Degradation of IRAK4 by conjugation of IRAK4 inhibitors with e3 ligase ligands and methods of use

Abstract

Disclosed herein are novel bifunctional compounds formed by conjugating IRAK4 inhibitor moieties with E3 ligase ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.

Description

[0001] DEGRADATION OF IRAK4 BY CONJUGATION OF IRAK4 INHIBITORS WITH E3 LIGASE LIGANDS AND METHODS OF USE

[0002] CROSS REFERENCE TO RELATED APPLICATION

[0003] The present application claims the benefit of priority of Application No. PCT / CN2023 / 138418, filed on December 13, 2023, the contents of which are specifically incorporated by reference.

[0004] FIELD OF THE INVENTION

[0005] Disclosed herein are novel bifunctional compounds formed by conjugating IRAK4 inhibitor moieties with E3 ligase ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.

[0006] BACKGROUND OF THE INVENTION

[0007] Proteolysis targeting chimera (PROTAC) consists of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and the other that binds to the protein of interest (POI) a target meant for degradation (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98: 8554- 9.; Sakamoto K. M. et al., Methods Enzymol. 2005; 399:833-847). Rather than inhibiting the target protein's enzymatic activity, recruitment of the E3 ligase to the specific unwanted proteins results in ubiquitination and subsequent degradation of the target protein by the proteasome. The whole process of ubiquitination and proteasomal degradation is known as the ubiquitin-proteasome pathway (UPP) (Ardley H.et al., Essays Biochem. 2005, 41, 15-30; Komander D. et al., Biochem. 2012, 81, 203-229; Grice G. L. et al., Cell Rep. 2015, 12, 545-553; Swatek K. N. et al., Cell Res. 2016, 26, 399-422; Lydia M. et al., ACS Infect. Dis. 2019, 5, 12, 2105-2117). Proteasomes are protein complexes which degrade unneeded, misfolded or abnormal proteins into small peptides and amino acids to maintain the health and productivity of the cells. Ubiquitin ligases, also called E3 ubiquitin ligases, directly catalyze the transfer of ubiquitin from the E2 to the target protein for degradation. Although the human genome encodes over 600 putative E3 ligases, only a limited number of E3 ubiquitin ligases have been widely applied by small molecule PROTAC technology: cereblon (CRBN), Von Hippel-Lindau (VHL), mouse double minute 2 homologue (MDM2) and cellular inhibitor of apoptosis protein (cIAP) (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578), recombinant Human Ring Finger Protein 114 (RNF114) (Spradlin, J. N. et al. Nat. Chem. Biol. 2019, 15, 747-755) and DDB1 And CUL4 Associated Factor 16 (DCAF16) (Zhang, X. et al. Nat. Chem. Biol. 2019, 15, 737-746). For example, cereblon (CRBN) forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cullin-4A (CUL4A) to ubiquitinate a number of other proteins followed by the degradation via proteasomes. (Yi-An Chen, et al., Scientific Reports 2015, 5, 1-13). Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, function as monovalent promoters of PPIs by binding to the cereblon (CRBN) subunit of the CRL4ACRBN E3 ligase complex and recruiting neosubstrate proteins. (Matyskiela, M. E. et al., Nat Chem Biol 2018, 14, 981-987.) As a consequence, the ability of thalidomide, and its derivatives, to recruit CRBN has been widely applied in proteolysis-targeting chimeras (PROTACs) related studies (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 are non-enzymatic proteins. (Chu TT. et al., Cell Chem Biol. 2016; 23:453-461. Qin C. et al., J Med Chem 2018; 61: 6685-6704. Winter GE. et al., Science 2015;348:1376-1381.) In recent years, PROTACs as useful modulators that promote selective degradations of a wide range of target proteins have been reported in antitumor studies. (Lu J. et al., Chem Biol. 2015;22(6):755-763; Ottis P. et al., Chem Biol. 2017; 12(4) : 892-898.; Crews C. M. et al., J Med Chem. 2018; 61(2)403-404; Neklesa T.K. et al., Pharmacol Ther. 2017, 174: 138-144.; Cermakova K. et al., Molecules, 2018.23(8).; An S. et al., EBioMedicine, 2018.; Lebraud H. et al., Essays Biochem. 2017;61(5): 517-527.; Sun Y.H. et al., Cell Res. 2018;28:779-81; Toure M. et al., Angew Chem Int Ed Engl. 2016;55(6): 1966- 1973; Yonghui Sun et al., Leukemia, volume 33, pages 2105-2110(2019); Shaodong Liu et al., Medicinal Chemistry Research, volume 29, pages 802-808 (2020); and has been disclosed or discussed in patent publications, e.g., US20160045607, US20170008904, US20180050021, US20180072711, W02002020740, WO2014108452, WO2016146985, WO2016149668, WO2016197032, WO2016197114, W02017011590, W02017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, W02017197051, WO2017197056, WO2017201449, and W02018071606.

[0008] Inter luekin-1 receptor associated kinases (IRAKI, IRAK2, IRAK3 and IRAK4) are serine-threonine kinases that regulate innate immune and inflammatory responses. In addition to performing normal kinase functions, IRAK4 has protein scaffolding functions and regulates downstream signaling via the myddosome protein complex. Activations of TLRs or IL-lRs initiate receptor dimerization and recruit the myeloid differentiation primary response 88 (MyD88) adaptor protein through their intracellular domains. MyD88 further recruits IRAK4 and IRAK1 / 2 to form a multiprotein complex, the myddosome. Interaction of MyD88 and IRAK4 firstly recruits pre-formed IRAK-1. Then IRAK4 phosphorylates and activates IRAK-1. Fully activated IRAK-1 recruits TRAF6-TAK1-TAB-1 / 2 complex. Activated TAK-1 phosphorylates downstream signaling cascades including the IKB kinase (IKK)-nuclear factor-KB (NF- KB) and MAPKs such as c-Jun N-terminal kinase (JNK) and p38, leading to the production of proinflammatory cytokines (including IL-ip, IL-6, IL-8, IL-12, TNF). These signaling pathways play crucial roles in both innate immune response and adaptive immunity (Elizabeth L. et al., Eur. J. Immunol.

[0009] 2008, 38, 3, 870-876.).

[0010] The pro-inflammatory role of IRAK4 has been demonstrated in studies of IRAK4 kinase dead, knock-in mice (W. Michael S., et al., ACS Med. Chem. Lett. 2015, 6, 942-947). Mice possessing this genotype are resistant to joint inflammation in several rodent arthritis models. (Koziczak-Holbro et al,

[0011] 2009, Arthritis & rheumatism). IRAK4 deficiency ameliorates disease activity in multiple RA animal models. Additionally, a small IRAK4 deficient human population has been identified. Reduced pro- inflammatory cytokine expressions from macrophage, reduced fibroblast like synoviocytes inflammation and migration were observed. Cells from these patients have 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 in rodents and humans imply that an IRAK4 inhibitor could modulate the production of key inflammatory cytokines and cytokine induced pathologies.

[0012] However, there are reports that pharmacological inhibition of IRAK4 did not result in IL-6 and TNF- a inhibition despite IRAK4 phosphorylation levels being reduced in IL- 1 p stimulated human dermal fibroblasts, which suggests that the kinase activity may not be the sole factor in certain cell types (O’Neill, L. A. Immunol. Rev. 2008, 226, 10-8; Nunes J., et al. ACS Med. Chem. Lett. 2019, 10, 1081). Therefore, removing the IRAK4 scaffolding function in addition to the inhibition of kinase activities may offer a better therapeutic outcome. In this regard, IRAK4-targeting PROTACs may serve as a potential strategy for targeting both IRAK4 kinase activity and scaffolding function. IRAK4 PROTACs could ultimately lead to new therapeutic opportunities to treat autoimmune, inflammatory, and oncological diseases. Following patents have disclosed or discussed the IRAK4 PROTACs: WO2019133531, US20190192668, WO2019099926, W02020113233, WO2020264499, WO2021158634, W02020264490, WO2021119159, WO2021168197 and WO2021127278.

[0013] Recently some IRAK4-targeting PROTACs have been published (Nunes J., et al. ACS Med. Chem. Lett. 2019, 10, 1081; Zhang et al., Cell Chem. Bio. 2020, 27, 1.; Robert B. K. et al. ACS Med. Chem. Lett. 2019, 10, 1251). Most of these molecules are based on published IRAK4 inhibitors as warheads. However, there were few data showing those IRAK4 PROTACs gave stronger inhibition of cytokine productions such as IL-6 and TNF-a than IRAK4 kinase inhibitors. There is a need for IRAK4 PROTACs showing stronger inhibition of cytokine productions such as IL-6 and TNF-a than IRAK4 kinase inhibitors.

[0014] SUMMARY OF THE INVENTION

[0015] In this following invention, well-designed IRAK4 PROTACs have demonstrated superior reductions of proinflammatory cytokines in multiple cell lines than small molecular inhibitors.

[0016] The present application provides novel bifunctional compounds and compositions for the treatment of autoimmune, inflammatory, and oncological diseases.

[0017] In one embodiment, disclosed herein are bifunctional compounds of Formula (X) that can selectively degrade IRAK4. The compounds described herein or salts thereof are useful in the treatment of a disease that can be affected by IRAK4 modulation. The present invention provides the use of the compounds described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease that can be affected by IRAK4 modulation. The present invention further provides a compound described herein or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease that can be affected by IRAK4 modulation. The present application further provides a method of treating a proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compounds described herein or a pharmaceutically acceptable salt thereof. The embodiment comprises the following aspects:

[0018] Aspect 1. A compound of formula (X) or a N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof, wherein:

[0019] Y1and Y9are each independently selected from C, N, O or S; Y2, Y3, Y4, Y5, Y6, Y7and Y8are each independently selected from C or N; provided that are each aromatic ring; si is 0, 1, or 2; s2 is 0, 1, 2 or 3; R1and R2are each independently hydrogen, halogen, -C1-C8alkyl, - C3-C8cycloalkyl, -CN, -OR1a, or - NR1aR1b; each of -C1-C8alkyl or -C3-C8cycloalkyl is optionally substituted with at least one substituent R1c;

[0020] R1aand R1bare each independently selected from hydrogen, -C1-C8alkyl, -C1-C8haloalkyl, C1-C8alkoxy-C1-C8alkyl- or C3-C8cycloalkyl; each of-C1-C8alkyl, -C1-C8haloalkyl, C1-C8alkoxy- C1-C8alkyl- or C3-C8cycloalkyl is optionally substituted with at least one substituent selected from halogen, -OH, -CN, oxo (=0), -C1-C8alkyl-OH or - C3-C8cycloalkyl;

[0021] Rlc, at each occurrence, is independently halogen, -OH, -CN, oxo (=0), -C1-C8alkyl, -Ci- Cshaloalkyl, -C;-Cxcycloalkyl, -C1-C8alkoxy, or C1-C8alkoxy-C1-C8alkyl-;

[0022] R"a, Rllb, R12aand R12bare each independently hydrogen, halogen, -C1-8alkyl, -C xalkoxy or -C3-

[0023] 8cycloalkyl; each of said -Ci xalkyl. -Ci xalkoxy or -Cs xcycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -Ci xalkoxy, -OH or -CN;

[0024] L1is selected from -C1-8alkylcnc-, -C2galkenylene-, -C2xalkynylenc-. wherein *L1refers to the position attached to the and **L1refers to the position attached to the moiety;

[0025] L2is selected from -C1-8alkylcnc-, -C2 8alkenylene-, -C2salkynylene-, wherein *L2refers to the position attached to thes1moiety, and **L2refers to the position attached to the moiety;

[0026] L3is selected from -C1-8alkylcnc-. -C2-8alkciiylcnc-. -C2-8alkynylene-, -O-, -NRa-, -CONRa-, -

[0027] is optionally substituted with at least one wherein *L3refers to the position attached to the moiety, and **L3refers to the position each of said RL1C, RL2cand RL3care independently oxo (=0), halogen, hydroxy, -CN, -C1-C8alkyl, -

[0028] C i-Cxalkoxy; each of said -C i-Cxalkyl or -C1-C8alkoxy is optionally substituted with at least one RLca,

[0029] RLcais independently oxo (=O), halogen, hydroxy, -CN, -C1-C8alkoxy or C3-C8cycloalkyl; is E3 ubiquitin ligase binding moiety; at each occurrence, X1and X2are each independently selected from -CRa, or N; at each occurrence, X3and X4are each independently selected from -NRa-, -0-, -S- and -CRaRb-; at each occurrence, X5and X6are each independently selected from absent, single bond, -C(0)-, -

[0030] NRa- and -O-; at each occurrence, Raand Rbare each independently selected from hydrogen or -Ci-C alkyl; ml and m3 are each independently 0, 1 or 2; m2 is 0 or 1 ; nl, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3.

[0031] In some embodiments, the compound is

[0032]

[0033] Z1and Z2are each independently N or CRZ;

[0034] Rz, and R13, at each occurrence, are each independently selected from hydrogen, halogen, -Ci 4alkyl or CN;

[0035] L4is selected from a single bond, -O-, -NRa-, or -C(O)NRa-;

[0036] L5and L6are each independently selected from a single bond, -O-, -NRa- or -C(O)-; n6 is 0, 1, 2, or 3; and at each occurrence, Raand Rcare each independently selected from hydrogen or -Ci-C4alkyl.

[0037] Aspect 3. The compound of Aspect 1 , wherein the compound is selected from formula (Ila),

[0038] In some specific embodiments, the compound is:

[0039] In some specific embodiments, the compound is:

[0040] In some other embodiments, the compound is:

[0041] In some other embodiments, the compound is:

[0042] In some other embodiments, the compound is:

[0043]

[0044] In some other embodiments, the compound is:

[0045] In some other embodiments, the compound is:

[0046] In some specific embodiments, the compound is:

[0047] Aspect 4. The compound of anyone of the preceding Aspects, wherein the

[0048]

[0049] Aspect 5. The compound of anyone of the preceding Aspects, wherein the

[0050] Aspect 6. The compound of anyone of the preceding Aspects, wherein R1and R2are each independently hydrogen, halogen, -C1-C8alkyl, -CN, or -OR1'; said -C1-C8alkyl is optionally substituted with at least one substituent Rlc;

[0051] Rlais independently selected from hydrogen, or -C1-C8alkyl; said -C1-C8alkyl is optionally substituted with at least one substituent selected from halogen, -OH, -CN, or -C1-C8alkyl-OH;

[0052] Rlc, at each occurrence, is independently halogen, -OH, -CN, oxo (=0), -C1-C8alkyl, -Ci- Cshaloalkyl or -C1-C8alkoxy.

[0053] In some preferable embodiments, R1and R2are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, -CN, or -ORla; each of said methyl, ethyl, propyl, butyl or pentyl is optionally substituted with at least one substituent Rlc;

[0054] Rlais independently selected from hydrogen, methyl, ethyl, propyl, butyl or pentyl; each of said methyl, ethyl, propyl, butyl or pentyl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, -OH, -CN, or -C1-C8alkyl-OH;

[0055] Rlc, at each occurrence, is independently -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, -C1-C8haloalkyl or -C1-C8alkoxy.

[0056] In some more preferable embodiments, R1and R2are each independently H, -F, -Cl, -Br, -I, -CH3, - CH2CH3, -CF3, -CF2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -CHF2, -CN, -OMe, -OEt, -OCH2CH2CH3, -

[0057] OCH(CH3)2, -OCH2CH2O

[0058] In some preferable embodiments, R1H, -CF3, -F or -CN; and

[0059] R2is H, -CH3, -CH(CH3)2, -OMe, -OCD3, -OEt, -OCH2CH2OH,

[0060] Aspect 7. The compound of anyone of the preceding Aspects, wherein R11a, R11b, R12aand R12bare each 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; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, -C i al koxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy or -CN.

[0061] In some preferable embodiments, R11a, R11b, R12aand R12bare each 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.

[0062] In some more preferable embodiments, R11a, R11b, R12aand R12bare each independently hydrogen.

[0063] Aspect 8. The compound of anyone of the preceding Aspects, wherein the

[0064]

[0065] each of said RLlcis independently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,

[0066] RLcais independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0067] In some embodiments, the compound of any one of the preceding Aspects, wherein L1is selected from said is optionally substituted with at least one RLlc; each of said RL1Cis independently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,

[0068] RLcais independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0069] Aspect 10. The compound of any one of the preceding Aspects, wherein L1is selected from  each of said RL2cis independently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,

[0070] RLcais independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or optionally substituted with at least one RL2c; each of said RL2cis independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,

[0071] RLcais independently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0072] Aspect 12. The compound of any one of the preceding Aspects, wherein L2is selected from

[0073] substituted with at least one RL3c; each of said RL3cis independently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,

[0074] RLcais independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;

[0075] Rais selected from hydrogen, methyl, ethyl, propyl or butyl.

[0076] In some embodiments L3is selected from -O- -C(O)NRa-, is optionally substituted with at least one RL3c; each of said RL3cis independently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,

[0077] RLcais independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;

[0078] Rais selected from hydrogen, methyl, ethyl, propyl or butyl.

[0079] Aspect 14. The compound of any one of the preceding Aspects, wherein L3is selected from -0-, -

[0080] 

[0081]

[0082] Aspect 15. The compound of any one of the preceding Aspects, wherein

[0083]

[0084] Aspect 16. The compound of any one of Aspects 2-15, wherein L4is independently selected from a single bond, -O-, -NRa- or -C(O)NRa-; at each occurrence, Rais independently selected from hydrogen, methyl, ethyl, propyl or butyl.

[0085] In some embodiments, L4is independently selected from a single bond, -NH- or -C(O)NH-.

[0086] Aspect 17. The compound of any one of Aspects 2-16, wherein at most one of Z1and Z2is N.

[0087] Aspect 18. The compound of any one of Aspects 2-17, wherein Z1and Z2are each independently

[0088] CRZ;

[0089] Rz, at each occurrence, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl or CN.

[0090] In some embodiments, Rzis selected from H, -CH3, F or -CL

[0091] Aspect 19. The compound of any one of Aspects 2-18, wherein R13is selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl or CN.

[0092] In some embodiments, R13is selected from H, -CH3, F or -Cl.

[0093] Aspect 20. The compound of any one of Aspects 2-19, wherein L5and L6are each independently selected from a single bond, -O-, -NRa- or -C(O)-;

[0094] Rais independently selected from hydrogen, methyl, ethyl, propyl or butyl.

[0095] In some embodiments, L5and L6are each independently a single bond, -O-, -NH-, -NMe-, or - N(CH2CH3)-.

[0096] In some preferable embodiments, L5is -CO-, and L6is -NH- or -NMe-. Aspect 21. The compound of any one of the preceding Aspects, wherein

[0097] Aspect 22. The compound of any one of the preceding Aspects, wherein is amino acid residue;

[0098]

[0099] Aspects 24. The compound of any one of the preceding Aspects, wherein the compound is selected from:

[0100]

[0101]

[0102] Aspect 25. A pharmaceutical composition comprising a compound of any one of Aspects 1-24 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, together with a pharmaceutically acceptable excipient.

[0103] Aspect 26. A method of treating a disease that can be affected by IRAK4 modulation, comprises administrating a subject in need thereof an effective amount of a compound of any one of Aspects 1-24 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof.

[0104] Aspect 27. The method of Aspect 26, wherein the disease is selected from Autoimmune disease and Inflammatory disorders, preferred Systemic Lupus, Hidradenitis suppurativa, Rheumatoid arthritis, Arthritis, Gout, Multiple sclerosis, Psoriasis and cancer, preferred Acute myeloid leukemia Cancer, Lymphoma, B-cell Myelodysplasia.

[0105] Aspect 28. Use of a 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 a disease that can be affected by IRAK4 modulation.

[0106] Aspect 29. The use of Aspect 28, wherein the disease is cancer, preferred pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0107] DETAILED DESCRIPTION OF THE INVENTION

[0108] The following terms have the indicated meanings throughout the specification:

[0109] As used herein, including the appended Aspects, the singular forms of words such as "a", "an", and "the", include their corresponding plural references unless the context clearly dictates otherwise.

[0110] The term "or" is used to mean, and is used interchangeably with, the term “and / or” unless the context clearly dictates otherwise.

[0111] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms. Examples of alkyl groups comprising from 1 to 6 carbon atoms (i.e., Ci-6 alkyl) include, but 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-l -propyl or isobutyl ("i-Bu"), 1 -methylpropyl or s-butyl ("s-Bu"), 1,1 -dimethylethyl or t-butyl ("t-Bu"), 1 -pentyl, 2- pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l-butyl, 2-methyl-l -butyl, 1-hexyl, 2- hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2 -pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3- pentyl, 2,3-dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups.

[0112] 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 spiro cycloalkyl. In one embodiment, said "cycloalkyl" is anyone of "-C;-C\cycloalkyl", "-C3- C cycloalkyl", "cyclopropyl", "cyclobutyl", "cyclopentyl", "cyclohexyl", "cycloheptyl" or "cyclooctyl" described in the specification or the claims.

[0113] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0114] 5- and 6-membered carbocyclic aromatic rings, e.g., phenyl; bicyclic ring systems such as 7- to 12-membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and, tricyclic ring systems such as 10- to 15 -membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, e.g., fluorenyl.

[0115] In one embodiment, said " aryl" is anyone of " C6-C12aryl" described in the specification or the claims.

[0116] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeable throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10aryl). Examples of a monocyclic or bicyclic aromatic hydrocarbon ring include, but not limited to, phenyl, naphth- 1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-l-yl or naphth-2- yl) or phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0117] The term “aryl-alkyl-” refers to an alkyl group as defined above which is further substituted by an aryl group. Examples of an aryl-alkyl group include aryl-C1-8lkyl, such as phenylethyl, or phenylmethyl (benzyl).

[0118] The term "heteroaryl" refers to a group selected from:

[0119] 5-, 6- or 7-membered aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N), sulfur (S) and oxygen (O), with the remaining ring atoms being carbon;

[0120] 7- to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0121] 11- to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

[0122] In one embodiment, said "heteroaryl" is anyone 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" described in the specification or the claims.

[0123] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides. The term “C-linked heteroaryl” as used herein means that the heteroaryl group is connected to the core molecule by a bond from a C-atom of the heteroaryl ring

[0124] The terms "aromatic heterocyclic ring" and "heteroaryl" are used interchangeable throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic heterocyclic ring has 5-, 6-, 7-, 8-, 9- or 10-ring forming members with 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O) and the remaining ring members being carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is a 5- to 6- membered heteroaryl ring, which is monocyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is an 8- to 10-membered heteroaryl ring, which is bicyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

[0125] "Heterocyclyl", "heterocycle" or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups. The term “optionally oxidized sulfur” used herein refers to S, SO or SO2.

[0126] Compounds disclosed herein may contain an asymmetric center and may thus exist as enantiomers. “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and / or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, the reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

[0127] The term "substantially pure" as used herein means that the target stereoisomer contains no more than 35%, such as no more than 30%, further such as no more than 25%, even further such as no more than 20%, by weight of any other stereoisomer(s). In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10%, for example, no more than 5%, such as no more than 1%, by weight of any other stereoisomer (s).

[0128] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are meant to include both E and Z geometric isomers.

[0129] When compounds disclosed herein contain a di-substituted cyclohexyl or cyclobutyl group, substituents found on cyclohexyl or cyclobutyl ring may adopt cis and trans formations. Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides.

[0130] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art will apply techniques most likely to achieve the desired separation.

[0131] “Diastereomers” refers to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0132] "Pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.

[0133] In addition, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and / or water and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0134] As defined herein, "a pharmaceutically acceptable salt thereof" includes salts of at least one compound of Formula (I), and salts of the stereoisomers of the compound of Formula (I), such as salts of enantiomers, and / or salts of diastereomers.

[0135] The terms “administration”, “administering”, “treating” and “treatment” herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as the contact of a reagent to a fluid, where the fluid is in contact with the cell. The term “administration” and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by 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.

[0136] The term "effective amount" or “therapeutically effective amount” refers to an amount of the active ingredient, such as a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. The “therapeutically effective amount” can vary with the compound, the disease, disorder, and / or symptoms of the disease or disorder, severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments. In some embodiments, “therapeutically effective amount” is an amount of at least one compound and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof disclosed herein effective to “treat” as defined above, a disease or disorder in a subject. In the case of combination therapy, the “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.

[0137] The pharmaceutical composition comprising the compound disclosed herein can be administrated via oral, inhalation, rectal, parenteral or topical administration to a subject in need thereof. For oral administration, the pharmaceutical composition may be a regular solid formulation such as tablets, powder, granule, capsules and the like, a liquid formulation such as water or oil suspension or other liquid formulation such as syrup, solution, suspension or the like; for parenteral administration, the pharmaceutical composition may be a solution, water solution, oil suspension concentrate, lyophilized powder or the like. Preferably, the formulation of the pharmaceutical composition is selected from a tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule. The pharmaceutical composition can be a single unit administration with an accurate dosage. In addition, the pharmaceutical composition may further comprise additional active ingredients. All formulations of the pharmaceutical composition disclosed herein can be produced by the conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients, then to make the desired formulation. The “pharmaceutically acceptable excipient” refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, for example: a diluent, a vehicle such as water, various organic solvents, etc., a filler such as starch, sucrose, etc. a binder such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); a wetting agent such as glycerol; a disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; an absorption enhancer such as quaternary ammonium compound; a surfactant such as hexadecanol; an absorption carrier such as Kaolin and soap clay; a lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition further comprises other pharmaceutically acceptable excipients such as a decentralized agent, a stabilizer, a thickener, a complexing agent, a buffering agent, a permeation enhancer, a polymer, aromatics, a sweetener, and a dye.

[0138] The term “disease” refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition”.

[0139] Throughout this specification and the Aspects which follow, unless the context requires otherwise, the term "comprise", and variations such as "comprises" and "comprising" are intended to specify the presence of the features thereafter, but do not exclude the presence or addition of one or more other features. When used herein the term "comprising" can be substituted with the term "containing", "including" or sometimes "having".

[0140] Throughout this specification and the Aspects which follow, the term “Cnm” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include Ci-s, Ci-6, and the like.

[0141] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0142] Examples

[0143] The examples below are intended to be purely exemplary and should not be considered to be limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc.), but some experimental errors and deviations should be accounted for. Unless indicated otherwise, temperature is in degrees Centigrade. Reagents were purchased from commercial suppliers such as Sigma- Aldrich, Alfa Aesar, Pharmablock, Bidepharm or TCI, and were used without further purification unless indicated otherwise. Unless indicated otherwise, the reactions set forth below were performed under a positive pressure of nitrogen or argon or with a drying tube in anhydrous solvents; the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven dried and / or heat dried.

[0144] 1H NMR spectra were recorded on Agilent instruments operating at 400 MHz or 500 MHz.1HNM R spectra were obtained using CDCL. CD2CI2, CD3OD, D2O, de-DMSO, de-acetone or (CDihCO as solvent and tetramethylsilane (0.00 ppm) or residual solvent (CDCU: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; dg-DMSO: 2.50 ppm; de -acetone: 2.05; (CDa^CO: 2.05) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintuplet), sx (sextuplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

[0145] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity) Detector: MWD (190-400 nm), Mass detector: 6120 SQ Mobile phase: A: water with 0.1% Formic acid, B: acetonitrile with 0.1% Formic acid Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7pm Gradient method: Flow: 1.8 mL / min Time (min) A (%) B (%)

[0146] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190-400 nm), Mass detector: G6125C SQ Mobile phase: A: water with 0.1% Formic acid, B: acetonitrile with 0.1% Formic acid Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7pm Gradient method: Flow: 1.8 mL / min Time (min) A (%) B (%)

[0147] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II) Detector: MWD (190-400 nm), Mass detector: G6125C SQ Mobile phase: A: water with 0.1% Formic acid, B: acetonitrile with 0.1% Formic acid Column: Poroshell 120 EC-C18, 4.6x50 mm, 2.7pm Gradient method: Flow: 1.2 mL / min Time (min) A (%) B (%)

[0148] Preparative HPLC was conducted on a column (150 x 21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml / min, injection volume 2 ml, at room temperature and UV Detection at 214 nm and 254 nm.

[0149] Example 029: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(6-((2,6-dioxopiperidin-3-yl)amino)-2-methylpyridin- 3-yl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[l,2- b] pyridazine-7-carboxamide

[0150] Step 1: 8-(2-methyl-6-nitropyridin-3-yl)-l,4-dioxa-8-azaspirol4.51decane

[0151] To the solution of 3-fhroro-2-methyl-6-nitropyridine (1.56 g, 10 mmol) and l,4-dioxa-8- azaspiro[4.5]decane (1.58 g, l lmmol) in 20 mL DMF were added K2CO3(2.07 g, 1.5 mmol). The resulting mixture was stirred at 80 °C for 16 hours. After LCMS showed the reaction was completed, the reaction was poured into water (150 mL), the precipitate formed was filtered, washed with water and dried under air to afford the desired product (2.4 g, 86.02%). [M+H]+= 280.5.

[0152] Step 2: 6-methyl-5-(L4-dioxa-8-azaspirol4.51decan-8-yl)pyridin-2-amine

[0153] To the solution of 8-(2-methyl-6-nitropyridin-3-yl)-l,4-dioxa-8-azaspiro[4.5]decane (2.4 g, 8.6 mmol) in 20 mL DCM and 20 mL MeOH was added Pd / C (1 g, 10 wt. %, wet) . The mixture was stirred at RT for 12 hours under hydrogen atmosphere (balloon). After LCMS showed the reaction was completed, the mixture was filtered through a celite pad and washed with DCM. The filtrate was concentrated in vacuum to afford the desired product (2 g, 93.28%). [M+H]+= 250.5.

[0154] Step 3: N-(2.6-bis(benzyloxy)pyridin-3-yl)-6-methyl-5-(L4-dioxa-8-azaspiro(4.51decan-8- yl)pyridin-2-amine

[0155] To a solution of 6-methyl-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-amine (700 mg, 2.81 mmol) and 2,6-bis(benzyloxy)-3-bromopyridine (1.14 g, 3.09 mmol) in dioxane(15 mL) was added Pd2(dba)s(128 mg, 0.14 mmol), xantphos(162 mg, 0.28 mmol) and Cs2CC>3(2.75 g, 8.43 mmol). The mixture was stirred at 110°C under N2for 16 hours. After LCMS showed the reaction was completed, the mixture was concentrated in vacuo. The residue was purified by silica column ( DCM / MeOH=30:l) to give the product(1.3 g, 85.9%). [M+H]+= 539.5.

[0156] Step 4: 3-((6-methyl-5-( 1 ,4-dioxa-8-azaspiror4.51decan-8-yl)pyridin-2-yl)amino)piperidine-2,6- dione

[0157] To a solution of N-(2,6-bis(benzyloxy)pyridin-3-yl)-6-methyl-5-(l,4-dioxa-8-azaspiro[4.5]decan-8- yl)pyridin-2-amine (1.3 g, 2.41 mmol) in i-PrOH(60 mL) and DMF(20 mL) was added anhydrous Pd / C(l g) at rt. Then the mixture was stirred at rt under hydrogen atmosphere (balloon) for 16 hours. After LCMS showed the reaction was completed, the mixture was filtered and washed with i-PrOH(50 mL). Then the filtrate was concentrated in vacuo to yield the product (510 mg, 58.7% yield). [M+H]+= 361.5.

[0158] Step 5: 3-((6-methyl-5-(4-oxopiperidin-l-yl)pyridin-2-yl)amino)piperidine-2.6-dione

[0159] 3-((6-methyl-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)amino)piperidine-2, 6-dione (510 mg, 1.41 mmol) was placed in 100 mL round bottom flask with a magnetic stir bar. Then 10 mL 8N HC1 aqueous was added. The mixture was stirred at room temperature for 2 hours. The mixture was added dropwise to sat. aq. NaHCCL solution and finally pH=6-7. The liquid was extracted with DCM (2 x 50 mL). The combined organic phase was concentrated in vacuum and purified with combiflash (DCM:MeOH= 25:1) to afford the title compound (420 mg, 94.15% yield). [M+H]+= 317.5.

[0160] Step 6: 3-cyanopyrrolo(l,2-b1pyridazine-7-carboxylic acid

[0161] To a solution of 7-bromopyrrolo[l,2-b]pyridazine-3-carbonitrile (600 mg, 2.70 mmol) in THF(12 mL) and water(4 mL) was added Pd(dppf)C12(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). Then the mixture was stirred at 95°C under CO (4 MPa) for 16 h. Then the mixture was concentrated in vacuo. The residue was purified by silica column (DCM / MeOH=10:l) to give the product(300 mg, 59.4%). [M+Na]+= 210.2.

[0162] Step 7: methyl 2-((lr,4r)-4-(4-(tert-butoxycarbonyl)piperazin-l-yl)cvclohexyl)-2H-indazole-6- carboxylate

[0163] To a solution of methyl 4-formyl-3-nitrobenzoate (105 g, 0.5 mol) in propan-2-ol ( 1000 mL) was added tert-butyl 4-((lr,4r)-4-aminocyclohexyl)piperazine-l-carboxylate(142 g, 0.5 mol). The mixture was stirred for 3 hours at 85 °C under N2. Then the reaction was cooled to rt.To the above solution was added tri-n-butylphosphane ( 303 g, 1.5 mol). The mixture was stirred 3 hours at 85°C under N2. The mixture was cooled to rt and precipitated. Then the mixture was filtered and the filter cake was washed with propan-2-ol(200 mLx2). The filter cake was collected and dried under reduce pressure to give the product (130 g , 58.75 %). [M+H]+= 443.3.

[0164] Step 8: methyl 5-nitro-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazole-6-carboxylate

[0165] To a solution of methyl 2-((lr,4r)-4-(4-(tert-butoxycarbonyl)piperazin-l-yl)cyclohexyl)-2H- indazole-6-carboxylate (130 g, 0.29 mol) in conc.tLSCL (500 mL) was slowed added N’aNC); (29.58 g,0.35 mol) batchwise at 0°C. The mixture was stirred for 3 hours at 0°C. The mixture was pour into ice-water, then adjusted to pH 9 with sat.Na2CC>3 solution and extracted with DCM. The combined organic layer was dried over anhydrous NazSCL, filtered and evaporated in vacuum to afford crude product (112 g, 100 %), which was used without further purification. [M+H]+= 388.2.

[0166] Step 9: methyl 2-((lr,4r)-4-(4-(tert-butoxycarbonyl)piperazin-l-yl)cyclohexyl)-5-nitro-2H-indazole- 6-carboxylate

[0167] To a solution of methyl 5-nitro-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazole-6-carboxylate (112 g, 0.29 mol) in DCM (1500 mL) was added Et;N (43.9 g, 0.435 mol) and BOC2O (69.6 g, 0.32 mol). The reaction mixture was stirred overnight at rt. The mixture was diluted with DCM(2000 mL), washed with saturated aqueous sodium carbonate(2000 mlx2) and brine(2000 ml x2), dried over NazSCL and concentrated under vacuum. The residue was purified with silica gel column chromatography (DCM: MeOH = 30: 1) to yield product (140 g, 98%). [M+H]+= 488.2.

[0168] Step 10: methyl 5-amino-2-((lr.4r)-4-(4-(tert-butoxycarbonyl)piperazin-l-yl)cvclohexyl)-2H- indazole-6-carboxylate

[0169] To a solution of methyl 2-((lr,4r)-4-(4-(tert-butoxycarbonyl)piperazin-l-yl)cyclohexyl)-5-nitro-2H- indazole-6-carboxylate ( 140 g, 0.287 mol) in THF(1500 mL) was added Pd / C(28 g). Then the mixture was stirred for 16 hours at rt under a hydrogen atmosphere . After the reaction was complete, the mixture was filtered and the filtrate was concentrated in vacuo to give the product (110 g, 0.24 mol) which was directly used in next step . [M+H]+= 458.3

[0170] Step 11: methyl 2-((lr,4r)-4-(4-(tert-butoxycarbonyl)piperazin-l-yl)cyclohexyl)-5-(2,2,2- trifluoroacetamido)-2H-indazole-6-carboxylate

[0171] To a solution of methyl 5-amino-2-((lr,4r)-4-(4-(tert-butoxycarbonyl)piperazin-l-yl)cyclohexyl)-2H- indazole-6-carboxylate (105 g, 229.4 mmol) in DCM (1000 mL) was added dropwise TFAA (50.6 g, 240.9 mmol) at 0°C The mixture was stirred for 2 hours at 0°C. The mixture was quenched with icewater, then adjusted to pH 8 with sat.NaHCO- solution and extracted with DCM (3x1000 mL). The combined organic layers were dried over anhydrous NaiSCU, filtered and evaporated in vacuum. The residue was purified with silica gel column chromatography (DCM: MeOH = 30: 1) to yield product (120 g, 94.5%). [M+H]+= 554.2

[0172] Step 12: tert-butyl 4-(( lr.4r)-4-(6-(2-hydroxypropan-2-yl)-5-(2.2.2-trifluoroacetamido)-2H-indazol- 2- vDcyclohexyDpiperazine- 1 -carboxylate

[0173] To a solution of methyl 2-((lr,4r)-4-(4-(tert-butoxycarbonyl)piperazin-l-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 THF (1500 mL) was added dropwise MeMgBr in THF (3 M, 692.4 mL, 2077.2mmol) at 0°C under N2. The resulting mixture was stirred overnight at 0°C. The mixture was quenched slowly with sat.NH^Cl solution(1500 mL) and acidified to PH 5 with HCl(lmol / L).Then the mixture was extracted with EtOAc (3x1000 mL). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified with silica gel column chromatography (DCM: MeOH = 20: 1) to yield product (100 g, 86.9%). [M+H]+= 554.2

[0174] Step 13: tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2- yDcyclohexyDpiperazine- 1 -carboxylate

[0175] To a solution of tert-butyl 4-((lr,4r)-4-(6-(2-hydroxypropan-2-yl)-5-(2,2,2-trifluoroacetamido)-2H- indazol-2-yl)cyclohexyl)piperazine-l-carboxylate (100 g, 180.62 mmol) in MeOH (1000 mL) was added NaOH solution (2 N, 903 mL, 1806.2 mmol) at room temperature. The mixture was stirred for 2hours at 70°C. The mixture was cooled to room temperature and solid was precipitated. The mixture was filtered and the filter cake was washed with water. Then the filter cake was collected and dried under reduce pressure to give the product (75 g, 90.7%). [M+H]+= 458.2. Step 14: tert-butyl 4-((lr,4r)-4-(5-(3-cyanopyrrolo(l,2-b1pyridazine-7-carboxamido)-6-(2- hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l -carboxylate

[0176] To a stirred solution of 3-cyanopyrrolo[l,2-b]pyridazine-7-carboxylic acid (36.81 g, 196.67 mmol) and tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l- carboxylate (75 g, 163.89 mmol) in DMF (1000 mL) was added HATU (74.73 g, 196.67 mmol) and DIEA (42.28 g, 327.78 mmol). The mixture was stirred for 5hours at room temperature. The mixture was diluted with water (3000 mL). The solid was collected by filtration and washed with water (3x100 mL). The solid was dried under vacuum to yield product (90 g, 87.62%). [M+H]+= 627.5

[0177] Step 15: 3-CYano-N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cvclohexyl)-2H-indazol- 5-yl)pyrrololl.2-blpyridazine-7-carboxamide

[0178] To a stirring solution of tert-butyl 4-((lr,4r)-4-(5-(3-cyanopyrrolo[l,2-b]pyridazine-7-carboxamido)- 6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l-carboxylate (90 g, 143.77 mmol) in MeOH (600 mL) was added dropwise conc.HCl (36%, 300 mL) at 0°C. The resulting mixture was stirred overnight at room temperature. The solid was collected by filtration. The solid was dissolve with water (500 mL), then adjusted to pH 8 with sat.XaHCCL solution and extracted with DCM / MeOH (V / V=10 / l, 5x2000 mL). The combined organic layers were dried over anhydrous NajSCL. filtered and evaporated in vacuum. The residue was slurried with petroleum ether (1000 mL) and filtered. The solid was filtered and dried under vacuum to yield product (70 g, 92.45%). [M+H]+= 527.4

[0179] Step 16: 3-cyano-N-(2-((lr.4r)-4-(4-(l-(6-((2.6-dioxopiperidin-3-yl)amino)-2-methylpyridin-3- yl)piperidin-4-yl)piperazin- 1 -yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolor 1 ,2- blpyridazine-7-carboxamide

[0180] To a stirred solution of 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l- yl)cyclohexyl)-2H-indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide (50 mg, 0.09 mmol) and 3-((6- methyl-5-(4-oxopiperidin-l-yl)pyridin-2-yl)amino)piperidine-2, 6-dione (57 mg, 0.18 mmol) in DCE (2 mL) was added AcOH (5.4 mg, 0.09 mmol) and NaBH(OAc)3 (39 mg, 0.18 mmol). The mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo. The residue was purified with silica gel column chromatography (DCM: MeOH = 15: 1) to give the impure product. Then the impure product was purified by prep-HPLC((C-18 column chromatography (0.1% FA in water : acetonitrile = 90 : 10 ~ 60 : 40 gradient elution) to yield the desired product (26 mg, 35 %) .1H NMR (500 MHz, DMSO) 5 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, 7= 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.

[0181] Example 006: N-(2-((lr,4r)-4-(4-((l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)methyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-

[0182] (trifluoromethyl)picolinamide

[0183] Step 1: tert-butyl 4-((lr.4r)-4-(6-(2-hvdroxypropan-2-yl)-5-(6-(trifluoromethyl)picolinamido)-2H- indazol-2-yl)cyclohexyl)piperazine-l-carboxylate

[0184] To a stirred solution of 6-(trifluoromethyl)picolinic acid (1.91 g, 10 mmol) and tert-butyl 4-((lr,4r)- 4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine- 1 -carboxylate (4.58 g, 10 mmol) in DCM (50 mL) was added HATU (3.80 g, 10 mmol) and DIPEA (2.58 g, 20 mmol). The solution was stirred at room temperature for 18 hours. The solution was concentrated under vacuum. The combined organic layer was concentrated under vacuum and purified on silica gel column chromatography (DCM : MeOH = 90 : 10) to afford product (5.9 g, 93.1 %). [M+H]+= 631.5.

[0185] Step 2: N-(6-(2-hydroxypropan-2-yl)-2-(( lr,4r)-4-(piperazin- l-yl)cyclohexyl)-2H-indazol-5-yl)-6- ( trifluorometh vDpicolinamide

[0186] To a stirring solution of tert-butyl 4-((lr,4r)-4-(6-(2-hydroxypropan-2-yl)-5-(6- (trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)piperazine-l-carboxylate (5.9 g, 9.3 mmol) in MeOH (50 mL) was added 12 N HC1 (50 mL) in MeOH (50 mL) at 0 °C. The reaction mixture was stirred for 2 hours at room temperature, adjusted to pH 7 with sat. NaHCOs and extracted with DCM (500 mL x 3). The combined organic layer was dried over Na^SOr and concentrated under vacuum. The combined organic layer was concentrated to dryness to afford product (4.9 g, 99.1 %). [M+H]+= 531.7.

[0187] Step 3: N-(2-((lr.4r)-4-(4-((l-(4-((R)-2.6-dioxopiperidin-3-yl)-3.5-difluorophenyl)azetidin-3- yl)methyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6- ( trifluorometh vDpicolinamide

[0188] A solution of N-(6-(24iydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-5- yl)-6-(trifluoromethyl)picolinamide (0.74 g, 1.46 mmol) and (R)-l-(4-(2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidine-3-carbaldehyde (0.45 g, 1.46 mmol, obtained by the same way of WO2022012622A1) in DCM (50 mL) was stirred at room temperature for 1 hour, then NaBH(OAc); (0.62 g, 2.92 mmol) was added portion wise. The solution was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified on silica gel column chromatography (DCM : MeOH = 90 : 10) to afford product (0.73 g, 60.7 %). ’H NMR (500 MHz, DMSO) 5 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.

[0189] Example 010: 3-cyano-N-(2-((lR,4r)-4-((2R)-4-(l-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2- methylpyridin-3-yl)piperidin-4-yl)-2-(methoxymethyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2- yl)-2H-indazol-5-yl)pyrrolo[ 1 ,2-b1pyridazine-7-carboxamide

[0190] The title compound (154 mg, 50.3 %) was prepared in a manner similar to that described in Example 029 'H NMR (500 MHz, DMSO) 8 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, 7= 5.0 Hz, 1H), 7.57 (s, 1H), 7.30 (d, J = 11.5 Hz, 1H), 7.09 (d, 7 = 5.0 Hz, 1H), 5.73 (s, 1H), 4.46 - 4.37 (m, 1H), 4.13 (dd, 7= 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, 7= 10.5 Hz, 1H). [M+H]+= 874.7.

[0191] Example 015: N-(2-((lr.4r)-4-(4-(l-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4- yl)piperazin-l-yl)cyclohexYl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)furor3,2-b1pyridine-3- carboxamide

[0192] To a solution of 2-bromopyridin-3-ol (130.0 g, 747.15 mmol) in 1,4-Dioxane (1300 mL) was added Trimethylsilylacetylene (95.4 g, 971.29 mmol), TEA (151.2 g, 1.49 mol), Pd(PPh3Cl2(10.5 g, 14.94 mmol) and Cui (28.5 g, 149.43 mmol) under nitrogen. The mixture was stirred at 45 °C for 3 hours. The mixture was filtered, and the filtrate was added water (500 mL) and extracted with EtOAc (400 mL x 3).

[0193] The combined organic phase was washed with brine (400 mL), dried over Na SCTi and concentrated to give product (148.0 g, crude). [M+H]+= 192.1.

[0194] Step 2: furo[3.2-blpyridine

[0195] To a solution of 2-(trimethylsilyl)furo[3,2-b]pyridine (148.0 g, 773.65 mmol) in MeOH (1.48 L) was added KF (161.8 g, 2.79 mol) . Then the reaction mixture was stirred at 70 °C for 3 hours . The mixture was concentrated, added water (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4and concentrated to give product (52.0 g, 58.4% yield for 2 steps). [M+H]+= 120.1.

[0196] Step 3: 3-bromofuro[3,2-b]pyridine

[0197] To a solution of furo[3,2-b]pyridine (26.0 g, 218.27 mmol) in CCL (260.0 mL) was added Br2(34.9 g, 218.27 mmol) dropwise at -10 °C. Then the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated and added EtOAc (100 mL). 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 into the solution of KOH dropwise at 0 °C. Then the reaction mixture was stirred at room temperature for 5 minutes. The mixture was concentrated, added water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over NaiSO- and concentrated to give a residue. The residue was purified by silica gel chromatography (Petroleum ether / EtOAc = 50 : 1) to give product (14.9 g, 34.5%). [M+H]+= 198.0.

[0198] Step 4: methyl furo[3,2-blpyridine-3-carboxylate

[0199] To a solution of 3-bromofuro[3,2-b]pyridine (10.0 g, 50.50 mmol) in Toluene / MeOH (37.5 mL / 12.5 mL) was added Pd(AcO)z (1.1 g, 5.05 mmol), Xantphos (5.8 g, 10.10 mmol) and DIEA (32.6 g, 252.51 mmol). The mixture was stirred for 12 hours at 70 °C under the atmosphere of CO. The residue was purified by silica gel chromatography (Petroleum ether / EtOAc = 4 : 1) to give product (5.1 g, 57.0%). [M+H]+= 178.1.

[0200] Step 5: furo[3,2-blpyridine-3-carboxylic acid

[0201] To a solution of methyl furo[3,2-b]pyridine-3-carboxylate (11.4 g, 64.35 mmol) in THF / H2O (76 mL / 38 mL) was added LiOH (2.31 g, 96.54 mmol). Then the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated and adjusted to pH~3 with HCLEtOAc (4N). The precipitate formed was collected by filtration, washed with Isopropyl alcohol, dried in vacuo to give the crude product, which was triturated with acetonitrile (4 mL) and filtered to give product (7.0 g, 66.7%). [M+H]+= 164.1. Step 6: tert-butyl 4-((lr,4r)-4-(5-(furor3,2-blpyridine-3-carboxamido)-6-(2-hydroxypropan-2-yl)-2H- indazol-2-yl)cyclohexyl)piperazine-l-carboxylate

[0202] To a stirred solution of furo[3,2-b]pyridine-3-carboxylic acid (1.68 g, 10 mmol) and tert-butyl 4- ((lr,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l -carboxylate (4.58 g, 10 mmol) in DCM (50 mL) was added HATU (3.80 g, 10 mmol) and DIPEA (2.58 g, 20 mmol). The solution was stirred at room temperature for 18 hours. The solution was added water (500 mL) and extracted with DCM (500 mL x 3). The combined organic layer was dried over NaiSCL and concentrated under vacuum. The combined organic layer was concentrated under vacuum and purified on silica gel column chromatography (DCM : MeOH = 90: 10) to afford product (5.5 g, 91.2 %). [M+H]+= 603.7.

[0203] Step 7: N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyf)-2H-indazol-5- yl)furol3,2-b1pyridine-3-carboxamide

[0204] To a stirring solution of tert-butyl 4-((lr,4r)-4-(5-(furo[3,2-b]pyridine-3-carboxamido)-6-(2- hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l-carboxylate (5.5 g, 9.12 mmol) in MeOH (100 mL) was added 12 M HC1 (60 mL) in MeOH (60 mL). The reaction mixture was stirred for 2 hours at room temperature, adjusted to pH 7 with sat. NaHCOs and extracted with DCM I MeOH (8 / 1, 150 mL x 4). The combined organic layer was dried over NaiSO4 and concentrated under vacuum. The combined organic layer was dried over NazSO4 and concentrated under vacuum. The combined organic layer was concentrated under vacuum and purified on Cl 8 column chromatography (water (0.1 % TFA) : ACETONITRILE = 20 : 80 to 60 : 40) to afford product (1.0 g, 20 %). [M+H]+= 503.7.

[0205] Step 8: N-(2-((lr,4r)-4-(4-(l-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4- yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)furol3.2-blpyridine-3- carboxamide

[0206] A solution of N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-5- yl)furo[3,2-b]pyridine-3-carboxamide (25 mg, 0.05 mmol) and 3-(6-methyl-5-(4-oxopiperidin-l- yl)pyridin-2-yl)piperidine-2, 6-dione (20 mg, 0.067 mmol, obtained through the same method of example 031) in DCE (5 mL) was stirred at room temperature for 1 hour, then NaBH(OAc ); (21 mg, 0.1 mmol) was added portion wise. The solution was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified on silica gel column chromatography (DCM : MeOH = 90 : 10) to give product (5 mg, 12.7 %). 'HNMR (500 MHz, DMSO) 5 11.41 (s, 1H), 10.78 (s, 1H), 8.93 (s, 1H), 8.68 (d, 7 = 5.0 Hz, 1H), 8.34 (s, 1H), 8.27 (d, 7 = 5.5 Hz, 2H), 8.22 (d, 7 = 8.5 Hz, 1H), 7.58 (s, 1H), 7.51 (dd, J= 8.5, 5.0 Hz, 1H), 7.36 (d, 7 = 8.0 Hz, 1H), 7.10 (d, 7= 8.0 Hz, 1H), 5.63 (s, 1H), 4.43 (t, 7 = 11.5 Hz, 1H), 3.89 (dd, 7 = 9.5, 5.5 Hz, 1H), 3.11 (d, 7 = 11.0 Hz, 3H), 2.67 - 2.53 (m, 11H), 2.42 - 2.36 (m, 4H), 2.29 (t, 7= 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. Example 019: N-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyPazetidin-3- yPpiperazin- 1 -yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrazolo[ 1 ,5-a]pyrimidine-3- carboxamide

[0207] Step 1: tert-butyl 4-((lr.4r)-4-(6-(2-hydroxypropan-2-yl)-5-(pyrazololl,5-a1pyrimidine-3- carboxamido)-2H-indazol-2-yl)cyclohexyl)piperazine-l-carboxylate

[0208] To a stirred solution of pyrazolo[l,5-a]pyrimidine-3-carboxylic acid (1.63 g, 10 mmol) and tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l -carboxylate (4.58 g, 10 mmol) in DCM (100 mL) was added HATU (3.80 g, 10 mmol) and DIPEA (2.58 g, 20 mmol). The solution was stirred at room temperature for 18 hours. The solution was added water (80 mL) and extracted with DCM (100 mL x 3). The combined organic layer was dried over NaiSOi and concentrated under vacuum. The combined organic layer was concentrated under vacuum and purified on silica gel column chromatography (DCM : MeOH = 90 : 10) to afford the product (6.0 g, 99.6 %). [M+H]+= 603.5.

[0209] Step 2: N-(6-(2-hydroxypropan-2-yl)-2-(( lr,4r)-4-(piperazin- l-yl)cyclohexyl)-2H-indazol-5- yDpyrazolol 1 ,5-a1pyrimidine-3-carboxamide

[0210] To a stirring solution of tert-butyl 4-((lr,4r)-4-(6-(2-hydroxypropan-2-yl)-5-(pyrazolo[l,5- a]pyrimidine-3-carboxamido)-2H-indazol-2-yl)cyclohexyl)piperazine-l -carboxylate (6.0 g, 9.96 mmol) in MeOH (100 mL) was added 12 M HC1 (50 mL) in MeOH (50 mL). The reaction mixture was stirred for 2 hours at room temperature, adjusted to pH 7 with sat. NaHCOs and extracted with DCM / MeOH (8 / 1, 150 mL x 4). The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The combined organic layer was dried over Na2SO4 and concentrated under vacuum to give product (5.0 g, 100 %). [M+H]+= 503.6.

[0211] Step 3: N-(2-((lR,4r)-4-(4-(l-(4-((R)-2.6-dioxopiperidin-3-yl)-3.5-difluorophenyl)azetidin-3- yDpiperazin- 1 -yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrazolol 1 ,5-a1pyrimidine-3- carboxamide

[0212] A solution of N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-5- yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide (50 mg, 0.1 mmol) and (R)-3-(2,6-difluoro-4-(3- oxoazetidin-l-yl)phenyl)piperidine-2, 6-dione (44 mg, 0.15 mmol, obtained through the same method of WO2023098656 Al) in DCE (10 mL) was stirred at room temperature for 1 hour, then NaBH(OAc)3 (42 mg, 0.2 mmol) was added portion wise. The solution was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified by PHLC to afford product (14 mg, 17.8 %). 'H

[0213] NMR (500 MHz, DMSO) 8 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, 7= 11.0 Hz, 2H), 8.28 (s, OH), 7.55 (s, 1H), 7.28 (dd, 7 = 7.0, 4.0 Hz, 1H), 6.12 (d, 7= 11.0 Hz, 2H), 5.69 (s, 1H), 4.42 (t, 7 = 11.5 Hz, 1H), 4.03 (dd, 7= 12.5, 5.0 Hz, 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.

[0214] Example 020: N-(2-((lr,4r)-4-(4-((l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)methyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrazolo[l,5- a]pyrimidine-3-carboxamide

[0215] The title compound (29 mg, 36.5 %) was prepared in a manner similar to that described in Example 029.1HNMR (500 MHz, DMSO) 511.24 (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, OH), 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.

[0216] Example 028: N-(2-((lr,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin- 4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrazolo[l,5-a]pyrimidine-3- carboxamide

[0217] The title compound (12 mg, 14.8 %) was prepared in a manner similar to that described in Example029. 'HNMR (500 MHz, DMSO) 511.23 (s, 1H), 10.87 (s, 1H), 9.31 (dd, 7= 7.0, 1.5 Hz, 1H), 8.80 (dd, 7= 4.0, 1.5 Hz, 1H), 8.65 (s, 1H), 8.32 (d, 7= 12.5 Hz, 2H), 8.17 (s, 1H), 7.56 (s, 1H), 7.28 (dd, 7= 7.0, 4.0 Hz, 1H), 6.63 (d, 7 = 12.5 Hz, 2H), 5.69 (s, 1H), 4.41 (t, 7 = 11.5 Hz, 1H), 4.04 (dd, 7 = 12.5, 5.0 Hz, 1H), 3.78 (d, 7= 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.

[0218] Example 022: N-(2-((lr,4r)-4-(4-(l-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4- yl)piperazin- 1 -yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrazolo[ 1 ,5-a]pyrimidine-3- carboxamide

[0219] The title compound (18 mg, 22.8 %) was prepared in a manner similar to that described in Example 029. 'H NMR (500 MHz, DMSO) 511.24 (s, 1H), 10.85 (s, 1H), 9.32 (dd, 7= 7.0, 1.5 Hz, 1H), 8.81 (dd, 7 = 4.0, 1.5 Hz, 1H), 8.65 (s, 1H), 8.34 (d, 7 = 7.0 Hz, 2H), 7.55 (s, 2H), 7.29 (dd, 7 = 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.

[0220] Example 023: N-(2-((lr,4r)-4-(4-(l-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin-3- yl)piperidin-4-yl)piperazin- 1 -yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrazolo[ 1 ,5- a]pyrimidine-3-carboxamide

[0221] The title compound (15 mg, 18.6 %) was prepared in a manner similar to that described in Example 029. 'H NMR (500 MHz, DMSO) 511.23 (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.

[0222] Example 032: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2,6- difluorophenyl)azetidin-3-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0223] Step 1: 3-((3,5-difluoro-4-(3-oxoazetidin-l-yl)phenyl)amino)piperidine-2, 6-dione

[0224] To a solution of (COCfh (129 mg, 1.0 mmol) dissolved in DCM (15 mL) was added DMSO (90 mg, 1.2 mmol) dropwised at -78 °C. The mixture was stirred for 0.5 hour at -78 °C. The mixture was added 3- ((3, 5-difluoro-4-(3-hydroxyazetidin-l-yl)phenyl)amino)piperidine-2, 6-dione (103 mg, 0.3 mmol, obtained through the same method of example 029) in DCM (5 mL) at -78 °C. The mixture was stirred for 1 hour at -78 °C. The mixture was added TEA (1.01 g,10 mmol) and stirred for 18 hours at room temperature. The mixture was concentrated under vacuum and purified on silica gel column chromatography (DCM : MeOH = 90 : 10) to give product (40 mg, 43.1 %). [M+H]+= 309.5.

[0225] Step 2: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)-2,6- difluorophenyl)azetidin-3-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- vDpyrrolol 1 ,2-b]pyridazine-7-carboxamide

[0226] A solution of 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H- indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide (26 mg, 0.05 mmol) and 3-((3,5-difluoro-4-(3- oxoazetidin-l-yl)phenyl)amino)piperidine-2, 6-dione (20 mg, 0.07 mmol) in DCM (5 mL) was stirred at room temperature for 1 hour, then NaBH(OAc)s (21 mg, 0.1 mmol) was added portion wise. The solution was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified on silica gel column chromatography (DCM : MeOH = 90 : 10) to give product. The product was chiral HPLC with Chiralpak IE column (MeOH : DCM=50 : 50 (0.2 % 2N NH3 in MeOH)) as mobile phase get product (2.82 mg, 6.8 %). ’H NMR (500 MHz, DMSO) 5 12.02 (s, 1H), 10.78 (s, 1H), 8.93 Hz, 1H), 8.74 (d, 7 = 2.0 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.71 (d, J = 5.0 Hz, 1H), 7.57 ( (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 (

[0227] - 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 (

[0228] - 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 (

[0229] - 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),

[0230] [M+H]+= 820.7.

[0231] Example 033: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-2- methylpyridin-3-yl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0232] Step 1: methyl 6-methyl-5-(1.4-dioxa-8-azaspirol4.51decan-8-yl)picolinate

[0233] To a solution of l,4-dioxa-8-azaspiro[4.5]decane (1.43 g, 10 mmol) in 1,4-Dioxane (50 mL) was added methyl 5-bromo-6-methylpicolinate (2.30 g, 10 mmol), Pdildba); (915 mg, 1.0 mmol), Xantphos (578 mg, 1.0 mmol) and K3PO4 (4.24 g, 20.0 mmol). The mixture was stirred for 18 hours at 110 °C under nitrogen. The mixture was concentrated under vacuum and purified by silica gel chromatography (Petroleum ether / EtOAc = 3 : 1) to give product (0.99 g, 33.9 %). [M+H]+= 293.3. Step 2: 6-methyl-5-(L4-dioxa-8-azaspirol4.51decan-8-yl)picolinic acid

[0234] To a solution of methyl 6-methyl-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinate (0.99 g, 3.39 mmol) in THF / MeOH (20 mL / 5 mL) was added LiOH (712 mg, 16.9 mol) in water (5 mL). Then the reaction mixture was stirred at 50 °C for 3 hours. The mixture was concentrated, adjusted to pH~7 with HC1 (IN) and extracted with DCM (500 mL x 3). The combined organic layer was dried over NioSCL and concentrated under vacuum to give product (930 mg, 3.3 mmol). [M+H]+= 279.2.

[0235] Step 3: (S)-N-(2,6-dioxopiperidin-3-yl)-6-methyl-5-(L4-dioxa-8-azaspiro[4.51decan-8- yl)picolinamide

[0236] To a stirred solution of 6-methyl-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)picolinic acid (930 mg, 3.3 mmol) and (S)-3-Amino-piperidine -2, 6-dione hydrochloride (560 mg, 3.4 mmol) in DCM (40 mL) was added 50% T3P in EtOAc (2.16 g, 3.4 mmol) and DIPEA (438 mg, 3.4 mmol). The solution was stirred at room temperature for 18 hours. The solution was added water (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was dried over NazSCL. concentrated under vacuum and purified on silica gel column chromatography (DCM : MeOH = 90: 10) to give product (760 mg, 57.7 %). [M+H]+= 389.5.

[0237] Step 4: (S)-N-(2,6-dioxopiperidin-3-yl)-6-methyl-5-(4-oxopiperidin-l-yl)picolinamide

[0238] To a solution of (S)-N-(2,6-dioxopiperidin-3-yl)-6-methyl-5-(l,4-dioxa-8-azaspiro[4.5]decan-8- yl)picolinamide (120 mg, 0.3 mmol) was added 6 N HC1 at 0 °C. The mixture was stirred for 2 hours at 0 °C. The mixture was adjusted to pH~7 with HC1 (IN) and extracted with DCM (25 mL x 3). The combined organic layer was dried over NazSC and concentrated under vacuum to give product (100 mg, 96.7 %). [M+H]+= 345.3.

[0239] Step 5: 3-cvano-N-(2-((lr,4r)-4-(4-(l-(6-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-2-methylpyridin- 3-yl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrololl.2- blpyridazine-7-carboxamide

[0240] A solution of 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H- indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide (53 mg, 0.1 mmol) and (S)-N-(2,6-dioxopiperidin- 3-yl)-6-methyl-5-(4-oxopiperidin-l-yl)picolinamide (50 mg, 0.15 mmol) in DCE I DMA (5 mL 15 mL) was stirred at room temperature for 1 hour, then NaBH(OAc)3 (42 mg, 0.2 mmol) was added portion wise. The solution was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum and purified on silica gel column chromatography (DCM : MeOH = 90 : 10) to afford product (26 mg, 30.4 %).1H NMR (500 MHz, DMSO) 5 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

[0241] - 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

[0242] - 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

[0243] - 1.44 (m, 2H). [M+H]+= 855.7.

[0244] Example 035: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(4-(((S)-2,6-dioxopiperidin-3- yl)carbamoyl)phenyl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0245] The title compound (33 mg, 22.8 %) was prepared in a manner similar to that described in Example 033. 'HNMR (500 MHz, DMSO) 5 12.02 (s, 1H), 10.82 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.74 (d, / = 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.

[0246] Example 007: N-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3- yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6- (trifhtoromethyl)picolinamide

[0247] The title compound (797 mg, 52.24%) was prepared in a manner similar to that described in Example 006. 'HNMR (500 MHz, DMSO) 5 12.36 (s, 1H), 10.86 (s, 1H), 8.71 (s, 1H), 8.45 (d, J= 7.8 Hz, 1H), 8.39 - 8.34 (m, 2H), 8.16 (d, J = 1.8 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.

[0248] Example 027: 3-cyano-N-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-5- fluoropyrrolo[l,2-b]pyridazine-7-carboxamide

[0249] Step 1: 7-bromo-5-fluoropyrrololl.2-b1pyridazine-3-carbonitrile

[0250] To a solution of 7-bromopyrrolo[l,2-b]pyridazine-3-carbonitrile (2 g, 9.0 mmol) in DMF(30 mL) was added selectfluar( 3.51 g,9.9 mmol) at 0°C. Then the solution was warmed to rt and stirred for 5 h. Then the solution was diluted with EA(100 mL) and washed with water(70 mLx2) and brine(60 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica column (DCM / EA=3: 1) to give the product (1.2 g, 55.6%). [M+H]+= 240.2

[0251] Step 2: 3-cyano-5-fluoropyrrolorL2-b]pyridazine-7-carboxylic acid

[0252] To a solution of 7-bromo-5-fluoropyrrolo[l,2-b]pyridazine-3-carbonitrile(600 mg, 2.50 mmol) in THF(12 mL) and water(4 mL) was added Pd(dppf)C12(183 mg, 0.25 mmol) and TEA(757.5 mg, 7.5 mmol). Then the mixture was stirred at 95°C under C0(4 MPa) for 16 h. Then the mixture was concentrated in vacuo. The residue was purified by silica column (DCM / MeOH= 10: 1) to give the product(300 mg, 58.5%). [M+Na]+= 228.2

[0253] Step 3: tert-butyl 4-((lr,4r)-4-(5-(3-cyano-5-fluoropyrrololL2-b1pyridazine-7-carboxamido)-6-(2- hvdroxypropan-2-yl)-2H-indazol-2-yl)cvclohexyl)piperazine-l -carboxylate

[0254] To a stirred solution of 3-cyano-5-fluoropyrrolo[l,2-b]pyridazine-7-carboxylic acid (80 mg, 0.39 mmol) and tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2- yl)cyclohexyl)piperazine-l -carboxylate (178.6 mg, 0.39 mmol) in DMF (3 mL) was added HATU (177.84 mg, 0.47 mmol) and DIEA (150.90 mg, 1.17 mmol). The mixture was stirred for 5 hours at room temperature. The mixture was diluted with water (10 mL). The solid was collected by filtration and washed with water (3x5 mL). The solid was dried under vacuum to yield product (190 mg, 75.56%). [M+H]+= 645.5

[0255] Step 4: 3-cyano-5-fluoro-N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H- indazol-5-yl)pyrrolo[ 1 ,2-b]pyridazine-7-carboxamide

[0256] To a stirring solution of tert-butyl 4-((lr,4r)-4-(5-(3-cyano-5-fluoropyrrolo[l,2-b]pyridazine-7- carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l -carboxylate (190 mg, 0.29 mmol) in MeOH (3 mL) was added dropwise conc.HCl (36%, 2 mL) at 0°C. The resulting mixture was stirred 3 hours at room temperature. The solid was collected by filtration. The solid was dissolve with water (5 mL), then adjusted to pH 8 with sat.NaHCO; solution and extracted with DCM / MeOH (V / V=10 / l, 3x10 mL). The combined organic layers were dried over anhydrous NioSCL. filtered and evaporated in vacuum to yield product (150 mg, 82.81%). [M+H]+= 545.4

[0257] Step 5: 3-cvano-N-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin- 3-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-5-fluoropyrrolorL2- blpyridazine-7-carboxamide

[0258] The title compound (14.5 mg, 62.21%) was prepared in a manner similar to that described in Example 029. 'H NMR (500 MHz, DMSO) 5 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.

[0259] Example 030: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(6-((2,6-dioxopiperidin-3-yl)amino)-4-methylpyridin- 3-yl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[l,2- b] pyridazine-7-carboxamide

[0260] The title compound (25 mg, 23.21%) was prepared in a manner similar to that described in Example 029.1H NMR (500 MHz, DMSO) 5 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.

[0261] Example 054: 5-amino-4-(5-(4-(4-((lr,4r)-4-(5-(3-cyanopyrrolo[l,2-b]pyridazine-7-carboxamido)- 6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazin-l-yl)piperidin-l-yl)-6-methylpyridin-2- yl)-5-oxopentanoic acid

[0262] The title compound (25 mg, 23.21%) was prepared in a manner similar to that described in Example 029. (320 mg, 62.7%). 'HNMR (500 MHz, DMSO) 5 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.

[0263] Example 004: 3-cyano-N-(2-((lR,4r)-4-((3R)-4-(l-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2- methylpyridin-3-yl)piperidin-4-yl)-3-(methoxymethyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2- yl)-2H-indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0264] The title compound (32 mg, 36.78%) was prepared in a manner similar to that described in Example 029. ’HNMR (500 MHz, DMSO) 5 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), 7.1O (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.

[0265] Example 014: 3-cyano-N-(2-((lS,4r)-4-(4-(2-(2-((S)-2,6- diaminohexanamido)ethoxy)ethyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0266] The title compound (5.29 mg, 7.12%) was prepared in a manner similar to that described in Example 029.1H NMR (500 MHz, DMSO) 5 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= 5.0 Hz, 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.

[0267] Example 021: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin- 3-yl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[l,2- b] pyridazine-7-carboxamide

[0268] The title compound (103 mg, 9.36%) was prepared in a manner similar to that described in Example 029.1HNMR (500 MHz, DMSO) 512.02 (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.

[0269] Example 024: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(6-((S)-2,6-dioxopiperidin-3-yl)-5-fluoro-2- methylpyridin-3-yl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine 7 carboxamide

[0270] The title compound (62mg, 5.64%) was prepared in a manner similar to that described in Example 029.1HNMR (500 MHz, DMSO) 512.02 (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.

[0271] Example 025: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(6-((R)-2,6-dioxopiperidin-3-yl)-5-fluoro-2- methylpyridin-3-yl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine 7 carboxamide The title compound (66 mg, 6.00%) was prepared in a manner similar to that described in Example 029.1HNMR (500 MHz, DMSO) 5 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.

[0272] Example 026: N-(2-((lr,4r)-4-(4-(l-(2-chloro-4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin- 4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-3-cyanopyrrolo[l,2- b] pyridazine-7-carboxamide

[0273] The title compound (53 mg, 62.35%) was prepared in a manner similar to that described in Example 029.1HNMR (500 MHz, DMSO) 5 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= 5.0 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J= 10.0 Hz, 1H), 7.10 (d, 7= 5.0 Hz, 1H), 6.94 (d, 7 = 10.0 Hz, 1H), 6.75 (d, 7 = 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.

[0274] Example 005: 3-cyano-N-(2-(3-(4-(l-(6-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-methylpyridin-3- yl)piperidin-4-yl)piperazin- 1 -yl)bicyclo[l .1.1 Jpentan- l-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0275] The title compound (132.61 mg, 84.14%) was prepared in a manner similar to that described in Example 029. (30 mg, 38.0%). H NMR (500 MHz, DMSO) 'H NMR (500 MHz, DMSO) 8 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, . / = 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 = 9.0 Hz, 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, / = 11.4 Hz, 2H), 1.70 - 1.46 (m, 8H).

[0276] [M+H]+= 814.4

[0277] Example 13: 3-cyano-N-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)piperazin-l-yl)cyclohexyl)-6-(2-methoxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0278] Step 1: 6-(2-methoxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-5-amine

[0279] To a solution of tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2- yl)cyclohexyl)piperazine-l -carboxylate (1 g, 2.18 mmol) in MeOH (50 mL) was added TsOH(0.38 g, 2.18 mmol) and H2SO4(0.218 g, 2.18 mmol). The mixture was stirred for 48hours at 80°C under N2. The solution was basified to pH~10 with Na2COs and extract with DCM. The organic layer was concentrated in vacuo. This gives crude product (0.8 g, 100%). [M+H]+= 372.2

[0280] Step 2: tert-butyl 4-((lr.4r)-4-(5-amino-6-(2-methoxypropan-2-yl)-2H-indazol-2- yl ic vclohex yl )pi pcrazi ne- 1 -carboxylate

[0281] To a solution of 6-(2-methoxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-5- amine (0.8 g, 2.18 mmol) in DCM (50 mL) was added (Boc^O (0.57g, 2.62 mmol) at rt. The mixture was stirred for 3hours at RT. The mixture was concentrated. The residue was purified by silica gel column chromatography (PE:EA = 3: 1 to 1 : 1) to give product (320 mg, 32.0%). [M+H]+=472.2

[0282] Step 3: tert-butyl 4-((lr.4r)-4-(5-(3-cyanopyrrolo[l,2-b1pyridazine-7-carboxamido)-6-(2- methoxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l-carboxylate

[0283] To a stirred solution of tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-methoxypropan-2-yl)-2H-indazol-2- yl)cyclohexyl)piperazine-l -carboxylate (320 mg, 0.68 mmol) in DMF (10 mL) was added TEA (206 mg, 2.04 mmol) and 3-cyanopyrrolo[l,2-b]pyridazine-7-carboxylic acid 127 mg, 0.68 mmol), HATU(310 mg, 0.82 mmol). The reaction mixture was stirred overnight at rt. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH= 40:1 to 20:1) to give product (200 mg, 46.1%). [M+H]+= 641.4

[0284] Step 4: 3-cyano-N-(6-(2-methoxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-

[0285] 5-yl)pyrrolo[l,2-blpyridazine-7-carboxamide

[0286] To a solution of tert-butyl 4-((lr,4r)-4-(5-(3-cyanopyrrolo[l,2-b]pyridazine-7-carboxamido)-6-(2- methoxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l-carboxylate (100 mg, 0.156 mmol) in DCM (4 mL) was added TFA(1 mL) . The mixture was stirred for 3hours at RT. The mixture was concentrated. The residue was disolved in DCM(20 mL). The solution was adjusted to pH 10 with saturated NazCCL solution and extracted with DCM. The combined organic layers were dried over anhydrous NaiSCh, filtered and evaporated in vacuum to afford product (50 mg, 58.8 %), which was used without further purification. [M+H]+= 541.4.

[0287] Step 5: 3-cyano-N-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin- 3-yl)piperazin-l-yl)cyclohexyl)-6-(2-methoxypropan-2-yl)-2H-indazol-5-yl)pyrrololl.2-b1pyridazine-7- carboxamide

[0288] To a solution of 3-cyano-N-(6-(2-methoxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H- indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide (50 mg, 0.093 mmol) in DCE (5 mL) was added (R)-3-(2,6-difluoro-4-(3-oxoazetidin-l-yl)phenyl)piperidine-2, 6-dione (54 mg, 0.185 mmol) and NaBH(OAc)a(39.2 mg, 0.185 mmol). The mixture was stirred for 14hours at RT. The mixture was concentrated and the residue was purified by Prep-HPLC (C-18 column chromatography (0.1% FA in water : acetonitrile = 90 : 10 ~ 60 : 40 gradient elution) to give the desired product (30 mg, 38.0%). H NMR (500 MHz, DMSO) 5 11.46 (s, 1H), 10.86 (s, 1H), 8.95 (d, 7= 2.0 Hz, 1H), 8.83 (d, 7= 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 = 9.3 Hz, 2H), 2.08 (dd, 7= 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

[0289] Example 018: 3-cyano-N-(2-(3-(4-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin- 4-yl)piperazin- l-yl)bicyclo[l .1. l]pentan-l-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[l ,2- b] pyridazine-7-carboxamide

[0290] The title compound (132.61 mg, 84.14%) was prepared in a manner similar to that described in Example 029. ’H NMR (500 MHz, DMSO) 5 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, 7= 4.6 Hz, 1H), 7.61 (s, 1H), 7.09 (d, 7= 4.6 Hz, 1H), 6.83 (t, 7= 9.4

[0291] 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

[0292] (d, 7 = 9.7 Hz, 3H), 2.78 - 2.67 (m, 1H), 2.66 - 2.53 (m, 9H), 2.31 (d, 7= 18.7 Hz, 8H), 2.07 (s, 1H), 1.92

[0293] - 1.75 (m, 3H), 1.71 - 1.48 (m, 8H); [M+H]+= 814.4

[0294] Example 031: 3-cyano-N-(2-((lr,4r)-4-(4-(7-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-

[0295] 7-azaspiro[3.5]nonan-2-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0296] Step 1: tert-butyl 2-(benzyloxy)-7-azaspiro[3.51nonane-7-carboxylate

[0297] To a solution of tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (5 g, 20.72 mmol) in THF (100 mL) was added NaH (1.65 g, 41.44 mmol) and BnBr (7.08 g, 41.44 mmol). The mixture was stirred for 14 hours at rt under Ni. The reaction was quenched with saturated NH4CI and extracted with DCM (50mLx3). The organic layer was dried with NJVSCL and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 20: 1 to 10:1) to give product (6.0 g, 87%). [M+H]+= 332.2

[0298] Step 2: 2-(benzYloxy)-7-azaspiror3.51non

[0299] 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) was slowed added TFA (lOmL) at 0°C. The mixture was stirred for 2 hours at RT. The mixture was concentrated. The residue was disolved in DCM (100 mL), then adjusted to pH 9 with sat. Na2CO3solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and evaporated in vacuum to afford product (3.5 g, 83.6%), which was used without further purification. [M+H]+= 232.2

[0300] Step 3: 2-(benzyloxY)-7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)-7- azaspiro[3.51nonane

[0301] To a stirred solution of methyl 2-(benzyloxy)-7-azaspiro[3.5]nonane (3.5 g, 15.15 mmol) in dioxane (50 mL) was added 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difhiorophenyl)pyridine (8.77 g, 18.18 mmol), CS2CO3 (9.82 g, 30.30 mmol) , Pd2(dba)3(690 mg, 0.76 mmol), X-phos(1.45 g, 3.03 mmol). The reaction mixture was stirred overnight at 100 °C. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 10:1 to 3:1) to give product (7.0 g, 73.2%). [M+H]+= 633.3

[0302] Step 4: 3-(2,6-difluoro-4-(2-hvdroxy-7-azaspiro[3.51nonan-7-yl)phenyl)piperidine-2.6-dione

[0303] To 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) in IPA (200 mL) , DMF (200 mL) and Pd / C (3 g). The mixture was stirred for 36 hours at 50 °C under Hi atmosphere. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was recrystallized in DCM to afford product (3.0 g, 74.4%). [M+H] = 365.2.

[0304] Step 5: (R)-3-(2,6-difluoro-4-(24iydroxy-7-azaspirol3.5]nonan-7-yl)phenyl)piperidine-2, 6-dione

[0305] After chiral separation by HPLC under neutral condition, 1.2 g of the R (Peak-l:ee=99.54%, chemical purity=97.73%) and 1.1 g of the S (Peak-2:ee=98.21%, chemical purity=96.90%) were obtained respectively.

[0306]

[0307] [M+H]+=365.2.

[0308] Step 6: (R)-3-(2,6-difluoro-4-(2-oxo-7-azaspirol3.51nonan-7-yl)phenyl)piperidine-2, 6-dione

[0309] To a solution of (R)-3-(2,6-difluoro-4-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)phenyl)piperidine-2,6- dione (300 mg, 0.83 mmol) in DMSO (3 mL) was added IBX(394 mg, 1.41 mmol). The mixture was stirred for 14hours at RT. The mixture was quenched with aqueous NazSzO ; and extracted with DCM washed with water. The combined organic layers were dried over anhydrous Na2SC>4, filtered and evaporated in vacuum. The residue was purified by prep-TLC (PE:EA = 1:1) to give product (200 mg, 66.7%). [M+H]+= 363.4

[0310] Step 7: 3-cyano-N-(2-((lr,4r)-4-(4-(7-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-7- azaspiro[3.51nonan-2-yl)piperazin-l-yl)cvclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- vDpyrrolol 1 ,2-b1pyridazine-7-carboxamide

[0311] To a solution of 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)- 2H-indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide(100 mg, 0.189 mmol) and (R)-3-(2,6-difluoro- 4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)phenyl)piperidine-2, 6-dione (103 mg, 0.283 mmol) in DCE (5 mL) was was added NaBH(OAc)s (80 mg, 0.378 mmol) at rt. The resulting mixture was stirred for 12 hours at 50°C. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SC>4, filtered and evaporated in vacuum. The residue was purified by Prep- HPLC (C-18 column chromatography (0.1% FA in water : acetonitrile = 90 : 10 ~ 60 : 40 gradient elution) to give the desired product (65 mg, 39.4.0%).

[0312] 1H NMR (500 MHz, DMSO) 5 12.03 (s, 1H), 10.86 (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), 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 = 12.9 Hz, 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, 7 = 17.8, 8.3 Hz, 1H), 2.01 - 1.89 (m, 7H), 1.66 - 1.56 (m, 10H), 1.50 (d, J = 23.0 Hz, 4H).

[0313] [M+H]+= 873.4

[0314] Example 037: 3-cyano-N-(2-((lr,4r)-4-(4-((l-(3-(((S)-2,6-dioxopiperidin-3- yl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H- indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0315] Step 1: N-(2.6-dioxopiperidin-3-yl)-3-(4-formylpiperidin-l-yl)benzamide

[0316] To a solution of N-(2,6-dioxopiperidin-3-yl)-3-(4-(hydroxymethyl)piperidin-l-yl)benzamide (100 mg, 0.29 mmol, obtained through the same method of example 033) in DMSO (3 mL) was added IBX(146 mg, 0.55 mmol). The mixture was stirred for 14hours at RT. The mixture was quenched with aqueous Na2S2Os and extracted with DCM washed with water. The combined organic layers were dried over anhydrous Na2SC>4, filtered and evaporated in vacuum. The residue was purified by prep-TLC (PE:EA = 1:1) to give product (65 mg, 65.4%). [M+H]+= 344.2.4

[0317] Step 2: 3-cyano-N-(2-((lr,4r)-4-(4-((l-(3-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)piperidin- 4-yl)methyl)piperazin- 1 -yl)cyclohexYl)-6-(2-hYdroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[ 1 ,2- blpyridazine-7-carboxamide

[0318] To a solution of 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H- indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide (80 mg, 0.152 mmol) and N-(2,6-dioxopiperidin-3- yl)-3-(4-formylpiperidin-l-yl)benzamide (63 mg, 0.182 mmol) in DCE (5 mL) was was added NaBH(OAc)3 (64 mg, 0.304 mmol) at rt. The resulting mixture was stirred for 12 hours at RT. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous NaiSO4, filtered and evaporated in vacuum. The residue was purified by Prep-HPLC (C-18 column chromatography (0.1% FA in water: acetonitrile = 90 : 10 ~ 60 : 40 gradient elution) to give the desired racemate product (50 mg, 38.5%). The racemate product was isolated with prep-chiral HPLC with the follow condition Column : i-Cellulose-5 46*250 mm 5 pm Flow Rate (mL / min): 50.0. Gradient: Time (min) MtBE(0.1% 2M NH3 in MeOH)(%) DCM: MeOH= 50:50 (%) to give the desired product (15 mg, 30.0%).

[0319] 'H NMR (500 MHz, DMSO) 5 12 02 (s, 1H), 10.86 (s, 1H), 8.93 (d, 7= 2.0 Hz, 1H), 8.74 (d, 7= 2.0 Hz, 1H), 8.67 (d, J = 8.2 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.72 (d, 7 = 4.8 Hz, 1H), 7.57 (s, 1H), 7.39 (s, 1H), 7.32 - 7.22 (m, 2H), 7.10 (t, 7= 6.0 Hz, 2H), 5.72 (s, 1H), 4.81 - 4.71 (m, 1H), 4.43 (s, 1H), 3.74 (d, 7 = 11.4 Hz, 2H), 2.79 (dd, 7 = 21.5, 9.2 Hz, 1H), 2.70 (t, 7 = 11.7 Hz, 2H), 2.56 (s, 2H), 2.36 (s, 5H), 2.12 (dd, 7= 19.8, 15.6 Hz, 5H), 1.94 (dd, 7 = 22.9, 11.0 Hz, 5H), 1.80 (d, 7= 11.6 Hz, 2H), 1.69 (s, 1H), 1.63 (s, 6H), 1.48 (d, 7= 11.7 Hz, 2H), 1.22 (d, 7= 19.1 Hz, 4H). [M+H]+= 854.4

[0320] Example 038: 3-cyano-N-(2-((lr,4r)-4-(4-((l-(3-(((S)-2,6-dioxopiperidin-3- yl)carbamoyl)phenyl)azetidin-3-yl)methyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H- indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0321] Step 1: N-(2,6-dioxopip eridin 3 yl) 3 (3 formylazetidin l yl)benzamide

[0322] To a solution of N-(2,6-dioxopiperidin-3-yl)-3-(3-(hydroxymethyl)azetidin-l-yl)benzamide (200 mg, 0.0.63 mmol, obtained through the similar method of example 033) in DMSO (3 mL) was added IBX(317 mg, 1.13 mmol). The mixture was stirred for 14hours at RT. The mixture was quenched with aqueous NaiSiO; and extracted with DCM washed with water. The combined organic layers were dried over anhydrous Na2SC>4, filtered and evaporated in vacuum. The residue was purified by prep-TLC (PE:EA = 1:1) to give product (130 mg, 65.4%). [M+H]+= 316.2

[0323] Step 2: 3-cvano-N-(2-((lr,4r)-4-(4-((l-(3-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)azetidin- 3-yl)methyl)piperazin- 1 -yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo( 1 ,2- blpyridazine-7-carboxamide

[0324] To a solution of 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H- indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide (160 mg, 0.304 mmol) and N-(2,6-dioxopiperidin- 3-yl)-3-(3-formylazetidin-l-yl)benzamide (115 mg, 0.365 mmol) in DCE (5 mL) was was added NaBH(OAc)s (130 mg, 0.608 mmol) at rt. The resulting mixture was stirred for 12 hours at RT. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous NazSCL, filtered and evaporated in vacuum. The residue was purified by Prep-HPLC (C-18 column chromatography (0.1% FA in water : acetonitrile = 90 : 10 ~ 60 : 40 gradient elution) to give the desired racemate product (120 mg, 47.8%). The racemate product was isolated with prep-chiral HPLC with the follow condition Column : YMC Amylose-SA 46*250 mm 5 pm Flow Rate (mL / min): 10. Gradient: MtBE(0.1%2M NH; MeOH)(%) DCM:MeOH=50:50 (%) to give the desired product (40 mg, 30.8%).

[0325] 1H NMR (500 MHz, DMSO) 5 12.02 (s, 1H), 10.85 (s, 1H), 8.93 (d, J= 2.1 Hz, 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, 7= 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, 7 = 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, 7 = 22.6, 11.9 Hz, 5H), 1.63 (s, 6H), 1.54 - 1.42 (m, 2H). [M+H]+= 826.4

[0326] Example 016: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2,6- difluorophenyl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0327] The title compound (26.29 mg, 32.65%) was prepared in a manner similar to that described in Example 029. 'H WIR (500 MHz, DMSO) 5 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, 7 = 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

[0328] Example 017: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0329] The title compound (132.61 mg, 84.14%) was prepared in a manner similar to that described in Example 029. 'H NMR (500 MHz, DMSO) 5 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, 7= 10 Hz, 1H), 6.50 (dd, J = 10 Hz, 5 Hz, 1H), 6.41 (dd, J = 10 Hz, 5 Hz, 1H), 5.79 (d, 7 = 10 Hz, 1H), 5.73 (s, 1H), 4.45 - 4.38 (m, 1H), 4.28 - 4.21 (m, 1H), 3.16 (d, 7= 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

[0330] Example 053: 3-cyano-N-(2-((lr,4r)-4-(4-((l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)methyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxyethoxy)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0331] Step 1 : 2-(benzyloxy)ethyl methanesulfonate

[0332] To a solution of 2-(benzyloxy)ethan-l-ol (1.52 g, 10 mmol) and E3N (3.03 g, 30 mmol) in DCM (40 mL) was added dropwise MsCl(1.38 g, 12 mmol) at 0 °C. The mixture was stirred for Ih at 0 °C. The mixture was diluted with water and extracted with DCM (3x30 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and evaporated in vacuum to yield product (1.8 g, 78.26%). [M+H]+= 231.1

[0333] Step 2: tert-butyl 4-((lr,4r)-4-(6-(2-(benzyloxy)ethoxy)-5-bromo-2H-indazol-2- vDcyclohexyDpiperazine- 1 -carboxylate

[0334] To a solution of tert-butyl 4-((lr,4r)-4-(5-bromo-6-hydroxy-2H-indazol-2-yl)cyclohexyl)piperazine- 1-carboxylate (478 mg, 1 mmol, obtained through the similar method of example 029) in CH3CN (20 mL) was slowed added K2CO3 (414 mg, 3 mmol) and 2-(benzyloxy)ethyl methanesulfonate (345 mg, 1.5 mmol). The mixture was stirred overnight at 80 °C. The mixture was diluted with water and extracted with DCM (3x20 L). The combined organic layers were dried over anhydrous NazSCL, filtered and evaporated in vacuum. The residue was purified with silica gel column chromatography (PE: EtOAc = 3: 1) to yield product (500 mg, 81.7%). [M+H]+= 613.2

[0335] Step 3: tert-butyl 4-((lr,4r)-4-(6-(2-(benzyloxy)ethoxy)-5-((diphenylmethylene)amino)-2H-indazol- 2-yl)cyclohexyl)piperazine- 1 -carboxylate

[0336] To a stirred solution of tert-butyl 4-((lr,4r)-4-(6-(2-(benzyloxy)ethoxy)-5-bromo-2H-indazol-2- yl)cyclohexyl)piperazine-l -carboxylate (500 mg, 0.817 mmol) and diphenylmethanimine (296 mg, 1.634 mmol) in toluene (20 mL) was added CS2CO3 (799 mg, 2.451 mmol), Xantphos (96 mg, 0.1634 mmol) and Pdzfdba); (74.76 mg, 0.0817 mmol). The reaction mixture was stirred overnight at 100 °C. The mixture was concentrated in vacuo. The residue was purified with silica gel column chromatography (PE: EtOAc = 1: 1) to yield product (480 mg, 82.4%). [M+H]+= 714.4

[0337] Step 4: tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-(benzyloxy)ethoxy)-2H-indazol-2- yDcyclohexyPpiperazine- 1 -carboxylate

[0338] To a solution of tert-butyl 4-((lr,4r)-4-(6-(2-(benzyloxy)ethoxy)-5-((diphenylmethylene)amino)-2H- indazol-2-yl)cyclohexyl)piperazine-l-carboxylate (480 mg, 0.672 mmol) in THF (10 mL) was added HC1 aq (1 N, 5 mL). The resulting mixture was stirred for 30 min. The mixture was dissolve with water, then adjusted to pH 8 with sat.NaHCO; solution and extracted with DCM (3x20 mL). The combined organic layers were dried over anhydrous NaiSCL, filtered and evaporated under vacuum to yield product (280 mg, 75.88%). [M+H]+= 550.3

[0339] Step 5: tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-hydroxyethoxy)-2H-indazol-2- vDcyclohexyDpiperazine- 1 -carboxylate

[0340] To a solution of tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-(benzyloxy)ethoxy)-2H-indazol-2- yl)cyclohexyl)piperazine-l -carboxylate (280 mg, 0.509 mmol) in THF (10 mL) was added Pd / C (5%, 20 mg) at room temperature. The resulting mixture was stirred overnight at room temperature under Hz. The solid was filtered and washed with MeOH (30 mL). The filtrate was evaporated in vacuum to yield product (150 mg, 64.1%). [M+H]+= 460.3

[0341] Step 6: tert-butyl 4-((lr,4r)-4-(5-(3-cyanopyrrok>ri,2-b1pyridazme-7-carboxamido)-6-(2- hvdroxyethoxy)-2H-indazol-2-yl)cvclohexyl)piperazine-l-carboxylate

[0342] To a solution of tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-hydroxyethoxy)-2H-indazol-2- yl)cyclohexyl)piperazine-l -carboxylate (46 mg, 0.1 mmol) and 3-cyanopyrrolo[l,2-b]pyridazine-7- carboxylic acid (22.44 mg, 0.12 mmol) in DMF (10 mL) was added DIEA (38.7 mg, 0.3 mmol) and HATU (38 mg, 0.1 mmol). The resulting mixture was stirred for Ih at room temperature. The mixture was diluted with water and extracted with DCM (3x20 mL). The combined organic layers were dried over anhydrous NaiSCL. filtered and evaporated in vacuum to yield product (50 mg, 79.62%). [M+H]+= 629.3

[0343] Step 7: 3-cvano-N-(6-(2-hvdroxyethoxy)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-5- yDpyrrolol 1.2-b1pyridazine-7-carboxamide

[0344] To a stirring solution of tert-butyl 4-((lr,4r)-4-(5-(3-cyanopyrrolo[l,2-b]pyridazine-7-carboxamido)-

[0345] 6-(2-hydroxyethoxy)-2H-indazol-2-yl)cyclohexyl)piperazine-l -carboxylate (50 mg, 0.08 mmol) in MeOH (8 mL) was added dropwise conc.HCl (36%, 2 mL) at 0 °C. The resulting mixture was stirred for 2 hours at 0 °C. The mixture was dissolve with water, then adjusted to pH 8 with sat.Nal ICC); solution and extracted with DCM / MeOH (V / V=10 / l, 3x20 mL). The combined organic layers were dried over anhydrous NajSCL, filtered and evaporated in vacuum to yield product (30 mg, 71%). [M+H]+= 529.3

[0346] Step 8: 3-cyano-N-(2-((lr,4r)-4-(4-((l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin- 3-yl)methyl)piperazin- 1 -yl)cvclohexyl)-6-(2-hvdroxyethoxy)-2H-indazol-5-yl)pyrrolol 1 ,2-blpyridazine-

[0347] 7-carboxamide

[0348] To a stirred solution of 3-cyano-N-(6-(2-hydroxyethoxy)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)- 2H-indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide (15 mg, 0.02 mmol) and (R)-l-(4-(2,6- dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbaldehyde (9.24 mg, 0.03 mmol) in DCE (8 mL) was added NaBH(OAc)s (8.48 mg, 0.04 mmol). The mixture was stirred for Ih at room temperature. The mixture was diluted with water and extracted with DCM (3x20 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered and evaporated in vacuum. The residue was purified by prep HPLC (Waters XSelect C18: RD-CO-094 column, eluting with 27%-52% water (containing 0.1% FA) in acetonitrile) to afford the product (2 mg, 12.2%).

[0349] 1H NMR (500 MHz, DMSO) 5 11.54 (s, IH), 10.85 (s, IH), 9.00 (d, J= 5 Hz, IH), 8.88 (d, J = 5 Hz, IH), 8.80 (s, IH), 8.29 (s, IH), 7.78 (d, J= 5 Hz, IH), 7.13 (d, J= 5 Hz, IH), 7.11 (s, IH), 6.10 (d, J = 10 Hz, 2H), 5.10 - 5.04 (m, IH), 4.38 - 4.30 (m, IH), 4.21 (t, J= 10 Hz, 2H), 4.05 - 3.97 (m, 3H), 3.92 (d, 7 = 10 Hz, 2H), 3.47 (d, J = 10 Hz, 2H), 2.95 - 2.87 (m, IH), 2.82 - 2.72 (m, IH), 2.59 - 2.51 (m, 6H), 2.47 - 2.31 (m, 6H), 2.20 - 2.13 (m, 2H), 2.10 - 2.02 (m, IH), 1.98 - 1.86 (m, 5H), 1.51 - 1.40 (m, 2H). [M+H]+= 821.67

[0350] Example 001: 3-cyano-N-(2-((lS,4r)-4-(4-(2-(((S)-l-((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin- 1 -yl)-3,3-dimethyl- 1 -oxobutan-2-yl)amino)-2- oxoethyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[l,2- b] pyridazine-7 -carboxamide

[0351] Step 1: (2S,4R)-l-((S)-2-(2-bromoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0352] To a solution of (2S,4R)-l-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4- methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.96 g, 2 mmol), Nal ICO; (0.67 g, 8 mmol) in THF / HiO (1:1, 30 mL) was added 2-bromoacetyl chloride (0.38 g, 2.4 mmol) in THF (2 mL) dropwise. After stirring for 2hs at room temperature, the mixture was concentrated to 20 mL and extracted with EA (30 mLX3). The organic phase was combined and concentrated. Purified by chromatography on silica gel column with DCM / MeOH (100:1 to 10:1) to give product (0.9 g, yield: 79.6%).

[0353] Step 2: 3-cyano-N-(2-((lS.4r)-4-(4-(2-(((S)-l-((2S.4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- vDphenvDethvDcarbamovDpyrrolidin- 1 -yl)-3 ,3-dimethyl- 1 -oxobutan-2-yl)amino)-2-oxoethyl)piperazin- l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolorL2-b1pyridazine-7-carboxamide

[0354] A solution of 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H- indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide (52 mg, 0.1 mmol), (2S,4R)-l-((S)-2-(2- bromoacetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)pyrrolidine-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 3hs. The mixture was concentrated and purified by pre-HPLC directly to give product (45 mg, yield: 44.5%).

[0355] 'H NMR (500 MHz, DMSO) 5 12.02 (s, 1H), 8.98 (s, 1H), 8.94 (d, J = 2.0 Hz, 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, I = 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

[0356] Example 003: l-((lr,4R)-4-(5-(3-cyanopyrrolo[l,2-b]pyridazine-7-carboxamido)-6-(2- hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)-4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)piperazine 1-oxide

[0357] To a solution of 3-cyano-N-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide (0.5 g, 0.6 mmol) which was synthesized with the same method as Example 029 in DCM / MeOH / HOAc (10:1:1, 20 V) was added H2O2 (3eq). After stirring at 40- 45°C for 3hs, the mixture was concentrated and purified by pre-HPLC to give product (2.3 mg, yield: 0.45%).

[0358] ’H NMR (500 MHz, DMSO) 5 12.03 (s, 1H), 11.78 (s, 1H), 8.94 (d, 7= 2.0 Hz, 1H), 8.74 (d, J= 2.5 Hz, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.72 (d, 7= 5.0 Hz, 1H), 7.57 (s, 1H), 7.10 (d, 7 = 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 = 12.0 Hz, 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

[0359] Example 002: 4-((lr,4R)-4-(5-(3-cyanopyrrolo[l,2-b]pyridazine-7-carboxamido)-6-(2- hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)-l-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)piperazine 1-oxide

[0360] The title compound (2.03 mg, 0.4%) was prepared in a manner similar to that described in Example 003.

[0361] 1H NMR (500 MHz, DMSO) 5 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, 7= 4.5 Hz, 1H), 7.58 (s, 1H), 7.09 (d, 7= 5.0 Hz, 1H), 6.17 (d, 7= 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, 7= 7.0 Hz, 2H), 3.13 (t, 7 = 10.0 Hz, 2H), 3.04 (t, 7= 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

[0362] Example 008: 3-cyano-N-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)piperazin-l-yl)cyclohexyl)-6-(3-hydroxypentan-3-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0363] Step 1: 3-CYano-N-(6-(3-hydroxypentan-3-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol- 5-yl)pyrrolol 1 ,2-blpyridazine-7 -carboxamide hydrochloride

[0364] To a solution of tert-butyl 4-((lr,4r)-4-(5-(3-cyanopyrrolo[l,2-b]pyridazine-7-carboxamido)-6-(3- hydroxypentan-3-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l -carboxylate (45 mg, 0.07 mmol, obtained through the similar method of Example 029) in H2O (15 mL) was added HC1 (cone., 5 mL). The mixture was stirred at 20-30°C for 2hs and concentrated for next step directly. Step 2: 3-cyano-N-(2-((lR.4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin- 3-yl)piperazin-l-yl)cyclohexyl)-6-(3-hydroxypentan-3-yl)-2H-indazol-5-yl)pyrrololL2-b1pyridazine-7- carboxamide

[0365] To a solution of 3-cyano-N-(6-(3-hydroxypentan-3-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H- indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide hydrochloride (55 mg, crude) and (R)-3-(2,6- difluoro-4-(3-oxoazetidin-l-yl)phenyl)piperidine-2, 6-dione (60 mg, 0.2 mmol) in i-PrOH (20 mL) was added DIEA (129 mg, 1 mmol), NaBH(OAc)3 (64 mg, 0.3 mmol). The mixture was stirred at 70°C for 3hs. After evaporating solvent, the residue was purified by pre-HPLC directly to give product (2.3 mg, yield: 3%).

[0366] ’H NMR CSOO MHz, DMSO) 5 12.05 (s, 1H), 10.85 (s, 1H), 8.93 (d, 7 = 2.0 Hz, 1H), 8.75 (d, 7= 2.0 Hz, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 7.69 (d, 7= 4.5 Hz, 1H), 7.47 (s, 1H), 7.08 (d, 7 = 4.5 Hz, 1H), 6.12 (d, 7 = 11.0 Hz, 2H), 5.39 (s, 1H), 4.42 (s, 1H), 4.03 (dd, 7= 12.5, 5.5 Hz, 1H), 3.91 (t, 7 = 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, 7 = 7.5 Hz, 6H). [M+H]+=833.7

[0367] Example 009: 3-cyano-N-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidin-3-yl)piperazin-l-yl)cyclohexyl)-6-isopropyl-2H-indazol-5-yl)pyrrolo[l,2- b] pyridazine-7 -carboxamide

[0368] Step 1: tert-butyl 4-((lr,4r)-4-(5-(L3-dioxoisoindolin-2-yl)-6-(prop-l-en-2-yl)-2H-indazol-2- vDcyclohexyDpiperazine- 1 -carboxylate

[0369] To a solution of tert-butyl 4-((lr,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2- yl)cyclohexyl)piperazine-l -carboxylate (7.3 g, 16 mmol) in DCM (200 mL) was added isobenzofuran- 1, 3-dione (2.4 g, 16 mmol). After stirring at 20°C-30°C for 3hs, the reaction mixture was concentrated to dryness. To the residue was added AC2O (150 mL) and NaOAc (1.3 g, 16 mmol). After refluxing for 3hs, the solvent was evaporated, followed by H2O (60 mL) was added. Extracting with EA (60 mLX2), the organic phase was combined and washed with NaHCCL solution (100 mL) and brine (100 mL). The organic phase was concentrated for next step directly.

[0370] Step 2: tert-butyl 4-((lr,4r)-4-(5-amino-6-(prop-l-en-2-Yl)-2H-indazol-2-yl)cyclohexyl)piperazine-l- carboxylate

[0371] To a solution of tert-butyl 4-((lr,4r)-4-(5-(l,3-dioxoisoindolin-2-yl)-6-(prop-l-en-2-yl)-2H-indazol-

[0372] 2-yl)cyclohexyl)piperazine-l -carboxylate (0.4 g, 0.8 mmol) in EtOH (10 mL) was added NH2NH2.H2O (0.5 mL). After stirring for 18hs, the solid was filtered off. Filtrate was concentrated for next step directly without further operation.

[0373] Step 3: tert-butyl 4-((lr,4r)-4-(5-amino-6-isopropyl-2H-indazol-2-yl)cyclohexyl)piperazine-l- carboxylate

[0374] A solution of tert-butyl 4-((lr,4r)-4-(5-amino-6-(prop-l-en-2-yl)-2H-indazol-2- yl)cyclohexyl)piperazine-l -carboxylate in THF / MeOH (1:1, 30 mL) with Pd / C (WAV, 10%) was stirred under Hz (1 atm) for 18hs. After filtrating off solid, the filtrate was concentrated and purified by chromatography on silica gel column with DCM / MeOH (100:1 to 10:1) to give product which was used directly in the next step.

[0375] Step 4: tert-butyl 4-((lr,4r)-4-(5-(3-cyanopyrrololl,2-b]pyridazine-7-carboxamido)-6-isopropyl-2H- indazol-2-yl)cyclohexyl)piperazine- 1 -carboxylate

[0376] To a solution of 3-cyanopyrrolo[l,2-b]pyridazine-7-carboxylic acid (0.2 g, 0.5 mmol), tert-butyl 4- ((lr,4r)-4-(5-amino-6-isopropyl-2H-indazol-2-yl)cyclohexyl)piperazine-l-carboxylate (0.09 g, 0.5 mmol) with DIEA (0.2 g, 1.5 mmol) in DMA (3 mL) was added T3P (0.3g, 1 mmol). After stirring for 18hs, the reaction was quenched with HzO and extracted with DCM / i-PrOH (10:1, 20 mLX2). Organic phase was combined , washed with brine (30 mLX2) and purified by column chromatography on silica gel with DCM / MeOH (100:1 to 15:1) to give product (0.15 g, yield: 50%).

[0377] Step 5: 3-cyano-N-(6-isopropyl-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-5- yl)pyrrolori,2-b1pyridazine-7-carboxamide hydrochloride

[0378] A solution of tert-butyl 4-((lr,4r)-4-(5-(3-cyanopyrrolo[l,2-b]pyridazine-7-carboxamido)-6- isopropyl-2H-indazol-2-yl)cyclohexyl)piperazine-l-carboxylate (0.15 g, 0.24 mmol) in HCl / dioxane (4N, 15 mL) was stirred at 20-30°C for 2hs. After evaporating solvent, the residue was used for next step directly.

[0379] Step 6: 3-cyano-N-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin- 3-yl)piperazin- 1 -yl)cyclohexyl)-6-isopropyl-2H-indazol-5-yl)pyrrolol 1 ,2-b1pyridazine-7-carboxamide

[0380] To a solution of 3-cyano-N-(6-isopropyl-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide hydrochloride (27 mg, 0.05mmol) and (R)-3-(2,6-difluoro-4- (3-oxoazetidin-l-yl)phenyl)piperidine-2, 6-dione (15 mg, 0.05 mmol) in DCE (3 mL) was added DIEA (32 mg, 0.25 mmol), followed by NaBH(OAc)s (21 mg, 0.1 mmol). After stirring for 18hs, the reaction was quenched with MeOH, and concentrated, purified by pre-HPLC directly to give product (8.7 mg, yield: 22%) ’H NMR CSOO MHz, DMSO) 5 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, 7 = 5.0 Hz, 1H), 7.54 (s, 1H), 7.13 (d, / = 5.0 Hz, 1H), 6.12 (d, 7 = 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

[0381] Example Oil: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3- yl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-isopropyl-2H-indazol-5-yl)pyrrolo[l,2-b]pyridazine-7- carboxamide

[0382] The title compound (65.4 mg, 41.1%) was prepared in a manner similar to that described in Example 009.

[0383] 1H NMR (500 MHz, DMSO) 5 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, 7 = 8.0 Hz, 1H), 7.14 (d, 7 = 5.0Hz, 1H) , 7.11 (d, 7 = 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, 7 = 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

[0384] Example 012: N-(2-((lr,4r)-4-(4-(2-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)piperidin-4-yl)ethyl)piperazin-l-yl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)furo[3,2- b] pyridine - 3 -carboxamide

[0385] Step 1: tert-butyl 4-((lr,4r)-4-(5-(furor3,2-blpyridine-3-carboxamido)-6-methoxy-2H-indazol-2- vDcyclohexyDpiperazine- 1 -carboxylate

[0386] To a solution of furo[3,2-b]pyridine-3-carboxylic acid (82 mg, 0.5 mmol) and tert-butyl 4-((lr,4r)-4- (5-amino-6-methoxy-2H-indazol-2-yl)cyclohexyl)piperazine-l-carboxylate (212 mg, 0.5 mmol, obtained through the similar method of example 029) in DMA was added DIEA (0.32 g, 2.5 mmol), T3P (318 mg, 1 mmol). After stirring for 0.5h, the reaction was quenched with HzO (20 mL). The product was collected by filtration and washed with H2O. The crude product was used for next step directly after drying under reduce pressure.

[0387] Step 2: N-(6-methoxy-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-5-yl)furo[3,2-b1pyridine- 3-carboxamide hydrochloride A solution of tert-butyl 4-((lr,4r)-4-(5-(furo[3,2-b]pyridine-3-carboxamido)-6-methoxy-2H-indazol- 2-yl)cyclohexyl)piperazine-l -carboxylate (0.15 g) in HCl / dioxane (4N,20 mL) was stirred at 20-30°C for 2hs. The solvent was evaporated and used for next step directly.

[0388] Step 3: N-(2-((lr,4r)-4-(4-(2-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4- yl)ethyl)piperazin-l-yl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)furor3,2-b1pyridine-3-carboxamide

[0389] To a solution of N-(6-methoxy-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H-indazol-5-yl)furo[3,2- b]pyridine-3-carboxamide hydrochloride (51 mg, 0.1 mmol) and (R)-2-(l-(4-(2,6-dioxopiperidin-3-yl)- 3, 5 -diflu orophenyl)piperidin-4-yl) acetaldehyde (35 mg, 0.1 mmol, obtained through the same method of WO2023098656 Al) in DCE (3 mL) was added DIEA (64 mg, 0.5 mmol), followed by NaBH(OAc)3(42 mg, 0.2 mmol). The mixture was concentrated and purified by pre-HPLC to give product (14.4 mg, yield: 15.3%).

[0390] 1H NMR (500 MHz, DMSO) 5 11.09 (s, 1H), 10.86 (s, 1H), 9.02 (s, 1H), 8.79 (dd, 7= 4.5, 1.0 Hz, 1H), 8.71 (s, 1H), 8.31 - 8.26 (m, 2H), 7.57 (dd, 7 = 8.5, 5.0 Hz, 1H), 7.12 (s, 1H), 6.60 (d, 7 = 13.0 Hz, 2H), 4.35 (br, 1H), 4.10 - 3.97 (m, 4H), 3.73 (d, 7= 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, 7 = 11.5 Hz, 2H), 1.52 - 1.32 (m, 5H), 1.21-1.14 (m, 2H). [M+H]+=809.7

[0391] Example 040: 3-cyano-N-(2-((lr,4r)-4-(4-((l-(3-((R)-2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[l,2- b] pyridazine-7-carboxamide

[0392] The title compound (98 mg, 60.4 %) was prepared in a manner similar to that described in Example 029. 'HNMR (500 MHz, DMSO) 5 12.03 (s, 1H), 10.79 (s, 1H), 8.93 (d, 7= 2.0 Hz, 1H), 8.74 (d, 7= 2.0 Hz, 1H), 8.55 (s, 1H), 8.34 (s, 1H), 7.73 (d, 7= 5.0 Hz, 1H), 7.57 (s, 1H), 7.14 (t, 7= 8.0 Hz, 1H), 7.09 (d, 7 = 5.0 Hz, 1H), 6.81 (d, 7 = 8.0 Hz, 1H), 6.78 (s, 1H), 6.58 (d, 7= 7.5 Hz, 1H), 5.81 - 5.69 (m, 1H), 4.49 - 4.33 (m, 1H), 3.75 (dd, 7 = 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.

[0393] Example 036: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(4-(((S)-2,6-dioxopiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0394] The title compound (21.5 mg, 26.24%) was prepared in a manner similar to that described in Example 29. 'H NMR (500 MHz, DMSO) 8 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, 7 = 4.1 Hz, 1H), 7.62 (t, 7 = 8.7 Hz, 1H), 7.57 (s, 1H), 7.09 (d, 7= 4.0 Hz, 1H), 6.82 (d, 7= 8.3 Hz, 1H), 6.76 (d, 7 = 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.

[0395] Example 055: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(4-((2,6-dioxopiperidin-3-yl)oxy)-2- fluorophenyl)piperidin-4-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0396] The title compound (15 mg, 18.07%) was prepared in a manner similar to that described in Example 029. 'HNMR (500 MHz, DMSO) 5 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.

[0397] Example 049: 3-cyano-N-(2-((lR,4r)-4-(4-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[l,2- b] pyridazine-7-carboxamide

[0398] The title compound was prepared in a manner similar to that described in Example 029.1H NMR (500 MHz, DMSO) 512.03 (s, 1H), 11.60 (s, 1H), 8.94 (d, 7 = 5.0 Hz, 1H), 8.74 (d, 7 = 5.0 Hz, 1H), 8.56 (s, 1H), 8.42 (s, 1H), 7.72 (d, 7 = 5.0 Hz, 1H), 7.59 (s, 1H), 7.10 (d, 7 = 5.0 Hz, 1H), 6.66 (d, 7 = 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.

[0399] Example 041: 3-cyano-N-(2-((lR,4r)-4-(4-((l-(3-((R)-2,6-dioxopiperidin-3-yl)phenyl)azetidin-3- yl)methyl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[l,2- b] pyridazine-7-carboxamide

[0400] 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) 5 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.

[0401] Example 061: 3-cyano-N-(2-((lr,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorobenzyl)azetidin-3-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0402] The title compound(49.2 mg, 52.24%) was prepared in a manner similar to that described in Example 029. 'HNMR (500 MHz, DMSO) 5 12.02 (s, 1H), 10.95 (s, 1H), 8.93 (d, 7= 2.1 Hz, 1H), 8.74 (d, 7= 2.1 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.72 (d, 7 = 4.8 Hz, 1H), 7.57 (s, 1H), 7.09 (d, 7 = 4.8 Hz, 1H), 7.01

[0403] (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),

[0404] 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 -

[0405] 1.88 (m, 5H), 1.63 (s, 6H), 1.47 (dd, 7= 24.0, 11.3 Hz, 2H).[M+H]+= 819.6.

[0406] Example 062: N7-(2-((lR,4r)-4-(4-(l-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-

[0407] 3-yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[l,2-b]pyridazine-3,7- dicarboxamide

[0408] The title compound (8.5 mg, 23.21%) was prepared in a manner similar to that described in Example 029.1HNMR (500 MHz, DMSO) 5 12.07 (s, 1H), 10.86 (s, 1H), 8.90 (d, 7= 2.1 Hz, 1H), 8.70 (d, 7= 2.1 Hz, 1H), 8.54 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.65 (d, 7 = 4.6 Hz, 2H), 7.57 (s, 1H), 6.97 (d, 7= 4.7

[0409] 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, 7 = 12.5, 4.9 Hz, 1H),

[0410] 3.91 (t, 7 = 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,

[0411] 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),

[0412] 1.54 - 1.43 (m, 2H).[M+H]+= 823.6.

[0413] Example 063: N7-(2-((lr,4r)-4-(4-(l-(6-(2,6-dioxopiperidin-3-yl)-2-methylpyridin-3-yl)piperidin-4- yl)piperazin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[l,2-b]pyridazine-3,7- dicarboxamide The title compound (31mg, 27.61%) was prepared in a manner similar to that described in Example 029. 'H NMR (500 MHz, DMSO) 5 12.08 (s, 1H), 10.78 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.70 (d, 7 = 2.1 Hz, 1H), 8.54 (s, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 7.65 (d, J = 4.6 Hz, 2H), 7.57 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.10 (d, 7 = 8.2 Hz, 1H), 6.97 (d, 7 = 4.7 Hz, 1H), 5.73 (s, 1H), 4.42 (t, 7= 11.4 Hz, 1H), 3.89 (dd, 7= 9.3, 5.3 Hz, 1H), 3.11 (d, 7 = 10.3 Hz, 2H), 2.65 - 2.52 (m, 12H), 2.42 - 2.35 (m, 4H), 2.33 - 2.25 (m, 1H), 2.24 - 2.14 (m, 3H), 2.12 - 2.04 (m, 1H), 2.00 - 1.85 (m, 6H), 1.64 (s, 6H), 1.57 (dd, 7 = 23.0, 13.1 Hz, 2H), 1.48 (dd, 7 = 23.1, 11.0 Hz, 2H).[M+H]+= 830.6.

[0414] Example 058: ethyl 2-(5-((S)-l-(5-(4-((4-((lr,4r)-4-(5-(3-cyanopyrrolo[l,2-b]pyridazine-7- carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazin-l-yl)methyl)piperidin-l- yl)pyridin-3-yl)piperidine-3-carboxamido)-2-oxopyridin-l(2H)-yl)acetate

[0415] Step 1: ethyl (S)-2-(5-(l-(5-(4-(1.3-dioxolan-2-yl)piperidin-l-yl)pyridin-3-yl)piperidine-3- c arboxamido) -2 - oxopyridin- 1 (2H) - yl) acet ate

[0416] To a solution of ethyl (S)-2-(5-(l-(5-bromopyridin-3-yl)piperidine-3-carboxamido)-2-oxopyridin- l(2H)-yl)acetate (CAS 2991251-11-5) (500 mg, 1.1 mmol, obtained through the same method of WO2023192586A1) in 1,4-dioxane (30 mL) was added 4-(l,3-dioxolan-2-yl)piperidine hydrochloride (590.7 mg, 3.3 mmol), Pd2(dba)3(202mg, 0.22mmol), ruphos (202mg, 0.43 mmol) and CS2CO3 (2.15g, 6.6 mmol). The mixture was stirred for overnight at 90°C under N2. The mixture was cooled to rt and concentrated under vacuum. To the residue was added H2O (50ml) and extracted with DCM(50ml * 3). The organic layer was dried over with Na2SC>4 and filtered to give the crude product which was further purified by combi flash, eluting with MeOH : DCM = 0 - 1: 10 to yield product (460 mg, 77%). [M+H]+= 540.3.

[0417] Step 2: ethyl (S)-2-(5-(l-(5-(4-formylpiperidin-l-yl)pyridin-3-yl)piperidine-3-carboxamido)-2- oxopyridin- 1 (2H)-yl)acetate

[0418] A solution of ethyl (S)-2-(5-(l-(5-(4-(l,3-dioxolan-2-yl)piperidin-l-yl)pyridin-3-yl)piperidine-3- carboxamido)-2-oxopyridin-l(2H)-yl)acetate (200 mg, 0.37 mmol) in HC1(2N, in H2O) (10 mL) was stirred for 2 hours at r.t. The mixture was adjusted to pH 9 with sat.Na2CO3 solution and extracted with DCM. The combined organic layer was dried over anhydrous Na2SC>4, filtered and evaporated in vacuum to afford crude product which was further purified by combi flash, eluting with MeOH : DCM = 0 - 1:10 to yield product (100 mg, 54%) [M+H]+= 496.2.

[0419] Step 3: ethyl 2-(5-((S)-l-(5-(4-((4-((lr,4r)-4-(5-(3-cyanopyrrolori,2-b1pyridazine-7-carboxamido)-6- (2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazin- 1 -yl)methyl)piperidin- 1 -yl)pyridin-3- yl)piperidine-3-carboxamido)-2-oxopyridin- 1 (2H)-yl)acetate

[0420] A solution of 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((lr,4r)-4-(piperazin-l-yl)cyclohexyl)-2H- indazol-5-yl)pyrrolo[l,2-b]pyridazine-7-carboxamide (20 mg, 0.04 mmol) and ethyl (S)-2-(5-(l-(5-(4- formylpiperidin-l-yl)pyridin-3-yl)piperidine-3-carboxamido)-2-oxopyridin- l(2H)-yl) acetate (20 mg, 0.04 mmol) in DCE (6 mL) was stirred at room temperature for 0.5 hours, then NaBH(OAc)s (10 mg, 0.048 mmol) was added portion wise. The solution was stirred at room temperature for another 2 hours. Then the mixture was purified with Combi-Flash (silica column, 4 g, DCM:MeOH=10:l) to yield the product (2 mg, 5.26%).

[0421] 'H NMR (500 MHz, DMSO)8 12.02 (s, 1H), 9.80 (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), 8.19 (d, J= 5.0 Hz, 1H), 7.75-7.71 (m, 3H), 7.57 (s, 1H), 7.47 - 7.44 (m, 1H), 7.10 (d, J= 5.0 Hz, 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.

[0422] Example 051: 3-cyano-N-(2-((lr,4r)-4-(4-((3-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)prop-2-yn-l-yl)oxy)piperidin-l-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)pyrrolo[l,2-b]pyridazine-7-carboxamide

[0423] The title compound was prepared in a manner similar to that described in Example 029.

[0424] 'H NMR (500 MHz, DMSO)8 12.02 (s, 1H), 11.00 (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), 8.19 (d, J= 5.0 Hz, 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.

[0425] Biological Assays

[0426] IRAK4 Degradation Assay of Karpas299

[0427] IRAK4 degradation was measured using a TR-FRET-based method (Degorce, Francois, et al. Current chemical genomics. 2009, 3: 22). Karpas299 maintained in RPMI 1640 medium (Thermo Scientific) supplemented with 20% fetal bovine serum (FBS, Thermo Scientific), 100 units / mL penicillin and 0.1 mg / mL streptomycin (Thermo Scientific) were seeded into 96-well plates at the density of 0.2 million cells per well and then treated with a series dilution of compounds. After 24 hours treatment, cells were pelleted via centrifugation and 40 pL lysis buffer (Cisbio) was added to each well after removal of the supernatant. Plates were then incubated at room temperature with shaking for 30 minutes. A total of 16 pL of cell lysates from each well of a 96-well plate was transferred to a 384-well white assay plate. IRAK4 level was quantitated using the HTRF kit as described by the manufacturer manual (Cisbio). FRET signals were measured using a PHERAstar FSX reader (BMG Labtech).

[0428] IRAK4 Degradation Assay of PBMC

[0429] IRAK4 degradation was measured using a TR-FRET-based method (Degorce, Francois, et al. Current chemical genomics. 2009, 3: 22). PBMC 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 into 96-well plates at the density of 0.5 million cells per well and then treated with a series dilution of compounds. After 24 hours treatment, cells were pelleted via centrifugation and 40 pL lysis buffer (Cisbio) was added to each well after removal of the supernatant. Plates were then incubated at room temperature with shaking for 30 minutes. A total of 16 pL of cell lysates from each well of a 96-well plate was transferred to a 384-well white assay plate. IRAK4 level was quantitated using the HTRF kit as described by the manufacturer manual (Cisbio). FRET signals were measured using a PHERAstar FSX reader (BMG Labtech).

[0430] IRAK4 Degradation Assay of Karpas299 Spiked in Human Serum

[0431] IRAK4 degradation was measured using a TR-FRET-based method (Degorce, Francois. et al. Current chemical genomics. 2009, 3: 22). Karpas299 resuspended in Human serum AB(GEMINI, 100- 512) were seeded into 96-well plates at the density of 0.2 million cells per well and then treated with a series dilution of compounds. After 24 hrs treatment, cells were pelleted via centrifugation and washed with PBS, add 40 pL lysis buffer (Cisbio) to each well after removal of the supernatant. Plates were then incubated at room temperature with shaking for 30 minutes. A total of 16 pL of cell lysates from each well of a 96-well plate was transferred to a 384-well white assay plate. IRAK4 level was quantitated using the HTRF kit as described by the manufacturer manual (Cisbio). FRET signals were measured using a PHERAstar FSX reader (BMG Labtech).

[0432] IRAK4 Degradation Assay of PBMC Spiked in Human Serum

[0433] IRAK4 degradation was measured using a TR-FRET-based method (Degorce, Franqois, et al. Current chemical genomics. 2009, 3: 22). PBMC resuspended in Human serum AB(GEMINI, 100-512) were seeded into 96-well plates at the density of 0.5 million cells per well and then treated with a series dilution of compounds. After 24 hrs treatment, cells were pelleted via centrifugation and washed with PBS, add 40 pL lysis buffer (Cisbio) to each well after removal of the supernatant. Plates were then incubated at room temperature with shaking for 30 minutes. A total of 16 pL of cell lysates from each well of a 96-well plate was transferred to a 384-well white assay plate. IRAK4 level was quantitated using the HTRF kit as described by the manufacturer manual (Cisbio). FRET signals were measured using a PHERAstar FSX reader (BMG Labtech).

[0434] IL-6 Production Assay in Human PBMC

[0435] Frozen human PBMC (AllCells) were thawed in RPMI 1640 medium (Thermo Scientific) supplemented with 10% heat-inactivated FBS (Thermo Scientific) and recovered at 37 °C overnight. The next day, PBMC were seeded into 96-well plates at the density of 0.2 million cells per well and treated with compounds for 24 h. Then lipopolysaccharide was added at the final concentration of 10 ng / mL for 5 h. Culture supernatant was collected for subsequent measurement of IL-6 concentration by a TR-FRET- based method (Degorce, Francois, et al. Current chemical genomics. 2009, 3: 22) as described by the manufacturer manual (Cisbio). FRET signals were measured with PHERAstar FSX reader (BMG Lab tech).

[0436] HTRF assay

[0437] After treatment, add HTRF lysis buffer to each well ; seal the plate and incubate 1 hour at room temperature on a plate shaker; Once the cells are lysed, 16 pL of cell lysate are transferred to a PE 384- well HTRF detection plate; 4 pL of pre-mixed HTRF antibodies are added to each well ; Cover the plate with a plate sealer, spin 1000 rpm for 1 min, Incubate overnight at room temperature; Read on BMG PheraStar with HTRF protocol (337nm-665nm-620nm).

[0438] The inhibition (degradation) percentage of the compound was calculated by the following equation: Inhibition percentage of Compound = 100-100 x (Signal-low control) / (High control-low control), wherein signal = each test compound group

[0439] Low control = only lysis buffer without cells, indicating that IRAK4 is completely degraded;

[0440] High control = Cell group with added DMSO and without compound, indicating microplate readings without IRAK4 degradation;

[0441] Dmax is the maximum percentage of inhibition (degradation).

[0442] The IC50 (DC50) value of a compound can be obtained by fitting the following equation

[0443] Y = Bottom + (TOP-Bottom) / (1 + ((IC50 / X)Ahillslope))

[0444] Wherein, X and Y are known values, and IC50, Hillslope, Top and Bottom are the parameters obtained by fitting with software. Y is the inhibition percentage (calculated from the equation), X is the concentration of the compound; IC50 is the concentration of the compound when the 50% inhibition is reached. The smaller the IC50 value is, the stronger the inhibitory ability of the compound is. Vice versa, the higher the IC50 value is, the weaker the ability the inhibitory ability of the compound is; Hillslope represents the slope of the fitted curve, generally around 1 *; Bottom represents the minimum value of the curve obtained by data fitting, which is generally 0% ± 20%; Top represents the maximum value of the curve obtained by data fitting, which is generally 100% ± 20%. The experimental data were fitted by calculating and analyzing with Dotmatics data analysis software.

[0445] It is to be understood that, if any prior art publication is referred to herein; such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country.

[0446] The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.

[0447] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

What is claimed is:

1. A compound of formula (X)or a N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof, wherein:Y1and Y9are each independently selected from C N O or S; Y2Y3Y4Y5Y6Y7and Y8are each independently selected from C or N; provided thatare each aromatic ring; si is 0, 1 or 2; s2 is 0, 1, 2 or 3;R1and R2are each independently hydrogen, halogen, -C1-C8alkyl, -C3-C8cycloalkyl, -CN, -ORlaor - NRlaRlb; each of -C1-C8alkyl or -C3-C8cycloalkyl is optionally substituted with at least one substituent Rlc;Rlaand Rlbare each independently selected from hydrogen, -C1-C8alkyl, -C1-C8haloalkyl, C1-C8alkoxy-C1-C8alkyl- or C;-C\cycloalkyl; each of-C1-C8alkyl, -C1-C8haloalkyl, C1-C8alkoxy- C1-C8alkyl- or Ch-Cxcycloalkyl is optionally substituted with at least one substituent selected from halogen, -OH, -CN, oxo (=O), -C1-C8alkyl-OH or -C3-C8cycloalkyl;Rlc, at each occurrence, is independently halogen, -OH, -CN, oxo (=0), -C1-C8alkyl, -Ci- Qhaloalkyl, -C:-C\cycloalkyl, -C1-C8alkoxy or Ci-Qalkoxy-C1-C8alkyl-;Rlla, Rllb, R12aand R12bare each independently hydrogen, halogen, -C1-8alkyl, -Ci-salkoxy or -C3 scycloalkyl; each of said -Ci-salkyl, -C1-8alkoxy or -C3 scycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -Ci-galkoxy, -OH or -CN;L2is selected from -C1-8alkylcnc-, -C2-8alkenylene-, -C2-8alkynylene-,substituted with at least one RL2c;wherein *L3refers to the position attached to theeach of said RL1C, RL2cand RL3care independently oxo (=0), halogen, hydroxy, -CN, -C -Qalkyl, - C i-C'xalkoxy; each of said -C i-C'xalkyl or -C1-C8alkoxy is optionally substituted with at least one RLca,RLcais independently oxo (=O), halogen, hydroxy, -CN, -C1-C8alkoxy or C3-C8cycloalkyl;( Degron J' is E3 ubiquitin ligase binding moiety; at each occurrence, X1and X2are each independently selected from -CRa, or N; at each occurrence, X3and X4are each independently selected from -NRa-, -O-, -S- and -CRaRb-; at each occurrence, X5and X6are each independently selected from absent, single bond, -C(O)-, -NRa- and -O-; at each occurrence, Raand Rbare each independently selected from hydrogen or -Ci-C4alkyl; ml and m3 are each independently 0, 1 or 2; m2 is 0 or 1 ; nl, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3.o - or amino acid residue;Z1and Z2are each independently N or CRZ;Rz, and R13, at each occurrence, are each independently selected from hydrogen, halogen, -C1-4alkyl or CN;L4is selected from a single bond, -O-, -NRa-, or -C(O)NRa-;L5and L6are each independently selected from a single bond, -O-, -NRa- or -C(O)-; at each occurrence, Raand Rcare each independently selected from hydrogen or -C1-C4alkyl; and n6 is each independently 0, 1, 2 or 3.

3. The compound of Claim 1, wherein the compound is selected from formula (Ila),4. The compound of Claim 1, wherein the compound is selected from formula (Illa), (Illb), (IIIc),5. The compound of Claim 1, wherein the compound is selected from formula (IVa), (IVb), (IVc),6. The compound of Claim 1, wherein the compound is selected from formula (Va)The compound of Claim 1 wherein the compound is selected from formula (Via)8. The compound of anyone of the preceding Claims, wherein themoiety is9. The compound of anyone of the preceding Claims, wherein themoiety is12. The compound of anyone of the preceding Claims, wherein R1and R2are each independently hydrogen, halogen, -Ci-C3alkyl. -CN or -0Rla; said -C1-C8alkyl is optionally substituted with at least one substituent Rlc;Rlais independently selected from hydrogen or -C1-C8alkyl; said -C1-C8alkyl is optionally substituted with at least one substituent selected from halogen, -OH, -CN or -Ci-C» alkyl- OH;Rlc, at each occurrence, is independently halogen, -OH, -CN, oxo (=0), -C1-C8alkyl, -Ci- Cshaloalkyl or -C1-C8alkoxy.

13. The compound of anyone of the preceding Claims, wherein, R1and R2are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, -CN or -0Rla; each of said methyl, ethyl, propyl, butyl or pentyl is optionally substituted with at least one substituent Rlc;Rlais independently selected from hydrogen, methyl, ethyl, propyl, butyl or pentyl; each of said methyl, ethyl, propyl, butyl or pentyl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, -OH, -CN, -C1-C8alkyl-OH;Rlc, at each occurrence, is independently -F, -Cl, -Br, -I, -OH, -CN, oxo (=0), methyl, ethyl, propyl, butyl, pentyl, -C1-C8haloalkyl or -C1-C8alkoxy.

14. The compound of anyone of the preceding Claims, wherein,, R1and R2are each independently16. The compound of anyone of the preceding Claims, wherein Rlla, Rllb, R12aand R12bare each 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; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, -C1-8alkoxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy or -CN.

17. The compound of anyone of the preceding Claims, wherein Rlla, Rllb, R12aand R12bare each 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 of anyone of the preceding Claims, wherein Rlla, Rllb, R12aand R12bare each independently hydrogen.

19. The compound of anyone of the preceding Claims, wherein the20. The compound of any one of the preceding claims, wherein L1is selected frompentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,RLcais independently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

21. The compound of any one of the preceding claims, wherein L1is selected from is optionally substituted with at least one RL1C;each of said RLlcis independently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,RLcais independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.each of said RL2cis independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,RLcais independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

25. The compound of any one of the preceding claims, wherein L2is selected fromeach of said RL2cis independently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,RLcais independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

26. The compound of any one of the preceding claims, wherein L2is selected from27. The compound of any one of the preceding claims, wherein L2is selected fromsubstituted with at least one RL3c; each of said RL3cis independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,RLca jsindependently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;Rais selected from hydrogen, methyl, ethyl, propyl or butyl.

29. The compound of any one of the preceding claims, wherein L3is selected from -O-, -C(O)NRa-,each of said RL3cis independently oxo (=O), F, Cl, Br, I, hydroxy, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy or octyloxy is optionally substituted with at least one RLca,RLcais independently oxo (=0), F, Cl, Br, I, hydroxy, -CN, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl;Rais selected from hydrogen, methyl, ethyl, propyl or butyl.

30. The compound of any one of the preceding claims, wherein L3is selected from -O-, -N(CH3)-, -33. The compound of any one of the preceding claims, wherein34. The compound of any one of the preceding claims, wherein L4is independently selected from a single bond, -O-, -NRa- or -C(O)NRa-; at each occurrence, Rais independently selected from hydrogen, methyl, ethyl, propyl or butyl.

35. The compound of any one of the preceding claims, wherein L4is independently selected from a single bond, -NH- or -C(O)NH-.

36. The compound of any one of the preceding claims, wherein at most one of Z1and Z2is N.

37. The compound of any one of the preceding claims, wherein Z1and Z2are each independently CRZ;Rz, at each occurrence, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl or CN.

38. The compound of any one of the preceding claims, wherein Rzis selected from H, -CH3, -F or - Cl.

39. The compound of any one of the preceding claims, wherein R13is selected from hydrogen, -F, - Cl, -Br, -I, methyl, ethyl, propyl, butyl or CN.

40. The compound of any one of the preceding claims, wherein R13is selected from H, -CH3, -F or - CL41. The compound of any one of the preceding claims, wherein L5and L6are each independently selected from a single bond, -O-, -NRa- or -C(O)-;Rais independently selected from hydrogen, methyl, ethyl, propyl or butyl.

42. The compound of any one of the preceding claims, wherein L5and L6are each independently a single bond, -O-, -NH-, -NMe-, or -NCCEfcCHs)-.

43. The compound of any one of the preceding claims, wherein L5is -CO-, and L6is -NH- or - NMe-.( Degron]44. The compound of any one of the preceding claims, wherein is45. The compound of any one of the preceding claims, whereinis amino acid residue.

46. The compound of any one of the preceding claims, whereinis Lysine amide; moreIZI49. A pharmaceutical composition comprising a compound of any one of Claims 1-48 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, together with a pharmaceutically acceptable excipient.

50. A method of treating a disease that can be affected by IRAK4 modulation, comprises administrating a subject in need thereof an effective amount of a compound 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 disease and Inflammatory disorders, preferred Systemic Lupus, Hidradenitis suppurativa, Rheumatoid arthritis, Arthritis, Gout, Multiple sclerosis, Psoriasis and cancer, preferred Acute myeloid leukemia Cancer, Lymphoma, B-cell Myelodysplasia.

52. Use of a compound of any one of Claims 1-48 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof in the preparation of a medicament for treating a disease that can be affected by IRAK4 modulation.

53. The use of Claim 52, wherein the disease is cancer, preferred pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

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