, 60.3%). 1H NMR(500 MHz, DMSO) δ 11.54(s, 1H), 11.09(s, 1H), 8.63(d, J=12.1 Hz, 1H), 8.31(s, 1H), 8.17(s, 1H), 7.95(d, J=9.2 Hz, 1H), 7.89(s, 1H), 7.39(s, 1H), 6.97(t, J=7.9 Hz, 1H), 6.91 - 6.82(m, 2H), 6.69(s, 1H), 5.35(dd, J=12.5, 5.3 Hz, 1H), 4.01(q, J=6.9Hz, 2H), 3.63(s, 3H), 3.23(s, 2H), 3.11(s, 2H), 3.00(s, 2H), 2.89(t, J=10.9 Hz, 3H), 2.76 - 2.53(m, 9H), 2.36(s, 1H), 2.18(d, J=6.0 Hz, 2H), 2.03 - 1.73(m, 13H), 1.34(d, J=9.9 Hz, 2H), 1.27(t, J=6.9 Hz, 3H), 0.71(s, 3H). [M+H] + =992.8.

[0207] Example 33: 3-(4-(3-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Step 1: N-(2,6-bis(benzyloxy)pyridin-3-yl)-1,1-diphenylmethanimine [ka] A mixture of 2,6-bis(benzyloxy)-3-bromopyridine (60 g, 162.1 mmol) and diphenylmethanimine (35.2 g, 194.5 mmol), Cs2CO3 (105.6 g, 324.1 mmol), BINAP (10.1 g, 16.2 mmol), Pd2(dba)3 (14.8 g, 16.2 mmol) in dioxane (600 mL) was stirred at 100° C. overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give the desired product (48 g, 62.9%). [M+H] + =471.3.

[0208] Step 2: 2,6-Bis(benzyloxy)pyridin-3-amine [ka] A mixture of N-(2,6-bis(benzyloxy)pyridin-3-yl)-1,1-diphenylmethanimine (48 g, 102.0 mmol) in THF (300 mL) and 1N HCl (360 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum. The precipitated solid was collected by filtration and washed with water (500 mL) and saturated aqueous NaHCO3. The residue was purified by trituration three times with EtOAc:PE (1:10) to give the product (25 g, 80.00%). [M+H] + =307.1.

[0209] Step 3: 2-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromoisoindolin-1-one [ka] A mixture of 2,6-bis(benzyloxy)pyridin-3-amine (5 g, 16.3 mmol) and methyl 3-bromo-2-(bromomethyl)benzoate (5 g, 16.3 mmol), Cs2CO3 (16 g, 49.0 mmol) in DMF (50 mL) was stirred at 100° C. overnight. The resulting mixture was extracted with EA (250 mL). The combined organic layers were washed with brine (500 mL) 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 (1:1) to give the desired product (4.2 g, 51.33%). [M+H] + =501.2.

[0210] Step 4: 4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(2,6-bis(benzyloxy)pyridin-3-yl)isoindolin-1-one [ka] To a solution of 2-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromoisoindolin-1-one (1 g, 2.0 mmol) in dioxane (20 mL) was added 3-((benzyloxy)methyl)azetidine (460 mg, 2.6 mmol), Ruphos (0.2 g, 0.4 mmol), Pd2(dba)3 (0.2 g, 0.2 mmol), and Cs2CO3 (3.3 g, 10.2 mmol). The resulting solution was stirred at 100° C. under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluting with PE / EtOAc (2:1) to give the desired product (1.1 g, 91.7%). [M+H] + =598.2.

[0211] Step 5: 3-(4-(3-(hydroxymethyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of 4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-(2,6-bis(benzyloxy)pyridin-3-yl)isoindolin-1-one (1 g, 1.7 mmol) in EtOAc (30 mL) was added Pd / C (1 g, 10 wt%) and CH3COOH (0.3 mL). The resulting solution was stirred at 50° C. under H2 atmosphere for 12 h. After filtration, the filtrate was concentrated under reduced pressure to give the pure product (0.5 g, 90.9%). [M+H] + =330.2.

[0212] Step 6: 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)azetidine-3-carbaldehyde [ka] A mixture of 3-(4-(3-(hydroxymethyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 0.607 mmol) and DMP (514.9 mg, 1.21 mmol) in DCM (10 mL) was stirred in a flask at room temperature for 2 h. The reaction was quenched with water and the mixture was extracted with DCM (20 mL×3). The combined organic layer was washed with saturated aqueous NaCl (30 mL×3) and saturated NaHCO3 (30 mL×2). The organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to give the product (140 mg, 70.5%). [M+H] + =328.1.

[0213] Step 7: 3-(4-(3-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (50 mg, 0.0705 mmol) and 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)azetidine-3-carbaldehyde (23.06 mg, 0.0705 mmol) in DCM (2 mL) was added NaBH(OAc)3 (44.82 mg, 0.2115 mmol) at 20° C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0 to 10:1 gradient elution) to give an impure product, which was further purified by preparative HPLC (C-18 column chromatography (0.1% FA aqueous solution:acetonitrile=90:10 to 60:40 gradient elution) to give the desired product (40 mg, 55.63%). 1 H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 10.97(s, 1H), 8.60(d, J=11.0 Hz, 1H), 8.22(s, 2H), 7.95(d, J=6.0 Hz, 2H), 7.31(t, J=7.5 Hz, 2H), 7.04(d, J=7.4 Hz, 1H), 6.78(s, 1H), 6.54(d, J=7.9 Hz,1H), 5.17 - 5.03(m, 1H), 4.42(s, 1H), 4.31(s, 1H), 4.14 - 4.01(m, 2H), 3.76(s, 3H), 3.64(d, J=6.1 Hz, 2H), 2.90-2.92(m, 2H), 2.71(s, 4H), 2.64(s, 4H), 2.57-2.59(m, 4H), 2.38(s, 4H), 2.19(s, 2H), 1.95(d, J=13.3 Hz,7H), 1.52(s, 7H), 0.71(s, 3H). [M+H] + =1021.4.

[0214] Example 34: 3-(4-((2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that of Example 33. 1 H NMR (500MHz, DMSO) 1 H NMR(500 MHz, DMSO) δ 11.33(s, 1H), 10.99(s, 1H), 8.60(d, J=12.5 Hz, 1H), 8.19 - 9.17(m, 2H), 7.94(d, J=12.9 Hz, 2H), 7.37(t, J=7.7 Hz, 1H), 7.30(s, 1H), 7.15(d, J=7.3 Hz, 1H), 7.01(d, J=7.9 Hz, 1H), 6.77(s, 1H), 5.12(dd, J=13.2, 4.9 Hz, 1H), 4.52 - 4.49(m, 1H), 4.42 - 4.32(m, 1H), 3.75(s, 3H), 2.99 - 2.85(m, 4H), 2.63(s, 9H), 2.42 - 2.39(m, 7H), 2.18(s, 2H), 1.95 - 1.91(m, 8H), 1.48 - 1.42(m, 8H), 0.71(s, 3H);[M+H] + =1009.5.

[0215] Example 35: 3-(5-(4-((4-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] To a suspension of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (80.0 mg, 0.11 mmol) and (1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl methanesulfonate (this intermediate was prepared according to the method set out in WO2021219070A1) (71.8 mg, 0.165 mmol) in acetonitrile (2 mL) and DMSO (0.5 mL) was added N,N-diethylpropylethylamine (43 mg, 0.33 mmol) and KI (55 mg, 0.33 mmol). After stirring at 80° C. for 15 h, the reaction mixture was diluted with brine (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (0-10% MeOH in DCM) followed by preparative HPLC chromatography (0.1% aqueous NH4OH:acetonitrile=90:10-50:50 gradient elution) afforded the title compound (35 mg, 29%). 1H NMR(500 MHz, DMSO) δ 11.61(s, 1H), 10.92(s, 1H), 9.85(s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8.05(s, 1H), 7.85(d, J=9.1 Hz, 1H), 7.48(d, J=8.8 Hz, 1H), 7.27(s, 1H), 6.74(s, 1H), 6.61(d, J=7.6 Hz, 2H), 5.03(dd, J=13.1, 5.1 Hz, 1H), 4.30(d, J=16.3 Hz, 1H), 4.18(d, J=16.9Hz, 1H), 3.75(s, 3H), 3.50(s, 1H), 3.40(s, 1H), 3.30 - 3.26(m, 1H), 3.05(q, J=7.5 Hz, 2H), 2.93(d, J=9.4 Hz, 3H), 2.88(d, J=13.4 Hz, 1H), 2.65(d, J=10.7 Hz, 2H), 2.57(d, J=25.9 Hz, 5H), 2.38(s, 3H), 2.36(s, 4H), 2.27(d, J=8.5 Hz, 4H), 2.15(s, 1H), 2.03(d, J=13.4 Hz, 6H), 1.95(d, J=5.2 Hz, 1H), 1.84(d, J=10.6 Hz, 2H), 1.66(d, J=8.7 Hz, 1H), 1.60(d, J=6.9 Hz, 2H), 1.54(d, J=9.7 Hz, 2H), 1.37(t, J=7.5 Hz, 3H), 0.76(s, 3H);[M+H] + =1061.5.

[0216] Example 36: (R)-3-(4-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that described in Example 1. 1 H NMR(500 MHz, DMSO) δ 12.75(s, 1H), 10.89(s, 1H), 8.88(s, 1H), 8.86(s, 2H), 8.38(s, 1H), 8.29(s, 1H), 7.93(d, J=8.8 Hz, 1H), 7.37(s, 1H), 6.84(s, 1H), 6.73(d, J=12.7 Hz, 2H), 4.07(dd, J=12.5, 4.8 Hz, 1H), 3.98(d, J=12.9 Hz, 2H), 3.79(s, 3H), 3.42(d, J=10.8 Hz, 3H), 3.12(d, J=11.1 Hz, 2H), 2.89 - 2.77(m, 6H), 2.11(s, 6H), 2.00(dd, J=33.6, 11.0 Hz, 10H), 1.79(s, 2H), 1.72 - 1.41(m, 7H). [M+H] + =971.8.

[0217] Example 37: (R)-3-(4-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that described in Example 1. 1H NMR(500 MHz, DMSO) δ 11.58(s, 1H), 10.88(s, 1H), 8.96(s, 1H), 8.60(d, J=11.1 Hz, 1H), 8.26(s, 2H), 7.97(d, J=9.3 Hz, 1H), 7.29(s, 1H), 6.73(d, J=12.7 Hz, 3H), 4.07(dd, J=12.8, 5.1 Hz, 1H), 3.98(d, J=12.6 Hz, 2H), 3.77(s, 3H), 3.39(s, 3H), 3.09(d, J=11.8 Hz, 2H), 2.87 - 2.73(m, 6H), 2.64(d, J=2.2 Hz, 3H), 2.51(s, 2H), 2.10(d, J=11.8 Hz, 3H), 1.96(d, J=13.4 Hz, 9H), 1.81(s, 5H), 1.65(d, J=11.0 Hz, 2H), 1.54(d, J=12.0 Hz, 4H). [M+H] + =1002.8.

[0218] Example 38: (R)-3-(4-(3-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that described in Example 1. 1H NMR(500 MHz, DMSO) δ 11.33(s, 1H), 10.86(s, 1H), 8.60(d, J=12.3 Hz, 1H), 8.22(s, 2H), 8.08 - 7.87(m, 2H), 7.30(s, 1H), 6.79(s, 1H), 6.12(d, J=11.3 Hz, 2H), 4.03(dd, J=12.2, 4.8 Hz, 1H), 3.92(t, J=7.0 Hz, 2H), 3.76(s, 3H), 3.61(s, 3H), 3.26(d, J=5.9 Hz, 1H), 2.82 - 2.68(m, 6H), 2.64(s, 3H), 2.31(s, 4H), 2.20(s, 2H), 2.12 - 2.04(m, 1H), 1.95(d, J=13.3 Hz, 6H), 1.54(s, 8H), 0.72(s, 3H). [M+H] + =988.4.

[0219] Example 39: (R)-3-(4-(3-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: Methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate [ka] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (3.00 g, 6.22 mmol), methyl azetidine-3-carboxylate hydrochloride (1.41 g, 9.33 mmol), Cs2CO3 (6.06 g, 18.66 mmol), and RuPhos PdG3 (520.7 mg, 0.622 mmol) in toluene (50 mL) was stirred at 100° C. overnight under nitrogen atmosphere. The resulting mixture was 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 (2:1) to give the product (1.7 g, 53%). [M+1] + =517.1.

[0220] Step 2: (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methanol [ka] To a stirred mixture of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate (1.7 g, 3.29 mmol) in THF (20 mL) was added LiAlH4 (1M in THF, 4.27 mL, 4.27 mmol) dropwise at 0°C. The mixture was then stirred for 2 h and the reaction was quenched with water (10 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 50 mL). 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 (1.4 g, 87%). [M+1] + =489.2.

[0221] Step 3: 3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)piperidine-2,6-dione [ka] To a solution of (1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methanol (1.40 g, 2.87 mmol) in iPrOH (20 mL) and DCM (20 mL) was added Pd / C (1.0 g, 10 wt%), which was stirred under hydrogen atmosphere at room temperature for 48 h. The resulting mixture was filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to give the product (450 mg, 51%). [M+1] + =311.3.

[0222] Step 4: 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbaldehyde [ka] The title compound (258 mg, 48%) was prepared from 3-(2,6-difluoro-4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)piperidine-2,6-dione and DMP in a manner similar to step 3 of example 7.

[0223] Step 5: (R)-3-(4-(3-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)azetidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound (18 mg, 38%) was prepared from (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide and 1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbaldehyde in a similar manner to step 8 of example 7. 1 H NMR(500 MHz, DMSO) δ 11.43(s, 1H), 10.87(s, 1H), 9.22(s, 1H), 8.69(d, J=11.3 Hz, 1H), 8.28(s, 2H), 7.97(d, J=9.0 Hz, 1H), 7.32(s, 1H), 6.84(s, 1H), 6.17(s, 1H), 6.15(s, 1H), 4.05(t, J=7.5 Hz, 3H), 3.78(s, 3H), 3.63(t, J=6.0 Hz, 2H), 3.46(s, 2H), 3.32(d, J=11.1 Hz, 2H), 3.24 - 3.16(m, 1H), 3.07(d, J=11.8 Hz, 2H), 2.84 - 2.70(m, 4H), 2.65(d, J=2.3 Hz, 4H), 2.17(s, 2H), 2.10 - 2.06(m, 1H), 1.97(s, 2H), 1.97(s, 3H), 1.94(s, 3H), 1.94 - 1.90(m, 2H), 1.76(s, 2H), 1.61 - 1.47(m, 4H), 0.69(s, 3H). [M+H] + =1002.7

[0224] Example 40: (R)-3-(4-(2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that described in Example 1. 1 H NMR(500 MHz, DMSO) δ 11.66(s, 1H), 10.95(s, 1H), 9.83(s, 1H), 8.47(s, 1H), 8.23(s, 1H), 8.08(s, 1H), 7.84(d, J=9.3 Hz, 1H), 7.25(s, 1H), 7.03(d, J=10.2 Hz, 2H), 6.82(s, 1H), 4.20(dd, J=12.5, 4.8 Hz, 1H), 3.76(s, 3H), 3.29(s, 1H), 3.05(q, J=7.5 Hz, 2H), 2.85 - 2.71(m, 7H), 2.57 - 2.53(m, 2H), 2.48 - 2.42(m, 4H), 2.33 - 2.22(m, 2H), 2.17 - 2.08(m, 1H), 2.06 - 1.97(m, 7H), 1.55(s, 8H), 1.38(t, J=7.6 Hz, 3H), 0.77(s, 3H);[M+H] + =958.6.

[0225] Example 41: (R)-3-(4-(2-(9-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 1. 1H NMR(500 MHz, DMSO) δ 11.68(s, 1H), 10.95(s, 1H), 8.53(d, J=11.0 Hz, 1H), 8.36(s, 1H), 8.15(s, 1H), 8.01(s, 1H), 7.93(d, J=9.2 Hz, 1H), 7.32(s, 1H), 7.02(d, J=10.1 Hz, 2H), 6.81(s, 1H), 4.23 - 4.17(m, 1H), 3.76(s, 3H), 2.85 - 2.69(m, 7H), 2.64(d, J=2.3 Hz, 3H), 2.58 - 2.53(m, 3H), 2.44(s, 4H), 2.26(d, J=6.4 Hz, 2H), 2.17 - 2.08(m, 1H), 2.02 - 1.93(m, 7H), 1.58 - 1.47(m, 8H), 0.77(s, 3H). [M+H] + =917.5.

[0226] Example 42: (R)-3-(4-(2-(9-(4-((5-chloro-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: (6-((2,5-dichloropyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide [ka] To a solution of (6-amino-2-ethylquinazolin-5-yl)dimethylphosphine oxide (500 mg, 2.0 mmol) in THF (10 mL) was added 2,4,5-trichloropyrimidine (548.19 g, 3.01 mmol). To the reaction mixture was added LiHMDS (1M in THF, 4 mL, 4 mmol) at 0°C. The mixture was stirred at 20°C for 3.5 hours. The mixture was diluted with water (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 20 / 1 to 10 / 1) to give the product (600 mg, 75.9%). [M+H] + =396.2.

[0227] Step 2: (6-((5-chloro-2-((2-methoxy-5-methyl-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide [ka] To a stirred solution of (6-((2,5-dichloropyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (600 mg, 1.52 mmol) and tert-butyl 9-(4-amino-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (intermediate obtained in a similar manner to step 7 of Example 1) (594.3 mg, 1.52 mmol) in n-BuOH (10 mL) was added TsOH (784.32 mg, 4.56 mmol). The resulting mixture was stirred at 95° C. for 16 h. The reaction mixture was concentrated under vacuum, and then aqueous NaOH (1 M, 10 mL) was added to the mixture. The mixture was then extracted with DCM (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=6:1) to give the title product (600 mg, 60.9%). [M+H] + =649.3.

[0228] Step 3: (R)-3-(4-(2-(9-(4-((5-chloro-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of (6-((5-chloro-2-((2-methoxy-5-methyl-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-ethylquinazolin-5-yl)dimethylphosphine oxide (50 mg, 0.077 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (40 mg, 0.15 mmol) in DCM (3 mL) at 20° C. The mixture was stirred at 20° C. for 1 h. The mixture was diluted with water (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (C-18 column chromatography (0.1% FA aqueous solution:acetonitrile = 90:10 to 60:40 gradient elution) to give the product (24.5 mg, 19.6%). 1 H NMR(500 MHz, DMSO) δ 11.61(s, 1H), 10.95(s, 1H), 9.86(s, 1H), 8.45(s, 1H), 8.24(s, 1H), 8.05(s, 1H), 7.85(d, J=8.8 Hz, 1H), 7.28(s, 1H), 7.06(d, J=10.2 Hz, 2H), 6.75(s, 1H), 4.21(dd, J=12.5, 4.7 Hz, 1H), 3.75(s, 3H), 3.52 - 3.44(m, 2H), 3.05(dd, J=15.1, 7.6 Hz, 2H), 2.94(d, J=10.2 Hz, 2H), 2.87 - 2.76(m, 2H), 2.72 - 2.63(m, 3H), 2.29(d, J=22.7 Hz, 7H), 2.20 - 2.12(m, 3H), 2.03(d, J=13.4 Hz, 7H), 1.84(s, 2H), 1.55(d, J=10.0 Hz, 2H), 1.38(s, 3H), 0.76(s, 3H). [M+H] + =900.5.

[0229] Example 43: (R)-3-(4-((2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione Step 1: 2-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)ethan-1-ol [ka] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (1.92 g, 4 mmol), 2-aminoethan-1-ol (488 mg, 8 mmol) and K3PO4 (1.7 g, 8 mmol) in 15 mL of DMSO, CuI (76 mg, 0.4 mmol) and L-proline (92 mg, 0.8 mmol) were added under N2 protection. The mixture was stirred at 100 °C for 16 h. After LCMS, the reaction was shown to be complete. The mixture was diluted with EtOAc and filtered. The filtrate was washed with saturated aqueous NaCl and concentrated in vacuum. The crude product was purified by silica column chromatography (EA:PE=0-50%) to give the title compound (1.5 g, 81.2% yield). [M+H] + =463.6.

[0230] Step 2: 3-(2,6-difluoro-4-((2-hydroxyethyl)amino)phenyl)piperidine-2,6-dione [ka] To a solution of 2-((4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)amino)ethan-1-ol (1.5 g, 3.2 mmol) in 5 mL of DCM and 40 mL of IPA was added Pd / C (1.5 g, 10 wt%). The mixture was stirred at 45° C. under H2 atmosphere for 16 hours. After LCMS, the reaction was shown to be complete. The mixture was filtered through celite. The filtrate was concentrated in vacuo to give the title compound (500 mg, 55% yield). [M+H] + =285.6.

[0231] Step 3: 2-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)ethyl methanesulfonate [ka] To a solution of 3-(2,6-difluoro-4-((2-hydroxyethyl)amino)phenyl)piperidine-2,6-dione (50 mg, 0.18 mmol) and Et3N (40 mg, 0.4 mmol) in 1.5 mL of DCM was added MsCl (23 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 h. After LCMS, the reaction was shown to be complete. The mixture was concentrated in vacuo and purified by preparative TLC (DCM:MeOH=15:1) to give the title compound (52 mg, 80% yield). [M+H] + =363.6.

[0232] Step 4: (R)-3-(4-((2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione [ka] To a solution of (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (100 mg, 0.14 mmol), 2-((4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)ethyl methanesulfonate (52 mg, 0.14 mmol), KI (33 mg, 0.2 mmol), and DIEA (40 mg, 0.31 mmol) in 3 mL of ACN and 0.5 mL of DMSO. The mixture was stirred at 80° C. for 16 hours. After LCMS, the reaction was shown to be complete. The mixture was concentrated in vacuo. The mixture was washed with water and extracted with DCM. The organic layer was concentrated in vacuo and purified by preparative TLC (DCM:MeOH=11:1) to give the crude product, which was separated by SFC (IF (2cm×25cm, 5um), MtBE (0.1%DEA):(MeOH:DCM=1:1)=50:50, 100 bar, 20ml / min) which corresponded to the title compound as peak A at 1.202 min / 254 nm (29.78mg, 22% yield). 1 H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 10.83(s, 1H), 8.60(d, J=12.3 Hz, 1H), 8.27 - 8.15(m, 2H), 8.02 - 7.90(m, 2H), 7.30(s, 1H), 6.79(s, 1H), 6.27(d, J=12.5 Hz, 2H), 6.07(s, 1H), 3.98(dd, J=12.0, 4.3 Hz, 1H), 3.76(s, 3H), 3.12(s, 2H), 2.83 - 2.69(m, 5H), 2.64(s, 3H), 2.49 - 2.32(m, 7H), 2.28 - 2.13(m, 2H), 2.09 - 2.01(m, 1H), 1.99 - 1.84(m, 7H), 1.55(s, 8H), 0.72(s, 3H);[M+H] + =976.6.

[0233] Example 44: (R)-3-(4-((2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)(methyl)amino)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that of Example 43. 1 H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 10.84(s, 1H), 8.59(d, J=12.1 Hz, 1H), 8.26 - 8.16(m, 2H), 8.01 - 7.89(m, 2H), 7.29(s, 1H), 6.79(s, 1H), 6.34(d, J=12.9 Hz, 2H), 4.01(dd, J=12.0, 3.5 Hz, 1H), 3.75(s, 3H), 3.44(s, 2H), 2.91(s, 3H), 2.82 - 2.67(m, 5H), 2.63(s, 3H), 2.47 - 2.36(m, 7H), 2.24 - 2.12(m, 2H), 2.11 - 2.04(m, 1H), 2.01 - 1.80(m, 7H), 1.52(s, 8H), 0.72(s, 3H);[M+H] + =990.6.

[0234] Example 45: 4-(4-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The title compound was prepared in a manner similar to that of Example 35. 1 H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 11.09(s, 1H), 8.61(d, J=12.6 Hz, 1H), 8.28 - 8.14(m, 2H), 8.03 - 7.90(m, 2H), 7.68(t, J=7.4 Hz, 1H), 7.41 - 7.22(m, 3H), 6.78(s, 1H), 5.09(dd, J=12.5, 5.2 Hz, 1H), 3.83 - 3.61(m, 6H), 2.91 - 2.83(m, 3H), 2.72(s, 3H), 2.66 - 2.57(m, 5H), 2.48 - 2.37(m, 3H), 2.31 - 2.17(m, 3H), 2.06 - 1.93(m, 9H), 1.86 - 1.66(m, 4H), 1.55(s, 7H), 1.37 - 1.22(m, 2H), 0.72(s, 3H);[M+H] + =1063.6.

[0235] Example 46: 5-(4-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The title compound was prepared in a manner similar to that of Example 35. 1H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 11.07(s, 1H), 8.60(d, J=11.7 Hz, 1H), 8.22(s, 2H), 8.01 - 7.84(m, 2H), 7.65(d, J=8.4 Hz, 1H), 7.30(s, 2H), 7.22(s, 1H), 6.78(s, 1H), 5.06(dd, J=12.7, 5.3 Hz, 1H), 4.04(d, J=12.3 Hz, 2H), 3.75(s, 3H), 2.92 - 2.89(m, 3H), 2.71(s, 4H), 2.65 - 2.52(m, 5H), 2.36(s, 4H), 2.17(s, 4H), 2.01 - 1.98(m, 2H), 1.95 - 1.91(m, 6H), 1.89 - 1.75(m, 3H), 1.53(s, 7H), 1.21 - 1.04(m, 2H), 0.72(s, 3H);[M+H] + =1063.5.

[0236] Example 47: 5-(4-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione [ka] The title compound was prepared in a manner similar to that of Example 35. 1H NMR(500 MHz, DMSO) δ 11.27(s, 1H), 11.11(s, 1H), 8.74(s, 1H), 8.66(d, J=9.7 Hz, 1H), 8.19(s, 1H), 7.95(d, J=4.5 Hz, 2H), 7.74(d, J=11.7 Hz, 1H), 7.48(d, J=7.3 Hz, 1H), 7.33(s, 1H), 6.80(s, 1H), 5.11(dd, J=12.6, 4.8 Hz, 1H), 3.77(s, 3H), 3.66(d, J=9.3 Hz, 2H), 3.46 - 3.37(m, 2H), 3.09(s, 4H), 2.97 - 2.85(m, 4H), 2.74(s, 3H), 2.66 - 2.60(m, 5H), 2.25 - 2.15(m, 2H), 2.08 - 2.00(m, 2H), 1.98 - 1.93(m, 8H), 1.89 - 1.85(m, 2H), 1.78 - 1.72(m, 2H), 1.67 - 1.59(m, 2H), 1.55 - 1.47(m, 2H), 1.45 - 1.36(m, 2H), 0.70(s, 3H);[M+H] + =1081.7.

[0237] Example 48: 3-(5-(4-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that of Example 35. 1H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 10.94(s, 1H), 8.60(d, J=12.1 Hz, 1H), 8.26 - 8.14(m, 2H), 8.01 - 7.89(m, 2H), 7.50(d, J=8.4 Hz, 1H), 7.30(s, 1H), 7.04(d, J=8.9 Hz, 2H), 6.78(s, 1H), 5.04(dd, J=13.3, 5.0 Hz, 1H), 4.38 - 4.16(m, 2H), 3.87(d, J=11.1 Hz, 2H), 3.76(s, 3H), 2.98 - 2.76(m, 4H), 2.71(s, 3H), 2.67 - 2.54(m, 6H), 2.42 - 2.34(m, 4H), 2.26 - 2.08(m, 4H), 2.00 - 1.91(m, 7H), 1.80 - 1.74(m, 2H), 1.54(s, 8H), 1.26 - 1.09(m, 2H), 0.72(s, 3H);[M+H] + =1049.9.

[0238] Example 49: 5-((S)-3-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The title compound was prepared in a manner similar to that of Example 35. 1H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 11.06(s, 1H), 8.60(d, J=11.8 Hz, 1H), 8.21(d, J=10.9 Hz, 2H), 7.94(d, J=13.8 Hz, 2H), 7.64(d, J=8.5 Hz, 1H), 7.31(s, 1H), 6.90(s, 1H), 6.85 - 6.75(m, 2H), 5.05(dd, J=12.8, 5.2 Hz, 1H), 3.76(s, 3H), 3.59 - 3.48(m, 2H), 3.42 - 3.38(m, 1H), 3.17 - 3.10(m, 1H), 2.92 - 2.84(m, 1H), 2.72(s, 4H), 2.67 - 2.52(m, 8H), 2.42 - 2.32(m, 4H), 2.20(s, 1H), 2.15 - 2.10(m, 1H), 2.02 - 1.92(m, 8H), 1.78 - 1.72(m, 1H), 1.55(s, 8H), 0.72(s, 3H);[M+H] + =1049.8.

[0239] Example 51: 3-(4-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that of Example 21. 1H NMR(500 MHz, DMSO) δ 11.31(s, 1H), 11.09(s, 1H), 8.64(d, J=12.2 Hz, 1H), 8.23(s, 1H), 8.20(s, 1H), 7.96(s, 1H), 7.94(s, 1H), 7.33(s, 1H), 6.99(t, J=7.9 Hz, 1H), 6.92(d, J=8.6 Hz, 1H), 6.89(s, 1H), 6.80(s, 1H), 5.36(dd, J=12.7, 5.2 Hz, 1H), 3.77(s, 3H), 3.64(s, 3H), 3.22(d, J=8.2 Hz, 2H), 2.95 - 2.84(m, 2H), 2.81 - 2.67(m, 8H), 2.65(d, J=2.1 Hz, 4H), 2.60(s, 1H), 2.19(s, 2H), 2.10(s, 2H), 2.03 - 1.90(m, 9H), 1.85(s, 2H), 1.60(s, 8H), 0.71(s, 3H). [M+H] + =1050.7

[0240] Example 52: 3-(4-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-3,3-dimethyl-2-oxoindolin-1-yl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that of Example 28. 1H NMR(500 MHz, DMSO) δ 11.31(s, 1H), 11.09(s, 1H), 8.64(d, J=12.2 Hz, 1H), 8.23(s, 1H), 8.20(s, 1H), 7.96(s, 1H), 7.94(s, 1H), 7.33(s, 1H), 6.99(t, J=7.9 Hz, 1H), 6.92(d, J=8.6 Hz, 1H), 6.89(s, 1H), 6.80(s, 1H), 5.36(dd, J=12.7, 5.2 Hz, 1H), 3.64(s, 3H), 3.22(d, J=8.2Hz, 2H), 2.95 - 2.84(m, 2H), 2.81 - 2.67(m, 8H), 2.65(d, J=2.1 Hz, 4H), 2.60(s, 1H), 2.19(m, 2H), 2.10(m, 2H), 2.03 - 1.98(m, 2H) 1.97(s, 3H), 1.94(s, 3H), 1..94 - 1.90(m, 1H), 1.85(s, 2H), 1.75(s, 6H), 1.60(m, 8H), 0.71(s, 3H). [M+H] + =1063.8

[0241] Example 54: (R)-3-(4-(4-(4-(1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that described in Example 1. 1H NMR(500 MHz, DMSO) δ 11.56(s, 1H), 10.87(s, 1H), 8.61(d, J=11.7 Hz, 1H), 8.31(s, 1H), 8.16(s, 1H), 7.95(d, J=9.2 Hz, 1H), 7.90(s, 1H), 7.38(s, 1H), 6.70(s, 1H), 6.62(d, J=12.8 Hz, 2H), 4.07 - 3.98(m, 3H), 3.78(d, J=11.5 Hz, 2H), 3.31 - 3.26(m, 1H), 2.94 - 2.86(m, 2H), 2.82 - 2.71(m, 3H), 2.67 - 2.57(m, 6H), 2.49 - 2.28(m, 8H), 2.27 - 2.18(m, 3H), 2.12 - 2.05(m, 1H), 1.99 - 1.91(m, 7H), 1.86 - 1.77(m, 4H), 1.55 - 1.39(m, 4H), 1.26(t, J=6.7 Hz, 3H), 0.71(s, 3H);[M+H] + =1001.5.

[0242] Example 55: (R)-3-(4-(1-((1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidin-3-yl)methyl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that of Example 30. 1H NMR(500 MHz, DMSO) δ 11.59(s, 1H), 10.95(s, 1H), 9.87(s, 1H), 8.44(s, 1H), 8.22(s, 1H), 8.03(s, 1H), 7.85(d, J=9.1 Hz, 1H), 7.27(s, 1H), 7.03(s, 1H), 7.01(s, 1H), 6.73(s, 1H), 4.35(s, 2H), 4.19(dd, J=12.4, 4.7 Hz, 1H), 3.75(s, 3H), 3.46 - 3.41(m, 3H), 3.05(dd, J=14.9, 7.4 Hz, 2H), 2.88(d, J=7.2 Hz, 2H), 2.83 - 2.72(m, 3H), 2.64 - 2.52(m, 2H), 2.27 - 2.16(m, 2H), 2.14 - 2.08(m, 2H), 2.04(s, 3H), 2.01(s, 3H), 1.97(d, J=11.0 Hz, 2H), 1.72(t, J=11.4 Hz, 4H), 1.66 - 1.57(m, 2H), 1.38(t, J=7.5 Hz, 3H), 1.29(d, J=9.6 Hz, 2H), 1.06(t, J=6.9Hz, 5H), 0.74(s, 3H). [M+H] + =1013.7

[0243] Example 56: (R)-3-(4-(1-((1-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)azetidin-3-yl)methyl)piperidin-4-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that of Example 30. 1H NMR(500 MHz, DMSO) δ 11.30(s, 1H), 10.94(s, 1H), 8.63(d, J=10.6 Hz, 1H), 8.22(s, 1H), 8.20 - 8.11(m, 1H), 7.95(s, 1H), 7.93(s, 1H), 7.32(s, 1H), 7.03(s, 1H), 7.01(s, 1H), 6.70(s, 1H), 4.19(dd, J=12.5, 4.7 Hz, 1H), 3.75(s, 3H), 3.35(s, 3H), 2.91 - 2.70(m, 6H), 2.64(d, J=2.1 Hz, 3H), 2.57(dd, J=19.7, 9.0 Hz, 4H), 2.48(s, 2H), 2.13(dd, J=21.8, 8.3 Hz, 4H), 1.98(d, J=11.4 Hz, 4H), 1.96(s, 3H), 1.93(s, 3H), 1.72(t, J=15.1 Hz, 4H), 1.61(d, J=11.4 Hz, 2H), 1.33 - 1.20(m, 3H), 0.70(s, 3H). [M+H] + =1016.7

[0244] Example 57: (R)-3-(4-(7-(1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 9. 1 H NMR(500 MHz, DMSO) δ H11.54(s, 1H), 10.86(s, 1H), 8.62(d, J=12.2 Hz, 1H), 8.31(s, 1H), 8.17(s, 1H), 7.95(d, J=9.2 Hz, 1H), 7.89(s, 1H), 7.40(s, 1H), 6.69(s, 1H), 6.10(d, J=11.3 Hz, 2H), 4.07 - 3.96(m, 3H), 3.55(s, 4H), 2.91(d, J=9.7 Hz, 2H), 2.78(s, 1H), 2.69 - 2.57(m, 6H), 2.48 - 2.35(m, 4H), 2.20(d, J=5.9 Hz, 2H), 2.06(s, 1H), 2.02 - 1.90(m, 8H), 1.81 - 1.70(m, 6H), 1.57(d, J=10.1 Hz, 2H), 1.26(t, J=6.9 Hz, 3H), 0.70(s, 3H). [M+H] + =958.5.

[0245] Example 58: (R)-3-(4-(2-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 9. 1H NMR(500 MHz, DMSO) δ 11.79(s, 1H), 10.87(s, 1H), 8.66(s, 1H), 8.53(s, 1H), 8.25(s, 1H), 8.07(s, 1H), 7.93(s, 1H), 7.49(s, 1H), 7.40(s, 1H), 6.75(s, 1H), 6.68(d, J=12.7 Hz, 2H), 4.05(dd, J=12.3, 4.6 Hz, 1H), 4.00 - 3.90(m, 4H), 3.78(s, 3H), 3.65 - 3.56(m, 3H), 3.30(s, 3H), 3.20(s, 2H), 3.15 - 3.11(m, 2H), 3.02(d, J=9.5 Hz, 2H), 2.96(d, J=7.2 Hz, 2H), 2.78(t, J=12.6 Hz, 1H), 2.68 - 2.62(m, 2H), 2.24(s, 2H), 2.08(d, J=9.4 Hz, 2H), 2.00(s, 3H), 1.98(s, 3H), 1.80(s, 2H), 1.60(s, 2H), 1.33(t, J=7.6 Hz, 3H), 0.74(s, 3H). [M+H] + =984.7.

[0246] Example 59: (R)-3-(4-(2-(1-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 9. 1H NMR(500 MHz, DMSO) δ 11.55(s, 1H), 10.86(s, 1H), 8.62(d, J=12.5 Hz, 1H), 8.31(s, 1H), 8.17(s, 1H), 7.95(d, J=9.1 Hz, 1H), 7.89(s, 1H), 7.38(s, 1H), 6.69(s, 1H), 6.63(d, J=12.9 Hz, 2H), 4.06 - 3.97(m, 3H), 3.19(s, 4H), 2.95(s, 3H), 2.84(s, 2H), 2.77(d, J=12.4Hz, 1H), 2.64(s, 3H), 2.58(t, J=9.9 Hz, 2H), 2.17(s, 2H), 2.09(d, J=11.4 Hz, 1H), 1.96(d, J=13.3 Hz, 7H), 1.72(s, 6H), 1.57(s, 1H), 1.34 - 1.24(m, 6H), 0.94(t, J=7.4 Hz, 1H), 0.71(s, 3H). [M+H] + =958.7.

[0247] Example 60: (R)-3-(4-(6-(1-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 9. 1H NMR(500 MHz, DMSO) δ 11.29(s, 1H), 10.85(s, 1H), 8.63(d, J=12.4 Hz, 1H), 8.20(d, J=19.9 Hz, 2H), 7.94(d, J=12.6 Hz, 2H), 7.32(s, 1H), 6.70(s, 1H), 6.14(d, J=11.1 Hz, 2H), 4.03(dd, J=12.7, 4.7 Hz, 1H), 3.91(s, 4H), 3.75(s, 3H), 3.28(s, 3H), 2.85(d, J=11.6 Hz, 2H), 2.78(t, J=12.9 Hz, 1H), 2.64(d, J=2.1 Hz, 3H), 2.58(t, J=10.2 Hz, 4H), 2.09(dd, J=39.2, 26.0 Hz, 4H), 1.95(d, J=13.4 Hz, 7H), 1.69(s, 2H), 1.29(d, J=9.9 Hz, 2H), 0.70(s, 3H). [M+H] + =960.6.

[0248] Example 61: (R)-3-(4-(4-(6-(4-((5-chloro-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound (30 mg, 40%) was prepared in a similar manner to Example 1. 1H NMR(500 MHz, CDCl3) δ 12.17(s, 1H), 8.82(d, J=6.5 Hz, 1H), 8.12(s, 1H), 8.03(d, J=9.5 Hz, 1H), 7.92(s, 1H), 7.79(s, 1H), 7.64(d, J=11.5 Hz, 1H), 7.15(s, 1H), 6.41(d, J=12.0 Hz, 2H), 6.07(s, 1H), 4.02 - 3.90(m, 5H), 3.83(s, 3H), 3.64 - 3.58(m, 1H), 3.47 - 3.30(m, 3H), 2.77 - 2.90(m, 3H), 2.75 - 2.62(m, 4H), 2.45 - 2.27(m, 3H), 2.20 - 2.06(m, 8H), 1.85 - 1.70(m, 10.4 Hz, 1H), 1.61 - 1.51(m, 2H), 1.45 - 1.35(m, 2H), 1.03 - 0.80(m, 4H). [M+H] + =916.70.

[0249] Example 62: (R)-3-(4-(4-(7-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 9. 1H NMR(500 MHz, DMSO) δ 11.30(s, 1H), 10.87(s, 1H), 8.64(s, 1H), 8.27 - 8.15(m, 2H), 8.01 - 7.89(m, 2H), 7.32(s, 1H), 6.78 - 6.62(m, 3H), 4.04(dd, J=11.8, 4.8 Hz, 1H), 3.86 - 3.72(m, 5H), 3.31 - 3.24(m, 2H), 2.87 - 2.67(m, 8H), 2.67 - 2.57(m, 4H), 2.39 - 2.49(m, 2H), 2.26 - 2.15(m, 2H), 2.12 - 2.03(m, 1H), 1.99 - 1.88(m, 7H), 1.87 - 1.62(m, 4H), 1.48 - 1.28(m, 4H), 0.71(s, 3H);[M+H] + =988.4.

[0250] Example 63: 3-(4-(1-(1'-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-[1,4'-bipiperidine]-4-yl)azetidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 25. 1H NMR (400 MHz, DMSO) δ 11.79(s, 1H), 11.09(s, 1H), 8.56(d, J=8.8 Hz, 1H), 8.27(s, 1H), 8.21(s, 1H), 8.00(s, 1H), 7.87(d, J=9.3 Hz, 1H), 7.44(d, J=8.9 Hz, 1H), 7.33(s, 1H), 7.17(d, J=7.8 Hz, 1H), 7.08 - 6.99(m, 2H), 6.74(s, 1H), 5.37(dd, J=12.6, 5.1 Hz, 1H), 4.22 - 4.16(m, 1H), 3.76(s, 3H), 3.62(t, J=6.8 Hz, 2H), 3.53(s, 3H), 3.18(s, 4H), 2.94(t, J=7.6 Hz, 4H), 2.86(d, J=6.2 Hz, 3H), 2.69 - 2.62(m, 3H), 2.38(d, J=11.7 Hz, 1H), 2.28 - 2.22(m, 3H), 2.07(s, 1H), 1.98(d, J=13.3 Hz, 7H), 1.81(d, J=11.1 Hz, 2H), 1.70(d, J=10.6 Hz, 2H), 1.58(d, J=9.2 Hz, 2H), 1.32(t, J=7.6 Hz, 3H), 1.21(d, J=10.0 Hz, 2H), 0.77(s, 3H);[M+H] + =1032.7

[0251] Example 64: (R)-3-(4-(4-(6-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that described in Example 1. 1H NMR(500 MHz, DMSO) δ 11.59(s, 1H), 10.87(s, 1H), 8.46(d, J=12.5 Hz, 1H), 8.31(s, 1H), 8.17(s, 1H), 7.97(s, 1H), 7.88(d, J=8.8 Hz, 1H), 7.04(s, 1H), 6.62(d, J=13.0 Hz, 2H), 6.11(s, 1H), 4.04(dd, J=12.5, 5.0 Hz, 1H), 3.88(s, 4H), 3.73(s, 3H), 3.60(s, 2H), 3.35 - 3.31(m, 5H), 2.91 - 2.73(m, 3H), 2.63(d, J=2.0 Hz, 3H), 2.25-2.05(m, 4H), 2.02 - 1.92(m, 7H), 1.75 - 1.60(m, 2H), 1.30 - 1.15(m, 2H), 0.82(s, 3H). [M+H] + =960.7.

[0252] Example 65: (R)-3-(4-(4-(6-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that described in Example 1. 1H NMR(500 MHz, DMSO) δ 11.76(s, 1H), 10.87(s, 1H), 8.43 - 8.33(m, 2H), 8.17(s, 1H), 7.97(s, 1H), 7.88(d, J=8.5 Hz, 1H), 7.04(s, 1H), 6.63(d, J=13.0 Hz, 2H), 6.12(s, 1H), 4.04(dd, J=12.5, 5.0 Hz, 1H), 3.90(s, 4H), 3.73(s, 3H), 3.66 - 3.55(s, 2H), 3.32(s, 6H), 2.90 - 2.75(m, 3H), 2.63(d, J=2.0 Hz, 3H), 2.21 - 2.04(m, 2H), 2.01 - 1.92(m, 8H), 1.84(s, 3H), 1.72 - 1.65(m, 2H). [M+H] + =946.7.

[0253] Example 66: (R)-3-(4-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinazolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that described in Example 1. 1H NMR(500 MHz, DMSO) δ 11.75(s, 1H), 10.86(s, 1H), 9.77(s, 1H), 8.54(s, 1H), 8.22(s, 1H), 8.05(s, 1H), 7.85(d, J=9.6 Hz, 1H), 7.24(s, 1H), 6.74(s, 1H), 6.63(d, J=12.9 Hz, 2H), 4.04(dd, J=12.9, 4.8 Hz, 1H), 3.80(d, J=12.0 Hz, 2H), 3.75(s, 3H), 2.85 - 2.67(m, 10H), 2.36(s, 4H), 2.15 - 1.92(m, 9H), 1.89(s, 3H), 1.81(d, J=11.2 Hz, 2H), 1.59 - 1.42(m, 10H), 1.23(s, 1H). [M+H] + =987.6.

[0254] Example 68: 3-(4-(2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-ethylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that of Example 28. 1H NMR(500 MHz, DMSO) δ 11.93(s, 1H), 11.09(s, 1H), 8.50(s, 1H), 8.35(s, 1H), 8.21(d, J=18.5 Hz, 1H), 8.03(s, 1H), 7.87(s, 1H), 7.43(d, J=9.0 Hz, 1H), 7.25(s, 1H), 6.95(d, J=31.2 Hz, 3H), 6.77(s, 1H), 5.36(s, 1H), 3.77(s, 3H), 3.59(s, 3H), 3.08(s, 2H), 2.95 - 2.69(m, 8H), 2.61(d, J=24.6 Hz, 7H), 2.04 - 1.87(m, 10H), 1.57(s, 8H), 1.39 - 1.26(m, 3H). [M+H] + =977.7.

[0255] Example 72: 3-(5-(4-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] The title compound (30 mg, 40.5%) was prepared in a similar manner to Example 33. 1H NMR(500 MHz, DMSO) δ 11.93(s, 1H), 10.94(s, 1H), 8.50(d, J=8.9 Hz, 1H), 8.39(d, J=5.7 Hz, 1H), 8.20(s, 1H), 7.99(s, 1H), 7.88(d, J=9.4 Hz, 1H), 7.50(d, J=8.4 Hz, 1H), 7.42(d, J=8.9 Hz, 1H), 7.32(s, 1H), 7.05(d, J=8.5 Hz, 2H), 6.75(s, 1H), 5.04(dd, J=13.2, 5.1 Hz, 1H), 4.32(d, J=16.9 Hz, 1H), 4.20(d, J=16.9 Hz, 1H), 3.88(d, J=12.2 Hz, 2H), 3.76(s, 3H), 2.96 - 2.81(m, 3H), 2.79(d, J=16.0 Hz, 5H), 2.64(s, 3H), 2.59(d, J=16.5 Hz, 2H), 2.54(s, 2H), 2.42 - 2.32(m, 2H), 2.29(s, 2H), 1.99(d, J=13.3 Hz, 6H), 1.94(d, J=16.8 Hz, 4H), 1.79(d, J=10.7 Hz, 3H), 1.58(s, 7H), 1.20(d, J=10.6Hz, 2H). [M+H] + =1017.4.

[0256] Example 73: (R)-3-(4-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that described in Example 1. 1H NMR(500 MHz, DMSO) δ 11.94(s, 1H), 10.87(s, 1H), 8.50(d, J=8.5 Hz, 1H), 8.38(s, 1H), 8.20(s, 1H), 8.00(s, 1H), 7.87(d, J=8.3 Hz, 1H), 7.41(s, 1H), 7.30(s, 1H), 6.75(s, 1H), 6.63(d, J=12.8 Hz, 2H), 4.04(s, 1H), 3.77(d, J=14.7 Hz, 5H), 3.32(s, 6H), 2.76(s, 7H), 2.63(s, 3H), 2.06(d, J=20.0 Hz, 1H), 1.99(d, J=13.3 Hz, 6H), 1.92(s, 3H), 1.81(s, 2H), 1.54(s, 11H). [M+H] + =984.3.

[0257] Example 79: (R)-3-(4-(4-((9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)piperidin-1-yl)-2,6-difluorophenyl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that described in Example 1. 1 H NMR(500 MHz, DMSO) δ H11.34(s, 1H), 10.86(s, 1H), 8.60(d, J=12.2 Hz, 1H), 8.22(s, 2H), 7.94(d, J=14.4 Hz, 2H), 7.30(s, 1H), 6.78(s, 1H), 6.60(d, J=12.9 Hz, 2H), 4.03(d, J=12.8 Hz, 1H), 3.78 - 3.70(m, 5H), 2.78 - 2.68(m, 7H), 2.63(s, 3H), 2.38 - 2.31(m, 4H), 2.22 - 2.05(m, 6H), 1.98 - 1.91(m, 7H), 1.74(d, J=11.7 Hz, 3H), 1.58 - 1.48(m, 8H), 1.12(d, J=11.0 Hz, 2H), 0.72(s, 3H). [M+H] + =1030.6.

[0258] Example 83: (S)-3-(4-(3-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl)-7-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 28. 1H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 11.10(s, 1H), 8.60(d, J=11.8 Hz, 1H), 8.22(s, 2H), 7.99 - 7.89(m, 2H), 7.30(s, 1H), 6.88(t, J=7.7 Hz, 2H), 6.78(s, 1H), 5.52(d, J=8.3 Hz, 1H), 3.75(s, 3H), 3.63(s, 2H), 3.00(s, 1H), 2.94 - 2.85(m, 2H), 2.74-2.69(m, 4H), 2.64(s, 3H), 2.60(s, 1H), 2.44-2.38(m, 6H), 2.19(s, 3H), 2.09(s, 1H), 1.96(s, 3H), 1.94(s, 3H), 1.75(s, 2H), 1.56-1.48(m, 8H), 1.23(s, 1H), 0.72(s, 3H). [M+H] + =1027.7.

[0259] Example 85: 3-(7-(2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione [ka] The title compound was prepared using a procedure similar to that of Example 28. 1H NMR(500 MHz, DMSO) δ 11.35(s, 1H), 11.21(s, 1H), 8.59(d, J=11.9 Hz, 1H), 8.22(s, 2H), 8.01 - 7.90(m, 2H), 7.30(s, 1H), 7.17 - 7.02(m, 3H), 6.80(s, 1H), 5.36(dd, J=12.9, 5.2 Hz, 1H), 3.76(s, 3H), 2.87(d, J=8.1 Hz, 4H), 2.76 - 2.59(m, 13H), 2.48 - 2.44(m, 1H), 2.27 - 2.13(m, 3H), 1.97(s, 3H), 1.94(s, 3H), 1.58-1.50(m, 8H), 0.72(s, 3H). [M+H] + =982.7.

[0260] Example 86: 3-(4'-(2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that of Example 52. 1H NMR(500 MHz, DMSO) δ 11.35(s, 1H), 11.08(s, 1H), 8.60(d, J=12.0 Hz, 1H), 8.22(s, 2H), 7.99 - 7.91(m, 2H), 7.30(s, 1H), 7.16(t, J=7.9 Hz, 1H), 6.87(d, J=7.8 Hz, 2H), 6.80(s, 1H), 5.31(s, 1H), 3.76(s, 3H), 2.86(d, J=13.1 Hz, 1H), 2.72(s, 4H), 2.66 - 2.55(m, 6H), 2.49 - 2.45(m, 5H), 2.20(s, 2H), 2.00 - 1.91(m, 10H), 1.60 - 1.44(m, 11H), 0.72(s, 3H). [M+H] + =1006.8.

[0261] Example 87: 3-(5-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] The title compound was prepared in a manner similar to that of Example 33. 1H NMR(500 MHz, DMSO) δ 11.34(s, 1H), 10.94(s, 1H), 8.59(s, 1H), 8.21(s, 2H), 8.00 - 7.91(m, 2H), 7.50(d, J=8.4 Hz, 1H), 7.30(s, 1H), 7.05(d, J=9.4 Hz, 2H), 6.78(s, 1H), 5.04(dd, J=13.4, 5.0 Hz, 1H), 4.32(d, J=16.9 Hz, 1H), 4.20(d, J=16.7 Hz, 1H), 3.91(d, J=12.1 Hz, 2H), 3.75(s, 3H), 2.98 - 2.77(m, 4H), 2.71(s, 4H), 2.61(dd, J=24.8, 9.4 Hz, 6H), 2.49 - 2.43(m, 3H), 2.41 - 2.33(m, 1H), 2.19(s, 2H), 1.95(d, J=13.4 Hz, 7H), 1.84(d, J=10.7 Hz, 2H), 1.52(s, 9H), 0.71(s, 3H). [M+H] + =1035.8.

[0262] Example 90: 3-(5-((2-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)(methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] In a 40 mL microwave vial equipped with a magnetic stir bar was added (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-fluoro-2-methylquinolin-5-yl)dimethylphosphine oxide (71.0 mg, 0.10 mmol), 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)(methyl)amino)acetaldehyde (compound obtained in a similar manner to step 6 of example 33) (63.2 mg, 0.20 mmol) and DCM (8 mL). After stirring at room temperature for 20 min, NaBH(OAc)3 (63.6 mg, 0.3 mmol) was added. After stirring at the same temperature for an additional 1 h, the reaction mixture was diluted with saturated aqueous NaHCO3 (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography followed by preparative HPLC chromatography (0.1% aqueous FA:acetonitrile = 90:10 to 50:50 gradient elution) afforded the title compound (52 mg, 52%). 1H NMR(500 MHz, DMSO) δ 11.27(s, 1H), 10.92(s, 1H), 8.54(d, J=9.5 Hz, 1H), 8.15 - 8.11(m, 2H), 7.88(s, 1H), 7.87(d, J=9.5 Hz, 1H), 7.30(t, J=8.0 Hz, 1H), 7.23(s, 1H), 7.08(d, J=7.5 Hz, 1H), 6.94(d, J=8.5 Hz, 1H), 6.71(s, 1H), 5.05(dd, J=13.0, 5.0 Hz, 1H), 4.45(d, J=16.5 Hz, 1H), 4.32(d, J=16.5 Hz, 1H), 3.68(s, 3H), 2.88(s, 3H), 2.88 - 2.81(m, 1H), 2.62(s, 3H), 2.56(d, J=2.0 Hz, 3H), 2.53 - 2.50(m, 1H), 2.41 - 2.35(m, 5H), 2.34 - 1.28(m, 4H), 2.15 - 2.07(m, 2H), 1.96 - 1.92(m, 2H), 1.88(d, J=13.5 Hz, 6H), 1.43 - 1.38(m, 8H), 0.64(t, J=8.0Hz, 3H), [M+H] + =1009.8.

[0263] Example 92: 5-(4-(9-(4-((5-bromo-4-((5-(dimethylphosphoryl)-3-fluoro-2-methylquinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)-3,9-diazaspiro[5.5]undecan-3-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka] The title compound was prepared in a manner similar to that of Example 33. 1H NMR(500 MHz, DMSO) δ 11.07(s, 1H), 8.61(s, 1H), 8.22(s, 2H), 7.98 - 7.90(m, 2H), 7.66(d, J=8.5 Hz, 1H), 7.28 - 7.24(m, 3H), 6.78(s, 1H), 5.10 - 5.05(m, 1H), 4.09(s, 2H), 3.75(s, 3H), 2.97 - 2.88(m, 4H), 2.71 -2.63(m, 16H), 2.19(s, 2H), 1.95 - 1.85(m, 8H), 1.85(s, 2H), 1.54 - 1.52(m, 8H), 0.72(s, 2H). [M+H] + =1049.5.

[0264]

Table 6-1

Table 6-2

Table 6-3

Table 6-4

Table 6-5

Table 6-6

Table 6-7

Table 6-8

Table 6-9

Table 6-10

Table 6-11

[0265] Generation of cell lines H1975-clone number 28 (Del19 / T790M / C797S) and H1975-clone number 25 (L858R / T790M / C797S). EGFR-Del19 / T790M / C797S and EGFR-L858R / T790M / C797S were stably expressed in H1975 cell line by lentivirus-mediated overexpression, respectively. EGFR-overexpressing cells were then knocked out, where EGFR-targeting sgRNA was designed to target only the endogenous EGFR copy and preserve the exogenous EGFR copy. Following knockout, edited H1975 cells were seeded in 96-well plates at a concentration of 1 cell / cell and cultured for approximately 2 weeks to form single clones. Screening was performed on the formed clones by DNA sequencing and whole-exon sequence analysis for the desired editing process. H1975-clone no. 28 and H1975-clone no. 25 were finally confirmed as homozygous Del19 / T790M / C797S EGFR and L858R / T790M / C797S EGFR clones, respectively.

[0266] cell degradation Cell treatment On day 1, H1975-clone no. 28 (Del19 / T790M / C797S) and H1975-clone no. 25 (L858R / T790M / C797S) cells are seeded in cell culture medium [RPMI1640 (Gibco, Cat. No. 72400-047), 10% heat-inactivated FBS, 1% PS (Gibco, Cat. No. 10378)] in Corning 96-well plates (Cat. No. 3599) at 20,000 cells / well, 30,000 cells / well, 10,000 cells / well, or 5,000 cells / well, respectively.

[0267] On day 2, H1975-25 and H1975-28 cells were treated with compounds diluted in 0.2% DMSO cell culture medium and incubated for 16 hours at 37° C. with 5% CO2. Final compound concentrations in all assays started at 10 uM and included a total of 8 doses, with 5-fold dilutions.

[0268] HTRF assay After 16 hours of treatment, add HTRF lysis buffer to each well. Seal plate and incubate for 1 hour at room temperature on a plate shaker. Once cells are lysed, transfer 16 μL of cell lysate to a PE384-well HTRF detection plate. Add 4 μL of premixed HTRF antibody to each well. Cover plate with plate sealer and spin at 1000 rpm for 1 minute. Incubate overnight at room temperature. Read on a BMG PheraStar following the HTRF protocol (337nm-665nm-620nm).

[0269] The percentage of inhibition (degradation) of the compound was calculated by the following formula: Percentage of inhibition of compound = 100 - 100 x (signal - low control) / (high control - low control) [where signal = each test compound group] Low control = lysis buffer only without cells (indicating complete degradation of EGFR); High control = cells with added DMSO and no compound (showing microplate readings without degradation of EGFR); Dmax is the maximum percentage of inhibition (degradation)].

[0270] Compound IC 50 (DC 50 ) values ​​can be obtained by applying the following formula:

[0271] Y=Bottom+(Top-Bottom) / (1+((IC 50 / X)^Hill slope)) where X and Y are known values ​​and IC 50, Hill slope, top, and bottom are parameters obtained by fitting with the software. Y is the inhibition percentage (calculated from the formula), X is the compound concentration, and IC 50 is the concentration of compound at which 50% inhibition is reached. IC 50 The smaller the value, the stronger the inhibitory ability of the compound. 50 The higher the value, the weaker the inhibitory potential of the compound. The Hill slope is the slope of the fitted curve, generally around 1. * where the bottom is the minimum value (typically 0%±20%) of the curve obtained by data fitting, and the top is the maximum value (typically 100%±20%) of the curve obtained by data fitting. The experimental data was fitted by calculation and analysis with Dotmatics data analysis software.

[0272] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] The foregoing examples and descriptions of specific embodiments should be construed as illustrative rather than limiting the invention defined by the claims. As will be readily appreciated, numerous variations and combinations of the features described above can be utilized without departing from the invention as set forth in the claims. All such variations are intended to be included within the scope of the present invention. All references are incorporated herein by reference in their entirety.

[0273] It will be understood that if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.

Claims

1. A compound of formula (I), 【Chemistry 1】 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof, During the ceremony, Z is N or CR z and R z is H, -C 1 -C 8 Alkyl, C 3 -C 8 cycloalkyl, or halogen; R 1 and R 2 are each independently -C 1-8 Alkyl or -C 3-8 cycloalkyl, and the —C 1 -C 8 Alkyl or C 3 -C 8 each cycloalkyl optionally substituted with at least one halogen; R 3 is hydrogen, -C 1 -C 8 Alkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 3 -C 8 Cycloalkyl, halogen, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, 5- to 12-membered heteroaryl, —OR 3a , -SR 3a , -CN, -C(O)R 3a , -CO 2 R 3a , —C(O)NR 3a R 3b , -NR 3a R 3b , -NR 3a COR 3b and -C 1 -C 8 Alkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 Each aryl, or 5- to 12-membered heteroaryl optionally contains 0 to 2 R 3c is replaced by; R 3a and R 3b are each independently hydrogen, —C 1 -C 8 Alkyl, —C 1 -C 8 Haloalkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 1 -C 8 Alkoxy-C 1 -C 8 Alkyl-, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5-12 membered heteroaryl; R 3c is, for each occurrence, independently selected from halogen, —OH, —CN, oxo (═O), —C 1 -C 8 Alkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, —C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, —C 6 -C 12 aryl, or 5-12 membered heteroaryl; R 4 is halogen, methyl, or methoxy; R 5 is hydrogen, halogen, -C 1 -C 8 Alkyl, —NR 5a R 5b , -OR 5a , -SR 5a , C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, 5- to 12-membered heteroaryl, or CN; 1 -C 8 Alkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 Each aryl, or 5- to 12-membered heteroaryl optionally contains at least one R 5c is replaced by; R 5a and R 5b are each independently hydrogen, —C 1 -C 8 Alkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5- to 12-membered heteroaryl; 1 -C 8 Alkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 Each aryl or 5- to 12-membered heteroaryl optionally contains at least one substituent R 5d is replaced by; R 5c and R 5d are each independently a halogen, a hydroxy, or —C 1 -C 8 Alkyl, —C 1 -C 8 Alkoxy, -C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5-12 membered heteroaryl; R 6 is hydrogen, halogen, -C 1 -C 8 Alkyl, —NR 6a R 6b , -OR 6a , -SR 6a , C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, 5- to 12-membered heteroaryl, or CN; 1 -C 8 Alkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 Each aryl, or 5- to 12-membered heteroaryl optionally contains at least one R 6c is replaced by; R 6a and R 6b are each independently hydrogen, —C 1 -C 8 Alkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5- to 12-membered heteroaryl; 1 -C 8 Alkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 Each aryl or 5- to 12-membered heteroaryl optionally contains at least one substituent R 6d is replaced by; R 6c and R 6d are each independently a halogen, a hydroxy, or —C 1 -C 8 Alkyl, —C 1 -C 8 Alkoxy, -C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 aryl, or 5-12 membered heteroaryl; R 7 and R 8 are each independently hydrogen, halogen, or —C 1 -C 8 Alkyl, —NR 7a R 7b , -OR 7a , -C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, —C 6 -C 12 aryl, 5- to 12-membered heteroaryl, or —CN; 1 -C 8 Alkyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 Each aryl or 5- to 12-membered heteroaryl optionally contains at least one substituent R 7c is replaced by; or R 7a and R 7b are each independently hydrogen, —C 1 -C 8 Alkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, —C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, —C 6 -C 12 aryl, or 5- to 12-membered heteroaryl; 1 -C 8 Alkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 12 Each aryl or 5- to 12-membered heteroaryl optionally contains at least one substituent R 7d is replaced by; R 7c and R 7d are each independently a halogen, a hydroxy, or —C 1 -C 8 Alkyl, —C 1 -C 8 Alkoxy, -C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, —C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, —C 6 -C 12 aryl, or 5-12 membered heteroaryl; 【Chemistry 2】 teeth, 【Transformation 3】 and L 1 teeth, 【Chemistry 4】 wherein *L1 teeth, 【Transformation 5】 indicates the position at which the nucleotide is attached to the moiety, and **L1 teeth, 【Transformation 6】 refers to the position at which the moiety is attached; L 2 teeth, 【Transformation 7】 or *L2 - (CH 2 ) 1-3 - **L2 wherein *L2 teeth, 【Transformation 8】 indicates the position at which the nucleotide is attached to the moiety, and **L2 teeth, 【Chemistry 9】 refers to the position at which the moiety is attached; L 3 teeth, 【Chemistry 10】 、-N(CH 3 )-、-NH-、 【Chemistry 11】 wherein *L3 teeth, 【Chemistry 12】 indicates the position at which the nucleotide is attached to the moiety, and **L3 teeth, 【Chemistry 13】 refers to the position at which the moiety is attached; The aforementioned 【Chemistry 14】 、 *L2 -(CH 2 ) 1-3 - **L2 、 【Chemistry 15】 each optionally containing 0 to 2 R La is replaced by; R La is, for each occurrence, independently selected from halogen, —OH, —CN, oxo (═O), —C 1 -C 8 Alkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, —C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, —C 6 -C 12 aryl, or 5-12 membered heteroaryl; n is 0 or 1; However, the compound is 【Chemistry 16】 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof, which is not

2. The compound is of formula (IIa) or (IIb): 【Chemistry 17】 During the ceremony, R z 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、 [Chemistry 18] , L 1 , L 2 , L 3 2. The compound of claim 1, wherein n is a substituted or unsubstituted aryl group, ... and n is a substituted or unsubstituted aryl group.

3. The compounds have formula (IIIa) to (IIIu): 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 【Chemistry 19-4】 【Chemistry 19-5】 【Chemistry 19-6】 【Chemistry 19-7】 During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Z, L 1 , L 2 , L 3 2. The compound of claim 1, wherein n is a substituted or unsubstituted aryl group, ... and n is a substituted or unsubstituted aryl group.

4. The compound has formula (IVa) to (IVh), 【Chemistry 20-1】 【Chemistry 20-2】 【Chemistry 20-3】 During the ceremony, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and 【Chemistry 21】 and each are defined as in claim 1.

5. Z is N or CR z and R z is H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -F, -Cl, -Br, or -I.

6. Z is N or CR z and R z is H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -F, -Cl, -Br, or -I.

7. R 1 and R 2 is each independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

8. R 1 and R 2 and each independently represents methyl.

9. R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -F, -Cl, -Br, -I, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, -OR 3a , -SR 3a , -CN, -C(O)R 3a , -CO 2 R 3a , —C(O)NR 3a R 3b , -NR 3a R 3b , -NR 3a COR 3b methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 Each alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -F, -Cl, -Br, -I, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally has 0, 1, or 2 R 3c is replaced by; R 3a and R 3b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 1 -C 8 Haloalkyl, —C 2 -C 8 Alkenyl, -C 2 -C 8 Alkynyl, C 1 -C 8 Alkoxy-C 1 -C 8 selected from alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; R 3c is, for each occurrence, independently selected from -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 The compound of claim 1, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

10. R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -F, -Cl, -Br, -I, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl; Preferably, R 3 is methyl, ethyl, propyl (n-propyl, iso-propyl), butyl (n-butyl, iso-butyl, sec-butyl, tert-butyl), pentyl, hexyl, heptyl, octyl.

11. R 4 The compound according to claim 1, wherein is -F, -Cl, -Br, -I, Me, OMe.

12. R 4 The compound of claim 1, wherein is -Cl or -Br.

13. R 5 is hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, —NR 5a R 5b , -OR 5a , -SR 5a or CN; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally comprises at least one R 5c is replaced by; R 5a and R 5b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally comprises at least one R 5d is replaced by; R 5c and R 5d are each independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2 -C 8 Alkenyl, -C 2 -C 8 The compound of claim 1, wherein the aryl is selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

14. R 5 is -OR 5a and R 5a is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally comprises at least one R 5d is replaced by; R 5d are independently —F, —Cl, —Br, —I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C 2 -C 8 Alkenyl, -C 2 -C 8 selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, R 5 is methoxy, ethoxy, propoxy (n-propoxy, isopropoxy), butoxy (n-butoxy, isobutoxy, sec-butoxy, tert-butoxy), pentoxy, hexoxy, heptoxy, or octoxy.

15. R 6 represents hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —NR 6a R 6b , -OR 6a , -SR 6a , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally is selected from the group consisting of at least one R 6c is replaced by; R 6a and R 6b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally comprises at least one R 6d is replaced by; R 6c and R 6d are each independently -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2 -C 8 Alkenyl, -C 2 -C 8 The compound of claim 1, wherein the aryl is selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl.

16. R 6 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally selected from the group consisting of at least one R 6c is replaced by; R 6c are independently —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, —C 2 -C 8 Alkenyl, -C 2 -C 8 selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, R 6 is hydrogen, methyl, ethyl, propyl (n-propyl, iso-propyl), butyl (n-butyl, sec-butyl, iso-butyl, tert-butyl), pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

17. R 7 and R 8 are each independently hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, —NR 7a R 7b , -OR 7a , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, or CN; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally selected from at least one R 7c is replaced by; or R 7a and R 7b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2 -C 8 Alkenyl, -C 2 -C 8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl optionally comprises at least one R 7d is replaced by; or R 7c and R 7d are each independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2 -C 8 Alkenyl, -C 2 -C 8 The compound of claim 1, which is alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

18. R 7 and R 8 are each independently selected from hydrogen, —F, —Cl, —Br, —I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3-8 membered heterocyclyl, phenyl, or 5-12 membered heteroaryl; Preferably, R 7 and R 8 The compound of claim 1 , wherein each of is hydrogen, —F, —Cl, —Br, or —I. 【Request Item 19】 【Chemistry 22】 The part is 【Chemistry 23】 2. The compound of claim 1 selected from: 【Request Item 20】 【Chemistry 24】 The part is 【Chemistry 25】 2. The compound of claim 1 selected from: 【Request Item 21】 【Chemistry 26】 The part is 【Chemistry 27】 2. The compound of claim 1 selected from: 【Request Item 22】 【Chemistry 28】 The part is 【Chemistry 29-1】 【Chemistry 29-2】 2. The compound of claim 1 selected from:

23. 2. The compound of claim 1, wherein the compound is selected from the following: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18

24. 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, together with a pharmaceutically acceptable excipient.

25. 25. The pharmaceutical composition of claim 24 for treating a disease in which EGFR modulation can be affected.

26. 26. The pharmaceutical composition of claim 25, wherein the disease is selected from cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

27. 24. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in the preparation of a medicament for treating a disease in which EGFR modulation can be affected.

28. 28. The use according to claim 27, wherein the disease is selected from cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

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