Bifunctional compounds for EGFR degradation and related usage methods

Abstract

Disclosed herein are novel bifunctional compounds formed by conjugating an EGFR inhibitor moiety to an E3 ligase ligand moiety, the function of which is to recruit a targeting protein to an E3 ubiquitin ligase to degrade mutant EGFR kinase; as well as methods of making and uses thereof.

Description

Technical Field

[0001] This article discloses a novel bifunctional compound formed by conjugating an EGFR inhibitor moiety with an E3 ligase ligand moiety, the function of which is to recruit target proteins to E3 ubiquitin ligase to degrade mutant EGFR kinase; as well as its preparation method and uses. Background Technology

[0002] Proteolytic targeting chimeras (PROTACs) consist of two covalently linked protein-binding molecules: one molecule binds to an E3 ubiquitin ligase, while the other binds to a target protein (POI) (the intended target for degradation) (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98: 8554-9.; Sakamoto KM et al., Methods Enzymol. 2005; 399: 833-847.). By recruiting the E3 ligase to a specific unwanted protein instead of inhibiting the enzymatic activity of the target protein, ubiquitination of the target protein and subsequent degradation of the target protein by the proteasome are achieved. The entire process of ubiquitination and proteasome degradation is known as the ubiquitin-proteasome pathway (UPP) (Ardley H. et al., Essays Biochem. 2005, 41, 15-30; Komander D. et al., Biochem. 2012, 81, 203-229; Grice GL et al., Cell Rep. 2015, 12, 545-553; Swatek KN et al., Cell Res. 2016, 26, 399-422). The proteasome is a protein complex that degrades unwanted, misfolded, or abnormal proteins into small peptides to maintain cellular health and productivity. Ubiquitin ligases (also known as E3 ubiquitin ligases) directly catalyze the transfer of ubiquitin from E2 to target proteins for degradation. Although the human genome encodes more than 600 putative E3 ligases, only a limited number of E3 ubiquitin ligases have been widely used by small molecule PROTAC technology: cereblon (CRBN), Von Hippel-Lindau (VHL), mouse two-microsome 2 homolog (MDM2), cellular inhibitor of apoptosis protein (cIAP) (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578), recombinant human ring finger protein 114 (RNF114) (Spradlin, JN et al., Nat. Chem. Biol. 2019, 15, 747-755), and DDB1 and CUL4-associated factor 16 (DCAF16) (Zhang, X. et al., Nat. Chem. Biol. 2019, 15, 737-746). For example, cereblon (CRBN) forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1) and Cullin-4A (CUL4A) to ubiquitinate many 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, bind to CRL4A. CRBNThe E3 ligase complex activates the cereblon (CRBN) subunit and recruits neosubstrate proteins to function as a monovalent promoter of PPIs (Matyskiela, ME et al., Nat ChemBiol 2018, 14, 981-987.). Therefore, the ability of thalidomide and its derivatives to recruit CRBN has been widely applied in research related to proteolytic targeting chimeras (PROTACs) (Christopher T. et al., ACS Chem.Biol. 2019, 14, 342-347.; Honorine L. et al., ACS Cent.Sci. 2016, 2, 927-934). PROTACs hold great potential in eliminating protein targets that are "undruggable" or non-enzymatic proteins by conventional inhibitors.(ChuTT et al., Cell Chem Biol. 2016; 23: 453-461. Qin C et al., J Med Chem 2018; 61: 6685-6704. Winter GE et al., Science 2015; 348: 1376-1381.) In recent years, PROTACs have been reported as useful regulators for promoting the selective degradation of a wide range of target proteins in anti-tumor studies (Lu J et al., ChemBiol. 2015; 22(6): 755-763; Ottis P et al., Chem Biol. 2017; 12(4): 892-898.; Crews CM et al., J Med Chem. 2018; 61(2): 403-404; Neklesa TK et al., Pharmacol Ther. 2017, 174: 138-144.; Cermakova K. et al., Molecules, 2018.23(8).; An S. et al., EBioMedicine, 2018.; Lebraud H. et al., Essays Biochem. 2017; 61(5): 517-527.; Sun YH et al., Cell Res. 2018; 28: 779-81; Toure M. et al., Angew Chem Iht Ed Engl. 2016; 55(6): 1966-1973; Yonghui Sun et al., Leukemia, Vol. 33, pp. 2105-2110 (2019); Shaodong Liu et al., Medicinal Chemistry Research, Vol. 29, pp. 802-808 (2020); and has been published in patents (e.g., US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO2016 WO2016197114, WO2017011590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449 and WO2018071606) are published or discussed.

[0003] Epidermal growth factor receptor (EGFR), belonging to the ErbB family, is a transmembrane receptor tyrosine kinase (RTK) that plays a fundamental and crucial role in cell proliferation, differentiation, and motility (Y. Yarden et al., Nat. Rev. Mol. Cell Biol. 2001; 2: 127-137.). Homodimerization or heterodimerization of EGFR and other ErbB family members activates the cytoplasmic tyrosine kinase domain to trigger intracellular signal transduction. Overexpression or activating mutations of EGFR are associated with the development of many types of cancer, such as pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, and non-small cell lung cancer (Yewale C. et al., Biomaterials. 2013, 34(34): 8690-8707.). Activating mutations in the EGFR tyrosine kinase domain (L858R mutation and exon 19 deletion) have been identified as oncogenic drivers of NSCLC (Konduri, K. et al., CancerDiscovery 2016, 6(6), 601-611.). First-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) (gefitinib and erlotinib) have been approved for patients with NSCLC having EGFR activating mutations (M. Maemondo, N. Engl. J. Med. 362 (2010) 2380-2388.). Although most patients with EGFR-mutant NSCLC respond to these therapies, patients typically develop resistance after an average of one year of treatment. Several mechanisms exist for acquired resistance to gefitinib and erlotinib, including the tert-threonine 790 to methionine 790 mutation (T790M), also known as the “gatekeeper” T790M mutation (Xu Y. et al., Cancer Biol Ther. 2010, 9(8): 572-582.). Therefore, the second-generation EGFR-TKI afatinib and the third-generation EGFR-TKI osimertinib (AZD9291) were developed as irreversible EGFR inhibitors binding to Cys797 for the treatment of patients with the T790M mutation. Specifically, osimertinib, which essentially does not target WT EGFR, achieved a higher clinical response rate in NSCLC patients with EGFR T790M. However, several recent studies have reported grade 3 Cys797 to Ser797 (C797S) point mutations accompanying osimertinib clinical therapy (Thress KS et al., Nat. Med. 2015, 21(6): 560-562.). There is a need for drugs that can overcome the EGFR (C797S) resistance barrier in non-small cell lung cancer (NSCLC).EGFR-targeting PROTACs are a potential strategy to overcome resistance mediated by these mutants, a strategy that has been disclosed or discussed in patent publications (e.g., WO2018119441, WO2019149922, WO2019183523, WO2019121562 and US20190106417).

[0004] Nevertheless, numerous EGFR-targeting protacos designed to degrade EGFR mutant proteins have been published (Zhang X. et al., Eur. J. Med. Chem. 2020, 192, 112-199.; Zhang H et al., Eur. J. Med. Chem. 2020, 189, 112-061.; Lu X, Med. Res. Rev. 2018, 38(5): 1550-1581; He K. et al., Bioorg. Med. Chem. Lett. 2020, 15, 127-167.). Most of the published molecules are based on first-, second-, and third-generation EGFR inhibitors. However, no data have shown that these EGFR-targeting protacos degrade all major EGFR mutations.

[0005] This application provides novel bifunctional compounds that degrade mutant EGFR kinases and compositions for treating serious diseases. Summary of the Invention

[0006] One object of the present invention is to provide compounds and derivatives formed by conjugating an EGFR inhibitor moiety with an E3 ligase ligand moiety, said compounds and derivatives being functional in recruiting target proteins to E3 ubiquitin ligases for degradation; and methods of their preparation and uses.

[0007] Aspect 1. A compound of formula (I):

[0008]

[0009] Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer or prodrug, wherein:

[0010] Cy1 is selected from aromatic rings or non-aromatic rings;

[0011] R 1 Selected from -S(O)R 1a -S(O)2R 1a -C(O)R 1a or -P(O)R 1a R 1b , where R 1a and R 1b Each is independently selected from -C 1-8 Alkyl, -C2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, heterocyclic, aryl, heteroaryl, -CN, -OR 1d -CH2CONR 1d R 1e -CH2CH2CONR 1d R 1e -CH2CH2CH2CONR 1d R 1e -NR 1d R 1e -CH2NR 1d R 1e -CH2CH2NR 1d R 1e -CH2CH2CH2NR 1d R 1e or -NR 1d COR 1e Wherein -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one R group. 1f replace;

[0012] R 1d and R 1e Each is independently hydrogen, -C 1-8 Alkyl, -C 1-8 Haloalkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; or

[0013] R 1d and R 1e Together with one or more atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0, 1, or 2 additional heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, the rings optionally being substituented by at least one R. 1f replace;

[0014] R 1f Each time it appears, it is independently hydrogen, halogen, hydroxyl, or -C. 1-8 Alkyl, -C 1-8 Haloalkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -OR 1g -COR 1g -CO2R 1g -CONR1g R 1h -NR 1g R 1h -NR 1g COR 1h or -NR 1g CO2R 1h Each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally derived from one, two, or three groups selected from halogens and -C 1-8 Alkyl substituents;

[0015] R 1g and R 1h Each is independently hydrogen, halogen, hydroxyl, -C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 1-8 Haloalkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0016] R 2 Each time it appears, it is selected from hydrogen, halogen, oxo group, -C. 1-8 Alkyl, cycloalkyl, heterocyclic, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OR 2a -COR 2a -CO2R 2a -CONR 2a R 2b -NR 2a R 2b -NR 2a COR 2b or -NR 2a CO2R 2b Wherein -C 1-8 Each of the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one substituent R. 2c Replace; or

[0017] When m≥2, two R 2 Together with one or more atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, the rings optionally being substituented by at least one R. 2c replace;

[0018] R 2a and R 2b Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8alkenyl, -C 2-8 alkynyl group, C 1-8 Alkoxy-C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, C 1-8 Alkoxy-C 1-8 Each of the alkyl-, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one R group. 2c replace;

[0019] R 2c Each time it appears, it is independently a halogen, hydroxyl group, or -C. 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -OR 2d -COR 2d -CO2R 2d -CONR 2d R 2e -NR 2d R 2e -NR 2d COR 2e or -NR 2d CO2R 2e ;

[0020] R 2d and R 2e Each is independently hydrogen, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0021] R 3 R 9 and R 10 Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl, -NR 3a R 3b -OR 3a cycloalkyl, heterocyclic, aryl, heteroaryl, -CN, -COR 3a or -CO2R 3a Wherein -C 1-8 Each of the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one substituent R. 3c replace;

[0022] R 3a and R 3b Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, C 1-8 Alkoxy-C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one R group. 3d Replace; or

[0023] R 3c and R 3d Each is independently a halogen, hydroxyl group, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0024] R 4 and R 11 Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkynyl group, -C 1-8 Alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -CN, -OR 4a -NR 4a R 4b -NR 4a COR 4b or CONR 4a R 4b Wherein -C 1-8 Alkyl, -C 2-8 alkynyl group, -C 1-8 Each of the alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally subjected to at least one R 4e Replace, or

[0025] R 4a and R 4b Each is independently hydrogen, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; or

[0026] R 4 and R 11Together with one or more atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, the rings optionally being substituented by at least one R. 4e replace;

[0027] R 4e Selected from halogens, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, -CN, -OR 4c -SO2R 4c -SO2NR 4c R 4d -COR 4c -CO2R 4c -CONR 4c R 4d -NR 4c R 4d -NR 4c COR 4d -NR 4c CO2R 4d or -NR 4c SO2R 4d ;

[0028] R 4c and R 4d Each is independently hydrogen, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0029] R 12 Independently selected from hydrogen, halogen, -C 1-8 Alkyl, -NR 12a R 12b -OR 12a , cycloalkyl, heterocyclic, aryl, heteroaryl, oxo, or -CN, wherein the -C 1-8 Each of the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one substituent R. 12c Replace; or

[0030] Two Rs 12 Together with one or more atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, the rings optionally being substituented by at least one R. 12c replace;

[0031] R 12a and R 12b Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one R group. 12d Replace; or

[0032] R 12c and R 12d Each is independently a halogen, hydroxyl group, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0033] Z 1 Z 2 Z 3 and Z 4 Each independently selected from -CR Z Or N;

[0034] R Z Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-8 Alkyl, -NR Za R Zb -OR Za cycloalkyl, heterocyclic, aryl, heteroaryl, or CN, wherein the -C 1-8 Each of the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally etched by at least one R Zc replace;

[0035] Or two Rs Z When attached to an adjacent carbon atom of the ring, a 3- to 12-membered ring is formed together with the two carbon atoms to which it is attached. The 3- to 12-membered ring contains 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members. The ring is optionally connected to at least one substituent R. Zc replace;

[0036] R Za and R Zb Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one R group. Zd replace;

[0037] R Zc Independently halogen, hydroxyl, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl; or

[0038] Two Rs Zc Together with one or more atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, the rings optionally being substituented by at least one R. Zd replace;

[0039] R Zd Independently halogen, hydroxyl, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0040] L 1 Selected from single bonds, -O-, -SO2-, -C(O)-, -NR L1a -、-C3-C8 cycloalkylene-、* L1 -OC 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-O-** L1 、* L1 -SO2-C 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-SO2-** L1 、* L1 -C(O)-C 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-C(O)-** L1 、*L1 -NR L1a -C 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-NR L1a -** L1 、* L1 -NR L1a C(O)-** L1 、* L1 -C(O)NR L1a -** L1 -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, -[O(CR) L1a R L1b ) m4 ] m5 -、

[0041] The -C3-C8 cycloalkyl group-, * L1 -OC 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-O-** L1 、* L1 -SO2-C 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-SO2-** L1 、* L1 -CO-C 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-CO-** L1 、* L1 -NR L1a -C 1-8 Alkylene-** L1 、* L1 -C 1-8 Alkylene-NR L1a -** L1 -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, Each of them is optionally transmitted through at least one R L1c replace;

[0042] in* L1 It refers to connecting to Partial location, and** L1 It refers to connecting to Partial location;

[0043] R L1a and R L1b Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one R group. L1d replace;

[0044] The R L1c and R L1d Each of these is independently a halogen, hydroxyl group, or -C group. 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0045] L2 is selected from single bond, -O-, -SO2-, -CO-, -NR L2a -、-C3-C8 cycloalkylene-、* L2 -OC 1-8 Alkylene-** L2 、* L2 -C 1-8 Alkylene-O-** L2 、* L2 -SO2-C 1-8 Alkylene-** L2 、* L2 -C 1-8 Alkylene-SO2-** L2 、* L2 -CO-C 1-8 Alkylene-** L2 、* L2 -C 1-8 Alkylene-CO-** L2 、* L2 -NR L2a -C 1-8 Alkylene-** L2 、* L2 -C 1-8Alkylene-NR L2a -** L2 、* L2 -NR L2a C(O)-** L2 、* L2 -C(O)NR L2a -** L2 -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, -[O(CR) L2a R L2b ) m4 ] m5 -、

[0046] The -C3-C8 cycloalkyl group-, * L2 -OC 1-8 Alkylene-** L2 、* L2 -C 1-8 Alkylene-O-** L2 、* L2 -SO2-C 1-8 Alkylene-** L2 、* L2 -C 1-8 Alkylene-SO2-** L2 、* L2 -CO-C 1-8 Alkylene-** L2 、* L2 -C 1-8 Alkylene-CO-** L2 、* L2 -NR L2a -C 1-8 Alkylene-** L2 、* L2 -C 1-8 Alkylene-NR L2a -** L2 -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, Each of them is optionally via at least one substituent R L2c replace;

[0047] in* L2 It refers to connecting to Partial location, and** L2 It refers to connecting to Partial location;

[0048] R L2a and R L2b Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one R group. L2d replace;

[0049] The R L2c and R L2d Each of these is independently a halogen, hydroxyl group, or -C group. 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0050] L 3 Selected from single bonds, -O-, -SO2-, -CO-, -NR L3a -、-C3-C8 cycloalkylene-、* L3 -OC 1-8 Alkylene-** L3 、* L3 -C 1-8 Alkylene-O-** L3 、* L3 -SO2-C 1-8 Alkylene-** L3 、* L3 -C 1-8 Alkylene-SO2-** L3 、* L3 -CO-C 1-8 Alkylene-** L3 、* L3 -C 1-8 Alkylene-CO-** L3 、* L3 -NR L3a -C 1-8 Alkylene-** L3 、* L3 -C 1-8 Alkylene-NR L3a -** L3 、* L3 -NR L3a C(O)-**L3 、* L3 -C(O)NR L3a -** L3 -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, -[O(CR) L3a R L3b ) m4 ] m5 -、

[0051] The -C3-C8 cycloalkyl group-, * L3 -OC 1-8 Alkylene-** L3 、* L3 -C 1-8 Alkylene-O-** L3 、* L3 -SO2-C 1-8 Alkylene-** L3 、* L3 -C 1-8 Alkylene-SO2-** L3 、* L3 -CO-C 1-8 Alkylene-** L3 、* L3 -C 1-8 Alkylene-CO-** L3 、* L3 -NR L3a -C 1-8 Alkylene-** L3 、* L3 -C 1-8 Alkylene-NR L3a -** L3 -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, Each of them is optionally via at least one substituent R L3c replace;

[0052] in* L3 It refers to connecting to Partial location, and** L3 It refers to connecting to Partial location;

[0053] R L3aand R L3b Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one R group. L3d replace;

[0054] The R L3c and R L3d Each of these is independently a halogen, hydroxyl group, or -C group. 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0055] Selected from

[0056] Where ring A is selected from 3-12 membered cycloalkyl, 3-12 membered heterocyclic, aryl or heteroaryl;

[0057] R 13 R 14 R 15 R 16 and R 17 Independently selected from hydrogen, halogen, CN, -C 1-8 Alkyl, -C 1-8 Alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 13a -COR 13a -CO2R 13a -NR 13a R 13b -NR 13a COR 13b or -NR 13a CO2R 13b Wherein -C 1-8 Alkyl, -C 1-8 Each of the alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one of the following substituents: halogen, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0058] R 13a and R 13b Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, C 1-8 Alkoxy-C 1-8 Alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, C 1-8 Alkoxy-C 1-8 Each of the alkyl-, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one of the following substituents: halogen, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0059] X 1 X 2 X 3 X 4 and X 8 Each independently selected from -CR a Or N;

[0060] X 5 X 6 X 7 and X 9 Each independently selected from -NR a -、-O-、-S- and -CR a R b -;

[0061] X 12 and X 13 Each is independently selected from single bonds, -NR a -and-O-;

[0062] L 4 Each is independently selected from single bonds, -O-, and -NR. a -、-(CR a R b ) n9 -、-O(CR a R b ) n9 -、-NR a(CR a R b ) n9 -or -C(O)-;

[0063] L 5 and L 6 Each independently selected from -CR a R b -or -C(O)-;

[0064] Q 1 Q 2 Q 3 Q 4 Y 1 Y 2 and Y 3 Each independently selected from CR a Or N;

[0065] Q 5 Each is independently selected from -O- and -NR. a -、-CR a R b -、-S- or -C(O)-;

[0066] P 1 It can be a single bond, -O-, -NH-, -CH2-, -S-, -SO-, or -SO2-;

[0067] R a and R b Each is independently selected from oxo groups, hydrogen, halogens, CN, and -C. 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally substituted with at least one of the following substituents: halogen, hydroxyl, halogen, -C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0068] m1 is 0, 1, or 2;

[0069] m2 and m3 are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0070] m4 and m5 are each independently 0, 1, 2 or 3;

[0071] m6 can be 0, 1, 2 or 3 independently;

[0072] Each m7 is independently 0, 1, 2, 3 or 4;

[0073] n, n1, n2, n3, n4, and n5 are each independently 0, 1, 2, or 3; and

[0074] n6, n7, n8, and n9 are each independently 0, 1, 2, 3, or 4.

[0075] Aspect 2. The compound as described in aspect 1, wherein R 1 -SO2R 1a , where R 1 Each is independently selected from -C 1-5 Alkyl, -C 6-8 Aryl, -C 3-7 cycloalkyl or 4- to 7-membered heterocyclic groups or -NR 1d R 1e Wherein -C 1-5 Alkyl, -C 6-8 Aryl, -C 3-7 Each of the cycloalkyl or 4- to 7-membered heterocyclic groups is optionally substituted with at least one R group. 1f replace;

[0076] R 1d and R 1e Each is independently hydrogen, -C 1-8 Alkyl, -C 1-8 Haloalkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0077] R 1f Each time it appears, it is independently hydrogen, halogen, or -C. 1-8 Alkyl, -C 1-8 Haloalkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, cycloalkyl, halocycloalkyl, heterocyclic, phenyl, heteroaryl, -CN or -OR 1g Each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally derived from one, two, or three groups selected from halogens and -C 1-8 Alkyl substituents;

[0078] R 1g For hydrogen, -C 1-8 Alkyl, -C 1-8 Haloalkyl, C 1-8 Alkoxy-C1-8 Alkyl-, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl.

[0079] Aspect 3. The compound as described in aspect 1, wherein R 1a Selected from -CH3, -C2H5, -C3H7, -tert-butyl, -n-butyl, -isobutyl, -C5H 11 ,-Cyclopropyl, -CH2F, -CHF2, -CF3, -N(CH3)2, -NHCH3, -NHC2H5 or -NHC3H7.

[0080] Aspect 4. The compound as described in aspect 1, wherein R 2 Independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -OR 2a or -COR 2a Each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl groups is optionally substituted with at least one substituent R. 2c Replace, or

[0081] Two twins (germinal) R 2 Together with the atoms they are attached to, they form spiro-3, 4, 5, or 6-membered cycloalkyl groups, which optionally are substituted with at least one R group. 2c Replace; or

[0082] Two Rs on different atoms 2 Together with the atoms they are attached to, they form 3-, 4-, 5-, or 6-membered cycloalkyl groups, which optionally are substituents R. 2c replace;

[0083] R 2a Selected from hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, C 1-8 Alkoxy-C 1-8 Alkyl- or C 3-8 cycloalkyl;

[0084] R 2c Each time it appears, it is independently -F, -Cl, -Br, -I, -OH, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C2-8 alkenyl, -C 2-8 alkynyl or -C 3-8 Cycloalkyl.

[0085] Aspect 5. The compound as described in aspect 1, wherein

[0086] R 2 Selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; or two twin Rs. 2 Together with the atoms they are attached to, they form spiro-3-membered and 4-membered cycloalkyl groups.

[0087] Aspect 6. The compound as described in aspect 1, wherein

[0088] R 2 Selected from hydrogen, F, Cl, Br, I, -CH3, -C2H5, -C3H7, -C4H9 or -C5H 11 ; or two twins R 2 Together with the atoms they are attached to, they form spiropropyl or spirobutyl.

[0089] Aspect 7. The compound as described in aspect 1, wherein

[0090] R 3 R 9 and R 10 Independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -NR 3a R 3b -CN, -OR 3a -COR 3a or -CO2R 3a Each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl is optionally substituted by at least one substituent R. 3c replace,

[0091] R 3a Each is independently selected from hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, C 1-8 Alkoxy-C 1-8 Alkyl- or C 3-8 cycloalkyl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, C 1-8 Alkoxy-C 1-8Alkyl- or C 3-8 Each of the cycloalkyl groups is optionally substituted with at least one R group. 3d replace;

[0092] R 3c and R 3d Each time it appears, it is independently a halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl or -C 3-8 Cycloalkyl.

[0093] Aspect 8. The compound as described in aspect 1, wherein

[0094] R 3 R 9 and R 10 Each is independently selected from H, F, Br, Cl, I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -NH2, -N(CH3)2, -N(CH3)C2H5, -N(C2H5)2, -OCH3, -OC2H5, -OC3H7, -OC4H9 or -OC5H 11 .

[0095] Aspect 9. The compound as described in aspect 1, wherein... Partially selected from

[0096] Aspect 10. The compound as described in aspect 1, wherein... Part of Preferred

[0097] Aspect 11. The compound as described in aspect 1, wherein R 4 and R 11 Each is independently selected from hydrogen, F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclic groups, -CN, -OR 4a or -NR 4a R 4b Each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3 to 8 membered heterocyclic groups is optionally oxidized by at least one R 4e replace;

[0098] R 4a and R4b Each is independently hydrogen, -C 1-8 Alkyl, -halogenated C1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0099] R 4e Selected from F, Br, Cl, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic groups, phenyl, 5 to 12-membered heteroaryl groups, oxo groups, -CN or -OR 4c ;

[0100] R 4c It can be hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or phenyl independently.

[0101] Aspect 12. The compound as described in aspect 1, wherein R 4 and R 11 Together with one or more atoms to which they are attached, they form 3-, 4-, 5-, 6-, 7-, or 8-membered rings, the rings containing 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, the rings optionally being substituented by at least one R. 4e replace;

[0102] R 4e Selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic groups, phenyl, 5 to 12-membered heteroaryl groups, oxo groups, -CN or -OR 4c ;

[0103] R 4c Independently hydrogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl or 5 to 12 heteroaryl groups.

[0104] Aspect 13. The compound as described in aspect 1, wherein R 4 and R 11 Together with one or more atoms to which they are attached, they form a 5- or 6-membered ring, the ring containing one or two heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, the ring optionally being converted by at least one substituent R. 4e replace;

[0105] R 4e Selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, 5 to 12-membered heteroaryl, oxoyl, -CN, -OCH3, -OC2H5, -OC3H7, -OC4H9 and -OC5H 11 .

[0106] Aspect 14. The compound as described in aspect 1, wherein Partially selected from

[0107]

[0108] Aspect 15. The compound as described in aspect 1, wherein R 12 Independently selected from hydrogen, F, Cl, Br, I, OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxo, or -CN; or

[0109] Two twins R 12 Together with the atoms they are attached to, they form spiro-3, 4, 5, or 6-membered cycloalkyl groups, wherein the cycloalkyl group is optionally substituted with at least one substituent R. 12c Replace; or

[0110] Two Rs on different atoms 12 Together with the atoms they are attached to, they form 3-, 4-, 5-, or 6-membered cycloalkyl groups, which are optionally substituted with at least one R group. 12c replace;

[0111] R 12c Independently halogen, hydroxyl, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl.

[0112] Aspect 16. The compound as described in aspect 1, wherein Selected from

[0113] Aspect 17. The compound as described in aspect 1, wherein Z 1 Z 2 Z 3 and Z 4 Each independently selected from -CR z Or N;

[0114] R Z Each time it appears, it is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -NR. Za R Zb -OR Za Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, 5 to 12-membered heteroaryl, or CN, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl groups is optionally oxidized by at least one R Zc Replace; or

[0115] Or two Rs Z When attached to an adjacent carbon atom of the ring, a 3- to 12-membered ring is formed together with the two carbon atoms to which it is attached. The 3- to 12-membered ring contains 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members. The ring is optionally connected to at least one substituent R. Zc replace;

[0116] R Za and R Zb Each of the following is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or phenyl groups is optionally substituted with at least one substituent R. Zd replace;

[0117] R Zc and R Zd Each of the following can be independently represented as -F, -Cl, -Br, -I, -OH, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or phenyl, or

[0118] Two Rs Zc Together with one or more atoms to which they are attached, they form 3 to 8-membered rings, which contain 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members.

[0119] Aspect 18. The compound as described in aspect 1, wherein Z 1 Z2 Z 3 and Z 4 Each independently as -CR z ;

[0120] R Z Each time it appears, it is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -OCH3, -OC2H5, -OC3H7, -OC4H9, or -OC5H. 11 ;or

[0121] Two Rs Z When attached to an adjacent carbon atom of the ring, together with the atoms to which they are attached, a 4-, 5-, 6-, or 7-membered ring is formed. The ring contains 0, 1, or 2 heteroatoms independently selected from nitrogen or oxygen, and the ring is optionally connected to at least one substituent R. Zc Replacement, in which two twins R Zc Together with the atoms they are attached to, they form spirocyclic 3-, 4-, 5-, or 6-membered cycloalkyl groups, or two R atoms on different atoms. Zc Together with the atoms they are attached to, they form 3-, 4-, 5-, or 6-membered cycloalkyl groups.

[0122] Aspect 19. The compound as described in aspect 1, wherein... Partially selected from

[0123] Where *a refers to the connection to The location of the part, and *b refers to the connection to. Partial location.

[0124] Aspect 20. The compound as described in aspect 1, wherein L 1 Selected from single bond, -C 1-8 Alkylene (preferably -CH2-, -C2H4-, -C3H6-),

[0125] Aspect 21. The compound as described in aspect 1, wherein X 1 and X 2 Each is independently selected from CH or N; m1 = 1 or 0; and R 12 It is hydrogen or -CH3.

[0126] Aspect 22. The compound as described in aspect 1, wherein m2 and m3 are selected from 0, 1, 2, 3, 4 or 5.

[0127] Aspect 23. The compound as described in aspect 1, wherein L 2 Selected from single bonds, -CO-, -O-, -NRL2a -、-C 1-8 Alkylene (preferably -CH2-, -C2H4-, -C3H6-), Where R L2a Selected from hydrogen, methyl, ethyl or propyl.

[0128] Aspect 24. The compound as described in aspect 1, wherein L 3 Selected from single bond, -O-, -NR L3a -、-C 1-8 Alkylene (preferably -CH2-, -C2H4-, -C3H6-),

[0129]

[0130] RL3a is selected from hydrogen, methyl, ethyl, or propyl. Aspect 25. The compound as described in aspect 1, wherein... Selected from

[0131]

[0132] Where * refers to the connection to Partial location, and **refers to the connection to Partial location.

[0133] Aspect 26. The compound of aspect 1 or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof or a prodrug thereof, wherein the compound is of formula (II):

[0134]

[0135] Where: R 1 R 2 R 3 R 4 R 9 R 10 R 11 R 12 Z 1 Z 2 Z 3 Z 4 X 1 X 2 X 3 X4 L 2 L 3 The degradation determinants (Degron), n, m1, m2, m3, and m7 have the same meaning as in aspect 1.

[0136] Aspect 27. The compound of aspect 1 or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof or a prodrug thereof, wherein the compound is of formula (III):

[0137]

[0138] Where: R 1 R 2 R 3 R 4 R 9 R 10 R 11 R 12 Z 1 Z 2 Z 3 Z 4 X 1 X 2 X 3 X 4 L 2 L 3 The degradation determinants, n, m1, m3 and m7 have the same meaning as in aspect 1, and m1 is preferably 0 or 1.

[0139] Aspect 28. The compound as described in aspect 1, wherein Selected from

[0140]

[0141] R 14 Independently selected from hydrogen, halogen, -C 1-8 Alkyl, -C 1-8 alkoxy or CN, wherein the -C 1-8 Alkyl or -C 1-8 Each of the alkoxy groups is optionally surrounded by one or more halogens or -C 1-8 Alkyl substitution; preferably, R 14 It is independently selected from H, F, Cl, Br, I, CH3, -OCH3, CH2F, CN, CHF2 or CF3;

[0142] X 8 It is independently selected from CF, CH, C(CH3), C(C2H5), C(C3H7), C(CN) or N;

[0143] L 4Independently selected from single bonds, -O-, -NH-, -CH2-, -CHF-, or -CF2-;

[0144] Y 1 Y 2 and Y 3 Each independently selected from CR a Or N, where R a Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl or -C 1-8 Alkoxy, wherein the -C 1-8 Alkyl or -C 1-8 Each of the alkoxy groups is optionally oxidized by at least one or more halogens, hydroxyl groups, halogens, or -C groups. 1-8 Alkyl or -C 1-8 Alkyl substitution;

[0145] X 9 It is CH2;

[0146] n6 can be 0, 1, or 2 independently.

[0147] Aspect 29. The compound as described in aspect 1, wherein for

[0148] Where ring A is selected from 5-7 membered cycloalkyl, 5-7 membered heterocyclic, aryl or heteroaryl;

[0149] X 8 It is independently selected from CF, CH, C(CH3), C(C2H5), C(C3H7), C(CN) or N;

[0150] L 4 Independently selected from single bonds, -O-, -NH-, -CH2-, -CHF-, or -CF2-;

[0151] Y 1 and Y 2 Each independently selected from CR a Or N;

[0152] R a Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl or -C 1-8 Alkoxy, the -C 1-8 Alkyl or -C 1-8 Each of the alkoxy groups is optionally oxidized by at least one or more halogens, hydroxyl groups, halogens, or -C groups. 1-8 Alkyl or -C 1-8 Alkyl substitution;

[0153] X 9 It is CH2; and

[0154] n6 can be 0, 1, or 2 independently.

[0155] Aspect 30. The compound as described in aspect 1, wherein for

[0156] Where R 14 Independently selected from hydrogen, halogen, -C 1-8 Alkyl or -C 1-8 Alkoxy groups, wherein each -C 1-8 Alkyl or -C 1-8 Each of the alkoxy groups is optionally surrounded by one or more halogens, -C 1-8 Alkyl or C 1-8 Alkoxy-C 1-8 Alkyl-substituted;

[0157] X 8 It is independently selected from CH, C(CH3), C(C2H5), C(C3H7), C(CN) or N;

[0158] L 4 Independently selected from single bonds, -O-, -NH-, -CH2-, -CHF-, or -CF2-;

[0159] Y 1 Y 2 and Y 3 Each independently selected from CR a Or N;

[0160] R a Each is independently selected from hydrogen, halogen, -C 1-8 Alkyl or -C 1-8 Alkoxy, the -C 1-8 Alkyl or -C 1-8 Each of the alkoxy groups is optionally oxidized by at least one or more halogens, hydroxyl groups, halogens, or -C groups. 1-8 Alkyl or -C 1-8 Alkyl substitution;

[0161] X 9 It is CH2; and

[0162] n6 can be 0, 1, or 2 independently.

[0163] Aspect 31. The compound as described in aspect 1, wherein for

[0164] Where L 5 and L 6 Each is independently selected from -CH2 or -CO-;

[0165] X9 It is CH2;

[0166] Each R 13 Independently selected from hydrogen, halogen, CN, -C 1-8 Alkyl or -C 1-8 Alkoxy;

[0167] n6 is either 0 or 1; and

[0168] n7 can be 0, 1, or 2.

[0169] Aspect 32. The compound as described in aspect 1, wherein for

[0170] Where R 13 and R 16 Independently selected from hydrogen, halogen, -C 1-8 Alkyl or -C 1-8 Alkoxy groups; each -C 1-8 Alkyl or -C 1-s Alkoxy groups are optionally converted by one or more halogens, -C 1-8 Alkyl or C 1-8 Alkoxy-C 1-8 Alkyl-substituted;

[0171] R 15 and R 14 Selected from 5- to 12-membered heteroaryl groups, 3- to 8-membered heterocyclic groups, and C6-C 12 The group consisting of aryl groups, and R 15 Optionally by one or more halogens, -C 1-8 Alkyl or C 1-8 Alkoxy-C 1-8 Alkyl-substituted; and

[0172] n7 can be 0, 1, 2, 3 or 4 independently.

[0173] Aspect 33. The compound as described in aspect 1, wherein Selected from

[0174]

[0175]

[0176] Aspect 34. The compound as described in Aspect 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its tautomer, or a prodrug, wherein the compound is selected from...

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195] Aspect 35. A pharmaceutical composition comprising a compound as described in any one of Aspects 1-34, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its tautomer or prodrug, and a pharmaceutically acceptable excipient.

[0196] Aspect 36. A method for treating a disease involving EGFR regulation, the method comprising administering to a subject in need a therapeutically effective amount of a compound or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a prodrug, as described in any one of Aspects 1-34.

[0197] Aspect 37. The method of aspect 36, wherein the disease is selected from cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer or non-small cell lung cancer.

[0198] Aspect 38. Use of any compound of any one of Aspects 1-34, or its N-oxide, or pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or prodrug, in the preparation of a medicament for treating diseases involving EGFR regulation.

[0199] Aspect 39. Use as described in aspect 38, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer or non-small cell lung cancer. Detailed Implementation

[0200] The following terms have the meanings indicated throughout this specification:

[0201] Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0202] The following terms have the meanings indicated throughout this specification:

[0203] As used herein (including the appended claims), unless the context clearly indicates otherwise, the singular forms of words such as “a” and “the” include their corresponding plural referents.

[0204] Unless the context clearly specifies otherwise, the term “or” is used to mean “and / or” and is used interchangeably with the term “and / or”.

[0205] The term "alkyl" includes alkyl groups selected from straight-chain and branched saturated hydrocarbon groups comprising 1 to 18 carbon atoms (such as 1 to 12, further such as 1 to 10, even further such as 1 to 8, or 1 to 6, or 1 to 4). Examples of alkyl groups comprising 1 to 6 carbon atoms (i.e., C1-6 alkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"). ”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl.

[0206] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0207] The term “butyl” includes 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), and 1,1-dimethylethyl or tert-butyl (“t-Bu”).

[0208] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl.

[0209] 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.

[0210] The term "alkylene" refers to a divalent alkyl group produced by removing two hydrogen atoms from an alkane. Alkylenes include, but are not limited to, methylene, ethylene, and propylene.

[0211] The term "halogen" includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0212] The term "alkenyl" includes hydrocarbon groups selected from straight-chain and branched hydrocarbon groups comprising at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alkenyl (e.g., C...) 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl (or vinyl), propenyl, propenyl-2-alkenyl, 2-methylpropenyl, butenyl, butenyl-2-alkenyl, butenyl-3-alkenyl, butenyl-1,3-dienyl, 2-methylbutenyl-1,3-dienyl, hexenyl-1-alkenyl, hexenyl-2-alkenyl, hexenyl-3-alkenyl, hexenyl-4-alkenyl, and hexenyl-1,3-dienyl.

[0213] The term "alkenyl" refers to a divalent alkenyl group produced by removing two hydrogens from an olefin. Alkenyl groups include, but are not limited to, vinylene and butene.

[0214] The term "alkynyl" includes hydrocarbon groups selected from straight-chain and branched hydrocarbon groups comprising at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alynyl (e.g., C...) 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl and 3-butynyl.

[0215] The term "ynynyl" refers to a divalent ynyl group produced by removing two hydrogens from an alkyne. Iynyl groups include, but are not limited to, ethynylene.

[0216] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged or screwed cycloalkyl groups.

[0217] For example, cycloalkyl groups may contain 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4) carbon atoms. Even further, for example, the cycloalkyl group may be selected from a monocyclic group containing 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In particular, saturated monocyclic cycloalkyl groups (e.g., C16, C26, C36, C46, ​​C56, C6 ... 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, the cycloalkyl group is a monocyclic ring (abbreviated as C10) containing 3 to 6 carbon atoms. 3-6 Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged in a fused bicyclic arrangement selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or arranged in a bridging bicyclic arrangement selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those bicyclic arrangements selected from the [5,6] and [6,6] ring systems.

[0218] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings sharing an atom.

[0219] The term “fused cycloalkyl” includes bicyclic cycloalkyl groups as defined herein, which are saturated and formed by two or more rings sharing two adjacent atoms.

[0220] The term "bridged cycloalkyl" includes a cyclic structure containing carbon atoms and formed by two rings sharing two non-adjacent atoms. The term "7- to 10-membered bridged cycloalkyl" includes a cyclic structure containing 7 to 10 carbon atoms and formed by two rings sharing two non-adjacent atoms.

[0221] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl groups include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, naphthane, and benzo3 to 8-membered cycloalkyl, benzoC 4-6 Cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. A preferred embodiment is an 8- to 9-membered fused ring; in the above examples, this refers to a cyclic structure containing 8 to 9 ring atoms.

[0222] The term "aryl" used alone or in combination with other terms includes groups selected from:

[0223] 5- and 6-membered carbocyclic aromatic rings, for example, phenyl;

[0224] Bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, wherein at least one ring is a carbocyclic ring and an aromatic ring, for example, naphthyl and indanyl; and

[0225] Tricyclic ring systems, such as 10- to 15-membered tricyclic ring systems, wherein at least one ring is a carbon ring and an aromatic ring, for example, a fluorene group.

[0226] The terms "aromatic ring" and "aryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic ring has 5 to 10 cyclic carbon atoms (i.e., C64, C16, C2 ... 5-10 Aryl). Examples of monocyclic or bicyclic aromatic rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic ring is a phenyl ring.

[0227] Specifically, the term "bicyclic fused aryl" includes a bicyclic aryl ring as defined herein. A typical bicyclic fused aryl is naphthalene.

[0228] The term "heteroaryl" includes groups selected from the following:

[0229] 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 to 4 (or in some embodiments, 1 to 3, in some embodiments, 1 to 2) heteroatoms, with the remaining ring atoms being carbon.

[0230] A 7- to 12-membered bicyclic ring comprising at least one heteroatom selected from N, O, and S, for example, 1 to 4 (or in some embodiments, 1 to 3, or in other embodiments, 1 or 2) heteroatoms, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0231] The 11- to 14-membered tricyclic ring contains at least one heteroatom selected from N, O, and S, for example, 1 to 4 (or 1 to 3 in some embodiments, or 1 or 2 in other embodiments) heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic and at least one heteroatom being present in the aromatic ring.

[0232] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. The nitrogen atom in one or more rings of the heteroaryl group can be oxidized to form an N-oxide.

[0233] Specifically, the term "bicyclic fused heteroaryl" includes 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl rings as defined herein. Typically, the bicyclic fused heteroaryl is a 5 / 5, 5 / 6, 6 / 6, or 6 / 7 bicyclic ring. The group can be attached to the remainder of the molecule via any one of the rings.

[0234] "Heterocyclic group", "heterocyclic" or "heterocyclic" are interchangeable and include non-aromatic heterocyclic 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, bridging and spirocyclic groups, i.e. containing monocyclic heterocyclic groups, bridging heterocyclic groups, spirocyclic groups and fused heterocyclic groups.

[0235] The term "at least one substituent" disclosed herein includes, for example, 1 to 4 (such as 1 to 3, further such as 1 or 2) substituents, provided that they conform to the theory of atomic valence. For example, "at least one substituent F" disclosed herein includes 1 to 4 (such as 1 to 3, further such as 1 or 2) substituents F.

[0236] The term "divalent" refers to a linking group capable of forming covalent bonds with two other moieties. For example, "divalent cycloalkyl" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkane to form a linking group. The terms "divalent aryl," "divalent heterocyclic," or "divalent heteroaryl" should be understood in a similar manner.

[0237] The compounds disclosed herein may contain 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. Where the compounds disclosed herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. This is intended to include all such possible stereoisomers in the form of substantially pure, separated enantiomers, racemic mixtures thereof, and mixtures of diastereomers. This is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise expressly stated, the mention of one isomer applies to any of the possible isomers. Where the isomer composition is not specified, all possible isomers are included.

[0238] Unless otherwise stated, when the compounds disclosed herein contain alkene double bonds, such double bonds are intended to include both E and Z geometric isomers.

[0239] When the compounds disclosed herein contain a disubstituted cyclic ring system, the substituents found on such a ring system can be in cis or trans form. The cis form means that both substituents are located above the two substituent positions on the carbon atom, while the trans form means that they are located on opposite sides. For example, the disubstituted cyclic ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0240] It may be advantageous to separate the reaction products from each other and / or from the 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 using techniques commonly used in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example: reversed-phase and normal-phase chromatography; size exclusion chromatography; ion exchange chromatography; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus; small-scale analytical chromatography; simulated moving bed (“SMB”) chromatography and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and rapid chromatography techniques. Those skilled in the art can select and apply the technique most likely to achieve the desired separation.

[0241] "Diasteromers" refer to stereoisomers of compounds having two or more chiral centers that are not mirror images of each other. Mixtures of diastereomers can be separated into their individual diastereomers based on their physicochemical differences, using methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by reacting an enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), converting the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0242] A single stereoisomer (e.g., a substantially pure enantiomer) can be obtained by resolving a racemic mixture using a method such as forming diastereomers with an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al., “Chromatographic resolution of enantiomers: a 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 comprising: (1) forming ionic diastereomeric salts with chiral compounds and separating them by fractional crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing reagents, separating the diastereomeric compounds and converting them into pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. See: Wainer, Irving W. (ed.), Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0243] Some of the compounds disclosed herein may have different hydrogen bonding sites, referred to as tautomers. 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 single keto and enol forms, as well as mixtures thereof, are also intended to be included.

[0244] A "prodrug" is an active agent derivative that needs to be converted in vivo to release the active agent. In some embodiments, this conversion is enzymatic. A prodrug is typically (but not necessarily) pharmacologically inactive before being converted to the active agent.

[0245] "Pharmaceutically acceptable salts" are those salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or individually by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base. This term also includes salts of stereoisomers (such as enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the present invention.

[0246] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, such as a pharmaceutically acceptable addition salt, can be prepared according to conventional methods for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize the various synthetic methods available for preparing non-toxic, pharmaceutically acceptable addition salts without excessive experimentation.

[0247] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the terms “administration,” “administering,” “treating,” and “treatment” herein mean contact between an exogenous drug, therapeutic agent, diagnostic agent, or composition and an animal, human, subject, cell, tissue, organ, or biological fluid. Cell treatment encompasses contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid contacts the cell. The terms “administration” and “treatment” also mean, for example, in vitro and in vitro treatment of cells by means of a reagent, diagnostic agent, conjugated compound, or by means of another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0248] The term "effective amount" or "therapeutic effective amount" refers to the amount of an active ingredient (such as a compound) that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or condition, is sufficient to affect treatment for that disease, condition, or symptom. The term "therapeutic effective amount" can vary depending on the compound, the disease, condition, and / or the symptoms of the disease or condition, the severity of the disease, condition, and / or the age of the subject being treated, and / or the weight of the subject being treated. In any given case, an appropriate amount may be obvious to those skilled in the art or may be determined by routine experiments. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug and / or at least one pharmaceutically acceptable salt thereof that effectively "treats" the disease or condition of a subject as defined herein. In the case of combination therapies, the term "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat the disease, condition, or symptom.

[0249] The term “disease” means any illness, discomfort, pain, symptom or indication, and is interchangeable with the terms “symptom” or “illness”.

[0250] Throughout the specification and appended claims, unless the context otherwise requires, the term "comprise" and variations such as "comprises" and "comprising" are intended to specify the presence of the following feature, but do not exclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced by the terms "containing," "including," or sometimes "having."

[0251] Throughout the specification and appended claims, the term "C" is used. n-m The indicator includes a range of endpoints, where n and m are integers and indicate the number of carbons. Examples include C. 1-8 C 1-6 wait.

[0252] Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0253] General reaction schemes for compound preparation

[0254] The subject compounds and their pharmaceutically acceptable salts can be prepared from (a) commercially available starting materials, (b) known starting materials (which can be prepared as described in the literature procedures), and (c) novel intermediates as described in the protocols and experimental methods herein. In preparing the compounds of the present invention, the order of synthetic steps can be altered to increase the yield of the desired product. Some compounds of the present invention can be generated by methods as shown in the following reaction schemes and their descriptions.

[0255] Option A

[0256]

[0257] Option B

[0258]

[0259] Option C

[0260]

[0261] Option D

[0262]

[0263] Example

[0264] The following examples are intended to be illustrative only and should not be considered as limiting in any way. Efforts have been made to ensure accuracy regarding the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be accounted for. Unless otherwise indicated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise indicated. Unless otherwise indicated, the reactions described below were carried out under positive pressure nitrogen or argon or in anhydrous solvents using a drying tube; reaction flasks were fitted with rubber septa for introducing substrates and reagents via syringe; and glassware was dried and / or heated to dryness.

[0265] 1 The H NMR spectra were recorded on an Agilent instrument operating at 400 MHz. 1H NMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, and tetramethylsilane (0.00 ppm) or residual solvents (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05 ppm; (CD3)3CO: 2.05 ppm) as reference standards. When reporting peak multiplicity, the following abbreviations are used: s (singleton), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad peak), dd (doublet), dt (doubletuplet). Coupling constants are reported in Hertz (Hz).

[0266] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity); Detector: MWD (190-400 nm), Mass detector: 6120SQ; Mobile phase: A: Water containing 0.1% formic acid, B: Acetonitrile containing 0.1% formic acid; Column: Poroshell 120EC-C18, 4.6 × 50 mm, 2.7 pm; Gradient method: Flow rate: 1.8 mL / min; Time (min) A (%) B (%)

[0267] Time (min) A(％) B(％) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0268] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II); Detector: MWD (190-400 nm), Mass detector: G6125C SQ; Mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid; Column: Poroshell 120EC-C18, 4.6 × 50 mm, 2.7 pm; Gradient method: Flow rate: 1.8 mL / min; Time (min) A (%) B (%)

[0269] Time (min) A(％) B(％) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0270] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II); Detector: MWD (190-400 nm), Mass detector: G6125C SQ; Mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid; Column: Poroshell 120EC-C18, 4.6 × 50 mm, 2.7 pm; Gradient method: Flow rate: 1.2 mL / min; Time (min) A (%) B (%)

[0271] Time (min) A(％) B(％) 0.00 90 10 1.5 5 95 2.0 5 95 2.1 90 10 3.0 90 10

[0272] Preparative HPLC was performed on a column (150×21.2mm ID, 5pm, Gemini NXC 18) at a flow rate of 20ml / min and an injection volume of 2ml, at room temperature, with UV detection at 214nm and 254nm.

[0273] In the following embodiments, the following abbreviations are used:

[0274]

[0275]

[0276]

[0277] Example 3: 3-(2-fluoro-4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0278] Step 1: 2-(4-bromo-3-fluorophenyl)ethyl-1-ol

[0279]

[0280] BH3·THF (1M, 386mL) was added to a solution of 45.0 g (193 mmol) of 2-(4-bromo-3-fluorophenyl)acetic acid in 270 mL of THF at 0 °C. The mixture was then stirred at 20 °C for 2 hours. After cooling with ice, MeOH (250 mL) was added dropwise until no foaming occurred in the system and the solvent was distilled off under reduced pressure. Water (50 mL) was added to the resulting residue for extraction with EtOAc (1000.0 mL). The combined organic phases were washed with brine (40.0 mL), dried over Na2SO4, filtered, and concentrated under vacuum. 2-(4-bromo-3-fluorophenyl)ethanol-1-ol (38.0 g, 89.8%) was obtained. 1 H NMR (400MHz, CDCl3-d) δppm [M+H] + =219.1.

[0281] Step 2: (4-bromo-3-fluorophenethoxy)(tert-butyl)dimethylsilane

[0282]

[0283] Imidazole (17.7 g, 260 mmol) was added to a solution of 2-(4-bromo-3-fluorophenyl)ethyl-1-ol (38.0 g, 173 mmol) in DCM (210 mL) at 20 °C. TBSCl (36.6 g, 242 mmol, 29.7 mL) was added to the reaction mixture at 0 °C. The mixture was then stirred at 20 °C for 3 hours. The mixture was then adjusted to pH 6 with 5% citric acid (180 mL) and extracted with DCM (150 mL). The organic phase was adjusted to pH 8 with NaHCO3, and the aqueous phase was extracted with DCM (100 mL). The combined organic phases were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain (4-bromo-3-fluorophenylethoxy)(tert-butyl)dimethylsilane (52.0 g, 156 mmol). 1 H NMR (400MHz, CDCl3-d) δppm 7.43 (t, J=7.72Hz, 1H), 7.00 (dd, J=9.56, 1.87Hz, 1H), 6.89 (dd, J=8.00, 1.87Hz, 1H), 3.8 0(t, J=6.48Hz, 2H), 2.78(t, J=6.48Hz, 2H), 0.84-0.89(m, 9H), -0.05-0.01(m, 6H); [M+H] + =333.2.

[0284] Step 3: 2,6-bis(benzylhydro)-3-(4-(2-((tert-butyldimethylsilyl)hydro)ethyl)-2-fluorobenzene pyridine

[0285]

[0286] KOAc (45.9 g, 468 mmol) was added to a solution of (4-bromo-3-fluorophenylethoxy)(tert-butyl)dimethylsilane (52.0 g, 156 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridine (65.1 g, 156 mmol) in dioxane (320 mL) at 20 °C. Pd(dppf)Cl2 (11.4 g, 15.6 mmol) was added to the mixture at 20 °C. The suspension was degassed under vacuum and purged three times with N2. The mixture was then stirred at 90 °C for 16 hours. Water (160 mL) was poured into the mixture, and the mixture was extracted with EtOAc (100 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography. 2,6-Bis(benzyloxy)-3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)pyridine (32.0 g, 37.8%) was obtained.

[0287] 1 H NMR (400MHz, CDCl3-d) δppm 7.55 (dd, J=8.04, 0.99Hz, 1H), 7.43-7.47 (m, 2H), 7.33-7.42 (m, 7H), 7.25-7.33 (m, 3H), 6.98-7.05 (m, 2H), 5.40 (d, J=18 [M+H] + =544.2.

[0288] Step 4: 3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)piperidine-2,6-di ketone

[0289]

[0290] Pd / C (0.800 g, 10.0% purity) was added to a solution of 2,6-bis(benzyloxy)-3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)pyridine (32.0 g, 58.8 mmol) in THF (50.0 mL) at 20 °C under Ar conditions. The suspension was degassed and purged three times with H2. The mixture was stirred at 50 °C for 16 hours under H2 (50 Psi). The suspension was filtered through a diatomaceous earth mat and the filter cake was washed with THF (200 mL × 3). The combined filtrates were concentrated to dryness to give a crude product. The crude product was milled at 20 °C with petroleum ether (50.0 mL) for 1 hour. 3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)piperidine-2,6-dione (12.0 g, 55.7%) was obtained. 1 H NMR (400MHz, CDCl3-d) δppm 7.06-7.12 (m, 1H) 7.93 (br s, 1H), 6.96-7.04 (m, 2H), 3.91 (dd, J=11.2, 5.04Hz, 1H), 3.81 (t, J=6.80Hz, 2H), 2.82 ( t, J=6.80Hz, 2H), 2.58-2.73(m, 2H), 2.18-2.34(m, 2H), 0.87(s, 9H), 0.00(s, 6H); [M+H] + =366.3.

[0291] Step 5: 3-(2-fluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione

[0292]

[0293] HCl (12M, 6 mL) was added to a solution of 3-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-fluorophenyl)piperidine-2,6-dione (12.0 g, 32.8 mmol) in MeOH (60 mL) at 20 °C. The mixture was then stirred at 20 °C for 3 hours. Water (60 mL) was poured into the mixture, and the mixture was extracted with EtOAc (40 mL). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The combined crude product was purified by recrystallization from toluene (32.0 mL) at 100 °C. 3-(2-fluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione (6.50 g, 78.8%) was obtained. 1H NMR (400MHz, DMSO-d6) δppm 10.8 (s, 1H), 7.19 (t, J=7.84Hz, 1H), 6.99-7.08 (m, 2H), 4.67 (t, J=5.18Hz, 1H), 3.99 (dd, J=12.6, 4.74 [M+H] + =252.2.

[0294] Step 6: 2-(4-(2,6-dihydropiperidin-3-yl)-3-fluorophenyl)acetaldehyde

[0295]

[0296] Add IBX (338 mg, 1.2 mmol) to a solution of 200 mg (0.8 mmol) of 3-(2-fluoro-4-(2-hydroxyethyl)phenyl)piperidine-2,6-dione in 10 mL of DMSO. Stir the mixture overnight in a flask at rt. After the reaction was confirmed to be complete by LCMS, extract the mixture with EA (30 mL x 3). Dry the combined organic phases over anhydrous Na₂SO₄ and evaporate under vacuum to give a crude product (100 mg, crude), which was used in the next step without further purification. [M+H] + =250.4.

[0297] Step 7: 4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0298]

[0299] A mixture of 1,2-difluoro-4-nitrobenzene (500 mg, 3.1 mmol), tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate (915 mg, 3.4 mmol), and K₂CO₃ (855 mg, 6.2 mmol) in DMF (15 mL) was stirred overnight at 80 °C in a round-bottom flask. The reaction mixture was cooled to room temperature, poured into water (50 mL), and stirred for 10 min. The solid was filtered, washed with water (30 mL × 2), and dried to give the product (750 mg, 58%). [M+H] + =409.4.

[0300] Step 8: 4-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0301]

[0302] 10% Pd / C (50 mg) was added to a solution of tert-butyl 4-(1-(2-fluoro-4-nitrophenyl)piperidin-4-yl)piperazine-1-carboxylate (220 mg, 0.54 mmol) in MeOH (20 mL) at 25 °C. The mixture was then exchanged twice with H2 and stirred at 25 °C for 2 h under H2 atmosphere. The mixture was filtered through a diatomaceous earth pad and washed with MeOH (20 mL). The filtrate was concentrated under vacuum to give the product (190 mg, 95%). [M+H] + =378.2.

[0303] Step 9: 1-(Methylsulfonyl-7-nitroindoline)

[0304]

[0305] Methanesulfonyl chloride (315 mg, 2.7 mmol) was added dropwise to a stirred solution of 7-nitroindoline (300 mg, 1.8 mmol) and NaH (146 mg, 3.6 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, and concentrated under vacuum to give a crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (390 mg, 88%). [M+H] + =243.1.

[0306] Step 10: 1-(Methylsulfonyl)indoline-7-amine

[0307]

[0308] Under N2 atmosphere at room temperature, 10% Pd / C (50 mg) was added to a solution of 1-(methanesulfonyl)-7-nitroindoline (390 mg, 1.6 mmol) in MeOH (20 mL). The mixture was then exchanged with H2 twice and stirred at room temperature for 2 h under H2 atmosphere. The reaction was monitored by LC-MS. The mixture was filtered through a diatomaceous earth pad and washed with MeOH (20 mL). The filtrate was concentrated under vacuum to give the title product (340 mg, 99%). [M+H] + =213.1.

[0309] Step 11: 2-Chloro-N-(1-(methanesulfonyl)indoline-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0310]

[0311] Concentrated HCl (0.2 mL) was added to a solution of 1-(methanesulfonyl)indoline-7-amine (60 mg, 0.28 mmol) and 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (79 mg, 0.42 mmol) in i-PrOH (8 mL). The resulting mixture was heated overnight at 80 °C. The organic solvent was removed under reduced pressure, and the residue was alkalized with a saturated aqueous solution of NaHCO3 and extracted with DCM (2 × 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain a crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 1:1 gradient elution) to give the title product (100 mg, 97%). [M+H] + =364.2.

[0312] Step 12: 4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo) [2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0313]

[0314] A mixture of 2-chloro-N-(1-(methanesulfonyl)indoline-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (40 mg, 0.11 mmol), 4-(1-(4-amino-2-fluorophenyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (45 mg, 0.12 mmol), G3BrettPhos Pd (10 mg, 0.011 mmol), and Cs2CO3 (72 mg, 0.22 mmol) in 1,4-dioxane (6 mL) was stirred overnight at 100 °C under a nitrogen atmosphere in a round-bottom flask. The mixture was evaporated under vacuum to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH = 100:0–5:1 gradient elution) to give the title product (60 mg, 78%). [M+H] + =706.2.

[0315] Step 13: N 2 -(3-Fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methylsulfonyl)indole (-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine

[0316]

[0317] A solution of tert-butyl 4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazine-1-carboxylate (750 mg, 1.06 mmol) in a TFA / DCM = 1 / 4 (5 mL) mixture was stirred in a round-bottom flask at room temperature for 2 h. The mixture was evaporated under vacuum to give a crude product (610 mg, 95%), which was used in the next step without further purification. [M+H] +=606.4.

[0318] Step 14: 3-(2-fluoro-4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino) )-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2, 6-Diketone

[0319]

[0320] N 2 -(3-Fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)-N 4 The mixture of 1-(1-(methanesulfonyl)indoline-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (40 mg, 0.066 mmol), 2-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)acetaldehyde (17 mg, 0.069 mmol), and NaOAc (14 mg, 0.17 mmol) in chloromethane (4 mL) and EtOH (0.5 mL) was stirred in a flask at room temperature for 2 hours. NaBH3CN (10 mg, 0.17 mmol) was added to the mixture, and the mixture was stirred again in the flask at room temperature for 2 hours. The mixture was then evaporated under vacuum to give a crude product, which was purified by HPLC (elution with a gradient of water:acetonitrile containing 0.1% FA = 90:10 to 50:50) to give the product (15 mg, 27%). 1 H NMR (400MHz, CD3OD) δ7.64 (s, 1H), 7.53 (s, 1H), 7.37 (s, 1H), 7.29 (s, 2H), 7. 19-7.07 (m, 4H), 7.03 (s, 1H), 4.12 (s, 2H), 4.03 (d, J=7.9Hz, 1H), 3.59 (d, 3H) , 3.47(s, 4H), 3.14-3.20(m, 4H), 2.95(s, 3H), 2.85-2.90(m, 2H), 2.61-2.68( s, 4H), 2.29 (s, 4H), 2.10-2.16 (m, 2H), 2.02-2.04 (m, 2H), 1.28 (s, 3H); [M+H] + =839.4.

[0321] Example 1: 3-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0322]

[0323] The title compound was prepared in a manner similar to that in Example 3.1 H NMR (400MHz, DMSO) δ11.60 (s, 1H), 10.84 (s, 1H), 9.44 (s, 1H), 8.09-7.72 (m, 2H), 7.2 4 (d, J=18.1Hz, 6H), 7.02 (s, 2H), 6.34 (s, 1H), 4.10 (s, 2H), 3.84 (d, J=11.5Hz, 6H), 3. 61(s, 2H), 3.30-3.21(m, 2H), 3.12-3.18(m, 3H), 3.10-2.88(m, 7H), 2.68(d, J=8.4Hz, [M+H] + =821.3.

[0324] Example 2: 3-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2-methoxyphenyl)piperidin-2,6-dione

[0325]

[0326] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ11.34 (s, 1H), 10.73 (s, 1H), 9.04 (s, 1H), 8.94 (s, 1H), 8.30 (d, J=6.7Hz, 1H), 7.87 (d, J=15. 1Hz, 1H), 7.31 (d, J = 9.1Hz, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 7.04-6.94 (m, 2H), 6.92 (d, J = 14.8Hz, 2H), 6.77 (d, J = 7.4Hz, 1H), 6.21 (s, 1H), 4.11 (s, 2H), 3.86 (s, 1H), 3.73 (s, 3H), 3.16-3.07 (m, 6H), 3.03-2.91 (m, 2H), 2.76-2.5 [M+H] + =851.2.

[0327] Example 4: 3-(4-(3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)propoxy)phenoxy)piperidin-2,6-dione

[0328] Step 1: 4-(3-((tert-butyldimethylsilyl)oxy)propoxy)phenol

[0329]

[0330] Hydroquinone (10.6 g, 96.1 mmol) was dissolved in DMF (100 mL). (3-bromopropoxy)(tert-butyl)dimethylsilane (23.0 g, 91 mmol) and Cs₂CO₃ (45.0 g, 138.1 mmol) were added to the solution. The mixture was stirred at 50 °C for 2 h. The mixture was diluted with water (100 mL) and extracted with EA (150 mL × 2). The combined organic layers were washed with water (50 mL × 3) and brine (50 mL × 2), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product (8.5 g, 31.3%). [M+H] + =283.2.

[0331] Step 2: 3-Bromopiperidine-2,6-dione

[0332]

[0333] Br2 (25.4 g, 158 mmol) was added to a solution of piperidine-2,6-dione (15.0 g, 132 mmol) in CHCl3 (30 mL), and the mixture was stirred at 110 °C for 4 h. After cooling, water (200 mL) was added to the mixture, and extraction was performed with EA (200 mL × 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product (7.9 g, 31%). [M+H] + =192.2.

[0334] Step 3: 3-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)phenoxy)piperidine-2,6-dione

[0335]

[0336] 4-(3-((tert-butyldimethylsilyl)oxy)propoxy)phenol (22.1 g, 78.1 mmol) was dissolved in THF (100 mL). NaH (4.7 g, 60%, 117.2 mmol) was added to the solution at 0 °C, and the mixture was stirred for 1 h. Then, 3-bromopiperidin-2,6-dione (15.0 g, 78.1 mmol) was added dropwise to a solution of THF (100 mL). The mixture was stirred at 60 °C for 2 h, and then saturated NH4Cl aqueous solution (100 mL) was added at 0 °C, followed by extraction with EA (100 mL × 4). The combined organic phases were washed with water (50 mL × 2) and brine (50 mL × 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product (14.5 g, 47%). [M+H] + =394.2.

[0337] Step 4: 3-(4-(3-hydroxypropoxy)phenoxy)piperidine-2,6-dione

[0338]

[0339] 3-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)phenoxy)piperidine-2,6-dione (19.0 g, 48.3 mmol) was dissolved in THF (200 mL), and TBAF (1 M in THF) (72.5 mL, 72.5 mmol) was added. The mixture was stirred at 25 °C for 5 h. Water (100 mL) was added to the mixture, and it was extracted with EA (150 mL × 2). The combined organic phases were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product (5.3 g, 39.3%). 1 H NMR (400MHz, DMSO)δ H 10.89 (s, 1H), 6.94 (d, J=9.1Hz, 2H), 6.84 (d, J=9.1Hz, 2H), 5.02 (dd, J=10.5, 4.9Hz, 1H), 4.51 (t, J=5.1Hz, 1 [M+H] + =280.2.

[0340] Step 5: 3-(4-((2,6-dioxopiperidin-3-yl)oxy)phenoxy)propyl methanesulfonate

[0341]

[0342] 3-(4-(3-hydroxypropoxy)phenoxy)piperidine-2,6-dione (279 mg, 1.0 mmol) and triethylamine (202 mg, 2.0 mmol) were dissolved in THF (5 mL), and methanesulfonyl chloride (136.1 mg, 1.2 mmol) was added. The mixture was stirred at 25 °C for 2 h. Water (10 mL) was added to the mixture, and it was extracted with EA (15 mL × 2). The combined organic phases were washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product (200 mg, 56%). [M+H] + =358.2.

[0343] Step 6: 3-(4-(3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H- Pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)propoxy)phenoxy)piperidin-2,6- diketone

[0344]

[0345] N 2 -(3-Fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)-N 4 A mixture of 1-(1-(methanesulfonyl)indoline-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (34 mg, 0.057 mmol), 3-(4-((2,6-dioxopiperidin-3-yl)oxy)phenoxy)propyl methanesulfonic acid (24 mg, 0.069 mmol), KI (11.6 mg, 0.069 mmol), and DIEA (14.7 mg, 0.114 mmol) in acetonitrile (4 mL) was stirred at 75 °C for 12 h in a round-bottom flask. The reaction mixture was quenched with water and extracted with DCM, washed three times with saturated brine, and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the product (10 mg, 20%). 1H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.90 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.86 (d, J=15.5Hz, 1H), 7.35-7.20 (m, 2H), 7.12 (d, J=7.2Hz, 1H), 7.02-6.77 (m, 5H ), 6.21 (s, 1H), 5.10-4.96 (m, 1H), 4.11 (s, 2H), 3.94 (s, 2H), 3.18-2.83 (m, 8H), 2.75-2.54 (m, 8H), 2.45-2.24 (m, 5H), 2.23-2.00 (m, 2H), 1.95-1.76 (m, 4H), 1.65-1.47 (m, 2H); [M+H] + =867.5.

[0346] Example 5: 3-(3-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethoxy)phenyl)piperidin-2,6-dione

[0347]

[0348] The title compound was prepared in a manner similar to that in Example 1. 1 H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.83 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.30 (d, J = 7.8Hz, 1H) , 7.86 (d, J=14.8Hz, 1H), 7.27-7.81 (m, 3H), 7.12 (d, J=6.8Hz, 1H), 7.01-6.75 (m, 5H), 6.21 (s, 1H ), 4.08-4.11(m, 4H), 3.81(s, 1H), 3.26-3.21(m, 3H), 3.17-3.07(m, 6H), 3.04-2.87(m, 2H), 2.74 -2.52(m, 10H), 2.32-2.14(m, 2H), 2.10-1.92(m, 1H), 1.95-1.75(m, 2H), 1.65-1.47(m, 2H); [M+H] + =837.

[0349] Example 6: 3-(3-((2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)(methyl)amino)phenyl)piperidin-2,6-dione

[0350]

[0351] The title compound was prepared in a manner similar to that in Example 1. 1 H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.80 (s, 1H), 9.02 (s, 1H), 8.92 (s, 1H), 8.30 (d, J=8.0Hz, 1H), 7.86 (d, J =15.8Hz, 1H), 7.35-7.20(m, 2H), 7.16-7.05(m, 2H), 6.92-6.95(m, 2H), 6.61-6.50(m, 2H), 6.44(d, J=7.1Hz, 1H), 6.21(s, 1H), 4.11(s, 2H), 3.74(s, 1H), 3.42(s, 3H), 3.l1(m, 6H), 3.05-2.92(m, 2H), 2.88(s, 3H), 2.62- 2.65(m,4H),2.44-2.48(m,5H),2.35-1.95(m,4H),1.83-1.86(m,2H),1.56-1.58(m,2H),1.24(s,2H);[M+H] + =850.

[0352] Example 8: 3-(4-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0353] Step 1: 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine

[0354]

[0355] At room temperature and under a nitrogen atmosphere, K₂CO₃ (16.6 g, 120 mmol) and Pd(dppf)Cl₂ (4.4 g, 6.0 mmol) were added to a stirred mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (the intermediate can be prepared according to the method described in WO2017197046) (25 g, 59.9 mmol) and 4-bromoiodobenzene (20.3 g, 71.9 mmol) in dioxane (250 mL) and H₂O (50 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature. The resulting mixture was 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 (10:1) to give the product (23 g, 86%); [M+H] + =446.2.

[0356] Step 2: 2-(1-[4-[26-bis(benzyloxy)pyridin-3-yl]phenyl]piperidin-4-yl)ethyl acetate

[0357]

[0358] Cs₂CO₃ (32.9 g, 100.8 mmol), DavePhos (2.7 g, 6.7 mmol), and Pd₂(dba)₃ (3.1 g, 3.4 mmol) were added to a stirred solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (15 g, 33.6 mmol) and 2-(piperidin-4-yl)ethyl acetate (8.6 g, 50.4 mmol) in 2-methyl-THF (150 mL) and H₂O (15 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL) and washed with water (3 × 200 mL) and brine (200 mL). The organic layer was 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 (14 g, 78%); [M+H] + =537.3.

[0359] Step 3: 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethanol-1-ol

[0360]

[0361] LiAlH4 (1 g, 26.6 mmol) was added fractionally to a stirred solution of ethyl 2-(1-[4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl]piperidin-4-yl)acetate (13 g, 24.2 mmol) in THF (130 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched at 0 °C by adding water / ice (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 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 (11 g, 92%); [M+H + =495.3.

[0362] Step 4: 3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0363]

[0364] Pd / C (wet, 10%) (5 g) was added to a stirred solution of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)ethanol-1-ol (10.5 g, 21.2 mmol) in EtOH (100 mL), EtOAc (100 mL), and DCM (20 mL) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The mixture was filtered, and the filter cake was washed with DCM / CH3OH (10:1, 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (1:10) to give the product (5.1 g, 76%). [M+H] + =317.1.

[0365] Step 5: 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)acetaldehyde

[0366]

[0367] A mixture of 3-(4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione (100 mg, 0.32 mmol) and IBX (132 mg, 0.47 mmol) in DMSO (10 mL) was stirred overnight at room temperature in a flask. The reaction mixture was quenched with water and extracted with EtOAc, washed three times with saturated aqueous NaCl solution and twice with saturated aqueous NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to give the product (70 mg, 70%). [M+H] + =315.2.

[0368] Step 6: 3-(4-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl) Piperidine-2,6-dione

[0369]

[0370] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.77 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.30 (d, J=8.3Hz, 1H), 7.86 (d, J=14 .7Hz, 1H), 7.28-7.30 (m, 2H), 7.13 (s, 1H), 7.03 (d, J=8.7Hz, 2H), 6.91-6.95 (m, 4H), 6.21 (s, 1H), 4.16-4.06 (m , 2H), 3.75-3.61(m, 3H), 3.20-3.03(m, 6H), 2.73-2.54(m, 10H), 2.49-2.21(m, 7H), 2.20-2.06(m, 1H), 2.05-1. [M+H] + =904.2.

[0371] Example 9: 3-(2-fluoro-4-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0372]

[0373] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (400MHz, DMSO) δ11.31 (s, 1H), 10.79 (s, 1H), 9.02 (s, 1H), 8.90 (s, 1H), 8.29 (d, J = 7.3Hz, 1H), 7.86 (d, J = 16.9Hz, 1H), 7.31 (d , J=7.7Hz, 1H), 7.24 (t, J=7.8Hz, 1H), 7.12 (d, J=7.0Hz, 1H), 7.04 (d, J=8.5Hz, 1H), 6.92 (m, 2H), 6.70 (d, J=10.8Hz, 2H), 6.21 (s, 1 H), 4.10 (s, 2H), 3.87 (d, J=7.8Hz, 1H), 3.69 (d, J=11.7Hz, 2H), 3.17-3.06 (m, 6H), 2.73-2.55 (m, 8H), 2.43-2.25 (m, 6H), 2.22-2. [M+H] + =922.3.

[0374] Example 10: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)benzylnitrile

[0375]

[0376] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ11.33 (s, 1H), 10.92 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.30 (d, J=8.1Hz, 1H), 7.86 (d, J =15.3Hz, 1H), 7.35-7.19 (m, 5H), 7.12 (d, J = 7.2Hz, 1H), 6.92-6.95 (m, 2H), 6.21 (s, 1H), 4.10 (d, J = 7.2Hz, 2H ), 3.99 (dd, J=12.5, 4.6Hz, 1H), 3.77 (d, J=12.1Hz, 2H), 3.18-3.07 (m, 6H), 2.85-2.53 (m, 10H), 2.44-2.22 ( m, 8H), 2.01-2.05 (m, 1H), 1.88-1.80 (m, 2H), 1.78-1.70 (m, 2H), 1.63-1.34 (m, 5H), 1.27-1.15 (m, 3H); [M+H] + =929.2.

[0377] Example 11: 3-(4-(1-(3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)piperidin-4-yl)phenyl)piperidin-2,6-dione

[0378] Step 1: 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0379]

[0380] 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)piperidin-1-carboxylic acid tert-butyl ester (17 g, 44 mmol), Pd(dppf)C12 (3.2 g, 4.4 mmol), 2,6-bis(benzyloxy)-3-bromopyridine (16.2 g, 44.0 mmol), and Cs2CO3 (28.7 g, 88 mmol) were placed in dioxane / water (300 mL, 10:1). The mixture was stirred overnight at 100 °C until LC-MS indicated that all starting materials had been consumed. The resulting solution was filtered and the filtrate was concentrated to provide a crude residue, which was purified by SiO2 gel column chromatography (eluting with EtOAc / hexane = 1:1) to give the desired product (5 g, 21%). [M+H] + =551.3.

[0381] step Step 2: 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-carboxylic acid tert-butyl ester

[0382]

[0383] 5 g (9.1 mmol) of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-1-carboxylate was dissolved in MeOH (50 mL), and Pd / C (10%, w / w, 0.5 g) was added to the solution in a single addition. The resulting mixture was stirred overnight under a H2 atmosphere until LC-MS indicated that all starting material had been consumed. The resulting solution was filtered and the filtrate was concentrated to give the desired product (1.9 g, 56.1%). [M+H] + =373.

[0384] Step 3: 3-(4-(piperidin-4-yl)phenyl)piperidin-2,6-dione hydrochloride

[0385]

[0386] 1.9 g (5.1 mmol) of tert-butyl 4-(4-(2,6-dioxadiazin-3-yl)phenyl)piperidin-1-carboxylate was placed in HCl-dioxane (4 M, 20 mL), and the mixture was stirred at room temperature for 2 h until LC-MS indicated that all starting material had been consumed. The resulting solution was concentrated to provide a crude residue, which was ground with MTBE (5 mL) to give the desired product (1.38 g, 88%). [M+H] + =273.2.

[0387] Step 4: tert-butyl 3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)propionate

[0388]

[0389] A mixture of 3-(4-(piperidin-4-yl)phenyl)piperidin-2,6-dione hydrochloride (228 mg, 0.74 mmol), tert-butyl acrylate (189 mg, 1.48 mmol), and DIEA (189 mg, 1.48 mmol) in MeCN (8 mL) was stirred overnight at 80 °C in a flask. The mixture was evaporated under vacuum to give a crude product, which was further purified by silica gel column chromatography (DCM:MeOH = 100:0–10:1 gradient elution) to give the product (178 mg, 60%); [M+H + =401.2.

[0390] Step 5: 3-(4-(4-(2,6-dihydropiperidin-3-yl)phenyl)piperidin-1-yl)propionic acid

[0391]

[0392] A solution of tert-butyl 3-(4-(4-(2,6-dioxadiazin-3-yl)phenyl)piperidin-1-yl)propionate (178 mg, 0.45 mmol) in HCl / 1,4-dioxane (8 mL) was stirred overnight at room temperature in a flask. The mixture was evaporated under vacuum to give a crude product (150 mg, 97%), which was used in the next step without further purification. [M+H] + =345.4.

[0393] Step 6: 3-(4-(1-(3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)piperidin-4- 2,6-dione (phenyl)piperidine-2,6-dione

[0394]

[0395] Add N to a solution of 3-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)propionic acid (24 mg, 0.069 mmol), HATU (27 mg, 0.073 mmol), and DIEA (34 mg, 0.264 mmol) in DMF (4 mL). 2 -(3-Fluoro-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methanesulfonyl)indoline-7-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (40 mg, 0.066 mmol). The resulting mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water and extracted with DCM. The organic phase was washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (elution gradient of water:acetonitrile = 90:10 to 50:50 containing 0.1% FA) to give the title product (13.6 mg, 22%). 1H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.81 (s, 1H), 9.02 (s, 1H), 8.92 (s, 1H), 8.30 (d, J=7.9Hz, 1H), 8.23 ​​(s, 1H), 7.86 (d, J=15. 7Hz, 1H), 7.32 (d, J=8.5Hz, 1H), 7.28-7.18 (m, 3H), 7.13 (d, J=7.7Hz, 3H), 6.98-6.87 (m, 2H), 6.21 (s, 1H), 4.11 (s, 2H), 3.80 (d . [M+H] + =932.8.

[0396] Example 12: 3-(4-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0397] Step 1: 4-(2,6-bis(benzyloxy)pyridin-3-yl)aniline

[0398]

[0399] 2,6-bis(benzyloxy)-3-bromopyridine (58.0 g, 156.7 mmol), pinacol 4-aminophenylboronic acid (44.6 g, 203.7 mmol), K₂CO₃ (65.0 g, 470.0 mmol), and Pd(dppf)Cl₂ (11.5 g, 15.7 mmol) were added to a reaction flask, the mixture was degassed, and purged three times with nitrogen. Then, 1,4-dioxane (1 L) and water (300 mL) were added to the reaction flask, and the mixture was again purged with nitrogen three times. The reaction mixture was heated to reflux. After stirring for 3 hours, the reaction mixture was cooled to room temperature, extracted with EtOAc (500 mL × 3), and the combined organic phases were washed with water and brine, dried, and concentrated. Following column separation (petroleum ether: ethyl acetate = 10:1), 4-(2,6-bis(benzyloxy)pyridin-3-yl)aniline (57.3 g, 95.6%) was obtained. 1 H NMR (400MHz, CDCl3) δ7.57 (d, J=8.0Hz, 1H), 7.50-7.27 (m, 12H), 6.72 (d, J=8. 5Hz, 2H), 6.45 (d, J=8.0Hz, 1H), 5.43 (s, 2H), 5.36 (s, 2H), 3.68 (s, 2H); [M+H] + =383.2.

[0400] Step 2: 2,6-bis(benzyloxy)-3-(4-iodophenyl)pyridine

[0401]

[0402] p-Toluenesulfonic acid monohydrate (106.0 g, 557 mmol) was added to tert-butanol (800 mL). 4-(2,6-bis(benzyloxy)pyridin-3-yl)aniline (78.5 g, 205 mmol) was dissolved in MeCN (400 mL) and added to the system, and the mixture was stirred at room temperature. NaNO2 (28.3 g, 404 mmol) and KI (85.2 g, 513.1 mmol) were added to water (400 mL). The system was then stirred at room temperature. After stirring for 1.5 h, the mixture was diluted with water (1.5 L) and the pH was adjusted to 10 with 2 M sodium hydroxide solution. 2 M sodium thiosulfate solution (1 L) was added to the mixture, and extraction was performed with DCM (1 L × 3). The combined organic phases were washed with water and brine, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) to give 2,6-bis(benzyloxy)-3-(4-iodophenyl)pyridine (31.2 g, 30.8%). 1[M+H] + =494.1.

[0403] Step 3: 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)tert-butyl acetate

[0404]

[0405] Under a nitrogen atmosphere, 2,6-bis(benzyloxy)-3-(4-iodophenyl)pyridine (45.4 g, 92.0 mmol), tert-butyl 2-(piperidin-4-yl)acetate (27.5 g, 138 mmol), and t-BuONa (13.3 g, 138 mmol) were added to 1,4-dioxane (450 mL). After three purgings with nitrogen, Pd2(dba)3 (4.2 g, 4.6 mmol) and X-Phos (4.4 g, 9.2 mmol) were added to the system, followed by three more purgings with nitrogen, and then the temperature was raised to reflux. After 1.5 h, the reaction mixture was cooled to room temperature, water (250 mL) was added, and extraction was performed using DCM (3 × 250 mL). The combined organic phases were washed with water and brine, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to give tert-butyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)acetate (31.1 g, 60.2%). 1 H NMR (400MHz, CDCl3) δ7.59 (d, J=8.1Hz, 1H), 7.50-7.28 (m, 12H), 6.96 (d, J=8.8Hz, 2H), 6.46 (d, J=8.0Hz, 1H), 5.43 (s, 2H), 5.36 (s, 2H), 3.73-3.70 (m, 2H), 2.80-2.74 (m, 2H), 2.21 (d, J=7.0Hz, 2H), 2.00-1.89 (m, 1H), 1.86-1.82 (m, 2H), 1.53-1.35 (m, 11H). [M+H] + =565.3

[0406] Step 4: 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)tert-butyl acetate

[0407]

[0408] 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperidin-4-yl)tert-butyl acetate (28.6 g, 50.6 mmol) and Pd / C (7.5 g) were added to DMF (500 mL). The mixture was stirred at 50 °C under a hydrogen atmosphere for 16 h, cooled to room temperature, filtered through a diatomaceous earth pad, and washed with DCM. The filtrate was concentrated to give 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)tert-butyl acetate (17.4 g, 89%). 1 H NMR (400MHz, CDCl3) δ7.97 (s, 1H), 7.07 (d, J=8.5Hz, 2H), 6.91 (d, J=8.4Hz, 2H), 3.79-3.49 (m, 3H) , 2.82-2.54(m, 4H), 2.27-2.18(m, 4H), 1.91-1.87(m, 1H), 1.83-1.80(m, 2H), 1.50-1.25(m, 11H). [M+H] + =387.2.

[0409] Step 5: 2-(1-(4-(2,6-dihydropiperidin-3-yl)phenyl)piperidin-4-yl)acetic acid trifluoroacetate

[0410]

[0411] 2-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)tert-butyl acetate (16.2 g, 41.9 mmol) and TFA (95.5 g, 838 mmol) were added to DCM (100 mL). The temperature was raised to 40 °C and stirred for 1.5 h. After cooling to room temperature, the mixture was concentrated and then recrystallized in MTBE (150 mL) to give the product (14.5 g, 77.9%). 1 HNMR (400MHz, MeOD) δ7.57 (d, J=8.6Hz, 2H), 7.47 (d, J=8.6Hz, 2H), 3.96 (dd, J=11.7, 5.0Hz, 1H), 3.71-3. 68 (m, 2H), 3.61-3.56 (m, 2H), 2.78-2.63 (m, 2H), 2.39-2.38 (m, 2H), 2.27-2.13 (m, 6H), 1.79-1.69 (m, 2H). [M+H] + =331.2.

[0412] Step 6: 3-(4-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)piperidin-1- 2,6-dione (phenyl)piperidine-2,6-dione

[0413]

[0414] The title compound was prepared in a manner similar to that in Example 11. 1 H NMR (400MHz, DMSO) δ11.38 (s, 1H), 10.77 (s, 1H), 10.37 (s, 1H), 9.07 (s, 2H), 7.82 (d, J=15.3Hz, 1H), 7.20 (m, 6H), 6.94 (s, 3H), 6.22 (s, 1H), 4.47 (s, 1H), 4.06 (s, 4H), 3.77 (s, 2H), 3.56 (s, 3H), 3.47 (s, 4H), 3.10 (s, 3H), 3.03 (s, 4H), 2.98 (s, 1H), 2.63 (s, 4H) , 2.35(s, 2H), 2.11(s, 3H), 1.98(s, 2H), 1.82(s, 4H), 1.45(s, 2H), 1.19(s, 1H); [M+H] + =918.8.

[0415] Example 13: 3-(4-((S)-3-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)pyrrolidine-1-yl)phenyl)piperidin-2,6-dione

[0416] Step 1: (S)-3-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0417]

[0418] BH3-THF (20 mL) was added dropwise to a stirred solution of ((3S)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)acetic acid (5 g, 21.81 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with MeOH at 0 °C. The solvent was removed and the residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give the product (3 g, 64%). [M+H] + =216.2.

[0419] Step 2: (S)-2-(pyrrolidone-3-yl)ethanol-1-ol hydrochloride

[0420]

[0421] 4M HCl (30 mL) in 1,4-dioxane was added dropwise to a stirred solution of (3S)-3-(2-hydroxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 13.934 mmol) at °C. The resulting mixture was stirred at room temperature for 3 h and then concentrated under vacuum. The crude product was used directly in the next step without further purification. [M+H] + =116.3.

[0422] Step 3: 3-(4-((S)-3-(2-hydroxyethyl)pyrrolidone-1-yl)phenyl)piperidine-2,6-dione

[0423]

[0424] At room temperature under a nitrogen atmosphere (S)-2-(pyrrolidone-3-yl)ethanol-1-ol hydrochloride (1.99 g, 13.02 mmol) and 3-(4-bromophenyl)piperidin-2,6-dione (3.12 g, 11.72 mmol) were added to a stirred solution of dioxane (30 mL) along with Cs₂CO₃ (12.73 g, 39.07 mmol) and Pd-PEPPSI-IPentCl₂-methylpyridine (o-methylpyridine) (CAS: 1612891-29-8, 413 mg, 0.49 mmol). The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The mixture was acidified to pH 6 with citric acid. The aqueous layer was extracted with CH₂Cl₂ (2 × 100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH₂Cl₂ / MeOH = 10:1) to give the product (212 mg, 6%). [M+H] + =303.1.

[0425] Step 4: Ethyl 2-((3S)-1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyrrolidine-3-yl)methanesulfonic acid

[0426]

[0427] The title compound (140 mg, 62%) was prepared from 3-(4-((S)-3-(2-hydroxyethyl)pyrrolidone-1-yl)phenyl)piperidine-2,6-dione and sulfoxide in a manner similar to that described in step 5 of Example 1. [M+H] + =381.2.

[0428] Step 5: 3-(4-((S)-3-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino) (yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)pyrrolidine-1-yl) (Phenyl)piperidine-2,6-dione

[0429]

[0430] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.74 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.30 (d, J=8.3Hz, 1H), 7.86 (d, J=15.3Hz, 1H), 7.36-7.19 (m, 2H), 7.12 (d, J=7.2Hz, 1H), 7.04-6.84 (m, 4H), 6.46 (d, J=8.6Hz, 2H), 6 .21(s, 1H), 4.10(s, 2H), 3.67(d, J=5.8Hz, 1H), 3.45-3.35(m, 3H), 3.22-3.05(m, 7H), 2.88-2.79(m, 1H ), 2.70-2.52(m, 7H), 2.47-2.20(m, 9H), 2.18-1.94(m, 3H), 1.89-1.79(m, 2H), 1.67-1.48(m, 5H); [M+H] + =890.2.

[0431] Example 14: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0432] Step 1: Benzyl 4-((4-(tert-butoxycarbonyl)piperidin-1-yl)methyl)piperidin-1-carboxylate

[0433]

[0434] STAB (5.14 g, 24.263 mmol) was added sequentially to a stirred solution of 4-formylpiperidin-1-carboxylic acid benzyl ester (1.01 g, 4.044 mmol), piperidine-4-carboxylic acid tert-butyl hydrochloride (897 mg, 4.044 mmol), AcONa (3.31 g, 40.4 mmol), and DCM (20 mL) at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with water at room temperature. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (1.20 g), which was used directly in the next step without further purification. [M+H] + =417.3.

[0435] Step 2: 1-(piperidin-4-ylmethyl)piperidin-4-carboxylic acid tert-butyl ester

[0436]

[0437] A suspension of 4-((4-(tert-butoxycarbonyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid benzyl ester (1.20 g, crude), AcOH (20 mL), and Pd / C (1.20 g, 10% wt) in MeOH (20 mL) was stirred for 1 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give a crude product (900 mg), which was used directly in the next step without further purification. [M+H] + =283.2.

[0438] Step 3: 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4- tert-butyl methylpiperidine-4-carboxylate

[0439]

[0440] A solution of tert-butyl 1-(piperidin-4-ylmethyl)piperidin-4-carboxylate (500 mg, crude), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (489 mg, 1.770 mmol), and DIEA (1.14 g, 8.852 mmol) in DMSO (6 mL) was stirred at 80 °C for 1 h. 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 to give a crude product (830 mg), which was used directly in the next step without further purification. [M+H] + =539.3.

[0441] Step 4: 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4- methylpiperidine-4-carboxylic acid

[0442]

[0443] A solution of 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-carboxylic acid tert-butyl ester (810.00 mg, crude) and TFA (8 mL) in DCM (8 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with water. The resulting mixture was concentrated under vacuum to give a crude product (725 mg), which was used directly in the next step without further purification. [M+H] + =483.2.

[0444] Step 5: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(4-(1-(2-fluoro-4-((4-((1-(methylsulfonyl) Acyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazine-1- Carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0445]

[0446] The title compound was prepared in a manner similar to that in Example 11. 1 H NMR (400MHz, DMSO) δ11.39 (s, 1H), 11.08 (s, 1H), 10.88 (s, 1H), 9.21 (s, 2H), 8.21 (s, 1H), 7.89 (d, J=15.4Hz, 1H), 7.69(d, J=8.2Hz, 1H), 7.37(s, 1H), 7.26(s, 3H), 7.17(s, 1H), 6.99(s, 2H), 6.25(s , 1H), 5.06(s, 1H), 4.10(s, 3H), 3.56(s, 1H), 3.14(s, 5H), 3.09(s, 3H), 3.00(s, 9H), 2.67(s, 2H), 2.54(s, 1H), 2.33(s, 1H), 2.16(s, 3H), 1.99(s, 4H), 1.87(s, 6H), 1.24(s, 8H), 0.85(s, 1H); [M+H] + =1070.2.

[0447] Example 15: 2-(2,6-dioxopiperidin-3-yl-5-(4-(3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)piperazin-1-yl)isoindoline-1,3-dione

[0448]

[0449] The title compound was prepared in a manner similar to that in Example 11. 1 H NMR (400MHz, DMSO) δ11.42 (s, 1H), 11.09 (s, 1H), 10.95 (s, 1H), 10.50 (s, 1H), 9.12 (s, 1H), 8.17 (s, 1H), 7 .77 (d, J=8.4Hz, 1H), 7.51 (s, 1H), 7.38 (d, J=7.0Hz, 1H), 7.28 (d, J=15.5Hz, 2H), 7.18 (s, 1H), 6.99 (s, 2H) , 6.26 (s, 1H), 5.10 (d, J = 7.9Hz, 1H), 4.48 (s, 1H), 4.25 (d, J = 12.2Hz, 2H), 4.10 (s, 3H), 3.61 (s, 5H), 3.14 (s,7H),3.08(s,3H),3.01(s,5H),2.65(m,4H),2.18(s,2H),2.01(s,2H),1.89(s,2H),1.24(s,4H);[M+H] + =1002.7.

[0450] Example 16: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

[0451]

[0452] The title compound was prepared in a manner similar to that in Example 1. 1 H NMR (400MHz, DMSO) δ11.32 (s, 1H), 11.07 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.29 (d, J=14.3Hz, 2H), 7.86 (d , J=16.2Hz, 1H), 7.64 (d, J=8.4Hz, 1H), 7.35-7.20 (m, 2H), 7.12 (d, J=7.3Hz, 1H), 6.93 (m, 3H), 6.80 (d, J=9. 0Hz, 1H), 6.21 (s, 1H), 5.04 (s, 1H), 4.11 (s, 2H), 3.60 (dd, J=16.3, 5.6Hz, 2H), 3.15-2.84 (m, 11H), 2.60-2 [M+H] +=959.

[0453] Example 17: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)isoindoline-1,3-dione

[0454]

[0455] The title compound was prepared in a manner similar to that in Example 1. 1 H NMR (400MHz, DMSO) δ11.31 (s, 1H), 11.06 (s, 1H), 9.02 (s, 1H), 8.90 (s, 1H), 8.30 (d, J = 8.2Hz, 1H), 8.20 (s, 1H), 7.86 (d, J =15.5Hz, 1H), 7.64 (d, J = 8.5Hz, 1H), 7.30 (s, 2H), 7.25 (d, J = 7.5Hz, 2H), 7.12 (d, J = 7.5Hz, 1H), 6.93 (m, 2H), 6.21 (s, 1H), 5.06 (d, J=7.7Hz, 1H), 4.16-3.94 (m, 4H), 3.14-3.08 (m, 9H), 3.00-2.83 (m, 7H), 2.61 (d, J=10.8Hz, 1H), 2.42-2.21 (m, 5H) , 2.05-1.97(m, 2H), 1.84-1.86(m, 1H), 1.75-1.78(m, 1H), 1.66-1.48(m, 4H), 1.42-1.31(m, 2H), 1.30-1.12(m, 4H); [M+H] + =973.

[0456] Example 18: 3-(5-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0457] Step 1: 3-(5-(4-(2-hydroxyethyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-di ketone

[0458]

[0459] Cs₂CO₃ (4.54 g, 13.926 mmol) and Pd-PEPPSI-IPentCl₂-methylpyridine (o-methylpyridine) (CAS: 1612891-29-8, 148.9 mg, 0.18 mmol) were added to a stirred solution / mixture of 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (1.5 g, 4.642 mmol) and 4-piperidineethanol (0.63 g, 4.874 mmol) in dioxane (20 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The mixture was acidified to pH 6 with citric acid (2 mL). The resulting mixture was concentrated under vacuum to give a crude residue, which was purified by preparative TLC (CH₂Cl₂ / MeOH = 10:1) to give the product (650 mg, 38%). [M+H] +＝ 372.2.

[0460] Step 2: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1-hydroisoindoline-5-yl)piperidin-4- ethyl acetate

[0461]

[0462] The title compound (210 mg, 34%) was prepared from 3-(5-(4-(2-hydroxyethyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione and sulfoxide in a manner similar to that described in step 5 of Example 1. [M+H] + =450.2.

[0463] Step 3: 3-(5-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-1-oxo (Isoindoline-2-yl)piperidine-2,6-dione

[0464]

[0465] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.94 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.30 (d, J = 8.2Hz, 1H), 7.86 (d, J = 17.1Hz, 1H), 7.49 (d, J = 8 .2Hz, 1H), 7.31 (d, J=8.9Hz, 1H), 7.24 (d, J=8.0Hz, 1H), 7.12 (d, J=7.4Hz, 1H), 7.05 (s, 2H), 6.96 (s, 1H), 6.92 (d, J=8.9Hz, 1H), 6.21 (s , 1H), 5.04 (d, J = 8.1Hz, 1H), 4.25 (m, 2H), 4.11 (s, 2H), 3.86 (d, J = 11.3Hz, 2H), 3.15-3.05 (m, 6H), 2.89 (m, 6H), 2.70-2.57 (m, 4H), 2.4 [M+H] + =959.2.

[0466] Example 19: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)propyl)azacyclobutane-1-yl)isoindoline-1,3-dione

[0467] Step 1: 3-(azacyclobutane-3-yl)prop-1-ol

[0468]

[0469] Add tert-butyl 3-(3-hydroxypropyl)azacyclobutane-1-carboxylate (950 mg, 4.413 mmol), DCM (4.0 mL), and TFA (2.0 mL, 2.693 mmol) to a 25 mL flask. Stir the resulting solution at room temperature for 1 hour. Concentrate the mixture under vacuum to give 1.4 g of crude product. [M+H] + =116.2.

[0470] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-hydroxypropyl)azacyclobutane-1-yl)isoindole 1,3-Lin-1,3-dione

[0471]

[0472] Add 3-(azacyclobutan-3-yl)prop-1-ol (1.40 g, crude), DMSO (10 mL), 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindole-1,3-dione (1.21 g, 4.38 mmol), and DIEA (2.83 g, 21.9 mmol) to a 50 mL flask. Stir the resulting solution at 80 °C for 1 hour. Cool the reaction mixture to room temperature. Dilute the resulting solution with EA. Extract the resulting solution with H₂O, and the organic layer is dried over anhydrous sodium sulfate and concentrated under vacuum. Plugging the residue onto a silica gel column (dichloromethane / methanol (8:1)) gives the product (550 mg, 33.6%, two-step). [M+H] + =372.3.

[0473] Step 3: 4-Methylbenzenesulfonic acid 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- (3-yl)-(azirocyclobutane-3-yl)propyl ester

[0474]

[0475] Add 2-(2,6-dioxadiazin-3-yl)-5-(3-(3-hydroxypropyl)azacyclobutan-1-yl)isoindoline-1,3-dione (480 mg, 1.29 mmol), DCM (10 mL), TEA (262 mg, 2.59 mmol), and TsCl (493 mg, 2.59 mmol) to a 25 mL flask. Stir the resulting solution overnight at room temperature. Concentrate the resulting mixture under vacuum. Plugging the residue onto a silica gel column (dichloromethane / methanol (7:1)) to give the product (400 mg, 58.89%). [M+H] + =526.2.

[0476] Step 4: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl) (indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl) (propyl)azacyclobutane-1-yl)isoindoline-1,3-dione

[0477]

[0478] The title compound was prepared in a manner similar to that in Example 1. 1 H NMR (400MHz, DMSO) δ11.32 (s, 1H), 11.07 (s, 1H), 9.02 (s, 1H), 8.92 (s, 1H), 8.29 (s, 1H), 7.84 (s, 1H), 7.63 (d, J=8 .3Hz, 1H), 7.30 (s, 1H), 7.24 (s, 1H), 7.13 (s, 1H), 6.96 (s, 1H), 6.90 (s, 1H), 6.76 (s, 1H), 6.62 (d, J=8.6Hz, 1H), 6 .21 (s, 1H), 5.04 (s, 1H), 4.12 (d, J = 8.3Hz, 4H), 3.65 (s, 2H), 3.28-3.24 (m, 3H), 3.13 (s, 2H), 3.09 (s, 3H), 2.76 (s [M+H] + =959.8.

[0479] Example 20: 3-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethoxy)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0480] Step 1: Methyl 2-formyl-3-hydroxybenzoate

[0481]

[0482] A solution of methyl 3-hydroxybenzoate (40.00 g, 262.90 mmol) in TFA (1.00 L) was stirred at room temperature. Hexamethylenetetramine (44.17 g, 315.48 mmol) was added fractionally to the mixture at room temperature. The resulting mixture was stirred at 80 °C for 4 h. The mixture was extracted with EtOAc. The combined organic layers were washed with ice water and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give methyl 2-formyl-3-hydroxybenzoate (20 g, 42%). m / z [M+H] + =181.1.

[0483] Step 2: Methyl 3-(2-(benzyloxy)ethoxy)-2-formylbenzoate

[0484]

[0485] A mixture of methyl 2-formyl-3-hydroxybenzoate (20.00 g, 111.01 mmol) and [(2-bromoethoxy)methyl]benzene (71.63 g, 333.03 mmol), K₂CO₃ (30.69 g, 222.02 mmol), and KI (9.21 g, 55.50 mmol) in DMF (300 mL) was stirred overnight at 70 °C. 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 (10 g, 29%). [M+H] + =315.1.

[0486] Step 3: 3-(4-(2-(benzyloxy)ethoxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione

[0487]

[0488] A mixture of 3-aminopiperidine-2,6-dione hydrochloride (6.26 g, 38.17 mmol) and DIEA (8.22 g, 63.62 mmol) in DCE (100 mL) and DMF (5 mL) was stirred at room temperature for 2 h. The mixture was acidified to pH 6 with AcOH. Methyl 3-(2-(benzyloxy)ethoxy)-2-carboxybenzoate (10.00 g, 31.81 mmol) was added to the resulting solution. The mixture was then stirred overnight at room temperature. NaBH3CN (6.00 g, 95.43 mmol) was then added fractionally to the mixture at room temperature. The resulting mixture was stirred at room temperature for another 5 h. The reaction mixture was quenched by adding water. The resulting mixture was extracted with CH2Cl2. 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 CH2Cl2 / MeOH (5:1) to give the crude product. The residue was then purified by reversed-phase rapid chromatography (0 to 50% MeCN in H2O) to give the product (4.1 g, 33%), [M+1] = 395.3.

[0489] Step 4: 3-(4-(2-hydroxyethoxy)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

[0490]

[0491] A mixture of 3-(4-(2-(benzyloxy)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (4.10 g, 10.39 mmol), Pd / C (2.00 g, 10% wt), AcOH (4 mL), THF (30 mL), and DCM (30 mL) was stirred overnight at 40 °C under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH and DCM. The filtrate was concentrated under reduced pressure to give the product (2.13 g, 67%). [M+1] + =305.3.

[0492] Step 5: 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oxy)ethyl mesylate

[0493]

[0494] The title compound (310 mg, 34%) was prepared from 3-(4-(2-hydroxyethoxy)-1-oxoisoindoline-2-yl)piperidine-2,6-dione and sulfoxide in a manner similar to that in step 5 of Example 1.

[0495] Step 6: 3-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H- Pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethhydro)-1-oxoisoindoline- 2-yl)piperidin-2,6-dione

[0496]

[0497] The title compound was prepared in a manner similar to that in Example 1. 1 H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.98 (s, 1H), 9.02 (s, 1H), 8.92 (s, 1H), 8.29 (d, J=8.2Hz, 1H), 7.86 (d, J =15.5Hz, 1H), 7.47 (d, J = 7.6Hz, 1H), 7.36-7.18 (m, 4H), 7.12 (d, J = 6.7Hz, 1H), 6.99-6.82 (m, 2H), 6.21 (s, 1 H), 5.10-5.12(m, 1H), 4.37-4.39(m, 1H), 4.25(s, 3H), 4.10(s, 2H), 3.92(s, 1H), 3.46-3.50(m, 3H), 3.26-2 .60 (m, 17H), 2.46-2.40 (m, 1H), 2.36-2.24 (m, 1H), 2.04-1.93 (m, 1H), 1.80-1.83 (m, 2H), 1.66-1.49 (m, 2H). [M+H] + =892.1.

[0498] Example 21: 3-(4-(2-(4-(1-(3-methoxy-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0499]

[0500] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ11.25 (s, 1H), 10.82 (s, 1H), 8.99 (s, 1H), 8.24-8.17 (m, 1H), 7.97 (d, J=8.5Hz, 1H), 7.25-7.15(m, 4H), 7.12(d, J=8.2Hz, 3H), 6.92(s, 1H), 6.63(s, 1H), 6.44(s, 1H), 6.19(s, 1H), 4.09 (s, 2H), 3.82 (s, 4H), 3.65 (s, 2H), 3.11 (d, J=14.1Hz, 5H), 3.04-2.87 (m, 2H), 2.76-2.52 (m, 11 [M+H] + =833.7.

[0501] Example 27: 3-(4-(4-(2-(4-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0502]

[0503] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (400MHz, DMSO) δ11.33 (s, 1H), 10.77 (s, 1H), 9.03 (s, 1H), 8.93 (s, 1H), 8.29 (s, 1H), 7.8 7(d, J=15.5Hz, 1H), 7.32(s, 1H), 7.25(s, 1H), 7.13(s, 1H), 7.02(s, 2H), 6.92-6.94(d, 4H), 6 .21(s, 1H), 4.11(s, 2H), 3.75-3.56(m, 4H), 3.17-3.05(m, 6H), 2.93(s, 4H), 2.61(s, 4H), 2. 39 (s, 3H), 2.11 (s, 1H), 2.01 (s, 1H), 1.76 (d, J = 10.2Hz, 2H), 1.43 (s, 3H), 1.24 (s, 3H); [M+H] + =821.

[0504] Example 34: 3-(4-(2-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0505]

[0506] The title compound was prepared in a manner similar to that described in Example 3. ¹H NMR (400 MHz, DMSO) δ 10.83 (s, 1H), 8.93 (s, 1H), 8.08 (s, 1H), 7.89 (s, 2H), 7.44 (s, 1H), 7.17 (d, J = 16.8 Hz, 6H), 6.42 (s, 1H), 4.09–4.00 (m, 2H), 3.88–3 .65(m, 6H), 3.14-2.98(m, 6H), 2.84-2.55(m, 11H), 2.45-2.28(m, 4H), 2.18- 2.20(m, 2H), 2.08-1.98(m, 2H), 1.96-1.84(m, 2H), 1.63-1.45(m, 2H); [M+H] + =828.

[0507] Example 35: 3-(4-(4-(2-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0508]

[0509] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ10.78 (s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.89 (s, 2H), 7. 43(s, 1H), 7.15(s, 2H), 7.01(s, 2H), 6.89(s, 2H), 6.60(s, 1H), 6.41(s, 1H), 4 .05(s, 2H), 3.60-3.80(m, 8H), 2.80-3.10(m, 7H), 2.70-2.60(m, 6H), 1.70-2 .35(m, 12H), 1.83(m, 2H), 1.73(m, 2H), 1.34-1.60(m, 4H), 1.25(m, 2H); [M+H] + =911.2.

[0510] Example 36: 3-(4-(4-(2-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)piperidin-2,6-dione

[0511]

[0512] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ10.78 (s, 1H), 8.91 (s, 1H), 8.08 (s, 1H), 7.86 (s, 2H), 7.45 (d, J=8.7Hz, 1H), 7.14 (s, 2H), 7.04 (d, J =8.8Hz, 1H), 6.69 (d, J = 12.5Hz, 2H), 6.59 (s, 1H), 6.40 (d, J = 6.8Hz, 1H), 4.05 (s, 2H), 3.87 (d, J = 7.6Hz, 1H), 3.76 (s, 3H ), 3.68 (d, J=11.6Hz, 4H), 3.10 (s, 3H), 3.04 (s, 4H), 2.75-2.59 (m, 6H), 2.48-2.25 (m, 8H), 2.19-2.07 (m, 1H), 2.02-1.8 [M+H] + =929.3.

[0513] Example 37: 5-(4-(2-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0514]

[0515] The title compound was prepared in a manner similar to that in Example 1. 1 H NMR (400MHz, DMSO) δ11.06 (s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.86 (s, 2H), 7.64 (d, J = 8.4Hz, 1H), 7.45 (d, J = 8.5Hz, 1 H), 7.30 (s, 1H), 7.23 (d, J = 8.1Hz, 1H), 7.14 (s, 2H), 6.59 (s, 1H), 6.40 (d, J = 8.4Hz, 1H), 5.06 (d, J = 12.7Hz, 1H), 4.05 (s, 4H), 3.76 (s, 3H), 3.68 (d, J = 11.4Hz, 2H), 3.16-2.82 (m, 12H), 2.70-2.54 (m, 5H), 2.43-2.25 (m, 6H), 2.08-1.95 (m , 1H), 1.85 (d, J = 12.1Hz, 2H), 1.75 (d, J = 12.6Hz, 2H), 1.62-1.46 (m, 3H), 1.41-1.32 (m, 2H), 1.26-1.12 (m, 2H); [M+H] + =980.2.

[0516] Example 38: 3-(4-(2-(4-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)piperidin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0517]

[0518] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (400MHz, DMSO) δ10.82 (s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.88 (s, 2H), 7.46 (d, J=8.6Hz, 1H), 7.15 (dt, J=14.2, 8.0Hz, 6H), 6.60 (s, 1H), 6.39 (d, J=8.6Hz, 1H), 4.05 (s, 2H), 3.81 (dd, J=11.5, 4.7Hz, 1H) , 3.76 (s, 3H), 3.10 (s, 6H), 3.02 (d, J = 13.7Hz, 6H), 2.71 (d, J = 8.1Hz, 2H), 2.64 (s, 5H), 2.54 (s, 1H), 2 .46 (s, 1H), 2.19 (m, 2H), 1.99 (t, J = 11.0Hz, 3H), 1.80 (d, J = 10.7Hz, 2H), 1.46 (d, J = 10.5Hz, 2H); [M+H] + =828.7.

[0519] Example 39: 3-(4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0520]

[0521] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ10.83 (s, 1H), 8.80 (s, 1H), 8.18 (s, 1H), 7.88 (s, 2H), 7.44 (s, 1H), 7.16 (m, 6H), 6.68 (s, 1H), 4.05 (s, [M+H] + =886.2.

[0522] Example 40: 3-(4-(4-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0523]

[0524] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ10.76 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.86 (s, 2H), 7 .44(s, 1H), 7.15(s, 2H), 7.03(d, J=8.5Hz, 2H), 6.88(d, J=8.5Hz, 2H), 6.68( s, 1H), 4.05 (s, 2H), 3.70 (m, 6H), 3.07 (m, 7H), 2.61 (m, 9H), 2.38 (s, 6H), 2.1 1 (m, 7H), 1.76 (s, 4H), 1.57 (d, J = 10.4Hz, 3H), 1.19 (d, J = 11.3Hz, 2H); [M+H] + =955.2.

[0525] Example 41: 3-(4-(4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0526]

[0527] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ10.77(s, 1H), 8.78(s, 1H), 8.16(s, 1H), 7.87(s, 1H), 7.78(s, 1H), 7.40(s, 1H), 7.13(s, 2H), 7.01 (d, J=8.8Hz, 2H), 6.86 (d, J=8.8Hz, 2H), 6.65 (s, 1H), 4.02 (d, J=7.7Hz, 2H), 3.73 (s, 3H), 3.71-3.6 6 (m, 1H), 3.62 (d, J=11.0Hz, 2H), 3.05-3.11 (m, 9H), 2.58 (m, 4H), 2.31 (m, 5H), 2.09 (m, 2H), 2.05 (s, 3H), 1.9 9(m,2H),1.82-1.85(m,3H),1.72-175(m,3H),1.55-1.60(m,3H),1.38-1.42(m,3H),1.18-1.21(m,3H);[M+H] + =969.3.

[0528] Example 42: 5-(4-(3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)-3-oxopropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0529]

[0530] The title compound was prepared in a manner similar to that in Example 11. 1 H NMR (400MHz, DMSO) δ11.08 (s, 1H), 8.80 (s, 1H), 8.17 (d, J=4.1Hz, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.68 (d, J=8.3Hz, 1H), 7.43 (s, 1H), 7.35 (s, 1H), 7.27 (d, J=8.9Hz, 1H), 7.15 (s, 2H), 6.68 (s, 1H), 5.07 (d, J =7.8Hz, 1H), 4.05 (s, 2H), 3.76 (s, 3H), 3.44 (s, 10H), 3.14-3.02 (m, 8H), 2.86 (d, J = 12.1Hz, 1H), 2.60 ( s, 4H), 2.54 (s, 9H), 2.37 (s, 1H), 2.07 (s, 3H), 2.02 (s, 1H), 1.83 (s, 2H), 1.58 (d, J=11.0Hz, 2H); [M+H] + =1067.3.

[0531] Example 43: 5-(4-((4-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0532] Step 1: 1-(Methylsulfonyl)-7-nitroindoline

[0533]

[0534] Methanesulfonyl chloride (315 mg, 2.7 mmol) was added dropwise to a stirred solution of 7-nitroindoline (300 mg, 1.8 mmol) and NaHH (146 mg, 3.6 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, and concentrated under vacuum to give a crude residue, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (390 mg, 88%). [M+H] + =243.1.

[0535] Step 2: 1-(Methylsulfonyl)indoline-7-amine

[0536]

[0537] Under N2 atmosphere at room temperature, 10% Pd / C (50 mg) was added to a solution of 1-(methanesulfonyl)-7-nitroindoline (390 mg, 1.6 mmol) in MeOH (20 mL). The mixture was then exchanged with H2 twice and stirred at room temperature for 2 h under H2 atmosphere. The reaction was monitored by LC-MS. The mixture was filtered through a diatomaceous earth pad and washed with MeOH (20 mL). The filtrate was concentrated under vacuum to give the title product (340 mg, 99%). [M+H] + =213.1.

[0538] Step 3: N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methanesulfonyl)indoline-7-amine

[0539]

[0540] A mixture of 1-(methanesulfonyl)indoline-7-amine (340 mg, 1.6 mmol), 5-bromo-2,4-dichloropyrimidine (729 mg, 3.2 mmol), and DIEA (412 mg, 3.2 mmol) in i-PrOH (20 mL) was stirred at 100 °C for 16 h in a round-bottom flask. The mixture was evaporated under vacuum to give a crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (550 mg, 85%). [M+H] + =402.8, 404.7.

[0541] Step 4: 5-Bromo-N 2 -(2-methoxy-5-methyl-4-(4-piperidin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1- (Methylsulfonyl)indololin-7-yl)pyrimidin-2,4-diamine

[0542]

[0543] A mixture of N-(5-bromo-2-chloropyrimidin-4-yl)-1-(methanesulfonyl)indoline-7-amine (500 mg, 1.24 mmol), 4-(1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (637 mg, 1.57 mmol), and MsOH (476 mg, 4.96 mmol) in t-BuOH (10 mL) was stirred at 100 °C for 16 hours in a round-bottom flask. The mixture was evaporated under vacuum to give a crude product, which was diluted with water and extracted with DCM (2 x 30 mL). The organic layer was washed with brine (2 x 50 mL), dried over Na2SO4, and concentrated under vacuum to give the crude title product (560 mg, 67%); [M+H] + =671.3, 673.3.

[0544] Step 5: 5-(4-((4-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)oxy)pyrimidine (Piridine-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carbonyl)piperidin-1-yl)methyl)piperidin- 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0545]

[0546] Add 5-bromo-N to a solution of 1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)piperidin-4-yl)methyl)piperidin-4-carboxylic acid (37.6 mg, 0.078 mmol), HATU (30.9 mg, 0.081 mmol), and DIEA (38 mg, 0.296 mmol) in DMF (5 mL). 2 -(2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(1-(methanesulfonyl)indololin-7-yl)pyrimidine-2,4-diamine (50 mg, 0.074 mmol). The resulting mixture was stirred at room temperature for 4 h. The reactants were quenched with water and the mixture was extracted with DCM, washed with saturated brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title product (23.4 mg, 27%). 1H NMR (400MHz, DMSO) δ11.08 (s, 1H), 8.80 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.65 (d, J=8.4Hz, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.23 (d, J=8.6Hz, 1H), 7.15 (s, 2H), 6.68 (s, 1H), 5.06 (d, J=7.2Hz, 1H), 4.05 (s, 4H) ,3.76(s,3H),3.47(s,4H),3.07(m,,8H),3.01-2.90(m,3H),2.84(s,3H),2.61(s,3H),2.53(s,3H),2.47-2.4 [M+H] + =1135.4.

[0547] Example 44: 5-(3-(3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)propyl)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0548]

[0549] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.80 (s, 1H), 7.64 (d, J=8.3Hz, 1H), 7.43 (s , 1H), 7.15 (s, 2H), 6.76 (s, 1H), 6.67 (s, 1H), 6.63 (d, J=8.6Hz, 1H), 5.05 (d, J=8.0Hz, 1H), 4.12 (d, J=8.3Hz, 2H), 4.0 5 (s, 2H), 3.76 (s, 3H), 3.65 (s, 3H), 3.10 (s, 3H), 3.05 (s, 5H), 2.86 (d, J=11.4Hz, 2H), 2.77 (s, 1H), 2.57 (m, 8H), 2.40 [M+H] + =1024.3.

[0550] Example 45: 3-(4-(2-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0551]

[0552] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ10.81 (s, 1H), 9.40 (s, 1H), 9.02 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.55 (d, J=15 .2Hz, 1H), 7.32-7.22 (m, 2H), 7.18 (d, J=8.0Hz, 3H), 7.12 (d, J=8.0Hz, 2H), 6.87 (t, J=9.4Hz, 1H), 4.0 7(s, 2H), 3.81(d, J=6.8Hz, 1H), 3.29-3.23(m, 3H), 3.10(m, 6H), 2.71(s, 2H), 2.60(m, 7H), 2.48-2.39 (m, 4H), 2.27 (s, 2H), 2.17 (d, J = 10.6Hz, 1H), 2.03 (s, 1H), 1.82 (s, 2H), 1.55 (d, J = 11.7Hz, 2H); [M+H] + =816.6.

[0553] Example 46: 3-(4-(4-(2-((1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)(methyl)amino)ethyl)piperidin-1-yl)-2-fluorophenyl)piperidin-2,6-dione

[0554]

[0555] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO)δ H 10.80 (s, 1H), 8.89 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H), 7.91 (d, J = 7.5Hz, 1H), 7.11 (d, J = 6.2Hz, 2H), 7.06 (t, J = 8.6 Hz, 2H), 6.70 (d, J=10.8Hz, 2H), 6.36 (d, J=8.5Hz, 1H), 4.45 (t, J=8.4Hz, 2H), 4.04 (t, J=6.6Hz, 2H), 3.87 (dd, J=12.1, 4.2Hz, 1 H), 3.70 (d, J = 12.6Hz, 3H), 3.17-3.06 (m, 6H), 3.03 (s, 3H), 2.72-2.57 (m, 4H), 2.54 (s, 3H), 2.24 (s, 3H), 2.14 (d, J = 12.5Hz, 1H ), 1.99-1.89 (m, 1H), 1.78 (dd, J=24.1, 12.5Hz, 4H), 1.64-1.45 (m, 3H), 1.43-1.34 (m, 2H), 1.22 (dd, J=20.3, 10.9Hz, 2H); [M+H] + =886.4.

[0556] Example 47: 5-(4-(2-((1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)(methyl)amino)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0557]

[0558] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO)δH 11.08 (s, 1H), 8.93-8.84 (m, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 7.92 (d, J=7.9Hz, 1H), 7.65 (d, J=8.4Hz, 1H), 7.31 (s, 1H), 7.2 4 (d, J=8.2Hz, 1H), 7.11 (d, J=7.5Hz, 2H), 7.06 (t, J=8.2Hz, 1H), 6.36 (d, J=8.4Hz, 1H), 5.06 (dd, J=13.5, 4.8Hz, 1H), 4.46 ( t, J=8.1Hz, 2H), 4.11-3.99 (m, 4H), 3.17-3.07 (m, 5H), 3.04 (s, 3H), 2.99-2.92 (m, 3H), 2.92-2.80 (m, 2H), 2.64-2.54 (m, 6 [M+H] + =937.4.

[0559] Example 48: 3-(4-(2-((1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)(methyl)amino)ethyl)-2-fluorophenyl)piperidin-2,6-dione

[0560]

[0561] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO)δ H10.86(s, 1H), 8.93-8.85(m, 1H), 8.27(s, 1H), 8.07(s, 1H), 7.96-7.87(m, 1H), 7.21(m, 1H), 7.08 (m, 5H), 6.35 (d, J=8.6Hz, 1H), 4.45 (t, J=8.6Hz, 2H), 4.08-3.96 (m, 4H), 3.30 ( s, 2H), 3.17-3.06 (m, 4H), 3.03 (s, 3H), 2.73 (s, 5H), 2.60 (m, 3H), 2.31 (s, 3H), 2.17 (t, J=11.8Hz, 1H), 1.98 (dd, J=14.0, 6.0Hz, 1H), 1.80 (d, J=12.7Hz, 2H), 1.57 (m, 2H); [M+H] +＝ 803.3.

[0562] Example 49: 3-(4-(4-(2-((1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)(methyl)amino)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0563]

[0564] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO)δ H10.76 (s, 1H), 8.94-8.84 (m, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.92 (d, J=8.5Hz, 1H), 7.15-6.99 (m, 5H), 6.88 (d, J=8.7Hz, 2H), 6. 36 (d, J=8.9Hz, 1H), 4.45 (t, J=8.7Hz, 2H), 4.04 (t, J=7.2Hz, 2H), 3.71 (dd, J=10.5, 4.6Hz, 1H), 3.65 (d, J=11.7Hz, 2H), 3.30-3. 27 (m, 4H), 3.12 (dt, J=14.7, 5.1Hz, 4H), 3.03 (s, 3H), 2.61 (t, J=11.1Hz, 5H), 2.49-2.40 (m, 2H), 2.22 (s, 3H), 2.12 (d, J=11.0Hz , 1H), 2.01 (dd, J=13.2, 9.1Hz, 1H), 1.76 (d, J=13.7Hz, 4H), 1.58 (dd, J=21.1, 9.5Hz, 2H), 1.49-1.36 (m, 3H), 1.25 (m, 2H); [M+H] + =868.4.

[0565] Example 50: 5-(3-(3-((1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)(methyl)amino)propyl)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0566]

[0567] The title compound was prepared in a manner similar to that in Example 1. 1 H NMR (400MHz, DMSO)δ H11.07 (s, 1H), 8.89 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 7.91 (d, J = 9.0Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.15-7. 03 (m, 3H), 6.77 (s, 1H), 6.63 (d, J = 7.7Hz, 1H), 6.36 (d, J = 8.7Hz, 1H), 5.05 (dd, J = 12.9, 5.7Hz, 1H), 4.45 (t, J = 9.0Hz, 2H) , 4.15 (d, J=7.8Hz, 2H), 4.04 (t, J=6.5Hz, 2H), 3.69-3.62 (m, 4H), 3.50 (s, 8H), 3.19-3.06 (m, 3H), 3.03 (s, 3H), 2.93-2.7 [M+H] + =923.4.

[0568] Example 51: 3-(4-(4-(2-(4-(1-(7-((5-chloro-4-((1-((methylsulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)piperidin-2,6-dione

[0569]

[0570] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (400MHz, DMSO) δ10.80 (s, 1H), 8.89 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.08 (m, 4H), 6. 70 (d, J=11.3Hz, 2H), 6.35 (d, J=8.3Hz, 1H), 4.45 (s, 2H), 4.04 (s, 2H), 3.85 (s, 1H), 3.69 (d, J=10.2Hz, 2 H), 3.09 (s, 5H), 3.03 (s, 4H), 2.73-2.58 (m, 6H), 2.52 (s, 4H), 2.39 (s, 3H), 2.32 (s, 4H), 2.13 (d, J=12.9 [M+H] + =941.7.

[0571] Example 52: 5-(4-(2-(4-(1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0572]

[0573] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ11.08 (s, 1H), 8.89 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.65 (d, J=8.5Hz, 1H), 7.3 0 (s, 1H), 7.23 (d, J = 8.3Hz, 1H), 7.09 (t, J = 13.2Hz, 3H), 6.35 (d, J = 8.5Hz, 1H), 5.06 (d, J = 7.6Hz, 1H), 4.45 (s, 2H), 4.03 (d, J=7.9Hz, 4H), 3.10 (d, J=11.8Hz, 5H), 3.04 (s, 4H), 2.92 (m, 5H), 2.60 (s, 6H), 2.39 (s, 2H), 2.31 (s, 5H), 2. [M+H] + =992.8.

[0574] Example 53: 3-(4-(2-(4-(1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazin-1-yl)ethyl)-2-fluorophenyl)piperidin-2,6-dione

[0575]

[0576] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ10.86 (s, 1H), 8.89 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7. 20 (t, J=7.6Hz, 1H), 7.15-7.01 (m, 5H), 6.36 (d, J=8.4Hz, 1H), 4.45 (s, 2H), 4.09-3.98 (m, 3H), 3.09(m, 8H), 2.74(s, 3H), 2.62(d, J=11.4Hz, 10H), 2.49-2.42(m, 4H), 2.33(s, 1H), 2 .18(d, J=10.8Hz, 1H), 1.99(s, 1H), 1.87(d, J=10.6Hz, 2H), 1.54(d, J=10.5Hz, 2H); [M+H] + =858.7.

[0577] Example 54: 3-(4-(4-(2-(4-(1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0578]

[0579] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ11.07 (s, 1H), 8.89 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.94-7.87 (m, 1H), 7.64 (d, J=8.2Hz , 1H), 7.10(s, 2H), 7.08-7.02(m, 1H), 6.76(s, 1H), 6.63(s, 1H), 6.34(s, 1H), 5.04(s, 1H), 4.45(s, 2H), 4.13( s, 2H), 4.04 (s, 2H), 3.66 (s, 3H), 3.46-3.41 (m, 2H), 3.06 (m, 8H), 2.91-2.73 (m, 3H), 2.57 (m, 9H), 2.40-2.24 ( m, 4H), 2.04-1.96 (m, 1H), 1.86 (s, 2H), 1.62 (s, 2H), 1.57-1.49 (m, 2H), 1.47-1.39 (m, 2H), 1.24 (s, 2H); [M+H] + =923.8.

[0580] Example 55: 5-(3-(3-(4-(1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazin-1-yl)propyl)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0581] Step 1: 4-(1-(7-nitro-2,3-dioxobenzofuran-4-yl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0582]

[0583] A mixture of 4-bromo-7-nitro-2,3-dihydrobenzofuran (1.0 g, 4.098 mmol), tert-butyl 4-(piperidin-4-yl)piperazin-1-carboxylate (1.32 g, 4.917 mmol), Pd2(dba)3 (375 mg, 0.409 mmol), BINAP (254 mg, 0.409 mmol), and K3PO4 (2.6 g, 12.29 mmol) in toluene (30 mL) was stirred overnight at 100 °C under N2 in a round-bottom flask. The mixture was evaporated under vacuum to give a crude product, which was further purified by silica gel column chromatography (DCM:MeOH = 100:0–50:1 gradient elution) to give the product (350 mg, 19%). [M+H] + =433.5.

[0584] Step 2: 4-(1-(7-oxy-2,3-dioxobenzofuran-4-yl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[0585]

[0586] 10% Pd / C (100 mg) was added to a solution of tert-butyl 4-(1-(7-nitro-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazine-1-carboxylate (350 mg, 0.809 mmol) in MeOH (5 mL) and DCM (5 mL) at 25 °C. The mixture was then exchanged with H2 three times and stirred at 25 °C for 12 h under H2 atmosphere. The reaction was monitored by LCMS. The mixture was filtered through a diatomaceous earth pad and washed with MeOH (20 mL). The filtrate was concentrated under vacuum to give the product (280 mg, 86%). [M+H] + =403.4.

[0587] Step 3: 4-(1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino tert-butyl 2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazine-1-carboxylate

[0588]

[0589] A mixture of N-(2,5-dichloropyrimidin-4-yl)-1-(methanesulfonyl)indoline-7-amine (210 mg, 0.588 mmol) (the intermediate was prepared from 2,4,5-trichloropyrimidin according to the same procedure as step 3 in Example 43), tert-butyl piperazine-1-carboxylate (260 mg, 0.647 mmol), Pd2(dba)3 (54 mg, 0.059 mmol), BINAP (37 mg, 0.059 mmol), and K3PO4 (373 mg, 1.764 mmol) in toluene (15 mL) was stirred overnight at 100 °C under N2 in a round-bottom flask. The mixture was evaporated under vacuum to obtain a crude product, which was further purified by silica gel column chromatography (DCM:MeOH = 100:0–50:1 gradient elution) to give the product (240 mg, 56%). [M+H] + =725.6.

[0590] Step 4: 5-Chloro-N 4 -(1-(methylsulfonyl)indololin-7-yl)-N 2 -(4-(4-(piperazin-1-yl)piperidine-1- 2,3-dihydrobenzofuran-7-yl)pyrimidin-2,4-diamine hydrochloride

[0591]

[0592] A solution of tert-butyl 4-(1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazin-1-carboxylate (230 mg, 0.317 mmol) in HCl / 1,4-dioxane (4 mL) was stirred in a round-bottom flask at room temperature for 2 h. The mixture was evaporated under vacuum to give a crude product (180 mg, 86%), which was used in the next step without further purification. [M+H] + =625.5.

[0593] Step 5: 5-(3-(3-(4-(1-(7-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidine (Pyridine-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)piperazin-1-yl)propyl)azacyclobutane-1- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0594]

[0595] The title compound was synthesized using a procedure similar to that of Example 1. 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 8.89 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H) ), 7.10(s, 3H), 6.76(s, 1H), 6.61(s, 1H), 6.37(s, 1H), 5.04(s, 1H), 4.45(s, 2H), 4.13(s, 2H), 4.0 4(s, 2H), 3.66(s, 3H), 3.42(s, 2H), 3.06(m, 7H), 2.92-2.72(m, 3H), 2.57(m, 7H), 2.29(s, 4H), 2.0 5-1.96(m,1H),1.86(s,2H),1.63(s,2H),1.57-1.48(m,2H),1.48-1.40(m,2H),1.24(s,2H);[M+H] + =978.4.

[0596] Example 56: 3-(4-(4-(2-(4-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0597]

[0598] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ10.77 (s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.89 (s, 2H), 7.47 (s, 1H), 7. 15(s, 2H), 7.03(d, J=8.3Hz, 2H), 6.88(d, J=8.7Hz, 2H), 6.61(s, 1H), 6.41(s, 1H), 4.05(s, 2H), 3.77(s, 3H), 3.64(s, 4H), 3.12(s, 6H), 3.04(s, 3H), 2.62(s, 4H), 2.53(s, 3H), 2.41( s,2H),2.17-2.07(m,1H),2.05-1.96(m,1H),1.76(s,2H),1.46(s,3H),1.29(s,2H);[M+H] + =828.3.

[0599] Example 58: 3-(4-(3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazine-1-carbonyl)azacyclobutane-1-yl)phenyl)piperidin-2,6-dione

[0600] Step 1: Methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azacyclobutane-3-carboxylate

[0601]

[0602] Pd₂(dba)₃ (824 mg, 0.9 mmol) and Xantphos (780 mg, 1.35 mmol) were added to a solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (4 g, 9 mmol), methyl aziridine-3-carboxylate hydrochloride (1.5 g, 9.9 mmol), and Cs₂CO₃ (7.3 g, 22.5 mmol) in 50 mL of dioxane. The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. After the reaction was complete as indicated by LCMS, the mixture was evaporated and purified by silica gel column chromatography (PE:EA = 10:1 to 1:1) to give the product (2.3 g, 53.2% yield). [M+H] +＝ 481.4.

[0603] Step 2: 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azacyclobutane-3-carboxylic acid

[0604]

[0605] A solution of methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azacyclobutane-3-carboxylate (1.3 g, 2.7 mmol) in 10 mL THF and 10 mL MeOH was added to 5 mL of water containing LiOH·H₂O (340 mg, 8.1 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under vacuum to obtain a residue, which was diluted with water (50 mL) and the pH was adjusted to 3 with 1 N HCl aqueous solution. The mixture was extracted and separated using EtOAc (50 mL × 2). The organic phase was dried over Na₂SO₄ and filtered. The filtrate was concentrated to give the product (1.26 g, 100% yield). [M+H] + =467.4.

[0606] Step 3: 1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azacyclobutane-3-carboxylic acid

[0607]

[0608] 130 mg Pd / C was added to a solution of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)azacyclobutane-3-carboxylic acid (1.3 g, 2.79 mmol) in 50 mL MeOH. The mixture was stirred at room temperature under a H2 atmosphere for 16 hours. After the reaction was complete as shown by LCMS, the mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated to give the product (240 mg, 29.8% yield). [M+H] + =289.2.

[0609] Step 4: 3-(4-(3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H- Pyrrolo[2,3-d]pyrimidin-2-yl)oxy)phenyl)piperidin-4-yl)piperazine-1-carbonyl)azacyclobutane-1-yl)phenyl) Piperidine-2,6-dione

[0610]

[0611] The title compound was prepared in a manner similar to that in Example 11. 1 H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.76 (s, 1H), 9.03 (s, 1H), 8.93 (s, 1H), 8.30 (d, J = 8.1Hz, 1H), 7.87 (d, J = 17.7Hz, 1H), 7.32 (d, J = 7.7Hz, 1H), 7.24 (d, J=7.9Hz, 1H), 7.12 (d, J=7.2Hz, 1H), 7.01 (d, J=8.4Hz, 2H), 6.98-6.86 (m, 2H), 6.42 (d, J=8.6Hz, 2H), 6.21 (s, 1H) , 4.11(t, J=7.4Hz, 2H), 4.00(s, 2H), 3.90-3.78(m, 3H), 3.70-3.73(m, 1H), 3.52-3.44(m, 2H), 3.31-3.23(m, 3H), 3.18-3.11(m, 2H), [M+H] +＝ 876.6.

[0612] Example 59: 3-(5-(3-((4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0613]

[0614] The title compound was prepared in a manner similar to that in Example 1 (the key intermediate 4-methylbenzenesulfonic acid (1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)azacyclobutane-3-yl) methyl ester was prepared in accordance with the method described in WO2020038415A1). 1 H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.94 (s, 1H), 9.03 (s, 1H), 8.93 (s, 1H), 8.30 (d, J = 7.9Hz, 1H), 7.87 (d, J = 15.5Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.30 (t, J=8.6Hz, 1H), 7.25 (t, J=7.7Hz, 1H), 7.13 (d, J=7.2Hz, 1H), 6.98-6.87 (m, 2H), 6.53-6.44 (m, 2H), 6.21 (s, 1H), 5.03 (dd . [M+H] + =917.5.

[0615] Example 60: 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)isoindoline-1,3-dione

[0616] Step 1: 2-(2,6-dihydropiperidin-3-yl)-5-(3-(hydroxymethyl)hydroheterocyclic butane-1-yl)isoindole 1,3-Lin-1,3-dione

[0617]

[0618] Add azirmonobutane-3-ylmethanol hydrochloride (500 mg, 4.05 mmol), DMSO (8 mL), 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindole-1,3-dione (1.23 g, 4.45 mmol), and DIEA (2.61 g, 20.25 mmol) to a 100 mL flask. Stir the resulting solution at 80 °C for 3 hours. Cool the reaction mixture to room temperature. Quench the reaction mixture with water and extract with DCM (2 × 50 mL). Wash the combined organic layers with brine, dry to anhydrous Na₂SO₄, and evaporate under vacuum to give a crude product, which is further purified by silica gel column chromatography (DCM:MeOH = 100:0–90:10 gradient elution) to give the product (600 mg, 43%). [M+H] + =344.1.

[0619] Step 2: Mesylate (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl) aziridine Cyclobutane-3-yl)methyl ester

[0620]

[0621] TEA (353 mg, 3.498 mmol) was added to a solution of 2-(2,6-dioxadiazin-3-yl)-5-(3-(hydroxymethyl)azacyclobutan-1-yl)isoindoline-1,3-dione (300 mg, 0.875 mmol) in DCM (10 mL). The reaction mixture was cooled to 0 °C, and then MsCl (152 mg, 1.313 mmol) was added. The mixture was stirred at 25 °C for 3 hours. The reaction mixture was quenched with water and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and evaporated under vacuum to give a crude product, which was further purified by silica gel column chromatography (DCM:MeOH = 100:0–20:1 gradient elution) to give the product (180 mg, 49%). [M+H] + =422.3.

[0622] Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-(3-((4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl) (indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl) (Methyl)-azacyclobutane-1-yl)isoindoline-1,3-dione

[0623]

[0624] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ11.33 (s, 1H), 11.07 (s, 1H), 9.03 (s, 1H), 8.93 (s, 1H), 8.32-8.25 (m, 2H), 7.86 (d, J=14 .5Hz, 1H), 7.63 (d, J=8.1Hz, 1H), 7.35-7.21 (m, 2H), 7.13 (d, J=6.8Hz, 1H), 6.94m, 2H), 6.77 (s, 1H), 6.64 (d, J=6.7Hz, 1H), 6.21 (s, 1H), 5.04 (s, 1H), 4.12 (d, J=8.2Hz, 4H), 3.68 (s, 2H), 3.15-3.06 (m, 6H), 3.02-2.85 ( m, 5H), 2.64-2.54 (m, 6H), 2.46-2.23 (m, 6H), 2.05-1.96 (m, 1H), 1.88-1.79 (m, 2H), 1.62-1.50 (m, 2H); [M+H] + =931.7.

[0625] Example 61: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)-2-oxoethyl)azacyclobutane-1-yl)isoindoline-1,3-dione

[0626] Step 1: 2-(1-(2-(2,6-dihydropiperidin-3-yl)-1,3-dihydroisoindoline-5-yl)azacyclobutane Alkyl-3-yl)acetic acid

[0627]

[0628] To a solution of 2-(azacyclobutan-3-yl)acetate hydrochloride (1 g, 6.6 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.66 g, 6 mmol) and DIEA (3.1 g, 24 mmol) were added in 10 mL of DMSO. The mixture was stirred at 80 °C for 16 h. After the reaction was complete as indicated by LCMS, the mixture was decanted into water (50 mL) and extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (50 mL) and dried over Na₂SO₄. The mixture was filtered and the filtrate was evaporated to give the product (100 mg, 4.5% yield). [M+H] + =372.2.

[0629] Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl) (indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazine-1- (2-oxoethyl)azacyclobutane-1-yl)isoindoline-1,3-dione

[0630]

[0631] The title compound was prepared in a manner similar to that in Example 11. 1 H NMR (400MHz, DMSO) δ11.60 (s, 1H), 10.84 (s, 1H), 9.44 (s, 1H), 8.09-7.72 (m, 2H), 7.2 4(m, 6H), 7.02(s, 2H), 6.34(s, 1H), 4.10(s, 2H), 3.84(d, J=11.5Hz, 6H), 3.61(s, 2H), 3.30-3.21 (m, 2H), 3.12-3.16 (m, 3H), 3.10-2.88 (m, 6H), 2.68-2.70 (m, 4H), 2.54 (m, 4 H), 2.19-2.20(m, 3H), 2.03-2.06(m, 1H), 1.90-2.00(m, 2H), 1.23-1.26(m, 2H); [M+H] + =959.7.

[0632] Example 62: 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)isoindoline-1,3-dione

[0633]

[0634] The title compound was prepared in a manner similar to that in Example 11. 1H NMR (400MHz, DMSO) δ11.32 (s, 1H), 11.07 (s, 1H), 9.03 (s, 1H), 8.93 (s, 1H), 8.30 (d, J = 8.1Hz, 1H), 7.87 (d, J = 17.6Hz, 1H), 7 .65 (d, J=8.3Hz, 1H), 7.26 (dd, J=19.5, 12.1Hz, 2H), 7.13 (d, J=7.2Hz, 1H), 6.93 (t, J=13.7Hz, 3H), 6.84 (d, J=8.7Hz, 1H), 6 .21 (s, 1H), 5.06 (d, J = 12.7Hz, 1H), 4.11 (s, 2H), 3.69-3.41 (m, 10H), 3.12 (d, J = 16.4Hz, 6H), 2.95-2.82 (m, 2H), 2.69-2.54 [M+H] + =959.6.

[0635] Example 63: 2-(2,6-dioxopiperidin-3-yl)-5-((S)-3-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)isoindoline-1,3-dione

[0636] Step 1: (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)pyrrolidine- 3-Formic acid

[0637]

[0638] Add (3S)-pyrrolidine-3-carboxylic acid (1.50 g, 13.03 mmol) and DIEA (9.5 mL, 54.31 mmol) to a stirred mixture of 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindole-1,3-dione (3.00 g, 10.86 mmol) in DMSO (50 mL), and stir overnight at 120 °C. Cool the mixture to room temperature and neutralize to pH 5 with 1N HCl (5 mL). Extract the resulting mixture with EtOAc. Wash the combined organic layers with brine and dry over anhydrous Na₂SO₄. After filtration, concentrate the filtrate under reduced pressure to give the product (3.37 g, 84%). [M+H] + =372.2.

[0639] Step 2: 2-(2,6-dihydropiperidin-3-yl)-5-((S)-3-(4-(1-(2-fluoro-4-((4-((1-(methylsulfonyl) Acyl)indoline-7-yl)oxy)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)phenyl)piperidin-4-yl)piperazine-1- (carbonyl)pyrrolidine-1-yl)isoindoline-1,3-dione

[0640]

[0641] The title compound was prepared in a manner similar to that in Example 11. 1 H NMR (400MHz, DMSO) δ11.32 (s, 1H), 11.07 (s, 1H), 9.03 (s, 1H), 8.93 (s, 1H), 8.30 (d, J = 8.0Hz, 1H), 7.87 (d, J = 15.7Hz, 1H), 7.65 (d, J = 8 .5Hz, 1H), 7.32 (d, J=7.1Hz, 1H), 7.25 (t, J=7.8Hz, 1H), 7.13 (d, J=7.3Hz, 1H), 6.99-6.88 (m, 3H), 6.84 (d, J=8.7Hz, 1H), 6.21 (s, 1H), 5.06 (dd, J=13.0, 5.3Hz, 1H), 4.11 (t, J=7.4Hz, 2H), 3.71-3.39 (m, 10H), 3.14 (t, J=7.6Hz, 2H), 3.10 (s, 3H), 2.89-2.91 (m, 2H), 2.69- [M+H] + =959.6.

[0642] Example 64: 3-(4-((R)-3-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)pyrrolidine-1-yl)phenyl)piperidin-2,6-dione

[0643]

[0644] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.74 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.30 (d, J = 8.1Hz, 1H), 7.86 (d, J = 15.7Hz, 1H), 7.31 ( d, J=8.7Hz, 1H), 7.25 (t, J=7.8Hz, 1H), 7.12 (d, J=7.4Hz, 1H), 7.04-6.94 (m, 3H), 6.91 (t, J=9.4Hz, 1H), 6.46 (d, J=8.6Hz, 2H), 6 .21 (s, 1H), 4.11 (t, J=7.6Hz, 2H), 3.67 (dd, J=10.5, 5.0Hz, 1H), 3.38 (dd, J=16.6, 8.4Hz, 3H), 3.21-3.07 (m, 7H), 2.83 (t, J=8.4 [M+H] + =890.6.

[0645] Example 66: 3-((4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)amino)piperidin-2,6-dione

[0646] Step 1: 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline

[0647]

[0648] 2-(4-aminophenyl)ethyl-1-ol (13.7 g, 100 mmol), TEA (20.0 g, 200 mmol), and DMAP (1.2 g, 10 mmol) were placed in DCM (150 mL). TBSCl (17.0 g, 110 mmol) was added dropwise to this solution at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with ice water, extracted with DCM, and the combined organic phases were washed three times with 0.5 M HCl solution and once with brine. The resulting organic phase was dried over Na₂SO₄ and concentrated to give the desired product (16.9 g, 67.3%), which was used directly without further purification. [M+H] + =252.2.

[0649] Step 2: 3-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)amino)piperidine-2,6-di ketone

[0650]

[0651] 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)aniline (9.4 g, 37.5 mmol), 3-bromopiperidin-2,6-dione (10.8 g, 56 mmol), and DIEA (9.7 g, 75 mmol) were placed in MeCN (200 mL). The mixture was stirred at 80 °C for 8 h. The reaction mixture was cooled to room temperature, concentrated, and purified by SiO2 gel column chromatography to give the desired product (4.8 g, 35.2%). [M+H] + =363.2.

[0652] Step 3: 3-((4-(2-hydroxyethyl)phenyl)amino)piperidine-2,6-dione hydrochloride

[0653]

[0654] 3-((4-(2-((tert-butyldimethylsilyl)oxy)ethyl)phenyl)amino)piperidin-2,6-dione (4.8 g, 13.2 mmol) was placed in HCl-dioxane (4 M, 30 mL), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and ground with MTBE to give the desired product (3.1 g, 95%). [M+H] + =249.1.

[0655] Step 4: 4-Methylbenzenesulfonic acid 4-((2,6-dioxopiperidin-3-yl)amino)phenethyl ester

[0656]

[0657] 3-((4-(2-hydroxyethyl)phenyl)amino)piperidine-2,6-dione hydrochloride (170.0 mg, 0.6 mmol) was added to a 25 mL flask and dissolved in pyridine (4.0 mL). TsCl (230.0 mg, 1.2 mmol) was then added. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was fed onto a silica gel column (dichloromethane / methanol (7:1)) to give the product (100 mg, 41.7%). [M+H] + =403.2.

[0658] Step 5: 3-((4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl)oxy)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)amino)piperidin- 2,6-Diketone

[0659]

[0660] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.77 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.30 (d, J=8.1Hz, 1H), 7.87 (d, J=15.4Hz, 1H), 7.37-7.18 (m, 2H), 7.13 (d, J=7.3Hz, 1H), 6.94 (d, J=8.4Hz, 4H), 6.60 (d, J=7.8Hz, 2H), 6.21 (s, 1H), 5.65 (d, J=7.4Hz, 1H), 4.26 (s, 1H), 4.11 (s, 2H), 3.14 (ddd, J=11.7, 6.1, 2.0Hz, 5H), 3.06-2.86 (m, [M+H] + =836.6.

[0661] Example 67: 3-(2,6-difluoro-4-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0662] Step 1: 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)pyridine pyridine

[0663]

[0664] A mixture of 2,6-bis(benzyloxy)-3-bromopyridine (15 g, 40.65 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2'-bi(1,3,2-dioxaborhexacyclopentane) (12.6 g, 49.61 mmol), Pd(dppf)Cl2 (3.32 g, 4.07 mmol), and KOAc (12 g, 122.45 mmol) in dioxane (200 mL) was stirred at 100 °C under a nitrogen atmosphere for 16 h. The resulting mixture was filtered, and the filter cake was washed with MeOH and DCM. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography, eluting with PE / EtOAc (8:1) to give the product (9.00 g, 53%). [M+H] + =418.2.

[0665] Step 2: 2,6-bis(benzylhydro)-3-(4-bromo-2,6-difluorophenyl)pyridine

[0666]

[0667] A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (9.00 g, 21.56 mmol) and 5-bromo-1,3-difluoro-2-iodobenzene (6.88 g, 21.57 mmol), K₂CO₃ (10.43 g, 75.48 mmol), and Pd(dppf)C₁₂ (789 mg, 1.078 mmol) in dioxane (90 mL) and H₂O (30 mL) was stirred overnight at 100 °C under a 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 (5:1) to give the product (4 g, 38%). [M+H] + =482.2, 484.3.

[0668] Step 3: 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetic acid Ethyl acetate

[0669]

[0670] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (4.00 g, 8.29 mmol), ethyl 2-(piperidin-4-yl)acetate (2.13 g, 12.43 mmol), Cs₂CO₃ (8.11 g, 24.89 mmol), DavePhos (652.7 mg, 1.659 mmol), and Pd₂(dba)₃ (759.4 mg, 0.829 mmol) in 2-methyl-THF (50 mL) and H₂O (5 mL) was stirred overnight at 100 °C under a 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 (1:1) to give the product (2 g, 42%). [M+H] + =573.5.

[0671] Step 4: 2-(1-(4-(2,6-bis(benzylhydropyridin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)ethyl-1- alcohol

[0672]

[0673] LiBH4 (1.52 g, 69.77 mmol) was added fractionally to a stirred mixture of ethyl 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetate (2.00 g, 3.49 mmol) in THF (50 mL) and allowed to stand overnight at room temperature. The reaction mixture was quenched with water at 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 to give the product (1.8 g, 97%). [M+H] = 531.4.

[0674] Step 5: 3-(2,6-difluoro-4-(4-(2-hydroxyethyl)piperidin-1-yl)phenylpiperidin-2,6-dione

[0675]

[0676] AcOH (20 mL) was added to a stirred mixture of 2-(1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)ethanol-1-ol (1.80 g, 3.39 mmol) and Pd / C (1 g, 10% wt) in EtOH (20 mL) and DCM (20 mL) and stirred overnight at 40 °C under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to give the product (1.2 g, 100%). [M+H] = 353.1.

[0677] Step 6: Ethyl 2-(1-(4-(2,6-dihydropiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)methanesulfonic acid

[0678]

[0679] The title compound (210 mg, 52%) was prepared from 3-(2,6-difluoro-4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione and sulfoxide in a manner similar to that in step 5 of Example 1. [M+H] = 431.1.

[0680] Step 7: 3-(2,6-difluoro-4-(4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7- (yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1- 2,6-dione (phenyl)piperidine-2,6-dione

[0681]

[0682] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.86 (s, 1H), 9.02 (s, 1H), 8.92 (s, 1H), 8.30 (d, J=7.9Hz, 1H), 8.18 (s, 1H), 7.86 ( d, J=17.4Hz, 1H), 7.27 (dd, J=29.6, 7.6Hz, 2H), 7.12 (d, J=7.6Hz, 1H), 6.99-6.87 (m, 2H), 6.60 (d, J=12.9Hz, 2H), 6.2 1 (s, 1H), 4.08 (d, J = 19.0Hz, 3H), 3.73 (d, J = 12.3Hz, 2H), 3.17-3.06 (m, 6H), 2.82-2.53 (m, 8H), 2.31-2.45 (m, 9H), 2. [M+H] + =940.5.

[0683] Example 68: 3-(2,6-difluoro-4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0684]

[0685] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.96 (s, 1H), 9.03 (s, 1H), 8.96 (s, 1H), 8.29 (d, J=8.0Hz, 1H), 7.90 (d, J=15. 4Hz, 1H), 7.33 (d, J=8.5Hz, 1H), 7.25 (t, J=7.7Hz, 1H), 7.10 (dd, J=23.0, 8.4Hz, 3H), 6.95 (d, J=13.1Hz, 2H), 6.21 (s, 1H), 4.28-4.17 (m, 1H), 4.15-4.06 (m, 2H), 3.60-3.38 (m, 6H), 3.19-2.89 (m, 10H), 2.90-2.74 (m, 3H), 2.71-2 [M+H] + =857.5.

[0686] Example 69: 3-(2,3-difluoro-4-(2-(4-(1-(2-fluoro-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0687]

[0688] The title compound was prepared in a manner similar to that in Example 3. 1 H NMR (400MHz, DMSO) δ11.32 (s, 1H), 10.92 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.30 (d, J = 8.0Hz, 1H), 8.21 (s, 1H), 7.86 (d, J=15.6Hz, 1H), 7.34-7.20 (m, 2H), 7.17-7.00 (m, 3H), 6.92 (dd, J=19.8, 10.5H z, 2H), 6.21 (s, 1H), 4.17-4.05 (m, 3H), 3.20-3.05 (m, 8H), 3.05-2.90 (m, 2H), 2.85-2.68 (m, 4H), 2. 66-2.52(m,7H),2.38-2.13(m,3H),2.07-1.96(m,1H),1.89-1.79(m,2H),1.63-1.49(m,2H);[M+H] +=857.5.

[0689] Example 73: 2-(2,6-dioxopiperidin-3-yl)-5-(3-(4-(1-(2-methoxy-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-carbonyl)azacyclobutane-1-yl)isoindoline-1,3-dione

[0690]

[0691] The title compound was prepared in a manner similar to that in Example 11. 1 H NMR (400MHz, DMSO) δ11.25 (s, 1H), 11.07 (s, 1H), 8.98 (s, 1H), 8.68 (s, 1H), 8 .39(d, J=7.9Hz, 1H), 8.21(s, 1H), 7.66(d, J=8.3Hz, 1H), 7.45(s, 1H), 7.34(d , J=8.3Hz, 1H), 7.22 (t, J=7.8Hz, 1H), 7.10 (d, J=7.0Hz, 1H), 6.97-6.92 (m, 1H ), 6.84 (d, J = 1.7Hz, 1H), 6.77 (d, J = 8.7Hz, 1H), 6.70 (d, J = 8.4Hz, 1H), 6.19 (s , 1H), 5.06 (dd, J=12.9, 5.2Hz, 1H), 4.24 (t, J=8.4Hz, 2H), 4.12 (dd, J=18.8, 7.1Hz, 4H), 3.92 (s, 1H), 3.73 (s, 3H), 3.51 (s, 3H), 3.39 (s, 3H), 3.29-3.25 (m , 2H), 3.16-3.08(m, 5H), 2.92-2.84(m, 1H), 2.57(m, 4H), 2.48-2.45(m, 1H), 2 .35(s, 1H), 2.03(s, 1H), 1.81(d, J=10.4Hz, 2H), 1.58(d, J=9.9Hz, 2H); [M+H] + =957.7.

[0692] Example 74: 2-(2,6-dioxopiperidin-3-yl)-5-((S)-3-(4-(1-(2-methoxy-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)isoindoline-1,3-dione

[0693]

[0694] The title compound was prepared in a manner similar to that in Example 11. ¹H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 11.07 (s, 1H), 8.98 (s, 1H), 8.68 (s, 1H), 8.39 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.94 (s, 2H), 6.84 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.19 (s, 1H), 5.06 (dd, 2H). J=12.9, 5.4Hz, 1H), 4.10 (t, J=7.5Hz, 2H), 3.73 (s, 3H), 3.61 (d, J=17.8Hz, 5H), 3.48 (d, J=15.0Hz, 8H), 3.15-3.08 (m, 5H), 2.87 (d, J=13.0Hz, 1H), 2.56 (d, J=12.9Hz, 5H), 2.48-2.45 (m, 1H), 2.36 (s, 1H), 2.23 (s, 1H ), 2.13(s, 1H), 2.03(s, 1H), 1.80(s, 2H), 1.58(d, J=10.2Hz, 2H); [M+H] + =971.8.

[0695] Example 75: 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-(4-(1-(2-methoxy-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)isoindoline-1,3-dione

[0696]

[0697] The title compound was prepared in a manner similar to that in Example 11. 1H NMR (400MHz, DMSO) δ11.21 (s, 1H), 11.02 (s, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 8.34 (d, J = 8.3Hz, 1H), 7.61 (d, J = 8.5Hz, 1H), 7.42 (s, 1H), 7.29 (d, J=8.3Hz, 1H), 7.18 (t, J=7.9Hz, 1H), 7.06 (d, J=7.6Hz, 1H), 6.90 (s, 2H), 6.80 (d, J=8.7Hz, 1H), 6.73 (d, J=8.7Hz, 1H), 6.15 (s, 1H), 5.02 (dd, J= 12.6, 5.6Hz, 1H), 4.06 (s, 2H), 3.69 (s, 3H), 3.51 (d, J=32.6Hz, 9H), 3.41 (d, J=7.5Hz, 1H), 3.29 (s, 3H), 3.07 (d, J=14.5Hz, 5H), 2.83 (d, J=13. 3Hz, 1H), 2.58-2.49(m, 5H), 2.45-2.42(m, 1H), 2.32(s, 1H), 2.19(s, 1H ), 2.09 (s, 1H), 1.98 (s, 1H), 1.76 (s, 2H), 1.54 (d, J=10.7Hz, 2H); [M+H] + =971.8.

[0698] Example 76: 5-(3-((4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0699]

[0700] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 9.41 (s, 1H), 9.03 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 6.9Hz, 1H), 7.63 (d, J = 8.2Hz, 1H), 7.55 ( d, J=15.3Hz, 1H), 7.28 (dd, J=14.9, 7.1Hz, 2H), 7.19 (d, J=9.0Hz, 1H), 6.88 (t, J=9.4Hz, 1H), 6.77 (s, 1H), 6.64 (d, J=8.3Hz, 1H ), 5.05 (dd, J=12.7, 5.3Hz, 1H), 4.16-4.03 (m, 4H), 3.68 (s, 2H), 3.28-3.24 (m, 4H), 3.14 (s, 3H), 3.06 (s, 3H), 2.99 (s, 2H), 2. [M+H] + =926.7.

[0701] Example 77: 5-(3-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-carbonyl)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0702]

[0703] The title compound was prepared in a manner similar to that in Example 11. 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 9.41 (s, 1H), 9.03 (s, 1H), 8.19 (s, 1H), 7.87 (s, 1H), 7.66 (d, J=8.3Hz, 1H), 7.55 (d, J=13.2Hz, 1H), 7.31-7.22 (m, 2H), 7.18 (s, 1H), 6.89 (d, J=9.5Hz, 1H), 6.83 (s, 1H), 6.70 (d, J=7.8Hz, 1H), 5.07 (d, J=1 2.4Hz, 1H), 4.22 (d, J=8.3Hz, 2H), 4.10 (d, J=23.3Hz, 4H), 3.92 (s, 1H), 3.50 (s, 2H), 3.30-3.25 (m, 3H), 3.14 (s, 2H), 3 .06 (s, 3H), 2.88 (s, 1H), 2.57 (d, J = 22.9Hz, 9H), 2.37 (s, 1H), 2.03 (s, 1H), 1.82 (s, 2H), 1.58 (d, J = 11.7Hz, 2H); [M+H] + =940.7.

[0704] Example 78: 5-(3-(3-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)propyl)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0705]

[0706] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 9.40 (s, 1H), 9.03 (s, 1H), 8.17 (d, J = 12.6Hz, 1H), 7.86 (s, 1H), 7.64 (d, J = 8.7Hz, 1H), 7.55 (d, J=14.5Hz, 1H), 7.27 (d, J=15.0Hz, 2H), 7.17 (s, 1H), 6.87 (s, 1H), 6.76 (s, 1H), 6.62 (d, J=7.9Hz, 1H), 5 .04 (s, 1H), 4.10 (d, J = 22.9Hz, 4H), 3.65 (s, 2H), 3.26-3.23 (m, 2H), 3.14 (s, 3H), 3.06 (s, 3H), 2.82 (d, J = 46.0Hz, 4H ), 2.67 (s, 1H), 2.55 (s, 4H), 2.44-2.23 (m, 7H), 2.02 (s, 1H), 1.82 (s, 2H), 1.59 (d, J=25.1Hz, 4H), 1.43 (s, 2H); [M+H] + =954.8.

[0707] Example 79: 3-(4-(4-(2-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0708]

[0709] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (400MHz, DMSO) δ10.77 (s, 1H), 9.40 (s, 1H), 9.03 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.55 (d, J=15.1Hz, 1H), 7.3 2-7.21 (m, 2H), 7.18 (s, 1H), 7.02 (d, J=8.4Hz, 2H), 6.88 (d, J=6.5Hz, 3H), 4.07 (s, 2H), 3.72 (s, 1H), 3.63 (d, J=11. 9Hz, 2H), 3.29-3.22 (m, 3H), 3.14 (s, 2H), 3.06 (s, 3H), 2.59 (dd, J=21.8, 13.0Hz, 8H), 2.37 (d, J=53.1Hz, 8H), 2.11 [M+H] + =899.8.

[0710] Example 80: 3-(4-(4-(2-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)piperidin-2,6-dione

[0711]

[0712] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (400MHz, DMSO) δ10.80 (s, 1H), 9.41 (s, 1H), 9.03 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.55 (d, J=15.6Hz, 1H), 7.28 (dd, J=15.2, 7.2H z, 2H), 7.18 (d, J = 7.3Hz, 1H), 7.05 (t, J = 8.6Hz, 1H), 6.88 (d, J = 8.7Hz, 1H), 6.70 (d, J = 11.2Hz, 2H), 4.07 (s, 2H), 3.87 (d, J = 7.3Hz, 1H), 3.69 (d, J=11.9Hz, 2H), 3.26 (s, 4H), 3.14 (s, 2H), 3.06 (s, 3H), 2.63 (dd, J=27.2, 13.1Hz, 8H), 2.35 (d, J=30.3Hz, 7H), 2.14 (d, J=12.7H [M+H] + =917.8.

[0713] Example 81: 5-(4-(2-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0714]

[0715] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ11.08 (s, 1H), 9.41 (s, 1H), 9.03 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.65 (d, J=8 .6Hz, 1H), 7.55 (d, J=14.7Hz, 1H), 7.36-7.14 (m, 5H), 6.87 (s, 1H), 5.06 (d, J=7.3Hz, 1H), 4.12-3.9 8(m, 4H), 3.29-3.23(m, 3H), 3.14(s, 2H), 3.06(s, 3H), 3.00-2.81(m, 4H), 2.57(d, J=25.4Hz, 6H), 2 .33(s, 7H), 2.01(s, 1H), 1.88-1.71(m, 4H), 1.56(s, 3H), 1.39(s, 2H), 1.18(d, J=10.6Hz, 2H); [M+H] + =968.8.

[0716] Example 82: 5-((S)-3-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0717]

[0718] The title compound was prepared in a manner similar to that in Example 11. 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 9.41 (s, 1H), 9.03 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 7.6Hz, 1H), 7.65 (d, J = 8.4Hz, 1H), 7.56 (d, J=15.6Hz, 1H), 7.27 (dt, J=14.6, 7.2Hz, 2H), 7.19 (d, J=8.2Hz, 1H), 6.93 (s, 1H), 6.87 (dd, J=21.9, 9.0Hz, 2H), 5.06 (dd, J=12.9, 5.4Hz, 1H), 4.07 (t, J=7.1Hz, 2H), 3.68-3.42 (m, 10H), 3.28 (s, 3H), 3.14 (t, J=7.2Hz, 2H), 3.06 (s, 3H), 2.93-2.84 (m, 1H), 2.64- [M+H] + =954.7.

[0719] Example 83: 5-((R)-3-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0720]

[0721] The title compound was prepared in a manner similar to that in Example 11. 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 9.41 (s, 1H), 9.03 (s, 1H), 8.19 (s, 1H), 7.87 (d, J = 7.5Hz, 1H), 7.65 (d, J = 8.4Hz, 1H), 7.55 (d, J =15.6Hz, 1H), 7.27 (dt, J=14.7, 7.3Hz, 2H), 7.19 (d, J=8.4Hz, 1H), 6.93 (s, 1H), 6.87 (dd, J=21.9, 8.9Hz, 2H), 5.06 (dd, J=12.9, 5. 4Hz, 1H), 4.07 (t, J=7.5Hz, 2H), 3.67-3.42 (m, 10H), 3.28 (s, 3H), 3.14 (t, J=7.3Hz, 2H), 3.06 (s, 3H), 2.89 (t, J=12.7Hz, 1H), 2.6 5-2.54 (m, 6H), 2.37 (s, 1H), 2.23 (s, 1H), 2.14 (d, J = 6.5Hz, 1H), 2.03 (s, 1H), 1.84 (d, J = 10.4Hz, 2H), 1.59 (d, J = 9.5Hz, 2H); [M+H] + =954.7.

[0722] Example 84: 3-(4-(3-(2-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)azacyclobutane-1-yl)phenyl)piperidin-2,6-dione

[0723]

[0724] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, CD3OD) δ8.16 (s, 1H), 7.63 (s, 2H), 7.40 (d, J=7.0Hz, 1H), 7.32 (t, J=7.7Hz, 1H), 7.1 9 (d, J=8.4Hz, 3H), 6.97 (d, J=8.0Hz, 2H), 6.90 (s, 1H), 4.09 (t, J=7.4Hz, 2H), 4.03 (s, 1H), 3.94 (s , 3H), 3.83 (tt, J=24.1, 11.9Hz, 10H), 3.52-3.40 (m, 7H), 3.20 (t, J=7.3Hz, 2H), 3.08-2.99 (m, 1H ), 2.95(s, 3H), 2.73-2.57(m, 3H), 2.45-2.50(m, 1H), 2.36-2.27(m, 2H), 2.25-2.07(m, 6H); [M+H] + =883.5.

[0725] Example 85: 3-(5-(3-((4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0726]

[0727] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ10.93 (s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.88 (s, 2H), 7.46 (dd, J=12.7, 8.5Hz, 2H), 7.16 (d, J=6.6Hz, 2H), 6.60 (s, 1H), 6.53-6.44 (m, 2H), 6.40 (d, J=8.6Hz, 1H), 5.03 (dd, J=13.3, 5.2Hz, 1H), 4.30 (d, J=17.0Hz, 1H), 4.17 (d, J=17.0Hz , 1H), 4.12-3.96 (m, 4H), 3.76 (s, 3H), 3.69 (d, J=11.8Hz, 2H), 3.60-3.50 (m, 2H), 3.10 (t, J=7.5Hz, 2H), 3.04 (s, 3H), 3.00-2.8 [M+H] + =924.5.

[0728] Example 86: 5-(3-((4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0729] Step 1: N-(2,5-dichloropyrimidin-4-yl)-1-(methanesulfonyl)indoline-7-amine

[0730]

[0731] A mixture of 1-(methanesulfonyl)indoline-7-amine (340 mg, 1.6 mmol), 2,4,5-trichloropyrimidine (584 mg, 3.2 mmol), and DIEA (412 mg, 3.2 mmol) in i-PrOH (20 mL) was stirred at 100 °C for 16 h in a round-bottom flask. The mixture was evaporated under vacuum to give a crude product, which was purified by silica gel column chromatography (PE:EA = 100:0 to 2:1 gradient elution) to give the title product (540 mg, 94%). [M+H] + =359.2.

[0732] Step 2: 5-Chloro-N 2 -(2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)-N4 -(1-(methylsulfonyl)indololin-7-yl)pyrimidin-2,4-diamine

[0733]

[0734] In a manner similar to step 4 of embodiment 43, by N-(2,5-Dichloropyrimidin-4-yl)-1-(Methylsulfonyl) Indoline-7-amine The title compound (170 mg, 44%) was prepared from tert-butyl 4-(1-(4-amino-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carboxylate. [M+H] + =613.2.

[0735] Step 3: 5-(3-((4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0736]

[0737] 5-chloro-N 2 -(2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)-N 4 A mixture of 1-(1-(methanesulfonyl)indoline-7-yl)pyrimidine-2,4-diamine (35 mg, 0.057 mmol) and methanesulfonic acid (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azacyclobutane-3-yl) methyl ester (30 mg, 0.069 mmol), KI (11.6 mg, 0.069 mmol), and DIEA (14.7 mg, 0.114 mmol) in acetonitrile (4 mL) was stirred at 75 °C for 12 hours in a round-bottom flask. The reaction mixture was quenched with water and extracted with DCM, washed with saturated brine, and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by HPLC to give the product (5 mg, 10%). 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.88 (s, 2H), 7.63 (d, J=8.4Hz, 1H ), 7.44 (s, 1H), 7.15 (s, 2H), 6.77 (s, 1H), 6.61 (d, J=12.5Hz, 2H), 6.41 (s, 1H), 5.04 (s, 1H), 4.1 8-4.10 (m, 2H), 4.09-4.00 (m, 2H), 3.76 (s, 3H), 3.69 (tt, J=6.3, 3.2Hz, 4H), 3.00 (s, 9H), 2.71- 2.54(m, 9H), 2.38-2.50(m, 4H), 2.06-1.96(m, 1H), 1.92-1.80(m, 2H), 1.60-1.45(m, 2H); [M+H] + =938.5.

[0738] Example 87: 5-((S)-3-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0739]

[0740] The title compound was prepared in a manner similar to that in Example 11. 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.88 (s, 2H), 7.65 (d, J = 8.4Hz, 1H), 7.45 (d, J = 8.7Hz, 1H), 7.16 (d, J =6.9Hz, 2H), 6.93 (s, 1H), 6.84 (d, J = 8.6Hz, 1H), 6.60 (s, 1H), 6.41 (d, J = 9.3Hz, 1H), 5.06 (dd, J = 12.8, 5.2Hz, 1H), 4.05 (t, J = 7.3 Hz, 2H), 3.77 (s, 3H), 3.71 (d, J=12.1Hz, 2H), 3.66-3.41 (m, 9H), 3.10 (t, J=7.2Hz, 2H), 3.04 (s, 3H), 2.93-2.82 (m, 1H), 2.71-2.5 [M+H] +＝ 966.5.

[0741] Example 88: 5-((R)-3-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-carbonyl)pyrrolidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0742]

[0743] The title compound was prepared in a manner similar to that in Example 11. 1H NMR (400MHz, DMSO) δ11.06 (s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.88 (s, 2H), 7.65 (d, J = 8.4Hz, 1H), 7.45 (d, J = 8.7Hz, 1H), 7.16 (d, J =6.9Hz, 2H), 6.93 (s, 1H), 6.84 (d, J = 8.6Hz, 1H), 6.60 (s, 1H), 6.41 (d, J = 9.3Hz, 1H), 5.07 (dd, J = 12.8, 5.2Hz, 1H), 4.05 (t, J = 7.3 Hz, 2H), 3.77 (s, 3H), 3.71 (d, J=12.1Hz, 2H), 3.66-3.41 (m, 9H), 3.10 (t, J=7.2Hz, 2H), 3.04 (s, 3H), 2.93-2.82 (m, 1H), 2.71-2.5 [M+H] + =966.5.

[0744] Example 90: 3-(4-(4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-fluorophenyl)piperidin-2,6-dione

[0745]

[0746] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (400MHz, DMSO) δ10.80 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.81 (d, J=6.0 Hz, 1H), 7.43 (s, 1H), 7.18-7.11 (m, 2H), 7.06 (t, J=8.7Hz, 1H), 6.69 (d, J=14.9Hz, 3H), 4 .05(t, J=7.3Hz, 2H), 3.90-3.85(m, 1H), 3.76(s, 3H), 3.69(d, J=12.7Hz, 2H), 3.13-3.00( m, 8H), 2.75-2.57 (m, 6H), 2.51 (s, 3H), 2.37 (s, 3H), 2.30 (s, 4H), 2.14 (d, J=12.1Hz, 1H) , 2.07 (s, 3H), 1.96 (s, 1H), 1.85 (d, J = 11.6Hz, 2H), 1.73 (d, J = 11.4Hz, 2H), 1.56 (d, J = 9.0 Hz, 2H), 1.39 (s, 3H), 1.21 (d, J=12.1Hz, 2H); [M+H] +＝ 987.5, 989.7.

[0747] Example 91: 5-(4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0748]

[0749] The title compound was prepared in a manner similar to that in Example 1. 1H NMR (400MHz, DMSO) δ11.07 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.81 (d, J=7.0 Hz, 1H), 7.65 (d, J=8.6Hz, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.23 (d, J=8.6Hz, 1H), 7.14 (d, J=7.5Hz, 2H), 6. 67 (s, 1H), 5.06 (dd, J=12.7, 5.2Hz, 1H), 4.04 (d, J=7.8Hz, 4H), 3.76 (s, 3H), 3.10 (t, J=7.4Hz, 3H), 3.05 (s , 4H), 2.93 (dd, J=24.5, 12.4Hz, 4H), 2.65-2.52 (m, 7H), 2.41 (s, 3H), 2.33 (s, 4H), 2.07 (s, 3H), 2.02 (s, 1H) ), 1.85 (d, J = 10.6Hz, 2H), 1.76 (d, J = 12.4Hz, 2H), 1.57 (s, 3H), 1.40 (s, 2H), 1.19 (d, J = 11.1Hz, 2H); [M+H] + =1038.7, 1040.9.

[0750] Example 151: 5-(3-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0751]

[0752] The title compound was prepared using a procedure similar to that in Example 3.

[0753] 1H NMR (500MHz, DMSO) δ11.07 (s, 1H), 8.80 (s, 1H), 8.17 (d, J=5.8Hz, 1H), 7.87 (s, 1H), 7.81 (d, J=7.2Hz, 1H), 7.63 (d, J=8. 3Hz, 1H), 7.43 (s, 1H), 7.15 (t, J=8.0Hz, 2H), 6.77 (s, 1H), 6.65 (dd, J=15.8, 7.5Hz, 2H), 5.05 (dd, J=12.9, 5.4Hz, 1H), 4 .13 (t, J=8.0Hz, 2H), 4.05 (t, J=7.4Hz, 2H), 3.76 (s, 3H), 3.70-3.63 (m, 2H), 3.13-2.96 (m, 8H), 2.88 (s, 1H), 2.66-2.51 [M+H] + =996.3.

[0754] Example 152: 3-((4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)amino)piperidin-2,6-dione

[0755]

[0756] The title compound was prepared using a procedure similar to that in Example 3.

[0757] 1H NMR (500MHz, DMSO) δ10.78 (s, 1H), 8.80 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.81 (d, J=8.1Hz, 1H), 7.43 (s, 1H), 7.15 (s, 2H), 6.93 (d, J = 8.3Hz, 2H), 6.68 (s, 1H), 6.59 (d, J = 8.4Hz, 2H), 5.65 (d, J = 7.2Hz, 1H), 4.27 (s, 1H), 4.05 (s, 2H), 3.76 (s, 3H), 3.08 (d, J=28.0Hz, 7H), 2.79-2.69 (m, 1H), 2.66-2.52 (m, 10H) , 2.42 (d, J = 8.1Hz, 5H), 2.29 (s, 1H), 2.08 (s, 4H), 1.86 (d, J = 11.7Hz, 3H), 1.56 (d, J = 9.1Hz, 2H); [M+H] +＝ 901.2.

[0758] Example 153: 3-((4-(2-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)amino)piperidin-2,6-dione

[0759]

[0760] The title compound was prepared using a procedure similar to that in Example 3.

[0761] 1 H NMR (500MHz, DMSO) δ10.78 (s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.88 (s, 2H), 7.44 (d, J=8.7Hz, 1H), 7.15 (d, J =6.9Hz, 2H), 6.93 (d, J = 8.4Hz, 2H), 6.59 (d, J = 8.0Hz, 3H), 6.40 (d, J = 8.8Hz, 1H), 5.65 (d, J = 7.4Hz, 1H), 4.2 9-4.23 (m, 1H), 4.05 (t, J=7.4Hz, 2H), 3.76 (s, 3H), 3.69 (d, J=12.0Hz, 2H), 3.10 (t, J=7.4Hz, 2H), 3.04 (s, [M+H] + =843.2.

[0762] Example 154: 3-(5-((S)-3-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0763]

[0764] The title compound was prepared using a procedure similar to that in Example 3.

[0765] 1 H NMR (500MHz, DMSO) δ10.93 (s, 1H), 8.80 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.52-7.42 (m, 2H) , 7.15 (s, 2H), 6.68 (s, 1H), 6.63 (s, 2H), 5.03 (d, J = 9.2Hz, 1H), 4.30 (d, J = 15.8Hz, 1H), 4.19 (d, J = 16.4Hz, 1H), 4.05(s, 2H), 3.76(s, 3H), 3.43-3.41(m, 2H), 3.17-3.02(m, 10H), 2.91-2.89(m, 1H), 2.63-2.59(m, 1 0H), 2.46-2.28(m, 5H), 2.13-2.11(m, 4H), 2.00-1.83(m, 3H), 1.79-1.70(m, 1H), 1.68-1.53(m, 2H); [M+H] + =996.3.

[0766] Example 155: 3-(4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,5-difluorophenyl)piperidin-2,6-dione

[0767]

[0768] The title compound was prepared using a procedure similar to that in Example 3.

[0769] 1H NMR (500MHz, DMSO) δ10.90 (s, 1H), 8.79 (s, 1H), 8.16 (d, J = 12.5Hz, 1H), 7.86 (s, 1H), 7 .80(s, 1H), 7.43(s, 1H), 7.22(s, 1H), 7.15(s, 3H), 6.68(s, 1H), 4.05(s, 3H), 3.76(s, 3H), 3.15-3.00(m, 7H), 2.80-2.68(m, 3H), 2.66-2.52(m, 11H), 2.40-2.17(m, 3H), 2.0 8(s, 3H), 2.00-1.97(m, 1H), 1.91-1.81(m, 2H), 1.57-1.54(m, 2H), 1.06(s, 1H); [M+H] + =922.2.

[0770] Example 156: 5-((R)-3-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0771]

[0772] The title compound was prepared using a procedure similar to that in Example 3.

[0773] 1 H NMR (500MHz, DMSO) δ11.06 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.65 (d, J=8.0Hz, 1H), 7. 44 (s, 1H), 7.15 (s, 2H), 6.90 (s, 1H), 6.82 (d, J=8.0Hz, 1H), 6.68 (s, 1H), 5.05 (d, J=7.7Hz, 1H), 4.05 (s, 2H), 3.7 6(s, 3H), 3.53(d, J=29.6Hz, 2H), 3.37(s, 2H), 3.17-3.O1(m, 9H), 2.94-2.82(m, 1H), 2.69-2.53(m, 10H), 2.41-2 [M+H] + =1010.3.

[0774] Example 157: 3-((4-(1-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-4-yl)phenyl)amino)piperidin-2,6-dione

[0775]

[0776] The title compound was prepared using a procedure similar to that in Example 3.

[0777] 1 H NMR (500MHz, DMSO) δ10.77 (s, 1H), 8.79 (s, 1H), 8.16 (d, J=9.0Hz, 1H), 7.83 (d, J=28.7Hz, 2H), 7.43 (s, 1H), 7.15 (s, 2 H), 6.95 (d, J=6.7Hz, 2H), 6.68 (s, 1H), 6.61 (d, J=6.6Hz, 2H), 5.65 (d, J=5.9Hz, 1H), 4.30 (d, J=40.6Hz, 1H), 4.05 (s, 2H), 3.76(s, 3H), 3.48-3.39(m, 2H), 3.14-2.97(m, 10H), 2.79-2.68(m, 1H), 2.66-2.56(m, 5H), 2.48-2.39(m, 5H), 2. [M+H] + =984.2.

[0778] Example 158: 5-(((1r,3r)-3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carbonyl)cyclobutyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0779]

[0780] The title compound was prepared using a procedure similar to that in Example 11.

[0781] 1HNMR (500MHz, DMSO) δ11.07 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.82 (s, 1H), 7.67 (d, J=7.7Hz, 1H), 7.44 (s, 1H), 7.15 (s, 2H), 7.03-6.91 (m, 2H), 6.68 (s, 1H), 5.06 (d, J=8.0Hz, 1H), 4.35 (s, 1H), 4.05 (s, 2H), 3.76 (s, 3H), 3.48-3.4 1(m, 4H), 3.26-3.21(m, 1H), 3.10-2.91(m, 12H), 2.88-2.71(m, 1H), 2.68-2.54(m, 7H), 2.44-2.28(m, 1H), 2.36(t, J=7.9H [M+H] + =1038.4.

[0782] Example 159: 3-(5-((1r,3r)-3-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclobutyl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0783]

[0784] The title compound was prepared using a procedure similar to that in Example 3.

[0785] 1 H NMR (500MHz, DMSO) δ10.98 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.65 (s, 1H), 7.51 (s, 1H), 7.42 (d, J=19.1Hz, 2H), 7.15 (s, 2H), 6.68 (s, 1H), 5.09 (s, 1H), 4.43-4.40 (m, 1H), 4.38-4.25 (m, 2H), 4.1 0-3.99(m, 2H), 3.78-3.66(m, 4H), 3.49-3.40(m, 3H), 3.15-2.99(m, 7H), 2.97-2.86(m, 1H), 2.60-2.55(m, 8H) , 2.43-2.31(m, 4H), 2.28-2.13(m, 4H), 2.08(s, 3H), 2.02-1.94(m, 1H), 1.91-1.81(m, 2H), 1.57-1.52(m, 2H). [M+H] + =981.2.

[0786] Example 160: 3-(4-(4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0787]

[0788] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (500MHz, DMSO) δ10.86 (s, 1H), 8.76 (s, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.77 (d, J = 8.0Hz, 1H), 7.45 (s, 1H), 7.15 (d, J = 7.0Hz, 1H), 7.10 (t, J=7.7Hz, 1H), 6.73 (s, 1H), 6.60 (d, J=12.8Hz, 2H), 4.04 (t, J=7.1Hz, 3H), 3.75 (s, 3H), 3.72 (s, 2H), 3.10 (t, J=7.4Hz, 2H), 3. 05 (s, 3H), 2.97 (d, J=10.9Hz, 2H), 2.82-2.62 (m, 6H), 2.54 (s, 4H), 2.49-2.25 (m, 9H), 2.14-2.03 (m, 1H), 1.98-1.92 (m, 1H), 1.88-1.8 [M+H] + =1021.7.

[0789] Example 161: 5-(4-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0790]

[0791] The title compound was prepared in a manner similar to that in Example 11. 1H NMR (500MHz, DMSO) δ11.07 (s, 1H), 8.92 (s, 1H), 8.08 (s, 1H), 7.87 (s, 2H), 7.66 (d, J = 8.5Hz, 1H), 7.45 (d, J = 8.7Hz, 1H), 7.33 (d, J = 1.9Hz, 1H), 7 .24 (dd, J=8.7, 2.1Hz, 1H), 7.19-7.12 (m, 2H), 6.60 (d, J=2.3Hz, 1H), 6.41 (dd, J=8.8, 2.2Hz, 1H), 5.07 (dd, J=12.8, 5.4Hz, 1H), 4.11-4.03 (m, 4H ), 3.77(s, 3H), 3.71(d, J=11.5Hz, 2H), 3.55(s, 2H), 3.46(s, 2H), 3.13- 3.05(m, 4H), 3.04(s, 3H), 3.03-2.93(m, 1H), 2.90-2.84(m, 1H), 2.69-2. 59(m, 3H), 2.57-2.52(m, 3H), 2.47(s, 2H), 2.44-2.35(m, 1H), 2.05-1.9 7(m, 1H), 1.88-1.81(m, 2H), 1.73-1.67(m, 2H), 1.66-1.49(m, 4H); [M+H] + =980.7.

[0792] Example 162: 3-(2-fluoro-4-(2-(4-(1-(5-methoxy-2-methyl-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0793]

[0794] The title compound was prepared using a procedure similar to that in Example 3. 1H NMR (400MHz, DMSO) δ11.25 (s, 1H), 10.86 (s, 1H), 9.04 (s, 1H), 8.20 (d, J=8.1Hz, 1H), 8.01 (s, 1H), 7.25 (s, 1H), 7.23-7 .19 (m, 2H), 7.12-7.03 (m, 3H), 6.96-6.92 (m, 1H), 6.70 (s, 1H), 6.21 (s, 1H), 4.10 (t, J=7.5Hz, 2H), 4.00 (dd, J=12.4, 5. 0Hz, 1H), 3.82 (s, 3H), 3.13 (t, J=7.5Hz, 2H), 3.09 (s, 3H), 3.06 (d, J=11.0Hz, 2H), 2.80-2.68 (m, 4H), 2.64-2.54 (m, 11 [M+H] + =865.7.

[0795] Example 163: 3-(2,6-difluoro-4-(2-(4-(1-(5-methoxy-2-methyl-4-((4-((1-(methanesulfonyl)indoline-7-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)piperidin-2,6-dione

[0796]

[0797] The title compound was prepared using a procedure similar to that in Example 3. 1H NMR (400MHz, DMSO) δ11.25 (s, 1H), 10.95 (s, 1H), 9.04 (s, 1H), 8.20 (d, J=8.4Hz, 1H), 8.01 (s, 1H), 7.25 (s, 1H), 7.21 (t, J=10.0 Hz, 2H), 7.10 (d, J=7.4Hz, 1H), 7.03 (d, J=10.0Hz, 2H), 6.97-6.93 (m, 1H), 6.70 (s, 1H), 6.21 (dd, J=3.3, 1.9Hz, 1H), 4.20 (dd, J= 13.0, 5.1Hz, 1H), 4.10 (t, J=7.5Hz, 2H), 3.82 (s, 3H), 3.13 (t, J=7.3Hz, 2H), 3.09 (s, 3H), 3.06 (d, J=11.3Hz, 2H), 2.85-2.75 (m, [M+H] + =883.6.

[0798] Example 164: 5-((S)-3-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0799]

[0800] The title compound was prepared using a procedure similar to that in Example 3.

[0801] 1H NMR (500MHz, DMSO) δ11.06 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.81 (d, J = 7.9Hz, 1H), 7.64 (d, J = 8.5Hz, 1H), 7.44 (s, 1H), 7.14 (q, J=7.4Hz, 2H), 6.90 (s, 1H), 6.82 (d, J=8.6Hz, 1H), 6.68 (s, 1H), 5.05 (dd, J=12.9, 5.3Hz, 1H), 4.05 (t, J=7.3Hz, 2H), 3.76 (s, 3H), 3.54-3.52 (m, 2H), 3.43-3.36 (m, 2H), 3.05-3.01 (m, 8H), 2.94-2.81 (m, 1H), 2.68-2.53 ( m, 9H), 2.35 (d, J=7.6Hz, 6H), 2.08 (s, 4H), 2.05-1.97 (m, 1H), 1.87-1.84 (m, 2H), 1.77-1.75 (m, 1H), 1.57-1.54 (m, 2H). [M+H] +＝ 1010.2.

[0802] Example 165: 5-(((1r,3r)-3-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclobutyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0803]

[0804] The title compound was prepared using a procedure similar to that in Example 3.

[0805] 1H NMR (500MHz, DMSO) δ11.07 (s, 1H), 8.79 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.81 (d, J=7.2Hz, 1H), 7.65 (d , J=8.5Hz, 1H), 7.43 (s, 1H), 7.13 (dt, J=7.6, 4.9Hz, 3H), 7.05-6.98 (m, 1H), 6.68 (s, 1H), 5.06 (dd, J=13.0, 5.3Hz, 1H ), 4.58-4.47(m, 1H), 4.05(t, J=7.4Hz, 2H), 3.76(s, 3H), 3.03-2.98(m, 8H), 2.88-2.86(m, 1H), 2.54-2.51(m, 7H), 2. [M+H] + =1024.3.

[0806] Example 166: 4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0807]

[0808] The title compound was prepared using a procedure similar to that in Example 3.

[0809] 1H NMR (500MHz, DMSO) δ11.10 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.83-7.81 (m, 3H), 7.55 (d, J=8.4Hz, 1H), 7.48-7.43 (m, 2H), 7.14 (q, J=7.5Hz, 2H), 6.67 (s, 1H), 5.09 (dd, J=12.7, 5.5Hz, 1H), 4.33 (t, J=5.3Hz, 2 H), 4.05 (t, J=7.3Hz, 2H), 3.76 (s, 3H), 3.09-3.07 (m, 3H), 3.05-3.02 (m, 5H), 2.87-2.85 (m, 1H), 2.75 ( [M+H] + =971.2.

[0810] Example 167: 5-(4-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0811]

[0812] The title compound was prepared using a procedure similar to that in Example 3.

[0813] 1 H NMR (500MHz, DMSO) δ11.12 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.87 (d, J=7.6Hz, 2H), 7.81 (d, J=7.4Hz, 1H), 7.74 (s, 2H), 7.44 (s, 1H), 7.15 (s, 2H), 6.68 (s, 1H), 5.14 (dd, J=12.8, 5 .4Hz, 1H), 4.05(s, 2H), 3.76(s, 3H), 3.08-3.06(m, 7H), 2.94-2.85(m, 2H), 2.71-2.51(m , 10H), 2.37-2.19(m, 3H), 2.08-2.06(m, 6H), 1.89-1.86(m, 4H), 1.56-1.52(m, 6H); [M+H] +＝ 1010.4.

[0814] Example 168: 3-(5-((R)-3-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)pyrrolidine-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0815]

[0816] The title compound was prepared using a procedure similar to that in Example 3.

[0817] 1 H NMR (500MHz, DMSO) δ10.93 (s, 1H), 8.79 (s, 1H), 8.18 (s, 2H), 7.86 (s, 1H), 7.81 (d, J=7.7Hz, 1H), 7.51-7.42 (m, 2H), 7. 14 (d, J=7.9Hz, 2H), 6.68 (s, 1H), 6.63 (s, 2H), 5.03 (dd, J=13.3, 5.0Hz, 1H), 4.30 (dd, J=16.9, 3.5Hz, 1H), 4.18 (dd, J=1 6.9, 2.8Hz, 1H), 4.05 (s, 2H), 3.76 (s, 3H), 3.45 (t, J=8.0Hz, 2H), 3.14-3.00 (m, 9H), 2.94-2.84 (m, 1H), 2.58-2.55 (m, [M+H] + =996.2.

[0818] Example 169: 3-(4-(3-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-2-fluorophenyl)piperidin-2,6-dione

[0819]

[0820] The title compound was prepared using a procedure similar to that in Example 3.

[0821] 1H NMR (500MHz, DMSO) δ10.78 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.86 (s, 2H), 7.44 (s, 1H), 7.15 (s, 2H) , 7.03 (t, J=8.6Hz, 1H), 6.68 (s, 1H), 6.19 (s, 2H), 4.05 (s, 2H), 3.92 (s, 2H), 3.85 (dd, J=12.3, 4.9Hz , 1H), 3.76 (s, 3H), 3.45 (s, 2H), 3.08-3.05 (m, 7H), 2.95-2.85 (m, 1H), 2.75-2.53 (m, 10H), 2.46-2.2 4 (m, 5H), 2.08-2.06 (m, 4H), 1.98-1.90 (m, 1H), 1.86 (d, J = 11.7Hz, 2H), 1.56 (d, J = 8.8Hz, 2H); [M+H] + =945.2.

[0822] Example 170: 3-(4-(((1r,3r)-3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carbonyl)cyclobutyl)(methyl)amino)phenyl)piperidin-2,6-dione

[0823]

[0824] The title compound was prepared using a procedure similar to that in Example 11.

[0825] 1 H NMR (500MHz, DMSO) δ10.76 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.88-7.78 (m, 2H), 7.43 (s, 1H), 7.14 (d , J=8.4Hz, 2H), 7.02 (dd, J=8.7, 2.3Hz, 2H), 6.76-6.65 (m, 3H), 4.05 (t, J=7.4Hz, 2H), 3.94-3.91 (m, 1H), 3.78-3.64(m, 5H), 3.43-3.41(m, 4H), 3.19-3.17(m, 1H), 3.13-2.96(m, 8H), 2.77-2.75(m, 3H), 2.67-2.55(m, 4H), 2.42-2.40(m, 6H), 2.22-1.96(m, 8H), 1.83-1.81(m, 2H), 1.58-1.56(m, 2H); [M+H] + =969.3.

[0826] Example 171: 3-(6-(3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carbonyl)azacyclobutane-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0827]

[0828] The title compound was prepared using a procedure similar to that in Example 11.

[0829] 1 H NMR (500MHz, DMSO) δ10.96 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.89-7.75 (m, 2H), 7.44 (s, 2H), 7.15 (s, 2 H), 6.70-6.68 (m, 3H), 5.09 (dd, J=13.3, 5.2Hz, 1H), 4.32 (d, J=16.7Hz, 1H), 4.20 (d, J=16.7Hz, 1H), 4.1 3-3.99(m, 4H), 3.93(s, 3H), 3.76(s, 3H), 3.50(s, 2H), 3.08-3.05(m, 7H), 2.89-2.87(m, 1H), 2.58-2.56 (m,6H),2.46-2.30(m,5H),2.08-2.06(m,3H),2.00-1.98(m,1H),1.85(m,2H),1.59-1.57(m,2H); [M+H] + =996.3.

[0830] Example 172: 3-(5-(3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carbonyl)azacyclobutane-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0831]

[0832] The title compound was prepared using a procedure similar to that in Example 11.

[0833] 1 H NMR (500MHz, DMSO) δ10.93 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.88-7.76 (m, 2H), 7.54-7.39 (m, 2H), 7.14 (d, J=7.9Hz, 2H), 6 .68 (s, 1H), 6.59-6.46 (m, 2H), 5.04 (dd, J=13.3, 5.0Hz, 1H), 4.31-4.29 (m, 1H), 4.17 (s, 1H), 4.13 (t, J=7.8Hz, 2H), 4.02-3 .99(m, 4H), 3.88-3.86(m, 1H), 3.76-3.74(m, 3H), 3.50-3.48(m, 2H), 3.35-3.32(m, 2H), 3.14-3.00(m, 7H), 2.95-2.83(m, 1 [M+H] + =996.3.

[0834] Example 173: 3-(4-((2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)amino)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0835]

[0836] The title compound was prepared using a procedure similar to that in Example 3.

[0837] 1H NMR (500MHz, DMSO) δ11.01 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.44 (s, 1H), 7.30 (t, J=7.7 Hz, 1H), 7.16 (s, 2H), 6.96 (d, J=7.3Hz, 1H), 6.80 (d, J=7.9Hz, 1H), 6.68 (s, 1H), 5.46 (s, 1H), 5.12-5.10 (m, 1H), 4.2 4-4.22(m, 1H), 4.13-4.15(d, 1H), 4.05-4.03(m, 2H), 3.76-3.74(m, 3H), 3.283.26(m, 3H), 3.16-3.02(m, 7H), 2.93- [M+H] + =956.2.

[0838] Example 174: 3-(4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2-chloro-5-fluorophenyl)piperidin-2,6-dione

[0839]

[0840] The title compound was prepared using a procedure similar to that in Example 3.

[0841] 1H NMR (500MHz, DMSO) δ10.91 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.81 (d, J=7.2Hz, 1H), 7.49- 7.40 (m, 2H), 7.22 (d, J=10.8Hz, 1H), 7.15 (t, J=8.2Hz, 2H), 6.68 (s, 1H), 4.18-4.16 (m, 1H), 4.05-4.03 (m, 2H), 3.76-3.74 (m, 3H), 3.29-3.27 (m, 3H), 3.05-3.03 (m, 8H), 2.75-2.73 (m, 3H), 2.67-2.53 (m, 7H) , 2.38-2.25(m, 4H), 2.08-2.06(m, 3H), 1.96-1.94(m, 1H), 1.85-1.83(m, 2H), 1.57-1.55(m, 2H); [M+H] + =938.2.

[0842] Example 175: 3-(5-(4-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0843]

[0844] The title compound was prepared using a procedure similar to that in Example 3.

[0845] 1H NMR (500MHz, DMSO) δ10.92 (s, 1H), 8.79 (s, 1H), 8.16-8.14 (m, 1H), 7.88-7.78 (m, 2H), 7.50-7.41 (m, 2H), 7.14-7.12 (m, 2 H), 6.68 (s, 1H), 6.61 (d, J=7.4Hz, 2H), 5.05-4.98 (m, 1H), 4.30 (d, J=16.6Hz, 1H), 4.18 (d, J=16.4Hz, 1H), 4.05 (t, J=7.4H z, 2H), 3.76-3.74 (m, 3H), 3.50-3.48 (m, 1H), 3.38-3.36 (m, 3H), 3.12-3.00 (m, 7H), 2.94-2.92 (m, 2H), 2.67-2.52 (m, 7H) , 2.34-2.32(m, 8H), 2.15-2.13(m, 1H), 2.07-2.05(m, 3H), 1.98-1.92(m, 1H), 1.86-1.84(m, 2H), 1.59-1.57(m, 5H); [M+H] + =1010.4.

[0846] Example 176: 3-(4-(((1r,3r)-3-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclobutyl)(methyl)amino)phenyl)piperidin-2,6-dione

[0847]

[0848] The title compound was prepared using a procedure similar to that in Example 3.

[0849] 1H NMR (500MHz, DMSO) δ10.75 (s, 1H), 8.79 (s, 1H), 8.17 (s, 3H), 7.88-7.71 (m, 2H), 7.43 (s, 1H), 7.14 (d, J =8.6Hz, 2H), 7.00 (d, J = 8.6Hz, 2H), 6.76-6.61 (m, 3H), 4.34-4.31 (m, 1H), 4.04-4.02 (m, 2H), 3.76-3.7 3(m, 6H), 3.04-2.98(m, 7H), 2.74-2.71(m, 2H), 2.66-2.57(m, 4H), 2.35-2.33(m, 8H), 2.11-2.09(m, 2H) ), 2.07-2.05(m, 2H), 2.01-1.98(m, 2H), 1.84-1.82(m, 2H), 1.60-1.57(m, 4H), 1.06-1.04(m, 2H); [M+H] + =955.2.

[0850] Example 177: 3-(3-(4-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)piperidin-1-yl)phenyl)piperidin-2,6-dione

[0851]

[0852] The title compound was prepared using a procedure similar to that in Example 3.

[0853] 1 H NMR (500MHz, DMSO) δ10.79 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.86 (s, 2H), 7.43 ( s, 1H), 7.15 (d, J=7.9Hz, 3H), 6.79 (s, 2H), 6.68-6.66 (m, 1H), 6.59-6.57 (m, 1H) , 4.05-4.02(m, 2H), 3.76-3.73(m, 6H), 3.07-3.04(m, 7H), 2.61-2.59(m, 14H), 2 .33-2.15(m, 3H), 2.07-2.05(m, 4H), 1.86-1.83(m, 4H), 1.60-1.43(m, 4H); [M+H] + =941.2.

[0854] Example 178: 5-(4-(4-(1-(4-((5-chloro-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0855]

[0856] The title compound was prepared in a manner similar to that in Example 11. 1 H NMR (500MHz, DMSO) δ11.07 (s, 1H), 8.95 (s, 1H), 8.12 (d, J = 1.1Hz, 1H), 7.86 (d, J = 7.6Hz, 2H), 7.67 (d, J = 8.5Hz, 1H), 7.4 7 (s, 1H), 7.33 (s, 1H), 7.25 (d, J=8.5Hz, 1H), 7.18-7.13 (m, 2H), 6.69 (s, 1H), 5.07 (dd, J=12.4, 5.3Hz, 1H), 4.10-4.01 ( m, 4H), 3.77 (s, 3H), 3.56 (s, 2H), 3.47 (s, 2H), 3.12-3.05 (m, 10H), 3.01-2.95 (m, 1H), 2.93-2.84 (m, 1H), 2.66-2.54 (m, [M+H] + =994.5.

[0857] Example 180: 3-(6-(3-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione

[0858]

[0859] The title compound was prepared using a procedure similar to that in Example 3.

[0860] 1H NMR (500MHz, DMSO) δ10.96 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.81 (d, J=7.6Hz, 1H), 7.44 (s, 1H), 7.37 (d, J=8.0Hz, 1H), 7.15 (s, 2H), 6.68 (d, J=3.1Hz, 3H), 5.08-1.05 (m, 1H), 4.31-4.29 (m, 1H), 4.19-4.16 (m, 1H), 4.05 -4.02(m, 2H), 3.98-3.97(m, 2H), 3.76-3.73(m, 3H), 3.50-3.48(m, 2H), 3.08-3.05(m, 8H), 2.98-2.84(m, 2H), 2.61- [M+H] + =982.2.

[0861] Example 181: 3-(4-(4-((4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0862]

[0863] The title compound was prepared using a procedure similar to that in Example 3.

[0864] 1H NMR (500MHz, DMSO) δ10.86 (s, 1H), 8.79 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.81 (d, J=7.2Hz, 1H), 7 .43(s, 1H), 7.14(q, J=7.9Hz, 2H), 6.68(s, 1H), 6.60-6.58(m, 2H), 4.35(s, 2H), 4.04-4.01(m, 3H), 3.76-3.72( m, 5H), 3.05-3.01 (m, 8H), 2.74-2.71 (m, 3H), 2.60-2.56 (m, 3H), 2.32-2.29 (m, 5H), 2.13-2.09 (m, 2H), 2.07-2. [M+H] + =991.3.

[0865] Example 182: 3-((4-(3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)cyclobutyl)phenyl)amino)piperidin-2,6-dione

[0866]

[0867] The title compound was prepared using a procedure similar to that in Example 3.

[0868] 1H NMR (500MHz, DMSO) δ10.76 (s, 1H), 8.79 (s, 1H), 8.17 (s, 2H), 7.86 (s, 1H), 7.81 (d, J=7.3Hz, 1H), 7.43 (s, 1H) , 7.20-7.10 (m, 2H), 6.95 (d, J = 8.4Hz, 2H), 6.68 (s, 1H), 6.62 (t, J = 9.4Hz, 2H), 5.67 (d, J = 7.6Hz, 1H), 4.26 (d , J=11.8Hz, 1H), 4.05 (t, J=7.6Hz, 2H), 3.76 (s, 3H), 3.05-3.02 (m, 7H), 2.95 (s, 1H), 2.78-2.68 (m, 1H), 2.60 -2.57(m, 6H), 2.34-2.31(m, 6H), 2.08(m, 5H), 1.86-1.84(m, 3H), 1.74-1.72(m, 2H), 1.57-1.53(m, 2H); [M+H] + =927.2.

[0869] Example 183: 3-(4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)phenyl)-3-methylpiperidin-2,6-dione

[0870]

[0871] The title compound was prepared using a procedure similar to that in Example 3.

[0872] 1 H NMR (500MHz, DMSO) δ10.90 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.83-7.80 (m, 2H) , 7.43 (s, 1H), 7.26-6.98 (m, 6H), 6.68 (s, 1H), 4.05 (t, J=7.3Hz, 2H), 3.76 (s, 3 H), 3.14-2.97(m, 7H), 2.74-2.67(m, 2H), 2.59-2.54(m, 5H), 2.46-2.22(m, 10H ), 2.13-1.96(m, 5H), 1.85-1.82(m, 2H), 1.56-1.52(m, 2H), 1.42(s, 3H); [M+H] + =900.2.

[0873] Example 184: 3-(4-(3-((4-(1-(4-((5-bromo-4-((1-((methylsulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazin-1-yl)methyl)azacyclobutane-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0874]

[0875] The title compound was prepared using a procedure similar to that in Example 3.

[0876] 1 H NMR (500MHz, DMSO) δ10.85 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.81 (d, J=7.6Hz, 1H), 7.43 (s, 1H), 7.1 5 (t, J=8.3Hz, 2H), 6.68 (s, 1H), 6.10 (d, J=11.6Hz, 2H), 4.09-3.98 (m, 3H), 3.93 (t, J=7.5Hz, 2H), 3.76 (s, 3H), 3. 51-3.44(m, 3H), 3.14-3.00(m, 8H), 2.95-2.85(m, 1H), 2.76-2.71(m, 1H), 2.61-2.56(m, 3H), 2.54-2.51(m, 5H), 2 [M+H] + =963.2.

[0877] Example 185: 3-(4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)-3-oxopiperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidin-2,6-dione

[0878]

[0879] The title compound was prepared using a procedure similar to that in Example 3.

[0880] 1H NMR (500MHz, DMSO) 610.95 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.81 (d, J = 7.1Hz, 1H), 7.44 (s, 1H), 7.15 (d, J=7.3Hz, 2H), 7.05 (d, J=10.1Hz, 2H), 6.73 (s, 1H), 4.38 (s, 1H), 4.20-4.18 (m, 1H), 4.05-4.01 (m, 2H), 3.77 (s, 3H), 3.29-3.23 (m, 3H), 3.09-3.04 (m, 9H), 2.85-2.68 (m, 7H) , 2.62-2.58(m, 2H), 2.18-2.04(m, 4H), 2.00-1.95(m, 1H), 1.87(m, 2H), 1.61-1.58(m, 2H); [M+H] + =936.2.

[0881] Example 186: 3-(4-(4-(2-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)-3-oxopiperazin-1-yl)ethyl)piperidin-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0882]

[0883] The title compound was prepared using a procedure similar to that in Example 3.

[0884] 1H NMR (500MHz, DMSO) 610.86 (s, 1H), 8.79 (s, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 7.15 (d, J=7.3 Hz, 2H), 6.73 (s, 1H), 6.61 (d, J=12.8Hz, 2H), 4.38 (t, J=12.0Hz, 1H), 4.05 (t, J=7.4Hz, 3H), 3.81-3.67 (m, 5H), 3.29 -3.22(m, 3H), 3.14-2.97(m, 9H), 2.72-2.68(m, 5H), 2.66-2.59(m, 2H), 2.42-2.33(m, 2H), 2.09-2.05(m, 4H), 1.86 -1.82(m, 3H), 1.72-1.68(m, 2H), 1.61-1.56(m, 2H), 1.50-1.46(m, 1H), 1.40-1.37(m, 2H), 1.18-1.09(m, 2H); [M+H] + =1019.3.

[0885] Example 187: 3-(4-(3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0886]

[0887] The title compound was prepared using a procedure similar to that in Example 11.

[0888] 1H NMR (500MHz, DMSO) δ10.84 (s, 1H), 8.79 (s, 1H), 8.18 (d, J = 3.6Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 6.1Hz, 1 H), 7.44 (s, 1H), 7.15 (d, J=10.5Hz, 2H), 6.68 (s, 1H), 6.23 (d, J=14.5Hz, 2H), 4.10-3.98 (m, 3H), 3.76 (d , J=3.3Hz, 3H), 3.62-3.40 (m, 7H), 3.32 (s, 3H), 3.26 (s, 2H), 3.07-3.01 (m, 7H), 2.78-2.74 (m, 1H), 2.62 -2.56(m, 4H), 2.39(s, 1H), 2.12-2.09(m, 6H), 1.96(s, 1H), 1.86-1.82(m, 2H), 1.60-1.56(m, 2H); [M+H] + =991.2.

[0889] Example 188: 3-(4-(3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-methylphenyl)piperidin-4-yl)piperazine-1-carbonyl)azacyclobutane-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0890]

[0891] The title compound was prepared using a procedure similar to that in Example 11.

[0892] 1 H NMR (500MHz, DMSO) δ10.86 (s, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.81 (d, J=6.9Hz, 1H ), 7.44 (s, 1H), 7.15 (s, 2H), 6.68 (s, 1H), 6.17 (d, J = 11.1Hz, 2H), 4.09-3.98 (m, 6H), 3.92 (s, 4 H), 3.76 (s, 3H), 3.49 (s, 2H), 3.07-3.04 (m, 8H), 2.77-2.74 (m, 1H), 2.61-2.58 (m, 3H), 2.36-2 .32(m, 4H), 2.08-2.05(m, 4H), 1.95-1.72(m, 1H), 1.84-1.81(m, 2H), 1.59-1.57(m, 2H); [M+H] + =977.2.

[0893] Example 192: 3-(4-(2-(4-(1-(4-((5-bromo-4-((4-ethyl-1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidin-2,6-dione

[0894]

[0895] The title compound was prepared in a manner similar to that in Example 43.

[0896] 1 H NMR (500MHz, DMSO) δ10.94 (s, 1H), 8.71 (s, 1H), 8.16 (s, 1H), 7.86 (s, 1H), 7.67 (d, J = 8.2Hz, 1H), 7.46 (s, 1H), 7.03 (d, J = 10.1Hz, 2H ), 6.96 (d, J = 8.3Hz, 1H), 6.74 (s, 1H), 4.20 (dd, J = 12.7, 4.9Hz, 1H), 4.04 (t, J = 7.3Hz, 2H), 3.75 (s, 3H), 3.26-3.18 (m, 2H), 3.08-3.0 0 (m, 5H), 2.97 (d, J=11.1Hz, 2H), 2.83-2.74 (m, 3H), 2.67 (t, J=11.OHz, 2H), 2.59-2.52 (m, 7H), 2.49-2.40 (m, 6H), 2.29 (t, J=11.2Hz , 1H), 2.18-2.07 (m, 1H), 2.03-1.95 (m, 1H), 1.84 (d, J=11.5Hz, 2H), 1.61-1.51 (m, 2H), 1.18 (t, J=7.6Hz, 3H), 0.98 (t, J=7.4Hz, 3H). [M+H] + =964.7.

[0897] Example 193: 3-(4-(2-(4-(1-(4-((5-bromo-4-((4-cyclopropyl-1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidin-2,6-dione

[0898]

[0899] The title compound was prepared in a manner similar to that in Example 43.

[0900] 1H NMR (500MHz, DMSO) δ10.94 (s, 1H), 8.70 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.62 (d, J = 8.4Hz, 1H), 7.41 (s, 1H), 7.03 (d, J = 10.1Hz, 2H), 6.74 ( s, 1H), 6.61 (d, J=8.5Hz, 1H), 4.20 (dd, J=12.6, 5.0Hz, 1H), 4.06 (t, J=7.4Hz, 2H), 3.75 (s, 3H), 3.29-3.22 (m, 2H), 3.14 (t, J=7.3Hz, 2H), 3. 04 (s, 3H), 2.98 (d, J=11.2Hz, 2H), 2.85-2.73 (m, 3H), 2.67 (t, J=11.2Hz, 2H), 2.59-2.52 (m, 7H), 2.49-2.39 (m, 6H), 2.31 (t, J=11.2Hz, 1H), 2.12 (tt, J=17.0, 8.6Hz, 1H), 2.04-1.97 (m, 1H), 1.84 (dd, J=17.7, 9.4Hz, 3H), 1.63-1.53 ​​(m, 2H), 1.02-0.92 (m, 5H), 0.65 (q, J=5.3Hz, 2H). [M+H] + =976.7.

[0901] Example 194: (R)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((4-fluoro-1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0902]

[0903] The title compound (32 mg, 46%) was prepared in a manner similar to that in Example 11. ¹H NMR (500 MHz, DMSO) δ 10.84 (s, 1H), 8.69 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 6.98 (t, J = 8.5 Hz, 1H), 6.74 (s, 1H), 6.23 (d, J = 12.0 Hz, 2H), 4.10 (t, J = 7.5 Hz, 2H), 4.02 (dd, J = 12.5, 5.0 Hz, 1H), 3.76 (s, 3H), 3.58–3.42 (m, 6H), 3.38–3.33 (m, 2H). 3.30-3.20 (m, 3H), 3.17-3.08 (m, 5H), 2.98 (d, J=11.0Hz, 2H), 2.82-2.74 (m, 1H), 2.72-2.63 (m, 2H), 2.60-2.55 (m, 2H), 2.49-2.43 (m , 3H), 2.38 (t, J=10.5Hz, 1H), 2.20-2.04 (m, 3H), 1.97-1.91 (m, 1H), 1.85 (d, J=11.1Hz, 2H), 1.65-1.53 ​​(m, 2H), 0.98 (t, J=7.4Hz, 3H). [M+H] + =1023.60.

[0904] Example 195: (R)-3-(4-(2-(4-(1-(4-((5-bromo-4-((4-fluoro-1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidin-2,6-dione

[0905]

[0906] The title compound (29 mg, 40%) was prepared in a manner similar to that described in Example 3. ¹H NMR (500 MHz, DMSO) δ 10.95 (s, 1H), 8.69 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.71 (dd, J = 8.0, 4.00 Hz, 1H), 7.44 (s, 1H), 7.06–6.95 (m, 3H), 6.74 (s, 1H), 4.20 (dd, J = 12.6, 5.01 Hz, 1H), 4.10 (t, J = 7.4 Hz, 2H), 3.76 (s, 3H), 3.18–3.09 (m, 5H), 2 .97 (d, J=11.0Hz, 2H), 2.85-2.74 (m, 3H), 2.66 (t, J=11.0Hz, 2H), 2.60-2.52 (m, 6H), 2.49-2.40 (m, 5H), 2.34-2.26 (m, 1 H), 2.17-2.07 (m, 1H), 2.03-1.96 (m, 1H), 1.85 (d, J=11.5Hz, 2H), 1.56 (dd, J=20.0, 11.5Hz, 2H), 0.97 (t, J=7.5Hz, 3H). [M+H] + =954.60.

[0907] Example 196: (R)-3-(4-(3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)-4-(trifluoromethyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)azacyclobutane-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0908]

[0909] The title compound was prepared in a manner similar to that in Example 11. 1H NMR (500MHz, DMSO-d6) δ10.86 (s, 1H), 8.90 (s, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.36-7.26 (m, 2H), 6.78 (s, 1H) , 6.17 (d, J=10Hz, 2H), 4.13 (t, J=10Hz, 2H), 4.06-4.01 (m, 3H), 3.95-3.90 (m, 2H), 3.86-3.81 (m, 1H), 3.75 (s, 3H), 3.53-3. 46 (m, 2H), 3.31-3.29 (m, 1H), 3.22 (t, J=10Hz, 2H), 3.14 (s, 3H), 3.02-2.97 (m, 2H), 2.82-2.66 (m, 3H), 2.62-2.51 (m, 5H), [M+H] + =1059.7.

[0910] Example 197: (R)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((1-(methanesulfonyl)-4-(trifluoromethyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0911]

[0912] The title compound was prepared in a manner similar to that in Example 11. 1H NMR (500MHz, DMSO-d6) δ10.84 (s, 1H), 8.90 (s, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.36-7.26 (m, 2H), 6. 78 (s, 1H), 6.23 (d, J = 10Hz, 2H), 4.13 (t, J = 10Hz, 2H), 4.02 (dd, J = 15Hz, 1H), 3.75 (s, 3H), 3.61-3.41 (m, 6H), 3.36 -3.34(m, 2H), 3.32-3.20(m, 3H), 3.14(s, 3H), 3.04-2.97(m, 2H), 2.82-2.66(m, 3H), 2.62-2.51(m, 5H), 2.49-2.4 5(m, 2H), 2.44-2.35(m, 1H), 2.21-2.03(m, 3H), 1.98-1.82(m, 3H), 1.67-1.57(m, 2H), 1.00(t, J=10Hz, 3H); [M+H] + =1073.7.

[0913] Example 198: (R)-3-(4-((R)-3-(4-(1-(4-((5-bromo-4-((4-ethyl-1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-yl)-2,6-difluorophenyl)piperidin-2,6-dione

[0914]

[0915] The title compound was prepared in a manner similar to that in Example 43.

[0916] 1H NMR (500MHz, DMSO) δ10.84 (s, 1H), 8.71 (s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.2Hz, 1H), 7.46 (s, 1H), 6.96 (d, J = 8.4Hz, 1H), 6 .75 (s, 1H), 6.23 (d, J=12.2Hz, 2H), 4.08-3.99 (m, 3H), 3.76 (s, 3H), 3.59-3.42 (m, 8H), 3.30-3.21 (m, 4H), 3.08-2.96 (m, 7H), 2.78 (ddd . Hz, 1H), 2.12-2.03 (m, 2H), 1.98-1.91 (m, 1H), 1.85 (d, J=10.7Hz, 2H), 1.65-1.53 ​​(m, 2H), 1.18 (t, J=7.6Hz, 3H), 0.98 (t, J=7.4Hz, 3H). [M+H] + =1033.7.

[0917] Example 200: (R)-3-(4-(2-(4-(1-(4-((5-bromo-4-((4-(dimethylamino)-1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-2-ethyl-5-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidin-2,6-dione

[0918]

[0919] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (500MHz, DMSO-d6) δ10.95 (s, 1H), 8.53 (s, 1H), 8.12 (s, 1H), 7.81 (s, 1H), 7.60 (d, J=8.5Hz, 1H), 7 .49 (s, 1H), 7.03 (d, J = 10Hz, 2H), 6.73 (s, 1H), 6.64 (d, J = 8.5Hz, 1H), 4.20 (dd, J = 13Hz, 1H), 4.00 (t, J =7Hz, 2H), 3.76 (s, 3H), 3.08-3.01 (m, 5H), 3.00-2.94 (m, 2H), 2.86-2.51 (m, 18H), 2.49-2.26 (m, 7H), 2.17-2.07(m, 1H), 2.03-1.95(m, 1H), 1.88-1.81(m, 2H), 1.61-1.51(m, 2H), 0.98(t, J=7Hz, 3H); [M+H] + =979.0.

[0920] Example 203: (R)-3-(4-(2-(4-(1-(4-((5-bromo-4-((4-ethyl-1-(methanesulfonyl)indoline-7-yl)amino)pyrimidin-2-yl)amino)-5-ethoxy-2-ethylphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)-2,6-difluorophenyl)piperidin-2,6-dione

[0921]

[0922] The title compound was prepared in a manner similar to that in Example 3. 1H NMR (500MHz, d-DMSO) δ10.95 (s, 1H), 8.73 (s, 1H), 8.17 (s, 1H), 7.79 (s, 1H), 7.65 (d, J=8.5Hz, 1H), 7.51 (s, 1H), 7.02 (d, J=1 0.0Hz, 2H), 6.97 (d, J=8.5Hz, 1H), 6.71 (s, 1H), 4.20 (dd, J=13.0, 5.5Hz, 1H), 4.06-3.98 (m, 4H), 3.08-2.99 (m, 5H), 2.95 (d, J =11.0Hz, 2H), 2.83-2.74 (m, 3H), 2.64 (t, J = 11.0Hz, 2H), 2.60-2.41 (m, 15H), 2.29 (t, J = 11.OHz, 1H), 2.14-2.11 (m, 1H), 2.03 -1.95 (m, 1H), 1.84 (d, J=11.0Hz, 2H), 1.61-1.49 (m, 2H), 1.27 (t, J=7.0Hz, 3H), 1.18 (t, J=7.5Hz, 3H), 0.96 (t, J=7.5Hz, 3H). [M+H] + =978.2.

[0923] Cellular degradation 1

[0924] Cell treatment

[0925] On day 1, H1975 cells were seeded in 90 μl / well of 30,000 cells / well in a Coming 96-well plate (catalog number 3599) in cell culture medium [RPMI 1640 (Gibco, catalog number 72400-047), 10% heat-inactivated FBS, 1% PS (Gibco, catalog number 10378)]. On day 2, H1975 cells were treated with a compound diluted in 0.2% DMSO according to the following dilution protocol: (1) a 1000× stock solution was prepared by diluting 10 mM 4 times in DMSO, comprising a total of 8 doses; (2) a 10× solution was prepared in cell culture medium by transferring 1 μl of the 1000× stock solution to 99 μl of culture medium; (3) 10 μl of the 10× solution was added to the cells and incubated for 16 h.

[0926] HTFR Measurement

[0927] After 16 hours of treatment, 100 μL of 1× lysis buffer was added to each well; the plate was sealed and incubated at room temperature for 1 hour on a plate shaker; after cell lysis, 16 μL of cell lysate was transferred to a PE 384-well HTRF detection plate; 4 μL of premixed HTRF antibody was added to each well; the plate was covered with a plate sealer, rotated at 1000 rpm for 1 min, and incubated overnight at room temperature; readings were taken on a BMG PheraStar using the HTRF protocol (337 nm-665 nm-620 nm).

[0928] The percentage of inhibition (degradation) of a compound is calculated using the following formula: Percentage of inhibition of compound = 100 - 100 × (signal - low control) / (high control - low control), where signal = for each test compound group

[0929] Low control = lysis buffer only, no cells, indicating complete EGFR degradation;

[0930] High control = cell group with added DMSO but no compound, indicating microplate readings without EGFR degradation;

[0931] Dmax is the maximum percentage of inhibition (degradation).

[0932] The IC of a compound can be obtained by fitting the following formula. 50 (DC 50 )value:

[0933] Y = Base value + (Top value - Base value) / (1 + (IC) 50 / X)^Hillslope

[0934] Where X and Y are known values, and IC 50 The Hill slope, peak value, and basal value are parameters obtained through software fitting. Y represents the inhibition percentage (calculated by a formula), and X represents the concentration of the compound; IC50... 50 The compound concentration required to achieve 50% inhibition. IC 50 The smaller the IC value, the stronger the inhibitory effect of the compound. Conversely, the larger the IC value, the stronger the inhibitory effect. 50 The higher the value, the weaker the inhibitory ability of the compound; the Hill slope represents the slope of the fitted curve, generally around 1*; the base value represents the minimum value of the curve obtained through data fitting, which is generally 0% ± 20%; the top value represents the maximum value of the curve obtained through data fitting, which is generally 100% ± 20%. The experimental data are fitted using Dotmatics data analysis software for calculation and analysis.

[0935] Table 1. Degradation Results

[0936]

[0937]

[0938] The foregoing embodiments and descriptions of certain implementations should be considered illustrative and not limiting of the invention as defined by the claims. It will be readily understood that various variations and combinations of the above features may be utilized without departing from the invention as described in the claims. All such variations are intended to be included within the scope of the invention. All cited references are incorporated herein by reference in their entirety.

[0939] It should be understood that if any prior art publications are mentioned in this document, such mentions do not constitute an acknowledgment that such publications constitute common general knowledge in the field in any country.

[0940] Cellular degradation 2

[0941] Cell treatment

[0942] On day 1, HCC827 cells were seeded in 90 μl per well in 20,000 cells / well in a Coming 96-well plate (catalog number 3599) at a volume of 90 μl / well in cell culture medium [RPMI 1640 (Gibco, catalog number 72400-047), 10% heat-inactivated FBS, 1% PS (Gibco, catalog number 10378)]. On day 2, HCC827 cells were treated with a compound diluted in 0.2% DMSO according to the following dilution protocol: (1) a 1000× stock solution was prepared by diluting 10 mM 4 times in DMSO, comprising a total of 8 doses; (2) a 10× solution was prepared in cell culture medium by transferring 1 μl of the 1000× stock solution to 99 μl of culture medium; (3) 10 μl of the 10× solution was added to the cells and incubated for 16 h.

[0943] HTFR Measurement

[0944] After 16 hours of treatment, 100 μl of 1× lysis buffer was added to each well; the plate was sealed and incubated on a plate shaker at room temperature for 1 hour; after cell lysis, 16 μl of cell lysate diluted (2 μL to 14 μl of 1× lysis buffer) was transferred to a PE 384-well HTRF assay plate; 4 μL of premixed HTRF antibody was added to each well; the plate was covered with a plate sealer, rotated at 1000 rpm for 1 min, and incubated overnight at room temperature; readings were taken on a BMG PheraStar using the HTRF protocol (337 nm-665 nm-620 nm).

[0945] The percentage of inhibition (degradation) of a compound is calculated using the following formula: Percentage of inhibition of compound = 100 - 100 × (signal - low control) / (high control - low control), where signal = for each test compound group

[0946] Low control = lysis buffer only, no cells, indicating complete EGFR degradation;

[0947] High control = cell group with added DMSO but no compound, indicating microplate readings without EGFR degradation;

[0948] Dmax is the maximum percentage of inhibition (degradation).

[0949] The IC of a compound can be obtained by fitting the following formula. 50 (DC 50 )value:

[0950] Y = Base value + (Top value - Base value) / (1 + (IC) 50 / X)^Hill slope))

[0951] Where X and Y are known values, and IC 50 The Hill slope, peak value, and basal value are parameters obtained through software fitting. Y represents the inhibition percentage (calculated by a formula), and X represents the concentration of the compound; IC50... 50 The compound concentration required to achieve 50% inhibition. IC 50 The smaller the IC value, the stronger the inhibitory effect of the compound. Conversely, the larger the IC value, the stronger the inhibitory effect. 50 The higher the value, the weaker the inhibitory ability of the compound; the Hill slope represents the slope of the fitted curve, generally around 1*; the base value represents the minimum value of the curve obtained through data fitting, which is generally 0% ± 20%; the top value represents the maximum value of the curve obtained through data fitting, which is generally 100% ± 20%. The experimental data are fitted using Dotmatics data analysis software for calculation and analysis.

[0952] Table 2. Degradation Results

[0953]

[0954]

[0955] Cellular degradation 3

[0956] Cell treatment

[0957] BaF3 cells were seeded in 100,000 cells / well at a volume of 30 μl / well in Coming 96-well plates (catalog number 3799) in cell culture medium [RPMI 1640 (Gibco, phenol red-free, catalog number 11835-030), 10% heat-inactivated FBS, 1% PS (Gibco, catalog number 10378)]. BaF3 cells were treated with a compound diluted in 0.2% DMSO according to the following dilution protocol: (1) a 500× stock solution was prepared by diluting 4 times with 5 mM in DMSO, comprising a total of 8 doses; (2) a 2× solution was prepared in cell culture medium by transferring 0.5 μl of the 500× stock solution to 125 μl of culture medium; (3) 30 μl of the 2× solution was added to the cells and incubated for 16 h.

[0958] HTFR Measurement

[0959] After 16 hours of treatment, 20 μl of 4× lysis buffer was added to each well; the plate was sealed and incubated at room temperature for 1 hour on a plate shaker; after cell lysis, 16 μl of cell lysate was transferred to a PE 384-well HTRF detection plate (for triple mutant cells, the lysate was diluted with an equal volume of 1× lysis buffer before transfer); 4 μl of premixed HTRF antibody was added to each well; the plate was covered with a plate sealer, rotated at 1000 rpm for 1 min, and incubated overnight at room temperature; readings were taken on a BMG PheraStar using the HTRF protocol (337 nm-665 nm-620 nm).

[0960] The percentage of inhibition (degradation) of a compound is calculated using the following formula: Percentage of inhibition of compound = 100 - 100 × (signal - low control) / (high control - low control), where signal = for each test compound group

[0961] Low control = lysis buffer only, no cells, indicating complete EGFR degradation;

[0962] High control = cell group with added DMSO but no compound, indicating microplate readings without EGFR degradation;

[0963] Dmax is the maximum percentage of inhibition (degradation).

[0964] The IC of a compound can be obtained by fitting the following formula. 50 (DC 50 )value:

[0965] Y = Base value + (Top value - Base value) / (1 + (IC) 50 / X)^Hill slope))

[0966] Where X and Y are known values, and IC50 The Hill slope, peak value, and basal value are parameters obtained through software fitting. Y represents the inhibition percentage (calculated by a formula), and X represents the concentration of the compound; IC50... 50 The compound concentration required to achieve 50% inhibition. IC 50 The smaller the IC value, the stronger the inhibitory effect of the compound. Conversely, the larger the IC value, the stronger the inhibitory effect. 50 The higher the value, the weaker the inhibitory ability of the compound; the Hill slope represents the slope of the fitted curve, generally around 1*; the base value represents the minimum value of the curve obtained through data fitting, which is generally 0% ± 20%; the top value represents the maximum value of the curve obtained through data fitting, which is generally 100% ± 20%. The experimental data are fitted using Dotmatics data analysis software for calculation and analysis.

[0967] Table 3. Degradation Results

[0968]

[0969]

[0970]

[0971] The foregoing embodiments and descriptions of certain implementations should be considered illustrative and not limiting of the invention as defined by the claims. It will be readily understood that various variations and combinations of the above features may be utilized without departing from the invention as described in the claims. All such variations are intended to be included within the scope of the invention. All cited references are incorporated herein by reference in their entirety.

[0972] It should be understood that if any prior art publications are mentioned in this document, such mentions do not constitute an acknowledgment that such publications constitute common general knowledge in the field in any country.

Claims

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein: Cy1is a non-aromatic ring; m1is 1; R 1 -SO2R 1a wherein R 1a -C 1-5 alkyl; R 2 is hydrogen, or two geminal R 2 together with the atom to which they are attached form a spiro 3-, 4-, 5-, or 6-membered cycloalkyl; R 3 , R 9 , and R 10 are each independently selected from H, F, Br, CI, I, -CH3, -C2H5, -C3H7, -C4H9, -C5H 11 , -CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -N(CH3)2, -N(CH3)C2H5, or -N(C2H5)2; R 4 and R 11 are each independently selected from hydrogen or halogen, or R 4 and R 11 together with the atom or atoms to which they are attached form a 5- or 6-membered ring comprising 1 nitrogen heteroatom as a ring member; R 12 -C 1-8 alkyl; Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from -CR Z ; R Z independently at each occurrence selected from hydrogen, halogen, -C 1-8 alkyl or -OR Za ; or two R Z when attached to adjacent carbon atoms of the ring, together with the two carbon atoms to which they are attached form a 4-, 5-, 6- or 7-membered ring, which comprises 1 oxygen or sulfur heteroatom as a ring member; R Za -C 1-8 alkyl; L 1 selected from a single bond or wherein L1 refers to the position of the attachment to the moiety, and L1 refers to the position of the attachment to the moiety; L 2 selected from a single bond, -CO-, -NR L2a - or wherein L2 refers to the position of the connection to the moiety, and L2 refers to the position of the connection to the moiety; R L2a selected from hydrogen or -C 1-8 alkyl; L 3 selected from a single bond, -O-, -NR L3a - or wherein L3 refers to the position of the attachment to the moiety, and L3 refers to the position of the attachment to the moiety; R L3a selected from hydrogen or -C 1-8 alkyl; selected from R 13 and R 14 is independently selected from hydrogen, halogen or CN; X 1 , X 2 , X 3 , X 4 and X 8 are each independently selected from -CR a or N; X 6 , X 7 , and X 9 are each independently -CR a R b -; L 4 are each independently selected from a single bond, -O- or -NR a -; L 5 and L 6 each independently is selected from -CR a R b - or -C(O)-; Y 1 , Y 2 , and Y 3 are each independently CR a ; R a and R b are each independently selected from hydrogen, halogen, -C 1-8 alkyl or -C 1-8 alkoxy; m2and m3are each independently 0, 1, or 2; m6is each independently 1 or 2; m7is each independently 1 or 2; n, n1, and n2are each independently 0 or 1; and n6and n7are each independently 0 or 1.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 1a is selected from -CH3, -C2H5, -C3H7, -tert-butyl, -n-butyl, -isobutyl, or -C5H 11 .

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein two geminal R 2 form, together with the atom to which they are attached, a spiro 3- or 4-membered cycloalkyl.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein m2and m3are selected from 0 or 1. two geminal R 2 together with the atom to which they are attached form a spiro cyclopropyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein the moiety is 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein the moiety is 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein the moiety is 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 4 and R 11 are each independently selected from hydrogen, F, Br, Cl, I.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 4 and R 11 together with the atom or atoms to which they are attached form a 5-membered ring comprising 1 nitrogen heteroatom.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein moieties are selected from 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 12 is independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein selected from 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R Z is independently selected for each occurrence from hydrogen, -F, -CI, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or -OR Za ; or or two R Z when attached to adjacent carbon atoms of the ring, together with the two carbon atoms to which they are attached form a 4-, 5-, 6- or 7-membered ring, which comprises 1 oxygen or sulfur heteroatom as a ring member; R Za is independently selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R Z is independently selected at each occurrence from hydrogen, -F, -CI, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -OCH3, -OC2H5, -OC3H7, -OC4H9, or -OC5H 11 ; or two R Z when attached to adjacent carbon atoms of the ring, together with the atoms to which they are attached form a 4-, 5-, 6-, or 7-membered ring comprising 1 oxygen heteroatom.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein the moiety is selected from wherein *a refers to the position of attachment to the moiety, and *b refers to the position of attachment to the moiety.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein L 1 is selected from a single bond, 17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein L 1 selected from 18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein X 1 and X 2 are each independently selected from CH or N; m1 = 1; and R 12 is -CH3.

25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein the compound is of Formula (II):

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein L 2 is selected from a single bond, -CO-, -NR L2a -, wherein R L2a is selected from hydrogen, methyl, ethyl, or propyl.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein L 2 is selected from a single bond, -CO-, -NR L2a -, wherein R L2a is selected from hydrogen, methyl or ethyl.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein L 3 is selected from a single bond, -0-, -NR L3a -, wherein R L3a is selected from hydrogen, methyl, ethyl, or propyl.

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein L 3 is selected from a single bond, -O-, -NR L3a -, wherein R L3a is selected from hydrogen, methyl, or ethyl.

24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein is selected from wherein * refers to the position of attachment to and ** refers to the position of attachment to ​ 26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein the compound is of Formula (III): wherein: R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , R 11 , R 12 , Z1, Z2, Z3, Z4, X1, X2, X3, X4, L2, L3, the degradation determinant, n, m1, m2, m3 and m7 have the same meaning as in claim 1. n6is independently 0 or 1. wherein: R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , R 11 , R 12 , Z1, Z2, Z3, Z4, X1, X2, X3, X4, L2, L3, the degradation determinant, n, m1, m3 and m7 have the same meaning as in claim 1.

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein is selected from R 14 is independently selected from hydrogen, halogen or CN; X 8 is independently selected from CF, CH, C(CH3), C(C2H5), C(C3H7) or N; L 4 is independently selected from a single bond, -O-, or -NH-; Y 1 , Y 2 , and Y 3 are each independently CR a wherein R a are each independently selected from hydrogen, halogen, -C 1-8 alkyl or -C 1-8 alkoxy; X 9 is CH2; n6is independently 0 or 1.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 14 is independently selected from H, F, Cl, Br, I, or CN.

29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein X 8 is independently selected from CF, CH, C(CH3), C(C2H5), C(C3H7), or N; L 4 is independently selected from a single bond, -O-, or -NH-; Y 1 and Y 2 each independently CR a ; R a each independently is selected from hydrogen, halogen, -C 1-8 alkyl or -C 1-8 alkoxy; X 9 is CH2; and n6is independently 0 or 1.

30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 14 is independently selected from hydrogen or halogen; X 8 is independently selected from CH, C(CH3), C(C2H5), C(C3H7) or N; L 4 is independently selected from a single bond, -O-, or -NH-; Y 1 , Y 2 , and Y 3 are each independently CR a ; R a each independently is selected from hydrogen, halogen, -C 1-8 alkyl or -C 1-8 alkoxy; X 9 is CH2; and n6is 0 or 1; and 31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein is wherein L 5 and L 6 are each independently selected from -CH2or -CO-; X 9 is CH2; Each R 13 Independently selected from hydrogen, halogen, or CN; n7is 0 or 1.

33. A compound, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, selected from 32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein selected from 34. A pharmaceutical composition comprising a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, and a pharmaceutically acceptable excipient.

35. Use of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, in the manufacture of a medicament for the treatment of a disease involving modulation of EGFR.

36. The use of claim 35, wherein the disease is cancer.

37. The use of claim 35, wherein the disease is pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer. ​

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