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

[0001] This application is a divisional application of Chinese patent application No. 202380045611.5 (filed on June 8, 2023, entitled "Degradation of IRAK4 by Conjugation of IRAK4 Inhibitor with E3 Ligase Ligand and Method Thereof"). Technical Field

[0002] This article discloses novel bifunctional compounds formed by conjugating the IRAK4 inhibitor moiety with the E3 ligase ligand moiety, as well as their preparation methods and uses. These bifunctional compounds recruit target proteins to E3 ubiquitin ligases for degradation. Background Technology

[0003] Proteolytic targeting chimeras (PROTACs) consist of two covalently linked protein-binding molecules: one that binds to an E3 ubiquitin ligase and the other that binds to a protein of interest (POI) (the target of degradation) (Sakamoto KM et al., Proc. Natl. Acad. Sci. [Proceedings of the National Academy of Sciences] 2001, 98: 8554-9.; Sakamoto KM et al., Methods Enzymol. [Enzymological Methods] 2005; 399: 833-847). Instead of inhibiting the enzymatic activity of the target protein, the recruitment of the E3 ligase to a specific unwanted protein leads to ubiquitination and subsequent degradation of the target protein by the proteasome. The entire process of ubiquitination and proteasome degradation is known as the ubiquitin-proteasome pathway (UPP) (Ardley H. et al., Essays Biochem. [Biochemistry Review] 2005, 41, 15-30; Komander D. et al., Biochem. [Biochemistry] 2012, 81, 203-229; Grice GL et al., Cell Reports. [Cell Reports] 2015, 12, 545-553; Swatek KN et al., Cell Research. [Cell Research] 2016, 26, 399-422; Lydia M. et al., ACS Infect. Dis. [ACS Infectious Diseases] 2019, 5, 12, 2105-2117). The proteasome is a protein complex that degrades unwanted, misfolded, or abnormal proteins into small peptides and amino acids to maintain cellular health and productivity. Ubiquitin ligases, also known as E3 ubiquitin ligases, directly catalyze the transfer of ubiquitin from E2 to target proteins for degradation. Although the human genome encodes more than 600 putative E3 ligases, only a limited number of E3 ubiquitin ligases have been widely used by small molecule PROTAC technology: cerebellar protein (CRBN), Von Hippel-Lindau (VHL), mouse two-microsome 2 homolog (MDM2) and cIAP (cIAP) (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578), recombinant human ring finger protein 114 (RNF114) (Spradlin, JN et al., Nat. Chem. Biol. 2019, 15, 747-755), and DDB1 and CUL4-associated factor 16 (DCAF16) (Zhang, X. et al., Nat. Chem. Biol. 2019, 15, 737-746).For example, cerebellar 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 via the proteasome (Yi-An Chen et al., Scientific Reports 2015, 5, 1-13). Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, act as monovalent promoters of PPIs by binding to the cerebellar protein (CRBN) subunit of the CRL4ACRBN E3 ligase complex and recruiting novel 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 applied in research related to proteolytic targeted chimeras (PROTACs) (Christopher T. et al., ACSChem. Biol., 2019, 14, 342-347; Honorine L. et al., ACSCent. Sci., 2016, 2, 927-934). PROTACs have great potential in eliminating protein targets that traditional inhibitors cannot act on or as protein targets for non-enzymatic proteins (Chu TT. et al., CellChem Biol., 2016; 23:453-461; Qin C. et al., J Med Chem., 2018; 61:6685-6704; Winter GE. et al., Science, 2015; 348:1376-1381).In recent years, PROTACs have been reported as useful regulators for promoting the selective degradation of various target proteins in anti-tumor research (Lu J. et al., Chem Biol. [Chemical and Biological] 2015; 22(6):755-763; Ottis P. et al., Chem Biol. [Chemical and Biological] 2017; 12(4):892-898.; Crews CM et al., J Med Chem. [Journal of Medicinal Chemistry] 2018; 61(2):403-404; Neklesa TK et al., Pharmacol Ther. [Pharmacology and Therapy] 2017, 174:138-144.; Cermakova K et al., Molecules [Molecular], 2018. 23(8).; An S. et al., E BioMedicine [E Biomedicine], 2018.; Lebraud H. et al., Essays Biochem. [Biochemistry Review] 2017; 61(5):517-527.; Sun Y.H. et al., Cell Res. 2018; 28:779-81; Toure M. et al., Angew Chem Int Ed Engl. [Applied Chemistry - English International Edition] 2016; 55(6):1966-1973; Yonghui Sun et al., Leukemia, Vol. 33, pp. 2105-2110 (2019); Shaodong Liu et al., Medicinal Chemistry Research, Vol. 29, pp. 802-808 (2020); and has been 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.

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

[0005] The pro-inflammatory effects of IRAK4 have been confirmed in studies of IRAK4 kinase death knock-in mice (W. Michael S. et al., ACS Med. Chem. Lett. [American Chemical Society Pharmaceutical Chemistry Letters] 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 improves disease activity in various RA animal models. Furthermore, a small subset of IRAK4-deficient individuals has been identified. Reduced expression of pro-inflammatory cytokines from macrophages, decreased inflammation and migration of fibroblast-like synovial cells were observed. Cells from these patients showed impaired responses to ILR / TLR receptor stimulation. No serious viral, fungal, or parasitic infections were observed in these adult patients (Gosu, V. et al., SciRep 4, 2014, 5748; Shichijo K. et al., Pediatrics International, 2015). These data from rodents and humans suggest that IRAK4 inhibitors can modulate the production of key inflammatory cytokines and cytokine-induced pathology.

[0006] However, reports indicate that although IRAK4 phosphorylation levels are reduced in IL-1β-stimulated human dermal fibroblasts, pharmacological inhibition of IRAK4 did not lead to inhibition of IL-6 and TNF-α, suggesting that kinase activity may not be the sole factor in certain cell types (O'Neill, LAImmunol. Rev. [Immunol Review] 2008, 226, 10-8; Nunes J. et al. ACS Med. Chem. Lett. [ACS Medical Chemistry Communications] 2019, 10, 1081). Therefore, in addition to inhibiting kinase activity, removing IRAK4 scaffold function may provide better therapeutic outcomes. In this regard, IRAK4-targeting PROTACs could serve as a potential strategy targeting both IRAK4 kinase activity and scaffold function. IRAK4 PROTACs may ultimately offer new therapeutic opportunities for autoimmune diseases, inflammatory diseases, and oncological diseases. The following patents disclose or discuss IRAK4 PROTAC: WO2019133531, US20190192668, WO 2019099926, WO 2020113233, WO 2020264499, WO2021158634, WO 2020264490, WO 2021119159, WO 2021168197 and WO 2021127278.

[0007] Several IRAK4-targeting protacos have recently been published (Nunes J. et al., ACS Med. Chem. Lett. [ACS Medical Chemistry Communications] 2019, 10, 1081; Zhang et al., Cell Chem. Bio. [Cell Chemical Biology] 2020, 27, 1.; Robert BK et al., ACS Med. Chem. Lett. [ACS Medical Chemistry Communications] 2019, 10, 1251). Most of these molecules are based on published IRAK4 inhibitors as warheads. However, few data suggest that IRAK4 protacos are more potent than IRAK4 kinase inhibitors in inhibiting cytokine production (such as IL-6 and TNF-α). In the following invention, a carefully designed IRAK4 protaco has been shown to reduce pro-inflammatory cytokines more effectively than small molecule inhibitors in a variety of cell lines.

[0008] This application provides novel bifunctional compounds and compositions for the treatment of autoimmune diseases, inflammatory diseases, and tumors. Summary of the Invention

[0009] In one embodiment, this document discloses a bifunctional compound having formula (I) that can selectively degrade IRAK4. The compounds described herein, or salts thereof, can be used to treat diseases that are affected by IRAK4 regulation. This invention provides the use of the compounds described herein, or pharmaceutically acceptable salts thereof, in the manufacture of medicaments for treating diseases affected by IRAK4 regulation. This invention further provides the compounds described herein, or pharmaceutically acceptable salts thereof, for treating diseases affected by IRAK4 regulation. This application further provides a method of treating proliferative disorders, the method comprising administering a therapeutically effective amount of the compounds described herein, or pharmaceutically acceptable salts thereof, to a subject in need. This embodiment includes the following aspects:

[0010] Aspect 1. A compound having formula (X)

[0011]

[0012] Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analogue, or its prodrug.

[0013] in:

[0014] L x yes *Lx -CONH- **Lx or *Lx -NHCO- **Lx ,in* Lx This refers to the position attached to the Cy2 part, and** L x refers to the position attached to the Cy3 part;

[0015] Cy1 is a hexa-membered partially or fully unsaturated ring; the ring is substituent for at least one R. 1 replace;

[0016] Y 1 Y 2 and Y 3 Each can be either C or N independently;

[0017] s1 is 0, 1, 2, 3, 4 or 5;

[0018] 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 substituented by at least one R. 2 replace;

[0019] s2 is 0, 1, or 2;

[0020] s4 is 0 or 1;

[0021] 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 substituented by at least one R. 3 replace;

[0022] s3 is 0, 1, 2, 3, 4, or 5;

[0023] R 1 R 2 and R 3 Each of these components is independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 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, C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally substituent R. 1c Replace; or

[0024] When adjacent, two R 1 Two Rs 2 Or two Rs 3 Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituents R. 1c replace;

[0025] 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 heterocyclic groups, C6-C 12 aryl or 5 to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3 to 8-membered heterocyclic, C6-C 12Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted by at least one substituent selected from the following: halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0026] R 1c Each time it appears, it is independently a halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0027] R 11a R 11b R 11c R 11d R 12a R 12b R 12c and R 12d Each independently exists: non-existent, oxidized, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 alkoxy or -C 3-8 cycloalkyl; the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally selected from at least one element selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; or

[0028] R 11a and R 12a Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0029] R 11b and R 12bTogether with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0030] R 11c and R 12c Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0031] R 11d and R 12d Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents;

[0032] Each time L appears, 1 Independently selected from -O- and -NR a -、-C(O)NR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L1c replace;

[0033] Where *L1 refers to the attachment to The location of the part, and **L1 refers to the part attached to it. Partial location;

[0034] Each time L appears, 2 Independently selected from -O- and -NR a -、-CONR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L2c replace;

[0035] Where *L2 refers to the attachment to The location of the part, and **L2 refers to the part attached to it. Partial location;

[0036] Each time L appears, 3 Independently selected from -O- and -NR a -、-CONR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L3c replace;

[0037] Where *L3 refers to the attachment to The location of the part, and **L3 refers to the part attached to it. Partial location;

[0038] The R L1c R L2c and R L3c Each of these elements is independent of the following: oxidized (=O), halogenated, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 aryl or 5 to 12-membered heteroaryl; wherein -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 and 5 to 12 heteroaryl groups is optionally separated by at least one R Lca replace,

[0039] R Lca Independently, it is absent, oxo (=O), halogen, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic groups, C6-C 12 aryl or 5 to 12 heteroaryl groups; or

[0040] Two Rs L1cTogether with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0041] Two Rs L2c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0042] Two Rs L3c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0043] Selected from

[0044] Z 1 Z 2 and Z 3 Each is independently N or CR z The condition is Z 1 Z 2 and Z 3 They are not both N;

[0045] R z Each time it appears, it is independently selected from non-existent, hydrogen, halogen, -C. 1-8 Alkyl, -NR Za R Zb -OR Za -SR Za C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups or CN;-C 1-8 Each of the alkyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclic groups is optionally surrounded by at least one R Zc replace;

[0046] Partially via Z 1 Z 2 or Z 3 any of the connections in Part, of which CR z and R z It does not exist;

[0047] R Za and R Zb Each is independently selected from non-existent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8-membered heterocyclic groups, C6-C12 aryl, or 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Each of the aryl group, or 5 to 12 heteroaryl groups, is optionally bounded by at least one R Zd Substituent substitution;

[0048] R Zc and R Zd Each is independently a halogen, hydroxyl group, -C1-C8 alkyl group, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, or 5 to 12 heteroaryl;

[0049] R 13 and R 14 Each is independently selected from non-existent, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -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 group, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally dilated by a halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c -SO2R 13c -SO2NR13c 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;

[0050] R each time it appears 13a R 13b R 13c and R 13d Each independently does not exist; hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, or 5 to 12 heteroaryl;

[0051] L 4 L 5 and L 6 Each is independently selected from non-existent, 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)-;

[0052] X appears each time 1 X 2 and X 7 Each independently selected from -CR a Or N;

[0053] X appears each time 3 X 4 and X 8 Each independently selected from -NR a -、-O-、-S- and -CR a R b -;

[0054] X appears each time 5 and X6 Each is independently selected from non-existent, single bond, -C(O)-, -NR a -and-O-;

[0055] Q 1 Q 2 Q 3 and Q 4 Each independently selected from CR a Or N;

[0056] R each time it appears a and R b Each is independently selected from hydrogen, hydroxyl, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic groups, -C6-C 12 aryl or 5- to 12-membered heteroaryl, wherein 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 bound by at least one halogen, hydroxyl group, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl or 5 to 12 heteroaryl substituents; or

[0057] R a and R b Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, said rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituted with at least one 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 heterocyclic group, C6-C 12 Aryl or 5 to 12 heteroaryl substitutions;

[0058] m1, m2, m3 and m4 are each independently 0, 1 or 2;

[0059] m5 and m7 are each independently 0 or 1;

[0060] m6 is 0, 1, or 2; when m6 is 2, the two L2s are either the same or different.

[0061] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0062] n6, n7, and n8 are each independently 0, 1, 2, 3, or 4.

[0063] Aspect 2. A compound having formula (I)

[0064]

[0065] Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analogue, or its prodrug.

[0066] in:

[0067] Cy1 is a hexa-membered partially or fully unsaturated ring; the ring is substituent for at least one R. 1 replace;

[0068] Y 1 Y 2 and Y 3 Each can be either C or N independently;

[0069] s1 is 0, 1, 2, 3, 4 or 5;

[0070] 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 substituented by at least one R. 2 replace;

[0071] s2 is 0, 1, or 2;

[0072] s4 is 0 or 1;

[0073] 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 substituented by at least one R. 3 replace;

[0074] s3 is 0, 1, 2, 3, 4, or 5;

[0075] R 1 R 2 and R 3 Each of these components is independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 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 -NR1a CO2R 1b ;-C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally substituent R. 1c Replace; or

[0076] When adjacent, two R 1 Two Rs 2 Or two Rs 3 Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituents R. 1c replace;

[0077] 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 heterocyclic groups, C6-C 12 aryl or 5 to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkoxy-C1-C8 alkyl-, 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 substituent selected from the following: halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0078] R 1c Each time it appears, it is independently a halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0079] R 11a R 11b R 11c R 11d R 12a R 12b R 12c and R 12d Each independently exists: non-existent, oxidized, hydrogen, halogen, -C 1-8 Alkyl, -C2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 alkoxy or -C 3-8 cycloalkyl; the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally selected from at least one element selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; or

[0080] R 11a and R 12a Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0081] R 11b and R 12b Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0082] R 11c and R 12c Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0083] R 11d and R 12d Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents;

[0084] Each time L appears, 1 Independently selected from -O- and -NR a -、-C(O)NR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L1c replace;

[0085] Where *L1 refers to the attachment to The location of the part, and **L1 refers to the part attached to it. Partial location;

[0086] Each time L appears, 2 Independently selected from -O- and -NR a -、-CONR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L2c replace;

[0087] Where *L2 refers to the attachment to The location of the part, and **L2 refers to the part attached to it. Partial location;

[0088] Each time L appears, 3 Independently selected from -O- and -NR a -、-CONR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L3c replace;

[0089] Where *L3 refers to the attachment to The location of the part, and **L3 refers to the part attached to it. Partial location;

[0090] The RL1c R L2c and R L3c Each of these elements is independent of the following: oxidized (=O), halogenated, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 aryl or 5 to 12-membered heteroaryl; wherein -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 and 5 to 12 heteroaryl groups is optionally separated by at least one R Lca replace,

[0091] R Lca Independently, it is absent, oxo (=O), halogen, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic groups, C6-C 12 aryl or 5 to 12 heteroaryl groups; or

[0092] Two Rs L1c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0093] Two Rs L2c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0094] Two Rs L3c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0095] Selected from

[0096] Z 1 Z 2 and Z 3 Each is independently N or CR z The condition is Z 1 Z 2 and Z 3 They are not both N;

[0097] R z Each time it appears, it is independently selected from non-existent, hydrogen, halogen, -C. 1-8 Alkyl, -NR Za R Zb -OR Za -SR Za C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups or CN;-C 1-8 Each of the alkyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclic groups is optionally surrounded by at least one R Zc replace;

[0098] Partially via Z 1 Z 2 or Z 3 any of the connections in Part, of which CR z and R z It does not exist;

[0099] R Za and R Zb Each is independently selected from non-existent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8-membered heterocyclic groups, C6-C 12 aryl, or 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Each of the aryl group, or 5 to 12 heteroaryl groups, is optionally bounded by at least one R Zd Substituent substitution;

[0100] R Zc and R Zd Each is independently a halogen, hydroxyl group, -C1-C8 alkyl group, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, or 5 to 12 heteroaryl;

[0101] R 13 and R 14 Each is independently selected from non-existent, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -SO2R 13a -SO2NR 13a R 13b -COR 13a -CO2R13a -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 group, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally dilated by a halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, 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;

[0102] R each time it appears 13a R 13b R 13c and R 13d Each independently does not exist; hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, or 5 to 12 heteroaryl;

[0103] L 4 L 5 and L 6 Each is independently selected from non-existent, 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)-;

[0104] X appears each time 1 X 2 and X 7 Each independently selected from -CR a Or N;

[0105] X appears each time 3 X 4 and X 8 Each independently selected from -NR a -、-O-、-S- and -CR a R b -;

[0106] X appears each time 5 and X 6 Each is independently selected from non-existent, single bond, -C(O)-, -NR a -and-O-;

[0107] Q 1 Q 2 Q 3 and Q 4 Each independently selected from CR a Or N;

[0108] R each time it appears a and R b Each is independently selected from hydrogen, hydroxyl, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic groups, -C6-C 12 aryl or 5- to 12-membered heteroaryl, wherein 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 bound by at least one halogen, hydroxyl group, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl or 5 to 12 heteroaryl substituents; or

[0109] R a and R b Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, said rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituted with at least one 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 heterocyclic group, C6-C 12 Aryl or 5 to 12 heteroaryl substitutions;

[0110] m1, m2, m3 and m4 are each independently 0, 1 or 2;

[0111] m5 and m7 are each independently 0 or 1;

[0112] m6 is 0, 1, or 2; when m6 is 2, the two L2s are either the same or different.

[0113] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0114] n6, n7, and n8 are each independently 0, 1, 2, 3, or 4.

[0115] Aspect 3. A compound having formula (I')

[0116]

[0117] Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analogue, or its prodrug.

[0118] in:

[0119] Cy1 is a hexa-membered partially or fully unsaturated ring; the ring is substituent for at least one R. 1 replace;

[0120] Y 1 Y 2 and Y 3 Each can be either C or N independently;

[0121] s1 is 0, 1, 2, 3, 4 or 5;

[0122] 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 substituented by at least one R. 2 replace;

[0123] s2 is 0, 1, or 2;

[0124] s4 is 0 or 1;

[0125] 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 substituented by at least one R. 3 replace;

[0126] s3 is 0, 1, 2, 3, 4, or 5;

[0127] R 1 R 2 and R 3 Each of these components is independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 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, C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally substituent R. 1c Replace; or

[0128] When adjacent, two R 1 Two Rs 2 Or two Rs 3 Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituents R. 1c replace;

[0129] 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 heterocyclic groups, C6-C 12 aryl or 5 to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3 to 8-membered heterocyclic, C6-C 12Each of the aryl or 5- to 12-membered heteroaryl groups is optionally substituted by at least one substituent selected from the following: halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0130] R 1c Each time it appears, it is independently a halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0131] R 11a R 11b R 11c R 11d R 12a R 12b R 12c and R 12d Each independently exists: non-existent, oxidized, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 alkoxy or -C 3-8 cycloalkyl; the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally selected from at least one element selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; or

[0132] R 11a and R 12a Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0133] R 11b and R 12bTogether with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0134] R 11c and R 12c Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0135] R 11d and R 12d Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents;

[0136] Each time L appears, 1 Independently selected from -O- and -NR a -、-C(O)NR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L1c replace;

[0137] Where *L1 refers to the attachment to The location of the part, and **L1 refers to the part attached to it. Partial location;

[0138] Each time L appears, 2 Independently selected from -O- and -NR a -、-CONR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L2c replace;

[0139] Where *L2 refers to the attachment to The location of the part, and **L2 refers to the part attached to it. Partial location;

[0140] Each time L appears, 3 Independently selected from -O- and -NR a -、-CONR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L3c replace;

[0141] Where *L3 refers to the attachment to The location of the part, and **L3 refers to the part attached to it. Partial location;

[0142] The R L1c R L2c and R L3c Each of these elements is independent of the following: oxidized (=O), halogenated, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 aryl or 5 to 12-membered heteroaryl; wherein -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 and 5 to 12 heteroaryl groups is optionally separated by at least one R Lca replace,

[0143] R Lca Independently, it is absent, oxo (=O), halogen, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic groups, C6-C 12 aryl or 5 to 12 heteroaryl groups; or

[0144] Two Rs L1cTogether with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0145] Two Rs L2c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0146] Two Rs L3c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0147] Selected from

[0148] Z 1 Z 2 and Z 3 Each is independently N or CR z The condition is Z 1 Z 2 and Z 3 They are not both N;

[0149] R z Each time it appears, it is independently selected from non-existent, hydrogen, halogen, -C. 1-8 Alkyl, -NR Za R Zb -OR Za -SR Za C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups or CN;-C 1-8 Each of the alkyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclic groups is optionally surrounded by at least one R Zc replace;

[0150] Partially via Z 1 Z 2 or Z 3 any of the connections in Part, of which CR z and R z It does not exist;

[0151] R Za and R Zb Each is independently selected from non-existent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8-membered heterocyclic groups, C6-C12 aryl, or 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Each of the aryl group, or 5 to 12 heteroaryl groups, is optionally bounded by at least one R Zd Substituent substitution;

[0152] R Zc and R Zd Each is independently a halogen, hydroxyl group, -C1-C8 alkyl group, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, or 5 to 12 heteroaryl;

[0153] R 13 and R 14 Each is independently selected from non-existent, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -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 group, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally dilated by a halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR 13c -SO2R 13c -SO2NR13c 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;

[0154] R each time it appears 13a R 13b R 13c and R 13d Each independently does not exist; hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, or 5 to 12 heteroaryl;

[0155] L 4 L 5 and L 6 Each is independently selected from non-existent, 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)-;

[0156] X appears each time 1 X 2 and X 7 Each independently selected from -CR a Or N;

[0157] X appears each time 3 X 4 and X 8 Each independently selected from -NR a -、-O-、-S- and -CR a R b -;

[0158] X appears each time 5 and X6 Each is independently selected from non-existent, single bond, -C(O)-, -NR a -and-O-;

[0159] Q 1 Q 2 Q 3 and Q 4 Each independently selected from CR a Or N;

[0160] R each time it appears a and R b Each is independently selected from hydrogen, hydroxyl, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic groups, -C6-C 12 aryl or 5- to 12-membered heteroaryl, wherein 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 bound by at least one halogen, hydroxyl group, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl or 5 to 12 heteroaryl substituents; or

[0161] R a and R b Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, said rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituted with at least one 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 heterocyclic group, C6-C 12 Aryl or 5 to 12 heteroaryl substitutions;

[0162] m1, m2, m3 and m4 are each independently 0, 1 or 2;

[0163] m5 and m7 are each independently 0 or 1;

[0164] m6 is 0, 1, or 2; when m6 is 2, the two L2s are either the same or different.

[0165] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0166] n6, n7, and n8 are each independently 0, 1, 2, 3, or 4.

[0167] Aspect 4. The compound as described in aspect 1, wherein the compound is selected from formulas (IIa), (IIa'), (IIb), (IIb'), (IIc), (IIc'), (IId), (IId'), (IIe) and (IIe').

[0168]

[0169]

[0170]

[0171] 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 aspect 1.

[0172] Aspect 5. The compound as described in 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'):

[0173]

[0174]

[0175]

[0176]

[0177] Where R 1 R 2 R 3 R 11a R11b 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 aspect 1.

[0178] 4. The compound as described in aspect 1, wherein the compound is selected from formulas (IVa), (IVva'), (IVb), (IVb'), (IVc) and (IVc').

[0179]

[0180] 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 as defined in aspect 1.

[0181] 5. The compound as described in aspect 1, wherein the compound is selected from formula (Va) or (Va').

[0182]

[0183] Preferably, the compound is selected from formulas (Vb), (Vb'), (Vc), and (Vc').

[0184]

[0185] More preferably, the compound is selected from formulas (Vd), (Vd'), (Ve), and (Ve').

[0186]

[0187]

[0188] 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').

[0189]

[0190]

[0191]

[0192]

[0193] 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').

[0194]

[0195]

[0196]

[0197]

[0198] 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 Each is independently selected from C or N; Y 5 and Y 6 Each is independently selected from C, N, O, or S; provided that It is a fragrant ring;

[0199] 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, m1, m2, m3, m4, m5, m6, m7 and degradation determinants are as defined in aspect 1.

[0200] Aspect 6. The compound as described in aspect 1, wherein the compound is selected from formula (VIa) or (Via').

[0201]

[0202] Preferably, the compound is selected from (VIb) or (VIb),

[0203]

[0204]

[0205] 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.

[0206] Aspect 7. The compound as described in any of the preceding aspects, wherein Y 1 Y 2 and Y 3 At least one of them is N; preferably, Y 1 It is N, Y 2 and Y 3 It is C; or Y 2 It is N, Y 1 and Y 3 It is C; or Y3 It is N, Y 1 and Y 2 It's C.

[0207] Aspect 8. The compound as described in any of the preceding aspects, wherein Cy1 is pyridinyl or pyridoneyl.

[0208] Aspect 9. The compound as described in any of the preceding aspects, wherein Part of it is Preferably, Part of it is

[0209] Aspect 10. The compound as described in any of the preceding aspects, wherein the Part of it is

[0210]

[0211] in* Cy2 It refers to attaching to Partial location, and** Cy2 It refers to attaching to Partial location;

[0212] Preferably, Part of it is

[0213] Aspect 11. The 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 comprises 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring is substituented by at least one R group. 3 replace;

[0214] In one embodiment, Cy3 is a 5, 6, 7, 8, 9, or 10 nucleotide aromatic ring, wherein each of the 5 and 6 nucleotide aromatic rings is a monocyclic ring, each of the 8, 9, or 10 nucleotide aromatic rings is a bicyclic ring, and the 7 nucleotide aromatic ring is either a monocyclic or bicyclic ring.

[0215] 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 substituented by at least one R group. 3 replace;

[0216] Even more preferably, yes

[0217] in* Cy3 It refers to attaching to Partial location, and**Cy3 It refers to attaching to Partial location;

[0218] Even more preferably, yes

[0219] Aspect 12. The compound as described in any of the preceding aspects, wherein R 1 R 2 and R 3 Each of the following can be independently: hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic groups, phenyl, 5 to 12-membered heteroaryl groups, oxo (=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 the following groups is optionally substituent R: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic, phenyl, or 5- to 12-membered heteroaryl. 1c replace,

[0220] R 1a and R 1bEach is 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 ynyl, C1-C8 alkoxy-C1-C8 alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclic, phenyl, or 5 to 12 membered heteroaryl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C1-C8 haloalkyl (preferably -CH2F, -CHF2, -C1-C8 alkyl (preferably -CH2F, -CHF2, -C1-C8 alkyl (preferably -CH2F, -CHF2, -CH2CF3), -C2-C8 alkenyl, -C2-C8 ynyl, -C2-C8 alken ... F3, -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 heterocyclic, phenyl, or 5 to 12-membered heteroaryl, each optionally substituted by at least one substituent selected from: -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 heterocyclic, phenyl or 5 to 12-membered heteroaryl;

[0221] R 1c Each time it appears independently, it is -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl.

[0222] Aspect 13. The compound as described in any of the preceding aspects, wherein R 1 R 2 and R 3 Each of the following can be independently: hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8 membered heterocyclic groups, oxo (=O), -CN, -OR 1a or -C(O)NR 1a R 1b -NR 1a R1b Each of the following groups—methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3 to 8 membered heterocyclic groups—is optionally substituent for at least one substituent R. 1c replace,

[0223] R 1a and R 1b Each is 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 by at least one substituent selected from the following: -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl;

[0224] R 1c Each time it appears, it is independently -F, -Cl, -Br, -I, -OH;

[0225] Preferably, R 1 R 2 and R 3 Each of these can be 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.

[0226] Even more preferably, R 1It is H, -CH3, -CH2CH3, -CF3, -CF2CH3, -CH(CH3)2, -C(CH3)3, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH3)2, oxo (=O), cyclopropyl,

[0227] R 2 It can be H, -CF3, cyclopropyl, oxo (=O), -F, -Cl, -Br, -I, or -CN;

[0228] R 3 It includes H, -CH3, oxo (=O), -CHF2, -CONH2, -OMe, -OCD3, -OEt, -OCH2CH2CH3, and -OCH(CH3)2.

[0229] Aspect 14. The compound as described in any of the preceding aspects, wherein two Rs 3 Together with the atoms to which they are attached, they form 3, 4, 5, 6, 7, or 8-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituented by at least one R. 1c replace;

[0230] R 1c Each time it appears independently, it is -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl.

[0231] Preferably, two R 3 Together with the atoms to which they are attached, they form 3, 4, 5, or 6-membered rings, the rings containing 0, 1, 2, or 3 heteroatoms independently selected from oxygen; the rings are optionally substituents R. 1c replace;

[0232] R 1c Each time it appears, it is independently -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0233] Aspect 15. The compound as described in any of the preceding aspects, wherein R 11a R 11b R 11c R 11d R 12a R 12bR 12c and R 12d Each of the following is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Alkyne, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; wherein methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Each of alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally selected from at least one of hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, or -CN groups; or

[0234] (R 11a and R 12a ), (R 11b and R 12b ), (R 11c and R 12c ) or (R 11d and R 12d These atoms, together with the carbon atoms to which they are attached, form 3, 4, 5, 6, 7, or 8-membered rings, said rings containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally separated by at least one atom selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Substitution with alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, or -CN substituents.

[0235] Aspect 16. The compound as described in any of the preceding aspects, wherein Part of it is

[0236] Aspect 17. The compound as described in any of the preceding aspects, wherein the Part of it is

[0237] Preferably, the Part of it is

[0238] Aspect 18. The compound as described in any of the preceding aspects, wherein R 11a R 11b R 11c R 11d R 12a R 12b R 12c and R 12d Each of the following is independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; preferably, R 11a R 11b R 11c R 11d R 12a R 12b R 12c and R 12d Each of the following is 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 Each is independently hydrogen or methyl; or

[0239] (R 11a and R 12a ), (R 11b and R 12b ), (R 11c and R 12c ) or (R 11d and R 12d These, together with the carbon atoms to which they are attached, form 3, 4, 5, 6, 7, or 8-membered rings, said rings containing 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 (R11d and R 12d Together with the carbon atoms to which they are attached, they form 3, 4, or 5-membered alkyl rings.

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

[0241] The above Each of them is optionally defined by at least one R L1c replace;

[0242] The R L1c Each of the following is independently an oxo (=O), F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, and 5 to 12-membered heteroaryl groups is optionally divided by at least one R Lca replace,

[0243] R Lca Independently, it is an oxo (=O), F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl; or

[0244] Two Rs L1cTogether with the carbon atoms to which they are attached, they form 3, 4, 5, 6, 7 or 8-membered rings, the rings containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the rings are optionally substituted by at least one F, Cl, Br, I, hydroxyl, 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 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl substituent.

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

[0247] Aspect 21. The compound as described in any of the preceding aspects, wherein L 2 Selected from -O-, -N(R) a )-、

[0248] The above Each of them is optionally defined by at least one R L2c replace;

[0249] The R L2cEach of the following is independently an oxo (=O), F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, and 5 to 12-membered heteroaryl groups is optionally divided by at least one R Lca replace,

[0250] R Lca Independently, it is an oxo (=O), F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl; or

[0251] Two Rs L2c Together with the carbon atoms to which they are attached, they form 3, 4, 5, 6, 7 or 8-membered rings, the rings containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the rings are optionally substituted by at least one F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl substituent.

[0252] R a Selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl substituent.

[0253] Aspect 22. The compound as described in any of the preceding aspects, wherein L 2 Selected from -O-, -N(CH3)-,

[0254] Aspect 23. The compound as described in any of the preceding aspects, wherein the Part of it is Preferred The place, Part of it is

[0255] More preferably, the Part of it is

[0256] Aspect 24. The compound as described in any of the preceding aspects, wherein L 3 Selected from -O-, -N(R) a )-、

[0257] The above Each of them is optionally defined by at least one R L3c replace;

[0258] The R L3cEach of the following is independently an oxo (=O), F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, and 5 to 12-membered heteroaryl groups is optionally divided by at least one R Lca replace,

[0259] R Lca Independently, it is an oxo (=O), F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl; or

[0260] Two Rs L3c Together with the carbon atoms to which they are attached, they form 3, 4, 5, 6, 7 or 8-membered rings, the rings containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the rings are optionally substituted by at least one F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl substituent.

[0261] R a Selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl substituent.

[0262] Aspect 25. The compound as described in any of the preceding aspects, wherein L 3 Selected from -O-, -N(CH3)-, -NH-,

[0263] Aspect 26. The compound as described in any of the preceding aspects, wherein Partially selected from

[0264] Preferably, Partially selected from

[0265] Aspect 27. The compound as described in any of the preceding aspects, wherein L 4 Independently selected from single bonds, -O-, -NR a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or -C(O)-;

[0266] R each time it appears a and R bEach is independently selected from hydrogen, hydroxyl, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C Each of the following groups is optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, or 5- to 12-membered heteroaryl group.

[0267] Aspect 28. The compound as described in any of the preceding aspects, wherein L 4 It is independently selected from a single bond or -NH-.

[0268] Aspect 29. The compound as described in any of the preceding aspects, wherein X 7 Independently selected from -CR a Or N;

[0269] R aIndependently selected from hydrogen, hydroxyl, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 Each of the following groups is optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, or 5- to 12-membered heteroaryl group.

[0270] Aspect 30. The compound as described in any of the preceding aspects, wherein X 7 Independently selected from -CH, -C(CH3), or N; preferably, X 7 Independently selected from -CH.

[0271] Aspect 31. The compound as described in any of the preceding aspects, wherein X 8 Independently selected from -NR a -、-O-、-S- and -CR a R b -;

[0272] R each time it appears a and R bEach is independently selected from hydrogen, hydroxyl, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C Each of the following groups is optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, or 5- to 12-membered heteroaryl group.

[0273] Aspect 32. The compound as described in any of the preceding aspects, wherein X 8 Independently selected from -NH- and -CH2-; preferably, X 8 It is selected independently from -CH2-.

[0274] Aspect 33. The compound as described in any of the preceding aspects, wherein Selected from Preferably, Selected from

[0275] More preferably, Selected from

[0276] Aspect 34. The compound as described in any of the preceding aspects, wherein Z 1 Z 2 and Z 3 At most one of them is N.

[0277] Aspect 35. The compound as described in any of the preceding aspects, wherein Z 1 Z 2 and Z 3 Each is CR independentlyz .

[0278] Aspect 36. The compound as described in any of the preceding aspects, wherein R Z Each time it appears, it is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -NR. Za R Zb -OR Za -SR Za Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic groups or CN; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or 3 to 8-membered heterocyclic groups is optionally surrounded by at least one R Zc replace;

[0279] R Za and R Zb Each of the following groups is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, wherein each of the following groups is optionally bound by at least one R Zd Substituent substitution;

[0280] R Zc and R Zd Each of these can be independently -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl.

[0281] Aspect 37. The compound as described in any 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.

[0282] Aspect 38. The compound as described in any of the preceding aspects, wherein R 13 and R 14Each is independently selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 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, pentoxy, hexoxy, heptoxy, 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, 5 to 12 heteroaryl groups is optionally prefixed with F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 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;

[0283] R 13a R 13b R 13c and R 13d Each of the following is 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 heteroaryl.

[0284] Aspect 39. The compound as described in any 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, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -CH2F, -CHF2, -CF3, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, or phenyl.

[0285] Aspect 40. The compound as described in any of the preceding aspects, wherein yes

[0286] Aspect 41. The compound as described in any of the preceding aspects, wherein L 5 and L 6 Each is independently selected from single bonds, -O-, and -NR. a -、-(CR a R b ) n8 -、-O(CR a R b ) n8 -、-NR a (CR a R b ) n8 -or -C(O)-;

[0287] X 8 Yes -CR a R b -;

[0288] R each time it appears a and R bEach is independently selected from hydrogen, hydroxyl, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C Each of the following groups is optionally substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclic group, phenyl, or 5- to 12-membered heteroaryl group.

[0289] Aspect 42. The compound as described in any of the preceding aspects, wherein L 5 and L 6 Each is a single key independently. -O-, -NH-, -NMe-, -N(CH2CH3)-, -CH2-, -CHF-, -CF2-, -C(CH3)2- or -CO- (preferably, L 5 It is -CO- or -CH2-, and L 6 yes -O-, -NH-, -NMe-, -N(CH2CH3)-, -CH2-, -CHF-, -CF2-, -C(CH3)2- or -CO-);

[0290] X 8 It is CH2; and

[0291] n6 is either 0 or 1.

[0292] Aspect 43. The 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, pentoxy, hexoxy, heptoxy, 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, pentoxy, hexoxy, heptoxy, 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, 5 to 12 heteroaryl groups is optionally prefixed with F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 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;

[0293] R each time it appears 13a R 13b R 13c and R 13dEach of the following is 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 heteroaryl.

[0294] Aspect 44. The compound as described in any of the preceding aspects, wherein R 13 Independently selected from hydrogen, F, Cl, Br, I, CN, -C1-C8 alkyl, or -C1-C8 alkoxy; preferably, R 13 It is independently selected from hydrogen, F, Cl, Br, I, CN, -Me, -Et, -C3H7, -C4H9, -OMe, -OEt, -OC3H7 or -OC4H9;

[0295] n7 can be 0, 1, or 2.

[0296] Aspect 45. The compound as described in any of the preceding aspects, wherein yes

[0297] Aspect 46. The compound as described in any of the preceding aspects, wherein the compound is selected from...

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341] Aspect 47. A pharmaceutical composition comprising a compound as described in any one of Aspects 1-45 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

[0342] Aspect 48. A method for treating a disease that can be regulated by IRAK4, the method comprising administering to a subject in need an effective amount of a compound as described in any one of Aspects 1-45, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

[0343] Aspect 49. The method as described in aspect 47, wherein the disease is selected from autoimmune diseases and inflammatory conditions, preferably systemic lupus erythematosus, hidradenitis suppurativa, rheumatoid arthritis, arthritis, gout, multiple sclerosis, psoriasis and cancer, preferably acute myeloid leukemia, cancer, lymphoma, B-cell myelodysplastic syndrome.

[0344] Aspect 50. Use of any compound of any one of Aspects 1-45, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in the preparation of a medicament for treating diseases that may be regulated by IRAK4.

[0345] Aspect 51. Use as described in aspect 49, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0346] The inventors of this invention have surprisingly discovered that the linker, such as the IRAK4 binding portion and the E3 ligase ligand portion, is... The increased degradation activity conferred by some of the compounds indicates that these compounds can efficiently degrade the target protein (in this case, the IRAK4 protein). Specifically, the DC of the compounds disclosed in this paper... 50 Values ​​below 20nm, preferably below 10nm, more preferably below 5nm, 3nm, 2nm, or 1nm; D maxThe value should be greater than 60%, preferably greater than 70% or 80%.

[0347] In the preferred connector, 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, this... Part of it is Among them, L 1 Selected from -O-, -N(R) a )-、 The above Each of them is optionally defined by at least one R L1c replace;

[0348] The R L1c Each of the following is independently an oxo (=O), F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, and 5 to 12-membered heteroaryl groups is optionally divided by at least one R Lca replace,

[0349] R Lca Independently, it is an oxo (=O), F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl; or

[0350] Two Rs L1cTogether with the carbon atoms to which they are attached, they form 3, 4, 5, 6, 7 or 8-membered rings, the rings containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the rings are optionally substituted by at least one F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl substituent.

[0351] R a Selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which is optionally selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl It is substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl substituent; preferably, L 1 Selected from -O-, -N(CH3)-,

[0352] Where L 2 Selected from -O-, -N(R) a )-、 The above Each of them is optionally defined by at least one R L2c replace;

[0353] The R L2cEach of the following is independently an oxo (=O), F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, or 5 to 12-membered heteroaryl; each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic, phenyl, and 5 to 12-membered heteroaryl groups is optionally divided by at least one R Lca replace,

[0354] R Lca Independently, it is an oxo (=O), F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl; or

[0355] Two Rs L2c Together with the carbon atoms to which they are attached, they form 3, 4, 5, 6, 7 or 8-membered rings, the rings containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; the rings are optionally substituted by at least one F, Cl, Br, I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl substituent.

[0356] R a Selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each of which is optionally selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 ynynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl It is substituted with at least one halogen, hydroxyl, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyl, -C2-C8 alkenyl, -C2-C8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3 to 8-membered heterocyclic group, phenyl, or 5 to 12-membered heteroaryl substituent; preferably, L 2Selected from -O-, -N(CH3)-,

[0357] Even more preferably, the Part of it is

[0358] More preferably, Part of it is

[0359] In one embodiment, a compound having formula (X)

[0360]

[0361] Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analogue, or its prodrug.

[0362] in:

[0363] L x yes *Lx -CONH- **Lx or *Lx -NHCO- **Lx ,in* Lx This refers to the position attached to the Cy2 part, and** L x refers to the position attached to the Cy3 part;

[0364] Cy1 is a hexa-membered partially or fully unsaturated ring; the ring is substituent for at least one R. 1 replace;

[0365] Y 1 Y 2 and Y 3 Each can be either C or N independently;

[0366] s1 is 0, 1, 2, 3, 4 or 5;

[0367] 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 substituented by at least one R. 2 replace;

[0368] s2 is 0, 1, or 2;

[0369] s4 is 0 or 1;

[0370] 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 substituented by at least one R. 3 replace;

[0371] s3 is 0, 1, 2, 3, 4, or 5;

[0372] R 1 R 2 and R 3 Each of these components is independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or 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, C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally substituent R. 1c Replace; or

[0373] When adjacent, two R 1 Two Rs 2 Or two Rs 3 Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituents R. 1c replace;

[0374] 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 heterocyclic groups, C6-C 12aryl or 5 to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkoxy-C1-C8 alkyl-, 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 substituent selected from the following: halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0375] R 1c Each time it appears, it is independently a halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0376] R 11a R 11b R 11c R 11d R 12a R 12b R 12c and R 12d Each independently exists: non-existent, oxidized, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 alkoxy or -C 3-8 cycloalkyl; the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally selected from at least one element selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; or

[0377] R 11a and R 12a Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0378] R 11b and R 12b Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0379] R 11c and R 12c Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0380] R 11d and R 12d Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents;

[0381] Each time L appears, 1 Independently selected from -O- and -NR a -、-C(O)NR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L1c replace;

[0382] Where *L1 refers to the attachment to The location of the part, and **L1 refers to the part attached to it. Partial location;

[0383] Each time L appears, 2 Independently selected from -O- and -NR a-、-CONR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L2c replace;

[0384] Where *L2 refers to the attachment to The location of the part, and **L2 refers to the part attached to it. Partial location;

[0385] Each time L appears, 3 Independently selected from -O- and -NR a -、-CONR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L3c replace;

[0386] Where *L3 refers to the attachment to The location of the part, and **L3 refers to the part attached to it. Partial location;

[0387] The R L1c R L2c and R L3c Each of these elements is independent of the following: oxidized (=O), halogenated, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 aryl or 5 to 12-membered heteroaryl; wherein -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 and 5 to 12 heteroaryl groups is optionally separated by at least one R Lca replace,

[0388] R Lca Independently, it is absent, oxo (=O), halogen, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic groups, C6-C 12 aryl or 5 to 12 heteroaryl groups; or

[0389] Two Rs L1c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0390] Two Rs L2c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0391] Two Rs L3c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0392] Selected from

[0393] Z 1 Z 2 and Z 3 Each is independently N or CR z The condition is Z 1 Z 2 and Z 3 They are not both N;

[0394] R z Each time it appears, it is independently selected from non-existent, hydrogen, halogen, -C. 1-8 Alkyl, -NR Za R Zb -OR Za -SR Za C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups or CN;-C 1-8 Each of the alkyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclic groups is optionally surrounded by at least one R Zc replace;

[0395] Partially via Z 1 Z 2 or Z 3 any of the connections in Part, of which CR z and R z It does not exist;

[0396] R Za and R ZbEach is independently selected from non-existent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8-membered heterocyclic groups, C6-C 12 aryl, or 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Each of the aryl group, or 5 to 12 heteroaryl groups, is optionally bounded by at least one R Zd Substituent substitution;

[0397] R Zc and R Zd Each is independently a halogen, hydroxyl group, -C1-C8 alkyl group, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, or 5 to 12 heteroaryl;

[0398] R 13 and R 14 Each is independently selected from non-existent, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -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 group, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally dilated by a halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12aryl, 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;

[0399] R each time it appears 13a R 13b R 13c and R 13d Each independently does not exist; hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, or 5 to 12 heteroaryl;

[0400] L 4 L 5 and L 6 Each is independently selected from non-existent, 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)-;

[0401] X appears each time 1 X 2 and X 7 Each independently selected from -CR a Or N;

[0402] X appears each time 3 X 4 and X 8 Each independently selected from -NR a -、-O-、-S- and -CR a Rb -;

[0403] X appears each time 5 and X 6 Each is independently selected from non-existent, single bond, -C(O)-, -NR a -and-O-;

[0404] Q 1 Q 2 Q 3 and Q 4 Each independently selected from CR a Or N;

[0405] R each time it appears a and R b Each is independently selected from hydrogen, hydroxyl, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic groups, -C6-C 12 aryl or 5- to 12-membered heteroaryl, wherein 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 bound by at least one halogen, hydroxyl group, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl or 5 to 12 heteroaryl substituents; or

[0406] R a and R b Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, said rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituted with at least one 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 heterocyclic group, C6-C 12 Aryl or 5 to 12 heteroaryl substitutions;

[0407] m1, m2, m3 and m4 are each independently 0, 1 or 2;

[0408] m5 and m7 are each independently 0 or 1;

[0409] m6 is 0, 1, or 2; when m6 is 2, the two L2s are either the same or different.

[0410] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0411] n6, n7, and n8 are each independently 0, 1, 2, 3, or 4.

[0412] In one embodiment, a compound having formula (I')

[0413]

[0414] Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analogue, or its prodrug.

[0415] in:

[0416] Cy1 is a hexa-membered partially or fully unsaturated ring; the ring is substituent for at least one R. 1 replace;

[0417] Y 1 Y 2 and Y 3 Each can be either C or N independently;

[0418] s1 is 0, 1, 2, 3, 4 or 5;

[0419] 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 substituented by at least one R. 2 replace;

[0420] s2 is 0, 1, or 2;

[0421] s4 is 0 or 1;

[0422] 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 substituented by at least one R. 3 replace;

[0423] s3 is 0, 1, 2, 3, 4, or 5;

[0424] R 1 R 2 and R 3 Each of these components is independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, or C6-C. 12 aryl, 5- to 12-membered heteroaryl, oxo (=O), -CN, -OR 1a -C(O)R 1a -CO2R 1a -C(O)NR1a 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, C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally substituent R. 1c Replace; or

[0425] When adjacent, two R 1 Two Rs 2 Or two Rs 3 Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituents R. 1c replace;

[0426] 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 heterocyclic groups, C6-C 12 aryl or 5 to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkoxy-C1-C8 alkyl-, 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 substituent selected from the following: halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0427] R 1c Each time it appears, it is independently a halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 ynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic group, -C6-C 12 aryl or 5 to 12 heteroaryl groups;

[0428] R 11a R 11b R 11c R 11d R12a R 12b R 12c and R 12d Each independently exists: non-existent, oxidized, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 alkoxy or -C 3-8 cycloalkyl; the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 alkoxy or -C 3-8 Each of the cycloalkyl groups is optionally selected from at least one element selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; or

[0429] R 11a and R 12a Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0430] R 11b and R 12b Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0431] R 11c and R 12c Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents; and / or

[0432] R 11d and R 12d Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally surrounded by at least one atom selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkyl or -CN substituents;

[0433] Each time L appears, 1 Independently selected from -O- and -NR a -、-C(O)NR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L1c replace;

[0434] Where *L1 refers to the attachment to The location of the part, and **L1 refers to the part attached to it. Partial location;

[0435] Each time L appears, 2 Independently selected from -O- and -NR a -、-CONR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L2c replace;

[0436] Where *L2 refers to the attachment to The location of the part, and **L2 refers to the part attached to it. Partial location;

[0437] Each time L appears, 3 Independently selected from -O- and -NR a -、-CONR a -、-C(O)O-、 The above Each of them is optionally defined by at least one R L3c replace;

[0438] Where *L3 refers to the attachment to The location of the part, and **L3 refers to the part attached to it. Partial location;

[0439] The R L1c R L2c and R L3c Each of these elements is independent of the following: oxidized (=O), halogenated, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 aryl or 5 to 12-membered heteroaryl; wherein -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 and 5 to 12 heteroaryl groups is optionally separated by at least one R Lca replace,

[0440] R Lca Independently, it is absent, oxo (=O), halogen, hydroxyl, -CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, C3-C8 cycloalkyl, 3 to 8 membered heterocyclic groups, C6-C 12 aryl or 5 to 12 heteroaryl groups; or

[0441] Two Rs L1c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0442] Two Rs L2c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0443] Two Rs L3c Together with the atoms to which they are attached, they form 3 to 12-membered rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; the rings are optionally substituted with at least one substituent halogen, hydroxyl, or -C1-C8 alkyl group;

[0444] Selected from

[0445] Z 1 Z 2 and Z3 Each is independently N or CR z The condition is Z 1 Z 2 and Z 3 They are not both N;

[0446] R z Each time it appears, it is independently selected from non-existent, hydrogen, halogen, -C. 1-8 Alkyl, -NR Za R Zb -OR Za -SR Za C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups or CN;-C 1-8 Each of the alkyl, C3-C8 cycloalkyl, and 3- to 8-membered heterocyclic groups is optionally surrounded by at least one R Zc replace;

[0447] Partially via Z 1 Z 2 or Z 3 any of the connections in Part, of which CR z and R z It does not exist;

[0448] R Za and R Zb Each is independently selected from non-existent, hydrogen, -C1-C8 alkyl, C3-C8 cycloalkyl, 3 to 8-membered heterocyclic groups, C6-C 12 aryl, or 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Each of the aryl group, or 5 to 12 heteroaryl groups, is optionally bounded by at least one R Zd Substituent substitution;

[0449] R Zc and R Zd Each is independently a halogen, hydroxyl group, -C1-C8 alkyl group, -C 1-8 Alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12 Aryl, or 5 to 12 heteroaryl;

[0450] R 13 and R 14 Each is independently selected from non-existent, hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -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 ;-C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl group, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic groups, -C6-C 12 Each of the aryl or 5 to 12 heteroaryl groups is optionally dilated by a halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, 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;

[0451] R each time it appears 13a R 13b R 13c and R 13d Each independently does not exist; hydrogen and -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, C6-C 12Aryl, or 5 to 12 heteroaryl;

[0452] L 4 L 5 and L 6 Each is independently selected from non-existent, 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)-;

[0453] X appears each time 1 X 2 and X 7 Each independently selected from -CR a Or N;

[0454] X appears each time 3 X 4 and X 8 Each independently selected from -NR a -、-O-、-S- and -CR a R b -;

[0455] X appears each time 5 and X 6 Each is independently selected from non-existent, single bond, -C(O)-, -NR a -and-O-;

[0456] Q 1 Q 2 Q 3 and Q 4 Each independently selected from CR a Or N;

[0457] R each time it appears a and R b Each is independently selected from hydrogen, hydroxyl, halogen, CN, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3 to 8 membered heterocyclic groups, -C6-C 12 aryl or 5- to 12-membered heteroaryl, wherein the -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic, -C6-C 12Each of the aryl or 5- to 12-membered heteroaryl groups is optionally bound by at least one halogen, hydroxyl group, halogen, -C1-C8 alkyl, -C1-C8 alkoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclic group, -C6-C 12 Aryl or 5 to 12 heteroaryl substituents; or

[0458] R a and R b Together with the carbon atoms to which they are attached, they form 3 to 12-membered rings, said rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said rings are optionally substituted with at least one 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 heterocyclic group, C6-C 12 Aryl or 5 to 12 heteroaryl substitutions;

[0459] m1, m2, m3 and m4 are each independently 0, 1 or 2;

[0460] m5 and m7 are each independently 0 or 1;

[0461] m6 is 0, 1, or 2; when m6 is 2, the two L2s are either the same or different.

[0462] n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3;

[0463] n6, n7, and n8 are each independently 0, 1, 2, 3, or 4. Detailed Implementation

[0464] The following terms have indicative meanings throughout the specification:

[0465] As used herein, including in the appendix, the singular forms of words such as “a / an” and “the” include their corresponding plural references, unless the context clearly indicates otherwise.

[0466] Unless the context clearly indicates otherwise, the term “or” means the term “and / or” and is used interchangeably with the term “and / or”.

[0467] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms (e.g., 1 to 12, further, for example, 1 to 10, even further, for example, 1 to 8, or 1 to 6, or 1 to 4). Alkyl groups containing 1 to 6 carbon atoms (i.e., C64) are also considered alkyl groups. 1-6Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or 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.

[0468] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups (including fused, bridged, or spirocycloalkyl). In one embodiment, the "cycloalkyl" is "-C3-C8 cycloalkyl" or "-C3-C8 cycloalkyl" as described in the specification or claims. 12 Any one of “cycloalkyl”, “cyclopropyl”, “cyclobutyl”, “cyclopentyl”, “cyclohexyl”, “cycloheptyl” or “cyclooctyl”.

[0469] The term "aryl" used alone or in combination with other terms refers to a group selected from the following:

[0470] 5- and 6-membered carbon-ring aromatic rings, such as phenyl;

[0471] Bicyclic systems (e.g., 7- to 12-membered bicyclic systems), wherein at least one ring is a carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0472] Tricyclic systems (e.g., 10- to 15-membered tricyclic systems), wherein at least one ring is a carbocyclic and aromatic, such as fluorene.

[0473] In one embodiment, the "aryl" is "C6-C" as described in the specification or claims. 12 Any of the aryl groups.

[0474] The terms "aromatic ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic ring has 5 to 10 cyclic carbon atoms (i.e., C10). 5-10 Aryl). Examples of monocyclic or bicyclic aromatic rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic ring is a phenyl ring.

[0475] The term "aryl-alkyl-" refers to an alkyl group further substituted with an aryl group as defined above. Examples of aryl-alkyl groups include aryl-C 1-8 Alkyl groups, such as phenylethyl or phenylmethyl (benzyl).

[0476] The term "heteroaryl" refers to a group selected from the following:

[0477] A 5-, 6-, or 7-membered aromatic monocyclic ring comprising at least one (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in some embodiments from 1 to 2 heteroatoms) selected from nitrogen (N), sulfur (S), and oxygen (O), with the remaining ring atoms being carbon;

[0478] A 7- to 12-membered bicyclic ring comprising at least one heteroatom selected from N, O, and S (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms), wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0479] The 11- to 14-membered tricyclic ring contains at least one heteroatom selected from N, O, and S (e.g., from 1 to 4, or from 1 to 3 in some embodiments, or 1 or 2 heteroatoms in other embodiments), and the remaining ring atoms are carbon, wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0480] In one embodiment, the "heteroaryl" is any one of "5 to 12-membered heteroaryl", "5-membered heteroaryl", "6-membered heteroaryl", "7-membered heteroaryl", "8-membered heteroaryl", "9-membered heteroaryl", "10-membered heteroaryl", "11-membered heteroaryl" or "12-membered heteroaryl" as described in the specification or claims.

[0481] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle does not exceed 1. When a 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 a heteroaryl group can be oxidized to form an N-oxide. As used herein, the term "C-linked heteroaryl" means that the heteroaryl group is linked to the core molecule via a bond of a C atom in the heteroaryl ring.

[0482] The terms “aromatic heterocycle” and “heteroaryl” are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 cyclic members, wherein 1, 2, 3, or 4 heteroatomic ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring, which is bicyclic and has 1 or 2 heteroatomic ring members independently selected from nitrogen, sulfur, and oxygen.

[0483] The terms “heterocyclic group,” “heterocyclic,” or “heterocyclic” are interchangeable and refer to a non-aromatic heterocyclic group (which contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members are carbon), including monocyclic, fused, bridged, and spirocyclic groups, i.e., containing monocyclic, bridged, spirocyclic, and fused heterocyclic groups. The term “optionally oxidized sulfur” as used herein refers to S, SO, or SO2.

[0484] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. This is intended to include all such possible stereoisomers, such as substantially pure, separated enantiomers, their racemic mixtures, and mixtures of diastereomers. This is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically stated, reference to one isomer applies to all possible isomers. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0485] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, for example no more than 30%, further for example no more than 25%, or even further for example 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, for example no more than 5%, or for example no more than 1% of any one or more other stereoisomers.

[0486] When the compounds disclosed herein contain olefinic double bonds, such double bonds are intended to include both E and Z geometric isomers, unless otherwise stated.

[0487] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can be formed in cis and trans arrangements. Cis formation means that both substituents are located above the two substituent positions on the carbon atom, while trans formation means that they are located on opposite sides.

[0488] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter referred to as separations) to the desired homogeneity using techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example: reversed-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-layer or thick-layer chromatography, as well as techniques for small-scale thin-layer and rapid chromatography. Those skilled in the art will apply the techniques most likely to achieve the desired separations.

[0489] "Diarrhetinic isomers" refer to stereoisomers of compounds having two or more chiral centers that are not mirror images of each other. Mixtures of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods well known to those skilled in the art (such as chromatography and / or fractional crystallization). Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating these diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0490] The term "pharmaceutically acceptable salt" refers to those salts that, to the extent of reasonable medical judgment, are suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid, or separately by reacting an acidic group with a suitable base.

[0491] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt (e.g., a pharmaceutically acceptable addition salt) can be produced by following the conventional procedure for preparing acid addition salts from base compounds, by dissolving the free base in a suitable organic solvent and / or water and treating the solution with acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts without excessive experimentation.

[0492] As defined herein, a “pharmaceutically acceptable salt” includes a salt of at least one compound having formula (I), and a salt of a stereoisomer of a compound having formula (I), such as an enantiomer salt and / or a diastereomer salt.

[0493] The terms “administration” and “administering” as used herein, when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, mean contact between an exogenous agent, therapeutic agent, diagnostic agent, or composition and the animal, human, subject, cell, tissue, organ, or biological fluid. Cellular treatment encompasses contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid contacts the cell. The terms “administration” and “administering” also mean, for example, in vitro and ex vivo treatment of cells by means of a reagent, diagnostic agent, conjugated compound, or another cell. The term “subject” as used herein includes any biological entity, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0494] The term "effective amount" or "therapeutic 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 disease, disorder, or symptom. "Therapeutic effective amount" can vary depending on the compound, the disease, disorder, and / or the symptom of the disease or disorder, the severity of the disease, disorder, and / or the age of the subject being treated, and / or the weight of the subject being treated. An appropriate amount in any given situation will be apparent to those skilled in the art or can be determined by routine experiments. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, as defined above, that is effective in treating a subject's disease or disorder. In the case of combination therapies, "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat a disease, disorder, or symptom.

[0495] Pharmaceutical compositions containing the compounds disclosed herein may be administered to subjects in need via oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition may be a conventional solid formulation, such as tablets, powders, granules, capsules, etc.; a liquid formulation, such as an aqueous or oil suspension; or other liquid formulations, such as syrups, solutions, suspensions, etc. For parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oil suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition may be administered as a single unit with a precise dosage. Furthermore, the pharmaceutical composition may further contain additional active ingredients.

[0496] All formulations of the pharmaceutical compositions disclosed herein can be produced using conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to form the desired formulation. "Pharmaceutically acceptable excipients" refer to conventional drug carriers suitable for the desired pharmaceutical formulation, such as: diluents, mediators (e.g., water, various organic solvents, etc.), fillers (e.g., starch, sucrose, etc.), binders (e.g., cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP)); wetting agents, such as glycerin; disintegrants, such as agar, calcium carbonate, and sodium bicarbonate; absorption enhancers, such as quaternary ammonium compounds; surfactants, such as hexadecyl alcohol; absorbent carriers, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical compositions may also contain other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners, and dyes.

[0497] The term “disease” refers to any illness, discomfort, ailment, symptom, or indication and is interchangeable with the terms “disorder” or “symptom”.

[0498] Throughout this specification and its accompanying aspects, unless the context otherwise requires, the term "comprise" and its variations, such as "comprises" and "comprising," are intended to specify the presence of the following feature, 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."

[0499] Throughout this specification and its accompanying aspects, the term "C" is used. n-m The indicator includes the range of endpoints, where n and m are integers, and indicates the number of carbons. Examples include C. 1-8 C 1-6 wait.

[0500] Unless otherwise defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0501] abbreviation

[0502]

[0503]

[0504] Example

[0505] The following examples are intended to be purely illustrative and should not be considered as limiting in any way. While efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), some experimental errors and biases should be accounted for. 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 unless otherwise specified, no further purification is required for use. Unless otherwise specified, the reactions described below are carried out under positive pressure of nitrogen or argon or in anhydrous solvent using a drying tube; reaction flasks are equipped with rubber septa for introducing substrates and reagents via syringe; and glassware is oven-dried and / or heated to dry.

[0506] Recording on Agilent instruments operating at 400MHz or 500MHz 1 H NMR spectrum. 1 ¹H NMR spectra were obtained using CDCl₃, CD₂Cl₂, CD₃OD, D₂O, d₆-DMSO, d₆-acetone, or (CD₃)₂CO as solvents, and tetramethylsilane (0.00 ppm) or residual solvents (CDCl₃: 7.25 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm; d₆-DMSO: 2.50 ppm; d₆-acetone: 2.05 ppm; (CD₃)₃CO: 2.05 ppm) as reference standards. When reporting multiplet numbers, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet). If coupling constants are given, they are reported in Hertz (Hz).

[0507] 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 pm; Gradient method; Flow rate: 1.8 mL / min; Time (min) A (%) B (%)

[0508]

[0509] 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 x 50 mm, 2.7 pm; Gradient method; Flow rate: 1.8 mL / min; Time (min) A (%) B (%)

[0510]

[0511] 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 x 50 mm, 2.7 pm; Gradient method; Flow rate: 1.2 mL / min; Time (min) A (%) B (%)

[0512]

[0513]

[0514] Preparative HPLC was performed on a column (150x21.2mm ID, 5pm, Gemini NXC 18) at a flow rate of 20ml / min, an injection volume of 2ml, at room temperature, and detected by UV at 214nm and 254nm.

[0515] Common intermediate A:

[0516] 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)benzene (By)-3-oxazine-butane-3-carboxaldehyde

[0517] Step 1: 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidine-1(2H)- phenyl trifluoromethanesulfonate

[0518]

[0519] Pyridine (235 mg, 2.98 mmol) was added to a solution of 1-(4-hydroxyphenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidin-2,4(1H,3H)-dione (obtained by a similar method as described in WO 2022012622 A1) (500 mg, 1.49 mmol) in DCM. Then, Tf₂O (630 mg, 2.24 mmol) was added between 0 °C and 5 °C. The mixture was slowly heated from 0 °C to room temperature and stirred at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc (100%:0% to 50%:50%)) to give 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyltrifluoromethanesulfonate (644 mg, 92%). [M+H] + =469.5.

[0520] Step 2: 1-(4-(3-(hydroxymethyl)azacyclobutane-1-yl)phenyl)-3-((2-(trimethylsilyl)) ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione

[0521]

[0522] A mixture of 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyltrifluoromethanesulfonate (100 mg, 0.213 mol), azacyclobutane-3-ylmethanol hydrochloride (39 mg, 0.32 mmol), Pd2(dba)3 (20 mg, 0.0213 mmol), Ruphos (20 mg, 0.0426 mmol), and Cs2CO3 (138 mg, 0.426 mmol) in dioxane (10 mL) was stirred overnight at 100 °C under nitrogen. 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)azacyclobutane-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (67 mg, 78%). [M+H] + =406.4.

[0523] Step 3: 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidine-1 (2H)-yl)phenyl)azacyclobutane-3-carboxaldehyde

[0524]

[0525] Add IBX (114 mg, 0.406 mmol) to a solution of 1-(4-(3-(hydroxymethyl)azacyclobutan-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione (132 mg, 0.325 mmol) in DMSO (10 mL). Stir the mixture overnight at room temperature. Extract the resulting mixture with EA (50 mL x 3), wash with brine (100 mL), dry to Na₂SO₄, and concentrate under reduced pressure to give 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidine-1(2H)-yl)phenyl)azacyclobutan-3-carboxaldehyde (140 mg, crude). [M+H] + =404.5

[0526] Common intermediate B:

[0527] 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carboxylic acid

[0528] Step 1: tert-butyl-1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidine 1(2H)-yl)phenyl)azacyclobutane-3-carboxylate

[0529]

[0530] A mixture of 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyltrifluoromethanesulfonate (468 mg, 1.0 mol), tert-butylazine-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 overnight at 90 °C under nitrogen. 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 the product (460 mg, 97%). [M+H] + =476.2.

[0531] Step 2: 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carboxylic acid

[0532]

[0533] TFA (10 mL) was added to a solution of tert-butyl-1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carboxylate (460 mg, 0.97 mmol) in dichloromethane (10 mL). The mixture was stirred overnight at room temperature. 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

[0534] Common intermediate C:

[0535] tert-butyl-4-((trans)-4-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-methyl esters

[0536] Step 1: (cis)-4-(4-benzylpiperazin-1-yl)cyclohexane-1-ol

[0537]

[0538] Sodium carbonate (224.2 g, 2.64 mol) was added 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) at 0 °C. After stirring at 90 °C for 5 hours, the mixture was filtered and concentrated to produce 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.

[0539] Step 2: (cis)-4-(piperazin-1-yl)cyclohexane-1-ol (intermediate 3)

[0540]

[0541] Palladium (10% loaded with activated carbon) (9.61 g) was added to a solution of (cis)-4-(4-benzylpiperazin-1-yl)cyclohexane-1-ol (82.6 g, 301 mmol) in EtOH (2 L) at room temperature. After stirring overnight at 40 °C under a 15 psi hydrogen atmosphere, the mixture was filtered and concentrated to yield 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

[0542] Step 3: (cis)-tert-butyl-4-(4-hydroxycyclohexyl)piperazine-1-carboxylate

[0543]

[0544] At 0 °C, a saturated aqueous solution of sodium bicarbonate (300 mL) and di-tert-butyl decarbonate (94.9 g, 435 mmol) were added to a solution of (cis)-4-(piperazin-1-yl)cyclohexane-1-ol (53.4 g, 290 mmol) in THF (600 mL). After stirring at 0 °C for 2 hours, the mixture was diluted with water (500 mL) and extracted with ethyl acetate (700 mL x 2). The combined organic layers were washed with brine (600 mL), dried over Na2SO4, filtered, and concentrated to produce an oil, which was then added dropwise to petroleum ether until a large amount of solid precipitate was formed. The solid was filtered, and the filter cake was washed with petroleum ether (100 mL), filtered again, and microwave-dried at 40 °C for 0.5 hours to produce the product (66 g, 76%). 1 HNMR (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.

[0545] Step 4: (cis)-tert-butyl 4-[4-(methanesulfonyloxy)cyclohexyl]piperazine-1-carboxylate

[0546]

[0547] At 0 °C, methanesulfonyl chloride (31.9 g, 279 mmol) was added 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). 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) and 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.

[0548] Step 5: tert-butyl 4-((trans)-4-(3-carbamoyl-4-nitro-1H-pyrazole-1-yl)cyclohexyl)piperyl Azine-1-carboxylate

[0549]

[0550] At room temperature, cesium carbonate (29.2 g, 89.6 mmol) was added 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). 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 by C18 column (acetonitrile:water = 50% to 75%) to produce the product (2 g, 11%). [M+H] + =423.2.

[0551] Step 6: tert-butyl 4-((trans)-4-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperyl Azine-1-carboxylate

[0552]

[0553] Palladium (10% loaded with activated carbon) (450 mg) was added to a THF solution (5.9 g, 14 mmol) of tert-butyl 4-((trans)-4-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (200 mL) at room temperature. After stirring for 5 hours at 25 °C under a hydrogen atmosphere of 15 psi, the mixture was filtered and concentrated to yield 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.

[0554] Common intermediate D:

[0555] tert-butyl-4-((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-methyl esters

[0556] Step 1: 1-Benzyl-1H-pyrazole-3-carboxaldehyde

[0557]

[0558] Cesium carbonate (423.9 g, 1.30 mol) was added 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). After stirring at 25 °C for 1 hour, the mixture was added to 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 Na2SO4, 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 the 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.

[0559] Step 2: 1-Benzyl-3-(difluoromethyl)-1H-pyrazole

[0560]

[0561] At 0 °C, diethylaminosulfur trifluoride (216.1 g, 1.34 mol) was added to a dichloromethane solution (500 mL) of 1-benzyl-1H-pyrazole-3-carboxaldehyde (65 g, 0.335 mol). 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).

[0562] [M+H] + =209.1

[0563] Step 3: 3-(difluoromethyl)-1H-pyrazole

[0564]

[0565] To a MeOH solution (500 mL) of 25 g (25 g, 0.120 mol) of 1-benzyl-3-(difluoromethyl)-1H-pyrazole, 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) were added. After stirring at 40 °C for 16 hours under H₂ (50 psi), the mixture was filtered and concentrated under reduced pressure to produce the product (14 g, 99%). 1 H NMR (300MHz, CDCl3) δ7.88 (s, 1H), 7.02 (t, J = 54.9Hz, 1H), 6.55 (s, 1H). [M+H] + =119.0

[0566] Step 4: 3-(difluoromethyl)-4-nitro-1H-pyrazole

[0567]

[0568] Concentrated nitric acid (28.7 g, 0.297 mol) was added to a concentrated sulfuric acid solution (150 mL) of 3-(difluoromethyl)-1H-pyrazole (14 g, 0.119 mol) at 0 °C. 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.

[0569] Step 5: tert-butyl 4-((trans)-4-(3-(difluoromethyl)-4-nitro-1H-pyrazole-1-yl)cyclohexyl)piperyl Azine-1-carboxylate

[0570]

[0571] Cesium carbonate (51.9 g, 0.159 mol) was added 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). 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.

[0572] Step 6: tert-butyl-4-((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperyl Azine-1-carboxylate

[0573]

[0574] Palladium (10% loaded on activated carbon) (1.2 g) was added to a THF solution (6.0 g, 13.7 mmol) of tert-butyl 4-((trans)-4-(3-(difluoromethyl)-4-nitro-1H-pyrazole-1-yl)cyclohexyl)piperazine-1-carboxylate (120 mL) at room temperature. After stirring for 16 hours at room temperature under a hydrogen atmosphere of 15 psi, the mixture was filtered and concentrated to produce a crude product, which was recrystallized from ACN (10 mL) at room temperature to give the product (4.99 g, 88%). 1H 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.

[0575] Common intermediate E: (R)-3-(2,6-difluoro-4-(3-oxoazapyridine-1-yl)phenyl)piperidine-2,6-di ketone

[0576] Step 1: 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azacyclobutane-1-yl)-2,6-difluorophenyl)pyridine pyridine

[0577]

[0578] A solution of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (20 g, 41.49 mmol), 3-(benzyloxy)azacyclobutane 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) was prepared. The mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. 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)azacyclobutane-1-yl)-2,6-difluorophenyl)pyridine (17 g, 72.6%). [M+H] + =565.3.

[0579] Step 2: 3-(2,6-difluoro-4-(3-hydroxyazacyclobutane-1-yl)phenyl)piperidine-2,6-dione

[0580]

[0581] Pd / C (10% wet, 17 g) was added to a solution of 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azacyclobutan-1-yl)-2,6-difluorophenyl)pyridine (17 g, 30.09 mmol) in DMF / i-PrOH = (200 mL / 600 mL). 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 grinding 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.

[0582] Step 3: (R)-3-(2,6-difluoro-4-(3-hydroxyazacyclobutane-1-yl)phenyl)piperidine-2,6-dione

[0583]

[0584] Crude 3-(2,6-difluoro-4-(3-hydroxyazacyclobutan-1-yl)phenyl)piperidin-2,6-dione (76 g) was purified by chiral separation under the following conditions (CHIRALPAK IF (10 cm × 25 cm, 10 μm), MtBE (0.1% DEA):(MeOH:DCM = 1:1) = 50:50, 250 mL / min) to give (R)-3-(2,6-difluoro-4-(3-hydroxyazacyclobutan-1-yl)phenyl)piperidin-2,6-dione (35.83 g, 47.14%, ee = 99.54%). [M+H] + =297.27

[0585] Step 4: (R)-3-(2,6-difluoro-4-(3-oxoazacyclobutane-1-yl)phenyl)piperidine-2,6-dione

[0586]

[0587] Under nitrogen atmosphere at 0 °C, Dys-Martin reagent (455.24 g, 1073.34 mmol) was added to a solution of (R)-3-(2,6-difluoro-4-(3-hydroxyazacyclobutan-1-yl)phenyl)piperidine-2,6-dione (106 g, 357.78 mmol) in DCM (2 L). The mixture was stirred at 0 °C for 3 h. The reaction mixture 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 sodium bicarbonate aqueous solution (2 L × 2) and brine (2 L × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The solution was concentrated under vacuum. The residue was combined with the collected filter cake and dried under reduced pressure to give (R)-3-(2,6-difluoro-4-(3-oxoazacyclobutane-1-yl)phenyl)piperidine-2,6-dione (91 g, 86.43%). [M+H]+ =295.27.

[0588] Example 1: N-(3-(difluoromethyl)-1-((1R,4r)-4-((4-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenylethyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0589] Step 1: tert-butyl(4-bromopyridin-2-yl)(2,2,2-trifluoroethyl)carbamate

[0590]

[0591] Add 2,2,2-trifluoroethyltrifluoromethanesulfonate (9 g, 39.96 mmol) and Cs₂CO₃ (22 g, 66.6 mmol) to a DMF solution (100 mL) of tert-butyl(4-bromopyridin-2-yl)carbamate (9 g, 33.3 mmol). Stir the mixture overnight at room temperature. Remove the solvent under vacuum and add water (100 mL) to the residue. Extract the mixture with EA (100 mL x 2). Concentrate the organic layer and purify by combi flash chromatography (eluting with EA:PE = 0:1–1:0) to give the product (9.6 g, 81%). [M+H] + =355.2.

[0592] Step 2: Ethyl 2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-methyl esters

[0593]

[0594] Ethyloxazole-4-carbamate (457 mg, 3.24 mmol), Pd(OAc)₂ (61 mg, 0.27 mmol), P(o-tol)₃ (164 mg, 0.54 mmol), and Cs₂CO₃ (1.8 g, 5.4 mmol) were added to a DMF solution (20 mL) of tert-butyl(4-bromopyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (960 mg, 2.7 mmol). The mixture was stirred at 80 °C under N₂ for 16 h. The solvent was removed under vacuum, and water (30 mL) was added, followed by extraction with EA (30 mL x 3). The organic layer was concentrated and purified by combiflash chromatography (eluting with EA:PE = 0:1–1:0) to give the product (600 mg, 54%). [M+H] + =416.4.

[0595] Step 3: 2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxylic acid

[0596]

[0597] Ethyl 2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxylate (600 mg, 1.45 mmol) and LiOH·H₂O (122 mg, 2.90 mmol) were added to THF (30 mL) and H₂O (10 mL). The mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and then water (10 mL) was added and acidified to pH 4 with an aqueous HCl solution. The solid was filtered and dried to yield the product (410 mg, 73%). [M+H] + =388.3.

[0598] Step 4: tert-butyl(4-(4-((3-(difluoromethyl)-1-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1H-pyridine) (Zyzol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate

[0599]

[0600] 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), 2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxylic acid (1200 mg, 3.13 mmol), HATU (1.2 g, 3.13 mmol), and DIEA (708 mg, 5.22 mmol) were added. The mixture was stirred overnight at room temperature under N2. The solvent was removed under vacuum, and water (50 mL) was added, followed by extraction 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.

[0601] 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

[0602]

[0603] IBX (224 mg, 0.8 mmol) was added to a DMSO solution (30 mL) 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). The mixture was stirred overnight at room temperature under N2. Water (100 mL) was added and extracted with EA (30 mL x 2). The organic layer was concentrated and purified by combi flash chromatography (eluting with EA:PE = 0:1–1:0) to give the product (140 mg, 29%). [M+H] + =613.4.

[0604] Step 6: tert-butyl 4-(((1r,4r)-4-(4-(2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino) Pyridin-4-yl)oxazol-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazine-1-carboxylic acid ester

[0605]

[0606] 63 mg of tert-butylpiperazine-1-carbamate (0.336 mmol) was added to a DCM solution (20 mL) of 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 (140 mg, 0.28 mmol). The mixture was stirred overnight at room temperature under N2. NaBH(Ac)3 (119 mg, 0.56 mmol) was added to the mixture, and the mixture was stirred at room temperature under N2 for 3 h. The reaction was quenched with an aqueous solution of 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.

[0607] Step 7: N-(3-(difluoromethyl)-1-((1r,4r)-4-(piperazin-1-ylmethyl)cyclohexyl)-1H-pyrazole-4- 2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0608]

[0609] HCl (4N, 6 mL) in 1,4-dioxane was added to a DCM solution (10 mL) of tert-butyl 4-(((1r,4r)-4-(4-(2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazine-1-carboxylate (200 mg, 0.26 mmol). The mixture was stirred overnight at room temperature under N2. The solvent was removed under vacuum and the residue was diluted with a saturated aqueous solution of K2CO3, extracted with DCM (3 x 20 mL), the organic layer was dried over Na2SO4, filtered, and concentrated to yield the product (148 mg, 100%). [M+H] + =583.4.

[0610] Step 8: N-(3-(difluoromethyl)-1-((1R,4r)-4-((4-(4-((R)-2,6-dioxoperidin-3-yl)-3, 5-Difluorophenylethyl)piperazine-1-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino) pyridin-4-yl)oxazol-4-carboxamide

[0611]

[0612] To a DCE solution (10 mL) 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)oxazol-4-carboxamide (50 mg, 0.086 mmol) and (R)-2-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)acetaldehyde (27 mg, 0.1029 mmol), NaBH(OAc)3 (37 mg, 0.173 mmol) was added, and the mixture was stirred at 70 °C under N2 for 2 h. The mixture was purified by combi flash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to obtain a crude product, which was further purified by preparative HPLC to obtain the product (14 mg, 19.5%).

[0613] 1H 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.

[0614] 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-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0615]

[0616] The title compound (6.0 mg, 27.3% yield) was prepared in a manner similar to that described in Example 1. 1 H 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=10.0H z,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.

[0617] Example 3: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-yl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0618]

[0619] The title compound (5.0 mg, 32.1% yield) was prepared in a manner similar to that described in Example 1. 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.

[0620] Example 4: N-(3-(difluoromethyl)-1-((1r,4r)-4-((4-(1-(4-((R)-2,6-dioxoperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0621]

[0622] The title compound was prepared in a manner similar to that described in Example 6.

[0623] 1H 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.

[0624] Example 5: N-(2-((1r,4r)-4-((4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0625]

[0626] The title compound was prepared in a manner similar to that described in Example 6.

[0627] 1 H 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.

[0628] 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-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0629] Step 1: tert-butyl 4-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperazine-1-carboxylate

[0630]

[0631] HATU (68.6 g, 180.35 mmol) was added in portions to a stirred solution of (1s,4s)-4-hydroxycyclohexane-1-carboxylic acid (20.0 g, 138.73 mmol) in THF (200 mL) at 0 °C. The resulting solution was stirred at 0 °C under a nitrogen atmosphere for 30 min. TEA (28.1 g, 277.45 mmol, 38.62 mL) and tert-butylpiperazine-1-carboxylate (28.4 g, 152.60 mmol) were added to the above solution at 0 °C under a nitrogen atmosphere. The resulting solution was stirred at 20 °C for 12 h. The reaction mixture was quenched at 20 °C by adding H₂O (20 mL) and then extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The crude product was ground together with EA at 20°C for 30 min, filtered, and concentrated under reduced pressure to yield the residual 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)

[0632] Step 2: tert-butyl 4-(((1s,4s)-4-hydroxycyclohexyl)methyl)piperazine-1-carboxylate

[0633]

[0634] At 0 °C, BH3·THF (1M, 140.8 mL) was added dropwise 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). The solution was stirred at 80 °C for 16 h. The resulting mixture was cooled to 0 °C, and then MeOH (2 mL) was slowly added at 0 °C. The mixture was stirred at 50 °C for 3 h and concentrated under reduced pressure. At 20 °C, the reaction mixture was quenched with H2O (20 mL) 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-hydroxycyclohexane-1-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)

[0635] Step 3: tert-butyl 4-(((1s,4s)-4-((methylsulfonyl)oxy)cyclohexyl)methyl)piperazine-1-carboxylate

[0636]

[0637] At 0 °C, TEA (339 mg, 3.35 mmol, 466 μL) and MsCl (288 mg, 2.51 mmol, 195 μL) were added to a solution of tert-butyl 4-(((1s,4s)-4-hydroxycyclohexyl)methyl)piperazine-1-carboxylate (500 mg, 1.68 mmol) in DCM (5 mL). The mixture was stirred at 20 °C for 2 hours. At 20 °C, the reaction mixture was quenched with an aqueous solution of Na₂CO₃ (20 mL) and then extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 40 / 1 to 0 / 1) to yield tert-butyl 4-(((1s,4s)-4-((methanesulfonyl)oxy)cyclohexyl)methyl)piperazine-1-carboxylate (280.0 mg, 44% yield). [M+H] + =377.3 1 ¹H NMR (400MHz, 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=7.1Hz, 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)

[0638] Step 4: tert-butyl 4-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H- Indazole-2-yl)cyclohexyl)methyl)piperazine-1-carboxylate

[0639]

[0640] Cs₂CO₃ (7.8 g, 23.79 mmol) was added to a solution of N-(6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (2.0 g, 5.95 mmol) (obtained by the same method described in Example 41) and tert-butyl-4-(((1s,4s)-4-((methanesulfonyl)oxy)cyclohexyl)methyl)piperazine-1-carboxylate (6.7 g, 17.84 mmol) in DMF (180 mL). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to produce 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)pyridinamide)-2H-indazole-2-yl)cyclohexyl)methyl)piperazine-1-carboxylate was obtained (300.0 mg, 7.85% yield). [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)

[0641] Step 5: N-(6-methoxy-2-((1r,4r)-4-(piperazin-1-ylmethyl)cyclohexyl)-2H-indazole-5-yl)- 6-(trifluoromethyl)pyridinecarboxamide, TFA salt

[0642]

[0643] A mixture of tert-butyl 4-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinylcarbamate)-2H-indazole-2-yl)cyclohexyl)methyl)piperazine-1-carboxylate (280.0 mg, 454 μmol) and TFA (8.6 g, 75.6 mmol, 5.60 mL) in DCM (5 mL) was degassed and purged three times with N2. The mixture was then stirred at 20 °C for 2 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give the residual compound N-(6-methoxy-2-((1r,4r)-4-(piperazine-1-ylmethyl)cyclohexyl)-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinylcarbamate (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).

[0644] Step 6: N-(2-((1R,4r)-4-((4-((1r,4R)-4-(4-(2,4-dioxo-3-((2-(trimethylsilane) yl)ethoxy)methyl)tetrahydropyrimidine-1(2H)-yl)phenoxy)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)cyclohexyl)- 6-Methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0645]

[0646] HATU (28 mg, 0.073 mmol) was added 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). The mixture was stirred at rt for 10 min. Then, N-(6-methoxy-2-((1r,4r)-4-(piperazin-1-ylmethyl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide TFA salt (42 mg, 0.066 mmol) and Et3N (46 mg, 0.45 mmol) in DMF (3 mL) were added to the reaction mixture. 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 a product (55 mg, 86% yield). [M+H] + =961.7.

[0647] Step 7: N-(2-((1R,4r)-4-((4-((1r,4R)-4-(4-(2,4-dioxatetrahydropyrimidin-1(2H)-yl)benzene (Oxy)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl) Pyridine carboxamide

[0648]

[0649] 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-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (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 obtain 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

[0650] 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).

[0651] 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-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0652]

[0653] The title compound was prepared in a manner similar to that described in Example 6.

[0654] 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.

[0655] Example 12: N-(3-carbamoyl-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0656] Step 1: tert-butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino) Pyridine-4-yl)oxazol-4-carboxamido)-3-carbamoyl-1H-pyrazole-1-yl)cyclohexyl)piperazine-1-carboxylate

[0657]

[0658] To a DMF solution (5 mL) of tert-butyl 4-((trans)-4-(4-amino-3-carbamoyl-1H-pyrazole-1-yl)cyclohexyl)piperazine-1-carboxylate (1.0 g, 2.54 mmol), 2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxylic acid (1.2 g, 3.048 mmol), DIEA (518 mg, 5.08 mmol), and HATU (1.45 g, 5.08 mmol) were added. The mixture was stirred overnight at room temperature. The mixture was purified by combi flash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to give the product (1.8 g, 93%). [M+H] + =761.8.

[0659] Step 2: N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)- 2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0660]

[0661] TFA (10 mL) was added to a DCM solution (1.8 g, 2.36 mmol) of tert-butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamido)-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (1.8 g, 2.36 mmol). The mixture was stirred overnight at room temperature. The solvent was removed under vacuum. The residue was alkalized 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 crude product (1.2 g, 91%).

[0662] Step 3: N-(3-carbamoyl-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxanil-3- (3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-) Trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0663]

[0664] Add (R)-1-(4-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide (100 mg, 0.18 mmol) to a DMF solution (6 mL), (R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (73 mg, 0.216 mmol) (obtained by the same method described in WO 2022012623A1), DIEA (1.0 mL), and HATU (103 mg, 0.27 mmol). Stir the mixture overnight at room temperature. The mixture was purified by combi flash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to obtain the crude product, which was further purified by preparative HPLC to produce 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.

[0665] Example 13: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0666] Step 1: tert-butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino) Pyridin-4-yl)oxazol-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate

[0667]

[0668] To a DMF solution (10 mL) of tert-butyl 4-((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (1.0 g, 2.54 mmol), 2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxylic acid (1.2 g, 3.05 mmol), DIEA (518 mg, 5.08 mmol), and HATU (1.45 g, 3.81 mmol) were added to the mixture. The mixture was stirred overnight at room temperature. The mixture was purified by combi flash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to give the product (1.8 g, 92%). [M+H] + =769.4.

[0669] Step 2: N-(3-(difluoromethyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)- 2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0670]

[0671] TFA (5 mL) was added to a 10 mL solution (1.8 g, 2.34 mmol) of tert-butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (2.34 mmol). The mixture was stirred overnight at room temperature. The solvent was removed under vacuum. The residue was alkalized to pH 10 with aqueous Na₂CO₃ solution and extracted with DCM (50 mL x 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated to give the crude product (1.2 g, 90%).

[0672] Step 3: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxatetrahydropyrimidine-1(2H)- (2,2,2-trifluoroethyl)phenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl) (4-yl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0673]

[0674] To a solution (5 mL) 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)oxazol-4-carboxamide (50 mg, 0.088 mmol) in DCM, 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carboxylic acid (31 mg, 0.1056 mmol), DIEA (0.5 mL), and HATU (50 mg, 0.132 mmol) were added. The mixture was stirred overnight at room temperature. The mixture was purified by combiflash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to give a crude product, which was further purified by preparative HPLC to produce 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.

[0675] 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-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0676]

[0677] The title compound was prepared in a manner similar to that described in Example 13.

[0678] 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.

[0679] 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-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0680]

[0681] The title compound was prepared in a manner similar to that described in Example 13.

[0682] 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.

[0683] Example 16: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0684]

[0685] The title compound was prepared in a manner similar to that described in Example 13.

[0686] 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.

[0687] Example 17: N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0688]

[0689] The title compound was prepared in a manner similar to that described in Example 13.

[0690] 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.

[0691] Example 18: N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0692]

[0693] The title compound was prepared in a manner similar to that described in Example 13.

[0694] 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.

[0695] Example 19: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxoperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0696]

[0697] The title compound was prepared in a manner similar to that described in Example 13.

[0698] 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.

[0699] Example 20: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0700]

[0701] The title compound was prepared in a manner similar to that described in Example 13.

[0702] 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

[0703] Example 21: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-yl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0704]

[0705] The title compound was prepared in a manner similar to that described in Example 13.

[0706] 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.

[0707] Example 175: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,6-dioxopiridine-3-yl)phenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0708]

[0709] The title compound was prepared in a manner similar to that described in Example 13.

[0710] 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.

[0711] 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-pyrazole-4-yl)oxazol-4-carboxamide

[0712]

[0713] The title compound was prepared in a manner similar to that described in Example 13.

[0714] 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.

[0715] 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-pyrazole-4-yl)oxazol-4-carboxamide

[0716]

[0717] The title compound was prepared in a manner similar to that described in Example 13.

[0718] 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.

[0719] 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)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazol-4-carboxamide

[0720]

[0721] The title compound was prepared in a manner similar to that described in Example 13.

[0722] 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.

[0723] Example 25: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxoperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)oxazol-4-carboxamide

[0724]

[0725] The title compound was prepared in a manner similar to that described in Example 13.

[0726] 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.

[0727] Example 26: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)oxazol-4-carboxamide

[0728]

[0729] The title compound was prepared in a manner similar to that described in Example 13.

[0730] 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.

[0731] Example 27: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxoperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)methyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)oxazol-4-carboxamide

[0732]

[0733] The title compound was prepared in a manner similar to that described in Example 13.

[0734] 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.

[0735] Example 85: N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-isopropylpyridin-4-yl)oxazol-4-carboxamide

[0736]

[0737] The title compound was prepared in a manner similar to that described in Example 13.

[0738] 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

[0739] Example 86: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-isopropylpyridin-4-yl)oxazol-4-carboxamide

[0740]

[0741] The title compound was prepared in a manner similar to that described in Example 13.

[0742] 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).

[0743] [M+H] + =820.7

[0744] Example 170: 2-(2-(sec-butyl)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)oxazol-4-carboxamide

[0745]

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

[0747] 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

[0748] Example 28: N-(3-carbamoyl-1-(6-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0749]

[0750] The title compound was prepared in a manner similar to that described in Example 166.

[0751] 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.

[0752] Example 8: N-(3-carbamoyl-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0753]

[0754] HATU (38 mg, 0.1 mmol) was added 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)oxazol-4-carboxamide (56 mg, 0.1 mmol), 1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carboxylic acid (30 mg, 0.1 mmol) and DIEA (65 mg, 0.5 mmol) in DMF (5 mL) 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.

[0755] Example 11: N-(3-carbamoyl-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0756] Step 1: Methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-methyl esters

[0757]

[0758] A mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyridine (3.00 g, 6.22 mmol), methyl aziridine-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 overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (2:1) to provide the product (1.7 g, 53%). [M+1] + =517.1.

[0759] Step 2: 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxylic acid

[0760]

[0761] At room temperature, LiOH·H₂O (168 mg, 4 mmol in 10 mL of water) was added dropwise to a stirred mixture of methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxylate (1.7 g, 3.29 mmol) in THF (20 mL). The mixture was then stirred for 2 hours. The resulting mixture was concentrated under vacuum. The aqueous layer was adjusted to pH < 5 with 1 N HCl and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to provide the product (1.4 g, 85%) [M+1]. + =503.2.

[0762] Step 3: (R)-1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxylic acid

[0763]

[0764] Pd / C (1.0 g, 10% wt) was added to a solution of 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxylic acid (1.40 g, 2.79 mmol) in iPrOH (20 mL) and DCM (20 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 48 h. The resulting mixture was filtered, and the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure to provide the crude product. The residue was purified by SFC (IH (3*25 cm, 5 μm), 13% EtOH / 87% CO2, 100 bar, 20 mL / min), and the title compound corresponds to peak A at 1.853 min / 254 nm (190 mg, 21%). [M+1] + =325.3.

[0765] Step 4: N-(3-carbamoyl-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxanidin-3-yl)- 3,5-Difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2- Trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0766]

[0767] HATU (38 mg, 0.1 mmol) was added 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)oxazol-4-carboxamide (56 mg, 0.1 mmol), (R)-1-(4-(2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxylic acid (32 mg, 0.1 mmol), and DIEA (65 mg, 0.5 mmol) in DMF (5 mL) 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.

[0768] Example 9: N-(3-carbamoyl-1-((1r,4r)-4-(4-(3-(4-(((R)-2,6-dioxopiridine-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0769]

[0770] A solution of N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide (56 mg, 0.1 mmol) and (R)-3-((4-(3-oxocyclobutyl)phenyl)amino)piperidine-2,6-dione (obtained by a similar method 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. NaBH(OAc)3 (106 mg, 0.5 mmol) was added to the resulting mixture 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 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.

[0771] Example 10: N-(3-carbamoyl-1-((1r,4r)-4-(4-(3-(4-(((S)-2,6-dioxopiridine-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0772]

[0773] A solution of N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide (56 mg, 0.1 mmol) and (S)-3-((4-(3-oxocyclobutyl)phenyl)amino)piperidine-2,6-dione (obtained by a similar method 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. NaBH(OAc)3 (106 mg, 0.5 mmol) was added to the resulting mixture and stirred at room temperature for 18 hours. The reaction was evaporated under vacuum to obtain a crude residue, which was purified by preparative HPLC to obtain 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.

[0774] Example 76: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0775]

[0776] The title compound was prepared in a manner similar to that described in Example 13.

[0777] 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.

[0778] Example 100: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxoperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)-2-oxopiperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)oxazol-4-carboxamide

[0779] Step 1: tert-butyl4-((1r,4r)-4-(4-(2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)oxazol-4- (formamido)-3-(difluoromethyl)-1H-pyrazole-1-yl)cyclohexyl)-3-oxopiperazine-1-carboxylate

[0780]

[0781] To a solution of tert-butyl 4-((1r,4r)-4-(4-(2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)oxazol-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (which was synthesized by the method of Example 13) (200 mg, 0.312 mmol), I2 (594 mg, 2.34 mmol) and NaHCO3 (262 mg, 3.12 mmol) were added to the solution of THF (10 mL) and H2O (4 mL). The mixture was stirred overnight at room temperature under N2. The reaction was quenched with an aqueous solution of Na2S2O3 (20 mL) and extracted with EA (30 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated to give the product (150 mg, 73%). [M+H] + =655.3.

[0782] Step 2: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-) (2-Oxopiperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)oxazol-4-carboxamide

[0783]

[0784] TFA (5 mL) was added to a DCM solution (10 mL) of tert-butyl 4-((1r,4r)-4-(4-(2-(2-(((cyclopropylmethyl)amino)amino)pyridin-4-yl)oxazol-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)-3-oxopiperazine-1-carboxylate (20 mg, 0.23 mmol). The mixture was stirred overnight at room temperature. The solvent was removed under vacuum. The residue was alkalized 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

[0785] Step 3: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-) (4-(1-(4-((R)-2,6-dioxoperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)-2-oxopiperazine- 1-yl)cyclohexyl)-1H-pyrazole-4-yl)oxazol-4-carboxamide

[0786]

[0787] Add (R)-1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxylic acid (35 mg, 0.108 mmol), DIEA (0.5 mL), and HATU (51 mg, 0.135 mmol) to a DMF solution (50 mg, 0.09 mmol) of 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(2-oxopirizin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazol-4-carboxamide (50 mg, 0.09 mmol) in 5 mL of DMF. Stir the mixture overnight at room temperature. Purify the mixture by combi flash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to obtain a crude product, which is further purified by preparative HPLC to give the product (13 mg, 17%).

[0788] 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.

[0789] Example 101: 2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxoperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-2-oxopiperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)oxazol-4-carboxamide

[0790]

[0791] The title compound was prepared in a manner similar to that described in Example 100.

[0792] 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.

[0793] Example 166: N-(3-carbamoyl-1-(6-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide

[0794] Step 1: (6-(4-(tert-butyloxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid

[0795]

[0796] A mixture of tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridin-2-yl)piperazine-1-carboxylate (1 g, 2.57 mmol), NaIO4 (2.75 g, 12.85 mmol), and NH4OAc (989 mg, 12.85 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was stirred overnight at room temperature in a round-bottom flask. The resulting mixture was extracted with DCM (3 x 10 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 yield the title product (780 mg, 99%). [M+H] + =308.

[0797] Step 2: tert-butyl4-(5-(3-(ethoxycarbonyl)-4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)piperazine- 1-Formate

[0798]

[0799] A mixture of (6-(4-(tert-butyloxycarbonyl)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 under oxygen at room temperature 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.

[0800] Step 3: tert-butyl-4-(5-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1- Formate

[0801]

[0802] 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 in a sealed tube at 80 °C for 15 h. The resulting solution was extracted with DCM (2 x 20.0 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to yield the product (194 mg). [M-55] + =362.2.

[0803] Step 4: tert-butyl 4-(5-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1- Formate

[0804]

[0805] At 25 °C, 10% wt Pd / C (20.0 mg) was added 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). The flask was then evacuated and backfilled twice with H2, and stirred at 25 °C for 15 h under H2 atmosphere. The reaction was monitored by LCMS. The mixture was filtered through a diatomaceous earth mat, 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.

[0806] Step 5: tert-butyl4-(5-(4-(2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridine-4- (Oxazol-4-carbamoyl)-3-carbamoyl-1H-pyrazole-1-yl)pyridin-2-yl)piperazine-1-carboxylate

[0807]

[0808] A mixture of 2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-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 min, and then 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 h. 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.

[0809] 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)oxazol-4-carboxamide hydrochloride

[0810]

[0811] At 25 °C, 15 mL of 4N HCl / dioxane was added to tert-butyl 4-(5-(4-(2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamido)-3-carbamoyl-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-carboxylate (360 mg, 0.476 mmol) in DCM (10 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.

[0812] Step 7: N-(3-carbamoyl-1-(6-(4-((R)-1-(4-((R)-2,6-dioxadiazin-3-yl)-3,5- (difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl) (4-yl)amino)pyridine-4-yl)oxazol-4-carboxamide

[0813]

[0814] A mixture of N-(3-carbamoyl-1-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxamide hydrochloride (30.0 mg, 0.051 mmol), (R)-1-(4-((R)-2,6-dioxopiridine-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 (2 x 15.0 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The crude product was purified by preparative HPLC to obtain 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.

[0815] Example 30: N-(3-carbamoyl-1-(6-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazole-4-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide

[0816]

[0817] The title compound was prepared in a manner similar to that described in Example 166.

[0818] 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.

[0819] Example 31: N-(3-carbamoyl-1-(6-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazole-4-yl)-2-(2-methylpyridin-4-yl)oxazol-4-carboxamide

[0820]

[0821] The title compound was prepared in a manner similar 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.

[0822] Example 51: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)-2H-1,2,3-triazol-4-carboxamide

[0823] Step 1: 2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-tri Azoxyl-4-carboxylic acid

[0824]

[0825] To a DMF solution (30 mL) of tert-butyl(4-bromopyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (3.1 g, 8.69 mmol), methyl 2H-1,2,3-triazole-4-carbamate (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) were added. 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.

[0826] Step 2: tert-butyl4-((1r,4r)-4-(4-(2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino) pyridin-4-yl)-2H-1,2,3-triazol-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1- Formate

[0827]

[0828] To a DMF solution (5 mL) of tert-butyl 4-((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (300 mg, 0.752 mmol), 2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazol-4-carboxylic acid (291 mg, 0.752 mmol), DIEA (1.0 mL), and HATU (429 mg, 1.128 mmol) were added. The mixture was stirred overnight at room temperature. The mixture was purified by combi flash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to give the product (300 mg, 52%). [M+H] + =769.4.

[0829] Step 3: N-(3-(difluoromethyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)- 2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazol-4-carboxamide

[0830]

[0831] TFA (10 mL) was added to a DCM solution (10 mL) of tert-butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butyloxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazol-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (800 mg, 1.04 mmol). The mixture was stirred overnight at room temperature. The solvent was removed under vacuum. The residue was alkalized 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.

[0832] Step 4: N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxanidin-3-yl)- 3,5-Difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2- Trifluoroethyl(amino)pyridin-4-yl)-2H-1,2,3-triazol-4-carboxamide

[0833]

[0834] Add (R)-1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxylic acid (7.0 mg, 0.0216 mmol), DIEA (0.5 mL), and HATU (14 mg, 0.036 mmol) to a DCM solution (3 mL) 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-triazol-4-carboxamide (10 mg, 0.018 mmol) (7.0 mg, 0.0216 mmol), (DIEA) (0.5 mL), and HATU (14 mg, 0.036 mmol) to the solution. Stir the mixture overnight at room temperature. The mixture was purified by combi flash chromatography (eluting with DCM:MeOH = 1-0 to 1:10) to obtain a crude product, which was further purified by preparative HPLC to produce the product (12 mg, 76%).

[0835] 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.

[0836] Example 52: N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazole-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridine-4-yl)-2H-1,2,3-triazol-4-carboxamide

[0837]

[0838] The title compound was prepared in a manner similar to that described in Example 51.

[0839] 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.

[0840] 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)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2H-1,2,3-triazol-4-carboxamide

[0841]

[0842] The title compound was prepared in a manner similar to that described in Example 51.

[0843] 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.

[0844] 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-pyrazole-4-yl)-2H-1,2,3-triazol-4-carboxamide

[0845]

[0846] The title compound was prepared in a manner similar to that described in Example 51.

[0847] 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.

[0848] Example 130: N-cyclopropyl-2-(trans)-4-(4-(1-(4-((R)-2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-6-carboxamide

[0849] Step 1: (cis)-4-(4-benzylpiperazin-1-yl)cyclohexane-1-ol

[0850]

[0851] 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 under reduced pressure. The residue was washed with water and extracted with dichloromethane (3 x 150 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 produce the product (7.6 g, 93%). [M+H] + =275.6.

[0852] Step 2: (cis)-4-(piperazin-1-yl)cyclohexane-1-ol

[0853]

[0854] A mixture of (cis)-4-(4-benzylpiperazin-1-yl)cyclohexane-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 diatomaceous earth and concentrated under reduced pressure to give the product (4.9 g, 96%). [M+H] + =185.2.

[0855] Step 3: tert-butyl 4-((cis)-4-hydroxycyclohexyl)piperazine-1-carboxylate

[0856]

[0857] At 0 °C, a mixture of (cis)-4-(piperazin-1-yl)cyclohexane-1-ol (4.9 g, 26.6 mmol) and (Boc)₂O (6.96 g, 31.9 mmol) in DCM (80 mL) was added to Et₃N (8.06 g, 79.8 mmol). The mixture was stirred at rt for 4 h. The mixture was washed with water (150 mL) and extracted with dichloromethane (3 x 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 (4.57 g, 60%). [M+H] + =285.6.

[0858] Step 4: Methyl 2-((trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-ind azole-6-carboxylate

[0859]

[0860] Under a nitrogen atmosphere at 0 °C, a mixture of tert-butyl 4-((cis)-4-hydroxycyclohexyl)piperazine-1-carboxylate (1.12 g, 3.93 mmol), methyl 5-nitro-2H-indazole-6-carboxylate (0.87 g, 3.93 mmol) (obtained by the same method described in WO 2020035019A1) and PPh3 (1.55 g, 5.92 mmol) was added dropwise to THF (50 mL). The mixture was stirred at 0 °C for 15 min, and then DIAD (1.19 g, 5.92 mmol) was added. The reaction was stirred at 0 °C for 1 h. The mixture was then slowly heated to room temperature and stirred for 16 h. The mixture was diluted with water (50 mL), extracted with dichloromethane (3 x 50 mL), and washed with brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was then 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 H NMR (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).

[0861] Step 5: Methyl 5-amino-2-((trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-ind azole-6-carboxylate

[0862]

[0863] NH₄Cl (121 mg, 2.26 mmol) in water was added to a solution of methyl 2-((trans)-4-(4-(tert-butyloxycarbonyl)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) (3 mL). The reaction was stirred at 80 °C for 4 h. The mixture was then cooled. The mixture was filtered through diatomaceous earth 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.

[0864] Step 6: Methyl 2-(trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl) pyridinecarbamate (2H-indazole-6-carboxylate)

[0865]

[0866] HATU (133 mg, 0.35 mmol) was added to a solution of 6-(trifluoromethyl)pyridinecarboxylic acid (61 mg, 0.32 mmol) in DMF (10 mL). The mixture was stirred at rt for 10 min. Then, methyl 5-amino-2-((trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (145 mg, 0.32 mmol) in Et3N (96 mg, 0.95 mmol) was added to the reaction mixture. 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 (3 x 50 mL), and washed with brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was then purified by silica gel column chromatography (DCM:MeOH = 100:0-20:1 gradient elution) to obtain the product (120 mg, 60%). [M+H] + =631.2

[0867] Step 7: 2-(trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridine) (formamido)-2H-indazole-6-carboxylic acid

[0868]

[0869] LiOH·H₂O (32 mg, 0.76 mmol) was added to a solution of methyl 2-(trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-6-carboxylate (120 mg, 0.19 mmol) in THF (2 mL) / MeOH (2 mL) / H₂O (2 mL). 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 1 N HCl. The mixture was filtered. The filter cake was concentrated under reduced pressure to give the product (115 mg, 98%). [M+H] + =617.2

[0870] Step 8: tert-butyl 4-((trans)-4-(6-(cyclopropylcarbamoyl)-5-(6-(trifluoromethyl)pyridinecarbamoyl) (amino)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate

[0871]

[0872] HATU (61 mg, 0.16 mmol) was added to a solution of 2-(trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-6-carboxylic acid (90 mg, 0.15 mmol) in DMF (3 mL). The mixture was stirred at rt for 10 min. Then cyclopropylamine (8 mg, 0.15 mmol) and Et3N (46 mg, 0.45 mmol) were added to the reaction. The reaction was stirred at rt for 4 h. The solvent was removed by vacuum. The residue was washed 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 obtain a crude product, which was then 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

[0873] Step 9: N-cyclopropyl-2-(trans)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridinecarboxyl (amino)-2H-indazole-6-carboxamide hydrochloride

[0874]

[0875] To a solution of tert-butyl 4-((trans)-4-(6-(cyclopropylcarbamoyl)-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (70 mg, 0.11 mmol) in DCM (5 mL), HCl / dioxane (1 mL, 4 N, 4 mmol) was added 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.

[0876] Step 10: N-Cyclopropyl-2-(trans)-4-(4-(1-(4-((R)-2,6-dioxadiazin-3-yl)-3,5-difluoro (phenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-ind azole-6-carboxamide

[0877]

[0878] HATU (18 mg, 0.046 mmol) was added to a solution of (R)-1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxylic acid (14 mg, 0.042 mmol) in DMF (3 mL). The mixture was stirred at rt for 10 min. Then, N-cyclopropyl-2-(trans)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridinicamido)-2H-indazole-6-carboxamide hydrochloride (25 mg, 0.042 mmol) and Et3N (46 mg, 0.45 mmol) in DMF (2 mL) were added to the reaction mixture. The reaction was stirred at rt for 4 h. The solvent was removed by vacuum. The residue was washed 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 obtain a crude product, which was then purified by silica gel column chromatography (DCM:MeOH = 100:0-10:1 gradient elution) to obtain the product (5 mg, 14%). [M+H] + =862.6

[0879] 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).

[0880] Example 129: N-cyclopropyl-2-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazole-6-carboxamide

[0881]

[0882] The title compound (5.24 mg, 20% yield) was prepared from N-cyclopropyl-2-(trans)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridinic carboxamido)-2H-indazole-6-carboxamide hydrochloride in a manner similar to that described in Example 130. 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,1H),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

[0883] Example 168: 2-((1R,4R)-4-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazole-6-carboxamide

[0884] Step 1: tert-butyl 4-((1R,4r)-4-(6-(((1r,3R)-3-(hydroxymethyl)cyclobutyl)carbamoyl)- 5-(6-(trifluoromethyl)pyridinecarbamate)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[0885]

[0886] HATU (42 mg, 0.11 mmol) was added to a solution of 2-(trans)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-6-carboxylic acid (62 mg, 0.10 mmol) in DMF (3 mL). 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 Et3N (46 mg, 0.45 mmol) in DMF (3 mL) were added to the reaction mixture. The reaction was stirred at rt for 4 h. The solvent was removed by vacuum. The residue was washed 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 obtain a crude product, which was then 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

[0887] Step 2: N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-2-((1r,4R)-4-(piperazin-1-yl)cyclohexyl)- 5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazole-6-carboxamide hydrochloride

[0888]

[0889] To a solution of tert-butyl 4-((1R,4r)-4-(6-(((1r,3R)-3-(hydroxymethyl)cyclobutyl)carbamoyl)-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (50 mg, 0.07 mmol) in DCM (3 mL), HCl / dioxane (1 mL, 4 N, 4 mmol) was added 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.

[0890] Step 3: 2-((1R,4R)-4-(4-((R)-1-(4-((R)-2,6-dioxadiazin-3-yl)-3,5-difluorophenyl) Pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-5-(6-(trifluoromethyl) (Pyridinecarboxamido)-2H-indazole-6-carboxamide

[0891]

[0892] HATU (11 mg, 0.03 mmol) was added to a solution of (R)-1-(4-((R)-2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (9 mg, 0.017 mmol) in DMF (1 mL). The mixture was stirred at rt for 10 min. Then, N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-2-((1r,4R)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)pyridinicamido)-2H-indazole-6-carboxamide hydrochloride (17 mg, 0.027 mmol) and Et3N (46 mg, 0.45 mmol) in DMF (2 mL) were added to the reaction mixture. The reaction was stirred at rt for 4 h. The solvent was removed by vacuum. 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 obtain the 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

[0893] 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).

[0894] Example 167: 2-((1r,4R)-4-(4-(1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazole-6-carboxamide

[0895]

[0896] 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)pyridinecarboxamido)-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

[0897] Example 35: N-(2-(1-((1r,4r)-4-(4-(2,6-dioxadiazin-3-yl)phenoxy)cyclohexane-1-carbonyl)piperidin-4-yl)-6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0898]

[0899] The title compound was prepared in a manner similar to that described in Example 41.

[0900] 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.

[0901] 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-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0902]

[0903] The title compound was prepared in a manner similar to that described in Example 6.

[0904] 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 Example 32: N-(2-((1r,4r)-4-(1-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindol-5-yl)piperidine-4-carboxamido)cyclohexyl)-6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0905] Step 1: (1s,4s)-4-((tert-Butoxycarbonyl)amino)cyclohexyl4-methylbenzenesulfonate

[0906]

[0907] TsCl (5.31 g, 27.87 mmol) was added 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) at 0 °C, and the mixture was stirred at 20 °C under N2 for 12 h. 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 0.1 M HCl (50.0 mL), Na2CO3 (50.0 mL), and brine (20.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was ground with MTBE (50 mL) at 20 °C for 20 min and filtered to give (1s,4s)-4- ((tert-Butoxycarbonyl)amino)cyclohexyl4-methylbenzenesulfonate (4.2g, 10.57mmol, 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.

[0908] Step 2: tert-butyl((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-in (2-Azolium)cyclohexyl)carbamate

[0909]

[0910] To (1) s,4s)-4-((tert-Butoxycarbonyl)amino)cyclohexyl4-methylbenzenesulfonate Cs₂CO₃ (3.5 g, 10.83 mmol) was added to a solution of N-(6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine-2-carboxamide (728 mg, 2.17 mmol) in DMF (50.0 mL). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was quenched with H₂O (5.0 mL) at 20 °C 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 obtain the 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)pyridinamide)-2H-indazole-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.

[0911] Step 3: N-(2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl) Pyridine carboxamide, hydrochloride

[0912]

[0913] HCl / EtOAc (4 M, 1.3 mL) was added to a solution of tert-butyl((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazole-2-yl)cyclohexyl)carbamate (280.0 mg, 0.525 mmol) in DCM (4.0 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-yl)-6-(trifluoromethyl)pyridinecarboxamide, hydrochloride (235.0 mg, 0.475 mmol, 91% yield) was given. 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.

[0914] Step 4: N-(2-((1r,4r)-4-(1-(2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindol-5-yl) Piperidine-4-carbamoyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0915]

[0916] HATU (42 mg, 0.11 mmol) was added to a solution of 1-(2-(2,6-dioxadiazin-3-yl)-1,3-dioxoisoindole-5-yl)piperidin-4-carboxylic acid (38.5 mg, 0.10 mmol) in DMF (3 mL). The mixture was stirred at rt for 10 min. Then, N-(2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide, hydrochloride (47 mg, 0.10 mmol), and Et3N (46 mg, 0.45 mmol) in DMF (3 mL) were added to the reaction mixture. The reaction was stirred at rt for 4 h. The solvent was removed by vacuum. 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 obtain a crude product, which was then purified by silica gel column chromatography (DCM:MeOH = 100:0-10:1 gradient elution) to produce the product (12 mg, 14%). [M+H] + =801.5; 1 HNMR(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).

[0917] Example 41: (R)-N-(2-(1-(1-(1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)azacyclobutane-3-yl)piperidin-4-yl)-6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0918] Step 1: N-(6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0919]

[0920] A mixture of 6-methoxy-2H-indazole-5-amine (2 g, 12.27 mmol), 6-(trifluoromethyl)pyridinecarboxylic acid (2.34 g, 12.27 mmol), T3P (12 mL), and DIEA (2.37 g, 18.4 mmol) in THF (60 mL) was stirred at room temperature for 16 h. The reaction was monitored by LCMS. The resulting solution was extracted with DCM (2 x 50.0 mL) and washed with water (60 mL). The combined organic layers were washed with brine (50 mL), 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 (2 g, 48.5%). [M+H] + =337.1.

[0921] Step 2: tert-butyl 4-(6-methoxy-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-2-yl)piperazine 1-Pyridine-carboxylate

[0922]

[0923] A mixture of N-(6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (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 yield the product (1.7 g, 54.6%). [M+H] + =520.5.

[0924] Step 3: N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide hydrochloride

[0925]

[0926] At 25 °C, 4N HCl / dioxane (30 mL) was added to tert-butyl 4-(6-methoxy-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-2-yl)piperidine-1-carboxylate (1.7 g, 3.27 mmol) in DCM (15 mL). 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.

[0927] Step 4: tert-butyl 3-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-2-yl) Piperidin-1-yl)azacyclobutane-1-carboxylate

[0928]

[0929] A mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide hydrochloride (300 mg, 0.66 mmol) and tert-butyl 3-oxoazacyclobutane-1-carboxylate (169 mg, 0.99 mmol) in DCM (30 mL) was stirred in a round-bottom flask for 16 h at room temperature. Then, NaBH(AcO)3 (419 mg, 1.98 mmol) was added, and the mixture was stirred for 3 h at room temperature. The reaction was quenched with water, and the mixture was washed once with a saturated aqueous solution of NaHCO3, followed by extraction with DCM. The organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to give the product (300 mg, 79.1%). [M+H] + =575.3.

[0930] Step 5: N-(2-(1-(azacyclobutane-3-yl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6- (trifluoromethyl)pyridinecarboxamide trifluoroacetate

[0931]

[0932] TFA (20 mL) was added to tert-butyl 3-(4-(6-methoxy-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-2-yl)piperidin-1-yl)azacyclobutane-1-carboxylate (300 mg, 0.52 mmol) in DCM (8 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.

[0933] Step 6: (R)-N-(2-(1-(1-(1-(4-(2,6-dioxadiazine-3-yl)-3,5-difluorophenyl)azacyclobutane (alkyl-3-carbonyl)azacyclobutane-3-yl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine formamide

[0934]

[0935] A mixture of (R)-1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-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 min, and N-(2-(1-(azacyclobutane-3-yl)piperidin-4-yl)-6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide trifluoroacetate (55 mg, 0.093 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS. The resulting solution was extracted with DCM (2 x 15.0 mL) and water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product. The crude product was purified by preparative HPLC to give the 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.

[0936] Example 42: N-(2-(1-(1-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)azacyclobutane-3-yl)piperidin-4-yl)-6-methoxy-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0937]

[0938] The title compound was prepared in a manner similar 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.

[0939] Example 43: N-(2-(1'-((R)-1-(4-((R)-2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-[1,4'-bipiperidine]-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0940]

[0941] The title compound was prepared in a manner similar 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.

[0942] Example 44: N-(2-(1'-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azacyclobutane-3-carbonyl)-[1,4'-piperidin]-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0943]

[0944] The title compound was prepared in a manner similar to that described in Example 41. 1 H NMR (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.

[0945] Example 45: (R)-N-(2-(1'-(1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)-[1,4'-bipiperidin]-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0946]

[0947] The title compound was prepared in a manner similar to that described in Example 41. 1H NMR (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,1H ),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.

[0948] Example 102: 1-Cyclopropyl-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0949] Step 1: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-methyl esters

[0950]

[0951] tert-butyl 4-((1r,4r)-4-aminocyclohexyl)piperazine-1-carboxylate (5.66 g, 20 mmol) was added to a solution of methyl 4-formyl-3-nitrobenzene ester (4.2 g, 20 mmol) in propan-2-ol (100 mL). 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 yield the product (7 g, 79%). [M+H] + =443.3

[0952] Step 2: Methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

[0953]

[0954] At 0 °C, NaNO3 (1.615 g, 19 mmol) was added to a solution of methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (7 g, 15.84 mmol) in concentrated H2SO4 (80 mL). 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 vacuum evaporated to give the product (4.8 g, 78%), which was used without further purification. [M+H] + =388.2

[0955] Step 3: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-ind azole-6-carboxylate

[0956]

[0957] Et3N (3.76 g, 37.2 mmol) and Boc2O (4.06 g, 18.6 mmol) were added 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). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to yield the product (4.9 g, 81%). [M+H] + =488.2

[0958] Step 4: Methyl 5-amino-2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-ind azole-6-carboxylate

[0959]

[0960] At room temperature, NH4Cl (2.69 g, 50.3 mmol) and Fe powder (2.82 g, 50.3 mmol) were added 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). 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

[0961] Step 5: tert-butyl-4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexane Piperazine-1-carboxylate

[0962]

[0963] At 0 °C, MeMgBr (1 M, 26.2 mL, 26.2 mmol) in THF was added dropwise to a solution of methyl 5-amino-2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)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). 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 under vacuum. 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

[0964] Step 6: tert-butyl-4-((1r,4r)-4-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide) 6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate

[0965]

[0966] At rt, DIPEA (0.406 g, 3.15 mmol) and HATU (0.4 g, 1.05 mmol) were added to a solution of tert-butyl-4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (0.48 g, 1.05 mmol) in DMF (10 mL). 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 under vacuum. 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

[0967] Step 7: 1-Cyclopropyl-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)- 2H-Indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0968]

[0969] TFA (2 mL) was added to a solution of tert-butyl 4-((1r,4r)-4-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-carboxamido)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (0.4 g, 0.647 mmol) in DCM (10 mL) under reflux. The resulting mixture was stirred under reflux for 1 h. The mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to give the product (0.275 g, 82%). [M+H] + =519.3

[0970] Step 8: 1-Cyclopropyl-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxadiazin-3-yl)-3,5- (difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)- 2-Oxo-1,2-dihydropyridine-3-carboxamide

[0971]

[0972] Under rt, DIPEA (31 mg, 0.24 mmol) and T3P (50%, 102 mg, 0.16 mmol) in EtOAc were added to a solution of 1-cyclopropyl-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (41.44 mg, 0.08 mmol) and (R)-1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxylic acid (25.92 mg, 0.08 mmol) in DCM (5 mL). The resulting mixture was stirred under 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 under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography) (eluting in water with a gradient of 0.1% FA:acetonitrile = 90:10-60:40) to obtain 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).

[0973] Example 103: 1-Cyclopropyl-N-(2-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0974]

[0975] Under rt, DIPEA (15.48 mg, 0.12 mmol) and T3P in EtOAc (50%, 50.78 mg, 0.08 mmol) were added to a solution of 1-cyclopropyl-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (20.72 mg, 0.04 mmol) in DCM (5 mL). The resulting mixture was stirred under 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 under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography) (eluting in water with a gradient of 0.1% FA:acetonitrile = 90:10-60:40) to yield 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).

[0976] Example 117: (R)-1-cyclopropyl-N-(2-(1'-(1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)-[1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0977] Step 1: Methyl 2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidine]-4-yl)-5-(1-cyclopropyl-2-oxo- 1,2-Dihydropyridine-3-carbamate)-2H-indazole-6-carboxylate

[0978]

[0979] At rest, DIPEA (0.339 g, 2.625 mmol) and HATU (0.332 g, 0.875 mmol) were added to a solution of methyl 5-amino-2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidine]-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). The resulting mixture was stirred at rest 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 under vacuum. 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

[0980] Step 2: tert-butyl-4-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-6-(2-hydroxy) (propyl-2-yl)-2H-indazole-2-yl)-[1,4'-bipiperidine]-1'-carboxylate

[0981]

[0982] At 0 °C, MeMgBr (1 M, 6.63 mL, 6.63 mmol) in THF was added dropwise to a solution of methyl 2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidine]-4-yl)-5-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-carboxamido)-2H-indazole-6-carboxylate (0.41 g, 0.663 mmol) and LiCl (0.141 g, 3.315 mmol) in THF (10 mL). 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 under vacuum. 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

[0983] Step 3: N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)-1-cyclo Propyl-2-oxo-1,2-dihydropyridine-3-carboxamide

[0984]

[0985] TFA (2 mL) was added to a solution of tert-butyl 4-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-carboxamido)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)-[1,4'-bipiperidine]-1'-carboxylate (0.18 g, 0.291 mmol) in DCM (10 mL) under reflux. The resulting mixture was stirred under reflux for 1 h. The mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to give the product (0.11 g, 73.3%). [M+H] + =519.3

[0986] Step 4: (R)-1-cyclopropyl-N-(2-(1'-(1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)nitrogen Heterocyclic butane-3-carbonyl)-[1,4'-bipiperidine]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-2-oxo- 1,2-Dihydropyridine-3-carboxamide

[0987]

[0988] Under rt, DIPEA (31 mg, 0.24 mmol) and T3P (50%, 102 mg, 0.16 mmol) in EtOAc were added to a solution of N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (41 mg, 0.08 mmol) in DCM (5 mL). The resulting mixture was stirred under 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 under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography) (eluting in water with a gradient of 0.1% FA:acetonitrile = 90:10-60:40) to obtain 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).

[0989] Example 118: 1-Cyclopropyl-N-(2-(1'-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-[1,4'-bipiperidine]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0990]

[0991] Under rt, DIPEA (31 mg, 0.24 mmol) and T3P (50%, 102 mg, 0.16 mmol) in EtOAc were added to a solution of N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropyl-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-dioxadipinidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (27 mg, 0.08 mmol) in DCM (5 mL). The resulting mixture was stirred under 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 under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography) (eluting in water with a gradient of 0.1% FA:acetonitrile = 90:10-60:40) to obtain 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).

[0992] Example 160: (R)-N-(2-(1'-(1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)-[1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0993] Step 1: tert-butyl 4-(6-bromo-2H-indazole-2-yl)-[1,4'-bipiperidine]-1'-carboxylate

[0994]

[0995] tert-butyl-4-amino-[1,4'-bipiperidine]-1'-carboxylate (2.83 g, 10 mmol) was added to a solution of 4-bromo-2-nitrobenzaldehyde (2.3 g, 10 mmol) in propan-2-ol (50 mL). 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 under vacuum. 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

[0996] Step 2: Methyl 2-(1'-(tert-Butoxycarbonyl)-[1,4'-Bipiperidine]-4-yl)-2H-indazole-6-carboxylate

[0997]

[0998] Under rt, Pd(dppf)Cl2 (0.555 g, 0.758 mmol) was added to a solution of tert-butyl 4-(6-bromo-2H-indazole-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). The mixture was stirred overnight at 80 °C under CO(g). 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

[0999] Step 3: Methyl 2-([1,4'-bipiperidine]-4-yl)-5-nitro-2H-indazole-6-carboxylate

[1000]

[1001] At 0 °C, NaNO3 (0.577 g, 6.792 mmol) was added to a solution of methyl 2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidine]-4-yl)-2H-indazole-6-carboxylate (2.5 g, 5.66 mmol) in concentrated H2SO4 (30 mL). 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 vacuum evaporated to give the product (1.5 g, 68.5%), which was used without further purification. [M+H] + =388.2

[1002] Step 4: Methyl 2-(1'-(tert-Butoxycarbonyl)-[1,4'-Bioperidinyl]-4-yl)-5-nitro-2H-indazole-6-methyl esters

[1003]

[1004] Et3N (1.176 g, 11.64 mmol) and Boc2O (1.269 g, 5.82 mmol) were added to a stirred solution of methyl 2-([1,4'-bipiperidin]-4-yl)-5-nitro-2H-indazole-6-carboxylate (1.5 g, 3.88 mmol) in DCM (20 mL). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to give the product (1.6 g, 84.5%). [M+H] + =488.2

[1005] Step 5: Methyl 5-amino-2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidine]-4-yl)-2H-indazole-6-methyl esters

[1006]

[1007] At room temperature, NH4Cl (0.88 g, 16.45 mmol) and Fe powder (0.92 g, 16.45 mmol) were added to a solution of methyl 2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidine]-4-yl)-5-nitro-2H-indazole-6-carboxylate (1.6 g, 3.29 mmol) in MeOH (20 mL) and water (4 mL). 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

[1008] Step 6: Methyl 2-(1'-(tert-butoxycarbonyl)-[1,4'-piperidin]-4-yl)-5-(6-(trifluoromethyl)pyridine) (formamido)-2H-indazole-6-carboxylate

[1009]

[1010] At rest, DIPEA (0.339 g, 2.625 mmol) and HATU (0.332 g, 0.875 mmol) were added to a solution of methyl 5-amino-2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidine]-4-yl)-2H-indazole-6-carboxylate (0.4 g, 0.875 mmol) and 6-(trifluoromethyl)pyridinecarboxylic acid (0.167 g, 0.875 mmol) in DMF (10 mL). The resulting mixture was stirred at rest 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 under vacuum. 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

[1011] Step 7: tert-butyl 4-(6-(2-hydroxypropyl-2-yl)-5-(6-(trifluoromethyl)pyridinamide)-2H-in (2-yl)-[1,4'-bipiperidine]-1'-carboxylate

[1012]

[1013] At 0 °C, MeMgBr (1 M, 6.4 mL, 6.4 mmol) was added dropwise to a solution of methyl 2-(1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidine]-4-yl)-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-6-carboxylate (0.4 g, 0.635 mmol) and LiCl (0.135 g, 3.175 mmol) in THF (10 mL). 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 under vacuum. 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

[1014] Step 8: N-(2-([1,4'-bipiperidine]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)-6-(tri-) Fluoromethyl)pyridinecarboxamide

[1015]

[1016] TFA (2 mL) was added to a solution of tert-butyl 4-(6-(2-hydroxypropyl-2-yl)-5-(6-(trifluoromethyl)pyridinamide)-2H-indazole-2-yl)-[1,4'-bipiperidine]-1'-carboxylate (0.24 g, 0.381 mmol) in DCM (10 mL) under reflux. The resulting mixture was stirred under reflux for 1 h. The mixture was quenched with saturated NaHCO3 solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum to give the product (0.17 g, 85%). [M+H] + =531.3

[1017] Step 9: (R)-N-(2-(1'-(1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane- 3-carbonyl)-[1,4'-bipiperidine]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridine formamide

[1018]

[1019] Under rt, DIPEA (15 mg, 0.12 mmol) and T3P (50%, 51 mg, 0.08 mmol) in EtOAc were added to a solution of N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (21 mg, 0.04 mmol) in DCM (5 mL). The resulting mixture was stirred under 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 under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography) (eluting in water with a gradient of 0.1% FA:acetonitrile = 90:10-60:40) to obtain 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).

[1020] Example 161: N-(2-(1'-((R)-1-(4-((R)-2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-[1,4'-bipiperidine]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[1021]

[1022] Under rt, DIPEA (31 mg, 0.24 mmol) and T3P (50%, 102 mg, 0.16 mmol) in EtOAc were added to a solution of N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (42 mg, 0.08 mmol) in DCM (5 mL). The resulting mixture was stirred under 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 under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography) (eluting in water with a gradient of 0.1% FA:acetonitrile = 90:10-60:40) to obtain 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).

[1023] Example 162: (R)-N-(2-(1'-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-[1,4'-piperidine]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[1024]

[1025] At rest, DIPEA (31 mg, 0.24 mmol) and T3P in EtOAc (50%, 102 mg, 0.16 mmol) were added to a solution of N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (42 mg, 0.08 mmol) and (R)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carboxylic acid (obtained in a manner similar to common intermediate B) (24 mg, 0.08 mmol) in DCM (5 mL). The resulting mixture was stirred at rest 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 under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography) (eluting in water with a gradient of 0.1% FA:acetonitrile = 90:10-60:40) to obtain 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).

[1026] Example 163: (S)-N-(2-(1'-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-[1,4'-piperidin]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[1027]

[1028] At rest, DIPEA (31 mg, 0.24 mmol) and T3P in EtOAc (50%, 102 mg, 0.16 mmol) were added to a solution of N-(2-([1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropyl-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide (42 mg, 0.08 mmol) and (S)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carboxylic acid (obtained in a manner similar to common intermediate B) (24 mg, 0.08 mmol) in DCM (5 mL). The resulting mixture was stirred at rest 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 under vacuum. The residue was purified by preparative HPLC (C-18 column chromatography) (eluting in water with a gradient of 0.1% FA:acetonitrile = 90:10-60:40) to obtain 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).

[1029] Example 178: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxoperidin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1030] Step 1: Potassium salt of 3,3-diethoxy-2-formylpropionitrile

[1031]

[1032] At 10 °C, 1.0 M potassium tert-butoxide (110 mL, 110 mmol) in THF was added to a stirred solution of 3,3-diethoxypropionitrile (14.3 g, 100 mmol) and methyl formate (7.5 g, 125 mmol) in anhydrous THF (100 mL). The temperature was maintained between 10 °C and 15 °C during the 45-minute addition. The resulting slurry was then stirred at ambient temperature for 2 hours. Hexane (400 mL) was then added, and the mixture was stirred again for 20 minutes. The slurry was filtered, and the filter cake was washed with 1:1 hexane / THF and dried under vacuum to provide the product (16 g, 76 mmol, 76%).

[1033] Step 2: Pyrrolo[1,2-b]pyridazine-3-carboxylon

[1034]

[1035] A stirred suspension of potassium 3,3-diethoxy-2-formylpropionitrile (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 mixture was stirred at room temperature for 20 min. 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 h, cooled to room temperature, and concentrated to about half the original volume. A saturated aqueous solution of sodium bicarbonate was carefully added to the resulting residue until bubbling ceased. 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.

[1036] Step 3: 7-bromopyrrolo[1,2-b]pyridazine-3-carboxylon

[1037]

[1038] N-bromosuccinimide (3.48 g, 19.6 mmol) was added in a single addition to a solution of pyrrolo[1,2-b]pyridazine-3-carboxynitrile (2.8 g, 19.6 mmol) in MeCN (50 mL) at room temperature. The reaction was stirred at room temperature for 30 min 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 aliquots 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.

[1039] Step 4: 3-Cyanopyrrolo[1,2-b]pyridazine-7-carboxylic acid

[1040]

[1041] A suspension of 7-bromopyrrolo[1,2-b]pyridazine-3-carboxynitrile (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 TEA (682 mg, 6.75 mmol) in THF / H2O (30 mL / 10 mL) was added to a high-pressure reactor. 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 combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Combi-Flash chromatography (silica gel column, 12 g, DCM:MeOH = 10:1) to yield the product (250 mg, 1.33 mmol, 59%). [M+H] + =188.6.

[1042] Step 5: tert-butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6- (2-hydroxypropyl-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[1043]

[1044] HATU (66 mg, 0.17 mmol) and DIEA (29 mg, 0.45 mmol) were added 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-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (66 mg, 0.15 mmol) in DMF (3 mL). The solution was stirred at rt for 4 h. The solution was then diluted with EA (20 mL) and 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 yield the product (55 mg, 0.09 mmol, 58%). [M+H] + =627.6.

[1045] Step 6: 3-Cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H- Indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1046]

[1047] TFA (1 mL) was added to a stirred solution of tert-butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazin-7-carboxamido)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (55 mg, 0.09 mmol) in DCM (3 mL). The reaction mixture was stirred at rt for 2 h and concentrated under vacuum to give crude product (60 mg). [M+H] + =527.6.

[1048] Step 7: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxadiazin-3-yl)-3,5-dioxadiazin-3-yl) (Fluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyridine P-[1,2-b]pyridazine-7-carboxamide

[1049]

[1050] At room temperature, T3P (72 mg, 0.227 mmol) was added dropwise to a solution of crude 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (60 mg, 0.09 mmol), (R)-1-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)azacyclobutane-3-carboxylic acid (32.4 mg, 0.10 mmol), and DIEA (35 mg, 0.272 mmol) in DCM (3 mL). 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 under vacuum to obtain a crude residue, which was purified by silica gel column chromatography (DCM:MeOH = 100:0-10:1 gradient elution) to obtain the product, which was further purified by preparative HPLC (C-18 column chromatography) (0.1% FA:acetonitrile = 90:10-60:40 gradient elution in water) to produce the desired product (23.5 mg, 31%).

[1051] 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.

[1052] Example 105: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azacyclobutane-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1053]

[1054] The title compound (15 mg, 23.7%) was prepared in a manner similar to that described in Example 178. 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.

[1055] Example 110: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1056]

[1057] The title compound (3 mg, 3.2%) was prepared in a manner similar to that described in Example 9. 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.

[1058] This compound can also be synthesized in another way.

[1059] Step 1: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-methyl esters

[1060]

[1061] tert-butyl-4-((1r,4r)-4-aminocyclohexyl)piperazine-1-carboxylate (141.5 g, 500 mmol) was added to a solution of methyl 4-formyl-3-nitrobenzene (104.5 g, 500 mmol) in propan-2-ol (1000 mL). 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 under vacuum. The residue was slurried with petroleum ether (3000 mL) and filtered. The solid was filtered and dried under vacuum to yield the product (160 g, 72.4%). [M+H] + =443.1

[1062] Step 2: Methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

[1063]

[1064] At 0 °C, NaNO3 (46.155 g, 543 mmol) was added to a solution of methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (160 g, 362 mmol) in concentrated H2SO4 (98%, 1000 mL). 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 treated with DCM (3... x Extracted (2000 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and vacuum evaporated to obtain the product (140 g, crude), which was used without further purification. [M+H] + =388.1

[1065] Step 3: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-ind azole-6-carboxylate

[1066]

[1067] Et3N (109.686 g, 1086 mmol) and Boc2O (94.7 g, 434.4 mmol) were added 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). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to yield the product (150 g, 84.9%). [M+H] + =488.1

[1068] Step 4: Methyl 5-amino-2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-ind azole-6-carboxylate

[1069]

[1070] Pd / C (5%, 30 g) was added to a solution of methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate (150 g, 308 mmol) in THF (1500 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under H2. The solid was filtered and washed with MeOH (800 mL). The filtrate was evaporated under vacuum to give the product (120 g, 85.2%). [M+H] + =458.2

[1071] Step 5: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(2,2,2-trifluoro Acetamido)-2H-indazole-6-carboxylate

[1072]

[1073] At 0 °C, trifluoroacetic anhydride (66.15 g, 315 mmol) was added dropwise to a solution of methyl 5-amino-2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (120 g, 262.58 mmol) in DCM (1000 mL). 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 then stirred with DCM (3... x Extracted (1000 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to yield the product (132 g, 90.9%). [M+H] + =554.2

[1074] Step 6: tert-butyl 4-((1r,4r)-4-(6-(2-hydroxypropyl-2-yl)-5-(2,2,2-trifluoroacetamido)- 2H-Indazole-2-yl)cyclohexyl)piperazine-1-carboxylate

[1075]

[1076] At 0 °C, MeMgBr (3 M, 795.66 mL, 2386.98 mmol) in THF was added dropwise to a solution of methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)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). The resulting mixture was stirred overnight at 0 °C. The mixture was quenched with saturated NH4Cl solution and treated with EtOAc (3 x Extracted (1000 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to yield the product (105 g, 79.55%). [M+H] + =554.2

[1077] Step 7: tert-butyl-4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexane Piperazine-1-carboxylate

[1078]

[1079] At room temperature, a solution of NaOH (2M, 950mL, 1898.7mmol) was added to a solution of tert-butyl 4-((1r,4r)-4-(6-(2-hydroxypropyl-2-yl)-5-(2,2,2-trifluoroacetamido)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (105g, 189.87mmol) in MeOH (1000mL). The mixture was stirred at 70°C for 2h. The mixture was cooled to room temperature, diluted with water (600mL), and mixed with DCM / MeOH (V / V = 10 / 1, 5). x Extracted with 1000 mL of the extract. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was slurried with petroleum ether (1000 mL) and filtered. The solids were filtered and dried under vacuum to yield the product (80 g, 92.2%). [M+H] + =458.2

[1080] Step 8: tert-butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6- (2-hydroxypropyl-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[1081]

[1082] 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-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (80 g, 175.05 mmol) in DMF (1000 mL), HATU (79.822 g, 210.06 mmol) and DIEA (67.744 g, 525.15 mmol) were added to the mixture. 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 diluted with water (3... x Wash with 100 mL of water. Dry the solid under vacuum to yield the product (90 g, 82.13%). [M+H] + =627.5

[1083] Step 9: 3-Cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H- Indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1084]

[1085] At 0 °C, concentrated HCl (36%, 300 mL) was added dropwise to a stirred solution of tert-butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazin-7-carboxamido)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (90 g, 143.77 mmol) in MeOH (600 mL). The resulting mixture was stirred overnight at room temperature. The solid was collected by filtration. The solid was dissolved in water (500 mL), then adjusted to pH 8 with saturated NaHCO3 solution, and the solution was diluted with DCM / MeOH (V / V = 10 / 1, 5). x Extracted with 2000 mL of the extract. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was slurried with petroleum ether (1000 mL) and filtered. The solids were filtered and dried under vacuum to yield the product (64 g, 84.63%). [M+H] + =527.4

[1086] Step 10: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxadiazine-3-yl)-3,5-dioxadiazine-3-yl) (Fluorophenyl)azacyclobutane-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrole [1,2-b]pyridazine-7-carboxamide

[1087]

[1088] Add AcOH (6.844 g, 114.07 mmol) and NaBH(OAc)3 (48.366 g, 228.14 mmol) to a stirred solution of 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazin-7-carboxamide (60 g, 114.07 mmol) and (R)-3-(2,6-difluoro-4-(3-oxoazacyclobutane-1-yl)phenyl)piperidine-2,6-dione (50.3 g, 171.1 mmol) in a DCE (1000 mL). Stir the mixture overnight at room temperature. Dilute the mixture with MeOH (500 mL) and concentrate under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 15:1). Then, acetonitrile (1600 mL), water (800 mL), and acetic acid (200 mL) were added and lyophilized to produce the product (66 g, 62.62%).

[1089] Example 181: 3-Cyano-N-(2-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1090]

[1091] The title compound (45 mg, 46.6%) was prepared in a manner similar to that described in Example 178. 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.

[1092] Example 182: 3-Cyano-N-(2-((1R,4r)-4-(4-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenylethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1093]

[1094] The title compound (18 mg, 32.9%) was prepared in a manner similar to that described in Example 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.

[1095] This compound can also be synthesized in another way.

[1096] Step 1: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-methyl esters

[1097]

[1098] tert-butyl-4-((1r,4r)-4-aminocyclohexyl)piperazine-1-carboxylate (141.5 g, 500 mmol) was added to a solution of methyl 4-formyl-3-nitrobenzene ester (104.5 g, 500 mmol) in propan-2-ol (1000 mL). 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 under vacuum. The residue was slurried with petroleum ether (3000 mL) and filtered. The solid was filtered and dried under vacuum to yield the product (130 g, 58.7%). [M+H] + =443.1

[1099] Step 2: Methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

[1100]

[1101] At 0 °C, NaNO3 (49.9 g, 587.4 mmol) was added in portions to a solution of methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (130 g, 293.7 mmol) in concentrated H2SO4 (98%, 1000 mL). The mixture was stirred at 0 °C for 2 h. The mixture was then poured into ice water, alkalized to pH 9 with a saturated aqueous Na2CO3 solution, and extracted with DCM (3 × 2000 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to yield the product (130 g, crude), which was used directly for the next step without any further purification. [M+H] + =388.1

[1102] Step 3: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-ind azole-6-carboxylate

[1103]

[1104] Et3N (44.50 g, 440.55 mmol) and Boc2O (64.1 g, 293.7 mmol) were added 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). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with DCM (2000 mL) and washed with water (1 L × 2) and saturated salt solution (1 L × 2). The organic layer was then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to yield the product (130 g, 90.8%, in 2 steps). [M+H] + =488.1

[1105] Step 4: Methyl 5-amino-2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-ind azole-6-carboxylate

[1106]

[1107] Pd / C (5%, 30 g) was added to a solution of methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate (130 g, 266.6 mmol) in THF (1300 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under H2. The solid was filtered and washed with MeOH (800 mL). The filtrate was evaporated under vacuum to yield the product (110 g, 90.3%). [M+H] + =458.2

[1108] Step 5: Methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(2,2,2-trifluoro Acetamido)-2H-indazole-6-carboxylate

[1109]

[1110] At 0 °C, trifluoroacetic anhydride (50.6 g, 240.9 mmol) was added dropwise to a solution of methyl 5-amino-2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate (105 g, 229.4 mmol) in DCM (1000 mL). 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 then stirred with DCM (3... x Extracted (1000 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to yield the product (120 g, 94.5%). [M+H] + =554.2

[1111] Step 6: tert-butyl 4-((1r,4r)-4-(6-(2-hydroxypropyl-2-yl)-5-(2,2,2-trifluoroacetamido)- 2H-Indazole-2-yl)cyclohexyl)piperazine-1-carboxylate

[1112]

[1113] Under N2 and at 0 °C, MeMgBr (3 M, 692.4 mL, 2077.2 mmol) in THF was added dropwise to a solution of methyl 2-((1r,4r)-4-(4-(tert-butyloxycarbonyl)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). The resulting mixture was stirred overnight at 0 °C. The mixture was slowly quenched with saturated NH4Cl solution (1500 mL) and acidified to pH 5 with HCl (1 mol / L). The mixture was then extracted with EtOAc (3 × 1000 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to yield the product (100 g, 86.9%). [M+H] + =554.2

[1114] Step 7: tert-butyl-4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexane Piperazine-1-carboxylate

[1115]

[1116] At room temperature, a solution of NaOH (2N, 903 mL, 1806.2 mmol) was added to a solution of tert-butyl 4-((1r,4r)-4-(6-(2-hydroxypropyl-2-yl)-5-(2,2,2-trifluoroacetamido)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (100 g, 180.62 mmol) in MeOH (1000 mL). The mixture was stirred at 70 °C for 2 h. The mixture was cooled to room temperature and the solid precipitated. The mixture was filtered and the filter cake was washed with water. The filter cake was then collected and dried under reduced pressure to give the product (75 g, 90.7%). [M+H] + =458.2

[1117] Step 8: tert-butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6- (2-hydroxypropyl-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

[1118]

[1119] HATU (74.73 g, 196.67 mmol) and DIEA (42.28 g, 327.78 mmol) were added to a stirred solution of 3-cyanopyrrolo[1,2-b]pyridazine-7-carboxylic acid (36.81 g, 196.67 mmol) and tert-butyl-4-((1r,4r)-4-(5-amino-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (75 g, 163.89 mmol) in DMF (1000 mL). The mixture was stirred at room temperature for 5 hours. The mixture was diluted with water (3000 mL). The solid was collected by filtration and diluted with water (3... x Wash with 100 mL of water. Dry the solid under vacuum to yield the product (90 g, 87.62%). [M+H] + =627.5

[1120] Step 9: 3-Cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H- Indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1121]

[1122] At 0 °C, concentrated HCl (36%, 300 mL) was added dropwise to a stirred solution of tert-butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazin-7-carboxamido)-6-(2-hydroxypropyl-2-yl)-2H-indazole-2-yl)cyclohexyl)piperazine-1-carboxylate (90 g, 143.77 mmol) in MeOH (600 mL). The resulting mixture was stirred overnight at room temperature. The solid was collected by filtration. The solid was dissolved in water (500 mL), then adjusted to pH 8 with saturated NaHCO3 solution, and the solution was diluted with DCM / MeOH (V / V = 10 / 1, 5).x Extracted with 2000 mL of the extract. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was slurried with petroleum ether (1000 mL) and filtered. The solids were filtered and dried under vacuum to yield the product (70 g, 92.45%). [M+H] + =527.4

[1123] Step 10: 3-Cyano-N-(2-((1R,4r)-4-(4-(4-((R)-2,6-dioxadiazin-3-yl)-3,5-difluoro Phenethyl)piperazine-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7- formamide

[1124]

[1125] Add AcOH (0.542 g, 9.30 mmol) and NaBH(OAc)3 (2.96 g, 13.95 mmol) to a stirred solution of 3-cyano-N-(6-(2-hydroxypropyl-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (4.9 g, 9.30 mmol) and (R)-2-(4-(2,6-dioxadiazin-3-yl)-3,5-difluorophenyl)acetaldehyde (3.23 g, 12.09 mmol) (CAS: 2758533-79-6, which was obtained by the same method described in WO 2022012622A1) in a DCE (100 mL). Stir the mixture overnight at room temperature. The mixture was diluted with MeOH (30 mL) and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give an impure product. The impure product was then 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

[1126] Example 193: 3-Cyano-N-(2-((1R,4r)-4-(4-((4-(((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)glycyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1127]

[1128] The title compound (18 mg, 28.9%) was prepared in a manner similar to that described in Example 178. 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,1H),4.48-4.38(m,1H),4.0 3-3.97(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.

[1129] Example 194: 3-Cyano-N-(2-((1R,4r)-4-(4-(2-((4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)amino)ethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1130]

[1131] The title compound (52 mg, 57.9%) was prepared in a manner similar to that described in Example 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),8.33(s,1H),7.72(d,J=4.5Hz,1H),7.57(s,1H),7.0 9(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.

[1132] Example 195: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-(2,6-dioxadiazin-3-yl)phenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1133]

[1134] The title compound was prepared in a manner similar to that described in Example 9.

[1135] [M+H] + =797.5.

[1136] Example 196: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiridine-3-yl)-3,5-difluorophenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropyl-2-yl)-2H-indazole-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[1137]

[1138] The title compound (6 mg, 9.4%) was prepared in a manner similar to that described in Example 9. 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.

[1139] Example 128: (S)-N-(2-(1'-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-[1,4'-piperidin]-4-yl)-7-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)pyridinecarboxamide

[1140] Step 1: Methyl 2-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-6-nitroimidazo[1,2-a]pyridine-7-carboxylic acid ester

[1141]

[1142] A mixture of methyl 2-amino-5-nitroisonicotinic acid ester (3.5 g, 17.77 mmol), tert-butyl-4-(2-bromoacetyl)piperidine-1-carboxylate ester (10.8 g, 35.54 mmol), and MgO (1.42 g, 35.54 mmol) in tetrahydrofuran (120 mL) was stirred at 100 °C for 16 h in a sealed tube. The mixture was evaporated under vacuum to give a crude product, which was further purif...

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is 13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is 18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is 20. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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