Degradation of IRAK4 by conjugation of IRAK4 inhibitors to E3 ligase ligands and methods of use

Abstract

Disclosed herein are novel bifunctional compounds formed by conjugating an IRAK4 inhibitor moiety to an E3 ligase ligand moiety, the function of these bifunctional compounds being to recruit a target protein to an E3 ubiquitin ligase for degradation, as well as methods of making and uses thereof.

Description

Technical Field

[0001] Disclosed herein are novel bifunctional compounds formed by conjugating an IRAK4 inhibitor moiety to an E3 ligase ligase moiety, and methods for their preparation and use. These bifunctional compounds function to recruit target proteins to E3 ubiquitin ligases for degradation. Background Art

[0002] Proteolysis targeting chimeras (PROTACs) consist of two covalently linked protein-binding molecules: one capable of binding to an E3 ubiquitin ligase and the other capable of binding to a protein of interest (POI) (target for degradation) (Sakamoto KM et al., Proc. Natl. Acad. Sci. [Proceedings of the National Academy of Sciences of the United States of America] 2001, 98: 8554-9.; Sakamoto KM et al., Methods Enzymol. [Enzymology Methods] 2005; 399: 833-847). Recruiting the E3 ligase to a specific unwanted protein does not inhibit the enzymatic activity of the target protein, but rather leads to ubiquitination and subsequent degradation of the target protein by the proteasome. The entire process of ubiquitination and proteasomal degradation is called the ubiquitin-proteasome pathway (UPP) (Ardley H. et al., Essays Biochem. 2005, 41, 15-30; Komander D. et al., Biochem. 2012, 81, 203-229; Grice GL et al., Cell Rep. 2015, 12, 545-553; Swatek KN et al., Cell Res. 2016, 26, 399-422; Lydia M. et al., ACS Infect. Dis. 2019, 5, 12, 2105-2117). The proteasome is a protein complex that degrades unwanted, misfolded, or abnormal proteins into small peptides and amino acids to maintain cell health and productivity. Ubiquitin ligases, also known as E3 ubiquitin ligases, directly catalyze the transfer of ubiquitin from E2 to target proteins for degradation. Although the human genome encodes more than 600 putative E3 ligases, only a limited number of E3 ubiquitin ligases have been widely used by small molecule PROTAC technology: cerebellin (CRBN), Von Hippel-Lindau (VHL), mouse double minute 2 homolog (MDM2) and cell inhibitor of apoptosis protein (cIAP) (Philipp O. et al., Chem. Biol. [Chemistry and Biology] 2017, 12, 2570-2578), recombinant human RING finger protein 114 (RNF114) (Spradlin, JN et al. Nat. Chem. Biol. [Nature Chemical Biology] 2019, 15, 747-755) and DDB1 and CUL4-associated factor 16 (DCAF16) (Zhang, X. et al. Nat. Chem. Biol. [Nature Chemical Biology] 2019, 15, 737-746).For example, cerebellum protein (CRBN) forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cullin-4A (CUL4A) to ubiquitinate many other proteins, which are then degraded by the proteasome (Yi-An Chen et al., Scientific Reports 2015, 5, 1-13). Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, act as monovalent promoters of PPIs by binding to the cerebellum protein (CRBN) subunit of the CRL4ACRBN E3 ligase complex and recruiting new substrate proteins (Matyskiela, ME et al., Nat ChemBiol 2018, 14, 981-987). Therefore, the ability of thalidomide and its derivatives to recruit CRBN has been widely used in studies related to proteolysis targeting chimeras (PROTACs) (Christopher T. et al. ACSChem.Biol. [American Chemical Society Chemical Biology] 2019, 14, 342-347; Honorine L. et al., ACSCent.Sci. [American Chemical Society Core Science] 2016, 2, 927-934). PROTACs have great potential in eliminating protein targets that are "ineffective" against traditional inhibitors or as protein targets of non-enzymatic proteins (Chu TT. et al., Cell Chem Biol. [Cell Chemistry Biology] 2016; 23: 453-461. Qin C. et al., J Med Chem [Journal of Medicinal Chemistry] 2018; 61: 6685-6704; Winter GE. et al., Science [Science] 2015; 348: 1376-1381).In recent years, PROTACs have been reported as useful modulators that promote the selective degradation of various target proteins in anti-tumor studies (Lu J. et al., Chem Biol. 2015; 22(6):755-763; Ottis P. et al., Chem Biol. 2017; 12(4):892-898.; Crews CM et al., J Med Chem. 2018; 61(2):403-404; Neklesa TK et al., Pharmacol Ther. 2017, 174:138-144.; Cermakova K. et al., Molecules, 2018. 23(8).; An S. et al., EBioMedicine, 2018.; Lebraud H. et al., Essays Biochem. [Biochemistry Short Review] 2017; 61(5): 517-527.; Sun Y.H. et al., Cell Res. [Cell Research] 2018; 28: 779-81; Touré M. et al., Angew Chem Int Ed Engl. [Applied Chemistry-English International Edition] 2016; 55(6): 1966-1973; Yonghui Sun et al., Leukemia [Leukemia], Vol. 33, pp. 2105-2110 (2019); Shaodong Liu et al., Medicinal Chemistry Research [Medicinal Chemistry Research], Vol. 29, pp. 802-808 (2020)); and has been disclosed or discussed in patent publications, such as US20160045607, US20170008904, US20180050021, US20180072711, WO 2002020740、WO2014108452、WO 2016146985、WO 2016149668、WO 2016197032、WO 2016197114、WO2017011590、WO 2017030814、WO 2017079267、WO 2017182418, WO 2017197036, WO2017197046, WO 2017197051, WO 2017197056, WO 2017201449, and WO 2018071606.

[0003] Interleukin-1 receptor-associated kinases (IRAK1, IRAK2, IRAK3, and IRAK4) are serine-threonine kinases that regulate innate immunity and inflammatory responses. In addition to performing normal kinase functions, IRAK4 also has a protein scaffold function and regulates downstream signaling through the myddosome protein complex. Activation of TLRs or IL-1R initiates receptor dimerization and recruits the myeloid differentiation primary response 88 (MyD88) adaptor protein through its intracellular domain. MyD88 further recruits IRAK4 and IRAK1 / 2 to form a multiprotein complex, the myddosome. The interaction between MyD88 and IRAK4 first recruits preformed IRAK-1. IRAK4 then phosphorylates and activates IRAK-1. Fully activated IRAK-1 recruits the TRAF6-TAK1-TAB-1 / 2 complex. Activated TAK-1 phosphorylates downstream signaling cascades, including IκB kinase (IKK)-nuclear factor-κB (NF-κB) and MAPKs, such as c-Jun N-terminal kinase (JNK) and p38, leading to the production of proinflammatory cytokines (including IL-1β, IL-6, IL-8, IL-12, TNF). These signaling pathways play a crucial role in innate and adaptive immunity (Elizabeth L. et al., Eur. J. Immunol. [European Journal of Immunology] 2008, 38, 3, 870-876.).

[0004] The pro-inflammatory effects of IRAK4 have been confirmed by studies of IRAK4 kinase-dead knock-in mice (W. Michael S. et al., ACS Med. Chem. Lett. [American Chemical Society Medicinal Chemistry Communications] 2015, 6, 942-947). Mice with this genotype are resistant to joint inflammation in several rodent arthritis models (Koziczak-Holbro et al., 2009, Arthritis & rheumatism [Arthritis and Rheumatism]). IRAK4 deficiency can improve disease activity in multiple RA animal models. In addition, a small group of IRAK4-deficient people has been identified. Reduced expression of pro-inflammatory cytokines from macrophages and reduced inflammation and migration of fibroblast-like synoviocytes were observed. Cells from these patients have impaired responses to ILR / TLR receptor stimulation. No serious viral, fungal, or parasitic infections were observed in these adult patients (Gosu, V. et al., Sci Rep 4, 2014, 5748; Shichijo K. et al., Pediatrics International, 2015). These data in rodents and humans suggest that IRAK4 inhibitors can modulate the production of key inflammatory cytokines and cytokine-induced pathologies.

[0005] However, it has been reported that although IRAK4 phosphorylation levels were reduced in IL-1β-stimulated human dermal fibroblasts, pharmacological inhibition of IRAK4 did not result in IL-6 and TNF-α inhibition, suggesting that kinase activity may not be the only factor in some cell types (O'Neill, L.A. Immunol. Rev. [Immunol. Rev.] 2008, 226, 10-8; Nunes J. et al. ACSM Med. Chem. Lett. [ACS Med. Chem. Lett.] 2019, 10, 1081). Therefore, in addition to inhibiting kinase activity, removing the IRAK4 scaffold function may provide better therapeutic effects. In this regard, PROTACs targeting IRAK4 can serve as a potential strategy to target both IRAK4 kinase activity and scaffold function. IRAK4 PROTACs may ultimately bring new therapeutic opportunities for the treatment of autoimmune diseases, inflammatory diseases, and tumor diseases. The following patents disclose or discuss IRAK4 PROTACs: WO2019133531, US20190192668, WO 2019099926, WO 2020113233, WO 2020264499, WO2021158634, WO 2020264490, WO 2021119159, WO 2021168197, and WO 2021127278.

[0006] Several PROTACs targeting IRAK4 have been recently published (Nunes J. et al. ACS Med. Chem. Lett. 2019, 10, 1081; Zhang et al. Cell Chem. Bio. 2020, 27, 1.; Robert BK et al. ACS Med. Chem. Lett. 2019, 10, 1251). Most of these molecules are based on published IRAK4 inhibitors as warheads. However, there is little data showing that IRAK4 PROTACs have a stronger inhibitory effect on cytokine production (such as IL-6 and TNF-α) than IRAK4 kinase inhibitors. In the following invention, carefully designed IRAK4 PROTACs have been shown to reduce proinflammatory cytokines more than small molecule inhibitors in multiple cell lines.

[0007] The present application provides novel bifunctional compounds and compositions for treating autoimmune diseases, inflammatory diseases and tumor diseases. Summary of the Invention

[0008] In one embodiment, disclosed herein are bifunctional compounds of formula (I) that can selectively degrade IRAK4. The compounds described herein or their salts can be used to treat diseases that can be affected by IRAK4 regulation. The present invention provides the use of compounds described herein or their pharmaceutically acceptable salts in the manufacture of medicaments for treating diseases that can be affected by IRAK4 regulation. The present invention further provides compounds described herein or their pharmaceutically acceptable salts for treating diseases that can be affected by IRAK4 regulation. The present application further provides a method for treating a proliferative disorder, the method comprising administering a therapeutically effective amount of a compound described herein or its pharmaceutically acceptable salt to a subject in need. This embodiment comprises the following aspects:

[0009] Aspect 1. A compound having formula (X)

[0010]

[0011] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof,

[0012] in:

[0013] L x yes *Lx -CONH- **Lx or *Lx -NHCO- **Lx ,in* Lx refers to the position of attachment to the Cy2 moiety, and ** Lx refers to the position of attachment to the Cy3 moiety;

[0014] Cy1 is a 6-membered partially or fully unsaturated ring; the ring is substituted by at least one R 1 replace;

[0015] Y 1 、Y 2 and Y 3 are each independently C or N;

[0016] s1 is 0, 1, 2, 3, 4, or 5;

[0017] Cy2 is a 5-, 6-, 7-, 8-, 9- or 10-membered partially or fully unsaturated ring (aromatic ring); said ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; said ring is substituted by at least one substituent R 2 replace;

[0018] s2 is 0, 1, or 2;

[0019] s4 is 0 or 1;

[0020] Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring being substituted by at least one substituent R 3 replace;

[0021] s3 is 0, 1, 2, 3, 4, or 5;

[0022] R 1 、R 2 and R 3 Each is independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a 、-C(O)R 1a 、-CO2R 1a 、-C(O)NR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b or -NR 1a CO2R 1b -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 1c replace; or

[0023] When adjacent, two R 1 , two R 2 or two R 3 Together with the atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring optionally substituted with at least one substituent R 1c replace;

[0024] R 1a and R 1b Each is independently selected from hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C8 alkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl;

[0025] R 1c , independently at each occurrence is halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 aryl or 5- to 12-membered heteroaryl;

[0026] R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c and R 12d are each independently absent, oxo, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Cycloalkyl; the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally substituted by at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; or

[0027] R 11a and R 12a Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0028] R 11b and R 12bTogether with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0029] R 11c and R 12c Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0030] R 11d and R 12d Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituent substitution;

[0031] Every time it appears, L 1 Independently selected from -O-, -NR a -、-C(O)NR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L1c replace;

[0032] in* L1 is attached to the Part of the location, and ** L1 is attached to the the location of the part;

[0033] Every time it appears, L 2 Independently selected from -O-, -NR a-、-CONR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L2c replace;

[0034] in* L2 is attached to the Part of the location, and ** L2 is attached to the the location of the part;

[0035] Every time it appears, L 3 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L3c replace;

[0036] in* L3 is attached to the Part of the location, and ** L3 is attached to the the location of the part;

[0037] The R L1c 、R L2c and R L3c Each of them is independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5 to 12 membered heteroaryl; the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted by at least one R Lca replace,

[0038] R Lca are independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl; or

[0039] Two R's L1c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0040] Two R's L2c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0041] Two R's L3c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0042] Selected from

[0043] Z 1 、Z 2 and Z 3 Each independently is N or CR z , the condition is Z 1 、Z 2 and Z 3 Not at the same time N;

[0044] R z , at each occurrence, is independently selected from absence, hydrogen, halogen, -C 1-8 Alkyl, -NR Za R Zb 、-OR Za 、-SR Za , C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl or CN; -C 1-8 Each of the alkyl group, the C3-C8 cycloalkyl group, and the 3- to 8-membered heterocyclic group is optionally substituted by at least one R Zc replace;

[0045] Partially via Z 1 、Z 2or Z 3 Connect any one of Part of which CR z and R z does not exist;

[0046] R Za and R Zb Each is independently selected from the group consisting of: absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl, or 5 to 12 membered heteroaryl, the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl, or 5 to 12 membered heteroaryl groups is optionally substituted by at least one R Zd Substituent substitution;

[0047] R Zc and R Zd are independently halogen, hydroxy, -C1-C8 alkyl, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0048] R 13 and R 14 are each independently selected from the group consisting of absence, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a SO2R 13b ;-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13c SO2R 13d replace;

[0049] At each occurrence, R 13a 、R 13b 、R 13c and R 13d are each independently absent, hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0050] L 4 、L 5 and L 6 are each independently selected from absence, a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-;

[0051] At each occurrence, X 1 、X 2 and X 7 Each independently selected from -CR a or N;

[0052] At each occurrence, X 3 、X 4 and X 8 Each independently selected from -NR a -, -O-, -S-, and -CR a R b -;

[0053] At each occurrence, X 5 and X 6 Each independently selected from absence, a single bond, -C(O)-, -NR a -and-O-;

[0054] Q 1 , Q 2 , Q 3 and Q 4 Each independently selected from CR a or N;

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

[0056] R a and R b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituted group halogen, hydroxyl, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl or 5- to 12-membered heteroaryl;

[0057] m1, m2, m3 and m4 are each independently 0, 1 or 2;

[0058] m5 and m7 are each independently 0 or 1;

[0059] m6 is 0, 1 or 2; when m6 is 2, the two L2s are the same or different;

[0060] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0061] n6, n7 and n8 are each independently 0, 1, 2, 3 or 4.

[0062] Aspect 2. A compound having formula (I)

[0063]

[0064] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof,

[0065] in:

[0066] Cy1 is a 6-membered partially or fully unsaturated ring; the ring is substituted by at least one R 1 replace;

[0067] Y 1 、Y 2 and Y 3 are each independently C or N;

[0068] s1 is 0, 1, 2, 3, 4, or 5;

[0069] Cy2 is a 5-, 6-, 7-, 8-, 9- or 10-membered partially or fully unsaturated ring (aromatic ring); said ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; said ring is substituted by at least one substituent R 2 replace;

[0070] s2 is 0, 1, or 2;

[0071] s4 is 0 or 1;

[0072] Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring being substituted by at least one substituent R 3 replace;

[0073] s3 is 0, 1, 2, 3, 4, or 5;

[0074] R 1 、R 2 and R 3 Each is independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a 、-C(O)R 1a 、-CO2R 1a 、-C(O)NR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b or -NR 1a CO2R 1b -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 1c replace; or

[0075] When adjacent, two R 1 , two R 2 or two R 3 Together with the atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring optionally substituted with at least one substituent R 1c replace;

[0076] R 1a and R 1b Each is independently selected from hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C8 alkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl;

[0077] R 1c , independently at each occurrence is halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12aryl or 5- to 12-membered heteroaryl;

[0078] R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c and R 12d are each independently absent, oxo, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Cycloalkyl; the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally substituted by at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; or

[0079] R 11a and R 12a Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0080] R 11b and R 12b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0081] R 11c and R 12c Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0082] R 11d and R 12d Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituent substitution;

[0083] Every time it appears, L 1 Independently selected from -O-, -NR a -、-C(O)NR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L1c replace;

[0084] in* L1 is attached to the Part of the location, and ** L1 is attached to the the location of the part;

[0085] Every time it appears, L 2 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L2c replace;

[0086] in* L2 is attached to the Part of the location, and **L2 is attached to the the location of the part;

[0087] Every time it appears, L 3 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L3c replace;

[0088] in* L3 is attached to the Part of the location, and ** L3 is attached to the the location of the part;

[0089] The R L1c 、R L2c and R L3c Each of them is independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5 to 12 membered heteroaryl; the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted by at least one R Lca replace,

[0090] R Lca are independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl; or

[0091] Two R's L1c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0092] Two R's L2c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0093] Two R's L3c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0094] Selected from

[0095] Z 1 , Z 2 and Z 3 Each independently is N or CR z , the condition is Z 1 , Z 2 and Z 3 Not at the same time N;

[0096] R z , at each occurrence, is independently selected from absence, hydrogen, halogen, -C 1-8 Alkyl, -NR Za R Zb 、-OR Za 、-SR Za , C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl or CN; -C 1-8 Each of the alkyl group, the C3-C8 cycloalkyl group, and the 3- to 8-membered heterocyclic group is optionally substituted by at least one R Zc replace;

[0097] Partially via Z 1 , Z 2 or Z 3 Connect any one of Part of which CR z and R z does not exist;

[0098] R Za and R Zb Each is independently selected from the group consisting of: absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl, or 5 to 12 membered heteroaryl, the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12Each of the aryl, or 5 to 12 membered heteroaryl groups is optionally substituted by at least one R Zd Substituent substitution;

[0099] R Zc and R Zd are independently halogen, hydroxy, -C1-C8 alkyl, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0100] R 13 and R 14 are each independently selected from the group consisting of absence, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a SO2R 13b ;-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13c SO2R 13d replace;

[0101] At each occurrence, R 13a 、R 13b 、R 13c and R 13d are each independently absent, hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0102] L 4 、L 5 and L 6 are each independently selected from absence, a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-;

[0103] At each occurrence, X 1 、X 2 and X 7 Each independently selected from -CR a or N;

[0104] At each occurrence, X 3 、X 4 and X 8 Each independently selected from -NR a -, -O-, -S-, and -CR a R b -;

[0105] At each occurrence, X 5 and X 6 Each independently selected from absence, a single bond, -C(O)-, -NR a -and-O-;

[0106] Q 1 , Q 2 , Q 3 and Q 4 Each independently selected from CR a or N;

[0107] At each occurrence, R a and R b Each is independently selected from hydrogen, hydroxy, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 Aryl or 5 to 12 membered heteroaryl, the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 Each of the aryl or 5 to 12 membered heteroaryl groups is optionally substituted by at least one halogen, hydroxyl, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C8 alkyl, -C8-C8 alkynyl, -C3-C8 cycloalkyl, -C6-C8 alkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl substituents; or

[0108] R a and R b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituted group halogen, hydroxyl, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl or 5- to 12-membered heteroaryl;

[0109] m1, m2, m3 and m4 are each independently 0, 1 or 2;

[0110] m5 and m7 are each independently 0 or 1;

[0111] m6 is 0, 1 or 2; when m6 is 2, the two L2s are the same or different;

[0112] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0113] n6, n7 and n8 are each independently 0, 1, 2, 3 or 4.

[0114] Aspect 3. A compound having formula (I')

[0115]

[0116] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof,

[0117] in:

[0118] Cy1 is a 6-membered partially or fully unsaturated ring; the ring is substituted by at least one R 1 replace;

[0119] Y 1 、Y 2 and Y 3 are each independently C or N;

[0120] s1 is 0, 1, 2, 3, 4, or 5;

[0121] Cy2 is a 5-, 6-, 7-, 8-, 9- or 10-membered partially or fully unsaturated ring (aromatic ring); said ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; said ring is substituted by at least one substituent R 2 replace;

[0122] s2 is 0, 1, or 2;

[0123] s4 is 0 or 1;

[0124] Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring being substituted by at least one substituent R 3 replace;

[0125] s3 is 0, 1, 2, 3, 4, or 5;

[0126] R 1 、R 2 and R 3 Each is independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a 、-C(O)R 1a 、-CO2R 1a 、-C(O)NR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b or -NR 1a CO2R 1b -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 1c replace; or

[0127] When adjacent, two R 1 , two R 2 or two R 3 Together with the atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring optionally substituted with at least one substituent R 1c replace;

[0128] R 1a and R 1b Each is independently selected from hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C8 alkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl;

[0129] R 1c , independently at each occurrence is halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 aryl or 5- to 12-membered heteroaryl;

[0130] R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c and R 12d are each independently absent, oxo, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8Cycloalkyl; the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally substituted by at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; or

[0131] R 11a and R 12a Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0132] R 11b and R 12b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0133] R 11c and R 12c Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0134] R 11d and R 12d Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8Alkoxy or -CN substituent substitution;

[0135] Every time it appears, L 1 Independently selected from -O-, -NR a -、-C(O)NR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L1c replace;

[0136] in* L1 is attached to the Part of the location, and ** L1 is attached to the the location of the part;

[0137] Every time it appears, L 2 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L2c replace;

[0138] in* L2 is attached to the Part of the location, and ** L2 is attached to the the location of the part;

[0139] Every time it appears, L 3 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L3c replace;

[0140] in* L3is attached to the Part of the location, and ** L3 is attached to the the location of the part;

[0141] The R L1c 、R L2c and R L3c Each of them is independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5 to 12 membered heteroaryl; the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted by at least one R Lca replace,

[0142] R Lca are independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl; or

[0143] Two R's L1c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0144] Two R's L2c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0145] Two R's L3c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0146] Selected from

[0147] Z 1 、Z 2 and Z 3Each independently is N or CR z , the condition is Z 1 , Z 2 and Z 3 Not at the same time N;

[0148] R z , at each occurrence, is independently selected from absence, hydrogen, halogen, -C 1-8 Alkyl, -NR Za R Zb 、-OR Za 、-SR Za , C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl or CN; -C 1-8 Each of the alkyl group, the C3-C8 cycloalkyl group, and the 3- to 8-membered heterocyclic group is optionally substituted by at least one R Zc replace;

[0149] Partially via Z 1 , Z 2 or Z 3 Connect any one of Part of which CR z and R z does not exist;

[0150] R Za and R Zb Each is independently selected from the group consisting of: absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl, or 5 to 12 membered heteroaryl, the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl, or 5 to 12 membered heteroaryl groups is optionally substituted by at least one R Zd Substituent substitution;

[0151] R Zc and R Zd are independently halogen, hydroxy, -C1-C8 alkyl, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0152] R 13 and R 14 are each independently selected from the group consisting of absence, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a SO2R 13b ;-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13c SO2R 13d replace;

[0153] At each occurrence, R 13a 、R 13b 、R 13c and R 13d are each independently absent, hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0154] L 4 、L 5 and L 6 are each independently selected from absence, a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-;

[0155] At each occurrence, X 1 、X 2 and X 7 Each independently selected from -CR a or N;

[0156] At each occurrence, X 3 、X 4 and X 8 Each independently selected from -NR a -, -O-, -S-, and -CR a R b -;

[0157] At each occurrence, X 5 and X 6 Each independently selected from absence, a single bond, -C(O)-, -NR a -and-O-;

[0158] Q 1 , Q 2 , Q 3 and Q 4 Each independently selected from CR a or N;

[0159] At each occurrence, R a and R b Each is independently selected from hydrogen, hydroxy, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 Aryl or 5 to 12 membered heteroaryl, the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12Each of the aryl or 5 to 12 membered heteroaryl groups is optionally substituted by at least one halogen, hydroxyl, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C8 alkyl, -C8-C8 alkynyl, -C3-C8 cycloalkyl, -C6-C8 alkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl substituents; or

[0160] R a and R b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituted group halogen, hydroxyl, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl or 5- to 12-membered heteroaryl;

[0161] m1, m2, m3 and m4 are each independently 0, 1 or 2;

[0162] m5 and m7 are each independently 0 or 1;

[0163] m6 is 0, 1 or 2; when m6 is 2, the two L2s are the same or different;

[0164] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0165] n6, n7 and n8 are each independently 0, 1, 2, 3 or 4.

[0166] Aspect 4. The compound according to aspect 1, wherein the compound is selected from the group consisting of formula (IIa), (IIa'), (IIb), (IIb'), (IIc), (IIc'), (IId), (IId'), (IIe) and (IIe'),

[0167]

[0168]

[0169]

[0170] where R 1 、R 2 、R 3 、R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R12c 、R 12d , L 1 , L 2 , L 3 , s1, s2, s3, m1, m2, m3, m4, m5, m6, m7, Cy2, Cy3, degradation determinants are as defined in aspect 1.

[0171] Aspect 5. The compound of Aspect 1, wherein the compound is selected from Formula (IIIa), (IIIa'), (IIIb), (IIIb'), (IIIc), (IIIc'), (IIId), (IIId'), (IIIe), (IIIe'), (IIIf), (IIIf'), (IIIg), (IIIg'), (IIIh), (IIIh'), (IIIi), (IIIi'), (IIIj), (IIIj'), (IIIk), (IIIk'), (IIIl) or (IIIl'):

[0172]

[0173]

[0174]

[0175]

[0176] where R 1 、R 2 、R 3 、R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c 、R 12d 、Y 1 、Y 2 、Y 3 , L 1 , L 2 , L 3 , s1, s2, s3, m1, m2, m3, m4, m5, m6, m7, Cy1, Cy3, degradation determinants are as defined in aspect 1.

[0177] 4. The compound according to aspect 1, wherein the compound is selected from the group consisting of formula (IVa), (Iva'), (IVb), (IVb'), (IVc) and (IVc'),

[0178]

[0179] where R1 、R 2 、R 3 、R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c 、R 12d 、Y 1 、Y 2 、Y 3 、Cy1、Cy2、L 1 、L 2 、L 3 , s1, s2, s3, s4, ml, m2, m3, m4, m5, m6, m7 and degradation determinants are as defined in aspect 1.

[0180] 5. The compound according to aspect 1, wherein the compound is selected from formula (Va) or (Va')

[0181]

[0182] Preferably, the compound is selected from the group consisting of formula (Vb), (Vb'), (Vc), and (Vc'),

[0183]

[0184] More preferably, the compound is selected from the group consisting of formula (Vd), (Vd'), (Ve) and (Ve'),

[0185]

[0186]

[0187] More preferably, the compound is selected from the group consisting of Formula (Vf), (Vf'), (Vg), (Vg'), (Vh), (Vh'), (Vi), (Vi'), (Vj), (Vj'), (Vk), (Vk'), (Vl), (Vl'), (Vm), (Vm'), (Vn), (Vn'), (Vo), (Vo'), (Vp), (Vp'), (Vq) or (Vq'),

[0188]

[0189]

[0190]

[0191]

[0192] Even more preferably, the compound is selected from the group consisting of formula (Vr), (Vr'), (Vs), (Vs'), (Vt), (Vt'), (Vu), (Vu'), (Vv), (Vv'), (Vw), (Vw'), (Vx), (Vx'), (Vy), (Vy'), (Vz), (Vz'), (Vaa), (Vaa'), (Vab), (Vab'), (Vac) or (Vac'),

[0193]

[0194]

[0195]

[0196]

[0197] Among them, Y 4 、Y 7 、Y 8 、Y 9 、Y 10 、Y 11 、Y 12 、Y 13 、Y 14 、Y 15 、Y 16 and Y 17 are each independently selected from C or N; Y 5 and Y 6 are independently selected from C, N, O or S; provided that It is an aromatic ring;

[0198] Among them, R 2 、R 3 、R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c 、R 12d 、L 1 、L 2 、L 3 , s2, s3, ml, m2, m3, m4, m5, m6, m7 and degradation determinants are as defined in aspect 1.

[0199] Aspect 6. The compound according to aspect 1, wherein the compound is selected from formula (VIa) or (Via')

[0200]

[0201] Preferably, the compound is selected from (VIb) or (VIb),

[0202]

[0203] Among them, Y 1 、Y 2 、Y 3 、Cy1、Cy2、Cy3、R 1 、R 2 、R 3 、R 11b 、R 11c 、R 11d 、R 12b 、R 12c 、R 12d 、L 1 、L 2 、L 3 , s1, s2, s3, s4, m2, m3, m4, m5, m6, m7 and degradation determinants are as defined in aspect 1.

[0204] Aspect 7. The compound according to any one of the preceding aspects, wherein Y 1 、Y 2 and Y 3 At least one of is N; preferably, Y 1 It's N, Y 2 and Y 3 C; or Y 2 It's N, Y 1 and Y 3 C; or Y 3 It's N, Y 1 and Y 2 It’s C.

[0205] Aspect 8. The compound of any one of the preceding aspects, wherein Cy1 is pyridyl or pyridonyl.

[0206] Aspect 9. The compound according to any one of the preceding aspects, wherein Partly Preferably, Partly

[0207] Aspect 10. The compound according to any one of the preceding aspects, wherein the Partly

[0208]

[0209] in* Cy2 is attached to the Part of the location, and ** Cy2 is attached to the the location of the part;

[0210] Preferably, Partly

[0211] Aspect 11. A compound as described in any of the preceding aspects, wherein Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring is substituted with at least one substituent R 3 replace;

[0212] In one embodiment, Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring, wherein each of the 5- and 6-membered aromatic rings is a monocyclic ring, each of the 8-, 9-, or 10-membered aromatic rings is a bicyclic ring, and the 7-membered aromatic ring is a monocyclic or bicyclic ring.

[0213] Preferably, Cy3 is a 5- or 9-membered aromatic ring; said ring contains 0, 1, 2 or 3 heteroatoms independently selected from nitrogen; said ring is substituted by at least one substituent R 3 replace;

[0214] Even more preferably, yes

[0215] in* Cy3 is attached to the Part of the location, and ** Cy3 is attached to the the location of the part;

[0216] Even more preferably, yes

[0217] Aspect 12. The compound according to any one of the preceding aspects, wherein R 1 、R 2 and R 3 are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a 、-C(O)R 1a 、-CO2R 1a 、-C(O)NR 1a R 1b 、-NR1a R 1b 、-NR 1a COR 1b or -NR 1a CO2R 1b ; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl is optionally substituted with at least one substituent R 1c replace,

[0218] R 1a and R 1b each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C1-C8 haloalkyl (preferably -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3), -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C1-C8 haloalkyl (preferably -CH2F, -CHF2, -C Each of -F, -CH2CH2F, -CH2CHF2, -CH2CF3), -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH2OH, -C2H4OH, -C3H6OH, -C4H8OH, -C5H 10 OH, -C6H 12 OH, -C7H 14 OH, -C8H 16 OH, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl;

[0219] R 1c is independently at each occurrence -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0220] Aspect 13. The compound according to any one of the preceding aspects, wherein R 1 、R 2 and R 3 are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, oxo (=O), -CN, -OR 1a or -C(O)NR 1a R 1b 、-NR 1a R 1b ; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3 to 8 membered heterocyclic radicals is optionally substituted with at least one substituent R 1c replace,

[0221] R 1a and R 1b each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH2OH, -C2H4OH, -C3H6OH, -C4H8OH, -C5H 10 OH, -C6H 12 OH, -C7H 14 OH, -C8H 16 each of OH, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl;

[0222] R 1c , independently at each occurrence is -F, -Cl, -Br, -I, -OH;

[0223] Preferably, R 1 、R 2 and R 3Each is independently H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CF3, -CF2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH3)2, -CHF2, oxo (=O), -CN, cyclopropyl, -CONH2, -OMe, -OEt, -OCH2CH2CH3, -OCH(CH3)2,

[0224] Even more preferably, R 1 is H, -CH3, -CH2CH3, -CF3, -CF2CH3, -CH(CH3)2, -C(CH3)3, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH3)2, oxo (=O), cyclopropyl,

[0225] R 2 is H, -CF3, cyclopropyl, oxo (=O), -F, -Cl, -Br, -I or -CN;

[0226] R 3 is H, -CH3, oxo (=O), -CHF2, -CONH2, -OMe, -OCD3, -OEt, -OCH2CH2CH3, -OCH(CH3)2,

[0227] Aspect 14. The compound according to any one of the preceding aspects, wherein both R 3 Together with the atoms to which they are attached, they form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring optionally substituted with at least one substituent R 1c replace;

[0228] R 1c is independently at each occurrence -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0229] Preferably, the two R 3 Together with the atoms to which they are attached, they form a 3-, 4-, 5-, or 6-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from oxygen; said ring optionally substituted with at least one substituent R1c replace;

[0230] R 1c , is independently at each occurrence -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0231] Aspect 15. The compound according to any one of the preceding aspects, wherein R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c and R 12d are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted by at least one radical selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or -CN is substituted; or

[0232] (R 11a and R 12a )、(R 11b and R 12b )、(R 11c and R 12c ) or (R 11d and R 12d ) together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 The alkylene group is substituted with an alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or -CN substituent.

[0233] Aspect 16. The compound according to any one of the preceding aspects, wherein Partly

[0234] Aspect 17. The compound according to any one of the preceding aspects, wherein the Partly

[0235]

[0236]

[0237] Preferably, the Partly

[0238] Aspect 18. The compound according to any one of the preceding aspects, wherein R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c and R 12d are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; preferably, R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c and R 12d are each independently hydrogen, F, Cl, Br, I, methyl, ethyl or propyl; more preferably, R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c and R 12d are each independently hydrogen or methyl; or

[0239] (R 11a and R 12a )、(R 11b and R 12b )、(R 11c and R 12c ) or (R11d and R 12d ) together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; preferably, (R 11a and R 12a )、(R 11b和 R 12b )、(R 11c and R 12c ) or (R 11d and R 12d ) together with the carbon atoms to which they are attached form a 3-, 4-, or 5-membered cycloalkyl ring.

[0240] Aspect 19. The compound according to any one of the preceding aspects, wherein L 1 Selected from -O-, -N(R a )-、

[0241] wherein Each of which is optionally replaced by at least one R L1c replace;

[0242] The R L1c wherein each of the groups is independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, —C2-C8 alkenyl, —C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; and wherein each of the groups is optionally substituted by at least one R Lca replace,

[0243] R Lcais independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or

[0244] Two R's L1c together with the carbon atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl substituent;

[0245] R a selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl substituent.

[0246] Aspect 20. The compound according to any one of the preceding aspects, wherein L 1 Selected from -O-, -N(CH3)-,

[0247]

[0248]

[0249]

[0250]

[0251] Aspect 21. The compound according to any one of the preceding aspects, wherein L 2 Selected from -O-, -N(R a )-、

[0252]

[0253] wherein Each of which is optionally replaced by at least one R L2c replace;

[0254] The R L2c wherein each of the groups is independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, —C2-C8 alkenyl, —C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; and wherein each of the groups is optionally substituted by at least one R Lca replace,

[0255] R Lca is independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or

[0256] Two R's L2c Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl substituent;

[0257] R aselected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl substituent.

[0258] Aspect 22. The compound of any one of the preceding aspects, wherein L 2 Selected from -O-, -N(CH3)-,

[0259]

[0260]

[0261]

[0262] Aspect 23. The compound according to any one of the preceding aspects, wherein the Partly Preferably, the Partly

[0263] More preferably, the Partly

[0264]

[0265] Aspect 24. The compound of any one of the preceding aspects, wherein L 3 Selected from -O-, -N(R a )-、

[0266] wherein Each of which is optionally replaced by at least one R L3c replace;

[0267] The R L3c wherein each of the groups is independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, —C2-C8 alkenyl, —C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; and wherein each of the groups is optionally substituted by at least one R Lca replace,

[0268] R Lca is independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or

[0269] Two R's L3c Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl substituent;

[0270] R aselected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl substituent.

[0271] Aspect 25. The compound of any one of the preceding aspects, wherein L 3 Selected from -O-, -N(CH3)-, -NH-,

[0272]

[0273]

[0274]

[0275] Aspect 26. The compound according to any one of the preceding aspects, wherein Partially selected

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] Preferably, Partially selected

[0282]

[0283]

[0284]

[0285]

[0286] Aspect 27. The compound of any one of the preceding aspects, wherein L 4 are independently selected from a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-;

[0287] At each occurrence, R a and R b each independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 each of -C-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl is optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl substituent.

[0288] Aspect 28. The compound of any one of the preceding aspects, wherein L 4 are independently selected from a single bond or -NH-.

[0289] Aspect 29. The compound according to any one of the preceding aspects, wherein X 7 Independently selected from -CR a or N;

[0290] Ra independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 Each of the -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl substituent.

[0291] Aspect 30. The compound of any one of the preceding aspects, wherein X 7 Independently selected from -CH, -C(CH3), or N; preferably, X 7 are independently selected from -CH.

[0292] Aspect 31. The compound according to any one of the preceding aspects, wherein X 8 Independently selected from -NR a -, -O-, -S-, and -CR a R b -;

[0293] At each occurrence, R a and R beach independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 each of -C-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl is optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl substituent.

[0294] Aspect 32. The compound of any one of the preceding aspects, wherein X 8 are independently selected from -NH- and -CH2-; preferably, X 8 are independently selected from -CH2-.

[0295] Aspect 33. The compound according to any one of the preceding aspects, wherein Selected from Preferably, Selected from

[0296] More preferably, Selected from

[0297] Aspect 34. The compound of any one of the preceding aspects, wherein Z 1 , Z 2 and Z 3 At most one of them is N.

[0298] Aspect 35. The compound of any one of the preceding aspects, wherein Z 1 , Z 2 and Z 3 Each is independently CR z .

[0299] Aspect 36. The compound of any one of the preceding aspects, wherein R Z , at each occurrence, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR Za R Zb 、-OR Za 、-SR Za , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl or CN; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3 to 8 membered heterocyclyl is optionally replaced by at least one R Zc replace;

[0300] R Za and R Zb R is each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, each of which is optionally replaced by at least one R Zd Substituent substitution;

[0301] R Zc and R Zd Each is independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

[0302] Aspect 37. The compound of any one of the preceding aspects, wherein R z Selected from H, -CH3, -C2H5, F, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -C3H7, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, -CF3 or -CH(OH)CH3.

[0303] Aspect 38. The compound of any one of the preceding aspects, wherein R 13 and R 14each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a SO2R 13b ; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally replaced by F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d, or -NR 13c SO2R 13d replace;

[0304] R 13a 、R 13b 、R 13c and R 13d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl, or 5- to 12-membered heteroaryl.

[0305] Aspect 39. The compound of any one of the preceding aspects, wherein R 13 and R 14 Each is independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, or phenyl.

[0306] Aspect 40. The compound of any one of the preceding aspects, wherein yes

[0307] Aspect 41. A compound according to any one of the preceding aspects, wherein L 5 and L 6 Each independently selected from a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-;

[0308] X 8 Yes-CR a R b -;

[0309] At each occurrence, R a and R beach independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 each of -C-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl is optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl substituent.

[0310] Aspect 42. The compound of any one of the preceding aspects, wherein L 5 and L 6 are each independently a single bond, -O-, -NH-, -NMe-, -N(CH2CH3)-, -CH2-, -CHF-, -CF2-, -C(CH3)2- or -CO- (preferably, L 5 is -CO- or -CH2-, and L 6 yes -O-, -NH-, -NMe-, -N(CH2CH3)-, -CH2-, -CHF-, -CF2-, -C(CH3)2-, or -CO-);

[0311] X 8 is CH2; and

[0312] n6 is 0 or 1.

[0313] Aspect 43. A compound as described in any of the preceding aspects, wherein R 13 independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a SO2R 13b ; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally replaced by F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13c SO2R 13d replace;

[0314] At each occurrence, R 13a 、R 13b 、R 13c and R 13dare each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl, or 5- to 12-membered heteroaryl.

[0315] Aspect 44. The compound of any one of the preceding aspects, wherein R 13 are independently selected from hydrogen, F, Cl, Br, I, CN, -C1-C8 alkyl, or -C1-C8 alkoxy; preferably, R 13 independently selected from hydrogen, F, Cl, Br, I, CN, -Me, -Et, -C3H7, -C4H9, -OMe, -OEt, -OC3H7 or -OC4H9;

[0316] n7 is 0, 1, or 2.

[0317] Aspect 45. The compound of any one of the preceding aspects, wherein yes

[0318]

[0319]

[0320] Aspect 46. The compound of any one of the preceding aspects, wherein the compound is selected from

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363] Aspect 47. A pharmaceutical composition comprising a compound according to any one of aspects 1 to 45 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

[0364] Aspect 48. A method of treating a disease that can be affected by IRAK4 modulation, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of aspects 1-45, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

[0365] Aspect 49. The method according to aspect 47, wherein the disease is selected from autoimmune diseases and inflammatory disorders, preferably systemic lupus, hidradenitis suppurativa, rheumatoid arthritis, arthritis, gout, multiple sclerosis, psoriasis and cancer, preferably acute myeloid leukemia, cancer, lymphoma, B-cell myelodysplasia.

[0366] Aspect 50. Use of a compound according to any one of aspects 1-45, 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.

[0367] Aspect 51. The use according to aspect 49, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0368] The present inventors surprisingly found that a linker such as between an IRAK4 binding moiety and an E3 ligase ligand moiety Some of the compounds disclosed herein confer increased degradation activity to other compounds, indicating that these compounds can efficiently degrade the target protein (here, IRAK4 protein). 50 The value is less than 20 nm, preferably less than 10 nm, more preferably less than 5 nm, 3 nm, 2 nm or 1 nm; D max The value is greater than 60%, preferably greater than 70% or 80%.

[0369] In preferred linkers, m1, m2, m3 and m4 are each independently 0, 1 or 2; m5 and m7 are each independently 0 or 1; and m6 is 0, 1 or 2; preferably, m1 and m2 are 0; m3 and m4 are each independently 0, 1 or 2; m5 and m7 are each independently 1; and m6 is 1 or 2. More preferably, the Partly Among them, L 1 Selected from -O-, -N(R a )-、 wherein Each of which is optionally replaced by at least one R L1c replace;

[0370] The R L1c wherein each of the groups is independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, —C2-C8 alkenyl, —C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; and wherein each of the groups is optionally substituted by at least one R Lca replace,

[0371] R Lca is independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or

[0372] Two R's L1ctogether with the carbon atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl substituent;

[0373] R a is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally is substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl substituent; preferably, L 1 Selected from -O-, -N(CH3)-,

[0374]

[0375]

[0376] Among them L 2 Selected from -O-, -N(R a )-、 wherein Each of which is optionally replaced by at least one R L2c replace;

[0377] The R L2cwherein each of the groups is independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, —C2-C8 alkenyl, —C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; and wherein each of the groups is optionally substituted by at least one R Lca replace,

[0378] R Lca is independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or

[0379] Two R's L2c Together with the carbon atoms to which they are attached, they form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl substituent;

[0380] R a is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally is substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl substituent; preferably, L 2Selected from -O-, -N(CH3)-,

[0381]

[0382]

[0383] Even more preferably, the Partly

[0384] More preferably, Partly

[0385] In one embodiment, a compound having formula (X)

[0386]

[0387] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof,

[0388] in:

[0389] L x yes *Lx -CONH- **Lx or *Lx -NHCO- **Lx ,in* Lx refers to the position of attachment to the Cy2 moiety, and ** Lx refers to the position of attachment to the Cy3 moiety;

[0390] Cy1 is a 6-membered partially or fully unsaturated ring; the ring is substituted by at least one R 1 replace;

[0391] Y 1 、Y 2 and Y 3 are each independently C or N;

[0392] s1 is 0, 1, 2, 3, 4, or 5;

[0393] Cy2 is a 5-, 6-, 7-, 8-, 9- or 10-membered partially or fully unsaturated ring (aromatic ring); said ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; said ring is substituted by at least one substituent R 2 replace;

[0394] s2 is 0, 1, or 2;

[0395] s4 is 0 or 1;

[0396] Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring being substituted by at least one substituent R 3 replace;

[0397] s3 is 0, 1, 2, 3, 4, or 5;

[0398] R 1 、R 2 and R 3 Each is independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a 、-C(O)R 1a 、-CO2R 1a 、-C(O)NR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b or -NR 1a CO2R 1b -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 1c replace; or

[0399] When adjacent, two R 1 , two R 2 or two R 3 Together with the atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring optionally substituted with at least one substituent R 1c replace;

[0400] R 1a and R 1b Each is independently selected from hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12Aryl or 5- to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C8 alkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl;

[0401] R 1c , independently at each occurrence is halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 aryl or 5- to 12-membered heteroaryl;

[0402] R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c and R 12d are each independently absent, oxo, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Cycloalkyl; the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally substituted by at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; or

[0403] R 11a and R 12a Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0404] R 11b and R 12b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0405] R 11c and R 12c Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0406] R 11d and R 12d Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituent substitution;

[0407] Every time it appears, L 1 Independently selected from -O-, -NR a -、-C(O)NR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L1c replace;

[0408] in* L1 is attached to the Part of the location, and ** L1 is attached to the the location of the part;

[0409] Every time it appears, L2 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L2c replace;

[0410] in* L2 is attached to the Part of the location, and ** L2 is attached to the the location of the part;

[0411] Every time it appears, L 3 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L3c replace;

[0412] in* L3 is attached to the Part of the location, and ** L3 is attached to the the location of the part;

[0413] The R L1c 、R L2c and R L3c Each of them is independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5 to 12 membered heteroaryl; the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted by at least one R Lca replace,

[0414] R Lcaare independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl; or

[0415] Two R's L1c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0416] Two R's L2c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0417] Two R's L3c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0418] Selected from

[0419] Z 1 、Z 2 and Z 3 Each independently is N or CR z , the condition is Z 1 、Z 2 and Z 3 Not at the same time N;

[0420] R z , at each occurrence, is independently selected from absence, hydrogen, halogen, -C 1-8 Alkyl, -NR Za R Zb 、-OR Za 、-SR Za , C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl or CN; -C 1-8 Each of the alkyl group, the C3-C8 cycloalkyl group, and the 3- to 8-membered heterocyclic group is optionally substituted by at least one R Zc replace;

[0421] Partially via Z 1 、Z 2 or Z 3 Connect any one of Part of which CR z and R z does not exist;

[0422] R Za and R Zb Each is independently selected from the group consisting of: absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl, or 5 to 12 membered heteroaryl, the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl, or 5 to 12 membered heteroaryl groups is optionally substituted by at least one R Zd Substituent substitution;

[0423] R Zc and R Zd are independently halogen, hydroxy, -C1-C8 alkyl, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0424] R 13 and R 14 are each independently selected from the group consisting of absence, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a SO2R 13b ;-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with halogen, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13c SO2R 13d replace;

[0425] At each occurrence, R 13a 、R 13b 、R 13c and R 13d are each independently absent, hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0426] L 4 、L 5 and L 6 are each independently selected from absence, a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-;

[0427] At each occurrence, X 1 、X 2 and X 7 Each independently selected from -CR a or N;

[0428] At each occurrence, X3 、X 4 and X 8 Each independently selected from -NR a -, -O-, -S-, and -CR a R b -;

[0429] At each occurrence, X 5 and X 6 Each independently selected from absence, a single bond, -C(O)-, -NR a -and-O-;

[0430] Q 1 , Q 2 , Q 3 and Q 4 Each independently selected from CR a or N;

[0431] At each occurrence, R a and R b Each is independently selected from hydrogen, hydroxy, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 Aryl or 5 to 12 membered heteroaryl, the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 Each of the aryl or 5 to 12 membered heteroaryl groups is optionally substituted by at least one halogen, hydroxyl, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C8 alkyl, -C8-C8 alkynyl, -C3-C8 cycloalkyl, -C6-C8 alkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl substituents; or

[0432] R a and R b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituted group halogen, hydroxyl, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl or 5- to 12-membered heteroaryl;

[0433] m1, m2, m3 and m4 are each independently 0, 1 or 2;

[0434] m5 and m7 are each independently 0 or 1;

[0435] m6 is 0, 1 or 2; when m6 is 2, the two L2s are the same or different;

[0436] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0437] n6, n7 and n8 are each independently 0, 1, 2, 3 or 4.

[0438] In one embodiment, a compound having formula (I')

[0439]

[0440] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof,

[0441] in:

[0442] Cy1 is a 6-membered partially or fully unsaturated ring; the ring is substituted by at least one R 1 replace;

[0443] Y 1 、Y 2 and Y 3 are each independently C or N;

[0444] s1 is 0, 1, 2, 3, 4, or 5;

[0445] Cy2 is a 5-, 6-, 7-, 8-, 9- or 10-membered partially or fully unsaturated ring (aromatic ring); said ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; said ring is substituted by at least one substituent R 2 replace;

[0446] s2 is 0, 1, or 2;

[0447] s4 is 0 or 1;

[0448] Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring being substituted by at least one substituent R 3 replace;

[0449] s3 is 0, 1, 2, 3, 4, or 5;

[0450] R 1 、R 2 and R 3 Each is independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a 、-C(O)R 1a 、-CO2R 1a 、-C(O)NR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b or -NR 1a CO2R 1b -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 1c replace; or

[0451] When adjacent, two R 1 , two R 2 or two R 3 Together with the atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring optionally substituted with at least one substituent R 1c replace;

[0452] R 1a and R 1b Each is independently selected from hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C8 alkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl;

[0453] R 1c , independently at each occurrence is halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 aryl or 5- to 12-membered heteroaryl;

[0454] R 11a 、R 11b 、R 11c 、R 11d 、R 12a 、R 12b 、R 12c and R 12d are each independently absent, oxo, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Cycloalkyl; the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally substituted by at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; or

[0455] R 11a and R 12a Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0456] R 11b and R 12b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0457] R 11c and R 12c Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or

[0458] R 11d and R 12d Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituent substitution;

[0459] Every time it appears, L 1 Independently selected from -O-, -NR a -、-C(O)NR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L1c replace;

[0460] in* L1 is attached to the Part of the location, and ** L1 is attached to the the location of the part;

[0461] Every time it appears, L 2 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L2c replace;

[0462] in* L2 is attached to the Part of the location, and ** L2 is attached to the the location of the part;

[0463] Every time it appears, L 3 Independently selected from -O-, -NR a -、-CONR a-、-C(O)O-、 wherein Each of which is optionally replaced by at least one R L3c replace;

[0464] in* L3 is attached to the Part of the location, and ** L3 is attached to the the location of the part;

[0465] The R L1c 、R L2c and R L3c Each of them is independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5 to 12 membered heteroaryl; the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted by at least one R Lca replace,

[0466] R Lca are independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl; or

[0467] Two R's L1c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0468] Two R's L2c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0469] Two R's L3cTogether with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxy, or -C1-C8 alkyl;

[0470] Selected from

[0471] Z 1 , Z 2 and Z 3 Each independently is N or CR z , the condition is Z 1 , Z 2 and Z 3 Not at the same time N;

[0472] R z , at each occurrence, is independently selected from absence, hydrogen, halogen, -C 1-8 Alkyl, -NR Za R Zb 、-OR Za 、-SR Za , C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl or CN; -C 1-8 Each of the alkyl group, the C3-C8 cycloalkyl group, and the 3- to 8-membered heterocyclic group is optionally substituted by at least one R Zc replace;

[0473] Partially via Z 1 , Z 2 or Z 3 Connect any one of Part of which CR z and R z does not exist;

[0474] R Za and R Zb Each is independently selected from the group consisting of: absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl, or 5 to 12 membered heteroaryl, the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Each of the aryl, or 5 to 12 membered heteroaryl groups is optionally substituted by at least one R Zd Substituent substitution;

[0475] R Zc and R Zd are independently halogen, hydroxy, -C1-C8 alkyl, -C 1-8Alkoxy, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0476] R 13 and R 14 are each independently selected from the group consisting of absence, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a SO2R 13b ;-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13cSO2R 13d replace;

[0477] At each occurrence, R 13a 、R 13b 、R 13c and R 13d are each independently absent, hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 aryl, or 5- to 12-membered heteroaryl;

[0478] L 4 , L 5 and L 6 are each independently selected from absence, a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-;

[0479] At each occurrence, X 1 、X 2 and X 7 Each independently selected from -CR a or N;

[0480] At each occurrence, X 3 、X 4 and X 8 Each independently selected from -NR a -, -O-, -S-, and -CR a R b -;

[0481] At each occurrence, X 5 and X 6 Each independently selected from absence, a single bond, -C(O)-, -NR a -and-O-;

[0482] Q 1 , Q 2 , Q 3 and Q 4 Each independently selected from CR a or N;

[0483] At each occurrence, R aand R b Each is independently selected from hydrogen, hydroxy, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 Aryl or 5 to 12 membered heteroaryl, the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 Each of the aryl or 5 to 12 membered heteroaryl groups is optionally substituted by at least one halogen, hydroxyl, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C8 alkyl, -C8-C8 alkynyl, -C3-C8 cycloalkyl, -C6-C8 alkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl substituents; or

[0484] R a and R b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituted group halogen, hydroxyl, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 substituted with aryl or 5- to 12-membered heteroaryl;

[0485] m1, m2, m3 and m4 are each independently 0, 1 or 2;

[0486] m5 and m7 are each independently 0 or 1;

[0487] m6 is 0, 1 or 2; when m6 is 2, the two L2s are the same or different;

[0488] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0489] n6, n7 and n8 are each independently 0, 1, 2, 3 or 4. DETAILED DESCRIPTION

[0490] The following terms have the indicated meanings throughout this specification:

[0491] As used herein, including the appended aspects, singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0492] Unless the context clearly indicates otherwise, the term "or" means and is used interchangeably with the term "and / or."

[0493] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing from 1 to 18 (e.g., from 1 to 12, further such as from 1 to 10, further such as from 1 to 8, or from 1 to 6, or from 1 to 4) carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0494] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups (including fused, bridged, or spiro cycloalkyl groups). In one embodiment, the "cycloalkyl" is a "-C3-C8 cycloalkyl," "-C3-C8 cycloalkyl," "-C3-C8 cycloalkyl," or "-C3-C8 cycloalkyl" as described in the specification or claims. 12 any of "cycloalkyl", "cyclopropyl", "cyclobutyl", "cyclopentyl", "cyclohexyl", "cycloheptyl" or "cyclooctyl".

[0495] The term "aryl" used alone or in combination with other terms refers to a group selected from:

[0496] 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0497] Bicyclic ring systems (eg, 7- to 12-membered bicyclic ring systems) in which at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0498] A tricyclic ring system (eg, a 10- to 15-membered tricyclic ring system) in which at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0499] In one embodiment, the "aryl" is a "C6-C 12 Any of "aryl".

[0500] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0501] The term "aryl-alkyl-" refers to an alkyl group as defined above that is further substituted with an aryl group. Examples of aryl-alkyl groups include aryl-C 1-8 Alkyl, such as phenylethyl, or phenylmethyl (benzyl).

[0502] The term "heteroaryl" refers to a group selected from:

[0503] a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one (e.g., from 1 to 4, or in some embodiments from 1 to 3, in some embodiments from 1 to 2 heteroatoms) heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), the remaining ring atoms being carbon;

[0504] 7- to 12-membered bicyclic rings containing at least one heteroatom (e.g., 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, and the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0505] An 11- to 14-membered tricyclic ring containing at least one heteroatom (e.g., 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, and the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0506] In one embodiment, the “heteroaryl” is any of the “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 claims.

[0507] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When the heteroaryl group contains more than one heteroatom ring member, these heteroatoms can be the same or different. The nitrogen atom in one or more rings of the heteroaryl group can be oxidized to form an N-oxide. As used herein, the term "C-connected heteroaryl" means that the heteroaryl group is connected to the core molecule through a bond of a C atom of the heteroaryl ring.

[0508] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure herein. In certain embodiments, monocyclic or bicyclic aromatic heterocycles have 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulphur (S) and oxygen (O), and the remaining ring members are carbon. In certain embodiments, monocyclic or bicyclic aromatic heterocycles are monocyclic or bicyclic rings comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulphur (S) and oxygen (O). In certain embodiments, monocyclic or bicyclic aromatic heterocycles are 5 to 6 yuan heteroaryl rings, which are monocyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulphur (S) and oxygen (O). In certain embodiments, monocyclic or bicyclic aromatic heterocycles are 8 to 10 yuan heteroaryl rings, which are bicyclic and have 1 or 2 heteroatom ring members independently selected from nitrogen, sulphur and oxygen.

[0509] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro rings, i.e., monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclyl groups. The term "optionally oxidized sulfur" as used herein refers to S, SO, or SO2.

[0510] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. It is intended to include all such possible stereoisomers, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically stated, reference to an isomer is applicable to any possible isomer. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0511] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, and even further such as no more than 20% of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, such as no more than 5%, such as no more than 1% of any one or more other stereoisomers.

[0512] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0513] When the compounds disclosed herein contain disubstituted cyclohexyl or cyclobutyl groups, the substituents found on the cyclohexyl or cyclobutyl ring can be formed in cis and trans forms. The cis form means that both substituents are located on the upper side of the carbon 2 substituent positions, while the trans form means that they are located on opposite sides.

[0514] It may be advantageous to separate the reaction products from each other and / or from the starting materials. By common techniques in the art, the desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) to the desired uniformity. 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 analysis; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. Those skilled in the art will apply the technology most likely to achieve the desired separation.

[0515] "Diastereoisomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of each other. Based on their physicochemical differences, diastereomeric mixtures can be separated into their individual diastereoisomers by methods well known to those skilled in the art (e.g., by chromatography and / or fractional crystallization). Enantiomers can be separated as follows: by reacting an enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), converting the enantiomeric mixture into a diastereomeric mixture, separating these diastereoisomers, and converting (e.g., hydrolyzing) the individual diastereoisomers into the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0516] The term "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. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0517] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt (e.g., a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and / or water and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0518] As defined herein, "pharmaceutically acceptable salts thereof" include salts of at least one compound of formula (I), and salts of stereoisomers of the compound of formula (I), such as enantiomeric salts and / or diastereomeric salts.

[0519] The terms "administration," "administering," and "treating," "treatment," as used herein, when applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ, or a biological fluid, mean contacting an exogenous agent, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. Treatment of cells encompasses contact of an agent with a cell and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treating" also mean, for example, in vitro and ex vivo treatment of a cell by an agent, a diagnostic agent, a binding compound, or another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0520] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a compound) that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or disorder, is sufficient to affect the treatment of such a disease, disorder, or symptom. A "therapeutically effective amount" can vary with the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, as defined above, that is effective to treat the disease or disorder of the subject. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination subject used to effectively treat the disease, disorder, or condition.

[0521] Pharmaceutical compositions comprising the compounds disclosed herein can be administered orally, by inhalation, rectally, parenterally, or topically to a subject in need thereof. For oral administration, the pharmaceutical composition can be a conventional solid formulation, such as a tablet, powder, granule, capsule, etc.; a liquid formulation, such as an aqueous or oily suspension; or other liquid formulations, such as a syrup, solution, suspension, etc.; for parenteral administration, the pharmaceutical composition can be a solution, an aqueous solution, an oily suspension concentrate, a lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition can be a single unit administration with a precise dosage. In addition, the pharmaceutical composition may further comprise another active ingredient.

[0522] All formulations of the pharmaceutical composition disclosed herein can be produced by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients and then made into the desired formulation. "Pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers suitable for desired pharmaceutical formulations, for example: diluents, vehicles (such as water, various organic solvents, etc.), fillers (such as starch, sucrose, etc.), adhesives (such as cellulose derivatives, alginates, gelatin and polyvinyl pyrrolidone (PVP)); Wetting agents, such as glycerol; Disintegrants, such as agar, calcium carbonate and sodium bicarbonate; Absorption enhancers, such as quaternary ammonium compounds; Surfactants, such as cetyl alcohol; Absorption carriers, such as kaolin and bentonite; Lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition also includes other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners and dyes.

[0523] The term "disease" refers to any illness, ailment, condition, symptom, or indication, and is interchangeable with the terms "disorder" or "condition."

[0524] Throughout this specification and the accompanying aspects, unless the context requires otherwise, the term "comprise" and variations such as "comprises and comprising" are intended to specify the presence of the following features, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced by the terms "containing," "including," or sometimes "having."

[0525] Throughout this specification and the accompanying aspects, the term "C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 、C 1-6 wait.

[0526] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0527] abbreviation

[0528]

[0529]

[0530] Examples

[0531] The following examples are intended to be purely exemplary and should not be considered as limiting in any way. Although efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), some experimental errors and deviations should be considered. Unless otherwise indicated, temperatures are expressed in degrees Celsius. Reagents are purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, Pharmablock, Bidepharm, or TCI, and are used without further purification unless otherwise indicated. Unless otherwise indicated, the reactions described below are carried out under a positive pressure of nitrogen or argon or in an anhydrous solvent with a drying tube; Reaction flasks are equipped with rubber septa for introducing substrates and reagents via syringes; and glassware is oven dried and / or heat dried.

[0532] Recorded on an Agilent instrument operating at 400 MHz or 500 MHz 1 H NMR spectroscopy.1 HNMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone, or (CD3)2CO as solvents and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05) as reference standards. When reporting the number of multiplets, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, if given, are reported in Hertz (Hz).

[0533] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity); detector: MWD (190-400 nm); mass detector: 6120SQ; mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid; column: Poroshell 120EC-C18, 4.6 x 50 mm, 2.7 μm; gradient method: flow rate: 1.8 mL / min; time (min) A (%) B (%)

[0534] Time (min) A(％) B(％) 0.00 95 5 1.5 5 95 2.0 5 95 2.1 95 5 3.0 95 5

[0535] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II); detector: MWD (190-400 nm); mass detector: G6125C SQ; mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid; column: Poroshell 120EC-C18, 4.6×50 mm, 2.7 μm; gradient method: flow rate: 1.8 mL / min; time (min) A (%) B (%)

[0536]

[0537]

[0538] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II); detector: MWD (190-400 nm); mass detector: G6125C SQ; mobile phase: A: water containing 0.1% formic acid, B: acetonitrile containing 0.1% formic acid; column: Poroshell 120EC-C18, 4.6×50 mm, 2.7 μm; gradient method: flow rate: 1.2 mL / min; time (min) A (%) B (%)

[0539] Time (min) A(％) B(％) 0.00 90 10 1.5 5 95 2.0 5 95 2.1 90 10 3.0 90 10

[0540] Preparative HPLC was performed on a column (150 x 21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml / min, an injection volume of 2 ml, at room temperature and UV detection at 214 nm and 254 nm.

[0541] Common intermediate A:

[0542] 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)benzene (4-amino)azetidine-3-carboxaldehyde

[0543] Step 1: 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidine-1(2H)- phenyl trifluoromethanesulfonate

[0544]

[0545] To a solution of 1-(4-hydroxyphenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (obtained by a similar manner as described in WO 2022012622 A1) (500 mg, 1.49 mmol) in DCM was added pyridine (235 mg, 2.98 mmol). Tf2O (630 mg, 2.24 mmol) was then added between 0°C and 5°C. The mixture was slowly warmed from 0°C to room temperature and stirred at room temperature for 3h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EtOAc (100%: 0% to 50%: 50%) to give 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidine-1(2H)-yl)phenyl trifluoromethanesulfonate (644 mg, 92%). [M+H] + =469.5.

[0546] Step 2: 1-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)-3-((2-(trimethylsilyl) (ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione

[0547]

[0548] A mixture of 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl trifluoromethanesulfonate (100 mg, 0.213 mol), azetidin-3-ylmethanol hydrochloride (39 mg, 0.32 mmol), Pd(dba) (20 mg, 0.0213 mmol), Ruphos (20 mg, 0.0426 mmol) and CsCO (138 mg, 0.426 mmol) in dioxane (10 mL) was stirred at 100° C. under nitrogen overnight. After completion (monitored by LCMS), the mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with PE / EA (100%:0% to 50%:50%) to give 1-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (67 mg, 78%). [M+H] + =406.4.

[0549] Step 3: 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidine-1 (2H)-(2H-amino)phenyl)azetidine-3-carbaldehyde

[0550]

[0551] To a solution of 1-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (132 mg, 0.325 mmol) in DMSO (10 mL) was added IBX (114 mg, 0.406 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was extracted with EA (50 mL*3), washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure to give 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbaldehyde (140 mg, crude). [M+H] + =404.5

[0552] Common intermediate B:

[0553] 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylic acid

[0554] Step 1: tert-Butyl 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidine (2H)-pyridin-1(2H)-yl)phenyl)azetidine-3-carboxylate

[0555]

[0556] A mixture of 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl trifluoromethanesulfonate (468 mg, 1.0 mol), tert-butylazetidine-3-carboxylate hydrochloride (188 mg, 1.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Ruphos (93.4 mg, 0.2 mmol) and Cs2CO3 (652 mg, 2.0 mmol) in dioxane (50 mL) was stirred at 90 ° C under nitrogen overnight. After completion (monitored by LCMS), the mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluted with PE / EA (100%:0% to 50%:50%) to give the product (460 mg, 97%). [M+H] + =476.2.

[0557] Step 2: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylic acid

[0558]

[0559] To a solution of tert-butyl 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylate (460 mg, 0.97 mmol) in dichloromethane (10 mL) was added TFA (10 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was diluted with MeOH (20 mL) and NH3.H2O (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 h and then concentrated under vacuum to give the desired product (260 mg, 93%). [M+H] + =290.1

[0560] Common intermediate C:

[0561] tert-Butyl 4-((trans)-4-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylic acid acid esters

[0562] Step 1: (cis)-4-(4-benzylpiperazin-1-yl)cyclohexan-1-ol

[0563]

[0564] To a solution of (cis)-4-aminocyclohexane-1-ol hydrochloride (100 g, 660 mmol) and benzylbis(2-chloroethyl)amine hydrochloride (212.6 g, 791 mmol) in EtOH (2 L) was added sodium carbonate (224.2 g, 2.64 mol) at 0° C. After stirring at 90° C. for 5 hours, the mixture was filtered and concentrated to give a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give the compound (82.6 g, 43%). 1 H NMR(400MHz,DMSO-d6)δ7.33-7.21(m,5H),4.30-4.20(m,1H),3.68(s,1H),3.42(s ,2H),2.45-2.35(m,7H),2.15-2.10(m,1H),1.66-1.58(m,4H),1.40-1.33(m,4H). [M+H] + =275.2.

[0565] Step 2: (cis)-4-(piperazin-1-yl)cyclohexan-1-ol (Intermediate 3)

[0566]

[0567] To a solution of (cis)-4-(4-benzylpiperazin-1-yl)cyclohexan-1-ol (82.6 g, 301 mmol) in EtOH (2 L) was added palladium (10% on activated carbon) (9.61 g) at room temperature. After stirring overnight at 40° C. under a 15 psi hydrogen atmosphere, the mixture was filtered and concentrated to give the product (53.4 g, 92%). 1 H NMR (400MHz, CDCl3) δ3.97-3.95(m,1H),2.91-2.88(m,4H),2.56-2.54(m,4H),2.27-2.21(m,1H),1.85-1.50(m,8H). [M+H] + =185.1

[0568] Step 3: (cis)-tert-Butyl 4-(4-hydroxycyclohexyl)piperazine-1-carboxylate

[0569]

[0570] At 0 ℃, to (cis) -4- (piperazine -1- base) cyclohexane -1- alcohol (53.4g, 290mmol) in THF (600mL) solution, add saturated sodium bicarbonate aqueous solution (300mL) and di-tert-butyl decarbonate (94.9g, 435mmol).After stirring at 0 ℃ for 2 hours, the mixture is diluted with water (500mL) and extracted with ethyl acetate (700mL x2).The organic layer merged is washed with salt water (600mL), through Na SO Drying, filter and concentrate to produce oily matter, it is dropped in petroleum ether until a large amount of solid precipitation.Solid is filtered and filter cake is washed with petroleum ether (100mL), filtered and microwave-dried at 40 ℃ for 0.5 hour to produce product (66g, 76%). 1 H NMR (400MHz, CDCl3) δ4.00-3.93(m,1H),3.44-3.41(m,4H),2.52-2.50(m,4H),2.32-2.25(m,1H),1.85-1.59(m,8H),1.46(s,9H). [M+H] + =285.2.

[0571] Step 4: (cis)-tert-Butyl 4-[4-(methanesulfonyloxy)cyclohexyl]piperazine-1-carboxylate

[0572]

[0573] To a solution of (cis)-tert-butyl 4-(4-hydroxycyclohexyl)piperazine-1-carboxylate (66.0 g, 232 mmol) and triethylamine (47.0 g, 464 mmol) in dichloromethane (1 L) was added methanesulfonyl chloride (31.9 g, 279 mmol) at 0°C. The mixture was stirred at 0°C for 2 hours and water (1 L) was added. The mixture was extracted with dichloromethane (300 mL x 3). The combined organic layers were washed with water (500 mL), brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (73 g, 78%). 1 H NMR (400MHz, CDCl3) δ4.97 (br s,1H),3.44-3.41(m,4H),3.01(s,3H),2.52-249(m,4H),2.34-2.29(m,1H),2.16-2.13(m,2H),1.70-1.64(m,6H),1.46(s,9H). [M+H] + =363.2.

[0574] Step 5: tert-Butyl 4-((trans)-4-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)cyclohexyl)piperidin Oxazine-1-carboxylate

[0575]

[0576] At room temperature, to a solution of 4-nitro-1H-pyrazole-3-carboxamide (7.0 g, 44.8 mmol) and (cis)-tert-butyl 4-[4-(methanesulfonyloxy)cyclohexyl]piperazine-1-carboxylate (17.9 g, 49.3 mmol) in DMF (300 mL) was added cesium carbonate (29.2 g, 89.6 mmol). After stirring at 130 ° C for 16 hours, the mixture was diluted with water (600 mL) and extracted with ethyl acetate (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude compound, which was purified with a C18 column (acetonitrile: water = 50% to 75%) to produce a product (2 g, 11%). [M+H] + =423.2.

[0577] Step 6: tert-Butyl 4-((trans)-4-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperidin Oxazine-1-carboxylate

[0578]

[0579] To a solution of tert-butyl 4-((trans)-4-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (5.9 g, 14 mmol) in THF (200 mL) was added palladium (10% on activated carbon) (450 mg) at room temperature. After stirring at 25° C. under a 15 psi hydrogen atmosphere for 5 hours, the mixture was filtered and concentrated to give the title compound (5.1 g, 88%). 1 H NMR (400MHz, CDCl3) δ6.95(s,1H),6.56(br s,1H),5.26(br s,1H),4.14(br s,2H),3.96-3.88(m,1H),3.45-3.42(m,4H),2.54-2.51(m,4H),2.43-2.34(m,1H), 2.19(d,J=12Hz,2H), 2.03(d,J=12.4Hz,2H), 1.80-1.71(m,2H), 1.46-1.40(m,11H). [M+H] + =393.2.

[0580] Common intermediate D:

[0581] tert-Butyl 4-((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylic acid acid esters

[0582] Step 1: 1-Benzyl-1H-pyrazole-3-carbaldehyde

[0583]

[0584] To a DMF solution (500 mL) of 1H-pyrazole-3-carboxaldehyde (50.0 g, 0.52 mol) and benzyl bromide (93.5 g, 0.546 mol) was added cesium carbonate (423.9 g, 1.30 mol). After stirring at 25 ° C for 1 hour, the mixture was added into water (2.0 L) and extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with brine (2.0 L), dried over Na SO , filtered and concentrated under reduced pressure to give a crude compound, which was purified by silica gel column chromatography (PE: EtOAc = 20: 1) to produce product (65 g, 64%). 1 H NMR (300MHz, CDCl3) δ10.00(s,1H),7.43-7.37(m,4H),7.32-7.27(m,2H),6.84(s,1H),5.41(s,2H). [M+H] + =187.0.

[0585] Step 2: 1-Benzyl-3-(difluoromethyl)-1H-pyrazole

[0586]

[0587] To a solution of 1-benzyl-1H-pyrazole-3-carboxaldehyde (65 g, 0.335 mol) in dichloromethane (500 mL) was added diethylaminosulfur trifluoride (216.1 g, 1.34 mol) at 0°C. After stirring at 20°C for 16 hours, the mixture was added to ice water (1.0 L) and extracted with dichloromethane (300 mL x 2). The combined organic layers were washed with brine (1.0 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude compound, which was purified by silica gel column chromatography (PE: EtOAc = 40: 1) to produce the product (48.5 g, 70%). 1 H NMR (300MHz, CDCl3) δ7.38-7.34(m,4H),7.26-7.21(m,2H),6.89-6.50(m,2H),5.32(s,2H). [M+H] + =209.1

[0588] Step 3: 3-(Difluoromethyl)-1H-pyrazole

[0589]

[0590] To a solution of 1-benzyl-3-(difluoromethyl)-1H-pyrazole (25 g, 0.120 mol) in MeOH (500 mL) was added 10% wt. Pd(OH)2 (supported on carbon) (2.5 g), 10% wt. Pd (supported on carbon) (2.5 g), and 12 M hydrochloric acid (13 mL). After stirring at 40° C. under H2 (50 psi) for 16 hours, the mixture was filtered and concentrated under reduced pressure to give the product (14 g, 99%). 1 HNMR (300MHz, CDCl3) δ7.88 (s, 1H), 7.02 (t, J = 54.9Hz, 1H), 6.55 (s, 1H). [M+H] + =119.0

[0591] Step 4: 3-(Difluoromethyl)-4-nitro-1H-pyrazole

[0592]

[0593] At 0 ° C, concentrated nitric acid (28.7 g, 0.297 mol) was added to a solution of 3-(difluoromethyl)-1H-pyrazole (14 g, 0.119 mol) in concentrated sulfuric acid (150 mL). The mixture was stirred at 115 ° C for 4 hours, then added to ice water (500 g) and extracted with ethyl acetate (250 mL x 2). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude compound, which was purified by silica gel column chromatography (PE: EtOAc = 3: 1) to produce the product (15 g, 78%). [MH] + =161.9.

[0594] Step 5: tert-Butyl 4-((trans)-4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)cyclohexyl)piperidin Oxazine-1-carboxylate

[0595]

[0596] To a solution of 3-(difluoromethyl)-4-nitro-1H-pyrazole (13.0 g, 79.7 mmol) and (cis)-tert-butyl 4-[4-(methanesulfonyloxy)cyclohexyl]piperazine-1-carboxylate (28.9 g, 79.7 mmol) in N,N-dimethylformamide (600 mL) was added cesium carbonate (51.9 g, 0.159 mol). After stirring at 130 ° C for 16 hours, the mixture was filtered and diluted with water (600 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude compound, which was purified by silica gel column chromatography (CH2Cl2: EtOAc = 4: 1) to produce the product (6.0 g, 17%). [M+H]+ =430.2.

[0597] Step 6: tert-Butyl 4-((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperidin Oxazine-1-carboxylate

[0598]

[0599] To a solution of tert-butyl 4-((trans)-4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (6.0 g, 13.7 mmol) in THF (120 mL) was added palladium (10% on activated carbon) (1.2 g) at room temperature. After stirring at room temperature under a 15 psi hydrogen atmosphere for 16 hours, the mixture was filtered and concentrated to give the crude product, which was recrystallized from ACN (10 mL) at room temperature to give the product (4.99 g, 88%). 1 H NMR (400MHz, CDCl3) δ7.00 (s, 1H), 6.67 (t, J = 54.8Hz, 1H), 3.96-3.89 (m, 1H), 3.44-3.42 (m, 4H), 3.19 (br s, 2H), 2.52 (br s,4H),2.42-2.36(m,1H),2.18(d,J=12Hz,2H),2.03(d,J=12.4Hz,2H),1.78-1.67(m,2H),1.46(s,9H),1.43-1.36(m,2H). [M+H] + =400.2.

[0600] Common intermediate E: (R)-3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidin-2,6-diol ketone

[0601] Step 1: 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidin-1-yl)-2,6-difluorophenyl)pyrrolidone pyridine

[0602]

[0603] To a solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (20 g, 41.49 mmol), 3-(benzyloxy)azetidine hydrochloride (9.96 g, 49.79 mmol), Pd2(dba)3(3.79 g, 4.15 mmol), RuPhos (3.88 g, 8.3 mmol) and Cs2CO3(40.58 g, 124.47 mmol) in dioxane (400 mL). Under a nitrogen atmosphere, the mixture was stirred at 100 ° C for 3 h. After cooling to room temperature, the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidin-1-yl)-2,6-difluorophenyl)pyridine (17 g, 72.6%). [M+H] + =565.3.

[0604] Step 2: 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione

[0605]

[0606] To a solution of 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidin-1-yl)-2,6-difluorophenyl)pyridine (17 g, 30.09 mmol) in DMF / i-PrOH=(200 mL / 600 mL) was added Pd / C (10% wet, 17 g). The mixture was stirred at rt under a hydrogen atmosphere for 2 days. The resulting mixture was filtered and the filter cake was washed with IPA. The filtrate was concentrated under reduced pressure and purified by trituration with DCM / MeOH (10 / 1) to give crude 3-(2,6-difluoro-4-(3-hydroxycyclobutyl)phenyl)piperidine-2,6-dione (8 g, 89.9%). [M+H] + =297.27.

[0607] Step 3: (R)-3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione

[0608]

[0609] The crude 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (76 g) was purified by chiral separation using the following conditions (CHIRALPAK IF (10 cm×25 cm, 10 um), MtBE (0.1% DEA):(MeOH:DCM=1:1)=50:50, 250 mL / min) to give (R)-3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (35.83 g, 47.14%, ee=99.54%). [M+H] + =297.27

[0610] Step 4: (R)-3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione

[0611]

[0612] To a solution of (R)-3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (106 g, 357.78 mmol) in DCM (2 L) was added Dess-Martin reagent (455.24 g, 1073.34 mmol) at 0 ° C under nitrogen. The mixture was stirred at 0 ° C for 3 hours. The reaction was then diluted with DCM (3 L) and filtered. The filter cake was washed with DCM (300 mL) and collected. The filtrate was washed with saturated aqueous sodium bicarbonate solution (2 L × 2) and brine (2 L × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The solution was concentrated in vacuo. The residue was combined with the collected filter cake and dried under reduced pressure to give (R)-3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione (91 g, 86.43%). [M+H] + =295.27.

[0613] Example 1: N-(3-(difluoromethyl)-1-((1R,4r)-4-((4-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0614] Step 1: tert-Butyl (4-bromopyridin-2-yl) (2,2,2-trifluoroethyl) carbamate

[0615]

[0616] To a DMF solution (100 mL) of tert-butyl (4-bromopyridin-2-yl) carbamate (9 g, 33.3 mmol) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (9 g, 39.96 mmol) and Cs2CO3 (22 g, 66.6 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum and water (100 mL) was added to the residue. The mixture was extracted with EA (100 mL x2). The organic layer was concentrated and purified by combi flash chromatography (eluting with EA:PE=0:1-1:0) to obtain the product (9.6 g, 81%). [M+H] + =355.2.

[0617] Step 2: Ethyl 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylate acid esters

[0618]

[0619] To a DMF solution (20 mL) of tert-butyl (4-bromopyridin-2-yl) (2,2,2-trifluoroethyl) carbamate (960 mg, 2.7 mmol) was added ethyl oxazole-4-carboxylate (457 mg, 3.24 mmol), Pd (OAc) 2 (61 mg, 0.27 mmol), P (o-tol) 3 (164 mg, 0.54 mmol) and Cs 2 CO 3 (1.8 g, 5.4 mmol). The mixture was stirred at 80 ° C under N 2 for 16 h. The solvent was removed under vacuum, and then water (30 mL) was added and extracted with EA (30 mL x 3). The organic layer was concentrated and purified by combiflash chromatography (eluted with EA: PE = 0: 1-1: 0) to give the product (600 mg, 54%). [M+H] + =416.4.

[0620] Step 3: 2-(2-((tert-Butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid

[0621]

[0622] Ethyl 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylate (600 mg, 1.45 mmol) and LiOH.HO (122 mg, 2.90 mmol) were added to THF (30 mL) and HO (10 mL). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and then water (10 mL) was added and acidified to pH = 4 with aqueous HCl. The solid was filtered and dried to give the product (410 mg, 73%). [M+H] + =388.3.

[0623] Step 4: tert-Butyl (4-(4-((3-(difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrrolidone) (2,2,2-trifluoroethyl)oxazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate

[0624]

[0625] To a DMF solution (20 mL) of ((1r, 4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methanol (639 mg, 2.61 mmol) was added 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid (1200 mg, 3.13 mmol), HATU (1.2 g, 3.13 mmol) and DIEA (708 mg, 5.22 mmol). The mixture was stirred at room temperature under N2 overnight. The solvent was removed under vacuum, and water (50 mL) was then added and extracted with EA (50 mL x 3). The organic layer was concentrated and purified by combi flash chromatography (eluting with EA:PE=0:1-1:0) to give the product (700 mg, 44%). [M+H] + =615.4.

[0626] Step 5: tert-Butyl (4-(4-((3-(difluoromethyl)-1-((1r,4r)-4-formylcyclohexyl)-1H-pyrazole- 4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate

[0627]

[0628] To a solution of tert-butyl (4-(4-((3-(difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (200 mg, 0.4 mmol) in DMSO (30 mL) was added IBX (224 mg, 0.8 mmol). The mixture was stirred at room temperature under N2 overnight. Water (100 mL) was added and extracted with EA (30 mL x 2). The organic layer was concentrated and purified by combi flash chromatography (eluted with EA:PE=0:1-1:0) to give the product (140 mg, 29%). [M+H] + =613.4.

[0629] Step 6: tert-Butyl 4-(((1r,4r)-4-(4-(2-(2-(tert-Butyloxycarbonyl)(2,2,2-trifluoroethyl)amino) (pyridin-4-yl)oxazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazine-1-carboxylic acid ester

[0630]

[0631] To a solution of tert-butyl (4-(4-((3-(difluoromethyl)-1-((1r,4r)-4-formylcyclohexyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (140 mg, 0.28 mmol) in DCM (20 mL) was added tert-butyl piperazine-1-carboxylate (63 mg, 0.336 mmol). The mixture was stirred at room temperature under N2 overnight. NaBH(Ac)3 (119 mg, 0.56 mmol) was added to the mixture, which was then stirred at room temperature under N2 for 3 h. The reaction was quenched with aqueous Na2CO3 (15 mL) and extracted with DCM (30 mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated to give the product (200 mg, 91%). [M+H] + =783.4.

[0632] Step 7: N-(3-(difluoromethyl)-1-((1r,4r)-4-(piperazin-1-ylmethyl)cyclohexyl)-1H-pyrazole-4-yl 2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0633]

[0634] To a solution of tert-butyl 4-(((1r,4r)-4-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazine-1-carboxylate (200 mg, 0.26 mmol) in DCM (10 mL) was added HCl (4N, 6 mL) in 1,4-dioxane. The mixture was stirred at room temperature under N2 overnight. The solvent was removed under vacuum and the residue was diluted with saturated aqueous K2CO3 solution, extracted with DCM (3×20 mL), and the organic layer was dried over Na2SO4, filtered and concentrated to give the product (148 mg, 100%). [M+H] + =583.4.

[0635] Step 8: N-(3-(difluoromethyl)-1-((1R,4r)-4-((4-(4-((R)-2,6-dioxopiperidin-3-yl)-3, (5-difluorophenethyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino) Pyridin-4-yl)oxazole-4-carboxamide

[0636]

[0637] To a solution of N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-ylmethyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide (50 mg, 0.086 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (27 mg, 0.1029 mmol) in DCE (10 mL) was added NaBH(OAc) (37 mg, 0.173 mmol) and the mixture was stirred at 70° C. under N for 2 h. The mixture was purified by combi flash chromatography (eluting with DCM:MeOH=1-0 to 1:10) to give a crude product, which was further purified by preparative HPLC to give the product (14 mg, 19.5%).

[0638] 1 H NMR (500MHz, DMSO) δ10.94(s,1H),9.70(s,1H),8.95(s,1H),8.24(d,J=5Hz,1H),8.18(s,1H),7.62 -7.59(m,1H),7.27-7.05(m,3H),7.02(d,J=10.0Hz,2H),4.28-4.17(m,4H),2.81-2.73(m,2H),2.54-2.51(m,5H), 2.44-2.24(m,5H),2.16-1.98(m,6H),1.98-1.88(m,2H),1.79-1.72(m,2H),1.62-1.56(m,1H),1.07-1.00(m,2H). [M+H] + =834.6.

[0639] Example 2: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0640]

[0641] The title compound was prepared in a similar manner to that described in Example 1 (6.0 mg, 27.3% yield). 1H NMR(500MHz,DMSO)δ10.21(s,1H),9.67(s,1H),8.89(s,1H),8.18(s,1H),8.11(s,1H),7.57 -7.54(m,1H),7.17(s,1H),7.13(d,J=10.0Hz,1H),7.09-6.98(m,3H),6.86(d,J=10.0Hz,2H),4.19-4.14(m,3H),3.65-3.61(m,5H), 2.62-2.56(m,5H),2.54-2.51(m,2H),2.30-2.22(m,5H),2.04-1.96(m,4H),1.84-1.67(m,6H),1.51-1.41(m,3H),1.01-0.95(m,2H). [M+H] + =854.6.

[0642] Example 3: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0643]

[0644] The title compound was prepared in a manner similar to that described in Example 1 (5.0 mg, 32.1% yield). 1 H NMR(500MHz,DMSO)δ10.25(s,1H),9.73(s,1H),8.96(s,1H),8.24-8.18(m,2H),7.64-7.61(m,1H),7.27 -7.05(m,5H),6.43(d,J=10.0Hz,2H),4.26-4.21(m,3H),3.90(t,J=5.0Hz,2H) ,3.67(t,J=5.0Hz,2H),3.57(t,J=5.0Hz,2H),3.25-3.22(m,2H),2.67(t,J=5. 0Hz,2H),2.43-2.25(m,7H),2.12(d,J=10.0Hz,2H),2.04(d,J=10.0Hz,2H),1. 90(d,J=10.0Hz,2H),1.77-1.74(m,2H),1.65-1.55(m,1H),1.05-1.03(m,2H). [M+H] + =826.6.

[0645] Example 4: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0646]

[0647] The title compound was prepared in a similar manner to that described in Example 6.

[0648] 1 H NMR(500MHz,DMSO)δ10.86(s,1H),9.71(s,1H),8.95(s,1H),8.24(d,J=5.0Hz,1H),8.19(s,1H),7 .62-7.59(m,1H),7.24(s,1H),7.19-7.05(m,2H),6.16(d,J=10.0Hz,2H),4.28-4.21(m,3H),4.04- 4.01(m,3H),3.91-3.83(m,3H),3.48(s,2H),2.81-2.74(m,1H),2.54-2.52(m,3H),2.35-2.32(m,4 H),2.15-2.04(m,5H),1.95-1.90(m,3H),1.80-1.73(m,2H),1.65-1.55(m,1H),1.10-1.13(m,2H). [M+H] + =889.7.

[0649] Example 5: N-(2-((1r,4r)-4-((4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0650]

[0651] The title compound was prepared in a similar manner to that described in Example 6.

[0652] 1H NMR(500MHz,DMSO)δ10.50(s,1H),10.23(s,1H),8.69(s,1H),8.51-8.38(m,2H),8.33(s,1H),8.2 2(d,J=7.7Hz,1H),7.20-7.06(m,3H),6.45(d,J=8.4Hz,2H),4.52-4.31(m,1H),4.06-3.94(m,5H), 3.89-3.79(m,3H),3.67(t,J=6.5Hz,2H),3.55-3.42(m,2H),3.38-3.33(m,2H),2.67(t,J=6.5Hz,2 H),2.40-2.29(m,4H),2.23-2.09(m,4H),2.00-1.84(m,4H),1.72-1.54(m,2H),1.16-1.09(m,1H). [M+H] + =788.6.

[0653] Example 6: N-(2-((1R,4r)-4-((4-((1r,4R)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0654] Step 1: tert-Butyl 4-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperazine-1-carboxylate

[0655]

[0656] To a stirred solution of (1s, 4s)-4-hydroxycyclohexane-1-carboxylic acid (20.0 g, 138.73 mmol) in THF (200 mL) was added HATU (68.6 g, 180.35 mmol) in batches at 0°C. The resulting solution was stirred at 0°C under a nitrogen atmosphere for 30 min. To the above solution was added TEA (28.1 g, 277.45 mmol, 38.62 mL) and tert-butylpiperazine-1-carboxylate (28.4 g, 152.60 mmol) at 0°C under a nitrogen atmosphere. The resulting solution was stirred at 20°C for 12 hours. At 20°C, the reaction mixture was quenched by the addition of H2O (20 mL) and then extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EA at 20 °C for 30 min, filtered and concentrated under reduced pressure to give a residue compound tert-butyl 4-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperazine-1-carboxylate (33.0 g, 75%). [M+H]+ =313.3 1 H NMR (400MHz, CDCl3) δ = 4.02 (br d, J = 2.9Hz, 1H), 3.58 (br s,3H),3.51-3.36(m,6H),2.58-2.45(m,1H),2.05-1.82(m,5H),1.77(s,1H),1.66-1.57(m,3H),1.50-1.44(m,9H)

[0657] Step 2: tert-Butyl 4-(((1s,4s)-4-hydroxycyclohexyl)methyl)piperazine-1-carboxylate

[0658]

[0659] To a solution of tert-butyl 4-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperazine-1-carboxylate (11.0 g, 35.2 mmol) in THF (120 mL) was added dropwise BH3.THF (1 M, 140.8 mL) at 0°C. The solution was stirred at 80°C for 16 hours. The resulting mixture was cooled to 0°C, followed by the slow addition of MeOH (2 mL) at 0°C. The mixture was stirred at 50°C for 3 hours and concentrated under reduced pressure. The reaction mixture was quenched with H2O (20 mL) at 20°C and then extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue compound tert-butyl 4-(((1s,4s)-4-hydroxycyclohexyl)methyl)piperazine-1-carboxylate (10.0 g, 32%). [M+H]+=299.3 1 H NMR (400MHz, chloroform-d) δ = 4.13 (q, J = 7.2Hz, 1H), 4.02-3.95 (m, 2H), 3.46-3.39 (m, 3 H),3.20-3.05(m,3H),2.84-2.74(m,5H),2.62(s,3H),2.50-2.41(m,2H),2.38 -2.32(m,3H),2.28(d,J=6.7Hz,2H),2.23-2.17(m,2H),2.05(s,2H),1.71(td, J=4.1,8.5Hz,7H),1.49-1.43(m,9H),1.43-1.33(m,5H),1.26(t,J=7.2Hz,2H)

[0660] Step 3: tert-Butyl 4-(((1s,4s)-4-((methylsulfonyl)oxy)cyclohexyl)methyl)piperazine-1-carboxylate

[0661]

[0662] To a solution of tert-butyl 4-(((1s,4s)-4-hydroxycyclohexyl)methyl)piperazine-1-carboxylate (500 mg, 1.68 mmol) in DCM (5 mL) was added TEA (339 mg, 3.35 mmol, 466 uL) and MsCl (288 mg, 2.51 mmol, 195 uL) at 0°C. The mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched with aqueous Na2CO3 (20 mL) at 20°C and then extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 40 / 1 to 0 / 1) to give tert-butyl 4-(((1s,4s)-4-((methylsulfonyl)oxy)cyclohexyl)methyl)piperazine-1-carboxylate (280.0 mg, 44% yield). [M+H] + =377.3 1 H NMR (400 MHz, chloroform-d) δ = 4.97 (br s, 1H), 3.47-3.33 (m, 4H), 3.07-2.96 (m, 3H), 2.39-2.26 (m, 4H), 2.18 (d, J = 7.1 Hz, 2H), 2.10-1.99 (m, 3H), 1.73-1.63 (m, 3H), 1.63-1.56 (m, 2H), 1.49-1.41 (m, 9H), 1.40-1.29 (m, 2H)

[0663] Step 4: tert-butyl 4-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H- (indazol-2-yl)cyclohexyl)methyl)piperazine-1-carboxylate

[0664]

[0665] To a solution of N-(6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (2.0 g, 5.95 mmol) (obtained by the same manner as described in Example 41) and tert-butyl 4-(((1s,4s)-4-((methylsulfonyl)oxy)cyclohexyl)methyl)piperazine-1-carboxylate (6.7 g, 17.84 mmol) in DMF (180 mL) was added CsCO (7.8 g, 23.79 mmol). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (water (NH4HCO3)-ACN]; B%: 55%-85%, 20 min). Tert-butyl 4-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)methyl)piperazine-1-carboxylate (300.0 mg, 7.85% yield) was obtained. [M+H]+=617.3 1 H NMR (400MHz, chloroform-d) δ = 10.71 (s, 1H), 8.83 (s, 1H), 8.50 (d, J = 7.9Hz, 1H), 8.18-8.05 (m, 1H), 7.95-7.83 (m, 2H), 7.08 (s,1H),4.43-4.24(m,1H),4.08-3.96(m,3H),3.56-3.33(m,4H),2.43-2.29(m,6H),2.22(d,J=7.0Hz,2H),2.06(br d,J=12.4Hz,2H),1.94(br dd,J=2.6,12.5Hz,2H),1.74-1.63(m,1H),1.48(s,9H),1.22-1.09(m,2H)

[0666] Step 5: N-(6-methoxy-2-((1r,4r)-4-(piperazin-1-ylmethyl)cyclohexyl)-2H-indazol-5-yl)- 6-(Trifluoromethyl)picolinamide, TFA salt

[0667]

[0668] A mixture of tert-butyl 4-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)methyl)piperazine-1-carboxylate (280.0 mg, 454 umol) and TFA (8.6 g, 75.6 mmol, 5.60 mL) in DCM (5 mL) was degassed and purged with N 2 three times, and then the mixture was stirred at 20° C. under N 2 atmosphere for 2 hours. The reaction mixture was concentrated under reduced pressure to give the residue compound N-(6-methoxy-2-((1r,4r)-4-(piperazin-1-ylmethyl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (TFA salt, 284 mg, 94%). [M+H] + =517.2 1 H NMR (400MHz, DMSO-d6)δ=10.55-10.47(m,1H),9.52-9.33(m,1H),8.72-8.66(m,1H),8.47-8.36(m,2H),8.32(s,1H),8.20(br d,J=7.5Hz,1H),7.14(s,1H),4.49-4.39(m,2H),3.98(s,3H),3.43(br s,6H),3.04(br d,J=5.2Hz,2H),2.16(br d,J=11.0Hz,2H),2.03-1.84(m,6H),1.31-1.16(m,3H).

[0669] Step 6: N-(2-((1R,4r)-4-((4-((1r,4R)-4-(4-(2,4-dioxo-3-((2-(trimethylsilane) (2H)-yl)phenoxy)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)cyclohexyl)- 6-(trifluoromethyl)-6-methoxy-2H-indazol-5-yl)-6-picolinamide

[0670]

[0671] To a solution of (trans)-4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenoxy)cyclohexane-1-carboxylic acid (obtained by a method similar to Common Intermediate B) (31 mg, 0.067 mmol) in DMF (3 mL) was added HATU (28 mg, 0.073 mmol). The mixture was stirred at rt for 10 min. N-(6-methoxy-2-((1r,4r)-4-(piperazin-1-ylmethyl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide TFA salt (42 mg, 0.066 mmol) and EtN (46 mg, 0.45 mmol) in DMF (3 mL) were then added to the reaction. The reaction was stirred at rt for 4 h. The solvent was removed under reduced pressure. The residue was diluted with water (15 mL), extracted with dichloromethane (3 x 20 mL), and washed with brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM: MeOH = 100: 0 to 19: 1) to give the product (55 mg, 86% yield). [M+H] + =961.7.

[0672] Step 7: N-(2-((1R,4r)-4-((4-((1r,4R)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzene (oxy)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl) Pyridinecarboxamide

[0673]

[0674] A solution of N-(2-((1R,4r)-4-((4-((1r,4R)-4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenoxy)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (50 mg, 0.052 mmol) in TFA (5 mL) was stirred at rt for 6 h. The solvent was removed under reduced pressure. The residue was dissolved in MeOH. The pH of the mixture was adjusted to 11 with NH3.H2O (1N). The mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0-9:1 gradient elution) to give the product (13 mg, 30% yield). [M+H] + =831.7

[0675] 1H NMR (500MHz, DMSO) δ10.50 (s, 1H), 10.29 (s, 1H), 8.69 (s, 1H), 8.42 (dt, J = 7.7, 5.2Hz, 2H), 8. 33(s,1H),8.22(d,J=7.7Hz,1H),7.21-7.16(m,3H),6.95(d,J=8.8Hz,2H),4.53-4.25(m,2H), 3.98(s,3H),3.71(t,J=6.6Hz,2H),3.56-3.41(m,4H),2.73-2.61(m,3H),2.40-2.23(m,5H),2 .19-2.06(m,5H),2.00-1.86(m,4H),1.77-1.71(m,2H),1.68-1.39(m,6H),1.16-1.08(m,2H).

[0676] Example 7: N-(2-((1r,4r)-4-((4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0677]

[0678] The title compound was prepared in a similar manner to that described in Example 6.

[0679] 1 H NMR (500MHz, DMSO) δ10.50(s,1H),10.25(s,1H),8.69(s,1H),8.46(d,J=7.6Hz,1H),8.41(t ,J=7.7Hz,1H),8.33(s,1H),8.22(d,J=7.8Hz,1H),7.17-7.10(m,3H),6.93(d,J=8.8Hz,2H), 4.43-4.32(m,1H),3.98(s,3H),3.71-3.67(m,4H),3.57-3.45(m,4H),2.82-2.72(m,3H),2. 70-2.62(m,3H),2.40-2.34(m,5H),2.20-2.10(m,4H),1.97-1.87(m,4H),1.72-1.63(m,5H). [M+H] + =816.7.

[0680] Example 12: N-(3-Carbamoyl-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0681] Step 1: tert-Butyl 4-((1r,4r)-4-(4-(2-(2-(tert-Butyloxycarbonyl)(2,2,2-trifluoroethyl)amino) (4-pyridinyl)oxazole-4-carboxamido)-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate

[0682]

[0683] To a solution of tert-butyl 4-((trans)-4-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (1.0 g, 2.54 mmol) in DMF (5 mL) was added 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid (1.2 g, 3.048 mmol), DIEA (518 mg, 5.08 mmol) and HATU (1.45 g, 5.08 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by combi flash chromatography (eluted with DCM:MeOH=1-0 to 1:10) to give the product (1.8 g, 93%). [M+H] + =761.8.

[0684] Step 2: N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)- 2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0685]

[0686] To a solution of tert-butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (1.8 g, 2.36 mmol) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was basified with aqueous NaCO solution to pH>7 and extracted with DCM (50 mL x 3). The organic layer was dried over NaSO, filtered and concentrated to give the crude product (1.2 g, 91%).

[0687] Step 3: N-(3-carbamoyl-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidine-3- (2-(2,2,2-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2- (trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0688]

[0689] To a solution of N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide (100 mg, 0.18 mmol) in DMF (6 mL) was added (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (73 mg, 0.216 mmol) (obtained by the same procedure described in WO 2022012623A1), DIEA (1.0 mL) and HATU (103 mg, 0.27 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by combi flash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to give the crude product, which was further purified by preparative HPLC to give the product (57 mg, 36%). 1 H NMR (500MHz, DMSO) δ10.94(s,1H),10.84(s,1H),8.97(s,1H),8.36(s,1H),8.25(d,J=5.0 Hz,1H),7.69-7.67(m,2H),7.50(s,1H),7.25(s,1H),7.16(d,J=5.0Hz,1H),6.23(d,J=10. 0Hz,2H),4.25-4.22(m,3H),4.04-4.00(m,1H),3.54-3.42(m,6H),3.28-3.24(m,4H),2.81 -2.76(m,1H),2.64-2.41(m,5H),2.14-2.07(m,5H),1.95-1.84(m,5H),1.47-1.43(m,2H). [M+H] + =882.3.

[0690] Example 13: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0691] Step 1: tert-Butyl 4-((1r,4r)-4-(4-(2-(2-(tert-Butyloxycarbonyl)(2,2,2-trifluoroethyl)amino) (4-(pyridin-4-yl)oxazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate

[0692]

[0693] To a solution of tert-butyl 4-((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (1.0 g, 2.54 mmol) in DMF (10 mL) was added 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid (1.2 g, 3.05 mmol), DIEA (518 mg, 5.08 mmol) and HATU (1.45 g, 3.81 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by combi flash chromatography (eluted with DCM:MeOH=1-0 to 1:10) to give the product (1.8 g, 92%). [M+H] + =769.4.

[0694] Step 2: N-(3-(difluoromethyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)- 2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0695]

[0696] To a solution of tert-butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (1.8 g, 2.34 mmol) in DCM (10 mL) was added TFA (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was basified to pH 10 with aqueous NaCO solution and extracted with DCM (50 mL x 3). The organic layer was dried over NaSO, filtered and concentrated to give the crude product (1.2 g, 90%).

[0697] Step 3: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidine-1(2H)- 1-Azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl) 4-Yl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0698]

[0699] To a solution of N-(3-(difluoromethyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide (50 mg, 0.088 mmol) in DCM (5 mL) was added 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylic acid (31 mg, 0.1056 mmol), DIEA (0.5 mL) and HATU (50 mg, 0.132 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by combiflash chromatography (eluting with DCM:MeOH=1-0 to 1:10) to give the crude product, which was further purified by preparative HPLC to yield the product (14 mg, 19%). 1 H NMR (500MHz, DMSO) δ10.23(s,1H),9.71(s,1H),8.95(s,1H),8.24(d,J=5.0Hz,1H),8.18(s,1H),7.62-7 .59(m,1H),7.24(s,1H),7.19-7.16(m,2H),7.12-7.05(m,2H),6.45(d,J=10.0Hz,2H),4.26-4.19(m,3H) ,4.03-4.00(m,2H),3.85-3.80(m,3H),3.67(t,J=10.0Hz,2H),3.47(s,2H),3.31-3.29(m,2H),2.69-2.6 6(m,2H),2.54-2.45(m,5H),2.10-2.08(m,2H),1.92-1.90(m,2H),1.83-1.76(m,2H),1.47-1.42(m,2H). [M+H] + =840.6.

[0700] Example 14: N-(3-(Difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0701]

[0702] The title compound was prepared in a similar manner to that described in Example 13.

[0703] 1H NMR(500MHz,DMSO)δ10.21(s,1H),9.71(s,1H),8.95(s,1H),8.24(d,J=5.0Hz,1H),8.19(s,1H), 7.62-7.60(m,1H),7.27-7.16(m,3H),7.10(d,J=10.0Hz,2H),6.53(d,J=10.0Hz,2H),4.28-4.20 (m,3H),3.68-3.65(m,2H),3.55-3.44(m,7H),3.29-3.26(m,3H),2.69-2.67(m,2H),2.55(s,2H) ,2.48-2.43(m,2H),2.19-2.08(m,4H),1.93-1.91(m,2H),1.83-1.76(m,2H),1.47-1.43(m,2H). [M+H] + =854.7.

[0704] Example 15: N-(3-(Difluoromethyl)-1-((1S,4r)-4-(4-((S)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0705]

[0706] The title compound was prepared in a similar manner to that described in Example 13.

[0707] 1 H NMR(500MHz,DMSO)δ10.21(s,1H),9.72(s,1H),8.95(s,1H),8.24(d,J=5.0Hz,1H),8.19(s,1H), 7.62-7.60(m,1H),7.27-7.16(m,3H),7.10(d,J=10.0Hz,2H),6.53(d,J=10.0Hz,2H),4.26-4.22 (m,3H),3.68-3.65(m,2H),3.48-3.44(m,6H),3.35-3.26(m,4H),2.69-2.66(m,2H),2.55(s,2H) ,2.48-2.43(m,2H),2.16-2.08(m,4H),1.93-1.91(m,2H),1.83-1.76(m,2H),1.47-1.43(m,2H). [M+H] + =854.7.

[0708] Example 16: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0709]

[0710] The title compound was prepared in a similar manner to that described in Example 13.

[0711] 1 H NMR (500MHz, DMSO) δ10.84(s,1H),9.71(s,1H),8.95(s,1H),8.24(d,J=5.0Hz,1H),8.18(s ,1H),7.62-7.60(m,1H),7.24-7.16(m,3H),6.23(d,J=10.0Hz,2H),4.26-4.22(m,3H),4.0 4-4.00(m,1H),3.54-3.42(m,6H),3.35-3.22(m,4H),2.81-2.74(m,1H),2.55(s,2H),2.48 -2.43(m,3H),2.16-2.08(m,5H),1.93-1.91(m,3H),1.83-1.76(m,2H),1.47-1.40(m,2H). [M+H] + =875.8.

[0712] Example 17: N-(3-(Difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0713]

[0714] The title compound was prepared in a similar manner to that described in Example 13.

[0715] 1H NMR (500MHz, DMSO) δ10.87(s,1H),9.73(s,1H),8.99(s,1H),8.24(d,J=5.0Hz,1H),8.18(s,1H),7.62-7.60(m,1H),7.24-7.06( m,3H),6.18(d,J=10.0Hz,2H),4.26-4.03(m,4H),3.58-3.43(m,11H),2.84-2.71(m,2H),2.09-1.82(m,13H),1.45-1.41(m,2H). [M+H] + =889.7.

[0716] Example 18: N-(3-(Difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0717]

[0718] The title compound was prepared in a similar manner to that described in Example 13.

[0719] 1 H NMR (500MHz, DMSO) δ10.84(s,1H),9.72(s,1H),8.95(s,1H),8.24(d,J=5.0Hz,1H),8.18(s,1 H),7.62-7.60(m,1H),7.24-7.06(m,3H),6.15(d,J=10.0Hz,2H),4.26-4.22(m,3H),4.04-4.0 0(m,1H),3.58-3.43(m,9H),3.09-3.06(m,2H),2.81-2.74(m,1H),2.55-2.40(m,4H),2.10-2. 07(m,3H),1.95-1.91(m,3H),1.82-1.77(m,2H),1.45-1.41(m,2H),1.47(s,3H),1.40(s,2H). [M+H] + =917.8.

[0720] Example 19: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxapiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0721]

[0722] The title compound was prepared in a similar manner to that described in Example 13.

[0723] 1 H NMR(500MHz,DMSO)δ10.85(s,1H),9.71(s,1H),8.95(s,1H),8.24(d,J=5.0Hz,1H),8.1 8(s,1H),7.61-7.59(m,1H),7.26-7.05(m,3H),6.10(d,J=10.0Hz,2H),4.26-4.18(m,3H ),4.03-4.00(m,1H),3.94-3.91(m,3H),3.48-3.45(m,2H),2.92-2.89(m,1H),2.81-2. 74(m,1H),2.55-2.39(m,12H),2.09-2.06(m,3H),1.82-1.75(m,2H),1.45-1.37(m,2H). [M+H] + =861.5.

[0724] Example 20: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0725]

[0726] The title compound was prepared in a similar manner to that described in Example 13.

[0727] 1H NMR(500MHz,DMSO)δ10.85(s,1H),9.72(s,1H),8.95(s,1H),8.24(d,J=5.0Hz,1H),8.1 8(s,1H),7.62-7.59(m,1H),7.27-7.05(m,3H),6.61(d,J=10.0Hz,2H),4.28-4.21(m,3 H),4.06-4.02(m,1H),3.76-3.73(m,2H),2.81-2.72(m,2H),2.64-2.36(m,9H),2.10-2 .05(m,5H),1.96-1.91(m,3H),1.83-1.73(m,5H),1.50-1.37(m,2H),1.16-1.09(m,2H). [M+H] + =889.6

[0728] Example 21: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidin-3-yl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0729]

[0730] The title compound was prepared in a similar manner to that described in Example 13.

[0731] 1 H NMR (500MHz, DMSO) δ10.20 (s, 1H), 9.71 (s, 1H), 8.95 (s, 1H), 8.24 (d, J = 5.0Hz, 1H), 8.18 (s, 1H), 7.62-7. 59(m,1H),7.27-7.05(m,5H),6.52(d,J=10.0Hz,2H),4.26-4.19(m,3H),3.67-3.65(m,2H),3.47-3.43(m ,1H),3.37-3.32(m,4H),3.23-3.21(m,1H),3.05-3.02(m,1H),2.90-2.87(m,1H),2.67-2.64(m,2H),2.5 4(s,4H),2.36-2.33(m,2H),2.18-2.07(m,3H),1.94-1.92(m,2H),1.83-1.75(m,3H),1.44-1.37(m,2H). [M+H] + =826.6.

[0732] Example 175: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0733]

[0734] The title compound was prepared in a similar manner to that described in Example 13.

[0735] 1 H NMR (500MHz, DMSO) δ10.75(s,1H),9.71(s,1H),8.95(s,1H),8.24(d,J=5.0Hz,1H),8.18(s,1H),7.61(t,J= 5.0Hz,1H),7.24-7.16(m,3H),7.01(d,J=10.0Hz,2H),6.42(d,J=10.0Hz,2H),4.28-4.19(m,3H),4.01-3.99 (m,2H),3.84-3.79(m,3H),3.72-3.69(m,1H),3.59(t,J=5.0Hz,2H),3.47(s,2H),2.66-2.60(m,1H),2.54- 2.44(m,8H),2.12-2.07(m,3H),2.01-1.98(m,1H),1.91-1.89(m,2H),1.83-1.76(m,2H),1.46-1.39(m,2H). [M+H] + =839.6.

[0736] Example 22: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1S,4r)-4-(4-((S)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0737]

[0738] The title compound was prepared in a similar manner to that described in Example 13.

[0739] 1H NMR(500MHz,DMSO)δ10.21(s,1H),9.70(s,1H),8.92(s,1H),8.18(s,1H),8.15(d,J=5.0Hz,1H),7.27-7.01 (m,6H),6.53(d,J=10.0Hz,2H),4.22-4.19(m,1H),3.68-3.65(m,2H),3.55-3.44(m,6H),3.35-3.24(m,4H), 3.18(t,J=5.0Hz,2H),2.68(t,J=5.0Hz,2H),2.57-2.55(m,1H),2.48-2.42(m,3H),2.16-2.08(m,4H),1.93- 1.91(m,2H),1.83-1.76(m,2H),1.47-1.43(m,2H),1.08-1.05(m,1H),0.47-0.43(m,2H),0.24-0.21(m,2H). [M+H] + =826.9.

[0740] Example 23: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0741]

[0742] The title compound was prepared in a similar manner to that described in Example 13.

[0743] 1H NMR(500MHz,DMSO)δ10.21(s,1H),9.70(s,1H),8.92(s,1H),8.18(s,1H),8.15(d,J=5.0Hz,1H),7.27-7.01 (m,6H),6.53(d,J=10.0Hz,2H),4.24-4.19(m,1H),3.68-3.65(m,2H),3.56-3.44(m,6H),3.35-3.24(m,4H), 3.18(t,J=5.0Hz,2H),2.68(t,J=5.0Hz,2H),2.57-2.55(m,1H),2.48-2.42(m,3H),2.16-2.08(m,4H),1.93- 1.91(m,2H),1.83-1.76(m,2H),1.47-1.40(m,2H),1.08-1.05(m,1H),0.47-0.43(m,2H),0.24-0.21(m,2H). [M+H] + =826.9.

[0744] Example 24: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0745]

[0746] The title compound was prepared in a similar manner to that described in Example 13.

[0747] 1H NMR(500MHz,DMSO)δ10.23(s,1H),9.70(s,1H),8.92(s,1H),8.18(s,1H),8.15(d ,J=5.0Hz,1H),7.27-7.01(m,6H),6.45(d,J=10.0Hz,2H),4.24-4.19(m,1H),4.03 -4.00(m,2H),3.87-3.81(m,3H),3.67(t,J=5.0Hz,2H),3.47(s,2H),3.18(t,J=5.0Hz,2H),2.67(t,J=5.0Hz,2H),2.57-2.42(m,7H), 2.10-2.08(m,2H),1.92-1.90(m,2H),1.83-1.76(m,2H),1.45-1.42(m,2H),1.08-1.05(m,1H),0.47-0.44(m,2H),0.23-0.21(m,2H). [M+H] + =812.6.

[0748] Example 25: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0749]

[0750] The title compound was prepared in a similar manner to that described in Example 13.

[0751] 1 H NMR (500MHz, DMSO) δ10.87 (s, 1H), 9.92-9.81 (m, 2H), 9.01 (s, 1H), 8.22 (s, 1H), 8.13 (d, J = 5. 0Hz,1H),7.35-7.07(m,3H),6.17(d,J=10.0Hz,2H),4.54-4.52(m,1H),4.33-4.30(m,1H),4.0 6-3.83(m,7H),3.49-3.40(m,4H),3.24-3.02(m,5H),2.82-2.75(m,1H),2.21-2.04(m,5H),1 .96-1.85(m,3H),1.71-1.64(m,2H),1.12-1.08(m,1H),0.52-0.51(m,2H),0.28-0.27(m,2H). [M+H]+ =848.0.

[0752] Example 26: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0753]

[0754] The title compound was prepared in a similar manner to that described in Example 13.

[0755] 1 H NMR (500MHz, DMSO) δ10.84(s,1H),9.70(s,1H),8.92(s,1H),8.18(s,1H),8.15(d,J=5.0Hz,1H),7.27-7. 01(m,4H),6.23(d,J=10.0Hz,2H),4.24-4.19(m,1H),4.04-4.00(m,1H),3.54-3.42(m,6H),3.35-3.22(m ,5H),3.19-3.17(m,2H),2.81-2.74(m,1H),2.55(s,2H),2.48-2.43(m,2H),2.18-2.05(m,5H),1.95-1.9 1(m,3H),1.83-1.76(m,2H),1.47-1.40(m,2H),1.09-1.04(m,1H),0.47-0.43(m,2H),0.24-0.21(m,2H). [M+H] + =861.7.

[0756] Example 27: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0757]

[0758] The title compound was prepared in a similar manner to that described in Example 13.

[0759] 1H NMR(500MHz,DMSO)δ10.85(s,1H),9.70(s,1H),8.92(s,1H),8.18(s,1H),8.15(d,J=5.0Hz,1H),7.26-7.0 1(m,4H),6.10(d,J=10.0Hz,2H),4.24-4.19(m,1H),4.04-4.00(m,1H),3.94-3.91(m,2H),3.48-3.46(m,2H ),3.19-3.17(m,2H),2.92-2.91(m,1H),2.77-2.74(m,1H),2.63-2.36(m,12H),2.18-2.05(m,3H),1.95-1 .93(m,3H),1.82-1.75(m,2H),1.45-1.40(m,2H),1.08-1.05(m,1H),0.46-0.43(m,2H),0.23-0.21(m,2H). [M+H] + =833.7.

[0760] Example 85: N-(3-(Difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-isopropylpyridin-4-yl)oxazole-4-carboxamide

[0761]

[0762] The title compound was prepared in a similar manner to that described in Example 13.

[0763] 1 H NMR(500MHz,DMSO)δ10.84(s,1H),9.85(s,1H),8.99(d,J=2.3Hz,1H),8.73(s,1H) ,7.15(t,J=54.6Hz,1H),6.22(d,J=13.4Hz,2H),4.26-4.20(m,1H),4.10-3.95(m,1 H),3.67-3.39(m,8H),3.30-2.99(m,4H),2.84-2.61(m,2H),2.58-2.49(m,3H),2. 24-2.01(m,5H),1.97-1.86(brs,3H),1.82-1.73(m,2H),1.48-1.31(m,2H),1.28(d J=15.1Hz,6H). [M+H] + =834.6

[0764] Example 86: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-isopropylpyridin-4-yl)oxazole-4-carboxamide

[0765]

[0766] The title compound was prepared in a similar manner to that described in Example 13.

[0767] 1 H NMR (500MHz, DMSO) δ10.86(s,1H),9.85(s,1H),8.99(s,1H),8.73(d,J=5.0Hz,1H),8.15(s,1H),7.84(s,1H),7.78( d,J=5.0Hz,1H),7.15(t,J=54.4Hz,1H),6.17(d,J=11.1Hz,2H),4.21(s,1H),4.03(t,J=7.3Hz,3H),3.91(d,J=6.2H z,2H),3.89-3.78(m,1H),3.47(s,2H),3.38-3.24(m,3H),3.23-3.10(m,1H),2.88(s,1H),2.84-2.71(m,1H),2.48- 2.36(m,3H),2.19-2.04(m,3H),1.96-1.81(m,3H),1.80-1.73(m,2H),1.43(d,J=11.5Hz,2H),1.29(d,J=6.9Hz,6H).

[0768] [M+H] + =820.7

[0769] Example 170: 2-(2-(sec-butyl)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0770]

[0771] The title compound was prepared in a similar manner to that described in Example 13.

[0772] 1H NMR (500MHz, DMSO) δ10.84(s,1H),9.85(s,1H),8.99(s,1H),8.75(d,J=5.0Hz,1H),8.15(s,1H),7.86-7.73 (m,2H),7.15(t,J=54.4Hz,1H),6.22(d,J=12.2Hz,2H),4.22(brs,1H),4.02(dd,J=12.5,4.8Hz,1H),3.66-3 .35(m,6H),3.28-3.15(m,5H),2.97-2.89(m,1H),2.86-2.73(m,2H),2.54(s,2H),2.22-2.00(m,6H),1.93( brs,3H),1.85-1.70(m,3H),1.69-1.60(m,1H),1.52-1.39(m,2H),1.32-1.20(m,4H),0.80(t,J=7.4Hz,3H). [M+H] + =848.6

[0773] Example 28: N-(3-Carbamoyl-1-(6-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0774]

[0775] The title compound was prepared in a manner analogous to that described in Example 166.

[0776] 1H NMR(500MHz,DMSO)δ10.95(s,1H),10.19(s,1H),8.96(s,1H),8.79(s,1H),8.65(d,J=5.0Hz,1H),8.1 9(d,J=5.0Hz,1H),8.08-8.06(m,1H),7.96(s,1H),7.64(s,2H),7.20(s,1H),7.11(d,J=10.0Hz,2H),7 .05(d,J=10.0Hz,2H),6.98(d,J=10.0Hz,1H),6.40(d,J=10.0Hz,2H),4.20-4.16(m,2H),4.01-3.98( m,2H),3.87-3.85(m,3H),3.62-3.59(m,2H),3.56-3.53(m,6H),3.44-3.40(m,2H),2.62-2.59(m,2H). [M+H] + =828.6.

[0777] Example 8: N-(3-carbamoyl-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0778]

[0779] To a solution of N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide (56 mg, 0.1 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylic acid (30 mg, 0.1 mmol) and DIEA (65 mg, 0.5 mmol) in DMF (5 mL) was added HATU (38 mg, 0.1 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The reaction was evaporated under vacuum to give a crude residue, which was purified by preparative TLC (DCM:MeOH=7:1) to give the product (41 mg, 49%). 1H NMR (500MHz, DMSO) δ10.94(s,1H),10.23(s,1H),8.97(s,1H),8.36(s,1H),8.24(d,J=5.5Hz,1H),7.71-7.64( m,2H),7.50(s,1H),7.25(s,1H),7.16(d,J=6.0Hz,1H),7.11(d,J=8.5Hz,2H),6.45(d,J=8.5Hz,2H),4.28-4. 19(m,3H),4.04-3.98(m,2H),3.89-3.78(m,3H),3.71-3.63(m,2H),3.51-3.42(m,2H),3.35-3.32(m,2H),2.7 1-2.64(m,2H),2.55-2.51(m,3H),2.47-2.40(m,2H),2.15-2.08(m,2H),1.96-1.79(m,4H),1.51-1.37(m,2H). [M+H] + =833.70.

[0780] Example 11: N-(3-carbamoyl-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0781] Step 1: Methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-yl acid esters

[0782]

[0783] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (3.00 g, 6.22 mmol), methyl azetidine-3-carboxylate hydrochloride (1.41 g, 9.33 mmol), Cs2CO3 (6.06 g, 18.66 mmol) and RuPhos Pd G3 (520.7 mg, 0.622 mmol) in toluene (50 mL) was stirred at 100 ° C under a nitrogen atmosphere overnight. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EtOAc (2: 1) to provide the product (1.7 g, 53%). [M+1] + =517.1.

[0784] Step 2: 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid

[0785]

[0786] To a stirred mixture of methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate (1.7 g, 3.29 mmol) in THF (20 mL) was added LiOH HO (168 mg, 4 mmol in 10 mL of water) dropwise at room temperature. The mixture was then stirred for 2 hours. The resulting mixture was concentrated in vacuo. The aqueous layer was adjusted to pH <5 with 1N HCl and then extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to provide the product (1.4 g, 85%) [M+1]. + =503.2.

[0787] Step 3: (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid

[0788]

[0789] To a solution of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (1.40 g, 2.79 mmol) in iPrOH (20 mL) and DCM (20 mL) was added Pd / C (1.0 g, 10% wt) and stirred at room temperature under a hydrogen atmosphere for 48 hours. The resulting mixture was filtered and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to provide a crude product. The residue was purified by SFC (IH (3*25 cm, 5 um), 13% EtOH / 87% CO , 100 bar, 20 ml / min) and the title compound corresponded to peak A @ 1.853 min / 254 nm (190 mg, 21%). [M+1] + =325.3.

[0790] Step 4: N-(3-carbamoyl-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2- (trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0791]

[0792] To a solution of N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide (56 mg, 0.1 mmol), (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (32 mg, 0.1 mmol) and DIEA (65 mg, 0.5 mmol) in DMF (5 mL) was added HATU (38 mg, 0.1 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The reaction was evaporated under vacuum to give a crude residue, which was purified by preparative TLC (DCM:MeOH=8:1) to give the product (36 mg, 42%). 1 H NMR (500MHz, DMSO) δ10.94(s,1H),10.86(s,1H),8.97(s,1H),8.36(s,1H),8.24(d,J=5.5Hz,1H),7.74-7.6 3(m,2H),7.50(s,1H),7.25(s,1H),7.16(d,J=5.5Hz,1H),6.17(d,J=11.0Hz,2H),4.29-4.18(m,3H),4.07- 3.98(m,3H),3.93-3.89(m,2H),3.86-3.76(m,1H),3.50-3.44(m,2H),3.30-3.26(m,2H),2.82-2.73(m,1H) ,2.56-2.52(m,2H),2.49-2.36(m,4H),2.16-2.04(m,3H),1.98-1.78(m,5H),1.43(dd,J=23.0,11.5Hz,2H). [M+H] + =868.80.

[0793] Example 9: N-(3-carbamoyl-1-((1r,4r)-4-(4-(3-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0794]

[0795] A solution of N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide (56 mg, 0.1 mmol) and (R)-3-((4-(3-oxocyclobutyl)phenyl)amino)piperidine-2,6-dione (obtained by a similar manner as described in WO 2021219070 A1) (30 mg, 0.11 mmol) in DCM / MeOH (5 mL / 1 mL) was stirred at room temperature for 2 hours. To the resulting mixture was added NaBH(OAc) (106 mg, 0.5 mmol) and stirred at room temperature for 18 hours. The reaction was evaporated under vacuum to give a crude residue, which was purified by preparative HPLC to give the product P1 (42 mg, 51.4% yield, trans:cis = 86:12). 1 HNMR(500MHz,DMSO)δ10.94(s,1H),10.76(s,1H),8.97(s,1H),8.36(s,1H),8.24(d,J=5.5Hz,1H),8.19(s,1H),7.7 2-7.62(m,2H),7.49(s,1H),7.25(s,1H),7.15(d,J=5.5Hz,1H),7.03-6.91(m,2H),6.61(d,J=8.5Hz,2H),5.67(d,J= 7.5Hz,1H),4.30-4.18(m,4H),2.99-2.90(m,1H),2.78-2.70(m,1H),2.67-2.58(m,2H),2.58-2.52(m,4H),2.42-2.2 5(m,6H),2.15-2.07(m,3H),1.99-1.91(m,2H),1.89-1.81(m,3H),1.79-1.69(m,2H),1.42(dd,J=23.0,11.5Hz,2H). [M+H] + =818.70. and P2 (8 mg, 9.8% yield, trans:cis=30:57). 1H NMR (500MHz, DMSO) δ10.94(s,1H),10.77(s,1H),8.97(s,1H),8.36(s,1H),8.24(d,J=5.5Hz,1H),8.17(s,1H),7.72-7. 61(m,2H),7.49(s,1H),7.25(s,1H),7.16(d,J=5.5Hz,1H),7.01(d,J=8.5Hz,1H),6.95(d,J=8.5Hz,1H),6.62(t,J=9.0H z,2H),5.67(d,J=7.5Hz,1H),4.31-4.17(m,4H),3.01-2.69(m,2H),2.67-2.52(m,6H),2.43-2.30(m,4H),2.29-2.19(m ,2H),2.15-2.07(m,3H),2.06-2.01(m,1H),1.99-1.91(m,2H),1.90-1.79(m,3H),1.78-1.63(m,1H),1.49-1.33(m,2H). [M+H] + =818.70.

[0796] Example 10: N-(3-Carbamoyl-1-((1r,4r)-4-(4-(3-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0797]

[0798] A solution of N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide (56 mg, 0.1 mmol) and (S)-3-((4-(3-oxocyclobutyl)phenyl)amino)piperidine-2,6-dione (obtained by a similar manner as described in WO 2021219070 A1) (30 mg, 0.11 mmol) in DCM / MeOH (5 mL / 1 mL) was stirred at room temperature for 2 hours. To the resulting mixture was added NaBH(OAc) (106 mg, 0.5 mmol) and stirred at room temperature for 18 hours. The reaction was evaporated under vacuum to give a crude residue, which was purified by preparative HPLC to give the product (16 mg, 20% yield, trans:cis = 72:18). 1H NMR(500MHz,DMSO)δ10.95(s,1H),10.79(s,1H),8.98(s,1H),8.39(s,1H),8.25(d,J=5.5Hz,1H),7.72 (t,J=6.0Hz,1H),7.60(s,1H),7.57(s,1H),7.25(s,1H),7.16(d,J=5.5Hz,1H),7.08-6.98(m,2H),6.6 9-6.59(m,2H),4.36-4.18(m,4H),3.66-3.22(m,5H),3.06-3.01(m,1H),2.83-2.67(m,2H),2.65-2.51 (m,5H),2.49-2.43(m,3H),2.32-2.17(m,3H),2.16-2.04(m,4H),1.96-1.83(m,3H),1.69-1.51(m,2H). [M+H] + =818.60.

[0799] Example 76: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0800]

[0801] The title compound was prepared in a similar manner to that described in Example 13.

[0802] 1H NMR (500MHz, DMSO) δ10.50(s,1H),9.71(s,1H),8.95(s,1H),8.24(d,J=5.0Hz,1H),8.18(s,1H),7.6 2-7.60(m,1H),7.24-7.05(m,3H),6.25(d,J=10.0Hz,2H),4.26-4.19(m,3H),4.07-4.04(m,2H),3.9 6-3.93(m,2H),3.85-3.82(m,1H),3.59(t,J=5.0Hz,2H),3.48(s,2H),3.34(s,2H),2.68(t,J=5.0Hz ,2H),2.48-2.43(m,5H),2.10-2.08(m,2H),1.92-1.89(m,2H),1.81-1.76(m,2H),1.47-1.42(m,2H). [M+H] + =876.7.

[0803] Example 100: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-2-oxopiperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0804] Step 1: tert-Butyl 4-((1r,4r)-4-(4-(2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-yl) (formamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)-3-oxopiperazine-1-carboxylate

[0805]

[0806] To a solution of tert-butyl 4-((1r, 4r)-4-(4-(2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (synthesized in the manner of Example 13) (200 mg, 0.312 mmol) in THF (10 mL) and H o (4 mL) was added I (594 mg, 2.34 mmol) and NaHCO (262 mg, 3.12 mmol). The mixture was stirred at room temperature under N overnight. The reaction was quenched with Na s o aqueous solution (20 mL) and extracted with EA (30 mL x 3). The organic layer was dried over Na s o , filtered and concentrated to give the product (150 mg, 73%). [M+H] + =655.3.

[0807] Step 2: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4- (2-oxopiperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0808]

[0809] To a solution of tert-butyl 4-((1r,4r)-4-(4-(2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)-3-oxopiperazine-1-carboxylate (20 mg, 0.23 mmol) in DCM (10 mL) was added TFA (5 mL). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was basified with aqueous Na2CO3 solution to pH>7 and extracted with DCM (50 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product (100 mg, 78%). [M+H] + =555.3

[0810] Step 3: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4- (4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-2-oxopiperazine- 1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0811]

[0812] To a solution of 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(2-oxopiperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide (50 mg, 0.09 mmol) in DMF (5 mL) was added (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (35 mg, 0.108 mmol), DIEA (0.5 mL) and HATU (51 mg, 0.135 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by combi flash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to give a crude product, which was further purified by preparative HPLC to give the product (13 mg, 17%).

[0813] 1H NMR(500MHz,DMSO)δ10.86(s,1H),9.73(s,1H),8.93(s,1H),8.22(s,1H),8.15(d,J=5.0Hz,1H),7.27- 7.01(m,4H),6.17(d,J=10.0Hz,2H),4.54-4.52(m,1H),4.36-4.26(m,2H),4.04-4.02(m,5H),3.94-3. 90(m,3H),3.68-3.57(m,2H),3.18(t,J=5.0Hz,2H),2.81-2.74(m,1H),2.54-2.51(m,3H),2.13-2.04( m,3H),1.94-1.89(m,3H),1.79-1.72(m,4H),1.12-1.08(m,1H),0.46-0.45(m,2H),0.23-0.22(m,2H). [M+H] + =861.6.

[0814] Example 101: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-2-oxopiperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0815]

[0816] The title compound was prepared in a manner analogous to that described in Example 100.

[0817] 1H NMR (500MHz, DMSO) δ10.84(s,1H),9.72(s,1H),8.93(s,1H),8.22(s,1H),8.15(d,J=5.0Hz,1H),7.27-7.01(m,4H) ,6.23(d,J=10.0Hz,2H),4.37-4.26(m,3H),4.04-4.00(m,2H),3.81-3.80(m,1H),3.68-3.67(m,1H),3.56-3.53(m, 1H),3.47-3.39(m,3H),3.29-3.19(m,2H),3.18(d,J=5.0Hz,2H),2.81-2.74(m,1H),2.55(s,2H),2.19-2.05(m,5H) ,1.94-1.88(m,3H),1.78-1.73(m,4H),1.47-1.40(m,2H),1.09-1.04(m,1H),0.46-0.45(m,2H),0.23-0.22(m,2H). [M+H] + =875.8.

[0818] Example 166: N-(3-Carbamoyl-1-(6-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0819] Step 1: (6-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid

[0820]

[0821] A mixture of tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (1 g, 2.57 mmol), NaIO4 (2.75 g, 12.85 mmol) and NHOAc (989 mg, 12.85 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was stirred in a round-bottom flask at room temperature overnight. The resulting mixture was extracted with DCM (3x10 mL) and water (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title product (780 mg, 99%). [M+H] + =308.

[0822] Step 2: tert-Butyl 4-(5-(3-(ethoxycarbonyl)-4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)piperazine- 1-formate

[0823]

[0824] A mixture of (6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid (780 mg, 2.54 mmol), ethyl 4-nitro-1H-pyrazole-3-carboxylate (235 mg, 1.27 mmol), pyridine (200 mg, 2.54 mmol) and copper acetate (346.7 mg, 1.9 mmol) in DCM (20.0 mL) was stirred at room temperature under oxygen for 16 h. The resulting mixture was extracted with DCM (3 x 20 mL) and washed with water (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE:EA=5:1-1:2 gradient elution) to give the product (250 mg, 44%). [M+H] + =447.2.

[0825] Step 3: tert-Butyl 4-(5-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-yl Formate

[0826]

[0827] A mixture of tert-butyl 4-(5-(3-(ethoxycarbonyl)-4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-carboxylate (250 mg, 0.56 mmol) and ammonium hydroxide (10 mL) in THF (10.0 mL) was stirred at 80 ° C in a sealed tube for 15 h. The resulting solution was extracted with DCM (2×20.0 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the product (194 mg). [M-55] + =362.2.

[0828] Step 4: tert-Butyl 4-(5-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-yl Formate

[0829]

[0830] To a solution of tert-butyl 4-(5-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-carboxylate (194 mg, 0.465 mmol) in THF (15.0 mL) was added 10% wt Pd / C (20.0 mg) at 25°C. The flask was then evacuated and backfilled with H2 twice and stirred at 25°C under an H2 atmosphere for 15 h. The reaction was monitored by LCMS. The mixture was filtered through a pad of celite, and the filter cake was washed with MeOH (20.0 mL). The filtrate was concentrated under vacuum to obtain the product (188.0 mg). [M+H] + =388.2.

[0831] Step 5: tert-Butyl 4-(5-(4-(2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridine-4-yl) 1-[4-[(2-[(2-[(2-[(2-[(2-( ...

[0832]

[0833] A mixture of 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid (188.0 mg, 0.486 mmol), HATU (277.0 mg, 0.728 mmol) and DIEA (188.0 mg, 1.457 mmol) in DMF (20 mL) was stirred at room temperature for 40 minutes, and tert-butyl 4-(5-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-carboxylate (188.0 mg, 0.486 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS. Water (80 mL) was added and the solid was collected by filtration, washed with water (50.0 mL), and dried to obtain the product (360 mg, 98%). [M-99] + =657.6.

[0834] Step 6: N-(3-carbamoyl-1-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2- ((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide hydrochloride

[0835]

[0836] To tert-butyl 4-(5-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-carbamoyl-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-carboxylate (360 mg, 0.476 mmol) in DCM (10 mL) at 25 ° C. was added 4N HCl / dioxane (15 mL). The mixture was stirred at 25 ° C. for 1 h. The reaction was monitored by LCMS. The solid was collected by filtration, washed with DCM (20.0 mL), and dried to obtain the product (260 mg, 93%). [M+H]+ =557.3.

[0837] Step 7: N-(3-carbamoyl-1-(6-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- (difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl) 4-Yl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0838]

[0839] A mixture of N-(3-carbamoyl-1-(6-(piperazine-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide hydrochloride (30.0 mg, 0.051 mmol), (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (19.0 mg, 0.056 mmol), T3P (1 mL) and DIEA (20 mg, 0.152 mmol) in DCM (8 mL) was stirred at room temperature for 16 h. The reaction was monitored by LCMS. The resulting solution was extracted with DCM (2x15.0 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a crude product. The crude product was purified by preparative HPLC to give the product (4 mg, 9%). 1 H NMR (500MHz, DMSO) δ11.01(s,1H),10.84(s,1H),9.01(s,1H),8.85(s,1H),8.71(d,J=2.5Hz,1H),8.26(d,J=5.2 Hz,1H),8.13(dd,J=9.1,2.5Hz,1H),8.00(s,1H),7.69(s,2H),7.27(s,1H),7.18(d,J=5.2Hz,1H),7.05(d,J=9.2 Hz,1H),6.24(d,J=12.2Hz,2H),4.30-4.18(m,2H),4.02(dd,J=12.4,4.9Hz,1H),3.79-3.53(m,10H),3.49(t,J= 8.8Hz,1H),3.37-3.42(m,1H),3.25-3.28(m,2H),2.82-2.74(m,1H),2.26-2.05(m,3H),1.99-1.91(m,1H);[M+H] + =877.6.

[0840] Example 30: N-(3-Carbamoyl-1-(6-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0841]

[0842] The title compound was prepared in a manner analogous to that described in Example 166.

[0843] 1 H NMR(500MHz,DMSO)δ11.02(s,1H),10.77(s,1H),9.00(s,1H),8.78(s,1H),8.64(d,J=4.6Hz,2H), 8.07(dd,J=9.1,2.7Hz,1H),7.94(s,1H),7.76(s,1H),7.69(d,J=5.9Hz,2H),6.98(d,J=9.3Hz,1H ),6.18(d,J=12.1Hz,2H),3.95(dd,J=12.6,5.1Hz,1H),3.58(dt,J=15.0,12.3Hz,9H),3.45-3.30 (m,3H),3.24-3.08(m,2H),2.76-2.67(m,1H),2.55(s,3H),2.18-1.96(m,3H),1.92-1.84(m,1H). [M+H] + =794.6.

[0844] Example 31: N-(3-Carbamoyl-1-(6-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

[0845]

[0846] The title compound was prepared in a manner analogous to that described in Example 166. 1H NMR (500MHz, DMSO) δ11.10(s,1H),10.27(s,1H),9.10(s,1H),8.86(s,1H),8.72(dd,J=9.3,3.8Hz ,2H),8.15(d,J=9.1Hz,1H),8.05(s,1H),7.88(s,1H),7.81(d,J=4.6Hz,1H),7.77(s,1H),7.12(d ,J=8.5Hz,2H),7.05(d,J=9.2Hz,1H),6.47(d,J=8.6Hz,2H),4.09-4.02(m,2H),3.95-3.87(s,3H) ,3.67(t,J=6.7Hz,2H),3.65-3.58(m,6H),3.53-3.47(m,2H),2.68(t,J=6.6Hz,2H),2.63(s,3H). [M+H] + =745.6.

[0847] Example 51: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxapiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamide

[0848] Step 1: 2-(2-((tert-Butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-trifluoromethane oxazole-4-carboxylic acid

[0849]

[0850] To a DMF solution (30 mL) of tert-butyl (4-bromopyridin-2-yl) (2,2,2-trifluoroethyl) carbamate (3.1 g, 8.69 mmol) was added methyl 2H-1,2,3-triazole-4-carboxylate (1.0 g, 7.9 mmol), Fe(acac)3 (837 mg, 2.37 mmol), CuO (63 mg, 0.79 mmol) and Cs2CO3 (5.2 g, 15.8 mmol). The mixture was stirred at 100 ° C under N2 for 16 h. The solid was filtered and the filtrate was purified by preparative HPLC to give the product (2.5 g, 74%). [M+H] + =388.1.

[0851] Step 2: tert-Butyl 4-((1r,4r)-4-(4-(2-(2-(tert-Butyloxycarbonyl)(2,2,2-trifluoroethyl)amino) (4-pyridinyl)-2H-1,2,3-triazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-yl Formate

[0852]

[0853] To a solution of tert-butyl 4-((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (300 mg, 0.752 mmol) in DMF (5 mL) was added 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxylic acid (291 mg, 0.752 mmol), DIEA (1.0 mL) and HATU (429 mg, 1.128 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by combi flash chromatography (eluted with DCM:MeOH=1-0 to 1:10) to give the product (300 mg, 52%). [M+H] + =769.4.

[0854] Step 3: N-(3-(difluoromethyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)- 2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamide

[0855]

[0856] To a solution of tert-butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (800 mg, 1.04 mmol) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was basified with aqueous Na2CO3 to pH>7 and extracted with DCM (50 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product (580 mg, 98%). [M+H] + =569.2.

[0857] Step 4: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)- 3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2- (Trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamide

[0858]

[0859] To a solution of N-(3-(difluoromethyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamide (10 mg, 0.018 mmol) in DCM (3 mL) was added (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (7.0 mg, 0.0216 mmol), DIEA (0.5 mL) and HATU (14 mg, 0.036 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by combi flash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to give the crude product, which was further purified by preparative HPLC to give the product (12 mg, 76%).

[0860] 1 H NMR (500MHz, DMSO) δ10.86(s,1H),10.24(s,1H),8.63(s,1H),8.25(d,J=5.0Hz,1H),8.15(s,1H),7.70-7.67(m ,1H),7.33-7.32(m,2H),7.24-7.03(m,1H),6.17(d,J=10.0Hz,2H),4.28-4.20(m,3H),4.04-4.01(m,3H),3.92 -3.90(m,2H),3.84-3.81(m,1H),3.47(s,2H),2.78-2.74(m,1H),2.54-2.41(m, 8H),2.11-2.07(m,3H),1.94-1.90(m,3H),1.84-1.77(m,2H),1.47-1.42(m,2H). [M+H] + =875.8.

[0861] Example 52: N-(3-(Difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamide

[0862]

[0863] The title compound was prepared in a manner analogous to that described in Example 51.

[0864] 1H NMR(500MHz,DMSO)δ10.77(s,1H),10.18(s,1H),8.56(s,1H),8.18-8.06( m,2H),7.62-7.61(m,1H),7.27-6.96(m,3H),6.16(d,J=10.0Hz,2H),4.19 -4.17(m,3H),3.97-3.94(m,1H),3.47-3.37(m,7H),2.71-2.68(m,1H),2. 54-2.41(m,8H),2.06-2.02(m,5H),1.86-1.73(m,5H),1.38-1.37(m,2H). [M+H] + =889.8.

[0865] Example 61: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2H-1,2,3-triazole-4-carboxamide

[0866]

[0867] The title compound was prepared in a manner analogous to that described in Example 51.

[0868] 1 H NMR(500MHz,DMSO)δ10.50(s,1H),10.22(s,1H),8.60(s,1H),8.16-8.14(m,2H),7.24-7.03(m,4H),6.25 (d,J=10.0Hz,2H),4.24-4.20(m,1H),4.07-4.04(m,2H),3.96-3.93(m,2H),3.87-3.82(m,1H),3.59(t,J =5.0Hz,2H),3.51-3.45(m,3H),3.20(t,J=5.0Hz,2H),2.68(t,J=5.0Hz,2H),2.54-2.41(m,6H),2.11-2. 09(m,2H),1.93-1.77(m,4H),1.48-1.41(m,2H),1.07-1.06(m,1H),0.46-0.45(m,2H),0.23-0.22(m,2H). [M+H] + =848.6.

[0869] Example 63: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1S,4r)-4-(4-((S)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2H-1,2,3-triazole-4-carboxamide

[0870]

[0871] The title compound was prepared in a manner analogous to that described in Example 51.

[0872] 1 H NMR(500MHz,DMSO)δ10.47(s,1H),10.22(s,1H),8.60(s,1H),8.16-8.14(m,2H),7.25-7.03(m,4H) ,6.31(d,J=10.0Hz,2H),4.26-4.20(m,1H),3.60-3.44(m,10H),3.37-3.35(m,2H),3.28-3.26(m,1H ),3.20(t,J=5.0Hz,2H),2.68(t,J=5.0Hz,2H),2.60-2.54(m,3H),2.18-2.06(m,4H),1.98-1.90(m, 2H),1.85-1.77(m,2H),1.48-1.41(m,2H),1.07-1.06(m,1H),0.46-0.45(m,2H),0.23-0.22(m,2H). [M+H] + =863.2.

[0873] Example 130: N-cyclopropyl-2-(trans)-4-(4-(1-(4-((R)-2,6-dioxapiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide

[0874] Step 1: (cis)-4-(4-benzylpiperazin-1-yl)cyclohexan-1-ol

[0875]

[0876] A mixture of N-benzyl-2-chloro-N-(2-chloroethyl)ethane-1-amine hydrochloride (8.04 g, 29.9 mmol) and (cis)-4-aminocyclohexane-1-ol (3.44 g, 29.9 mmol) in EtOH (180 mL) was added to Na2CO3 (11.09 g, 104.6 mmol). The mixture was stirred at 90 ° C for 16 hours under a nitrogen atmosphere. The solvent was then removed by decompression. The residue was washed with water and extracted with dichloromethane (3x150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (DCM: MeOH = 100: 0-20: 1 gradient elution) to produce product (7.6 g, 93%). [M+H] + =275.6.

[0877] Step 2: (cis)-4-(piperazin-1-yl)cyclohexan-1-ol

[0878]

[0879] A mixture of (cis)-4-(4-benzylpiperazin-1-yl)cyclohexan-1-ol (7.6 g, 27.7 mmol) in MeOH (100 mL) and AcOH (5 mL) was added to Pd / C (760 mg, 10% w). The reaction was stirred at 45 ° C under a hydrogen atmosphere for 16 hours. The mixture was then cooled. The mixture was filtered through celite and concentrated under reduced pressure to give the product (4.9 g, 96%). [M+H] + =185.2.

[0880] Step 3: tert-Butyl 4-((cis)-4-hydroxycyclohexyl)piperazine-1-carboxylate

[0881]

[0882] At 0 ° C, a mixture of (cis) -4- (piperazin-1-yl) cyclohexane-1-ol (4.9g, 26.6mmol) and (Boc) 2 O (6.96g, 31.9mmol) in DCM (80mL) was added to Et 3 N (8.06g, 79.8mmol). The mixture was stirred at rt for 4 hours. The mixture was washed with water (150mL) and extracted with dichloromethane (3x100mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM: MeOH = 100: 0-20: 1 gradient elution) to give the product (4.57g, 60%). [M+H] + =285.6.

[0883] Step 4: Methyl 2-((trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indole oxazole-6-carboxylate

[0884]

[0885] At 0 DEG C under a nitrogen atmosphere, tert-butyl 4-((cis)-4-hydroxycyclohexyl)piperazine-1-carboxylate (1.12g, 3.93mmol), methyl 5-nitro-2H-indazole-6-carboxylate (0.87g, 3.93mmol) (obtained in the same manner as described in WO 2020035019A1) and PPh3(1.55g, 5.92mmol) were added dropwise to THF (50mL). The mixture was stirred at 0 DEG C for 15min, and DIAD (1.19g, 5.92mmol) was then added. The reaction was stirred at 0 DEG C for 1 hour. The mixture was slowly warmed to room temperature and stirred for 16h. The mixture was diluted with water (50mL), extracted with dichloromethane (3x50mL), and washed with brine (100mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0-20:1 gradient elution) to give the product (220 mg, 56%). [M+H] + =488.6. 1 HNMR(500MHz, CDCl3)δ8.41(s,1H),8.21(s,1H),8.02(s,1H),4.48-4.41(m,1H),3.93(s,3H),3.63-3.36(m,4H ),2.65-2.46(m,4H),2.44-2.34(m,2H),2.20-2.09(m,2H),2.09-1.96(m,3H),1.66-1.51(m,2H),1.47(s,9H).

[0886] Step 5: Methyl 5-amino-2-((trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indole oxazole-6-carboxylate

[0887]

[0888] To a solution of methyl 2-((trans)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate (220 mg, 0.45 mmol) in EtOH (10 mL) and Fe powder (126 mg, 2.26 mmol) was added NH4Cl (121 mg, 2.26 mmol) (3 mL in water). The reaction was stirred at 80°C for 4 h. The mixture was then cooled. The mixture was filtered through celite and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0-20:1 gradient elution) to give the product (145 mg, 70%). [M+H]+ =458.6.

[0889] Step 6: Methyl 2-(trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl) (Pyridinecarboxamido)-2H-indazole-6-carboxylate

[0890]

[0891] To a solution of 6-(trifluoromethyl)picolinic acid (61 mg, 0.32 mmol) in DMF (10 mL) was added HATU (133 mg, 0.35 mmol). The mixture was stirred at rt for 10 min. The reaction was then stirred at rt for 4 h using methyl 5-amino-2-((trans)-4-(4-(tert-butyloxycarbonyl)piperazine-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (145 mg, 0.32 mmol) in EtN (96 mg, 0.95 mmol). The reaction was stirred at rt for 4 h. The solvent was removed under reduced pressure. The residue was washed with water (50 mL), extracted with dichloromethane (3x50 mL), and washed with brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0-20:1 gradient elution) to give the product (120 mg, 60%). [M+H] + =631.2

[0892] Step 7: 2-(trans)-4-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridine (formamido)-2H-indazole-6-carboxylic acid

[0893]

[0894] To a solution of methyl 2-(trans)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxylate (120 mg, 0.19 mmol) in THF (2 mL) / MeOH (2 mL) / H2O (2 mL) was added LiOH.H2O (32 mg, 0.76 mmol). The mixture was stirred at rt for 5 h. The solvent was removed under reduced pressure. The pH of the residue was adjusted to 4-5 with 1N HCl. The mixture was filtered. The filter cake was concentrated under reduced pressure to give the product (115 mg, 98%). [M+H] + =617.2

[0895] Step 8: tert-Butyl 4-((trans)-4-(6-(cyclopropylcarbamoyl)-5-(6-(trifluoromethyl)picolinoyl) (amino)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[0896]

[0897] To a solution of 2-(trans)-4-(4-(tert-butyloxycarbonyl)piperazine-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxylic acid (90 mg, 0.15 mmol) in DMF (3 mL) was added HATU (61 mg, 0.16 mmol). The mixture was stirred at rt for 10 min. Cyclopropylamine (8 mg, 0.15 mmol) and EtN (46 mg, 0.45 mmol) were then added to the reaction. The reaction was stirred at rt for 4 h. The solvent was removed under reduced pressure. The residue was washed with water (15 mL), extracted with dichloromethane (3x20 mL), and washed with brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0-20:1 gradient elution) to give the product (70 mg, 73%). [M+H] + =656.6

[0898] Step 9: N-cyclopropyl-2-(trans)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinyl (amino)-2H-indazole-6-carboxamide hydrochloride

[0899]

[0900] To a solution of tert-butyl 4-((trans)-4-(6-(cyclopropylcarbamoyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (70 mg, 0.11 mmol) in DCM (5 mL) was added HCl / dioxane (1 mL, 4 N, 4 mmol) dropwise. The reaction was stirred at rt for 4 h. The mixture was concentrated under reduced pressure to give the product (55 mg, 92%). [M+H] + =556.3.

[0901] Step 10: N-cyclopropyl-2-(trans)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluoro (phenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indole oxazole-6-carboxamide

[0902]

[0903] To a solution of (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (14 mg, 0.042 mmol) in DMF (3 mL) was added HATU (18 mg, 0.046 mmol). The mixture was stirred at rt for 10 min. Then N-cyclopropyl-2-(trans)-4-(piperazine-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide hydrochloride (25 mg, 0.042 mmol) and Et in DMF (2 mL) N (46 mg, 0.45 mmol) were added to the reaction. The reaction was stirred at rt for 4 h. The solvent was removed by decompression. The residue was washed with water (15 mL), extracted with dichloromethane (3x20 mL), and washed with brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0-10:1 gradient elution) to give the product (5 mg, 14%). [M+H] + =862.6

[0904] 1 H NMR (500MHz, DMSO) δ12.39(s,1H),10.86(s,1H),8.88(s,1H),8.79(d,J=4.3Hz,1H),8.49(s,1H),8.43(d,J=7.9Hz,1H), 8.37(t,J=7.8Hz,1H),8.18(d,J=7.7Hz,1H),8.00(s,1H),6.17(d,J=11.1Hz,2H),4.58-4.41(m,1H),4.11-3.98(m,3H), 3.96-3.77(m,3H),3.54-3.44(m,2H),3.30-3.26(m,1H),3.00-2.87(m,1H),2.86-2.71(m,1H),2.57-2.52(m,2H),2.26- 1.86(m,10H),1.56-1.46(m,3H),1.31-1.18(m,2H),0.83(dt,J=24.3,8.6Hz,1H),0.75-0.70(m,2H),0.65-0.58(m,2H).

[0905] Example 129: N-cyclopropyl-2-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide

[0906]

[0907] The title compound was prepared in a manner similar to that described in Example 130 from N-cyclopropyl-2-(trans)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide hydrochloride (5.24 mg, 20% yield). 1 H NMR (500MHz, DMSO) δ12.39(s,1H),10.84(s,1H),8.88(s,1H),8.79(d,J=4.2Hz,1H),8.49(s,1H),8.43(d,J=7.4Hz,1 H),8.38(d,J=7.9Hz,1H),8.18(d,J=7.7Hz,1H),8.00(s,1H),6.23(d,J=12.2Hz,2H),4.55-4.46(m,1H),4.05-3.97(m ,1H),3.60-3.41(m,6H),3.37-3.33(m,1H),3.30-3.21(m,2H),2.97-2.90(m,1H),2.82-2.73(m,1H),2.65-2.56(m,2H) ),2.25-1.91(m,11H),1.58-1.44(m,2H),1.30-1.21(m,2H),0.90-0.78(m,1H),0.75-0.70(m,2H),0.65-0.57(m,2H). [M+H] + =876.6

[0908] Example 168: 2-((1R,4R)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide

[0909] Step 1: tert-Butyl 4-((1R,4r)-4-(6-(((1r,3R)-3-(hydroxymethyl)cyclobutyl)carbamoyl)- 5-(6-(Trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[0910]

[0911] To a solution of 2-(trans)-4-(4-(tert-butyloxycarbonyl)piperazine-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxylic acid (62 mg, 0.10 mmol) in DMF (3 mL) was added HATU (42 mg, 0.11 mmol). The mixture was stirred at rt for 10 min. Then ((1r, 3r)-3-aminocyclobutyl)methanol 2,2,2-trifluoroacetate (22 mg, 0.10 mmol) and EtN (46 mg, 0.45 mmol) in DMF (3 mL) were added to the reaction. The reaction was stirred at rt for 4 h. The solvent was removed by decompression. The residue was washed with water (15 mL), extracted with dichloromethane (3x20 mL), and washed with brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0-10:1 gradient elution) to give the product (50 mg, 72%). [M+H] + =700.2

[0912] Step 2: N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-2-((1r,4R)-4-(piperazin-1-yl)cyclohexyl)- 5-(6-(Trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide hydrochloride

[0913]

[0914] To a solution of tert-butyl 4-((1R,4r)-4-(6-(((1r,3R)-3-(hydroxymethyl)cyclobutyl)carbamoyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (50 mg, 0.07 mmol) in DCM (3 mL) was added HCl / dioxane (1 mL, 4 N, 4 mmol) dropwise. The reaction was stirred at rt for 4 h. The mixture was then cooled. The mixture was concentrated under reduced pressure to give the product (40 mg, 90%). [M+H] + =600.3.

[0915] Step 3: 2-((1R,4R)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl) (1-Pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-5-(6-(trifluoromethyl)cyclohexyl)-N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)- (2H-indazole-6-carboxamide)

[0916]

[0917] To a solution of (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (9 mg, 0.017 mmol) in DMF (1 mL) was added HATU (11 mg, 0.03 mmol). The mixture was stirred at room temperature for 10 min. N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-2-((1r,4R)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide hydrochloride (17 mg, 0.027 mmol) and EtN (46 mg, 0.45 mmol) in DMF (2 mL) were then added to the reaction. The reaction was stirred at room temperature for 4 h. The solvent was removed under reduced pressure. The residue was diluted with water (15 mL), extracted with dichloromethane (3 x 20 mL), and washed with brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM: MeOH = 100: 0-10: 1 gradient elution) to give the product (10 mg, 42%). [M+H] + =920.8

[0918] 1 H NMR (500MHz, DMSO) δ12.40 (s, 1H), 10.84 (s, 1H), 9.02 (d, J = 7.3Hz, 1H), 8.89 (s, 1H), 8.50 (s, 1H), 8.45-8. 34(m,2H),8.17(d,J=7.8Hz,1H),8.08(s,1H),6.23(d,J=12.3Hz,2H),4.60(t,J=5.2Hz,1H),4.55-4.41(m, 2H),4.06-4.00(m,1H),3.60-3.42(m,8H),3.37-3.33(m,1H),3.30-3.24(m,2H),3.15-2.95(m,3H),2.84-2 .73(m,2H),2.24-2.06(m,9H),2.01-1.91(m,5H),1.86-1.78(m,2H),1.68-1.61(m,1H),1.58-1.47(m,2H).

[0919] Example 167: 2-((1r,4R)-4-(4-(1-(4-((R)-2,6-dioxapiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide

[0920]

[0921] The title compound (7.24 mg, 30% yield) was prepared from N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-2-((1r,4R)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide hydrochloride in a manner similar to that described in Example 168. 1 H NMR(500MHz,DMSO)δ12.39(s,1H),10.86(s,1H),9.02(d,J=7.2Hz,1H),8.89(s,1H),8.50(s,1H), 8.44-8.33(m,2H),8.17(d,J=7.8Hz,1H),8.08(s,1H),6.17(d,J=11.1Hz,2H),4.67-4.43(m,3H), 4.09-3.99(m,3H),3.95-3.80(m,3H),3.53-3.42(m,4H),3.30-3.26(m,1H),2.82-2.73(m,1H),2. 32-2.04(m,9H),2.02-1.89(m,5H),1.57-1.47(m,2H),1.29-1.10(m,4H),0.89-0.72(m,2H).[M+H] + =906.7

[0922] Example 35: N-(2-(1-((1r,4r)-4-(4-(2,6-dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carbonyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0923]

[0924] The title compound was prepared in a manner analogous to that described in Example 41.

[0925] 1H NMR (500MHz, DMSO) δ10.79(s,1H),10.51(s,1H),8.69(s,1H),8.46(d,J=7.8Hz,1H),8.43-8.38(m,2H),8.22(d,J=7 .7Hz,1H),7.17(s,1H),7.11(d,J=8.6Hz,2H),6.91(d,J=8.6Hz,2H),4.75-4.67(m,1H),4.57-4.53(m,1H),4.34-4.2 5(m,1H),4.17-4.13(m,1H),3.98(s,3H),3.79-3.75(m,1H),3.31-3.22(m,2H),2.83-2.70(m,2H),2.68-2.61(m,1H ),2.22-2.06(m,5H),2.07-1.94(m,2H),1.93-1.82(m,1H),1.83-1.72(m,2H),1.67-1.51(m,2H),1.50-1.41(m,2H). [M+H] + =733.6.

[0926] Example 36: N-(2-((1R,4r)-4-((4-((R)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0927]

[0928] The title compound was prepared in a similar manner to that described in Example 6.

[0929] 1H NMR(500MHz,DMSO)δ10.50(s,1H),10.21(s,1H),8.69(s,1H),8.50-8.37(m,2H),8.33(s,1H),8.22( d,J=7.7Hz,1H),7.14(dd,J=35.1,10.4Hz,3H),6.53(d,J=8.7Hz,2H),4.54-4.29(m,1H),3.98(s,3H ),3.67(t,J=6.6Hz,2H),3.59-3.41(m,5H),3.38-3.34(m,1H),3.31-3.22(m,2H),2.68(t,J=6.6Hz, 2H),2.43-2.28(m,4H),2.23-2.09(m,5H),1.95-1.80(m,4H),1.71-1.57(m,2H),1.29-1.08(m,3H). [M+H] + =802.6

[0930] Example 32: N-(2-((1r,4r)-4-(1-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-carboxamido)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0931] Step 1: (1s,4s)-4-((tert-Butyloxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate

[0932]

[0933] To a mixture of tert-butyl ((1s, 4s)-4-hydroxycyclohexyl) carbamate (5.0 g, 23.22 mmol) and DMAP (284 mg, 2.32 mmol) in pyridine (50.0 mL) was added TsCl (5.31 g, 27.87 mmol) at 0 ° C and stirred at 20 ° C under N2 for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (40.0 mL) and extracted with EtOAc (50.0 mL). The organic layer was washed with 0.1M HCl (50.0 mL), Na2CO3 (50.0 mL) and brine (20.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was triturated with MTBE (50 ml) at 20 ° C for 20 min and filtered to give (1 s,4s)-4-((tert-Butyloxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate (4.2 g, 10.57 mmol, 45.52% yield). 1HNMR(400MHz, CDCl3-d)δppm 7.79(d,J=8.3Hz,2H),7.34(d,J=8.0Hz,2H),4.66(br s,1H),4.44(br s,1H),3.46(br s,1H),2.45(s,3H),1.87(br d,J=9.5Hz,2H),1.80-1.72(m,2H),1.62-1.55(m,2H),1.54-1.49(m,2H),1.43(s,9H); [M+Na] + =392.1.

[0934] Step 2: tert-Butyl ((1r, 4r)-4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indole oxazol-2-yl)cyclohexyl)carbamate

[0935]

[0936] To(1 s,4s)-4-((tert-Butyloxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate To a solution of 4-(6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (4.0 g, 10.83 mmol) and N-(6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (728 mg, 2.17 mmol) in DMF (50.0 mL) was added CsCO (3.5 g, 10.83 mmol). The mixture was stirred at 80° C. for 12 hours. At 20° C., the reaction mixture was quenched with H O (5.0 mL) and then extracted with EtOAc (5.0 mL*3). The combined organic layers were washed with brine (5 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC ([water(NH4HCO3)-ACN]; B%: 55%-75%, 20 min) to give tert-butyl ((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)carbamate (300.0 mg, 0.545 mmol, 25% yield). 1 HNMR(400MHz,CDCl3-d)δppm 10.74-10.67(m,1H),8.82(s,1H),8.50(d,J=7.8Hz,1H),8.12(t,J=7.9Hz,1H),7.86(t,J=3.8Hz,2H),7.07(s,1H),4.46(br d,J=3.5Hz,1H),4.37-4.27(m,1H),4.03(s,3H),3.68-3.54(m,1H),2.37-2.23(m,4H),2.13-2.03(m,2H),1.47(s,9H),1.38(br dd,J=2.9,12.1Hz,2H);[M+H] +=534.4.

[0937] Step 3: N-(2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl) Picolinamide, hydrochloride

[0938]

[0939] To a solution of tert-butyl ((1r, 4r) -4- (6- methoxy -5- (6- (trifluoromethyl) picolinamido) -2H- indazole -2- bases) cyclohexyl) carbamate (280.0 mg, 0.525 mmol) in DCM (4.0 mL) was added HCl / EtOAc (4 M, 1.3 mL). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give the product. N- (2- ((1r, 4r) -4- aminocyclohexyl) -6- methoxy -2H- indazole -5- bases) -6- (trifluoromethyl) picolinamide, hydrochloride (235.0 mg, 0.475 mmol, 91% yield) was obtained. 1 HNMR(400MHz,DMSO-d6)δpmm 10.50(s,1H),8.69(s,1H),8.48-8.44(m,1H),8.43-8.38(m,1H),8.34(s,1H),8.22(dd,J=1.1,7.6Hz,1H),8.09-8.05(m,2H), [M+H] + =434.2.

[0940] Step 4: N-(2-((1r,4r)-4-(1-(2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoindole-5-yl) (piperidine-4-carboxamido)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0941]

[0942] To a solution of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperidine-4-carboxylic acid (38.5 mg, 0.10 mmol) in DMF (3 mL) was added HATU (42 mg, 0.11 mmol). The mixture was stirred at rt for 10 min. N-(2-((1r, 4r)-4-aminocyclohexyl)-6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl)picolinamide, hydrochloride (47 mg, 0.10 mmol) and Et3N (46 mg, 0.45 mmol) in DMF (3 mL) were then added to the reaction. The reaction was stirred at rt for 4 h. The solvent was removed by decompression. The residue was diluted with water (15 mL), extracted with dichloromethane (3x20 mL), and washed with brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (DCM:MeOH=100:0-10:1 gradient elution) to give the product (12 mg, 14%). [M+H] + =801.5; 1 H NMR (500MHz, DMSO) δ11.08(s,1H),10.50(s,1H),8.68(s,1H),8.49-8.38(m,2H),8.35(s,1H),8.22(d,J=7.5Hz,1H) ,7.82(d,J=5Hz,1H),7.67(d,J=5Hz,1H),7.34(s,1H),7.26(d,J=10Hz,1H),7.17(s,1H),5.09-5.03(m,1H),4.50-4. 35(m,1H),4.17-4.03(m,2H),3.98(s,3H),3.71-3.60(m,1H),3.06-2.96(m,2H),2.89-2.84(m,1H),2.65-2.54(m,2H ),2.43-2.38(m,1H),2.17-2.09(m,2H),2.05-1.91(m,5H),1.82-1.73(m,2H),1.68-1.57(m,2H),1.50-1.36(m,2H).

[0943] Example 41: (R)-N-(2-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)azetidin-3-yl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0944] Step 1: N-(6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0945]

[0946] A mixture of 6-methoxy-2H-indazole-5-amine (2g, 12.27mmol), 6-(trifluoromethyl)picolinic acid (2.34g, 12.27mmol), T3P (12mL) and DIEA (2.37g, 18.4mmol) in THF (60mL) was stirred at room temperature for 16h. The reaction was monitored by LCMS. The resulting solution was extracted with DCM (2x50.0mL) and washed with water (60mL). The combined organic layers were washed with brine (50mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was further purified by silica gel column chromatography (PE:EA=5:1-1:2 gradient elution) to produce the product (2g, 48.5%). [M+H] + =337.1.

[0947] Step 2: tert-Butyl 4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)piperidin Pyridine-1-carboxylate

[0948]

[0949] A mixture of N-(6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (2 g, 6 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (3.6 g, 18 mmol) and cyanomethylenetri-n-butylphosphine (4.3 g, 18 mmol) in PhMe (80 mL) was stirred overnight at 100 ° C. in a round-bottom flask. The mixture was evaporated under vacuum to give a crude product, which was further purified by silica gel column chromatography (PE:EA=3:1-1:5 gradient elution) to produce the product (1.7 g, 54.6%). [M+H] + =520.5.

[0950] Step 3: N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide hydrochloride

[0951]

[0952] To tert-butyl 4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)piperidine-1-carboxylate (1.7 g, 3.27 mmol) in DCM (15 mL) was added 4N HCl / dioxane (30 mL) at 25 ° C. The mixture was stirred at 25 ° C for 1 h. The reaction was monitored by LCMS. The solid was filtered, washed with DCM (20.0 mL), and dried to obtain the product (1.3 g, 94.9%). [M+H] + =420.2.

[0953] Step 4: tert-Butyl 3-(4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl) Piperidin-1-yl)azetidine-1-carboxylate

[0954]

[0955] At room temperature, a mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazole-5-yl)-6-(trifluoromethyl)picolinamide hydrochloride (300 mg, 0.66 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (169 mg, 0.99 mmol) in DCM (30 mL) was stirred in a round-bottom flask for 16 h. NaBH(AcO)3 (419 mg, 1.98 mmol) was then added and stirred at room temperature for 3 hours. The reaction was quenched with water, and the mixture was washed once with a saturated NaHCO3 aqueous solution and then extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo to give the product (300 mg, 79.1%). [M+H] + =575.3.

[0956] Step 5: N-(2-(1-(azetidin-3-yl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6- (Trifluoromethyl)picolinamide trifluoroacetate

[0957]

[0958] To tert-butyl 3-(4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)piperidin-1-yl)azetidine-1-carboxylate (300 mg, 0.52 mmol) in DCM (8 mL) was added TFA (20 mL) at 25 ° C. The mixture was stirred at 25 ° C for 2 h. The reaction was monitored by LCMS. The solid was filtered, washed with DCM (20.0 mL), and dried to obtain the product (300 mg, 98%). [M+H] + =475.3.

[0959] Step 6: (R)-N-(2-(1-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine (trifluoromethyl)pyridine Formamide

[0960]

[0961] A mixture of (R) -1- (4- (2,6- dioxopiperidin-3-yl) -3,5- difluorophenyl) azetidine -3- carboxylic acid (30 mg, 0.093 mmol), HATU (43 mg, 0.112 mmol) and DIEA (36 mg, 0.279 mmol) in DMF (8 mL) was stirred at room temperature for 15 minutes, and N- (2- (1- (azetidine -3- bases) piperidin-4-yl) -6- methoxy -2H- indazole -5- bases) -6- (trifluoromethyl) picolinamide trifluoroacetate (55 mg, 0.093 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was monitored with LCMS. The resulting solution was extracted with DCM (2x15.0 mL) and water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give a crude product. The crude product was purified with preparative HPLC to obtain product (6 mg, 8%). 1 HNMR(500MHz,DMSO)δ10.86(s,1H),10.52(s,1H),8.71(s,1H),8.47(d,J=7.7Hz,1H),8.44-8 .37(m,2H),8.23(d,J=7.7Hz,1H),7.17(s,1H),6.17(d,J=11.2Hz,2H),4.53-4.29(m,1H),4.2 6-4.09(m,2H),4.10-3.92(m,7H),3.90-3.80(m,2H),3.66-3.54(m,2H),3.21-3.10(m,2H),3 .02-2.85(m,1H),2.83-2.73(m,1H),2.48-2.22(m,4H),2.20-2.01(m,4H),1.99-1.89(m,1H). [M+H] + =781.5.

[0962] Example 42: N-(2-(1-(1-((R)-1-(4-((R)-2,6-dioxapiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)azetidin-3-yl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0963]

[0964] The title compound was prepared in a manner analogous to that described in Example 41. 1H NMR (500MHz, DMSO) δ10.77(s,1H),10.44(s,1H),8.63(s,1H),8.40(d,J=7.8Hz,1H),8.37-8.30(m,2H ),8.15(d,J=7.7Hz,1H),7.10(s,1H),6.17(dd,J=12.0,8.5Hz,2H),4.43-4.33(m,1H),4.27-4.17(m,1 H),4.09-4.00(m,1H),3.99-3.90(m,4H),3.86(dt,J=14.9,4.2Hz,1H),3.73-3.61(m,1H),3.44-3.34( m,1H),3.23-3.06(m,6H),2.95-2.82(m,2H),2.77-2.65(m,1H),2.16-1.94(m,9H),1.93-1.82(m,1H). [M+H] + =795.6.

[0965] Example 43: N-(2-(1'-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-[1,4'-bipiperidinyl]-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0966]

[0967] The title compound was prepared in a manner analogous to that described in Example 41. 1 H NMR (500MHz, DMSO) δ10.84(s,1H),10.52(s,1H),8.72(s,1H),8.47(d,J=7.7Hz,1H),8.40(dd,J=15.8,7.9Hz, 2H),8.23(d,J=7.7Hz,1H),7.16(s,1H),6.23(d,J=12.8Hz,2H),4.87-4.69(m,1H),4.65-4.47(m,1H),4.30-4. 12(m,1H),4.08-3.93(m,4H),3.75-3.51(m,3H),3.49-3.43(m,2H),3.42-3.34(m,2H),3.17-3.05(m,2H),2.8 5-2.72(m,1H),2.68-2.52(m,2H),2.47-2.29(m,5H),2.22-2.01(m,6H),1.99-1.89(m,1H),1.76-1.40(m,2H). [M+H] + =823.7.

[0968] Example 44: N-(2-(1'-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)-[1,4'-bipiperidinyl]-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0969]

[0970] The title compound was prepared in a manner analogous to that described in Example 41. 1 HNMR(500MHz,DMSO)δ10.50(s,1H),10.23(s,1H),8.69(s,1H),8.46(d,J=7.6Hz,1H),8.41(t,J=7.8Hz,1H) ,8.37(s,1H),8.22(d,J=7.6Hz,1H),7.16(s,1H),7.11(d,J=8.5Hz,2H),6.46(d,J=8.6Hz,2H),4.48-4.29(m ,2H),4.10-3.95(m,5H),3.93-3.78(m,3H),3.74-3.58(m,3H),3.07-2.94(m,3H),2.76-2.64(m,2H),2.65- 2.59(m,2H),2.40-2.30(m,2H),2.16-1.98(m,4H),1.85-1.74(m,2H),1.47-1.37(m,1H),1.36-1.28(m,1H). [M+H] + =774.8.

[0971] Example 45: (R)-N-(2-(1'-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-[1,4'-bipiperidinyl]-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0972]

[0973] The title compound was prepared in a manner analogous to that described in Example 41. 1HNMR (500MHz, DMSO) δ10.79(s,1H),10.44(s,1H),8.62(s,1H),8.40(d,J=7.7Hz,1H),8.34(t,J=7.8Hz,1 H),8.30(s,1H),8.15(d,J=7.7Hz,1H),7.09(s,1H),6.10(d,J=11.1Hz,2H),4.45-4.28(m,2H),4.02-3.93 (m,3H),3.92(s,3H),3.89-3.82(m,3H),3.81-3.73(m,1H),3.66-3.56(m,1H),3.06-2.88(m,4H),2.76-2. 66(m,1H),2.60-2.50(m,3H),2.14-1.93(m,5H),1.93-1.82(m,1H),1.81-1.68(m,2H),1.44-1.21(m,2H). [M+H] + =809.5.

[0974] Example 102: 1-Cyclopropyl-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0975] Step 1: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate acid esters

[0976]

[0977] To a solution of methyl 4-formyl-3-nitrobenzoate (4.2 g, 20 mmol) in propan-2-ol (100 mL) was added tert-butyl 4-((1r, 4r)-4-aminocyclohexyl)piperazine-1-carboxylate (5.66 g, 20 mmol). The mixture was stirred at 80 ° C under N2 for 3 h. Tributylphosphine (12.12 g, 60 mmol) was added to the above solution. The mixture was stirred at 80 ° C under N2 overnight. The mixture was cooled to rt and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM: MeOH = 30: 1) to produce the product (7 g, 79%). [M+H] + =443.3

[0978] Step 2: Methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

[0979]

[0980] To a solution of methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (7 g, 15.84 mmol) in concentrated H2SO4 (80 mL) was added NaNO3 (1.615 g, 19 mmol) at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was quenched with ice water, then adjusted to pH 9 with saturated Na2CO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the product (4.8 g, 78%), which was used without further purification. [M+H] + =388.2

[0981] Step 3: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indole oxazole-6-carboxylate

[0982]

[0983] To a solution of methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (4.8 g, 12.4 mmol) in DCM (60 mL) was added Et3N (3.76 g, 37.2 mmol) and Boc2O (4.06 g, 18.6 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH=30:1) to give the product (4.9 g, 81%). [M+H] + =488.2

[0984] Step 4: Methyl 5-amino-2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indole oxazole-6-carboxylate

[0985]

[0986] To a solution of methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate (4.9 g, 10.06 mmol) in MeOH (50 mL) and water (10 mL) was added NH4Cl (2.69 g, 50.3 mmol) and Fe powder (2.82 g, 50.3 mmol) at room temperature. The resulting mixture was stirred at 70 ° C for 2 hours. The mixture was cooled to rt and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH=15:1) to give the product (3.2 g, 70%). [M+H] + =458.3

[0987] Step 5: tert-Butyl 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexane 1-Methyl-1-piperazine-1-carboxylate

[0988]

[0989] To a solution of methyl 5-amino-2-((1r, 4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (1.2 g, 2.62 mmol) and LiCl (0.557 g, 13.1 mmol) in THF (20 mL) was added dropwise MeMgBr (1 M, 26.2 mL, 26.2 mmol) in THF at 0°C. The resulting mixture was stirred at 0°C for 2 hours. The mixture was quenched with saturated NH4Cl solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to give the product (0.48 g, 40%). [M+H] + =458.3

[0990] Step 6: tert-Butyl 4-((1r,4r)-4-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide 2-(2-Hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[0991]

[0992] To a solution of tert-butyl 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (0.48 g, 1.05 mmol) and 1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.189 g, 1.05 mmol) in DMF (10 mL) was added DIPEA (0.406 g, 3.15 mmol) and HATU (0.4 g, 1.05 mmol) at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the product (0.4 g, 62%). [M+H] + =619.4

[0993] Step 7: 1-cyclopropyl-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0994]

[0995] To a solution of tert-butyl 4-((1r,4r)-4-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (0.4 g, 0.647 mmol) in DCM (10 mL) was added TFA (2 mL) at rt. The resulting mixture was stirred at rt for 1 h. The mixture was quenched with saturated NaHCO solution and extracted with DCM. The combined organic layers were dried over anhydrous NaSO, filtered and evaporated in vacuo to give the product (0.275 g, 82%). [M+H] + =519.3

[0996] Step 8: 1-cyclopropyl-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5- difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)- 2-Oxo-1,2-dihydropyridine-3-carboxamide

[0997]

[0998] To a solution of 1-cyclopropyl-N-(6-(2-hydroxypropan-2-yl)-2-((1r, 4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (41.44 mg, 0.08 mmol) and (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (25.92 mg, 0.08 mmol) in DCM (5 mL) was added DIPEA (31 mg, 0.24 mmol) and T3P (50%, 102 mg, 0.16 mmol) in EtOAc at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography) (0.1% FA in water: acetonitrile = 90:10-60:40 gradient elution) to give the desired product (20 mg, 30%). [M+H] + =825.4 1H NMR (500MHz, DMSO) δ12.04(s,1H),10.86(s,1H),8.38(d,J=5.0Hz,1H),8.28(s,1H),8.16(s,1H),7.92(d,J=5.0Hz, 1H),7.58(s,1H),6.46(t,J=10.0Hz,2H),6.18(s,1H),6.16(s,1H),5.40(s,1H),4.46-4.38(m,1H),4.07-4.02(m,3 H),3.94-3.89(m,2H),3.86-3.80(m,1H),3.52-3.45(m,3H),3.29-3.27(m,2H),2.81-2.73(m,1H),2.56-2.51(m,2H ),2.49-2.41(m,4H),2.20-2.01(m,3H),2.00-1.89(m,5H),1.59-1.41(m,8H),1.10-1.03(m,2H),0.97-0.92(m,2H).

[0999] Example 103: 1-Cyclopropyl-N-(2-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[1000]

[1001] To a solution of 1-cyclopropyl-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (20.72 mg, 0.04 mmol) and (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (13.52 mg, 0.04 mmol) in DCM (5 mL) was added DIPEA (15.48 mg, 0.12 mmol) and T3P (50%, 50.78 mg, 0.08 mmol) in EtOAc at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography) (0.1% FA in water: acetonitrile = 90:10-60:40 gradient elution) to give the desired product (9.75 mg, 30.4%). [M+H]+ =839.4 1 H NMR(500MHz,DMSO)δ12.05(s,1H),10.85(s,1H),9.65(s,1H),8.38(d,J=5.0Hz,1H),8.31(s,1H),8.18(s,1H), 7.93(d,J=5.0Hz,1H),7.58(s,1H),6.47(t,J=10.0Hz,2H),6.26(s,1H),6.23(s,1H),5.42(s,1H),4.58-4.50(m ,2H),4.31-4.24(m,1H),4.02(dd,J=10.0Hz,5.0Hz,1H),3.61-3.40(m,8H),3.29-3.18(m,4H),3.15-2.97(m,2H ),2.82-2.71(m,1H),2.33-1.90(m,10H),1.80-1.70(m,2H),1.57(s,6H),1.10-1.05(m,2H),0.97-0.93(m,2H).

[1002] Example 117: (R)-1-Cyclopropyl-N-(2-(1'-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-[1,4'-bipiperidinyl]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[1003] Step 1: Methyl 2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-5-(1-cyclopropyl-2-oxo- 1,2-Dihydropyridine-3-carboxamido)-2H-indazole-6-carboxylate

[1004]

[1005] To a solution of methyl 5-amino-2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-2H-indazole-6-carboxylate (0.4 g, 0.875 mmol) and 1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.157 g, 0.875 mmol) in DMF (10 mL) was added DIPEA (0.339 g, 2.625 mmol) and HATU (0.332 g, 0.875 mmol) at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the product (0.41 g, 75.8%). [M+H] + =619.3

[1006] Step 2: tert-Butyl 4-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-6-(2-hydroxy Propan-2-yl)-2H-indazol-2-yl)-[1,4'-bipiperidinyl]-1'-carboxylate

[1007]

[1008] To a solution of methyl 2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-5-(1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-2H-indazole-6-carboxylate (0.41 g, 0.663 mmol) and LiCl (0.141 g, 3.315 mmol) in THF (10 mL) was added dropwise MeMgBr (1 M, 6.63 mL, 6.63 mmol) in THF at 0°C. The resulting mixture was stirred at 0°C for 2 hours. The mixture was quenched with saturated NH4Cl solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the product (0.18 g, 43.9%). [M+H] + =619.4

[1009] Step 3: N-(2-([1,4'-bipiperidinyl]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-1-cyclohexane Propyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[1010]

[1011] To a solution of tert-butyl 4-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)-[1,4'-bipiperidine]-1'-carboxylate (0.18 g, 0.291 mmol) in DCM (10 mL) was added TFA (2 mL) at rt. The resulting mixture was stirred at rt for 1 h. The mixture was quenched with saturated NaHCO solution and extracted with DCM. The combined organic layers were dried over anhydrous NaSO, filtered and evaporated in vacuo to give the product (0.11 g, 73.3%). [M+H] + =519.3

[1012] Step 4: (R)-1-cyclopropyl-N-(2-(1'-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)-1-nitropropane Heterocyclobutane-3-carbonyl)-[1,4'-bipiperidinyl]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo- 1,2-Dihydropyridine-3-carboxamide

[1013]

[1014] To a solution of N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (41 mg, 0.08 mmol) and (R)-1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (26 mg, 0.08 mmol) in DCM (5 mL) was added DIPEA (31 mg, 0.24 mmol) and T3P (50%, 102 mg, 0.16 mmol) in EtOAc at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography) (0.1% FA in water: acetonitrile = 90:10-60:40 gradient elution) to give the desired product (32.08 mg, 48.7%). [M+H] + =825.4 1 H NMR (500MHz, DMSO) δ12.05(s,1H),10.85(s,1H),8.38(d,J=5.0Hz,1H),8.33(s,1H),8.16(s,1H),7.93(d,J=5.0Hz,1H),7.58(s, 1H),6.46(t,J=10.0Hz,2H),6.18(s,1H),6.16(s,1H),5.40(s,1H),4.45-4.38(m,2H),4.07-4.00(m,3H),3.95-3.89(m,2H),3.8 5-3.80(m,1H),3.68-3.62(m,1H),3.53-3.46(m,1H),3.14-2.95(m,3H),2.81-2.72(m,1H),2.63-2.56(m,2H),2.43-2.32(m,2H) ,2.12-2.01(m,5H),1.97-1.90(m,1H),1.82-1.75(m,2H),1.57(s,6H),1.45-1.25(m,2H),1.10-1.04(m,2H),0.97-0.92(m,2H).

[1015] Example 118: 1-Cyclopropyl-N-(2-(1'-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-[1,4'-bipiperidinyl]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[1016]

[1017] To a solution of N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (41 mg, 0.08 mmol) and (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (27 mg, 0.08 mmol) in DCM (5 mL) was added DIPEA (31 mg, 0.24 mmol) and T3P (50%, 102 mg, 0.16 mmol) in EtOAc at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography) (0.1% FA in water: acetonitrile = 90:10-60:40 gradient elution) to give the desired product (20.81 mg, 31%). [M+H] + =839.4 1 H NMR (500MHz, DMSO) δ12.04(s,1H),10.84(s,1H),8.38(d,J=5.0Hz,1H),8.33(s,1H),8.16(s,1H),7.92(d,J=5.0Hz,1H),7.58(s,1H), 6.46(t,J=10.0Hz,2H),6.23(s,1H),6.20(s,1H),5.41(s,1H),4.44-4.38(m,2H),4.10-3.98(m,2H),3.95-3.89(m,2H),3.85-3.80(m ,1H),3.68-3.62(m,1H),3.53-3.46(m,1H),3.14-2.95(m,3H),2.81-2.72(m,1H),2.63-2.56(m,2H),2.48-2.33(m,4H),2.20-2.01(m ,7H),1.97-1.90(m,1H),1.87-1.77(m,2H),1.57(s,6H),1.53-1.40(m,1H),1.33-1.21(m,1H),1.10-1.02(m,2H),0.97-0.92(m,2H).

[1018] Example 160: (R)-N-(2-(1'-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-[1,4'-bipiperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[1019] Step 1: tert-Butyl 4-(6-bromo-2H-indazol-2-yl)-[1,4'-bipiperidine]-1'-carboxylate

[1020]

[1021] To a solution of 4-bromo-2-nitrobenzaldehyde (2.3 g, 10 mmol) in propan-2-ol (50 mL) was added tert-butyl 4-amino-[1,4'-bipiperidine]-1'-carboxylate (2.83 g, 10 mmol). The mixture was stirred at 80 ° C under N2 for 3 h. Tributylphosphine (6.06 g, 30 mmol) was added to the above solution. The mixture was stirred at 80 ° C under N2 overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH = 30: 1) to give the product (3.5 g, 76%). [M+H] + =463.2

[1022] Step 2: Methyl 2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-2H-indazole-6-carboxylate

[1023]

[1024] To a solution of tert-butyl 4-(6-bromo-2H-indazol-2-yl)-[1,4'-bipiperidine]-1'-carboxylate (3.5 g, 7.58 mmol) and Et3N (2.3 g, 22.74 mmol) in MeOH (40 mL) was added Pd(dppf)Cl2 (0.555 g, 0.758 mmol) at rt. The mixture was stirred at 80°C under CO(g) overnight. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH=30:1) to give the product (2.5 g, 75%). [M+H] + =443.3

[1025] Step 3: Methyl 2-([1,4'-bipiperidinyl]-4-yl)-5-nitro-2H-indazole-6-carboxylate

[1026]

[1027] To a solution of methyl 2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-2H-indazole-6-carboxylate (2.5 g, 5.66 mmol) in concentrated H2SO4 (30 mL) was added NaNO3 (0.577 g, 6.792 mmol) at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was quenched with ice water, then adjusted to pH 9 with saturated Na2CO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the product (1.5 g, 68.5%), which was used without further purification. [M+H] + =388.2

[1028] Step 4: Methyl 2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-5-nitro-2H-indazole-6-carboxylate acid esters

[1029]

[1030] To a stirred solution of methyl 2-([1,4'-bipiperidinyl]-4-yl)-5-nitro-2H-indazole-6-carboxylate (1.5 g, 3.88 mmol) in DCM (20 mL) was added Et3N (1.176 g, 11.64 mmol) and Boc2O (1.269 g, 5.82 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH=30:1) to give the product (1.6 g, 84.5%). [M+H] + =488.2

[1031] Step 5: Methyl 5-amino-2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-2H-indazole-6-carboxylate acid esters

[1032]

[1033] To a solution of methyl 2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-5-nitro-2H-indazole-6-carboxylate (1.6 g, 3.29 mmol) in MeOH (20 mL) and water (4 mL) was added NH4Cl (0.88 g, 16.45 mmol) and Fe powder (0.92 g, 16.45 mmol) at room temperature. The resulting mixture was stirred at 70 ° C for 2 h. The mixture was cooled to rt and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH=15:1) to give the product (0.9 g, 60%). [M+H] + =458.3

[1034] Step 6: Methyl 2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-5-(6-(trifluoromethyl)pyridine (formamido)-2H-indazole-6-carboxylate

[1035]

[1036] To a solution of methyl 5-amino-2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-2H-indazole-6-carboxylate (0.4 g, 0.875 mmol) and 6-(trifluoromethyl)picolinic acid (0.167 g, 0.875 mmol) in DMF (10 mL) was added DIPEA (0.339 g, 2.625 mmol) and HATU (0.332 g, 0.875 mmol) at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the product (0.4 g, 72.6%). [M+H] + =631.3

[1037] Step 7: Tert-butyl 4-(6-(2-hydroxypropan-2-yl)-5-(6-(trifluoromethyl)picolinamido)-2H-indole oxazol-2-yl)-[1,4'-bipiperidinyl]-1'-carboxylate

[1038]

[1039] To a solution of methyl 2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidinyl]-4-yl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxylate (0.4 g, 0.635 mmol) and LiCl (0.135 g, 3.175 mmol) in THF (10 mL) was added dropwise MeMgBr (1 M, 6.4 mL, 6.4 mmol) in THF at 0°C. The resulting mixture was stirred at 0°C for 2 h. The mixture was quenched with saturated NH4Cl solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the product (0.24 g, 60%). [M+H] + =631.3

[1040] Step 8: N-(2-([1,4'-bipiperidinyl]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(tri (fluoromethyl)picolinamide

[1041]

[1042] To a solution of tert-butyl 4-(6-(2-hydroxypropan-2-yl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)-[1,4'-bipiperidine]-1'-carboxylate (0.24 g, 0.381 mmol) in DCM (10 mL) was added TFA (2 mL) at rt. The resulting mixture was stirred at rt for 1 h. The mixture was quenched with saturated NaHCO solution and extracted with DCM. The combined organic layers were dried over anhydrous NaSO, filtered and evaporated in vacuo to give the product (0.17 g, 85%). [M+H] + =531.3

[1043] Step 9: (R)-N-(2-(1'-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine- 3-carbonyl)-[1,4'-bipiperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine Formamide

[1044]

[1045] To a solution of N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (21 mg, 0.04 mmol) and (R)-1-(4-(2,6-dioxopiperidine-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (13 mg, 0.04 mmol) in DCM (5 mL) was added DIPEA (15 mg, 0.12 mmol) and T3P (50%, 51 mg, 0.08 mmol) in EtOAc at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography) (0.1% FA in water: acetonitrile = 90:10-60:40 gradient elution) to give the desired product (7.27 mg, 22%). [M+H] + =837.3 1H NMR (500MHz, DMSO) δ12.37(s,1H),10.86(s,1H),8.72(s,1H),8.45(d,J=10.0Hz,1H),8.40(s,1H),8.38(t,J=5.0H z,1H),8.16(d,J=10.0Hz,1H),7.57(s,1H),6.18(s,1H),6.16(s,1H),5.94(s,1H),4.44-4.38(m,2H),4.10-3.98( m,3H),3.95-3.89(m,2H),3.85-3.79(m,1H),3.68-3.62(m,1H),3.04-2.95(m,3H),2.81-2.72(m,1H),2.64-2.55( m,3H),2.45-2.32(m,2H),2.23-2.01(m,5H),1.97-1.90(m,1H),1.82-1.75(m,2H),1.62(s,6H),1.44-1.24(m,2H).

[1046] Example 161: N-(2-(1'-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-[1,4'-bipiperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[1047]

[1048] To a solution of N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (42 mg, 0.08 mmol) and (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (27 mg, 0.08 mmol) in DCM (5 mL) was added DIPEA (31 mg, 0.24 mmol) and T3P (50%, 102 mg, 0.16 mmol) in EtOAc at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography) (0.1% FA in water: acetonitrile = 90:10-60:40 gradient elution) to give the desired product (27 mg, 39%). [M+H] + =851.4 1H NMR (500MHz, DMSO) δ12.37(s,1H),10.84(s,1H),8.72(s,1H),8.45(d,J=10.0Hz,1H),8.40(s,1H),8.37(t,J=5.0Hz,1H),8 .16(d,J=10.0Hz,1H),7.57(s,1H),6.23(t,J=10.0Hz,2H),5.94(s,1H),4.44-4.38(m,2H),4.10-3.98(m,2H),3.58-3.50(m ,1H),3.48-3.40(m,1H),3.36-3.31(m,2H),3.29-3.21(m,2H),3.10-2.98(m,3H),2.81-2.72(m,1H),2.64-2.55(m,2H),2.4 4-2.35(m,2H),2.20-2.01(m,7H),1.97-1.90(m,1H),1.87-1.76(m,2H),1.62(s,6H),1.52-1.38(m,1H),1.35-1.22(m,1H).

[1049] Example 162: (R)-N-(2-(1'-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-[1,4'-bipiperidinyl]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[1050]

[1051] To a solution of N-(2-([1,4'-bipiperidinyl]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (42 mg, 0.08 mmol) and (R)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carboxylic acid (obtained in a similar manner to common intermediate B) (24 mg, 0.08 mmol) in DCM (5 mL) was added DIPEA (31 mg, 0.24 mmol) and T3P (50%, 102 mg, 0.16 mmol) in EtOAc at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography) (0.1% FA in water: acetonitrile = 90:10-60:40 gradient elution) to give the desired product (25.18 mg, 39%). [M+H] +=816.4 1 H NMR (500MHz, DMSO) δ12.37(s,1H),10.21(s,1H),8.72(s,1H),8.45(d,J=10.0Hz,1H),8.40(s,1H),8.37(t,J=5 .0Hz,1H),8.16(d,J=10.0Hz,1H),7.58(s,1H),7.10(d,J=10.0Hz,2H),6.54(t,J=10.0Hz,2H),5.94(s,1H),4.4 4-4.38(m,2H),4.14-4.05(m,1H),3.67(t,J=10.0Hz,2H),3.58-3.42(m,2H),3.29-3.23(m,2H),3.11-2.98(m,3 H),2.69-2.55(m,4H),2.44-2.35(m,3H),2.21-2.01(m,6H),1.89-1.78(m,2H),1.62(s,6H),1.52-1.26(m,2H).

[1052] Example 163: (S)-N-(2-(1'-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-[1,4'-bipiperidinyl]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[1053]

[1054] To a solution of N-(2-([1,4'-bipiperidinyl]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (42 mg, 0.08 mmol) and (S)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carboxylic acid (obtained in a similar manner to common intermediate B) (24 mg, 0.08 mmol) in DCM (5 mL) was added DIPEA (31 mg, 0.24 mmol) and T3P (50%, 102 mg, 0.16 mmol) in EtOAc at rt. The resulting mixture was stirred at rt for 2 hours. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography) (0.1% FA in water: acetonitrile = 90:10-60:40 gradient elution) to give the desired product (32.95 mg, 51%). [M+H] + =816.4 1H NMR (500MHz, DMSO) δ12.37(s,1H),10.21(s,1H),8.72(s,1H),8.45(d,J=10.0Hz,1H),8.40(s,1H),8.37(t,J=5.0Hz ,1H),8.16(d,J=10.0Hz,1H),7.58(s,1H),7.10(d,J=10.0Hz,2H),6.54(t,J=10.0Hz,2H),5.94(s,1H),4.44-4.38(m ,2H),4.14-4.05(m,1H),3.67(t,J=10.0Hz,2H),3.58-3.42(m,2H),3.38-3.31(m,1H),3.29-3.23(m,2H),3.11-2.98 (m,3H),2.69-2.55(m,4H),2.44-2.35(m,2H),2.21-2.01(m,6H),1.89-1.78(m,2H),1.62(s,6H),1.50-1.25(m,2H).

[1055] Example 178: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxapiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1056] Step 1: 3,3-diethoxy-2-formylpropionitrile potassium salt

[1057]

[1058] At 10 ℃, to 3,3-diethoxypropionitrile (14.3g, 100mmol) and methyl formate (7.5g, 125mmol) in anhydrous THF (100mL) stirring solution, add 1.0M potassium tert-butoxide (110ml, 110mmol) in THF.During 45 minutes of addition, the temperature was maintained at 10 ℃ to 15 ℃.Then the resulting slurry was stirred at ambient temperature for 2 hours.Then hexane (400mL) was added and the mixture was stirred for another 20min.The slurry was filtered and the filter cake was washed with 1:1 hexane / THF and dried under vacuum to provide product (16g, 76mmol, 76%).

[1059] Step 2: Pyrrolo[1,2-b]pyridazine-3-carbonitrile

[1060]

[1061] A stirred suspension of 3,3-diethoxy-2-formylpropionitrile potassium salt (9 g, 42.85 mmol) in MeOH (80 ml) was cooled to 0 ° C, and concentrated HCl (13.73 mL, 178.5 mmol) was added dropwise. After the addition was complete, the reaction was stirred at room temperature for 20 minutes. A solution of 1-aminopyrrole (1.95 g, 23.80 mmol) in methanol (10 mL) was added to the reaction mixture. After the addition, the reaction mixture was refluxed and stirred at 90 ° C for 2 hours, cooled to room temperature and concentrated to about half of the original volume. Saturated aqueous sodium bicarbonate solution was carefully added to the resulting residue until bubbling stopped. The solution was extracted with two portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (PE: EA = 3: 1) to provide the product (2.1 g, 14.6 mmol, 61.7%). [M+H] + = 144.6.

[1062] Step 3: 7-Bromopyrrolo[1,2-b]pyridazine-3-carbonitrile

[1063]

[1064] To a solution of pyrrolo[1,2-b]pyridazine-3-carbonitrile (2.8 g, 19.6 mmol) in MeCN (50 mL) was added N-bromosuccinimide (3.48 g, 19.6 mmol) at room temperature. The reaction was stirred at room temperature for 30 minutes and then poured into saturated aqueous sodium bicarbonate. The solution was concentrated under vacuum to remove acetonitrile. The resulting aqueous layer was extracted with three portions of EtOAc. The combined organic layers were dried over sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (PE: DCM = 7: 3) to provide the product (1.5 g, 6.75 mmol, 34%). [M+H] + =222.6.

[1065] Step 4: 3-cyanopyrrolo[1,2-b]pyridazine-7-carboxylic acid

[1066]

[1067] To a high pressure reactor was added 7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (500 mg, 2.25 mmol), Pd(dppf)Cl2(79.86 mg, 0.11 mmol), Pd(OAc)2(25.28 mg, 0.11 mmol), Xantphos(130 mg, 0.23 mmol) and a suspension of TEA(682 mg, 6.75 mmol) in THF / H2O(30 mL / 10 mL). The reactor was stirred at 100 ° C under a CO atmosphere (40 atm) for 15 h. The suspension was then concentrated under vacuum. The residue was diluted with water (30 mL) and acidified to pH=3 with HCl (2 N in water). The mixture was then extracted with DCM / i-PrOH=3 / 1 (50 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by Combi-Flash chromatography (silica gel column, 12 g, DCM:MeOH=10:1) to give the product (250 mg, 1.33 mmol, 59%). [M+H] + =188.6.

[1068] Step 5: tert-Butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6- (2-Hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[1069]

[1070] To a stirred solution of 3-cyanopyrrolo[1,2-b]pyridazine-7-carboxylic acid (30 mg, 0.16 mmol) and tert-butyl 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (66 mg, 0.15 mmol) in DMF (3 mL) was added HATU (66 mg, 0.17 mmol) and DIEA (29 mg, 0.45 mmol). The solution was stirred at rt for 4 h. The solution was then diluted with EA (20 mL), washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by Combi-Flash chromatography (silica gel column, 4 g, DCM:MeOH=20:1) to give the product (55 mg, 0.09 mmol, 58%). [M+H] + =627.6.

[1071] Step 6: 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H- Indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1072]

[1073] To a stirred solution of tert-butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (55 mg, 0.09 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at rt for 2 h and concentrated under vacuum to give the crude product (60 mg). [M+H] + =527.6.

[1074] Step 7: 3-cyano-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-dioxopiperidin-3-yl)- (fluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolidone Pyrrolidine[1,2-b]pyridazine-7-carboxamide

[1075]

[1076] At room temperature, to a solution of crude 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r, 4r)-4-(piperazine-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (60 mg, 0.09 mmol), (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (32.4 mg, 0.10 mmol) and DIEA (35 mg, 0.272 mmol) in DCM (3 mL) was added dropwise T3P (72 mg, 0.227 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (20 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give a crude residue, which was purified by silica gel column chromatography (DCM:MeOH=100:0-10:1 gradient elution) to give the product, which was further purified by preparative HPLC (C-18 column chromatography) (0.1% FA in water:acetonitrile=90:10-60:40 gradient elution) to give the desired product (23.5 mg, 31%).

[1077] 1H NMR (500MHz, DMSO) δ12.02(s,1H),10.86(s,1H),8.93(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.55(s,1H),8.34( s,1H),7.72(d,J=4.7Hz,1H),7.57(s,1H),7.09(d,J=4.7Hz,1H),6.17(d,J=11.1Hz,2H),5.72(s,1H),4.43(t,J=1 1.4Hz,1H),4.10-4.00(m,3H),3.92(t,J=6.3Hz,2H),3.86-3.79(m,1H),3.49(s,2H),2.83-2.73(m,1H),2.58-2. 44(m,8H),2.18(d,J=8.8Hz,2H),2.09-2.03(m,1H),1.99-1.94(m,5H),1.63(s,6H),1.50(q,J=11.8Hz,2H).[M+H] + =833.5.

[1078] Example 105: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1079]

[1080] The title compound was prepared in a manner similar to that described in Example 178 (15 mg, 23.7%). 1H NMR (500MHz, DMSO) δ12.02(s,1H),10.50(s,1H),8.93(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.55(s,1H),8.34(s,1H ),7.72(d,J=4.5Hz,1H),7.57(s,1H),7.09(d,J=4.5Hz,1H),6.25(d,J=10.0Hz,2H),5.73(s,1H),4.48-4.35(m,1H),4 .06(t,J=8.0Hz,2H),3.95(t,J=6.5Hz,2H),3.88-3.82(m,1H),3.59(t,J=6.6Hz,2H),3.51-3.46(m,2H),2.68(t,J=6. 6Hz,2H),2.60-2.52(m,5H),2.41-2.34(m,2H),2.22-2.15(m,2H),1.99-1.92(m,4H),1.63(s,6H),1.53-1.47(m,2H). [M+H] + =834.5.

[1081] Example 110: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxapiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1082]

[1083] The title compound was prepared in a similar manner to that described in Example 9 (3 mg, 3.2%). 1H NMR(500MHz,DMSO)δ12.02(s,1H),10.86(s,1H),8.93(s,1H),8.74(s,1H),8.55(s,1H),8.33(s,1H),7.71(s ,1H),7.57(s,1H),7.09(s,1H),6.12(d,J=11.5Hz,2H),5.72(s,1H),4.45-4.38(m,1H),4.21(s,1H),4.05-4 .01(m,1H),3.93-3.87(m,2H),3.66-3.61(m,2H),3.25-3.23(m,2H),2.80-2.75(m,1H),2.60-2.55(s,4H),2 .36(s,4H),2.25(s,1H),2.19-2.14(s,2H),2.06(s,1H),1.97-1.91(m,4H),1.63(s,6H),1.53-1.45(m,3H). [M+H] + =805.7.

[1084] The compound can also be synthesized in another way.

[1085] Step 1: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate acid esters

[1086]

[1087] To a solution of methyl 4-formyl-3-nitrobenzoate (104.5 g, 500 mmol) in propan-2-ol (1000 mL) was added tert-butyl 4-((1r, 4r)-4-aminocyclohexyl)piperazine-1-carboxylate (141.5 g, 500 mmol). The mixture was stirred at 80 ° C under N2 for 3 h. Tri-n-butylphosphine (303 g, 1500 mmol) was added to the above solution. The mixture was stirred at 80 ° C under N2 overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was slurried with petroleum ether (3000 mL) and filtered. The solid was filtered and dried under vacuum to produce the product (160 g, 72.4%). [M+H] + =443.1

[1088] Step 2: Methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

[1089]

[1090] To a solution of methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (160 g, 362 mmol) in concentrated H2SO4 (98%, 1000 mL) was added NaNO3 (46.155 g, 543 mmol) at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was quenched with ice water, then adjusted to pH 9 with saturated Na2CO3 solution and dried over DCM (3% HCl). x The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give the product (140 g, crude), which was used without further purification. [M+H] + =388.1

[1091] Step 3: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indole oxazole-6-carboxylate

[1092]

[1093] To a stirred solution of methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (140 g crude, 362 mmol) in DCM (1200 mL) was added Et3N (109.686 g, 1086 mmol) and Boc2O (94.7 g, 434.4 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=30:1) to give the product (150 g, 84.9%). [M+H] + =488.1

[1094] Step 4: Methyl 5-amino-2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indole oxazole-6-carboxylate

[1095]

[1096] To a solution of methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate (150 g, 308 mmol) in THF (1500 mL) was added Pd / C (5%, 30 g) at room temperature. The resulting mixture was stirred at room temperature under H2 overnight. The solid was filtered and washed with MeOH (800 mL). The filtrate was evaporated in vacuo to give the product (120 g, 85.2%). [M+H] + =458.2

[1097] Step 5: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(2,2,2-trifluoromethyl) (acetylamino)-2H-indazole-6-carboxylate

[1098]

[1099] To a solution of methyl 5-amino-2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (120 g, 262.58 mmol) in DCM (1000 mL) was added trifluoroacetic anhydride (66.15 g, 315 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was quenched with ice water, then adjusted to pH 8 with saturated NaHCO3 solution and washed with DCM (3% HCl). x The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=30:1) to give the product (132 g, 90.9%). [M+H] + =554.2

[1100] Step 6: tert-butyl 4-((1r,4r)-4-(6-(2-hydroxypropan-2-yl)-5-(2,2,2-trifluoroacetylamino)- 2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[1101]

[1102] To a solution of methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(2,2,2-trifluoroacetamido)-2H-indazole-6-carboxylate (132 g, 238.698 mmol) and LiCl (50.723 g, 1193.49 mmol) in THF (1500 mL) was added dropwise MeMgBr (3 M, 795.66 mL, 2386.98 mmol) in THF at 0°C. The resulting mixture was stirred at 0°C overnight. The mixture was quenched with saturated NH4Cl solution and quenched with EtOAc (3 mL). x The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the product (105 g, 79.55%). [M+H] + =554.2

[1103] Step 7: tert-Butyl 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexane 1-Methyl-1-piperazine-1-carboxylate

[1104]

[1105] To a solution of tert-butyl 4-((1r,4r)-4-(6-(2-hydroxypropan-2-yl)-5-(2,2,2-trifluoroacetamido)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (105 g, 189.87 mmol) in MeOH (1000 mL) was added NaOH solution (2 M, 950 mL, 1898.7 mmol) at room temperature. 。 The mixture was stirred at 70°C for 2 h. The mixture was cooled to room temperature, diluted with water (600 mL) and washed with DCM / MeOH (V / V=10 / 1, 5 x The product was extracted with 1000 mL of ethanol (1000 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was slurried with petroleum ether (1000 mL) and filtered. The solid was filtered and dried under vacuum to yield the product (80 g, 92.2%). [M+H] + =458.2

[1106] Step 8: tert-Butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6- (2-Hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[1107]

[1108] To a stirred solution of 3-cyanopyrrolo[1,2-b]pyridazine-7-carboxylic acid (36 g, 192.56 mmol) and tert-butyl 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (80 g, 175.05 mmol) in DMF (1000 mL) was added HATU (79.822 g, 210.06 mmol) and DIEA (67.744 g, 525.15 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (3000 mL). The solid was collected by filtration and washed with water (3000 mL). x The solid was dried under vacuum to give the product (90 g, 82.13%). [M+H] + =627.5

[1109] Step 9: 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H- Indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1110]

[1111] To a stirred solution of tert-butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (90 g, 143.77 mmol) in MeOH (600 mL) was added concentrated HCl (36%, 300 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The solid was collected by filtration. The solid was dissolved in water (500 mL), then adjusted to pH 8 with saturated NaHCO3 solution and washed with DCM / MeOH (V / V=10 / 1, 5 x The product was extracted with 4% paraformaldehyde (2000 mL) and the mixture was dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was slurried with petroleum ether (1000 mL) and filtered. The solid was filtered and dried under vacuum to yield the product (64 g, 84.63%). [M+H] + =527.4

[1112] Step 10: 3-cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-dioxopiperidin-3-yl)- (fluorophenyl)azetidin-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrole 1,2-b]pyridazine-7-carboxamide

[1113]

[1114] To a stirred solution of 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (60 g, 114.07 mmol) and (R)-3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione (50.3 g, 171.1 mmol) in DCE (1000 mL) was added AcOH (6.844 g, 114.07 mmol) and NaBH(OAc) (48.366 g, 228.14 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with MeOH (500 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=15:1), followed by addition of acetonitrile (1600 mL), water (800 mL) and acetic acid (200 mL) and lyophilization to give the product (66 g, 62.62%).

[1115] Example 181: 3-Cyano-N-(2-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1116]

[1117] The title compound was prepared in a manner similar to that described in Example 178 (45 mg, 46.6%). 1 H NMR (500MHz, DMSO) δ12.02(s,1H),10.84(s,1H),8.93(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.55(s,1H), 8.34(s,1H),7.72(d,J=4.5Hz,1H),7.57(s,1H),7.09(d,J=4.5Hz,1H),6.23(d,J=12.0Hz,2H),5.72(s,1H) ,4.47-4.44(m,1H),4.02(dd,J=12.5,5.0Hz,1H),3.60-3.42(m,7H),3.30-3.20(m,4H),2.82-2.74(m,1H), 2.61-2.55(m,2H),2.20-2.15(m,3H),2.11-2.05(m,2H),2.00-1.89(m,6H),1.63(s,6H),1.57-1.44(m,3H). [M+H] + =847.5.

[1118] Example 182: 3-Cyano-N-(2-((1R,4r)-4-(4-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1119]

[1120] The title compound was prepared in a similar manner to that described in Example 9 (18 mg, 32.9%). 1H NMR (500MHz, DMSO) δ12.02(s,1H),10.94(s,1H),8.93(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.5 5(s,1H),8.33(s,1H),8.14(s,1H),7.72(d,J=4.5Hz,1H),7.57(s,1H),7.09(d,J=4.5Hz,1H),7.03 (d,J=10.0Hz,2H),5.71(s,1H),4.46-4.38(m,1H),4.23-4.17(m,1H),2.81-2.75(m,3H),2.65-2.5 3(m,7H),2.36-2.33(m,1H),2.20-2.10(m,4H),2.01-1.90(m,6H),1.63(s,6H),1.54-1.45(m,3H). [M+H] + =778.7.

[1121] The compound can also be synthesized in another way.

[1122] Step 1: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate acid esters

[1123]

[1124] To a solution of methyl 4-formyl-3-nitrobenzoate (104.5 g, 500 mmol) in propan-2-ol (1000 mL) was added tert-butyl 4-((1r, 4r)-4-aminocyclohexyl)piperazine-1-carboxylate (141.5 g, 500 mmol). The mixture was stirred at 80 ° C under N2 for 3 h. The mixture was then cooled to rt and tri-n-butylphosphine (303 g, 1500 mmol) was slowly added. The mixture was stirred at 80 ° C under N2 overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was made into a slurry with petroleum ether (3000 mL) and filtered. The solid was filtered and dried under vacuum to produce the product (130 g, 58.7%). [M+H] + =443.1

[1125] Step 2: Methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

[1126]

[1127] To a solution of methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (130 g, 293.7 mmol) in concentrated H2SO4 (98%, 1000 mL) was added NaNO3 (49.9 g, 587.4 mmol) in portions at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was then poured into ice water, basified to pH 9 with saturated aqueous Na2CO3 solution, and extracted with DCM (3×2000 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the product (130 g, crude), which was used directly in the next step without any further purification. [M+H] + =388.1

[1128] Step 3: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indole oxazole-6-carboxylate

[1129]

[1130] To a stirred solution of methyl 5-nitro-2-((1r, 4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (140 g crude) in DCM (1000 mL) was added Et3N (44.50 g, 440.55 mmol) and Boc2O (64.1 g, 293.7 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM (2000 mL) and washed with water (1 L×2) and saturated saline solution (1 L×2). The organic layer was then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=30:1) to give the product (130 g, 90.8% over 2 steps). [M+H] + =488.1

[1131] Step 4: Methyl 5-amino-2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indole oxazole-6-carboxylate

[1132]

[1133] To a solution of methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate (130 g, 266.6 mmol) in THF (1300 mL) was added Pd / C (5%, 30 g) at room temperature. The resulting mixture was stirred at room temperature under H2 overnight. The solid was filtered and washed with MeOH (800 mL). The filtrate was evaporated in vacuo to give the product (110 g, 90.3%). [M+H] + =458.2

[1134] Step 5: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(2,2,2-trifluoromethyl) (acetylamino)-2H-indazole-6-carboxylate

[1135]

[1136] To a solution of methyl 5-amino-2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (105 g, 229.4 mmol) in DCM (1000 mL) was added trifluoroacetic anhydride (50.6 g, 240.9 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was quenched with ice water, then adjusted to pH 8 with saturated NaHCO3 solution and washed with DCM (3% HCl). x The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=30:1) to give the product (120 g, 94.5%). [M+H] + =554.2

[1137] Step 6: tert-butyl 4-((1r,4r)-4-(6-(2-hydroxypropan-2-yl)-5-(2,2,2-trifluoroacetylamino)- 2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[1138]

[1139] To a solution of methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(2,2,2-trifluoroacetamido)-2H-indazole-6-carboxylate (115 g, 207.7 mmol) and LiCl (44.03 g, 1038.7 mmol) in THF (1500 mL) was added dropwise MeMgBr (3 M, 692.4 mL, 2077.2 mmol) in THF under N₂ at 0°C. The resulting mixture was stirred at 0°C overnight. The mixture was slowly quenched with saturated NH₄Cl solution (1500 mL) and acidified to pH 5 with HCl (1 mol / L). The mixture was then extracted with EtOAc (3×1000 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the product (100 g, 86.9%). [M+H] + =554.2

[1140] Step 7: tert-Butyl 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexane 1-Methyl-1-piperazine-1-carboxylate

[1141]

[1142] To a solution of tert-butyl 4-((1r,4r)-4-(6-(2-hydroxypropan-2-yl)-5-(2,2,2-trifluoroacetamido)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (100 g, 180.62 mmol) in MeOH (1000 mL) was added NaOH solution (2N, 903 mL, 1806.2 mmol) at room temperature. The mixture was stirred at 70 ° C for 2 h. The mixture was cooled to room temperature and a solid was precipitated. The mixture was filtered and the filter cake was washed with water. The filter cake was then collected and dried under reduced pressure to give the product (75 g, 90.7%). [M+H] + =458.2

[1143] Step 8: tert-Butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6- (2-Hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[1144]

[1145] To a stirred solution of 3-cyanopyrrolo[1,2-b]pyridazine-7-carboxylic acid (36.81 g, 196.67 mmol) and tert-butyl 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-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 at room temperature for 5 hours. The mixture was diluted with water (3000 mL). The solid was collected by filtration and washed with water (3000 mL). x The solid was dried under vacuum to give the product (90 g, 87.62%). [M+H] + =627.5

[1146] Step 9: 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H- Indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1147]

[1148] To a stirred solution of tert-butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (90 g, 143.77 mmol) in MeOH (600 mL) was added concentrated HCl (36%, 300 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The solid was collected by filtration. The solid was dissolved in water (500 mL), then adjusted to pH 8 with saturated NaHCO3 solution and washed with DCM / MeOH (V / V=10 / 1, 5x The product was extracted with 4% paraformaldehyde (2000 mL) and the mixture was dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was slurried with petroleum ether (1000 mL) and filtered. The solid was filtered and dried under vacuum to yield the product (70 g, 92.45%). [M+H] + =527.4

[1149] Step 10: 3-cyano-N-(2-((1R,4r)-4-(4-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluoro (phenethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-yl Formamide

[1150]

[1151] To a stirred solution of 3-cyano-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (4.9 g, 9.30 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (3.23 g, 12.09 mmol) (CAS: 2758533-79-6, obtained by the same procedure described in WO 2022012622A1) in DCE (100 mL) was added AcOH (0.542 g, 9.30 mmol) and NaBH(OAc) (2.96 g, 13.95 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with MeOH (30 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH = 15: 1) to give an impure product. The impure product was then slurried with MeOH (30 mL) and filtered. The filter cake was collected and dried under reduced pressure to give the product (3.8 g, 52.53%). 1H NMR (500MHz, DMSO) δ12.02(s,1H),10.95(s,1H),8.93(d,J=2.2Hz,1H),8.74(d,J=2.2Hz,1H),8.55(s ,1H),8.33(s,1H),8.15(s,1H),7.72(d,J=4.8Hz,1H),7.57(s,1H),7.09(d,J=4.8Hz,1H),7.03(d,J= 10.0Hz,2H),5.72(s,1H),4.47-4.39(m,1H),4.20(dd,J=12.6,5.0Hz,1H),2.85-2.73(m,3H),2.62-2 .52(m,7H),2.48-2.36(m,5H),2.21-2.08(m,3H),2.02-1.90(m,5H),1.63(s,6H),1.52-1.43(m,2H). [M+H] + =778.6

[1152] Example 193: 3-Cyano-N-(2-((1R,4r)-4-(4-((4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)glycyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1153]

[1154] The title compound was prepared in a manner similar to that described in Example 178 (18 mg, 28.9%). 1 H NMR(500MHz,DMSO)δ12.02(s,1H),10.83(s,1H),8.93(s,1H),8.74(s,1H),8.55(s,1H),8.34(s,1H),7 .72(d,J=4.5Hz,1H),7.57(s,1H),7.09(d,J=4.5Hz,1H),6.41(d,J=12.0Hz,2H),6.23(s,1H),5.72(s,1 H),4.48-4.38(m,1H),4.03-3.97(m,1H),3.95-3.86(m,2H),3.55-3.40(m,5H),2.83-2.72(m,1H),2.62 -2.54(m,3H),2.22-2.14(m,2H),2.10-2.03(m,1H),2.00-1.88(m,6H),1.63(s,6H),1.56-1.40(m,3H). [M+H] +=807.6.

[1155] Example 194: 3-Cyano-N-(2-((1R,4r)-4-(4-(2-((4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)ethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1156]

[1157] The title compound was prepared in a similar manner to that described in Example 9 (52 mg, 57.9%). 1 H NMR (500MHz, DMSO) δ12.02(s,1H),10.83(s,1H),8.93(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.55(s,1H),8.3 3(s,1H),7.72(d,J=4.5Hz,1H),7.57(s,1H),7.09(d,J=4.5Hz,1H),6.27(d,J=12.0Hz,2H),6.07(s,1H),5.72(s ,1H),4.48-4.38(m,1H),3.98(dd,J=12.5,5.0Hz,1H),3.14-3.11(m,3H),2.80-2.74(m,1H),2.70-2.55(m,6H), 2.40-2.27(m,3H),2.21-2.16(m,2H),2.10-1.92(m,7H),1.63(s,6H),1.56-1.48(m,2H),1.22(d,J=6.5Hz,1H). [M+H] + =793.5.

[1158] Example 195: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1159]

[1160] The title compound was prepared in a similar manner to that described in Example 9.

[1161] [M+H] + =797.5.

[1162] Example 196: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1163]

[1164] The title compound was prepared in a similar manner to that described in Example 9 (6 mg, 9.4%). 1 H NMR (500MHz, DMSO) δ12.02(s,1H),10.87(s,1H),8.93(d,J=2.0Hz,1H),8.74(d,J=2.0Hz,1H),8.55(s,1H),8.33 (s,1H),7.72(d,J=4.5Hz,1H),7.57(s,1H),7.09(d,J=4.5Hz,1H),6.62(d,J=12.9Hz,2H),5.72(s,1H),4.45-4. 38(m,1H),4.08-4.03(m,1H),3.78(d,J=12.0Hz,2H),3.56-3.47(m,2H),2.80-2.70(m,4H),2.58-2.52(m,5H),2 .40-2.30(m,3H),2.18-2.07(m,3H),1.98-1.90(m,5H),1.82(d,J=11.0Hz,2H),1.63(s,6H),1.49-1.39(m,4H). [M+H] + =833.6.

[1165] Example 128: (S)-N-(2-(1'-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-[1,4'-bipiperidinyl]-4-yl)-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)picolinamide

[1166] Step 1: Methyl 2-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-6-nitroimidazo[1,2-a]pyridine-7-carboxylic acid ester

[1167]

[1168] A mixture of methyl 2-amino-5-nitroisonicotinate (3.5 g, 17.77 mmol), tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (10.8 g, 35.54 mmol) and MgO (1.42 g, 35.54 mmol) in tetrahydrofuran (120 mL) was stirred in a sealed tube at 100 ° C. for 16 h. The mixture was evaporated under vacuum to give a crude product, which was further purified by silica gel column chromatography (PE: EA = 3: 1-1: 2 gradient elution) to give the product (3.9 g, 54.3%). [M+H] + =405.5.

[1169] Step 2: Methyl 6-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)imidazo[1,2-a]pyridine-7-carboxylic acid ester

[1170]

[1171] A solution of methyl 2-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-6-nitroimidazo[1,2-a]pyridine-7-carboxylate (3.9 g, 11.6 mmol), Fe (6.5 g, 116 mmol) and NH4Cl (1.86 g, 34.8 mmol) in EtOH (80.0 mL) and water (20.0 mL) was stirred at 90 ° C for 16 h. The reaction was monitored by LCMS. The mixture was filtered through a celite pad and washed with EtOH (60.0 mL). The filtrate was concentrated under vacuum and extracted with EA (3x15.0 mL) and extracted with NaHCO3 aqueous solution (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the product (2.5 g, 58%). [M+H] + =375.3.

[1172] Step 3: Methyl 2-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-6-(6-(trifluoromethyl)picolinamido)imidazole Azoxazo[1,2-a]pyridine-7-carboxylate

[1173]

[1174] A mixture of 6-(trifluoromethyl)picolinic acid (1.28 g, 6.68 mmol), HATU (3.81 g, 10.03 mmol) and DIEA (2.6 g, 20.06 mmol) in DMF (100 mL) was stirred at room temperature for 30 minutes, and methyl 6-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)imidazo[1,2-a]pyridine-7-carboxylate (2.5 g, 6.68 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was monitored with LCMS. Water (80 mL) was added and the solid was filtered, washed with water (50.0 mL), and dried to obtain a crude product, which was further purified by silica gel column chromatography (PE:EA=3:1-1:2 gradient elution) to give the product (2.5 ...

Claims

1. A compound having formula (X) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof, in: L x yes *Lx -CONH- **Lx or *Lx -NHCO- **Lx ,in* Lx refers to the position of attachment to the Cy2 moiety, and ** Lx refers to the position of attachment to the Cy3 moiety; Cy1 is a 6-membered partially or fully unsaturated ring; the ring is substituted by at least one R 1 replace; Y 1 , Y 2 and Y 3 each independently is C or N; s1 is 0, 1, 2, 3, 4, or 5; Cy2 is a 5-, 6-, 7-, 8-, 9- or 10-membered partially or fully unsaturated ring (aromatic ring); the ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; the ring is substituted by at least one substituent R 2 replace; s2 is 0, 1, or 2; s4 is 0 or 1; Cy3 is a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring; the ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; the ring is substituted by at least one substituent R 3 replace; s3 is 0, 1, 2, 3, 4, or 5; R 1 , R 2 and R 3 are each independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a 、-C(O)R 1a 、-CO2R 1a 、-C(O)NR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b or -NR 1a CO2R 1b ; -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted by at least one substituent R 1c replace; or When adjacent, two R 1 , two R 2 or two R 3 Together with the atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent R 1c replace; R 1a and R 1b Each is independently selected from hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5 to 12 membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C8 alkyl, -C8 ... alkyl-OH, -C2-C8 alkyl-OH, -C2-C8 alkyl-OH, -C2-C8 alkyl-OH, -C3-C8 cycloalkyl, 3 to 12 Aryl or 5- to 12-membered heteroaryl; R 1c , independently at each occurrence is halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 Aryl or 5- to 12-membered heteroaryl; R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d are each independently absent, oxo, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Cycloalkyl; the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; or R 11a and R 12a Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or R 11b and R 12b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or R 11c and R 12c Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or R 11d and R 12d Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituent substitution; Every time it appears, L 1 Independently selected from -O-, -NR a -、-C(O)NR a -、-C(O)O-、 It is stated Each of which is optionally represented by at least one R L1c replace; in* L1 is attached to the The location of the part, and L1 is attached to the the location of the part; Every time it appears, L 2 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 It is stated Each of which is optionally represented by at least one R L2c replace; in* L2 is attached to the The location of the part, and L2 is attached to the the location of the part; Every time it appears, L 3 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 It is stated Each of which is optionally represented by at least one R L3c replace; in* L3 is attached to the The location of the part, and L3 is attached to the the location of the part; The R L1c , R L2c and R L3c Each of the above is independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl or 5 to 12 membered heteroaryl; the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one R Lca replace, R Lca are independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; or Two R's L1c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxyl, -C1-C8 alkyl; Two R's L2c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxyl, -C1-C8 alkyl; Two R's L3c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxyl, -C1-C8 alkyl; Selected from Z 1 , Z 2 and Z 3 Each independently is N or CR z , the condition is that Z 1 , Z 2 and Z 3 Not at the same time, it is N; R z , at each occurrence, is independently selected from absence, hydrogen, halogen, -C 1-8 Alkyl, -NR Za R Zb 、-OR Za 、-SR Za , C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or CN; -C 1-8 Each of the alkyl group, the C3-C8 cycloalkyl group, and the 3- to 8-membered heterocyclic group is optionally substituted by at least one R Zc replace; Partially via Z 1 , Z 2 or Z 3 Connect any of Part of which CR z and R z does not exist; R Za and R Zb Each is independently selected from the group consisting of absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5 to 12 membered heteroaryl, the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl group, or the 5- to 12-membered heteroaryl group is optionally substituted by at least one R Zd Substituent substitution; R Zc and R Zd are independently halogen, hydroxy, -C1-C8 alkyl, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, or 5- to 12-membered heteroaryl; R 13 and R 14 are each independently selected from the group consisting of absence, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a S02R 13b ;-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13c S02R 13d replace; At each occurrence, R 13a , R 13b , R 13c and R 13d each independently is absent, hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, or 5- to 12-membered heteroaryl; L 4 , L 5 and L 6 are each independently selected from absence, a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-; At each occurrence, X 1 , X 2 and X 7 Each independently selected from -CR a or N; At each occurrence, X 3 , X 4 and X 8 Each independently selected from -NR a -, -O-, -S-, and -CR a R b -; At each occurrence, X 5 and X 6 are each independently selected from absence, a single bond, -C(O)-, -NR a - and -O-; Q 1 , Q 2 , Q 3 and Q 4 Each independently selected from CR a or N; At each occurrence, R a and R b Each is independently selected from hydrogen, hydroxy, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 The -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl or 5 to 12 membered heteroaryl groups is optionally substituted by at least one halogen, hydroxyl, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C8 cycloalkyl, -C8-C8 cycloalkyl, -C1-C8 cycloalkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl substituents; or R a and R b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituted halogen, hydroxyl, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl substituted; m1, m2, m3 and m4 are each independently 0, 1 or 2; m5 and m7 are each independently 0 or 1; m6 is 0, 1 or 2; when m6 is 2, the two L2s are the same or different; n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3; n6, n7 and n8 are each independently 0, 1, 2, 3 or 4.

2. A compound having formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof, in: Cy1 is a 6-membered partially or fully unsaturated ring; the ring is substituted by at least one R 1 replace; Y 1 , Y 2 and Y 3 each independently is C or N; s1 is 0, 1, 2, 3, 4, or 5; Cy2 is a 5-, 6-, 7-, 8-, 9- or 10-membered partially or fully unsaturated ring (aromatic ring); the ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; the ring is substituted by at least one substituent R 2 replace; s2 is 0, 1, or 2; s4 is 0 or 1; Cy3 is a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring; the ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; the ring is substituted by at least one substituent R 3 replace; s3 is 0, 1, 2, 3, 4, or 5; R 1 , R 2 and R 3 are each independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a 、-C(O)R 1a 、-CO2R 1a 、-C(O)NR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b or -NR 1a CO2R 1b ; -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 1c replace; or When adjacent, two R 1 , two R 2 or two R 3 Together with the atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent R 1c replace; R 1a and R 1b Each is independently selected from hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5 to 12 membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C8 alkyl, -C8 ... alkyl-OH, -C2-C8 alkyl-OH, -C2-C8 alkyl-OH, -C2-C8 alkyl-OH, -C3-C8 cycloalkyl, 3 to 12 Aryl or 5- to 12-membered heteroaryl; R 1c , independently at each occurrence is halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 Aryl or 5- to 12-membered heteroaryl; R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d are each independently absent, oxo, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Cycloalkyl; the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; or R 11a and R 12a Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or R 11b and R 12b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or R 11c and R 12c Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or R 11d and R 12d Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituent substitution; Every time it appears, L 1 Independently selected from -O-, -NR a -、-C(O)NR a -、-C(O)O-、 It is stated Each of which is optionally represented by at least one R L1c replace; in* L1 is attached to the The location of the part, and L1 is attached to the the location of the part; Every time it appears, L 2 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 It is stated Each of which is optionally represented by at least one R L2c replace; in* L2 is attached to the The location of the part, and L2 is attached to the the location of the part; Every time it appears, L 3 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 It is stated Each of which is optionally represented by at least one R L3c replace; in* L3 is attached to the The location of the part, and L3 is attached to the the location of the part; The R L1c , R L2c and R L3c Each of the above is independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl or 5 to 12 membered heteroaryl; the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one R Lca replace, R Lca are independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; or Two R's L1c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxyl, -C1-C8 alkyl; Two R's L2c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxyl, -C1-C8 alkyl; Two R's L3c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxyl, -C1-C8 alkyl; Selected from Z 1 , Z 2 and Z 3 Each independently is N or CR z , the condition is that Z 1 , Z 2 and Z 3 Not at the same time, it is N; R z , at each occurrence, is independently selected from absence, hydrogen, halogen, -C 1-8 Alkyl, -NR Za R Zb 、-OR Za 、-SR Za , C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or CN; -C 1-8 Each of the alkyl group, the C3-C8 cycloalkyl group, and the 3- to 8-membered heterocyclic group is optionally substituted by at least one R Zc replace; Partially via Z 1 , Z 2 or Z 3 Connect any of Part of which CR z and R z does not exist; R Za and R Zb Each is independently selected from the group consisting of absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5 to 12 membered heteroaryl, the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl group, or the 5- to 12-membered heteroaryl group is optionally substituted by at least one R Zd Substituent substitution; R Zc and R Zd are independently halogen, hydroxy, -C1-C8 alkyl, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, or 5- to 12-membered heteroaryl; R 13 and R 14 are each independently selected from the group consisting of absence, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a S02R 13b ;-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13c S02R 13d replace; At each occurrence, R 13a , R 13b , R 13c and R 13d each independently is absent, hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, or 5- to 12-membered heteroaryl; L 4 , L 5 and L 6 are each independently selected from absence, a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-; At each occurrence, X 1 , X 2 and X 7 Each independently selected from -CR a or N; At each occurrence, X 3 , X 4 and X 8 Each independently selected from -NR a -, -O-, -S-, and -CR a R b -; At each occurrence, X 5 and X 6 are each independently selected from the group consisting of absence, a single bond, -C(O)-, -NR a - and -O-; Q 1 , Q 2 , Q 3 and Q 4 Each independently selected from CR a or N; At each occurrence, R a and R b Each is independently selected from hydrogen, hydroxy, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 The -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl or 5 to 12 membered heteroaryl groups is optionally substituted by at least one halogen, hydroxyl, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C8 cycloalkyl, -C8-C8 cycloalkyl, -C1-C8 cycloalkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl substituents; or R a and R b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituted halogen, hydroxyl, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl substituted; m1, m2, m3 and m4 are each independently 0, 1 or 2; m5 and m7 are each independently 0 or 1; m6 is 0, 1 or 2; when m6 is 2, the two L2s are the same or different; n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3; n6, n7 and n8 are each independently 0, 1, 2, 3 or 4.

3. A compound having formula (I') or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof, in: Cy1 is a 6-membered partially or fully unsaturated ring; the ring is substituted by at least one R 1 replace; Y 1 , Y 2 and Y 3 each independently is C or N; s1 is 0, 1, 2, 3, 4, or 5; Cy2 is a 5-, 6-, 7-, 8-, 9- or 10-membered partially or fully unsaturated ring (aromatic ring); the ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; the ring is substituted by at least one substituent R 2 replace; s2 is 0, 1, or 2; s4 is 0 or 1; Cy3 is a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic ring; the ring contains 0-3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; the ring is substituted by at least one substituent R 3 replace; s3 is 0, 1, 2, 3, 4, or 5; R 1 , R 2 and R 3 are each independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a 、-C(O)R 1a 、-CO2R 1a 、-C(O)NR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b or -NR 1a CO2R 1b ; -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with at least one substituent R 1c replace; or When adjacent, two R 1 , two R 2 or two R 3 Together with the atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent R 1c replace; R 1a and R 1b Each is independently selected from hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 Each of the aryl or 5 to 12 membered heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C8 alkyl, -C8 ... alkyl-OH, -C2-C8 alkyl-OH, -C2-C8 alkyl-OH, -C2-C8 alkyl-OH, -C3-C8 cycloalkyl, 3 to 12 Aryl or 5- to 12-membered heteroaryl; R 1c , independently at each occurrence is halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 Aryl or 5- to 12-membered heteroaryl; R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d are each independently absent, oxo, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Cycloalkyl; the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; or R 11a and R 12a Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or R 11b and R 12b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or R 11c and R 12c Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituents; and / or R 11d and R 12d Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy or -CN substituent substitution; Every time it appears, L 1 Independently selected from -O-, -NR a -、-C(O)NR a -、-C(O)O-、 It is stated Each of which is optionally represented by at least one R L1c replace; in* L1 is attached to the The location of the part, and L1 is attached to the the location of the part; Every time it appears, L 2 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 It is stated Each of which is optionally represented by at least one R L2c replace; in* L2 is attached to the The location of the part, and L2 is attached to the the location of the part; Every time it appears, L 3 Independently selected from -O-, -NR a -、-CONR a -、-C(O)O-、 It is stated Each of which is optionally represented by at least one R L3c replace; in* L3 is attached to the The location of the part, and L3 is attached to the the location of the part; The R L1c , R L2c and R L3c Each of the above is independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl or 5 to 12 membered heteroaryl; the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one R Lca replace, R Lca are independently absent, oxo (=O), halogen, hydroxy, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, C6-C 12 Aryl or 5- to 12-membered heteroaryl; or Two R's L1c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxyl, -C1-C8 alkyl; Two R's L2c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxyl, -C1-C8 alkyl; Two R's L3c Together with the atoms to which they are attached, they form a 3- to 12-membered ring comprising 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituent halogen, hydroxyl, -C1-C8 alkyl; Selected from Z 1 , Z 2 and Z 3 Each independently is N or CR z , the condition is that Z 1 , Z 2 and Z 3 Not at the same time, it is N; R z , at each occurrence, is independently selected from absence, hydrogen, halogen, -C 1-8 Alkyl, -NR Za R Zb 、-OR Za 、-SR Za , C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl or CN; -C 1-8 Each of the alkyl group, the C3-C8 cycloalkyl group, and the 3- to 8-membered heterocyclic group is optionally substituted by at least one R Zc replace; Via Z 1 , Z 2 or Z 3 Connect any of Part of which CR z and R z does not exist; R Za and R Zb Each is independently selected from the group consisting of absent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5 to 12 membered heteroaryl, the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Each of the aryl group, or the 5- to 12-membered heteroaryl group is optionally substituted by at least one R Zd Substituent substitution; R Zc and R Zd are independently halogen, hydroxy, -C1-C8 alkyl, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, or 5- to 12-membered heteroaryl; R 13 and R 14 are each independently selected from the group consisting of absence, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a S02R 13b ;-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted with halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13c S02R 13d replace; At each occurrence, R 13a , R 13b , R 13c and R 13d each independently is absent, hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, C6-C 12 Aryl, or 5- to 12-membered heteroaryl; L 4 , L 5 and L 6 are each independently selected from absence, a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-; At each occurrence, X 1 , X 2 and X 7 Each independently selected from -CR a or N; At each occurrence, X 3 , X 4 and X 8 Each independently selected from -NR a -, -O-, -S-, and -CR a R b -; At each occurrence, X 5 and X 6 are each independently selected from the group consisting of absence, a single bond, -C(O)-, -NR a - and -O-; Q 1 , Q 2 , Q 3 and Q 4 Each independently selected from CR a or N; At each occurrence, R a and R b Each is independently selected from hydrogen, hydroxy, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C 12 The -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 Each of the aryl or 5 to 12 membered heteroaryl groups is optionally substituted by at least one halogen, hydroxyl, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclyl, -C6-C8 cycloalkyl, -C8-C8 cycloalkyl, -C1-C8 cycloalkyl, -C8 ... 12 aryl or 5- to 12-membered heteroaryl substituents; or R a and R b Together with the carbon atoms to which they are attached, they form a 3- to 12-membered ring containing 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the ring is optionally substituted with at least one substituted halogen, hydroxyl, -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl or 5- to 12-membered heteroaryl substituted; m1, m2, m3 and m4 are each independently 0, 1 or 2; m5 and m7 are each independently 0 or 1; m6 is 0, 1 or 2; when m6 is 2, the two L2s are the same or different; n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3; n6, n7 and n8 are each independently 0, 1, 2, 3 or 4.

4. The compound of claim 1, wherein the compound is selected from the group consisting of formula (IIa), (IIa'), (IIb), (IIb'), (IIc), (IIc'), (IId), (IId'), (IIe) and (IIe'), Where R 1 , R 2 , R 3 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 , s1, s2, s3, m1, m2, m3, m4, m5, m6, m7, Cy2, Cy3, degradation determinants as defined in claim 1.

5. The compound of claim 1, wherein the compound is selected from the group consisting of Formula (IIIa), (IIIa'), (IIIb), (IIIb'), (IIIc), (IIIc'), (IIId), (IIId'), (IIIe), (IIIe'), (IIIf), (IIIf'), (IIIg), (IIIg'), (IIIh), (IIIh'), (IIIi), (IIIi'), (IIIj)(IIIj'), (IIIk), (IIIk'), (IIIl) or (IIIl'): Where R 1 , R 2 , R 3 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , Y 1 , Y 2 , Y 3 , L 1 , L 2 , L 3 , s1, s2, s3, m1, m2, m3, m4, m5, m6, m7, Cy1, Cy3, degradation determinants as defined in claim 1.

6. The compound of claim 1, wherein the compound is selected from the group consisting of formula (IVa), (Iva'), (IVb), (IVb'), (IVc) and (IVc'), Where R 1 , R 2 , R 3 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , Y 1 , Y 2 , Y 3 、Cy1、Cy2、L 1 , L 2 , L 3 , s1, s2, s3, s4, m1, m2, m3, m4, m5, m6, m7 and degradation determinants are defined in claim 1.

7. The compound of claim 1, wherein the compound is selected from formula (Va) or (Va') Preferably, the compound is selected from the group consisting of formula (Vb), (Vb'), (Vc), and (Vc'), More preferably, the compound is selected from the group consisting of formula (Vd), (Vd'), (Ve) and (Ve'), More preferably, the compound is selected from the formula (Vf), (Vf'), (Vg), (Vg'), (Vh), (Vh'), (Vi), (Vi'), (Vj), (Vj'), (Vk), (Vk'), (Vl), (Vl'), (Vm), (Vm'), (Vn), (Vn'), (Vo), (Vo'), (Vp), (Vp'), (Vq) or (Vq'), Even more preferably, the compound is selected from the formula (Vr), (Vr'), (Vs), (Vs'), (Vt), (Vt'), (Vu), (Vu'), (Vv), (Vv'), (Vw), (Vw'), (Vx), (Vx'), (Vy), (Vy'), (Vz), (Vz'), (Vaa), (Vaa'), (Vab), (Vab'), (Vac) or (Vac'), in, Y 4 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 and Y 17 are each independently selected from C or N; Y 5 and Y 6 are independently selected from C, N, O or S; provided that It is an aromatic ring; Among them, R 2 , R 3 , R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 , s2, s3, ml, m2, m3, m4, m5, m6, m7 and degradation determinants are as defined in claim 1.

8. The compound of claim 1, wherein the compound is selected from formula (VIa) or (Via') Preferably, the compound is selected from (VIb) or (VIb), in, Y 1 , Y 2 , Y 3 、Cy1、Cy2、Cy3、R 1 , R 2 , R 3 , R 11b , R 11c , R 11d , R 12b , R 12c , R 12d , L 1 , L 2 , L 3 , s1, s2, s3, s4, m2, m3, m4, m5, m6, m7 and degradation determinants are defined in claim 1.

9. A compound as claimed in any one of the preceding claims, wherein Y 1 , Y 2 and Y 3 At least one of is N; preferably, Y 1 Yes N, Y 2 and Y 3 is C; or Y 2 Yes N, Y 1 and Y 3 is C; or Y 3 Yes N, Y 1 and Y 2 It is C.

10. The compound as claimed in any one of the preceding claims, wherein Cy1 is pyridyl or pyridonyl.

11. A compound as claimed in any one of the preceding claims, wherein Part is Preferably, Part is 12. A compound as claimed in any one of the preceding claims, wherein the Part is in* Cy2 is attached to the The location of the part, and Cy2 is attached to the the location of the part; Preferably, Part is 13. A compound as claimed in any one of the preceding claims, wherein Cy3 is a 5, 6, 7, 8, 9 or 10 membered aromatic ring; said ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur; said ring being substituted by at least one substituent R 3 replace; Preferably, Cy3 is a 5- or 9-membered aromatic ring; the ring contains 0, 1, 2 or 3 heteroatoms independently selected from nitrogen; the ring is substituted by at least one substituent R 3 replace; Even more preferably, yes in* Cy3 is attached to the The location of the part, and Cy3 is attached to the the location of the part; Even more preferably, yes 14. A compound as claimed in any one of the preceding claims, wherein R 1 , R 2 and R 3 are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a 、-C(O)R 1a 、-CO2R 1a 、-C(O)NR 1a R 1b 、-NR 1a R 1b 、-NR 1a COR 1b or -NR 1a CO2R 1b ; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl is optionally substituted by at least one substituent R 1c replace, R 1a and R 1b each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C1-C8 haloalkyl (preferably -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3), -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C1-C8 haloalkyl (preferably -CH2F, -CHF2, -C2 Each of -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH2OH, -C2H4OH, -C3H6OH, -C4H8OH, -C5H 10 OH, -C6H 12 OH, -C7H 14 OH, -C8H 16 OH, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; R 1c is independently at each occurrence -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

15. A compound as claimed in any one of the preceding claims, wherein R 1 , R 2 and R 3 are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, oxo (=O), -CN, -OR 1a or -C(O)NR 1a R 1b 、-NR 1a R 1b ; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3 to 8 membered heterocyclic radicals is optionally substituted by at least one substituent R 1c replace, R 1a and R 1b each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH2OH, -C2H4OH, -C3H6OH, -C4H8OH, -C5H 10 OH, -C6H 12 OH, -C7H 14 OH, -C8H 16 Each of OH, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl; R 1c , independently at each occurrence is -F, -Cl, -Br, -I, -OH; Preferably, R 1 , R 2 and R 3 are each independently H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CF3, -CF2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH3)2, -CHF2, oxo (=O), -CN, cyclopropyl, -CONH2, -OMe, -OEt, -OCH2CH2CH3, -OCH(CH3)2, Even more preferably, R 1 is H, -CH3, -CH2CH3, -CF3, -CF2CH3, -CH(CH3)2, -C(CH3)3, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH3)2, oxo (=O), cyclopropyl, R 2 is H, -CF3, cyclopropyl, oxo (=O), -F, -Cl, -Br, -I or -CN; R 3 is H, -CH3, oxo (=O), -CHF2, -CONH2, -OMe, -OCD3, -OEt, -OCH2CH2CH3, -OCH(CH3)2, 16. A compound as claimed in any one of the preceding claims, wherein both R 3 Together with the atoms to which they are attached, they form a 3, 4, 5, 6, 7 or 8 membered ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one substituent R 1c replace; R 1c is independently at each occurrence -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, the two R 3 Together with the atoms to which they are attached, they form a 3, 4, 5 or 6 membered ring comprising 0, 1, 2 or 3 heteroatoms independently selected from oxygen; said ring is optionally substituted with at least one substituent R 1c replace; R 1c , is independently at each occurrence -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, cyclopropyl, cyclobutyl or cyclopentyl.

17. A compound as claimed in any one of the preceding claims, wherein R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted by at least one selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or -CN is substituted; or (R 11a and R 12a )、(R 11b and R 12b )、(R 11c and R 12c ) or (R 11d and R 12d ) together with the carbon atoms to which they are attached form a 3, 4, 5, 6, 7 or 8 membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring optionally being substituted with at least one selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 The alkylene group is substituted with alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy or -CN.

18. A compound as claimed in any one of the preceding claims, wherein Part is 19. A compound as claimed in any one of the preceding claims, wherein the Part is Preferably, the Part is 20. A compound as claimed in any one of the preceding claims, wherein R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; preferably, R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d are each independently hydrogen, F, Cl, Br, I, methyl, ethyl or propyl; more preferably, R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c and R 12d are each independently hydrogen or methyl; or (R 11a and R 12a )、(R 11b and R 12b )、(R 11c and R 12c ) or (R 11d and R 12d ) together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7- or 8-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; preferably, (R 11a and R 12a )、(R 11b和 R 12b )、(R 11c and R 12c ) or (R 11d and R 12d ) together with the carbon atoms to which they are attached form a 3-, 4- or 5-membered cycloalkyl ring.

21. A compound as claimed in any one of the preceding claims, wherein L 1 Selected from -O-, -N(R a )-、 It is stated Each of which is optionally represented by at least one R L1c replace; The R L1c R is independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl and 5 to 12 membered heteroaryl is optionally replaced by at least one R Lca replace, R Lca are independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or Two R's L1c together with the carbon atoms to which they are attached form a 3, 4, 5, 6, 7 or 8 membered ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl substituent; R a selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl The alkylene groups are optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl substituent.

22. A compound as claimed in any one of the preceding claims, wherein L 1 Selected from -O-, -N(CH3)-, 23. A compound as claimed in any one of the preceding claims, wherein L 2 Selected from -O-, -N(R a )-、 It is stated Each of which is optionally represented by at least one R L2c replace; The R L2c R is independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl and 5 to 12 membered heteroaryl is optionally replaced by at least one R Lca replace, R Lca are independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or Two R's L2c Together with the carbon atoms to which they are attached, they form a 3, 4, 5, 6, 7 or 8 membered ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl substituent; R a selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl The alkylene groups are optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl substituent.

24. A compound as claimed in any one of the preceding claims, wherein L 2 Selected from -O-, -N(CH3)-, 25. A compound as claimed in any one of the preceding claims, wherein the Part is Preferably, the Part is More preferably, the Part is 26. A compound as claimed in any one of the preceding claims, wherein L 3 Selected from -O-, -N(R a )-、 It is stated Each of which is optionally represented by at least one R L3c replace; The R L3c R is independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl and 5 to 12 membered heteroaryl is optionally replaced by at least one R Lca replace, R Lca are independently oxo (═O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or Two R's L3c Together with the carbon atoms to which they are attached, they form a 3, 4, 5, 6, 7 or 8 membered ring comprising 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring is optionally substituted with at least one F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl substituent; R a selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl The alkylene groups are optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl substituent.

27. A compound as claimed in any one of the preceding claims, wherein L 3 Selected from -O-, -N(CH3)-, -NH-, 28. A compound as claimed in any one of the preceding claims, wherein Partially selected Preferably, Partially selected 29. A compound as claimed in any one of the preceding claims, wherein L 4 are independently selected from a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-; At each occurrence, R a and R b each independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyl, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy ... each of the -C-8 alkenyl, -C-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl is optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl substituent.

30. A compound as claimed in any one of the preceding claims, wherein L 4 are independently selected from a single bond or -NH-.

31. A compound as claimed in any one of the preceding claims, wherein X 7 Independently selected from -CR a or N; R a independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyl, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 Each of the -C-C alkenyl, -C-C alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl is optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C-C alkenyl, -C-C alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl substituent.

32. A compound as claimed in any one of the preceding claims, wherein X 7 are independently selected from -CH, -C(CH3), or N; preferably, X 7 are independently selected from -CH.

33. A compound as claimed in any one of the preceding claims, wherein X 8 Independently selected from -NR a -, -O-, -S-, and -CR a R b -; At each occurrence, R a and R b each independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyl, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy ... each of the -C-8 alkenyl, -C-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl is optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl substituent.

34. A compound as claimed in any one of the preceding claims, wherein X 8 are independently selected from -NH- and -CH2-; preferably, X 8 are independently selected from -CH2-.

35. A compound as claimed in any one of the preceding claims, wherein Selected from Preferably, Selected from More preferably, Selected from 36. A compound as claimed in any one of the preceding claims, wherein Z 1 , Z 2 and Z 3 At most one of them is N.

37. A compound as claimed in any one of the preceding claims, wherein Z 1 , Z 2 and Z 3 Each is independently CR z .

38. A compound as claimed in any one of the preceding claims, wherein R Z , at each occurrence, is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR Za R Zb 、-OR Za 、-SR Za , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl or CN; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3 to 8 membered heterocyclyl each optionally replaced by at least one R Zc replace; R Za and R Zb R is each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, each of which is optionally replaced by at least one R Zd Substituent substitution; R Zc and R Zd Each is independently -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyl, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl.

39. A compound as claimed in any one of the preceding claims, wherein R z Selected from H, -CH3, -C2H5, F, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -C3H7, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, -CF3 or -CH(OH)CH3.

40. A compound as claimed in any one of the preceding claims, wherein R 13 and R 14 each independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyl, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a S02R 13b ; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally replaced by F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13c S02R 13d replace; R 13a , R 13b , R 13c and R 13d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl, or a 5- to 12-membered heteroaryl.

41. A compound as claimed in any one of the preceding claims, wherein R 13 and R 14 Each is independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyl, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, or phenyl.

42. A compound as claimed in any one of the preceding claims, wherein yes 43. A compound as claimed in any one of the preceding claims, wherein L 5 and L 6 Each independently selected from a single bond, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or-C(O)-; X 8 is - CR a R b -; At each occurrence, R a and R b each independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyl, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl or 5 to 12 membered heteroaryl, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy ... each of the -C-8 alkenyl, -C-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl is optionally substituted with at least one halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclyl, phenyl, or 5 to 12 membered heteroaryl substituent.

44. A compound as claimed in any one of the preceding claims, wherein L 5 and L 6 are each independently a single bond, -O-, -NH-, -NMe-, -N(CH2CH3)-, -CH2-, -CHF-, -CF2-, -C(CH3)2- or -CO- (preferably, L 5 is -CO- or -CH2-, and L 6 yes -O-, -NH-, -NMe-, -N(CH2CH3)-, -CH2-, -CHF-, -CF2-, -C(CH3)2-, or -CO-); X 8 is CH2; and n6 is 0 or 1.

45. A compound as claimed in any one of the preceding claims, wherein R 13 independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a 、-SO2NR 13a R 13b 、-COR 13a 、-CO2R 13a 、-CONR 13a R 13b 、-NR 13a R 13b 、-NR 13a COR 13b 、-NR 13a CO2R 13b , or -NR 13a S02R 13b ; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally replaced by F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c 、-SO2R 13c 、-SO2NR 13c R 13d 、-COR 13c 、-CO2R 13c 、-CONR 13c R 13d 、-NR 13c R 13d 、-NR 13c COR 13d 、-NR 13c CO2R 13d , or -NR 13c S02R 13d replace; At each occurrence, R 13a , R 13b , R 13c and R 13d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl, or a 5- to 12-membered heteroaryl.

46. ​​A compound as claimed in any one of the preceding claims, wherein R 13 are independently selected from hydrogen, F, Cl, Br, I, CN, -C1-C8 alkyl, or -C1-C8 alkoxy; preferably, R 13 independently selected from hydrogen, F, Cl, Br, I, CN, -Me, -Et, -C3H7, -C4H9, -OMe, -OEt, -OC3H7 or -OC4H9; n7 is 0, 1 or 2.

47. A compound as claimed in any one of the preceding claims, wherein yes 48. A compound as claimed in any of the preceding claims, wherein the compound is selected from compound numbers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 ,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112, 113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、1 44, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 1 75, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206 6, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237 、238、239、240、241、242、243、244、245、246、247、248、249、250、251、252、253、254、255、256、257、258、259、260、261、262、263、264、265、266、267、268、269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312 12, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355 5.356,357,358,359,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398 , 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, or 441. , 49. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 48 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

50. A method of treating a disease that can be affected by IRAK4 modulation, the method comprising administering to 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 diseases and inflammatory disorders, preferably systemic lupus, hidradenitis suppurativa, rheumatoid arthritis, arthritis, gout, multiple sclerosis, psoriasis and cancer, preferably acute myeloid leukemia, cancer, lymphoma, B-cell myelodysplasia.

52. Use of a compound as claimed in any one of claims 1 to 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, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

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