Degradation of irak4 by conjugating irak4 inhibitors to e3 ligase ligands and methods of use

Abstract

Disclosed herein are novel bifunctional compounds formed by conjugating an IRAK4 inhibitor moiety to an E3 ligase ligand moiety, which function to recruit targeted proteins to E3 ubiquitin ligases for degradation; as well as methods of making and uses thereof.

Description

Cross-reference to related applications

[0001] This application claims priority to application number PCT / CN2023 / 138418, filed on December 13, 2023, the contents of which are expressly incorporated by reference. Technical Field

[0002] This article discloses a novel bifunctional compound formed by conjugating an IRAK4 inhibitor moiety with an E3 ligase ligand moiety, the function of which is to recruit target proteins to E3 ubiquitin ligases for degradation; as well as its preparation method and uses. Background Technology

[0003] Proteolytic targeting chimeras (PROTACs) consist of two covalently linked protein-binding molecules: one molecule binds to an E3 ubiquitin ligase, and the other binds to the protein of interest (POI), the target protein intended for degradation (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98: 8554–9.; Sakamoto KM et al., Methods Enzymol. 2005; 399:833–847). Recruiting the E3 ligase to a specific unwanted protein, rather than inhibiting the enzymatic activity of the target protein, leads to ubiquitination of the target protein and subsequent degradation of the target protein by the proteasome. The entire process of ubiquitination and proteasome degradation is known as the ubiquitin-proteasome pathway (UPP) (Ardley H. et al., EssaysBiochem. 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; Lydia M. et al., ACS Infect. Dis. 2019, 5, 12, 2105-2117). The proteasome is a protein complex that degrades unwanted, misfolded, or abnormal proteins into small peptides and amino acids 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 are widely used in small molecule PROTAC technology: cereblon (CRBN), Von Hippel-Lindau (VHL), mouse two-microsome 2 homolog (MDM2) and apoptosis inhibitor 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 impaired 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, act as monovalent promoters of PPIs by binding to the cereblon (CRBN) subunit of the CRL4ACRBN E3 ligase complex and recruiting novel substrate proteins (Matyskiela, ME et al., Nat Chem Biol 2018, 14, 981-987). Therefore, the ability of thalidomide and its derivatives to recruit CRBN has been widely applied in 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 have great potential to eliminate protein targets that are "undruggable" by traditional inhibitors or that are non-enzymatic proteins (Chu TT. et al., CellChem 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 promoting the selective degradation of various target proteins in anti-tumor research.(Lu J. et al., Chem Biol. 2015;22(6):755-763; Ottis P. et al., Chem Biol. 2017; 12(4):892-898.; Crews CM et al., J MedChem. 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 Int Ed. Engl. 2016;55(6):1966‐1973;Yonghui Sun et al., Leukemia, Vol. 33, pp. 2105-2110 (2019); Shaodong Liu et al., Medicinal Chemistry Research, Vol. 29, pp. 802-808 (2020); and has been published in patents, such as US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO201 WO2016197114, WO2017011590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449 and WO2018071606 are publicly disclosed or discussed.

[0004] Interleukin-1 receptor-associated kinases (IRAK1, IRAK2, IRAK3, and IRAK4) are serine-threonine kinases that regulate innate immune and inflammatory responses. In addition to performing normal kinase functions, IRAK4 also functions as a protein scaffold and regulates downstream signaling via the myddosome protein complex. Activation of the TLR or IL-1R initiates receptor dimerization and recruits the myeloid differentiation primary response 88 (MyD88) adaptor protein through its intracellular domain. MyD88 further recruits IRAK4 and IRAK1 / 2 to form a multi-protein complex, the mydosome. The interaction between MyD88 and IRAK4 first recruits the pre-formed IRAK-1. IRAK4 then phosphorylates and activates IRAK-1. Fully activated IRAK-1 recruits the TRAF6-TAK1-TAB-1 / 2 complex. Activated TAK-1 phosphorylation leads to downstream signaling cascades, including IκB kinase (IKK)-nuclear factor-κB (NF-κB) and MAPKs such as c-Jun N-terminal kinase (JNK) and p38, resulting in the production of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, IL-12, and TNF. These signaling pathways play crucial roles in innate and adaptive immune responses (Elizabeth L. et al., Eur. J. Immunol. 2008, 38, 3, 870-876.

[0005] The pro-inflammatory effect of IRAK4 has been confirmed in studies of knock-in mice with IRAK4 kinase death (W. Michael S. et al., A CS Med. Chem. Lett. 2015, 6, 942-947). Mice with this genotype are resistant to joint inflammation in several rodent models of arthritis. (Koziczak-Holbro et al., 2009) Arthritis rheumatism IRAK4 deficiency improves disease activity in various animal models of rheumatoid arthritis (RA). Furthermore, small human populations of IRAK4 deficiency have been identified. Reduced expression of pro-inflammatory cytokines from macrophages, and decreased inflammation and migration of fibroblast-like synovial cells were observed. Cells from these patients showed impaired responses to ILR / TLR receptor stimulation. No severe viral, fungal, or parasitic infections were observed in those adult patients (Gosu, V. et al.). Sci Rep 4 , 2014, 5748; Shichijo K. et al., Pediatrics International (2015). These data from rodents and humans suggest that IRAK4 inhibitors can modulate the production of key inflammatory cytokines and cytokine-induced pathologies.

[0006] However, reports indicate that although IRAK4 phosphorylation levels are reduced in IL-1β-stimulated human dermal fibroblasts, pharmacological inhibition of IRAK4 does not lead to IL-6 and TNF-α inhibition, suggesting that kinase activity may not be the sole factor in certain cell types (O'Neill, LA). Immunol. Rev. 2008, 226, 10-8; Nunes J., et al. ACS Med. Chem. Lett. (2019, 10, 1081). Therefore, in addition to inhibiting kinase activity, removing IRAK4 scaffold function can provide better therapeutic outcomes. In this regard, IRAK4-targeting PROTACs can serve as a potential strategy for targeting both IRAK4 kinase activity and scaffold function. IRAK4 PROTACs may ultimately bring new therapeutic opportunities for the treatment of autoimmune diseases, inflammatory diseases, and oncological diseases. The following patents disclose or discuss IRAK4 PROTACs: WO2019133531, US20190192668, WO2019099926, WO2020113233, WO2020264499, WO2021158634, WO2020264490, WO2021119159, WO2021168197, and WO2021127278.

[0007] Recently, some PROTACs targeting IRAK4 have been published (Nunes J., et al.). ACS Med. Chem. Lett. 2019, 10, 1081; Zhang et al. ., Cell Chem. Bio. 2020, 27, 1; Robert BK et al. ACS Med. Chem. Lett. (2019, 10, 1251). Most of these molecules are based on published IRAK4 inhibitors as warheads. However, little data shows that those IRAK4 PROTACs exert stronger inhibition of cytokine production such as IL-6 and TNF-α compared to IRAK4 kinase inhibitors. There is a need for IRAK4 PROTACs that demonstrate stronger inhibition of cytokine production such as IL-6 and TNF-α compared to IRAK4 kinase inhibitors. Summary of the Invention

[0008] In the following invention, a well-designed IRAK4 PROTAC has shown superior reduction of pro-inflammatory cytokines in a variety of cell lines compared to small molecule inhibitors.

[0009] This application provides novel bifunctional compounds and compositions for the treatment of autoimmune diseases, inflammatory diseases, and tumors.

[0010] In one embodiment, this document discloses a bifunctional compound of formula (X) that can selectively degrade IRAK4. The compound described herein, or a salt thereof, can be used to treat diseases that may be affected by IRAK4 regulation. This invention provides the use of the compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating diseases that may be affected by IRAK4 regulation. This invention further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for treating diseases that may be affected by IRAK4 regulation. This application further provides a method of treating a proliferative condition, the method comprising administering a therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need. Embodiments include the following aspects: Aspect 1. A compound of formula (X) (X) Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analogue or prodrug, in: Y 1 and Y 9 Each is independently selected from C, N, O, or S; Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Each is independently selected from C or N; the condition is that and Each is an aromatic ring; s1 is 0, 1, or 2; s2 is 0, 1, 2, or 3; R 1 and R 2 Each can be independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -CN, or -OR. 1a or -NR 1a R 1b Each of the -C1-C8 alkyl or -C3-C8 cycloalkyl groups is optionally substituent R. 1c replace; R 1a and R 1bEach of the following is independently selected from hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, C1-C8 alkoxy-C1-C8 alkyl- or C3-C8 cycloalkyl; each of the following is optionally substituted by at least one substituent selected from halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl-OH or -C3-C8 cycloalkyl; R 1c Each time it appears, it is independently a halogen, -OH, -CN, oxo group (=O), -C1-C8 alkyl, -C1-C8 haloalkyl, -C3-C8 cycloalkyl, -C1-C8 alkoxy or C1-C8 alkoxy-C1-C8 alkyl-; R 11a R 11b R 12a and R 12b Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C 1-8 alkoxy or -C 3-8 cycloalkyl; the -C 1-8 Alkyl, -C 1-8 alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally selected from at least one element selected from hydrogen, halogen, -C 1-8 Substitution with alkoxy, -OH, or -CN groups; L 1 Selected from -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, , , , , , , , , , and ; wherein , , , , , , , , , and Each of them is optionally controlled by at least one R L1c replace; in It refers to and The location of partial connections, and It refers to and The location of the partial connection; L 2 Selected from -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, , , , , , and ; wherein , , , , , and Each of them is optionally controlled by at least one R L2c replace; in It refers to and The location of partial connections, and It refers to and The location of the partial connection; L 3 Selected from -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 -, -O, -NR ethynyl groups a -、-CONR a -、-C(O)O-、 , , , , , and ; wherein -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, , , , , , and Each of them is optionally controlled by at least one R L3c replace; in It refers to and The location of partial connections, and It refers to and The location of the partial connection; The RL1c R L2c and R L3c Each of these is independently an oxo group (=O), a halogen, a hydroxyl group, a -CN group, a -C1-C8 alkyl group, or a -C1-C8 alkoxy group; each of the -C1-C8 alkyl or -C1-C8 alkoxy groups is optionally surrounded by at least one R group. Lca replace, R Lca It can be independently an oxo group (=O), halogen, hydroxyl group, -CN, -C1-C8 alkoxy group or C3-C8 cycloalkyl group; It is the E3 ubiquitin ligase binding site; X appears each time 1 and X 2 Each independently selected from -CR a Or N; X appears each time 3 and X 4 Each independently selected from -NR a -、-O-、-S- and -CR a R b -; X appears each time 5 and X 6 Each is independently selected from non-existent, single bond, -C(O)-, -NR a -and-O-; R each time it appears a and R b Each is independently selected from hydrogen or -C1-C4 alkyl groups; m1 and m3 are each independently 0, 1 or 2; m2 is 0 or 1; n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3.

[0011] In some implementations, the compound is .

[0012] Aspect 2. The compound as described in aspect 1, wherein Partially selected from , , , , or amino acid residues; Z 1 and Z 2 Each is independently N or CR z ; R z and R 13Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-4 Alkyl or CN; L 4 Selected from single bond, -O-, -NR a -or-C(O)NR a -; L 5 and L 6 Each is independently selected from single bonds, -O-, and -NR. a -or -C(O)-; n6 is 0, 1, 2, or 3; and R each time it appears a and R c Each is independently selected from hydrogen or -C1-C4 alkyl groups.

[0013] Aspect 3. The compound as described in aspect 1, wherein the compound is selected from formula (IIa), (IIa).

[0014] In some specific implementations, the compound is: .

[0015] In some specific implementations, the compound is: .

[0016] In some specific implementations, the compound is: .

[0017] In some specific implementations, the compound is: .

[0018] In some specific implementations, the compound is: .

[0019] In some other embodiments, the compound is: .

[0020] In some other embodiments, the compound is: .

[0021] In some other embodiments, the compound is: .

[0022] In some other embodiments, the compound is: .

[0023] In some other embodiments, the compound is: .

[0024] In some other embodiments, the compound is: .

[0025] In some other embodiments, the compound is: .

[0026] In some other embodiments, the compound is: .

[0027] In some other embodiments, the compound is: .

[0028] In some specific implementations, the compound is: .

[0029] Aspect 4. The compound as described in any of the preceding aspects, wherein Partially selected from , or ; Preferably, Partially selected from , or .

[0030] Aspect 5. The compound as described in any of the preceding aspects, wherein Partially selected from , or ; Preferably, Partially selected from , or .

[0031] Aspect 6. The compound as described in any of the preceding aspects, wherein R 1 and R 2 Each can be independently hydrogen, halogen, -C1-C5 alkyl, -CN, or -OR 1a The -C1-C5 alkyl group is optionally substituent R. 1c replace; R 1aIndependently selected from hydrogen or -C1-C8 alkyl; the -C1-C8 alkyl is optionally substituted by at least one substituent selected from halogen, -OH, -CN or -C1-C8 alkyl-OH; R 1c Each time it appears, it is independently a halogen, -OH, -CN, oxo group (=O), -C1-C8 alkyl, -C1-C8 haloalkyl or -C1-C8 alkoxy.

[0032] In some preferred embodiments, R 1 and R 2 Each can be independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, -CN, or -OR. 1a Each of the methyl, ethyl, propyl, butyl, or pentyl groups is optionally substituent R. 1c replace; R 1a The group is independently selected from hydrogen, methyl, ethyl, propyl, butyl, or pentyl; each of the methyl, ethyl, propyl, butyl, or pentyl groups is optionally substituted by at least one substituent selected from -F, -Cl, -Br, -I, -OH, -CN, or -C1-C8 alkyl-OH. R 1c Each time it appears, it is independently -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, -C1-C8 haloalkyl or -C1-C8 alkoxy.

[0033] In some preferred embodiments, R 1 and R 2 Each of these can be independently represented as H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CF3, -CF2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CHF2, -CN, -OMe, -OEt, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2OH. , or .

[0034] In some preferred embodiments, R 1 It is H, -CF3, -F, or -CN; and R 2 Is H, -CH3, -CH(CH3)2, -OMe, -OCD3, -OEt, -OCH2CH2OH, , or .

[0035] Aspect 7. The compound as described in any of the preceding aspects, wherein R 11a R 11b R 12a and R 12b Each of the following is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; each of the following is optionally selected from hydrogen, F, Cl, Br, I, -C 1-8 Substitution with alkoxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, or -CN substituents.

[0036] In some preferred embodiments, R 11a R 11b R 12a and R 12b Each of the following is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0037] In some preferred embodiments, R 11a R 11b R 12a and R 12b Each is hydrogen independently.

[0038] Aspect 8. The compound as described in any of the preceding aspects, wherein... Part of it is , , , , , , , , , , , or .

[0039] Aspect 9. The compound as described in any of the preceding aspects, wherein L 1 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; The above , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by at least one R L1c replace; The R L1c Each of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca It can be independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0040] In some embodiments, the compound of any one of the foregoing aspects, wherein L 1 Selected from The Optionally by at least one R L1c replace; The R L1cEach of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca It can be independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0041] Aspect 10. The compound as described in any of the preceding aspects, wherein L 1 Selected from , , ( or ), , , , , , , , , , , , , , , , , , , , , , , , , , , ( or ), ( or ), , ( or ), , ( or ), ( or ), ( or ), ( or ), , , , , , ( or ), , , , , , , , , , , , , ( or ), ( or ), ( , , or ), , , , ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), , , ( or ), , , , , , , , , , , ( or ), ( or ), , or ; In some preferred embodiments, L 1 Selected from , or .

[0042] Aspect 11. The compound as described in any of the preceding aspects, wherein L 2 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; The above , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by at least one R L2c replace; The R L2cEach of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca It can be independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0043] In some implementations, L 2 Selected from , or ; wherein , or Each of them is optionally controlled by at least one R L2c replace; The R L2c Each of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca It can be independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0044] Aspect 12. The compound as described in any of the preceding aspects, wherein L 2 Selected from , , , , , , , , , , , , , , , , , , , , , , , ( or ), ( or ), , ( or ), , ( or ), ( or ), ( or ), ( or ), , , , , , ( or ), , , , , , , , , , , , ( or ), ( or ), ( , , or ), , , , ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), , , ( or ), , , , , , , , , , , ( or ), ( or ), , or .

[0045] In some implementations, L 2 Selected from , ( or ), ( or ), , , or .

[0046] Aspect 13. The compound as described in any of the preceding aspects, wherein L 3 Selected from -O-, -N(R) a )-、-C(O)NR a -、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; The above , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by at least one R L3c replace; The R L3c Each of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca Independently, it can be an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; R a It is selected from hydrogen, methyl, ethyl, propyl or butyl.

[0047] In some implementations, L 3 Selected from -O-, -C(O)NR a -、 , , and ; The above , , and Each of them is optionally controlled by at least one R L3c replace; The R L3c Each of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca Independently, it can be an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; R a It is selected from hydrogen, methyl, ethyl, propyl or butyl.

[0048] Aspect 14. The compound as described in any of the preceding aspects, wherein L 3 Selected from -O-, -N(CH3)-, -NH-, -C(O)NH-, , , , , , , , , , , , , , , , , , , , , , , , , , ( or ), ( or ), , ( or ), ( or ), ( or ), , ( or ), ( or ), ( or ), ( , ), , , , , , , ( or ), , , , , , , , , , , , ( or ), ( or ), ( , , or ), , , , ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), , , ( or ), , , , , , , , , , , ( or ), ( or ), , or .

[0049] In some implementations, L 3 Selected from -O-, -C(O)NH-, , , and .

[0050] Aspect 15. The compound as described in any of the preceding aspects, wherein Partially selected from , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , or .

[0051] In some implementation schemes, Partially selected from , , , , , , , , , , , , , or , .

[0052] Aspect 16. The compound as described in any one of Aspects 2-15, wherein L 4 Independently selected from single bonds, -O-, -NR a -or-C(O)NR a -; R each time it appears a It is independently selected from hydrogen, methyl, ethyl, propyl or butyl.

[0053] In some implementations, L 4 It is independently selected from single bonds, -NH- or -C(O)NH-.

[0054] Aspect 17. The compound as described in any one of Aspects 2-16, wherein Z 1 and Z 2 At most one of them is N.

[0055] Aspect 18. The compound as described in any one of Aspects 2-17, wherein Z 1 and Z 2 Each independently for CR z ; R z Each time it appears, it is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, or CN.

[0056] In some implementation schemes, R z Selected from H, -CH3, F or -Cl.

[0057] Aspect 19. The compound as described in any one of Aspects 2-18, wherein R 13 Selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, or CN.

[0058] In some implementation schemes, R 13 Selected from H, -CH3, F or -Cl.

[0059] Aspect 20. The compound as described in any one of Aspects 2-19, wherein L 5 and L 6 Each is independently selected from single bonds, -O-, and -NR. a -or -C(O)-; R a It is independently selected from hydrogen, methyl, ethyl, propyl or butyl.

[0060] In some implementations, L 5 and L 6 Each can be a single bond, -O-, -NH-, -NMe-, or -N(CH2CH3)-.

[0061] In some preferred embodiments, L 5 It is -CO-, and L 6 It is -NH- or -NMe-.

[0062] Aspect 21. The compound as described in any of the preceding aspects, wherein yes .

[0063] Aspect 22. The compound as described in any of the preceding aspects, wherein They are amino acid residues; In some implementation schemes, It is lysine amide; In some preferred embodiments, yes .

[0064] Aspect 23. The compound as described in any of the preceding aspects, wherein yes , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , or .

[0065] Aspect 24. The compound as described in any of the preceding aspects, wherein the compound is selected from:

[0066] Aspect 25. A pharmaceutical composition comprising any one of aspects 1 to 24, or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

[0067] Aspect 26. A method for treating a disease that may be affected by IRAK4 regulation, the method comprising administering to a subject in need an effective amount of any one of Aspects 1 to 24, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, or thereof.

[0068] Aspect 27. The method as described in aspect 26, wherein the disease is selected from autoimmune diseases and inflammatory conditions, preferably systemic lupus erythematosus, hidradenitis suppurativa, rheumatoid arthritis, arthritis, gout, multiple sclerosis, psoriasis and cancer, preferably acute myeloid leukemia, cancer, lymphoma, B-cell myelodysplastic syndrome.

[0069] Use of any compound of any one of aspects 1-24, or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, in the preparation of a medicament for treating diseases that may be affected by IRAK4 regulation.

[0070] Aspect 29. Use as described in aspect 28, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer or non-small cell lung cancer. Detailed Implementation

[0071] The following terms have the meanings indicated throughout this specification: As used herein (including the appended aspects), unless the context clearly indicates otherwise, the singular forms of words such as “a / an” and “the” include their corresponding plural referents.

[0072] Unless the context clearly specifies otherwise, the term “or” is used to mean “and / or” and is used interchangeably.

[0073] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18, 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 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C64 ... 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or 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.

[0074] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocyclic alkyl groups. In one embodiment, the "cycloalkyl" is "-C3-C8 cycloalkyl", "-C3-C8 cycloalkyl", or "-C3-C8 cycloalkyl" as described in the specification or claims. 12 Any one of “cycloalkyl”, “cyclopropyl”, “cyclobutyl”, “cyclopentyl”, “cyclohexyl”, “cycloheptyl” or “cyclooctyl”.

[0075] The term "aryl" used alone or in combination with other terms refers to a group selected from the following: - 5- and 6-membered carbon rings, aromatic rings, such as phenyl; - Bicyclic systems, such as 7- to 12-membered bicyclic systems, wherein at least one ring is a carbocyclic and aromatic, such as naphthyl and indanyl; and - Tricyclic systems, such as decacyclic to 15-membered tricyclic systems, wherein at least one ring is a carbocyclic ring and an aromatic ring, such as fluorene.

[0076] In one embodiment, the "aryl" is "C6-C" as described in the specification or claims. 12 Any of the aryl groups.

[0077] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 cyclic carbon atoms (i.e., C64, C16, C2 ... 5-10Aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0078] The term "aryl-alkyl-" refers to an alkyl group as defined above that is further substituted with an aryl group. Examples of aryl-alkyl groups include aryl-C 1-8 Alkyl groups, such as phenylethyl or phenylmethyl (benzyl).

[0079] The term "heteroaryl" refers to a group selected from the following: - 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, or in some embodiments 1 to 2 heteroatoms, the remaining ring atoms being carbon; - A 7- to 12-membered bicyclic ring comprising at least one heteroatom, such as 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and - An 11- to 14-membered tricyclic ring containing at least one heteroatom, such as 1 to 4, or 1 to 3 in some embodiments, or 1 or 2 heteroatoms selected from N, O and S in other embodiments, 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.

[0080] In one embodiment, the "heteroaryl" is any one of "5 to 12-membered heteroaryl", "5-membered heteroaryl", "6-membered heteroaryl", "7-membered heteroaryl", "8-membered heteroaryl", "9-membered heteroaryl", "10-membered heteroaryl", "11-membered heteroaryl" or "12-membered heteroaryl" as described in the specification or claims.

[0081] 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 is no greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no greater than 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. As used herein, the term "C-linked heteroaryl group" means that the heteroaryl group is linked to the core molecule by a bond from a C atom of the heteroaryl ring. The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 cyclic members, wherein 1, 2, 3, or 4 heteroatomic ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring, which is bicyclic and has one or two heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0082] The terms “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, bridging, spirocyclic, and fused heterocyclic groups. The term “optionally oxidized sulfur” as used herein refers to S, SO, or SO2.

[0083] 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-overlapping 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 specifically indicated, reference to one isomer applies to any possible isomer. All possible isomers are included unless the isomer composition is specified.

[0084] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight (e.g., no more than 30%, further such as no more than 25%, or even further such as no more than 20%) of any other stereoisomer. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight (e.g., no more than 5%, such as no more than 1%) of any other stereoisomer.

[0085] Unless otherwise stated, when the compounds disclosed herein contain olefinic double bonds, such double bonds are intended to include both E and Z geometric isomers.

[0086] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring 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.

[0087] 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 a 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 many methods, including, for example: reversed-phase and normal-phase; size exclusion; ion exchange; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus; small-scale analytical; simulated moving bed (“SMB”) and preparative thin-layer or thick-layer chromatography, as well as techniques for small-scale thin-layer and rapid chromatography. Those skilled in the art will apply the techniques most likely to achieve the desired separation.

[0088] "Diarrhetinic isomers" 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 stepwise crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher's acid chloride) to convert the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0089] "Pharmaceutically acceptable salts" are those salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or individually by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0090] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing the acid salt solution. Conversely, if the product is a free base, the addition salt, such as a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and / or water and treating the solution with acid. Those skilled in the art will recognize that various synthetic methods can be used to prepare non-toxic, pharmaceutically acceptable addition salts without excessive experimentation.

[0091] As defined herein, “pharmaceutically acceptable salts” include salts of at least one compound of formula (I) and salts of stereoisomers of the compound of formula (I), such as enantiomer salts and / or diastereomer salts.

[0092] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the terms “administration” 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. Cellular 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 ex vivo 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.

[0093] The term "effective amount" or "therapeutic effective amount" refers to an amount of active ingredient (such as a compound) sufficient to affect such treatment against a disease, condition, or symptom when administered to a subject to treat a disease, or at least one clinical symptom of a disease or condition. 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 symptoms of the disease or condition; the age of the subject to be treated; and / or the weight of the subject to be treated. In any given case, the 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 thereof and / or at least one pharmaceutically acceptable salt thereof that effectively "treats" a subject's disease or condition as defined above. In the case of combination therapies, "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat a disease, condition, or symptom.

[0094] Pharmaceutical compositions comprising the compounds disclosed herein may be administered to subjects in need via oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition may be a conventional solid formulation, such as tablets, powders, granules, capsules, etc.; a liquid formulation, such as an aqueous or oil suspension, or other liquid formulations, such as syrups, solutions, suspensions, etc.; for parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oil suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition may be administered as a single unit with a precise dosage. Additionally, the pharmaceutical composition may contain additional active ingredients.

[0095] All formulations of the pharmaceutical compositions disclosed herein can be produced using conventional methods in the pharmaceutical industry. For example, the active ingredient can be mixed with one or more excipients and then formulated into the desired formulation. "Pharmaceutically acceptable excipients" refer to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as: diluents; mediators, such as water, various organic solvents, etc.; fillers, such as starch, sucrose, etc.; binders, such as cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP); wetting agents, such as glycerin; disintegrants, such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as cetyl alcohol; absorbent carriers, such as kaolin and soap clay; lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical compositions may also contain other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, flavorings, sweeteners, and dyes.

[0096] The term “disease” means any illness, discomfort, ailment, symptom or indication and is interchangeable with the terms “symptom” or “illness”.

[0097] Throughout this specification and the appended aspects, unless the context otherwise requires, the term "comprise" and its variations (such as "comprises / comprising") are intended to specify the presence of the feature that follows, 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 "contains," "including," or sometimes "has."

[0098] Throughout this specification and the appended aspects, 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 carbon atoms. Examples include C. 1-8 C 1-6 wait.

[0099] Unless otherwise explicitly 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.

[0100] Example 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 the accuracy of 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, Pharmablock, Bidepharm, 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; the reaction flasks were equipped with rubber septa for introducing the substrate and reagents via syringe; and the glassware was dried by drying and / or heat-drying.

[0101] 1 H NMR spectra were recorded on Agilent instruments operating at 400 MHz or 500 MHz. 1 H 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 were used: s (singleton), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad peak), dd (doublet), dt (doubletuplet). Coupling constants were reported in Hertz (Hz).

[0102] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity), detector: MWD (190-400 nm), mass detector: 6120 SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120EC-C18, 4.6 × 50 mm, 2.7 pm, gradient method: flow rate: 1.8 mL / min, time (min) A (%) B (%)

[0103] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120 EC-C18, 4.6 × 50 mm, 2.7 pm, gradient method: flow rate: 1.8 mL / min, time (min) A (%) B (%)

[0104] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II), detector: MWD (190-400 nm), mass detector: G6125C SQ, mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid, column: Poroshell 120 EC-C18, 4.6 × 50 mm, 2.7 pm, gradient method: flow rate: 1.2 mL / min, time (min) A (%) B (%)

[0105] Preparative HPLC was performed on a column (150 x 21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml / min, an injection volume of 2 ml, at room temperature, and with UV detection at 214 nm and 254 nm.

[0106] Example 029: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(6-((2,6-dioxopiperidin-3-yl)amino)-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: 8-(2-methyl-6-nitropyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane K₂CO₃ (2.07 g, 1.5 mmol) was added to a solution of 3-fluoro-2-methyl-6-nitropyridine (1.56 g, 10 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (1.58 g, 11 mmol) in 20 mL of DMF. The resulting mixture was stirred at 80 °C for 16 hours. After LCMS showed that the reaction was complete, the reactants were poured into water (150 mL), the precipitate was filtered, washed with water, and dried in air to give the desired product (2.4 g, 86.02%). [M+H] + = 280.5.

[0107] Step 2: 6-Methyl-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridine-2-amine Pd / C (1 g, 10 wt.%, wet) was added to a solution of 2.4 g (8.6 mmol) of 8-(2-methyl-6-nitropyridin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane in 20 mL DCM and 20 mL MeOH. The mixture was stirred at room temperature under a hydrogen atmosphere (balloon) for 12 hours. After the reaction was complete as shown by LCMS, the mixture was filtered through a diatomaceous earth pad and washed with DCM. The filtrate was concentrated under vacuum to give the desired product (2 g, 93.28%). [M+H] + = 250.5.

[0108] Step 3: N-(2,6-bis(benzyloxy)pyridin-3-yl)-6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]) (dec-8-yl)pyridine-2-amine Pd2(dba)3 (128 mg, 0.14 mmol), xantphos (162 mg, 0.28 mmol), and Cs2CO3 (2.75 g, 8.43 mmol) were added to a solution of 6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridine-2-amine (700 mg, 2.81 mmol) and 2,6-bis(benzyloxy)-3-bromopyridine (1.14 g, 3.09 mmol) in dioxane (15 mL). The mixture was stirred at 110 °C under N2 for 16 h. After the reaction was complete as indicated by LCMS, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH = 30:1) to give the product (1.3 g, 85.9%). [M+H] + =539.5.

[0109] Step 4: 3-((6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridin-2-yl)amino)piperyl 2,6-Diketone Anhydrous Pd / C (1 g) was added to a solution of N-(2,6-bis(benzyloxy)pyridin-3-yl)-6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridin-2-amine (1.3 g, 2.41 mmol) in i-PrOH (60 mL) and DMF (20 mL) at room temperature. The mixture was then stirred at room temperature under a hydrogen atmosphere (balloon) for 16 hours. LCMS showed that the reaction was complete. The mixture was then filtered and washed with i-PrOH (50 mL). The filtrate was then concentrated under vacuum to give the product (510 mg, 58.7% yield). [M+H] + = 361.5.

[0110] Step 5: 3-((6-methyl-5-(4-oxopiperidin-1-yl)pyridin-2-yl)amino)piperidin-2,6-dione 3-((6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridin-2-yl)amino)piperidin-2,6-dione (510 mg, 1.41 mmol) was placed in a 100 mL round-bottom flask equipped with a magnetic stir bar. Then, 10 mL of 8N HCl aqueous solution was added. The mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to a saturated NaHCO3 aqueous solution, with the final pH being 6–7. The liquid was extracted with DCM (2 x 50 mL). The combined organic phases were concentrated under vacuum and purified by combiflash (DCM:MeOH = 25:1) to give the title compound (420 mg, 94.15% yield). [M+H] + = 317.5.

[0111] Step 6: 3-Cyanopyrrolo[1,2-b]pyridazine-7-carboxylic acid Pd(dppf)Cl₂ (98.9 mg, 0.14 mmol), Pd(AcO)₂ (31.7 mg, 0.14 mmol), Xantphos (160.85 mg, 0.28 mmol), and TEA (818.5 mg, 8.1 mmol) were added to a solution of 7-bromopyrrolo[1,2-b]pyridazine-3-carboxynitrile (600 mg, 2.70 mmol) in THF (12 mL) and water (4 mL). The mixture was then stirred at 95 °C under CO₂ (4 MPa) for 16 hours. The mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the product (300 mg, 59.4%). [M+Na] + = 210.2.

[0112] Step 7: 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylic acid Methyl ester 4-((1r,4r)-4-aminocyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (142 g, 0.5 mol) was added to a solution of methyl 4-formyl-3-nitrobenzene (105 g, 0.5 mol) in propan-2-ol (1000 mL). The mixture was stirred at 85 °C under N2 for 3 hours. The reaction was then cooled to room temperature. Tri-n-butylphosphine (303 g, 1.5 mol) was added to the above solution. The mixture was stirred at 85 °C under N2 for 3 hours. The mixture was cooled to room temperature and precipitated. The mixture was then filtered, and the filter cake was washed with propan-2-ol (200 mL × 2). The filter cake was collected and dried under reduced pressure to give the product (130 g, 58.75%). [M+H] + = 443.3.

[0113] Step 8: Methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate NaNO3 (29.58 g, 0.35 mol) was slowly added in portions to a solution of methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (130 g, 0.29 mol) in concentrated H2SO4 (500 mL) at 0 °C. The mixture was stirred at 0 °C for 3 hours. The mixture was poured into ice water, then adjusted to pH 9 with saturated Na2CO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to give a crude product (112 g, 100%), which was used without further purification. [M+H] + = 388.2.

[0114] Step 9: 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole- Methyl 6-formate Et3N (43.9 g, 0.435 mol) and Boc2O (69.6 g, 0.32 mol) were added to a solution of methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (112 g, 0.29 mol) in DCM (1500 mL). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with DCM (2000 mL), washed with saturated aqueous sodium carbonate solution (2000 mL × 2) and brine (2000 mL × 2), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM: MeOH = 30: 1) to give the product (140 g, 98%). [M+H] + = 488.2.

[0115] Step 10: 5-Amino-2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indyl Methyl 6-azole carboxylate Pd / C (28 g) was added to a solution of methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate (140 g, 0.287 mol) in THF (1500 mL). The mixture was then stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under vacuum to give the product (110 g, 0.24 mol), which was used directly in the next step. [M+H] + = 458.3 Step 11: 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(2,2,2-trifluoro Methyl acetamyl-2H-indazole-6-carboxylic acid TFAA (50.6 g, 240.9 mmol) was added dropwise to a solution of methyl 5-amino-2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (105 g, 229.4 mmol) in DCM (1000 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was quenched with ice water, then adjusted to pH 8 with saturated NaHCO3 solution and extracted with DCM (3 x 1000 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The residue was purified by silica gel column chromatography (DCM: MeOH = 30: 1) to give the product (120 g, 94.5%). [M+H] + = 554.2 Step 12: 4-((1r,4r)-4-(6-(2-hydroxypropyl-2-yl)-5-(2,2,2-trifluoroacetamido)-2H-indyl tert-butyl 2-azolylcyclohexylpiperazine-1-carboxylate MeMgBr (3 M, 692.4 mL, 2077.2 mmol) in THF was added dropwise to a solution of methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(2,2,2-trifluoroacetamido)-2H-indazole-6-carboxylate (115 g, 207.7 mmol) and LiCl (44.03 g, 1038.7 mmol) in 1500 mL of THF. The resulting mixture was stirred overnight at 0 °C. The mixture was slowly quenched with saturated NH4Cl solution (1500 mL) and acidified to pH 5 with HCl (1 mol / L). The mixture was then extracted with EtOAc (3 × 1000 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM: MeOH = 20:1) to give the product (100 g, 86.9%). [M+H] + = 554.2 Step 13: 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine tert-butyl 1-azine carboxylate A solution of NaOH (2 N, 903 mL, 1806.2 mmol) was added to a solution of 100 g (180.62 mmol) of 4-((1r,4r)-4-(6-(2-hydroxypropyl-2-yl)-5-(2,2,2-trifluoroacetamido)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester in MeOH (1000 mL) at room temperature. The mixture was stirred at 70 °C for 2 hours. The mixture was cooled to room temperature and a solid precipitated. The mixture was filtered and the filter cake was washed with water. The filter cake was then collected and dried under reduced pressure to give the product (75 g, 90.7%). [M+H] + = 458.2.

[0116] Step 14: 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carbamate)-6-(2-hydroxy) propyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester HATU (74.73 g, 196.67 mmol) and DIEA (42.28 g, 327.78 mmol) were added to a stirred solution of 3-cyanopyrrolo[1,2-b]pyridazin-7-carboxylic acid (36.81 g, 196.67 mmol) and 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (75 g, 163.89 mmol) in DMF (1000 mL). The mixture was stirred at room temperature for 5 hours. The mixture was diluted with water (3000 mL). The solid was collected by filtration and washed with water (3 x 100 mL). The solid was dried under vacuum to give the product (90 g, 87.62%). [M+H] + =627.5 Step 15: 3-Cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 2H-Indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Concentrated HCl (36%, 300 mL) was added dropwise to a stirred solution of 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (90 g, 143.77 mmol) in MeOH (600 mL). The resulting mixture was stirred overnight at room temperature. The solid was collected by filtration. The solid was dissolved in water (500 mL), then adjusted to pH 8 with saturated NaHCO3 solution and mixed with DCM / MeOH (V / V = 10 / 1, 5). xExtracted with 2000 mL of petroleum ether. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was slurried with 1000 mL of petroleum ether and filtered. The solids were filtered and dried under vacuum to give the product (70 g, 92.45%). [M+H] + = 527.4 Step 16: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(6-((2,6-dioxopiridine-3-yl)amino)-2- Methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrole [1,2-b]pyridazine-7-carboxamide AcOH (5.4 mg, 0.09 mmol) and NaBH(OAc)3 (39 mg, 0.18 mmol) were added to a stirred solution of 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (50 mg, 0.09 mmol) and 3-((6-methyl-5-(4-oxopiridin-1-yl)pyridin-2-yl)amino)piperidin-2,6-dione (57 mg, 0.18 mmol) in a DCE (2 mL). The mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM: MeOH = 15:1) to give an impure product. The impure product was then purified by preparative HPLC (C-18 column chromatography with FA gradient elution of 0.1% in water:acetonitrile = 90:10 to 60:40) to obtain the desired product (26 mg, 35%). 1 H NMR (500 MHz, DMSO)δ 12.03 (s, 1H), 10.73 (s, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz,1H), 8.56 (s, 1H), 8.33 (s, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 7.22(d, J = 8.7 Hz, 1H), 7.09 (d, J = 4.7 Hz, 1H), 6.41 (d, J = 7.8 Hz, 1H), 6.37 (d, J=8.6 Hz, 1H), 5.72 (s, 1H), 4.71 – 4.61 (m, 1H), 4.46 – 4.37 (m, 1H), 3.64 –3.48 (m, 2H), 2.94 – 2.87 (m, 2H), 2.78 – 2.69 (m, 1H), 2.59 – 2.51 (m, 9H), 2.42 – 2.34 (m, 1H), 2.25 (s, 3H), 2.24 – 2.13 (m, 3H), 2.10 – 2.04 (m, 1H), 2.02 – 1.89 (m, 5H), 1.85 – 1.79 (m, 2H), 1.63 (s, 6H), 1.58 – 1.43 (m, 4H). [M+H] + = 827.6.

[0117] Example 006: N-(2-((1r,4r)-4-(4-((1-(4-(((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)-6-(trifluoromethyl)pyridineamide Step 1: 4-((1r,4r)-4-(6-(2-hydroxypropyl-2-yl)-5-(6-(trifluoromethyl)pyridinamidyl)-2H- Indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester HATU (3.80 g, 10 mmol) and DIPEA (2.58 g, 20 mmol) were added to a stirred solution of 6-(trifluoromethyl)pyridinecarboxylic acid (1.91 g, 10 mmol) and 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (4.58 g, 10 mmol) in DCM (50 mL). The solution was stirred at room temperature for 18 hours. The solution was concentrated under vacuum. The combined organic layers were concentrated under vacuum and purified by silica gel column chromatography (DCM:MeOH = 90:10) to give the product (5.9 g, 93.1%). [M+H] + = 631.5.

[0118] Step 2: N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5- 6-(trifluoromethyl)pyridine amide 12 N HCl (50 mL) in MeOH (50 mL) was added to a stirred solution of 4-((1r,4r)-4-(6-(2-hydroxypropyl-2-yl)-5-(6-(trifluoromethyl)pyridinamido)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (5.9 g, 9.3 mmol) in MeOH (50 mL). The reaction mixture was stirred at room temperature for 2 hours, adjusted to pH 7 with saturated NaHCO3, and extracted with DCM (500 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The combined organic layers were concentrated to dryness to give the product (4.9 g, 99.1%). [M+H] + = 531.7.

[0119] Step 3: N-(2-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorobenzene) (3-yl)-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)-6- (trifluoromethyl)pyridine amide A solution of N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridineamide (0.74 g, 1.46 mmol) and (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxaldehyde (0.45 g, 1.46 mmol, obtained by the same method as WO2022012622A1) in DCM (50 mL) was stirred at room temperature for 1 hour, followed by the addition of NaBH(OAc)3 (0.62 g, 2.92 mmol) in portions. The solution was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified by silica gel column chromatography (DCM: MeOH = 90:10) to give the product (0.73 g, 60.7%). 1 H NMR (500 MHz, DMSO) δ 12.36 (s,1H), 10.85 (s, 1H), 8.71 (d, J = 1.4 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.39 –8.32 (m, 2H), 8.16 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 6.10 (d, J = 11.0 Hz, 2H), 5.93 (d, J = 10.1 Hz, 1H), 4.42 (t, J= 11.0 Hz, 1H), 4.02 (dd, J = 12.5, 5.0 Hz, 1H), 3.92 (t, J = 7.5 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 3.32 (s, 2H), 2.95 –2.86 (m, 1H), 2.82 – 2.74 (m, 1H), 2.56 – 2.52 (m, 4H), 2.49 – 2.46 (m, 1H),2.43 – 2.33 (m, 4H), 2.20 – 2.13 (m, 2H), 2.12 – 2.03 (m, 1H), 1.99 – 1.89 (m, 6H), 1.61 (s, 6H), 1.52 – 1.42 (m, 2H). [M+H] + = 823.6.

[0120] Example 010: 3-Cyano-N-(2-((1R,4r)-4-((2R)-4-(1-(6-(2,6-dioxopiperidin-3-yl)- 5-Fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-2-(methoxymethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl) 2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (154 mg, 50.3%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.86 (s, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.74(d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.57(s, 1H), 7.30 (d, J = 11.5 Hz, 1H), 7.09 (d, J = 5.0 Hz, 1H), 5.73 (s, 1H), 4.46– 4.37 (m, 1H), 4.13 (dd, J= 11.5, 5.5 Hz, 1H), 3.57-3.50 (m, 1H), 3.39-3.35 (m, 1H), 3.30-3.24 (m, 4H), 3.19-3.10 (m, 2H), 2.87-2.79 (m, 2H),2.75 – 2.66 (m, 3H), 2.65 – 2.56 (m, 3H), 2.47 – 2.42 (m, 1H), 2.37 (s, 3H), 2.35 – 2.20 (m, 4H), 2.19 – 2.12 (m, 2H), 2.07 – 1.95 (m, 3H), 1.93 – 1.83(m, 3H), 1.81 – 1.74 (m, 1H), 1.70 – 1.61 (m, 7H), 1.60 – 1.51 (m, 2H), 1.46– 1.36 (m, J = 10.5 Hz, 1H). [M+H] + = 874.7.

[0121] Example 015: N-(2-((1r,4r)-4-(4-(1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridine- 3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)furano[3,2-b] Pyridine-3-carboxamide Step 1: 2-(trimethylsilyl)furano[3,2-b]pyridine Trimethylsilylacetylene (95.4 g, 971.29 mmol), TEA (151.2 g, 1.49 mol), Pd(PPh3)2Cl2 (10.5 g, 14.94 mmol), and CuI (28.5 g, 149.43 mmol) were added to a solution of 2-bromopyridin-3-ol (130.0 g, 747.15 mmol) in 1,4-dioxane (1300 mL) under nitrogen atmosphere. The mixture was stirred at 45 °C for 3 hours. The mixture was filtered, and water (500 mL) was added to the filtrate, followed by extraction with EtOAc (400 mL x 3). The combined organic phases were washed with brine (400 mL), dried over Na2SO4, and concentrated to give the product (148.0 g, crude). [M+H] + =192.1.

[0122] Step 2: Furano[3,2-b]pyridine KF (161.8 g, 2.79 mol) was added to a solution of 2-(trimethylsilyl)furano[3,2-b]pyridine (148.0 g, 773.65 mmol) in MeOH (1.48 L). The reaction mixture was then stirred at 70 °C for 3 hours. The mixture was concentrated, water (500 mL) was added, and extraction was performed with EtOAc (200 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na₂SO₄, and concentrated to give the product (52.0 g, 58.4% yield for two steps). [M+H] + =120.1.

[0123] Step 3: 3-Bromofurano[3,2-b]pyridine Br2 (34.9 g, 218.27 mmol) was added dropwise to a solution of furano[3,2-b]pyridine (26.0 g, 218.27 mmol) in CCl4 (260.0 mL) at -10 °C. The reaction mixture was then stirred at room temperature for 3 hours. The mixture was concentrated and EtOAc (100 mL) was added. The mixture was filtered and the filtrate was concentrated to give a residue. KOH (24.5 g, 436.53 mmol) was dissolved in EtOH (52 mL) and cooled to 0 °C. The residue dissolved in EtOH (104 mL) was added dropwise to the KOH solution at 0 °C. The reaction mixture was then stirred at room temperature for 5 minutes. The mixture was concentrated, water (200 mL) was added, and the mixture was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 50:1) to give the product (14.9 g, 34.5%). [M+H] + = 198.0.

[0124] Step 4: Methyl furano[3,2-b]pyridine-3-carboxylate Pd(AcO)₂ (1.1 g, 5.05 mmol), Xantphos (5.8 g, 10.10 mmol), and DIEA (32.6 g, 252.51 mmol) were added to a solution of 3-bromofurano[3,2-b]pyridine (10.0 g, 50.50 mmol) in toluene / MeOH (37.5 mL / 12.5 mL). The mixture was stirred at 70 °C for 12 hours under a CO atmosphere. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 4:1) to give the product (5.1 g, 57.0%). [M+H] + = 178.1.

[0125] Step 5: Furano[3,2-b]pyridine-3-carboxylic acid LiOH (2.31 g, 96.54 mmol) was added to a solution of methyl furano[3,2-b]pyridine-3-carboxylate (11.4 g, 64.35 mmol) in THF / H2O (76 mL / 38 mL). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was concentrated and adjusted to pH approximately 3 with HCl-EtOAc (4N). The precipitate formed was collected by filtration, washed with isopropanol, dried under vacuum to give a crude product, which was then ground with acetonitrile (4 mL) and filtered to give the product (7.0 g, 66.7%). [M+H] + = 164.1.

[0126] Step 6: 4-((1r,4r)-4-(5-(furano[3,2-b]pyridine-3-carboxamido)-6-(2-hydroxypropyl-2- tert-butyl 2-H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate HATU (3.80 g, 10 mmol) and DIPEA (2.58 g, 20 mmol) were added to a stirred solution of furano[3,2-b]pyridine-3-carboxylic acid (1.68 g, 10 mmol) and 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (4.58 g, 10 mmol) in DCM (50 mL). The solution was stirred at room temperature for 18 hours. Water (500 mL) was added to the solution and extracted with DCM (500 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The combined organic layers were concentrated under vacuum and purified by silica gel column chromatography (DCM:MeOH = 90:10) to give the product (5.5 g, 91.2%). [M+H] + = 603.7.

[0127] Step 7: N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5- (3,2-b)furano[3,2-b]pyridine-3-carboxamide Add 12 M HCl (60 mL) to a stirred solution of 4-((1r,4r)-4-(5-(furano[3,2-b]pyridin-3-carboxamido)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (5.5 g, 9.12 mmol) in MeOH (100 mL). Stir the reaction mixture at room temperature for 2 hours, adjust the pH to 7 with saturated NaHCO3, and extract with DCM / MeOH (8 / 1, 150 mL × 4). Dry the combined organic layers with Na2SO4 and concentrate under vacuum. The combined organic layers were concentrated under vacuum and purified by C18 column chromatography (water (0.1% TFA):acetonitrile = 20:80 to 60:40) to give the product (1.0 g, 20%). [M+H] + = 503.7.

[0128] Step 8: N-(2-((1r,4r)-4-(4-(1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl) Piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)furano[3,2-b]pyridine- 3-Formamide A solution of N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)furano[3,2-b]pyridine-3-carboxamide (25 mg, 0.05 mmol) and 3-(6-methyl-5-(4-oxopiridin-1-yl)pyridin-2-yl)piperidine-2,6-dione (20 mg, 0.067 mmol, obtained by the same method as in Example 031) in DCE (5 mL) was stirred at room temperature for 1 hour, followed by the addition of NaBH(OAc)3 (21 mg, 0.1 mmol) in portions. The solution was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified by silica gel column chromatography (DCM: MeOH = 90:10) to give the product (5 mg, 12.7%). 1 H NMR (500 MHz, DMSO) δ 11.41 (s, 1H), 10.78 (s,1H), 8.93 (s, 1H), 8.68 (d, J = 5.0 Hz, 1H), 8.34 (s, 1H), 8.27 (d, J= 5.5 Hz, 2H), 8.22 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.51 (dd, J = 8.5, 5.0 Hz, 1H), 7.36(d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.63 (s, 1H), 4.43 (t, J = 11.5 Hz, 1H), 3.89 (dd, J = 9.5, 5.5 Hz, 1H), 3.11 (d, J = 11.0 Hz, 3H), 2.67 – 2.53 (m,11H), 2.42 – 2.36 (m, 4H), 2.29 (t, J = 11.0 Hz, 1H), 2.24 – 2.14 (m, 3H), 2.11 – 2.04 (m, 1H), 2.02 – 1.90 (m, 4H), 1.90 – 1.83 (m, 2H), 1.62 – 1.55 (m, 7H), 1.53 – 1.42 (m, 2H). [M+H] + = 788.6.

[0129] Example 019: N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Step 1: 4-((1r,4r)-4-(6-(2-hydroxypropyl-2-yl)-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamide) tert-butyl 2-H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate HATU (3.80 g, 10 mmol) and DIPEA (2.58 g, 20 mmol) were added to a stirred solution of pyrazolo[1,5-a]pyrimidin-3-carboxylic acid (1.63 g, 10 mmol) and 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (4.58 g, 10 mmol) in DCM (100 mL). The solution was stirred at room temperature for 18 hours. Water (80 mL) was added to the solution and extracted with DCM (100 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The combined organic layers were concentrated under vacuum and purified by silica gel column chromatography (DCM:MeOH = 90:10) to give the product (6.0 g, 99.6%). [M+H] + = 603.5.

[0130] Step 2: N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5- pyrazolo[1,5-a]pyrimidine-3-carboxamide To a stirred solution of 4-((1r,4r)-4-(6-(2-hydroxypropyl-2-yl)-5-(pyrazolo[1,5-a]pyrimidin-3-carboxamido)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (6.0 g, 9.96 mmol) in MeOH (100 mL), 12 M HCl (50 mL) in MeOH (8 / 1, 150 mL × 4) was added. The reaction mixture was stirred at room temperature for 2 hours, adjusted to pH 7 with saturated NaHCO3, and extracted with DCM / MeOH (8 / 1, 150 mL × 4). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give the product (5.0 g, 100%). [M+H] + = 503.6.

[0131] Step 3: N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorobenzene (3-yl)piperazine-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrazolo[1, [5-a]pyrimidine-3-carboxamide A solution of N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.1 mmol) and (R)-3-(2,6-difluoro-4-(3-oxoazacyclobutane-1-yl)phenyl)piperidine-2,6-dione (44 mg, 0.15 mmol, obtained by the same method as WO2023098656 A1) in DCE (10 mL) was stirred at room temperature for 1 hour, followed by the addition of NaBH(OAc)3 (42 mg, 0.2 mmol) in portions. The solution was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified by PHLC to give the product (14 mg, 17.8%). 1 H NMR (500 MHz, DMSO) δ 11.23 (s, 1H), 10.86 (s, 1H), 9.31 (dd, J =7.0, 1.5 Hz, 1H), 8.80 (dd, J = 4.5, 1.5 Hz, 1H), 8.65 (s, 1H), 8.32 (d, J = 11.0Hz, 2H), 8.28 (s, 0H), 7.55 (s, 1H), 7.28 (dd, J = 7.0, 4.0 Hz, 1H), 6.12 (d, J =11.0 Hz, 2H), 5.69 (s, 1H), 4.42 (t, J = 11.5 Hz, 1H), 4.03 (dd, J = 12.5, 5.0Hz, 1H), 3.91 (t, J = 7.0 Hz, 2H), 3.68 – 3.60 (m, 2H), 3.27 – 3.20 (m, 2H), 2.83 – 2.73 (m, 1H), 2.61 – 2.52 (m, 4H), 2.45 – 2.27 (m, 5H), 2.20 – 2.13(m, 2H), 2.13 – 2.00 (m, 1H), 2.00 – 1.86 (m, 5H), 1.60 (s, 6H), 1.53 – 1.42(m, 2H). [M+H] + = 781.6.

[0132] Example 020: N-(2-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide The title compound (29 mg, 36.5%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 11.24 (s, 1H), 10.85 (s, 1H), 9.31 (dd, J = 7.0, 1.5 Hz, 1H), 8.81 (dd, J = 4.0, 1.5 Hz, 1H), 8.66 (s, 1H), 8.38 – 8.28 (m, 2H), 8.22 (s,0H), 7.56 (d, J = 7.5 Hz, 1H), 7.33 – 7.23 (m, 1H), 6.10 (d, J = 11.0 Hz, 2H),5.69 (s, 1H), 4.41 (t, J = 11.5 Hz, 1H), 4.02 (dd, J = 12.5, 5.0 Hz, 1H), 3.93(t, J = 7.5 Hz, 2H), 3.47 (t, J = 6.0 Hz, 3H), 2.95 – 2.88 (m, 1H), 2.82 – 2.74(m, 1H), 2.57 – 2.52 (m, 5H), 2.50 – 2.46 (m, 2H), 2.44 – 2.35 (m, 4H), 2.20– 2.13 (m, 2H), 2.11 – 2.02 (m, 1H), 1.99 – 1.89 (m, 5H), 1.60 (s, 6H), 1.52– 1.40 (m, 2H). [M+H] + = 795.7.

[0133] Example 028: N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide The title compound (12 mg, 14.8%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 11.23 (s, 1H), 10.87 (s, 1H), 9.31 (dd, J = 7.0, 1.5 Hz, 1H), 8.80 (dd, J = 4.0, 1.5 Hz, 1H), 8.65 (s, 1H), 8.32 (d, J = 12.5 Hz, 2H), 8.17 (s,1H), 7.56 (s, 1H), 7.28 (dd, J = 7.0, 4.0 Hz, 1H), 6.63 (d, J = 12.5 Hz, 2H),5.69 (s, 1H), 4.41 (t, J = 11.5 Hz, 1H), 4.04 (dd, J = 12.5, 5.0 Hz, 1H), 3.78(d, J = 12.0 Hz, 2H), 2.82 – 2.71 (m, 3H), 2.61 – 2.51 (m, 8H), 2.41 – 2.32 (m,2H), 2.20 – 2.14 (m, 2H), 2.11 – 2.04 (m, 1H), 2.00 – 1.89 (m, 5H), 1.85 –1.78 (m, 2H), 1.60 (s, 6H), 1.53 – 1.34 (m, 4H). [M+H] + = 809.7.

[0134] Example 022: N-(2-((1r,4r)-4-(4-(1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide The title compound (18 mg, 22.8%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 11.24 (s, 1H), 10.85 (s, 1H), 9.32 (dd, J = 7.0, 1.5 Hz, 1H), 8.81 (dd, J = 4.0, 1.5 Hz, 1H), 8.65 (s, 1H), 8.34 (d, J = 7.0 Hz, 2H), 7.55 (s,2H), 7.29 (dd, J = 7.0, 4.0 Hz, 1H), 5.70 (s, 1H), 4.55 – 4.47 (m, 1H), 3.28 –3.17 (m, 4H), 2.73 – 2.65 (m, 3H), 2.64 – 2.53 (m, 9H), 2.47 – 2.41 (m, 4H), 2.40 – 2.35 (m, 1H), 2.33 – 2.19 (m, 4H), 2.15 – 1.94 (m, 6H), 1.81 – 1.65 (m, 4H), 1.60 (s, 6H). [M+H] + = 788.9.

[0135] Example 023: N-(2-((1r,4r)-4-(4-(1-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide The title compound (15 mg, 18.6%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 11.23 (s, 1H), 10.86 (s, 1H), 9.31 (dd, J = 7.0, 1.5 Hz, 1H), 8.81 (dd, J = 4.0, 1.5 Hz, 1H), 8.66 (s, 1H), 8.32 (d, J= 9.5 Hz, 2H), 8.17 (s,1H), 7.55 (s, 1H), 7.34 – 7.25 (m, 2H), 5.69 (s, 1H), 4.42 (t, J = 11.5 Hz, 1H), 4.13 (dd, J = 11.5, 5.5 Hz, 1H), 3.18 – 3.13 (m, 2H), 2.73 – 2.67 (m, 1H), 2.65 – 2.53 (m, 10H), 2.43 – 2.35 (m, 5H), 2.33 – 2.22 (m, 2H), 2.20 – 2.13(m, 2H), 2.07 – 2.02 (m, 1H), 2.00 – 1.92 (m, 4H), 1.91 – 1.86 (m, 2H), 1.64 – 1.54 (m, 7H), 1.52 – 1.43 (m, 2H). [M+H] + = 806.6.

[0136] Example 032: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: 3-((3,5-difluoro-4-(3-oxoazacyclobutane-1-yl)phenyl)amino)piperidine-2,6-dione DMSO (90 mg, 1.2 mmol) was added dropwise to a solution of (COCl)₂ (129 mg, 1.0 mmol) dissolved in DCM (15 mL) at -78 °C. The mixture was stirred at -78 °C for 0.5 h. 3-((3,5-difluoro-4-(3-hydroxyazacyclobutan-1-yl)phenyl)amino)piperidine-2,6-dione (103 mg, 0.3 mmol, obtained by the same method as in Example 029) was added to the mixture in DCM (5 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h. TEA (1.01 g, 10 mmol) was added to the mixture and stirred at room temperature for 18 h. The mixture was concentrated under vacuum and purified by silica gel column chromatography (DCM: MeOH = 90:10) to give the product (40 mg, 43.1%). [M+H] + = 309.5.

[0137] Step 2: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-(((S)-2,6-dioxopiperidin-3-yl)amino) (2,6-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole- 5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide A solution of 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazin-7-carboxamide (26 mg, 0.05 mmol) and 3-((3,5-difluoro-4-(3-oxoazacyclobutane-1-yl)phenyl)amino)piperidine-2,6-dione (20 mg, 0.07 mmol) in DCM (5 mL) was stirred at room temperature for 1 hour, followed by the addition of NaBH(OAc)3 (21 mg, 0.1 mmol) in portions. The solution was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified by silica gel column chromatography (DCM: MeOH = 90:10) to give the product. The product was subjected to chiral HPLC with a Chiralpak IE column (MeOH : DCM = 50 : 50 (0.2% 2N NH3 in MeOH)) as the mobile phase, yielding the product (2.82 mg, 6.8%). 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.78 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.71 (d, J = 5.0 Hz, 1H), 7.57 (s, 1H), 7.09 (d, J = 5.0 Hz, 1H), 6.39 – 6.25 (m, 2H), 5.85 (d, J= 8.0 Hz, 1H), 5.72 (s, 1H), 4.47 – 4.36 (m,1H), 4.27 – 4.19 (m, 1H), 4.05 – 3.96 (m, 2H), 3.75 – 3.66 (m, 2H), 3.31 –3.27 (m, 2H), 3.12 – 3.04 (m, 1H), 2.76 – 2.67 (m, 1H), 2.59 – 2.52 (m, 3H), 2.43 – 2.35 (m, 2H), 2.33 – 2.26 (m, 2H), 2.19 – 2.14 (m, 2H), 2.10 – 2.04(m, 1H), 1.99 – 1.91 (m, 4H), 1.87 – 1.77 (m, 1H), 1.63 (s, 6H), 1.52 – 1.43 (m, 2H), 1.24 (s, 1H). [M+H] + = 820.7.

[0138] Example 033: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: Methyl 6-methyl-5-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)pyridinecarboxylate A solution of 1,4-dioxane (1.43 g, 10 mmol) in 1,4-dioxane (50 mL) was supplemented with methyl 5-bromo-6-methylpyridinecarboxylate (2.30 g, 10 mmol), Pd2(dba)3 (915 mg, 1.0 mmol), Xantphos (578 mg, 1.0 mmol), and K3PO4 (4.24 g, 20.0 mmol). The mixture was stirred at 110 °C under nitrogen for 18 hours. The mixture was concentrated under vacuum and purified by silica gel chromatography (petroleum ether / EtOAc = 3:1) to give the product (0.99 g, 33.9%). [M+H] + = 293.3.

[0139] Step 2: 6-Methyl-5-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)pyridinecarboxylic acid A solution of methyl 6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridinecarboxylate (0.99 g, 3.39 mmol) in THF / MeOH (20 mL / 5 mL) was mixed with LiOH (712 mg, 16.9 mol) in 5 mL of water. The reaction mixture was then stirred at 50 °C for 3 hours. The mixture was concentrated, adjusted to pH 7 with HCl (1N), and extracted with DCM (500 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to give the product (930 mg, 3.3 mmol). [M+H] + = 279.2.

[0140] Step 3: (S)-N-(2,6-dioxopiperidin-3-yl)-6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]) (dec-8-yl)pyridine amide T3P in 50% of EtOAc (2.16 g, 3.4 mmol) and DIPEA (438 mg, 3.4 mmol) was added to a stirred solution of 6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridinecarboxylic acid (930 mg, 3.3 mmol) and (S)-3-amino-piperidine-2,6-dione hydrochloride (560 mg, 3.4 mmol) in DCM (40 mL). The solution was stirred at room temperature for 18 hours. Water (50 mL) was added to the solution and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM: MeOH = 90: 10) to give the product (760 mg, 57.7%). [M+H] + = 389.5.

[0141] Step 4: (S)-N-(2,6-dioxopiperidin-3-yl)-6-methyl-5-(4-oxopiperidin-1-yl)pyridineamide 6 N HCl was added to a solution of (S)-N-(2,6-dioxopiperidin-3-yl)-6-methyl-5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)pyridine amide (120 mg, 0.3 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 hours. The mixture was adjusted to pH 7 with HCl (1 N) and extracted with DCM (25 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give the product (100 mg, 96.7%). [M+H] + = 345.3.

[0142] Step 5: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(6-(((S)-2,6-dioxopiperidin-3-yl)amino) (formyl)-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-ind (Azol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide A solution of 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (53 mg, 0.1 mmol) and (S)-N-(2,6-dioxopiperidin-3-yl)-6-methyl-5-(4-oxopiperidin-1-yl)pyridineamide (50 mg, 0.15 mmol) in DCE / DMA (5 mL / 5 mL) was stirred at room temperature for 1 hour, followed by the addition of NaBH(OAc)3 (42 mg, 0.2 mmol) in portions. The solution was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified by silica gel column chromatography (DCM: MeOH = 90:10) to give the product (26 mg, 30.4%). 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.86 (s,1H), 8.94 (d, J = 2.0 Hz, 1H), 8.78 (d, J = 8.5 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H),8.55 (s, 1H), 8.34 (s, 1H), 8.23 ​​(s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.72 (d, J =4.5 Hz, 1H), 7.57 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 4.5 Hz, 1H),5.72 (s, 1H), 4.80 – 4.67 (m, 1H), 4.49 – 4.38 (m, 1H), 3.27 – 3.19 (m, 3H),2.83 – 2.75 (m, 1H), 2.71 – 2.65 (m, 2H), 2.58 – 2.52 (m, 11H), 2.35 – 2.27(m, 1H), 2.24 – 2.12 (m, 3H), 2.04 – 1.87 (m, 7H), 1.65 – 1.57 (m, 8H), 1.52– 1.44 (m, 2H). [M+H] += 855.7.

[0143] Example 035: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (33 mg, 22.8%) was prepared in a manner similar to that described in Example 033. 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.82 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.74(d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.33 (s, 1H), 7.73(dd, J = 14.0, 8.5 Hz, 3H), 7.57 (s, 1H), 7.09 (d, J = 5.0 Hz, 1H), 6.97 (d, J =9.0 Hz, 2H), 5.72 (s, 1H), 4.80 – 4.70 (m, 1H), 4.47 – 4.38 (m, 1H), 3.96 –3.85 (m, 2H), 3.29 (s, 3H), 2.83 – 2.75 (m, 5H), 2.57 – 2.54 (m, 5H), 2.19 –2.09 (m, 3H), 1.99 – 1.90 (m, 5H), 1.88 – 1.81 (m, 2H), 1.63 (s, 6H), 1.52 –1.41 (m, 4H), 1.25 – 1.22 (m, 1H). [M+H] + = 840.6.

[0144] Example 007: N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)-6-(trifluoromethyl)pyridineamide The title compound (797 mg, 52.24%) was prepared in a manner similar to that described in Example 006. 1 H NMR (500 MHz, DMSO) δ 12.36 (s, 1H), 10.86 (s, 1H), 8.71 (s, 1H), 8.45 (d, J = 7.8Hz, 1H), 8.39 – 8.34 (m, 2H), 8.16 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 6.13 (s,1H), 6.11 (s, 1H), 5.94 (s, 1H), 4.47 –4.37(m, 1H), 4.03 (dd, J = 12.6, 5.0 Hz, 1H), 3.91 (t, J = 7.2 Hz, 2H), 3.66 – 3.61 (m, 2H), 3.28 – 3.21 (m, 1H), 2.82 –2.72 (m, 1H), 2.66 – 2.51 (m, 4H), 2.49 – 2.26 (m, 6H), 2.20 – 2.13 (m, 2H), 2.12 – 2.02 (m, 1H), 2.00 – 1.88 (m, 5H), 1.62 (s, 6H), 1.52 – 1.41 (m, 2H). [M+H] + = 809.6.

[0145] Example 027: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)-5-fluoropyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: 7-Bromo-5-fluoropyrrolo[1,2-b]pyridazine-3-carboxylon Selectfluar (3.51 g, 9.9 mmol) was added to a solution of 7-bromopyrrolo[1,2-b]pyridazine-3-carboxynitrile (2 g, 9.0 mmol) in DMF (30 mL) at 0 °C. The solution was then warmed to room temperature and stirred for 5 hours. The solution was then diluted with EA (100 mL) and washed with water (70 mL × 2) and brine (60 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / EA = 3:1) to give the product (1.2 g, 55.6%). [M+H] + = 240.2 Step 2: 3-Cyano-5-fluoropyrrolo[1,2-b]pyridazine-7-carboxylic acid Pd(dppf)Cl2 (183 mg, 0.25 mmol) and TEA (757.5 mg, 7.5 mmol) were added to a solution of 7-bromo-5-fluoropyrrolo[1,2-b]pyridazine-3-carboxynitrile (600 mg, 2.50 mmol) in THF (12 mL) and water (4 mL). The mixture was then stirred at 95 °C under CO (4 MPa) for 16 hours. The mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the product (300 mg, 58.5%). [M+Na] + = 228.2 Step 3: 4-((1r,4r)-4-(5-(3-cyano-5-fluoropyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2- Hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester HATU (177.84 mg, 0.47 mmol) and DIEA (150.90 mg, 1.17 mmol) were added to a stirred solution of 3-cyano-5-fluoropyrrolo[1,2-b]pyridazine-7-carboxylic acid (80 mg, 0.39 mmol) and 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (178.6 mg, 0.39 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 5 hours. The mixture was diluted with water (10 mL). The solid was collected by filtration and washed with water (3 × 5 mL). The solid was dried under vacuum to give the product (190 mg, 75.56%). [M+H] + =645.5 Step 4: 3-Cyano-5-Fluoro-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexane (2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Concentrated HCl (36%, 2 mL) was added dropwise to a stirred solution of 4-((1r,4r)-4-(5-(3-cyano-5-fluoropyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (190 mg, 0.29 mmol) in MeOH (3 mL). The resulting mixture was stirred at room temperature for 3 hours. The solid was collected by filtration. The solid was dissolved in water (5 mL), then adjusted to pH 8 with saturated NaHCO3 solution and mixed with DCM / MeOH (V / V = 10 / 1, 3). x Extracted by 10 mL. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum to give the product (150 mg, 82.81%). [M+H] + = 545.4 Step 5: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- (difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)-5- Fluoropyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (14.5 mg, 62.21%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.86 (s, 1H), 9.07 (d, J = 2.1 Hz, 1H), 8.69(d, J = 2.1 Hz, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 6.12 (d, J = 11.1 Hz, 2H), 5.73 (s, 1H), 4.46 – 4.38 (m, 1H), 4.03 (dd, J = 12.6, 5.0 Hz, 1H), 3.91 (t, J = 7.2 Hz, 2H), 3.66 – 3.61 (m, 2H), 3.27 – 3.21 (m,2H), 2.82 – 2.73 (m, 1H), 2.62 – 2.52 (m, 4H), 2.44 – 2.28 (m, 5H), 2.19 –2.13 (m, 2H), 2.11 – 2.02 (m, 1H), 1.99 – 1.88 (m, 5H), 1.63 (s, 6H), 1.52 –1.41 (m, 2H). [M+H]+ = 823.6.

[0146] Example 030: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(6-((2,6-dioxopiperidin-3-yl)amino)-4-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (25 mg, 23.21%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.03 (s, 1H), 10.73 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.74(d, J = 2.0 Hz, 1H), 8.56 (s, 1H), 8.33 (s, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.66(s, 1H), 7.57 (s, 1H), 7.09 (d, J = 4.8 Hz, 1H), 6.43 (d, J = 7.7 Hz, 1H), 6.41(s, 1H), 5.73 (s, 1H), 4.73 – 4.59 (m, 1H), 4.46 – 4.37 (m, 1H), 3.71 – 3.55(m, 2H), 3.02 – 2.94 (m, 2H), 2.80 – 2.69 (m, 1H), 2.64 – 2.52 (m, 9H), 2.42 – 2.35 (m, 1H), 2.28 – 2.21 (m, 1H), 2.19 – 2.12 (m, 5H), 2.09 – 2.03 (m,1H), 2.02 – 1.89 (m, 5H), 1.85 – 1.78 (m, 2H), 1.63 (s, 6H), 1.57 – 1.41 (m, 4H). [M+H]+ = 827.6.

[0147] Example 054: 5-amino-4-(5-(4-(4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carbamate)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-yl)piperidin-1-yl)-6-methylpyridin-2-yl)-5-oxovaleric acid The title compound (25 mg, 23.21%) was prepared in a manner similar to that described in Example 029. (320 mg, 62.7%). 1 H NMR (500 MHz, DMSO) δ 12.03 (s, 1H), 8.93 (d, J = 1.9 Hz, 1H), 8.74(d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.72 (d, J = 4.7 Hz, 1H), 7.57(s, 1H), 7.41 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.15 – 7.06 (m, 2H), 6.89 (s,1H), 5.72 (s, 1H), 4.46 – 4.37 (m, 1H), 3.60 – 3.50 (m, 1H), 3.13 – 3.07 (m,2H), 2.68 – 2.53 (m, 10H), 2.44 – 2.38 (m, 4H), 2.37 – 2.29 (m, 1H), 2.20 –2.06 (m, 5H), 2.00 – 1.85 (m, 7H), 1.63 (s, 6H), 1.60 – 1.52 (m, 2H), 1.51 –1.43 (m, 2H). [M+H] + = 830.6.

[0148] Example 004: 3-Cyano-N-(2-((1R,4r)-4-((3R)-4-(1-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)-3-(methoxymethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (32 mg, 36.78%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.86 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.74(d, J = 5.0 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.58(s, 1H), 7.31 (d, J = 10.0 Hz, 1H), 7.10 (d, J = 5.0 Hz, 1H), 5.72 (s, 1H), 4.43– 4.40 (m, 1H), 4.15 – 4.11 (m, 1H), 3.53 – 3.51 (m, 1H), 3.41 – 3.38 (m,1H), 3.27 (s, 3H), 3.18 – 3.15 (m, 2H), 2.89 – 2.85 (m, 1H), 2.80 – 2.54 (m,9H), 2.43 – 2.374 (m, 6H), 2.26 – 2.16 (m, 3H), 2.09 – 2.02 (m, 1H), 1.98 –1.86 (m, 5H), 1.75 – 1.71 (m, 2H), 1.63 (s, 6H), 1.57 – 1.44 (m, 3H). [M+H]+ =874.77.

[0149] Example 014: 3-Cyano-N-(2-((1S,4r)-4-(4-(2-(2-((S)-2,6-diaminohexamido)ethoxy)ethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (5.29 mg, 7.12%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.03 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.74 (d, J= 5.0 Hz,1H), 8.55 (s, 1H), 8.34 – 8.31 (m, 3H), 8.02 – 8.01 (m, 1H), 7.72 (d, J = 5.0Hz, 1H), 7.57 (s, 1H), 7.10 (d, J = 5.0 Hz, 1H), 4.43 – 4.40 (m, 1H), 3.51 –3.50 (m, 1H), 3.54 – 3.24 (m, 10H), 2.75 – 2.72(m, 2H), 2.46 – 2.37(m, 8H),2.19 – 2.17 (m, 3H), 1.97 – 1.93 (m, 5H), 1.63 (s, 6H), 1.51 – 1.35 (m, 9H). [M+H]+ = 742.74.

[0150] Example 021: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (103 mg, 9.36%) was prepared in a manner similar to that described in Example 029. 1 H NMR(500 MHz, DMSO) δ12.02 (s, 1H),10.86 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.74(d, J = 5.0 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.57(s, 1H), 7.31 (d, J = 10.0 Hz, 1H), 7.10 (d, J= 5.0 Hz, 1H), 5.72 (s, 1H), 4.43– 4.40 (m, 1H), 4.15 – 4.12 (m, 1H), 3.16 – 3.15 (m, 2H), 2.73 – 2.54 (m,11H), 2.40 – 2.37 (m, 4H), 2.31 – 2.16 (m, 4H), 2.05 – 1.86 (m, 8H), 1.63 (s,6H), 1.58 – 1.44 (m, 4H). [M+H]+ = 830.71.

[0151] Example 024: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(6-((S)-2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (62 mg, 5.64%) was prepared in a manner similar to that described in Example 029. 1 H NMR(500 MHz, DMSO) δ12.02 (s, 1H),10.86 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.74(d, J = 5.0 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.57(s, 1H), 7.31 (d, J = 10.0 Hz, 1H), 7.10 (d, J = 5.0 Hz, 1H), 5.72 (s, 1H), 4.43– 4.40 (m, 1H), 4.15 – 4.12 (m, 1H), 3.16 – 3.15 (m, 2H), 2.73 – 2.54 (m,11H), 2.40 – 2.37 (m, 4H), 2.31 – 2.16 (m, 4H), 2.05 – 1.86 (m, 8H), 1.63 (s,6H), 1.58 – 1.44 (m, 4H). [M+H]+ = 830.71.

[0152] Example 025: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(6-((R)-2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (66 mg, 6.00%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.86 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.74(d, J = 5.0 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.57(s, 1H), 7.31 (d, J = 10.0 Hz, 1H), 7.10 (d, J = 5.0 Hz, 1H), 5.72 (s, 1H), 4.45– 4.40 (m, 1H), 4.15 – 4.11 (m, 1H), 3.16 – 3.15 (m, 2H), 2.73 – 2.54 (m,11H), 2.40 – 2.37 (m, 4H), 2.31 – 2.16 (m, 4H), 2.05 – 1.86 (m, 8H), 1.63 (s,6H), 1.58 – 1.44 (m, 4H). [M+H]+ = 830.71.

[0153] Example 026: N-(2-((1r,4r)-4-(4-(1-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)-3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (53 mg, 62.35%) was prepared in a manner similar to that described in Example 029. 1H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.77 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.74(d, J = 5.0 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 8.18(s, 1H), 7.72 (d, J = 5.0Hz, 1H), 7.57 (s, 1H), 7.31 (d, J = 10.0 Hz, 1H), 7.10 (d, J = 5.0 Hz, 1H), 6.94(d, J = 10.0 Hz, 1H), 6.75 (d, J = 5.0 Hz, 1H), 6.59 (d, J = 10.0 Hz, 1H), 5.84 (d, J = 10.0 Hz, 1H), 5.72 (s, 1H), 4.45 – 4.40 (m, 1H), 4.31 – 4.26 (m, 1H), 3.12– 3.10 (m, 2H), 2.76 – 2.70 (m, 11H), 2.65 – 2.52 (m, 11H), 2.41 – 2.36 (m,1H), 2.30 – 2.25 (m, 1H), 2.18 – 2.16 (m, 2H), 2.09 – 2.05 (m, 1H), 1.98 –1.81 (m, 7H), 1.63 (s, 6H), 1.58 – 1.48 (m ,4H). [M+H]+ = 846.43.

[0154] Example 005: 3-Cyano-N-(2-(3-(4-(1-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)bicyclo[1.1.1]pentan-1-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazin-7-carboxamide The title compound (132.61 mg, 84.14%) was prepared in a manner similar to that described in Example 029. (30 mg, 38.0%). 1 H NMR (500 MHz, DMSO)1 H NMR (500 MHz, DMSO) δ 12.06 (s, 1H), 10.86 (s, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.62 – 8.55 (m, 1H), 8.34 (d, J = 17.8 Hz, 1H), 7.31 (d, J = 11.6 Hz, 1H), 7.09 (d, J = 4.8 Hz, 1H), 5.78 (brs, 1H), 4.13 (dd, J = 11.1, 5.2 Hz, 1H), 3.50 (s, 2H), 3.16 (d, J = 9.0Hz, 2H), 2.77 – 2.54 (m, 10H), 2.35 (d, J = 17.9 Hz, 10H), 2.30 – 2.16 (m, 1H), 2.13 – 1.97 (m, 1H), 1.88 (d, J = 11.4 Hz, 2H), 1.70 – 1.46 (m, 8H).

[0155] [M+H] + = 814.4 Example 13: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-methoxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: 6-(2-methoxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5- amine TsOH (0.38 g, 2.18 mmol) and H₂SO₄ (0.218 g, 2.18 mmol) were added to a solution of tert-butyl piperazine-1-carboxylate (1 g, 2.18 mmol) in MeOH (50 mL). The mixture was stirred at 80 °C under N₂ for 48 h. The solution was alkalized to pH 10 with Na₂CO₃ and extracted with DCM. The organic layer was concentrated under vacuum. This gave the crude product (0.8 g, 100%). [M+H] + = 372.2 Step 2: 4-((1r,4r)-4-(5-amino-6-(2-methoxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine tert-butyl 1-azine carboxylate (Boc)₂O (0.57 g, 2.62 mmol) was added to a solution of 6-(2-methoxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-amine (0.8 g, 2.18 mmol) in DCM (50 mL) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated. The residue was purified by silica gel column chromatography (PE:EA = 3:1 to 1:1) to give the product (320 mg, 32.0%). [M+H] + =472.2 Step 3: 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carbamate)-6-(2-methoxy) tert-butyl propyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate TEA (206 mg, 2.04 mmol) and 3-cyanopyrrolo[1,2-b]pyridazine-7-carboxylic acid (127 mg, 0.68 mmol) and HATU (310 mg, 0.82 mmol) were added to a stirred solution of 4-((1r,4r)-4-(5-amino-6-(2-methoxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid (320 mg, 0.68 mmol) in DMF (10 mL). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 40:1 to 20:1) to give the product (200 mg, 46.1%). [M+H] + = 641.4 Step 4: 3-Cyano-N-(6-(2-methoxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 2H-Indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide TFA (1 mL) was added to a solution of 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-methoxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.156 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated. The residue was dissolved in DCM (20 mL). The solution was adjusted to pH 10 with saturated Na2CO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to give the product (50 mg, 58.8%), which was used without further purification. [M+H] + = 541.4.

[0156] Step 5: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- (difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-methoxypropyl-2-yl)-2H-indazole-5-yl) Pyrrolo[1,2-b]pyrrolopyrazine-7-carboxamide To a solution of 3-cyano-N-(6-(2-methoxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (50 mg, 0.093 mmol) in a DCE (5 mL), (R)-3-(2,6-difluoro-4-(3-oxoazacyclobutane-1-yl)phenyl)piperidine-2,6-dione (54 mg, 0.185 mmol) and NaBH(OAc)3 (39.2 mg, 0.185 mmol) were added. The mixture was stirred at room temperature for 14 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (C-18 column chromatography with FA gradient elution of 0.1% in water:acetonitrile = 90:10 to 60:40) to give the desired product (30 mg, 38.0%). 1 H NMR (500 MHz, DMSO) δ 11.46 (s, 1H), 10.86 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.83 (d, J = 2.0 Hz, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 7.74 (d, J = 4.8 Hz, 1H), 7.60 (s, 1H), 7.10 (d, J = 4.8 Hz, 1H), 6.12 (d, J= 11.1 Hz, 2H), 4.44 (s, 1H), 4.03 (dd, J = 12.6, 5.0 Hz, 1H), 3.91(t, J = 7.3 Hz, 2H), 3.64 (s, 2H), 3.27 – 3.20 (m, 2H), 3.17 (s, 3H), 2.83 –2.73 (m, 1H), 2.62 – 2.53 (m, 4H), 2.39 (d, J = 27.0 Hz, 5H), 2.17 (d, J = 9.3Hz, 2H), 2.08 (dd, J = 22.6, 13.0 Hz, 1H), 1.95 (d, J = 10.3 Hz, 5H), 1.61 (s, 6H), 1.55 – 1.42 (m, 2H). [M+H] + = 819.4 Example 018: 3-Cyano-N-(2-(3-(4-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)bicyclo[1.1.1]pentan-1-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazin-7-carboxamide The title compound (132.61 mg, 84.14%) was prepared in a manner similar to that described in Example 029. 1 HNMR (500 MHz, DMSO) δ 12.05 (s, 1H), 10.77 (s, 1H), 8.93 (s, 1H), 8.74 (s,1H), 8.59 (s, 1H), 8.36 (s, 1H), 7.72 (d, J = 4.6 Hz, 1H), 7.61 (s, 1H), 7.09(d, J = 4.6 Hz, 1H), 6.83 (t, J = 9.4 Hz, 1H), 6.50 (d, J = 15.1 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 5.79 (d, J= 6.8 Hz, 2H), 4.25 (s, 1H), 3.16 (d, J = 9.7 Hz, 3H), 2.78 – 2.67 (m, 1H), 2.66 – 2.53 (m, 9H), 2.31 (d, J = 18.7 Hz, 8H), 2.07 (s,1H), 1.92 – 1.75 (m, 3H), 1.71 – 1.48 (m, 8H); [M+H] + = 814.4 Example 031: 3-Cyano-N-(2-((1r,4r)-4-(4-(7-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: 2-(benzyloxy)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester To a solution of tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (5 g, 20.72 mmol) in THF (100 mL), NaH (1.65 g, 41.44 mmol) and BnBr (7.08 g, 41.44 mmol) were added. The mixture was stirred at room temperature under N2 for 14 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with DCM (50 mL x 3). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 20:1 to 10:1) to give the product (6.0 g, 87%). [M+H] + = 332.2 Step 2: 2-(benzyloxy)-7-azaspiro[3.5]nonane TFA (10 mL) was slowly added to a solution of tert-butyl 2-(benzyloxy)-7-azaspiro[3.5]nonane-7-carboxylate (6.0 g, 18.1 mmol) in DCM (40 mL) at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated. The residue was dissolved in DCM (100 mL), adjusted to pH 9 with saturated Na₂CO₃ solution, and extracted with DCM. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum to give the product (3.5 g, 83.6%), which was used without further purification. [M+H] + = 232.2 Step 3: 2-(benzyloxy)-7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-7-aza Spiro[3.5]nonane Add 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (8.77 g, 18.18 mmol), Cs₂CO₃ (9.82 g, 30.30 mmol), Pd₂(dba)₃ (690 mg, 0.76 mmol), and X-phos (1.45 g, 3.03 mmol) to a stirred solution of methyl 2-(benzyloxy)-7-azaspiro[3.5]nonane (3.5 g, 15.15 mmol), to dioxane (50 mL), 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (8.77 g, 18.18 mmol), Cs₂CO₃ (9.82 g, 30.30 mmol), Pd₂(dba)₃ (690 mg, 0.76 mmol), and X-phos (1.45 g, 3.03 mmol) to a stirred solution of dioxane (50 mL). Stir the reaction mixture overnight at 100 °C. Concentrate the mixture under vacuum. Purify the residue by silica gel column chromatography (PE:EA = 10:1 to 3:1) to give the product (7.0 g, 73.2%). [M+H] + = 633.3 Step 4: 3-(2,6-difluoro-4-(2-hydroxy-7-azaspiro[3.5]non-7-yl)phenyl)piperidine-2,6-dione A solution of 2-(benzyloxy)-7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-7-azaspiro[3.5]nonane (7.0 g, 11.07 mmol) was prepared in IPA (200 mL), DMF (200 mL), and Pd / C (3 g). The mixture was stirred at 50 °C under a H2 atmosphere for 36 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was recrystallized in DCM to give the product (3.0 g, 74.4%). [M+H] + = 365.2.

[0157] Step 5: (R)-3-(2,6-difluoro-4-(2-hydroxy-7-azaspiro[3.5]non-7-yl)phenyl)piperidine-2,6-di ketone After chiral separation by HPLC under neutral conditions, 1.2 g of R (peak-1:ee=99.54%, chemical purity=97.73%) and 1.1 g of S (peak-2:ee=98.21%, chemical purity=96.90%) were obtained.

[0158] [M+H] + =365.2.

[0159] Step 6: (R)-3-(2,6-difluoro-4-(2-oxo-7-azaspiro[3.5]non-7-yl)phenyl)piperidine-2,6-di ketone IBX (394 mg, 1.41 mmol) was added to a solution of (R)-3-(2,6-difluoro-4-(2-hydroxy-7-azaspiro[3.5]non-7-yl)phenyl)piperidin-2,6-dione (300 mg, 0.83 mmol) in DMSO (3 mL). The mixture was stirred at room temperature for 14 hours. The mixture was quenched with aqueous Na2S2O3 and extracted with DCM, followed by washing with water. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The residue was purified by preparative TLC (PE:EA = 1:1) to give the product (200 mg, 66.7%). [M+H] + = 363.4 Step 7: 3-Cyano-N-(2-((1r,4r)-4-(4-(7-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- (difluorophenyl)-7-azaspiro[3.5]non-2-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5- pyrrolo[1,2-b]pyridazine-7-carboxamide NaBH(OAc)3 (80 mg, 0.378 mmol) was added to a solution of 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (100 mg, 0.189 mmol) and (R)-3-(2,6-difluoro-4-(2-oxo-7-azaspiro[3.5]non-7-yl)phenyl)piperidine-2,6-dione (103 mg, 0.283 mmol) in a DCE (5 mL) at room temperature. The resulting mixture was stirred at 50 °C for 12 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography (FA gradient elution of 0.1% in water:acetonitrile = 90:10 to 60:40) to obtain the desired product (65 mg, 39.4.0%).

[0160] 1 H NMR (500 MHz, DMSO) δ 12.03 (s, 1H), 10.86 (s, 1H), 8.93 (d, J = 2.1Hz, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.15 (s, 1H),7.72 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 7.09 (d, J = 4.8 Hz, 1H), 6.61 (d, J = 12.9Hz, 2H), 5.73 (s, 1H), 4.42 (t, J = 11.1 Hz, 1H), 4.04 (dd, J = 12.6, 4.9 Hz,1H), 3.20 (s, 4H), 3.12 (s, 3H), 2.82 – 2.71 (m, 2H), 2.57 (d, J = 27.3 Hz, 4H), 2.41 (d, J = 48.7 Hz, 4H), 2.17 (d, J = 10.4 Hz, 2H), 2.07 (dd, J = 17.8, 8.3Hz, 1H), 2.01 – 1.89 (m, 7H), 1.66 – 1.56 (m, 10H), 1.50 (d, J = 23.0 Hz, 4H).

[0161] [M+H] + = 873.4 Example 037: 3-Cyano-N-(2-((1r,4r)-4-(4-((1-(3-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: N-(2,6-dioxopiperidin-3-yl)-3-(4-formylpiperidin-1-yl)benzamide IBX (146 mg, 0.55 mmol) was added to a solution of N-(2,6-dioxadiazin-3-yl)-3-(4-(hydroxymethyl)piperidin-1-yl)benzamide (100 mg, 0.29 mmol, obtained by the same method as in Example 033) in DMSO (3 mL). The mixture was stirred at room temperature for 14 hours. The mixture was quenched with aqueous Na₂S₂O₃ and extracted with DCM, followed by washing with water. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by preparative TLC (PE:EA = 1:1) to give the product (65 mg, 65.4%). [M+H] + = 344.2.4 Step 2: 3-Cyano-N-(2-((1r,4r)-4-(4-((1-(3-(((S)-2,6-dioxopiperidin-3-yl)amino) (formyl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl) Pyrrolo[1,2-b]pyrrolopyrazine-7-carboxamide NaBH(OAc)3 (64 mg, 0.304 mmol) was added to a solution of 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazin-7-carboxamide (80 mg, 0.152 mmol) and N-(2,6-dioxopiperidin-3-yl)-3-(4-formylpiperidin-1-yl)benzamide (63 mg, 0.182 mmol) in a DCE (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography with FA gradient elution in water:acetonitrile = 90:10 to 60:40, 0.1%) to obtain the desired racemic product (50 mg, 38.5%). The racemic product was then separated by preparative chiral HPLC under the following conditions: column: i-Cellulose-5 46. 250 mm 5 μm flow rate (mL / min): 50.0. Gradient: time (min) MtBE (0.1% in 2M NH3 in MeOH) (%) DCM: MeOH = 50:50 (%), to obtain the desired product (15 mg, 30.0%).

[0162] 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.86 (s, 1H), 8.93 (d, J = 2.0Hz, 1H), 8.74 (d,J = 2.0 Hz, 1H), 8.67 (d, J = 8.2 Hz, 1H), 8.55 (s, 1H), 8.34(s, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 7.39 (s, 1H), 7.32 – 7.22 (m,2H), 7.10 (t, J = 6.0 Hz, 2H), 5.72 (s, 1H), 4.81 – 4.71 (m, 1H), 4.43 (s, 1H), 3.74 (d, J = 11.4 Hz, 2H), 2.79 (dd, J = 21.5, 9.2 Hz, 1H), 2.70 (t, J = 11.7 Hz,2H), 2.56 (s, 2H), 2.36 (s, 5H), 2.12 (dd, J = 19.8, 15.6 Hz, 5H), 1.94 (dd, J =22.9, 11.0 Hz, 5H), 1.80 (d, J = 11.6 Hz, 2H), 1.69 (s, 1H), 1.63 (s, 6H), 1.48(d, J = 11.7 Hz, 2H), 1.22 (d, J = 19.1 Hz, 4H). [M+H] + = 854.4 Example 038: 3-Cyano-N-(2-((1r,4r)-4-(4-((1-(3-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: N-(2,6-dioxopiperidin-3-yl)-3-(3-formylazonobutane-1-yl)benzamide IBX (317 mg, 1.13 mmol) was added to a solution of N-(2,6-dioxopiperidin-3-yl)-3-(3-(hydroxymethyl)azacyclobutane-1-yl)benzamide (200 mg, 0.63 mmol, obtained by a similar method to Example 033) in DMSO (3 mL). The mixture was stirred at room temperature for 14 hours. The mixture was quenched with aqueous Na₂S₂O₃ and extracted with DCM, followed by washing with water. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by preparative TLC (PE:EA = 1:1) to give the product (130 mg, 65.4%). [M+H] + = 316.2 Step 2: 3-Cyano-N-(2-((1r,4r)-4-(4-((1-(3-(((S)-2,6-dioxopiperidin-3-yl)amino) (formyl)phenyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole- 5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide NaBH(OAc)3 (130 mg, 0.608 mmol) was added to a solution of 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (160 mg, 0.304 mmol) and N-(2,6-dioxopiperidin-3-yl)-3-(3-formylazacyclobutane-1-yl)benzamide (115 mg, 0.365 mmol) in a DCE (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography with FA gradient elution in water:acetonitrile = 90:10 to 60:40, 0.1%) to obtain the desired racemic product (120 mg, 47.8%). The racemic product was separated by preparative chiral HPLC under the following conditions: column: YMC Amylose-SA 46. Flow rate (mL / min): 10 at 250 mm 5 μm gradient: MtBE (0.1% 2MNH3MeOH) (%) DCM:MeOH=50:50 (%), yielding the desired product (40 mg, 30.8%).

[0163] 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.85 (s, 1H), 8.93 (d, J = 2.1Hz, 1H), 8.74 (d,J = 2.1 Hz, 1H), 8.62 (d, J = 8.4 Hz, 1H), 8.54 (d, J = 11.6 Hz,1H), 8.33 (s, 1H), 8.16 (s, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 7.25(t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 4.8 Hz, 1H), 6.89 (s,1H), 6.58 (d, J = 7.8 Hz, 1H), 5.73 (s, 1H), 4.80 – 4.72 (m, 1H), 4.42 (t, J =11.5 Hz, 1H), 3.97 (t, J = 7.4 Hz, 2H), 3.48 (dd, J = 14.2, 7.9 Hz, 4H), 2.94(dt, J = 13.5, 6.8 Hz, 1H), 2.79 (ddd, J = 17.7, 11.6, 5.0 Hz, 1H), 2.62 – 2.51(m, 6H), 2.39 (d, J = 23.3 Hz, 4H), 2.12 (ddd, J = 18.4, 17.6, 7.6 Hz, 3H), 1.94(dd, J = 22.6, 11.9 Hz, 5H), 1.63 (s, 6H), 1.54 – 1.42 (m, 2H). [M+H] + = 826.4 Example 016: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6-difluorophenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (26.29 mg, 32.65%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.80 (s, 1H), 8.93 (d, J = 5 Hz, 1H), 8.74(d, J = 5 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.71 (d, J = 5 Hz, 1H), 7.57 (s,1H), 7.09 (d, J = 5 Hz, 1H), 6.31 (d, J = 10 Hz, 2H), 6.23 (d, J = 5 Hz, 1H), 5.72(s, 1H), 4.45 – 4.38 (m, 1H), 4.34 – 4.28 (m, 1H), 3.01 – 2.91 (m, 4H), 2.70 – 2.68 (m, 1H), 2.62 – 2.51 (m, 9H), 2.41 – 2.35 (m, 1H), 2.30 – 2.13 (m,3H), 2.10 – 2.03 (m, 1H), 2.00 – 1.72 (m, 7H), 1.63 (s, 6H), 1.55 – 1.42 (m,4H). [M+H] + = 848.72 Example 017: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (132.61 mg, 84.14%) was prepared in a manner similar to that described in Example 029. 1 HNMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.77 (s, 1H), 8.93 (d, J = 5 Hz, 1H), 8.74 (d, J = 5 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.71 (d,J = 5 Hz, 1H), 7.57(s, 1H), 7.09 (d, J = 5 Hz, 1H), 6.83 (t, J = 10 Hz, 1H), 6.50 (dd, J = 10 Hz, 5Hz, 1H), 6.41 (dd, J = 10 Hz, 5 Hz, 1H), 5.79 (d, J = 10 Hz, 1H), 5.73 (s, 1H), 4.45 – 4.38 (m, 1H), 4.28 – 4.21 (m, 1H), 3.16 (d, J = 10 Hz, 2H), 2.77 – 2.69(m, 1H), 2.62 – 2.51 (m, 11H), 2.43 – 2.35 (m, 1H), 2.29 – 2.13 (m, 3H), 2.12– 2.05 (m, 1H), 2.01 – 1.78 (m, 7H), 1.63 (s, 6H), 1.59 – 1.42 (m, 4H). [M+H] + = 830.68 Example 053: 3-Cyano-N-(2-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxyethoxy)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: 2-(benzyloxy)ethyl methanesulfonate MsCl (1.38 g, 12 mmol) was added dropwise to a solution of 2-(benzyloxy)ethanol-1-ol (1.52 g, 10 mmol) and E3N (3.03 g, 30 mmol) in DCM (40 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was diluted with water and extracted with DCM (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to give the product (1.8 g, 78.26%). [M+H] + = 231.1 Step 2: 4-((1r,4r)-4-(6-(2-(benzyloxy)ethoxy)-5-bromo-2H-indazole-2-yl)cyclohexyl)piperazine tert-butyl 1-azine carboxylate To a solution of tert-butyl piperazine-1-carboxylate (478 mg, 1 mmol, obtained by a similar method to Example 029) in CH3CN (20 mL), K2CO3 (414 mg, 3 mmol) and 2-(benzyloxy)ethyl methanesulfonate (345 mg, 1.5 mmol) were slowly added. The mixture was stirred overnight at 80 °C. The mixture was diluted with water and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to give the product (500 mg, 81.7%). [M+H] + = 613.2 Step 3: 4-((1r,4r)-4-(6-(2-(benzyloxy)ethoxy)-5-((diphenylmethylene)amino)-2H-indyl tert-butyl 2-azolylcyclohexylpiperazine-1-carboxylate Cs₂CO₃ (799 mg, 2.451 mmol), Xantphos (96 mg, 0.1634 mmol), and Pd₂(dba)₃ (74.76 mg, 0.0817 mmol) were added to a stirred solution of 4-((1r,4r)-4-(6-(2-(benzyloxy)ethoxy)-5-bromo-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 0.817 mmol) and benzophenone imine (296 mg, 1.634 mmol) in toluene (20 mL). The reaction mixture was stirred overnight at 100 °C. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:1) to give the product (480 mg, 82.4%). [M+H] + = 714.4 Step 4: 4-((1r,4r)-4-(5-amino-6-(2-(benzyloxy)ethoxy)-2H-indazole-2-yl)cyclohexyl) Piperazine-1-carboxylic acid tert-butyl ester An aqueous solution of HCl (1 N, 5 mL) was added to a solution of 4-((1r,4r)-4-(6-(2-(benzyloxy)ethoxy)-5-((diphenylmethylene)amino)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (480 mg, 0.672 mmol) in THF (10 mL). The resulting mixture was stirred for 30 min. The mixture was dissolved in water, then adjusted to pH 8 with saturated NaHCO3 solution and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to give the product (280 mg, 75.88%). [M+H]+ = 550.3 Step 5: 4-((1r,4r)-4-(5-amino-6-(2-hydroxyethoxy)-2H-indazole-2-yl)cyclohexyl)piperazine- 1-Tert-butyl formate Pd / C (5%, 20 mg) was added to a solution of tert-butyl piperazine-1-carboxylate (280 mg, 0.509 mmol) in THF (10 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under H2. The solid was filtered and washed with MeOH (30 mL). The filtrate was evaporated under vacuum to give the product (150 mg, 64.1%). [M+H] + = 460.3 Step 6: 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carbamate)-6-(2-hydroxy) ethoxy-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester DIEA (38.7 mg, 0.3 mmol) and HATU (38 mg, 0.1 mmol) were added to a solution of 4-((1r,4r)-4-(5-amino-6-(2-hydroxyethoxy)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (46 mg, 0.1 mmol) and 3-cyanopyrrolo[1,2-b]pyridazine-7-carboxylic acid (22.44 mg, 0.12 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to give the product (50 mg, 79.62%). [M+H] + = 629.3 Step 7: 3-Cyano-N-(6-(2-hydroxyethoxy)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H- Indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Concentrated HCl (36%, 2 mL) was added dropwise to a stirred solution of 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxyethoxy)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.08 mmol) in MeOH (8 mL). The resulting mixture was stirred at 0 °C for 2 hours. The mixture was dissolved in water, then adjusted to pH 8 with saturated NaHCO3 solution and extracted with DCM / MeOH (V / V = 10 / 1, 3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to give the product (30 mg, 71%). [M+H] + =529.3 Step 8: 3-Cyano-N-(2-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- (difluorophenyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxyethoxy)-2H-indazole-5- pyrrolo[1,2-b]pyridazine-7-carboxamide To a stirred solution of 3-cyano-N-(6-(2-hydroxyethoxy)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (15 mg, 0.02 mmol) and (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxaldehyde (9.24 mg, 0.03 mmol) in a DCE (8 mL), NaBH(OAc)3 (8.48 mg, 0.04 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and treated with DCM (3 x Extracted by 20 mL. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The residue was purified by preparative HPLC (Waters XSelect C18: RD-CO-094 column, eluted with 27%–52% water in acetonitrile (containing 0.1% FA)) to give the product (2 mg, 12.2%).

[0164] 1 H NMR (500 MHz, DMSO) δ 11.54 (s, 1H), 10.85 (s, 1H), 9.00 (d, J = 5Hz, 1H), 8.88 (d, J = 5 Hz, 1H), 8.80 (s, 1H), 8.29 (s, 1H), 7.78 (d, J = 5 Hz, 1H), 7.13 (d, J= 5 Hz, 1H), 7.11 (s, 1H), 6.10 (d, J = 10 Hz, 2H), 5.10 – 5.04(m, 1H), 4.38 – 4.30 (m, 1H), 4.21 (t, J = 10 Hz, 2H), 4.05 – 3.97 (m, 3H), 3.92 (d, J = 10 Hz, 2H), 3.47 (d, J = 10 Hz, 2H), 2.95 – 2.87 (m, 1H), 2.82 –2.72 (m, 1H), 2.59 – 2.51 (m, 6H), 2.47 – 2.31 (m, 6H), 2.20 – 2.13 (m, 2H),2.10 – 2.02 (m, 1H), 1.98 – 1.86 (m, 5H), 1.51 – 1.40 (m, 2H). [M+H] + = 821.67 Example 001: 3-Cyano-N-(2-((1S,4r)-4-(4-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobut-2-yl)amino)-2-oxoethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: (2S,4R)-1-((S)-2-(2-bromoacetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N- ((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide 2-Bromoacetyl chloride (0.38 g, 2.4 mmol) in THF was added dropwise to a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.96 g, 2 mmol) and NaHCO3 (0.67 g, 8 mmol) in THF / H2O (1:1, 30 mL). After stirring at room temperature for 2 hours, the mixture was concentrated to 20 mL and extracted with EA (30 mL x 3). The organic phase was combined and concentrated. Purification was performed by silica gel column chromatography with DCM / MeOH (100:1 to 10:1) to give the product (0.9 g, yield: 79.6%).

[0165] Step 2: 3-Cyano-N-(2-((1S,4r)-4-(4-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1- (4-(4-methylthiazo-5-yl)phenyl)ethyl)carbamoyl)pyrrolid-1-yl)-3,3-dimethyl-1-oxobut-2- (2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo [1,2-b]pyridazine-7-carboxamide A solution of 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (52 mg, 0.1 mmol), (2S,4R)-1-((S)-2-(2-bromoacetamyl)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidin-2-carboxamide (56 mg, 0.1 mmol), DIEA (130 mg, 1 mmol) and KI (25 mg, 0.15 mmol) in DMA / acetonitrile (2 mL / 2 mL) was stirred at 75 °C for 3 hours. The mixture was concentrated and purified directly by preparative HPLC to obtain the product (45 mg, yield: 44.5%).

[0166] 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 8.98 (s, 1H), 8.94 (d, J = 2.0Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.44 (d, J = 7.5 Hz, 1H), 8.34(s, 1H), 7.72 (d, J= 4.5 Hz, 2H), 7.58 (s, 1H), 7.49 – 7.40 (m, 2H), 7.40 –7.33 (m, 2H), 7.09 (d, J = 4.5 Hz, 1H), 5.72 (s, 1H), 5.12 (d, J = 3.0 Hz, 1H), 4.94 – 4.84 (m, 1H), 4.51 (d, J = 11 Hz, 1H), 4.46-438 (m, 2H), 4.28 (s, 1H),3.62-3.55 (m, 2H), 3.07 (d, J = 15.5 Hz, 1H), 2.94 (d, J = 15.5 Hz, 1H), 2.64(br, 4H), 2.46 (s, 5H), 2.19 (d, J = 9.5 Hz, 2H), 2.10 – 1.91 (m, 6H), 1.81 –1.73 (m, 1H), 1.63 (s, 7H), 1.53-1.46 (m, 3H), 1.39 (d, J = 7.0 Hz, 3H), 0.95(s, 9H). [M+H] + = 1011.8 Example 003: 1-((1r,4R)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)-4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazine 1-oxide H₂O₂ (3 equivalents) was added to a solution of 3-cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (0.5 g, 0.6 mmol) in DCM / MeOH / HOAc (10:1:1, 20 V). After stirring at 40-45°C for 3 hours, the mixture was concentrated and purified by preparative HPLC to give the product (2.3 mg, yield: 0.45%).

[0167] 1 H NMR (500 MHz, DMSO) δ 12.03 (s, 1H), 11.78 (s, 1H), 8.94 (d, J = 2.0Hz, 1H), 8.74 (d, J = 2.5 Hz, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.72 (d, J = 5.0Hz, 1H), 7.57 (s, 1H), 7.10 (d, J = 4.5 Hz, 1H), 6.16 (d, J = 11 Hz, 2H), 5.73(s, 1H), 4.58 (s, 1H), 4.03 (dd, J = 12.5, 10.0 Hz, 1H), 3.97 (t, J = 7.0 Hz,2H), 3.90 (br, 1H), 3.83 – 3.64 (m, 7H), 3.53 – 3.45 (m, 1H), 2.96 (d, J = 12.0Hz, 2H), 2.86 – 2.73 (m, 1H), 2.64 (t, J = 11.0 Hz, 2H), 2.44 – 2.28 (m, 4H), 2.14 – 1.82 (m, 6H), 1.63 (s, 6H). [M+H]+ =821.8 Example 002: 4-((1r,4R)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)-1-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazine 1-oxide The title compound (2.03 mg, 0.4%) was prepared in a manner similar to that described in Example 003.

[0168] 1 H NMR (500 MHz, DMSO) δ 12.03 (s, 1H), 10.87 (s, 1H), 8.94 (s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.72 (d, J= 4.5 Hz, 1H), 7.58 (s,1H), 7.09 (d, J = 5.0 Hz, 1H), 6.17 (d, J = 11.5 Hz, 2H), 5.76 (s, 1H), 4.44 (s, 2H), 4.25 (s, 2H), 4.07 – 3.99 (m, 1H), 3.91 (t, J = 7.0 Hz, 2H), 3.13 (t, J =10.0 Hz, 2H), 3.04 (t, J = 10.0 Hz, 2H), 2.84 – 2.63 (m, 7H), 2.18 (s, 2H), 2.08 (br, 1H), 1.96 (s, 5H), 1.63 (s, 6H), 1.51 (br, 2H). [M+H]+ =821.6 Example 008: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(3-hydroxypent-3-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: 3-Cyano-N-(6-(3-hydroxypent-3-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H- Indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide hydrochloride HCl (concentrated, 5 mL) was added to a solution of 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazin-7-carboxamido)-6-(3-hydroxypent-3-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (45 mg, 0.07 mmol, obtained by a similar method to Example 029) in H2O (15 mL). The mixture was stirred at 20°C–30°C for 2 hours and concentrated for direct use in the next step.

[0169] Step 2: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- (difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(3-hydroxypent-3-yl)-2H-indazole-5-yl)pyridine P-[1,2-b]pyridazine-7-carboxamide DIEA (129 mg, 1 mmol) and NaBH(OAc)3 (64 mg, 0.3 mmol) were added to a solution of 3-cyano-N-(6-(3-hydroxypentan-3-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide hydrochloride (55 mg, crude) and (R)-3-(2,6-difluoro-4-(3-oxoazacyclobutane-1-yl)phenyl)piperidine-2,6-dione (60 mg, 0.2 mmol) in i-PrOH (20 mL). The mixture was stirred at 70 °C for 3 hours. After evaporation of the solvent, the residue was purified directly by preparative HPLC to give the product (2.3 mg, yield: 3%).

[0170] 1 H NMR (500 MHz, DMSO) δ 12.05 (s, 1H), 10.85 (s, 1H), 8.93 (d, J = 2.0Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 7.69 (d, J = 4.5Hz, 1H), 7.47 (s, 1H), 7.08 (d, J = 4.5 Hz, 1H), 6.12 (d, J = 11.0 Hz, 2H), 5.39(s, 1H), 4.42 (s, 1H), 4.03 (dd, J = 12.5, 5.5 Hz, 1H), 3.91 (t, J = 7.5 Hz, 2H),3.64 (s, 2H), 3.27 – 3.20 (m, 1H), 2.82 – 2.75 (m, 1H), 2.63-2.55 (m, 5H),2.46 – 2.33 (m, 4H), 2.18 (d, J = 8.0 Hz, 2H), 2.13 – 1.81 (m, 11H), 1.48(br, 2H), 0.77 (t, J = 7.5 Hz, 6H). [M+H] + =833.7 Example 009: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-isopropyl-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide Step 1: 4-((1r,4r)-4-(5-(1,3-dioxoisoindoline-2-yl)-6-(prop-1-en-2-yl)-2H- Indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester To a solution of tert-butyl piperazine-1-carboxylate (7.3 g, 16 mmol) in DCM (200 mL), add isobenzofuran-1,3-dione (2.4 g, 16 mmol). After stirring at 20-30 °C for 3 hours, concentrate the reaction mixture to dryness. Add Ac₂O (150 mL) and NaOAc (1.3 g, 16 mmol) to the residue. After reflux for 3 hours, evaporate the solvent, then add H₂O (60 mL). Extract with EA (60 mL x 2), combine the organic phases, and wash with NaHCO₃ solution (100 mL) and brine (100 mL). Concentrate the organic phase directly for the next step.

[0171] Step 2: 4-((1r,4r)-4-(5-amino-6-(prop-1-en-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine- 1-Tert-butyl formate Add 0.5 mL of NH₂NH₂·H₂O to a solution of 0.4 g (0.8 mmol) of 4-((1r,4r)-4-(5-(1,3-dioxoisoindoline-2-yl)-6-(prop-1-en-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester in EtOH (10 mL). After stirring for 18 hours, filter off the solid. Concentrate the filtrate and use it directly in the next step without further processing.

[0172] Step 3: 4-((1r,4r)-4-(5-amino-6-isopropyl-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert- Butyl acetate A solution of tert-butyl piperazine-1-carboxylate in THF / MeOH (1:1, 30 mL) and Pd / C (w / w, 10%) was stirred at H2 (1 atm) for 18 hours. After filtering off the solids, the filtrate was concentrated and purified by silica gel column chromatography with DCM / MeOH (100:1 to 10:1) to obtain the product, which was used directly in the next step.

[0173] Step 4: 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carbamate)-6-isopropyl- 2H-Indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester T3P (0.3 g, 1 mmol) was added to a solution of 3-cyanopyrrolo[1,2-b]pyridazin-7-carboxylic acid (0.2 g, 0.5 mmol), 4-((1r,4r)-4-(5-amino-6-isopropyl-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (0.09 g, 0.5 mmol), and DIEA (0.2 g, 1.5 mmol) in DMA (3 mL). After stirring for 18 hours, the reaction mixture was quenched with H2O and extracted with DCM / i-PrOH (10:1, 20 mL x 2). The organic phases were combined, washed with brine (30 mL x 2), and purified by silica gel column chromatography with DCM / MeOH (100:1 to 15:1) to give the product (0.15 g, yield: 50%).

[0174] Step 5: 3-Cyano-N-(6-Isopropyl-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5- pyrrolo[1,2-b]pyrrolo[1,2-b]pyridazine-7-carboxamide hydrochloride A solution of 0.15 g (0.24 mmol) of 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazin-7-carboxamido)-6-isopropyl-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester in HCl / dioxane (4N, 15 mL) was stirred at 20-30 °C for 2 hours. After evaporating the solvent, the residue was used directly in the next step.

[0175] Step 6: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- (difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-isopropyl-2H-indazole-5-yl)pyrrolo[1,2-] b] Pyridazine-7-formamide DIEA (32 mg, 0.25 mmol) was added to a solution of 3-cyano-N-(6-isopropyl-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide hydrochloride (27 mg, 0.05 mmol) and (R)-3-(2,6-difluoro-4-(3-oxozylate-1-yl)phenyl)piperidine-2,6-dione (15 mg, 0.05 mmol) in DCE (3 mL), followed by the addition of NaBH(OAc)3 (21 mg, 0.1 mmol). After stirring for 18 hours, the reaction mixture was quenched with MeOH and concentrated, and then purified directly by preparative HPLC to give the product (8.7 mg, yield: 22%). 1 H NMR (500 MHz, DMSO) δ 10.86 (s, 1H), 10.73 (s, 1H), 8.99 (dd, J =10.5, 2.0 Hz, 2H), 8.42 (s, 1H), 8.34 (s, 1H), 7.77 (d, J = 5.0 Hz, 1H), 7.54(s, 1H), 7.13 (d, J = 5.0 Hz, 1H), 6.12 (d, J = 11.0 Hz, 2H), 4.73 (s, 2H), 4.42(br, 2H), 4.13 – 3.99 (m, 2H), 3.91 (t, J = 7.5 Hz, 2H), 3.64 (t, J = 5.5 Hz,2H), 2.83 – 2.75 (m, 1H), 2.57 (s, 3H), 2.41-2.36 (m, 4H), 2.24 – 2.03 (m,4H), 2.01 – 1.89 (m, 5H), 1.49-1.47 (m, 2H), 1.35(d, J = 6.0 Hz, 6H). [M+H] + =789.7 Example 011: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-isopropyl-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (65.4 mg, 41.1%) was prepared in a manner similar to that described in Example 009.

[0176] 1 H NMR (500 MHz, DMSO) δ 10.78 (s, 1H), 10.74 (s, 1H), 8.99 (dd, J =10.5, 2.5 Hz, 2H), 8.42 (s, 1H), 8.35 (s, 1H), 7.77 (d, J = 5.0 Hz, 1H), 7.54(s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 5.0Hz, 1H), 7.11 (d, J = 8.5 Hz,1H), 4.42 (br, 1H), 3.89 (dd, J = 9.0, 5.0 Hz, 1H),3.33 (br, 2H), 3.11 (d, J =11.0 Hz, 2H), 2.68 – 2.52 (m, 11H), 2.41 – 2.34 (m, 4H), 2.28 (br, 1H), 2.22-2.15 (m, 3H), 2.09-2.05 (m, 1H), 2.03 – 1.83 (m, 6H), 1.63 – 1.42 (m, 4H), 1.36 (d, J = 6.5 Hz, 6H). [M+H] + =796.7 Example 012: N-(2-((1r,4r)-4-(4-(2-(1-(4-(((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)ethyl)piperazin-1-yl)cyclohexyl)-6-methoxy-2H-indazole-5-yl)furano[3,2-b]pyridine-3-carboxamide Step 1: 4-((1r,4r)-4-(5-(furano[3,2-b]pyridine-3-carboxamido)-6-methoxy-2H-ind tert-butyl 2-azolylcyclohexylpiperazine-1-carboxylate DIEA (0.32 g, 2.5 mmol) and T3P (318 mg, 1 mmol) were added to a solution of furano[3,2-b]pyridine-3-carboxylic acid (82 mg, 0.5 mmol) and 4-((1r,4r)-4-(5-amino-6-methoxy-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (212 mg, 0.5 mmol, obtained by a similar method to Example 029) in DMA. After stirring for 0.5 hours, the reaction mixture was quenched with H2O (20 mL). The product was collected by filtration and washed with H2O. The crude product was dried under reduced pressure and used directly in the next step.

[0177] Step 2: N-(6-methoxy-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)furano [3,2-b]pyridine-3-carboxamide hydrochloride A solution of 0.15 g of 4-((1r,4r)-4-(5-(furano[3,2-b]pyridin-3-carboxamido)-6-methoxy-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester in HCl / dioxane (4N, 20 mL) was stirred at 20-30°C for 2 hours. The solvent was evaporated and used directly in the next step.

[0178] Step 3: N-(2-((1r,4r)-4-(4-(2-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluoro (Phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)furano[3,2-b]pyrene Pyridine-3-carboxamide DIEA (64 mg, 0.5 mmol) was added to a solution of N-(6-methoxy-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)furano[3,2-b]pyridine-3-carboxamide hydrochloride (51 mg, 0.1 mmol) and (R)-2-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)acetaldehyde (35 mg, 0.1 mmol, obtained by the same method as WO2023098656 A1) in DCE (3 mL), followed by the addition of NaBH(OAc)3 (42 mg, 0.2 mmol). The mixture was concentrated and purified by preparative HPLC to give the product (14.4 mg, yield: 15.3%).

[0179] 1 H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 10.86 (s, 1H), 9.02 (s, 1H), 8.79 (dd, J= 4.5, 1.0 Hz, 1H), 8.71 (s, 1H), 8.31 – 8.26 (m, 2H), 7.57 (dd, J =8.5, 5.0 Hz, 1H), 7.12 (s, 1H), 6.60 (d, J = 13.0 Hz, 2H), 4.35 (br, 1H), 4.10– 3.97 (m, 4H), 3.73 (d, J = 12.0 Hz, 2H), 2.83 – 2.66 (m, 4H), 2.51-2.50 (m,4H), 2.43 – 2.23 (m, 7H), 2.21 – 2.05 (m, 3H), 1.98 – 1.87 (m, 5H), 1.71 (d, J =11.5 Hz, 2H), 1.52 – 1.32 (m, 5H), 1.21-1.14 (m, 2H). [M+H] + =809.7 Example 040: 3-Cyano-N-(2-((1r,4r)-4-(4-((1-(3-((R)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (98 mg, 60.4%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.03 (s, 1H), 10.79 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.74(d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.73 (d, J = 5.0 Hz, 1H), 7.57(s, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 5.0 Hz, 1H), 6.81 (d, J = 8.0 Hz,1H), 6.78 (s, 1H), 6.58 (d, J= 7.5 Hz, 1H), 5.81 – 5.69 (m, 1H), 4.49 – 4.33(m, 1H), 3.75 (dd, J = 11.0, 5.0 Hz, 1H), 3.70 – 3.61 (m, 2H), 2.68 – 2.53 (m,6H), 2.49 – 2.41 (m, 5H), 2.39 – 2.34 (m, 1H), 2.26 – 2.10 (m, 5H), 2.08 – 1.86 (m, 6H), 1.81 – 1.73 (m, 2H), 1.71 – 1.57 (m, 7H), 1.57 – 1.43 (m, 2H), 1.25 – 1.16 (m, 2H). [M+H] + = 811.6.

[0180] Example 036: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (21.5 mg, 26.24%) was prepared in a manner similar to that described in Example 29. 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.84 (s, 1H), 8.93 (s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.72 (d, J = 4.1 Hz, 1H), 7.62 (t, J =8.7 Hz, 1H), 7.57 (s, 1H), 7.09 (d, J = 4.0 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 15.7 Hz, 1H), 5.72 (s, 1H), 4.77 – 4.68 (m, 1H), 4.46 – 4.36 (m,1H), 3.90 (d, J= 11.2 Hz, 2H), 2.86 – 2.73 (m, 3H), 2.62 – 2.53 (m, 8H), 2.43 – 2.33 (m, 3H), 2.19 – 2.09 (m, 3H), 2.04 – 1.90 (m, 5H), 1.86 – 1.79 (m,2H), 1.63 (s, 6H), 1.46 (d, J = 11.8 Hz, 4H). [M+H] + = 858.6.

[0181] Example 055: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((2,6-dioxopiperidin-3-yl)oxy)-2-fluorophenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (15 mg, 18.07%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.92 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.74(d, J = 5.0 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.57(s, 1H), 7.10 (d, J = 5.0 Hz, 1H), 6.99 – 6.88 (m, 2H), 6.77 – 6.75 (m, 1H), 5.72 (s, 1H), 5.14 – 5.11 (m, 1H), 4.44 – 4.40 (m, 1H), 3.30 – 3.25 (m, 4H),2.72 – 2.55 (m, 10H), 2.41 – 2.36 (m, 1H), 2.30 – 2.06 (m, 5H), 1.98 – 1.91(m, 4H), 1.86 – 1.83 (m, 2H), 1.63 (s, 6H), 1.56 – 1.46 (m , 4H). [M+H] + =831.59.

[0182] Example 049: 3-Cyano-N-(2-((1R,4r)-4-(4-(4-(((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO)δ12.03 (s, 1H),11.60 (s, 1H), 8.94 (d, J = 5.0 Hz, 1H), 8.74 (d, J = 5.0 Hz, 1H),8.56 (s, 1H), 8.42 (s, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.59 (s, 1H), 7.10 (d, J =5.0 Hz, 1H), 6.66 (d, J = 5.0 Hz, 2H), 5.72 (s, 1H), 4.47 – 4.42 (m, 1H), 4.08 – 4.04 (m, 1H), 3.20 – 3.18 (m, 4H), 2.79 – 2.75 (m, 1H), 2.67 – 2.63 (m,4H), 2.20 – 2.18 (m, 2H), 2.11 – 2.06 (m, 1H), 2.01 -1.93 (m, 5H), 1.63 (s,6H), 1.55 – 1.48 (m,2H). [M+H] + = 750.32.

[0183] Example 041: 3-Cyano-N-(2-((1R,4r)-4-(4-((1-(3-((R)-2,6-dioxopiperidin-3-yl)phenyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (22.6 mg, 19.2%) was prepared in a manner similar to that described in Example 029. 1H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.79 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.74(d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.72 (d, J = 4.5 Hz, 1H), 7.57(s, 1H), 7.11-7.08 (m, 2H), 6.50 (d, J = 7.5 Hz, 1H), 6.31 (d, J = 8.5 Hz, 1H), 6.25 (s, 1H), 5.72 (s, 1H), 4.42 (t, J = 11.5 Hz, 1H), 3.92-3.88 (m, 2H), 3.73(dd, J = 11.0, 5.0 Hz, 1H), 3.42 (dd, J = 11.5, 6.0 Hz, 2H), 2.94 – 2.84 (m, 1H), 2.69 – 2.52 (m, 8H), 2.45 – 2.32 (m, 5H), 2.22 – 2.09 (m, 3H), 2.04 – 1.87(m, 5H), 1.63 (s, 6H), 1.54 – 1.40 (m, 2H). [M+H] + = 783.6.

[0184] Example 061: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorobenzyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound (49.2 mg, 52.24%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.95 (s, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.74(d, J= 2.1 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.57(s, 1H), 7.09 (d, J = 4.8 Hz, 1H), 7.01 (d, J = 9.9 Hz, 2H), 5.72 (s, 1H), 4.41(t, J = 11.6 Hz, 1H), 4.21 (dd, J = 12.6, 5.0 Hz, 1H), 3.58 (s, 2H), 3.39 (s,2H), 2.92 – 2.77 (m, 4H), 2.58 – 2.51 (m, 6H), 2.43 – 2.35 (m, 1H), 2.30 –2.10 (m, 6H), 2.03 – 1.88 (m, 5H), 1.63 (s, 6H), 1.47 (dd, J = 24.0, 11.3 Hz, 2H). [M+H] + = 819.6.

[0185] Example 062: N 7 -(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-3,7-dicarboxamide The title compound (8.5 mg, 23.21%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.07 (s, 1H), 10.86 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.70(d, J = 2.1 Hz, 1H), 8.54 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.65 (d, J = 4.6Hz, 2H), 7.57 (s, 1H), 6.97 (d, J = 4.7 Hz, 1H), 6.12 (d, J= 11.1 Hz, 2H), 5.73(s, 1H), 4.42 (t, J = 11.5 Hz, 1H), 4.03 (dd, J = 12.5, 4.9 Hz, 1H), 3.91 (t, J =7.1 Hz, 2H), 3.67 – 3.59 (m, 2H), 3.28 – 3.19 (m, 2H), 2.82 – 2.72 (m, 1H), 2.65 – 2.54 (m, 4H), 2.46 – 2.25 (m, 5H), 2.21 – 2.14 (m, 2H), 2.13 – 2.04(m, 1H), 2.00 – 1.88 (m, 5H), 1.63 (s, 6H), 1.54 – 1.43 (m, 2H).[M+H] + =823.6.

[0186] Example 063: N 7 -(2-((1r,4r)-4-(4-(1-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-3,7-dicarboxamide The title compound (31 mg, 27.61%) was prepared in a manner similar to that described in Example 029. 1 H NMR (500 MHz, DMSO) δ 12.08 (s, 1H), 10.78 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.70(d, J = 2.1 Hz, 1H), 8.54 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 7.65 (d, J = 4.6Hz, 2H), 7.57 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.97(d, J = 4.7 Hz, 1H), 5.73 (s, 1H), 4.42 (t, J= 11.4 Hz, 1H), 3.89 (dd, J = 9.3, 5.3 Hz, 1H), 3.11 (d, J 2.00 –1.85 (m, 6H), 1.64 (s, 6H), 1.57 (dd, J = 23.0, 13.1 Hz, 2H), 1.48 (dd, J = 23.1, 11.0 Hz, 2H). [M+H] + = 830.6.

[0187] Example 058: 2-(5-((S)-1-(5-(4-((4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carbamoyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-yl)methyl)piperidin-1-yl)pyridin-3-yl)piperidin-3-carbamoyl)-2-oxopyridin-1(2H)-yl)ethyl acetate Step 1: (S)-2-(5-(1-(5-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)pyridin-3-yl)piperidin- ethyl 3-formamido(2-oxopyridine-1(2H)-yl)ethyl acetate To a solution of ethyl (S)-2-(5-(1-(5-bromopyridin-3-yl)piperidin-3-carboxamido)-2-oxopyridin-1(2H)-yl)acetate (CAS 2991251-11-5) (500 mg, 1.1 mmol, obtained by the same method as WO2023192586A1) in 1,4-dioxane (30 mL), 4-(1,3-dioxolane-2-yl)piperidine hydrochloride (590.7 mg, 3.3 mmol), Pd2(dba)3 (202 mg, 0.22 mmol), ruphos (202 mg, 0.43 mmol), and Cs2CO3 (2.15 g, 6.6 mmol) were added. The mixture was stirred overnight at 90 °C under N2. The mixture was cooled to room temperature and concentrated under vacuum. Add H2O (50 ml) to the residue and use DCM (50 ml) 3) Extraction. The organic layer was dried over Na₂SO₄ and filtered to obtain the crude product. The crude product was further purified by combi flash elution with MeOH:DCM = 0 - 1:10 to obtain the product (460 mg, 77%). [M+H] + = 540.3.

[0188] Step 2: (S)-2-(5-(1-(5-(4-formylpiperidin-1-yl)pyridin-3-yl)piperidin-3-carboxamido)-2- ethyl oxopyridine-1(2H)-yl)ethyl acetate A solution of (S)-2-(5-(1-(5-(4-(1,3-dioxolane-2-yl)piperidin-1-yl)pyridin-3-yl)piperidin-3-carboxamido)-2-oxopyridin-1(2H)-yl)ethyl acetate (200 mg, 0.37 mmol) in HCl (2N, in H2O) (10 mL) was stirred at room temperature for 2 hours. The mixture was adjusted to pH 9 with saturated Na2CO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to give a crude product. The crude product was further purified by combi flash elution with MeOH : DCM = 0 - 1:10 to give product (100 mg, 54%) [M+H). + = 496.2.

[0189] Step 3: 2-(5-((S)-1-(5-(4-((4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7- (formamido)-6-(2-hydroxypropyl-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridine (Pinidin-3-yl)piperidin-3-carbamate-2-oxopyridine-1(2H)-yl)ethyl acetate A solution of 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazin-7-carboxamide (20 mg, 0.04 mmol) and (S)-2-(5-(1-(5-(4-formylpiperidin-1-yl)pyridin-3-yl)piperidin-3-carboxamido)-2-oxopyridin-1(2H)-yl)ethyl acetate (20 mg, 0.04 mmol) in a DCE (6 mL) was stirred at room temperature for 0.5 hours, followed by dropwise addition of NaBH(OAc)3 (10 mg, 0.048 mmol). The solution was then stirred at room temperature for another 2 hours. The mixture was then purified using a Combi-Flash column (4 g, DCM:MeOH = 10:1) to give the product (2 mg, 5.26%).

[0190] 1H NMR (500 MHz, DMSO)δ 12.02 (s, 1H), 9.80 (s, 1H), 8.94 (d, J = 5.0Hz, 1H), 8.74 (d, J = 5.0 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.19 (d, J = 5.0Hz, 1H), 7.75-7.71 (m, 3H), 7.57 (s, 1H), 7.47 – 7.44 (m, 1H), 7.10 (d, J = 5.0Hz, 1H), 6.78 (s, 1H), 6.43 (d, J = 10.0 Hz, 1H), 5.72 (s, 1H), 4.69 (s, 2H), 4.43 – 4.40 (m, 1H), 4.14 (q, J = 10.0Hz, 2H ), 3.85 – 3.82 (m, 1H ), 3.72 -3.70 (m, 3H ), 2.83 (t, J = 10.0Hz, 1H), 2.73 – 2.54 (m, 9H), 2.40 – 2.36 (m, 4H), 2.17 – 2.13 (m, 4H), 1.97 – 1.92 (m, 5H), 1.77 – 1.75 (m, 3H), 1.73–1.46 (m, 11H), 1.24 – 1.15 (m, 5H). [M+H] + =1006.59.

[0191] Example 051: 3-Cyano-N-(2-((1r,4r)-4-(4-((3-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)prop-2-yn-1-yl)oxy)piperidin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide The title compound was prepared in a manner similar to that described in Example 029.

[0192] 1 H NMR (500 MHz, DMSO)δ 12.02 (s, 1H), 11.00 (s, 1H), 8.94 (d, J= 5.0Hz, 1H), 8.74 (d, J = 5.0 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.19 (d, J = 5.0Hz, 1H), 7.72 (d, J = 5.0 Hz, 1H), 7.57 (s, 1H), 7.72 (d, J = 10.0 Hz, 2H), 7.09(d, J = 5.0 Hz, 1H), 5.72 (s, 1H), 4.43 – 4.40 (m, 3H), 4.30 – 4.26 (m, 1H ), 3.56 – 3.48 (m, 1H ), 2.81 -2.78 (m, 3H ), 2.49 – 2.45 (m, 2H), 2.34 – 2.30(m, 2H), 2.17 – 2.11 (m, 3H), 2.04 – 1.90 (m, 7H), 1.63 (s, 6H), 1.51 – 1.45(m, 4H). [M+H] + =803.62.

[0193] Bioassay IRAK4 Degradation Determination of Karpas299 IRAK4 degradation was measured using a TR-FRET-based method (Degorce, François, et al. Currentchemical Genomics. 2009, 3: 22). Karpas299 cells maintained in RPMI 1640 medium (Thermo Scientific) supplemented with 20% fetal bovine serum (FBS, Thermo Scientific), 100 IU / mL penicillin, and 0.1 mg / mL streptomycin (Thermo Scientific) were seeded at a density of 200,000 cells per well into 96-well plates and treated with serial dilutions of the compound. After 24 hours of treatment, cells were centrifuged to pellet the cells, and after removing the supernatant, 40 μL of lysis buffer (Cisbio) was added to each well. The plates were then incubated with shaking at room temperature for 30 minutes. A total of 16 μL of cell lysate from each well of the 96-well plate was transferred to a 384-well white assay plate. IRAK4 levels were quantified using the HTRF kit as described in the manufacturer's manual (Cisbio). The FRET signal was measured using a PHERAstar FSX reader (BMG Labtech).

[0194] Determination of IRAK4 in PBMC IRAK4 degradation was measured using a TR-FRET-based method (Degorce, François, et al. Currentchemical Genomics. 2009, 3: 22). PBMCs cultured in RPMI 1640 medium (Thermo Scientific) supplemented with 10% heat-inactivated fetal bovine serum (FBS, Thermo Scientific), 100 units / mL penicillin, and 0.1 mg / mL streptomycin (Thermo Scientific) were seeded at a density of 500,000 cells per well into 96-well plates and treated with serial dilutions of the compounds. After 24 hours of treatment, the cells were centrifuged to pellet the cells, and after removing the supernatant, 40 μL of lysis buffer (Cisbio) was added to each well. The plates were then incubated with shaking at room temperature for 30 minutes. A total of 16 μL of cell lysate from each well of the 96-well plate was transferred to a 384-well white assay plate. IRAK4 levels were quantified using the HTRF kit as described in the manufacturer's manual (Cisbio). The FRET signal was measured using a PHERAstar FSX reader (BMG Labtech).

[0195] Degradation of Karpas299 doped with IRAK4 in human serum IRAK4 degradation was measured using a TR-FRET-based method (Degorce, François, et al. Currentchemical Genomics. 2009, 3: 22). Karpas299 cells resuspended in human serum AB (GEMINI, 100-512) were seeded at a density of 200,000 cells per well in 96-well plates and treated with serial dilutions of the compound. After 24 hours of treatment, cells were centrifuged to precipitate and washed with PBS. After removing the supernatant, 40 μL of lysis buffer (Cisbio) was added to each well. The plates were then incubated with shaking at room temperature for 30 minutes. A total of 16 μL of cell lysate from each well of the 96-well plate was transferred to a 384-well white assay plate. IRAK4 levels were quantified using the HTRF kit as described in the manufacturer's manual (Cisbio). FRET signals were measured using a PHERAstar FSX reader (BMG Labtech).

[0196] IRAK4 degradation assay of PBMCs doped in human serum IRAK4 degradation was measured using a TR-FRET-based method (Degorce, François, et al. Currentchemical Genomics. 2009, 3: 22). PBMCs resuspended in human serum AB (GEMINI, 100-512) were seeded at a density of 500,000 cells per well in 96-well plates and treated with serial dilutions of the compound. After 24 hours of treatment, cells were centrifuged to precipitate and washed with PBS. After removing the supernatant, 40 μL of lysis buffer (Cisbio) was added to each well. The plates were then incubated with shaking at room temperature for 30 minutes. A total of 16 μL of cell lysate from each well of the 96-well plate was transferred to a 384-well white assay plate. IRAK4 levels were quantified using the HTRF kit as described in the manufacturer's manual (Cisbio). FRET signal was measured using a PHERAstar FSX reader (BMG Labtech).

[0197] Measurement of IL-6 production in human PBMCs Frozen human PBMCs (AllCells) were thawed in RPMI 1640 medium (Thermo Scientific) supplemented with 10% heat-inactivated FBS (Thermo Scientific) and allowed to recover overnight at 37°C. The next day, PBMCs were seeded into 96-well plates at a density of 200,000 cells per well and treated with the compound for 24 hours. Lipopolysaccharide was then added to a final concentration of 10 ng / mL for 5 hours. The culture supernatant was collected, and IL-6 concentrations were subsequently measured using a TR-FRET-based method (Degorce, François, et al. Current chemical genomics. 2009, 3: 22) as described in the manufacturer's manual (Cisbio). FRET signals were measured using a PHERAstar FSX reader (BMG Labtech).

[0198] HTRF Measurement After treatment, add HTRF lysis buffer to each well; seal the plate and incubate on a plate shaker at room temperature for 1 hour; once cells are lysed, transfer 16 µL of cell lysate to a PE 384-well HTRF assay plate; add 4 µL of premixed HTRF antibody to each well; cover the plate with a plate sealer, rotate at 1000 rpm for 1 minute, and incubate overnight at room temperature; read using the HTRF protocol (337 nm–665 nm–620 nm) on a BMG PheraStar.

[0199] The percentage of inhibition (degradation) of a compound is calculated using the following equation: Percentage of inhibition of compound = 100 - 100 × (signal - low control) / (high control - low control), where signal = each test compound group Low control = lysis buffer only, no cells, indicating complete IRAK4 degradation; High control = cell group with added DMSO and no compound, indicating microplate readings without IRAK4 degradation; Dmax is the maximum percentage of inhibition (degradation).

[0200] IC of the compound 50 (DC 50 The value can be obtained by fitting the following equation: Y = base value + (top value - base value) / (1 + (IC) 50 / X) ^Hill slope)) Where X and Y are known values, and IC 50 Hill slope, peak value, and basal value are parameters obtained through software fitting. Y represents the inhibition percentage (calculated from the equation), and X represents the concentration of the compound; IC 50 The concentration of the compound 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, typically around 1. The base value represents the minimum value of the curve obtained through data fitting, typically 0% ± 20%; the top value represents the maximum value of the curve obtained through data fitting, typically 100% ± 20%. Experimental data are fitted using Dotmatics data analysis software for calculation and analysis.

[0201] It should be understood that if this document references any prior art publications, such reference does not constitute an acknowledgment that such publications constitute common general knowledge in the art in any country.

[0202] All publications, patents, patent applications, and published patent applications mentioned in this document by way of reference are incorporated herein by reference in their entirety.

[0203] Although the foregoing invention has been described in considerable detail by way of illustration and example for purposes of clarity, it will be apparent to those skilled in the art that certain minor changes and modifications will be made. Therefore, the description and embodiments should not be construed as limiting the scope of the invention.

Claims

1. A compound of formula (X) (X) Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analogue or prodrug, in: Y 1 and Y 9 Each is independently selected from C, N, O, or S; Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 and Y 8 Each is independently selected from C or N; the condition is that and Each is an aromatic ring; s1 is 0, 1, or 2; s2 is 0, 1, 2, or 3; R 1 and R 2 Each can be independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, -CN, or -OR. 1a or -NR 1a R 1b Each of the -C1-C8 alkyl or -C3-C8 cycloalkyl groups is optionally substituent R. 1c replace; R 1a and R 1b Each of the following is independently selected from hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, C1-C8 alkoxy-C1-C8 alkyl- or C3-C8 cycloalkyl; each of the following is optionally substituted by at least one substituent selected from halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl-OH or -C3-C8 cycloalkyl; R 1c Each time it appears, it is independently a halogen, -OH, -CN, oxo group (=O), -C1-C8 alkyl, -C1-C8 haloalkyl, -C3-C8 cycloalkyl, -C1-C8 alkoxy or C1-C8 alkoxy-C1-C8 alkyl-; R 11a R 11b R 12a and R 12b Each is independently hydrogen, halogen, -C 1-8 Alkyl, -C 1-8 alkoxy or -C 3-8 cycloalkyl; the -C 1-8 Alkyl, -C 1-8 alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally selected from at least one element selected from hydrogen, halogen, -C 1-8 Substitution with alkoxy, -OH, or -CN groups; L 1 Selected from -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, , , , , , , , , , and ; wherein , , , , , , , , , and Each of them is optionally controlled by at least one R L1c replace; in It refers to and The location of partial connections, and It refers to and The location of the partial connection; L 2 Selected from -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, , , , , , and ; wherein , , , , , and Each of them is optionally controlled by at least one R L2c replace; in It refers to and The location of partial connections, and It refers to and The location of the partial connection; L 3 Selected from -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 -, -O, -NR ethynyl groups a -、-CONR a -、-C(O)O-、 , , , , , and ; wherein -C 1-8 alkylene-, -C 2-8 imidene-, -C 2-8 Ethyne-, , , , , , and Each of them is optionally controlled by at least one R L3c replace; in It refers to and The location of partial connections, and It refers to and The location of the partial connection; The R L1c R L2c and R L3c Each of these is independently an oxo group (=O), a halogen, a hydroxyl group, a -CN group, a -C1-C8 alkyl group, or a -C1-C8 alkoxy group; each of the -C1-C8 alkyl or -C1-C8 alkoxy groups is optionally surrounded by at least one R group. Lca replace, R Lca It can be independently an oxo group (=O), halogen, hydroxyl group, -CN, -C1-C8 alkoxy group or C3-C8 cycloalkyl group; It is the E3 ubiquitin ligase binding site; X appears each time 1 and X 2 Each independently selected from -CR a Or N; X appears each time 3 and X 4 Each independently selected from -NR a -、-O-、-S- and -CR a R b -; X appears each time 5 and X 6 Each is independently selected from non-existent, single bond, -C(O)-, -NR a -and-O-; R each time it appears a and R b Each is independently selected from hydrogen or -C1-C4 alkyl groups; m1 and m3 are each independently 0, 1 or 2; m2 is 0 or 1; n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3.

2. The compound of claim 1, wherein... Partially selected from , , , or amino acid residues; Z 1 and Z 2 Each is independently N or CR z ; R z and R 13 Each time it appears, it is independently selected from hydrogen, halogen, -C. 1-4 Alkyl or CN; L 4 Selected from single bond, -O-, -NR a -or-C(O)NR a -; L 5 and L 6 Each is independently selected from single bonds, -O-, and -NR. a -or -C(O)-; R each time it appears a and R c Each is independently selected from hydrogen or -C1-C4 alkyl; and n6 can be 0, 1, 2 or 3 independently.

3. The compound of claim 1, wherein the compound is selected from formula (IIa). (IIa)。 4. The compound of claim 1, wherein the compound is selected from formulas (IIIa), (IIIb), (IIIc), (IIId), and (IIIe). (IIIa)、 (IIIb)、 (IIIc)、 (IIId) or (IIIe) 5. The compound of claim 1, wherein the compound is selected from formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh): (IVa)、 (IVb)、 (IVc)、 (IVd)、 (IVe)、 (IVf)、 (IVg) or (IVh).

6. The compound of claim 1, wherein the compound is selected from formula (Va). (And)。 7. The compound of claim 1, wherein the compound is selected from formula (VIa). (VIa)。 8. The compound as claimed in any one of the preceding claims, wherein Partially selected from , or .

9. The compound as claimed in any of the preceding claims, wherein... Partially selected from , or .

10. The compound as claimed in any one of the preceding claims, wherein Partially selected from , or .

11. The compound as claimed in any of the preceding claims, wherein... Partially selected from , or .

12. The compound as claimed in any of the preceding claims, wherein R 1 and R 2 Each can be independently hydrogen, halogen, -C1-C5 alkyl, -CN, or -OR 1a The -C1-C5 alkyl group is optionally substituent R. 1c replace; R 1a Independently selected from hydrogen or -C1-C8 alkyl; the -C1-C8 alkyl is optionally substituted by at least one substituent selected from halogen, -OH, -CN or -C1-C8 alkyl-OH; R 1c Each time it appears, it is independently a halogen, -OH, -CN, oxo group (=O), -C1-C8 alkyl, -C1-C8 haloalkyl or -C1-C8 alkoxy.

13. The compound as claimed in any one of the preceding claims, wherein, R 1 and R 2 Each can be independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, -CN, or -OR. 1a Each of the methyl, ethyl, propyl, butyl, or pentyl groups is optionally substituent R. 1c replace; R 1a The group is independently selected from hydrogen, methyl, ethyl, propyl, butyl, or pentyl; each of the methyl, ethyl, propyl, butyl, or pentyl groups is optionally substituted by at least one substituent selected from -F, -Cl, -Br, -I, -OH, -CN, or -C1-C8 alkyl-OH. R 1c Each time it appears, it is independently -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, -C1-C8 haloalkyl or -C1-C8 alkoxy.

14. The compound as claimed in any of the preceding claims, wherein, R 1 and R 2 Each of these can be independently represented as H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CF3, -CF2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CHF2, -CN, -OMe, -OEt, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2OH. , or .

15. The compound as claimed in any one of the preceding claims, wherein, R 1 It can be H, -CF3, -F, or -CN; R 2 Is H, -CH3, -CH(CH3)2, -OMe, -OCD3, -OEt, -OCH2CH2OH, , or .

16. The compound as claimed in any of the preceding claims, wherein R 11a R 11b R 12a and R 12b Each of the following is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; each of the following is optionally selected from hydrogen, F, Cl, Br, I, -C 1-8 Substitution with alkoxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, or -CN substituents.

17. The compound as claimed in any of the preceding claims, wherein R 11a R 11b R 12a and R 12b Each of the following is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

18. The compound as claimed in any of the preceding claims, wherein R 11a R 11b R 12a and R 12b Each is hydrogen independently.

19. The compound as claimed in any of the preceding claims, wherein... Part of it is , , , , , , , , , , or .

20. The compound as claimed in any of the preceding claims, wherein L 1 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; The above , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by at least one R L1c replace; The R L1c Each of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca It can be independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

21. The compound as claimed in any of the preceding claims, wherein L 1 Selected from The Optionally by at least one R L1c replace; The R L1c Each of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca It can be independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

22. The compound as claimed in any of the preceding claims, wherein L 1 Selected from , , ( or ), , , , , , , , , , , , , , , , , , , , , , , , , , , ( or ), ( or ), , ( or ), , ( or ), ( or ), ( or ), ( or ), , , , , , ( or ), , , , , , , , , , , , , ( or ), ( or ), ( , , or ), , , , ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), , , ( or ), , , , , , , , , , , ( or ), ( or ), , or .

23. The compound as claimed in any of the preceding claims, wherein L 1 Selected from , or .

24. The compound as claimed in any of the preceding claims, wherein L 2 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; The above , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by at least one R L2c replace; The R L2c Each of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca It can be independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

25. The compound as claimed in any of the preceding claims, wherein L 2 Selected from , or ; wherein , or Each of them is optionally controlled by at least one R L2c replace; The R L2c Each of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca It can be independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

26. The compound as claimed in any one of the preceding claims, wherein L 2 Selected from , , , , , , , , , , , , , , , , , , , , , , , ( or ), ( or ), , ( or ), , ( or ), ( or ), ( or ), ( or ), , , , , , ( or ), , , , , , , , , , , , ( or ), ( or ), ( , , or ), , , , ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), , , ( or ), , , , , , , , , , , ( or ), ( or ), , or 。 27. The compound as claimed in any of the preceding claims, wherein L 2 Selected from , ( or ), ( or ), , , or .

28. The compound as claimed in any of the preceding claims, wherein L 3 Selected from -O-, -N(R) a )-、-C(O)NR a -、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; The above , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by at least one R L3c replace; The R L3c Each of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca Independently, it can be an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; R a It is selected from hydrogen, methyl, ethyl, propyl or butyl.

29. The compound as claimed in any of the preceding claims, wherein L 3 Selected from -O-, -C(O)NR a -、 , , and ; The above , , and Each of them is optionally controlled by at least one R L3c replace; The R L3c Each of these groups is independently an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, or octyloxy groups is optionally influenced by at least one R group. Lca replace, R Lca Independently, it can be an oxo group (=O), F, Cl, Br, I, hydroxyl, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; R a It is selected from hydrogen, methyl, ethyl, propyl or butyl.

30. The compound as claimed in any of the preceding claims, wherein L 3 Selected from -O-, -N(CH3)-, -NH-, -C(O)NH-, , , , , , , , , , , , , , , , , , , , , , , , , , ( or ), ( or ), , ( or ), ( or ), ( or ), , ( or ), ( or ), ( or ), ( , ), , , , , , , ( or ), , , , , , , , , , , , ( or ), ( or ), ( , , or ), , , , ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), ( or ), , , ( or ), , , , , , , , , , , ( or ), ( or ), , or .

31. The compound as claimed in any of the preceding claims, wherein L 3 Selected from -O-, -C(O)NH-, , , and .

32. The compound as claimed in any one of the preceding claims, wherein Partially selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , or .

33. The compound as claimed in any of the preceding claims, wherein Partially selected from , , , , , , , , , , , , , , or .

34. The compound as claimed in any of the preceding claims, wherein L 4 Independently selected from single bonds, -O-, -NR a -or-C(O)NR a -; R each time it appears a It is independently selected from hydrogen, methyl, ethyl, propyl or butyl.

35. The compound as claimed in any of the preceding claims, wherein L 4 It is independently selected from single bonds, -NH- or -C(O)NH-.

36. The compound as claimed in any of the preceding claims, wherein Z 1 and Z 2 At most one of them is N.

37. The compound as claimed in any of the preceding claims, wherein Z 1 and Z 2 Each independently for CR z ; R z Each time it appears, it is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, or CN.

38. The compound as claimed in any of the preceding claims, wherein R z Selected from H, -CH3, -F or -Cl.

39. The compound as claimed in any of the preceding claims, wherein R 13 Selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, or CN.

40. The compound as claimed in any of the preceding claims, wherein R 13 Selected from H, -CH3, -F or -Cl.

41. The compound as claimed in any of the preceding claims, wherein L 5 and L 6 Each is independently selected from single bonds, -O-, and -NR. a -or -C(O)-; R a It is independently selected from hydrogen, methyl, ethyl, propyl or butyl.

42. The compound as claimed in any of the preceding claims, wherein L 5 and L 6 Each can be a single bond, -O-, -NH-, -NMe-, or -N(CH2CH3)-.

43. The compound as claimed in any of the preceding claims, wherein L 5 It is -CO-, and L 6 It is -NH- or -NMe-.

44. The compound as claimed in any of the preceding claims, wherein yes .

45. The compound as claimed in any one of the preceding claims, wherein It is an amino acid residue.

46. ​​The compound as claimed in any of the preceding claims, wherein It is lysine amide; more preferably, yes .

47. The compound as claimed in any of the preceding claims, wherein... yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

48. The compound as claimed in any of the preceding claims, wherein the compound is 。 49. A pharmaceutical composition comprising the compound of any one of claims 1-48 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

50. A method for treating a disease that may be affected by IRAK4 regulation, the method comprising administering to a subject in need an effective amount of any one of claims 1-48, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

51. The method of claim 50, wherein the disease is selected from autoimmune diseases and inflammatory conditions, preferably systemic lupus erythematosus, hidradenitis suppurativa, rheumatoid arthritis, arthritis, gout, multiple sclerosis, psoriasis and cancer, preferably acute myeloid leukemia, lymphoma, B-cell myelodysplastic syndrome.

52. Use of any compound of claims 1-48 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof in the preparation of a medicament for treating diseases that may be affected by IRAK4 regulation.

53. The use as described in claim 52, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

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