Degradation of IRAK4 by the binding of an E3 ligase ligand and an IRAK4 inhibitor and methods of use thereof

Abstract

Disclosed herein are novel bifunctional compounds formed by linking an IRAK4 inhibitor moiety and an E3 ligase ligand moiety, compounds that function to recruit and degrade a target protein to an E3 ubiquitin ligase, as well as methods for their preparation and use.

Description

Technical Field

[0001] Disclosed herein are novel bifunctional compounds formed by linking an IRAK4 inhibitor moiety and an E3 ligase ligand moiety, compounds that function to recruit and degrade a target protein to an E3 ubiquitin ligase, as well as methods for preparing and using the same.

Background Art

[0002] Proteolysis-targeting chimeric molecules (PROTACs) are composed of two covalently linked protein-binding molecules, one of which can bind to an E3 ubiquitin ligase and the other to a target protein of interest (POI) to be degraded (Sakamoto KM et al., Proc. Natl. Acad. Sci. 2001, 98:8554-9 and Sakamoto K.M. et al., Methods Enzymol. 2005; 399:833-847). Instead of inhibiting the enzymatic activity of the target protein, recruitment of the E3 ligase to a specific unwanted protein results in ubiquitination and subsequent degradation of the target protein by the proteasome. The entire process of ubiquitination and proteasomal degradation is known as the ubiquitin-proteasome pathway (UPP) (Ardley H. et al., Essays Biochem. 2005, 41, 15-30, Komander D. et al., Biochem. 2012, 81, 203-229, Grice G.L. et al., Cell Rep. 2015, 12, 545-553, and Swatek K.N. et al., Cell Res. 2016, 26, 399-422; Lydia M. et al., ACS Infect. Dis. 2019, 5, 12, 2105-2117). The proteasome is a protein complex that degrades unwanted, misfolded, or abnormal proteins into small peptides and amino acids to maintain cell health and productivity. The ubiquitin ligase, also called the E3 ubiquitin ligase, directly catalyzes the transfer of ubiquitin from E2 to the target protein for degradation.The human genome is estimated to encode more than 600 types of E3 ligases, but only the following limited number of E3 ubiquitin ligases have been widely applied to small molecule PROTAC technology: cereblon (CRBN), Von Hippel-Lindau (VHL), mouse double minute 2 homologue (MDM2), and cellular inhibitor of apoptosis protein (cIAP) (Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578), recombinant Human Ring Finger Protein 114 (RNF114) (Spradlin, J.N. et al. Nat. Chem. Biol. 2019, 15, 747-755), and DDB1 And CUL4 Associated Factor 16 (DCAF16) (Zhang, X. et al. Nat. Chem. Biol. 2019, 15, 737-746). For example, cereblon (CRBN) forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and cullin 4A (CUL4A), ubiquitinates several other proteins, and then degrades them via the proteasome. (Yi-An Chen, et al., Scientific Reports 2015, 5, 1-13). Immunomodulatory drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide bind to the cereblon (CRBN) subunit of the CRL4ACRBN E3 ligase complex and function as monovalent promoters of PPIs by recruiting neo-substrate proteins. (Matyskiela, M.E. et al., Nat Chem Biol 2018, 14, 981-987). As a result, the ability of thalidomide and its derivatives to recruit CRBN has been widely applied to studies related to target protein degradation-inducing chimeric molecules (PROTACs) (Christopher T. et al. ACS Chem. Biol. 2019, 14, 342-347; Honorine L. et al, ACS Cent. Sci. 2016, 2, 927-934).PROTACs have great potential to remove protein targets that are "undruggable" with conventional inhibitors or are non-enzymatic proteins. (Chu TT.et al., Cell Chem Biol. 2016;23:453-461, Qin C.et al., J Med Chem 2018;61:6685-6704, Winter GE.et al., Science 2015;348:1376-1381). In recent years, in anti-tumor research, PROTACs have been reported as useful regulators that promote the selective degradation of a wide range of target proteins.(Lu J.et al., Chem Biol. 2015; 22(6): 755-763, Ottis P.et al., Chem Biol. 2017; 12(4): 892-898, Crews C.M.et al., J Med Chem. 2018; 61(2): 403-404, Neklesa T.K.et al., Pharmacol Ther. 2017, 174: 138-144, Cermakova K.et al., Molecules, 2018. 23(8), An S.et al., EBioMedicine, 2018, Lebraud H.et al., Essays Biochem. 2017; 61(5): 517-527, Sun Y.H.et al., Cell Res. 2018; 28: 779-81, Toure M.et al., Angew Chem Int Ed Engl. 2016; 55(6): 1966-1973, Yonghui Sun et al., Leukemia, volume 33, pages 2105-2110(2019), Shaodong Liu et al., Medicinal Chemistry Research, volume 29, pages 802-808(2020)), and also disclosed or discussed, for example, in patent publications US20160045607, US20170008904, US20180050021, US20180072711, WO2002020740, WO2014108452, WO2016146985, WO2016149668, WO2016197032, WO2016197114, WO2017011590, WO2017030814, WO2017079267, WO2017182418, WO2017197036, WO2017197046, WO2017197051, WO2017197056, WO2017201449, and WO2018071606.

[0003] Interleukin-1 receptor-associated kinases (IRAK1, IRAK2, IRAK3, and IRAK4) are serine-threonine kinases that regulate innate immune responses and inflammatory responses. In addition to performing normal kinase functions, IRAK4 has a protein scaffold function and regulates downstream signaling through the myddosome protein complex. When TLR or IL-1R is activated, receptor dimerization is initiated, and the myeloid differentiation primary response 88 (MyD88) adapter protein is recruited through their intracellular domains. MyD88 further recruits IRAK4 and IRAK1 / 2 to form a multi-protein complex, namely, the myddosome.

[0004] The interaction between MyD88 and IRAK4 first recruits pre-formed IRAK-1. Next, IRAK4 phosphorylates and activates IRAK-1. Fully activated IRAK-1 recruits the TRAF6-TAK1-TAB-1 / 2 complex. Activated TAK-1 phosphorylates downstream signaling cascades including IκB kinase (IKK)-nuclear factor-κB (NF-κB) as well as MAPKs such as c-Jun N-terminal kinase (JNK) and p38, resulting in the production of pro-inflammatory cytokines (including IL-1β, IL-6, IL-8, IL-12, TNF). These signaling pathways play important roles in both innate and adaptive immune responses (Elizabeth L. et al., Eur. J. Immunol. 2008, 38, 3, 870-876).

[0005] The pro-inflammatory effect of IRAK4 has been demonstrated by studies in IRAK4 kinase-inactive knock-in mice (W. Michel S., et al., ACS Med. Chem. Lett. 2015, 6, 942-947). Mice with this genotype are resistant to arthritis in multiple rodent arthritis models (Koziczak-Holbro et al, 2009, Arthritis & rheumatism). IRAK4 deficiency improves disease activity in multiple RA animal models. Furthermore, a small human population with IRAK4 deficiency has been identified. A decrease in inflammatory cytokine expression from macrophages and a decrease in inflammation and migration of fibroblast-like synoviocytes were observed. The cells from these patients have a defective response to ILR / TLR receptor stimulation. No severe viral, fungal, or parasitic infections were observed in these adult patients (Gosu, V. et al., Sci Rep 4, 2014, 5748, Shichijo K. et al., Pediatrics International, 2015). The data in these rodents and humans suggest that IRAK4 inhibitors may be able to modulate the production of major inflammatory cytokines and cytokine-induced pathologies.

[0006] However, there are reports that pharmacological inhibition of IRAK4 decreased the phosphorylation level of IRAK4 in human dermal fibroblasts stimulated by IL-1β, but did not lead to inhibition of IL-6 and TNF-α, suggesting that kinase activity may not be the only factor in certain cell types (O’Neill, L.A. Immunol. Rev. 2008, 226, 10-8; Nunes J., et al. ACS Med. Chem. Lett. 2019, 10, 1081). Therefore, better therapeutic outcomes may be obtained by removing the scaffolding function of IRAK4 in addition to inhibiting kinase activity. In this regard, PROTAC targeting IRAK4 can function as a potential strategy to target both IRAK4 kinase activity and scaffolding function. IRAK4 PROTAC may ultimately lead to new therapeutic opportunities for treating autoimmune diseases, inflammatory diseases, and neoplastic diseases. IRAK4 PROTACs are disclosed or discussed in the patents of WO2019133531, US20190192668, WO2019099926, WO2020113233, WO2020264499, WO2021158634, WO2020264490, WO2021119159, WO2021168197, and WO2021127278.

[0007] Recently, several PROTACs targeting IRAK4 have been published (Nunes J., et al. ACS Med. Chem. Lett. 2019, 10, 1081; Zhang et al., Cell Chem. Bio. 2020, 27, 1; Robert B. K. et al. ACS Med. Chem. Lett. 2019, 10, 1251). Most of these molecules are based on the IRAK4 inhibitors published as warheads. However, there is little data showing that these IRAK4 PROTACs more potently inhibit cytokine production such as IL-6 and TNF-α than IRAK4 kinase inhibitors. In the present invention, it has been demonstrated that appropriately designed IRAK4 PROTACs more potently inhibit inflammatory cytokines than small molecule inhibitors in multiple cell lines.

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

Summary of the Invention

Means for Solving the Problems

[0009] In one embodiment, the present specification discloses a bifunctional compound of formula (I) that can selectively degrade IRAK4. The compounds or salts thereof described herein are useful for the treatment of diseases that can be affected by IRAK4 regulation. The present invention provides the use of the compounds or pharmaceutically acceptable salts thereof described herein in the manufacture of a medicament for the treatment of diseases that can be affected by IRAK4 regulation. The present invention further provides the compounds or pharmaceutically acceptable salts thereof described herein for use in the treatment of diseases that can be affected by IRAK4 regulation. The present specification further provides a method for treating a proliferative disease, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof described herein to a subject in need of treatment for the proliferative disease. Embodiments include the following aspects.

[0010] Aspect 1. A compound of formula (X), [Chemical] or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its deuterated analog, or its prodrug, wherein In the formula, L x is *Lx -CONH- **Lx or *Lx -NHCO- **Lx and *Lx refers to the position bonded to the Cy2 moiety, **Lx and refers to the position bonded to the Cy3 moiety; 1 Cy1 is a 6-membered partially or fully unsaturated ring; the ring is substituted with at least one substituent R Y 1 Y 2 and Y 3 are each independently C or N; s1 is 0, 1, 2, 3, 4, or 5; Cy2 is a 5-, 6-, 7-, 8-, 9-, or 10-membered partially or fully unsaturated ring (aromatic ring); the ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; the ring is substituted with at least one substituent R 2 and s2 is 0, 1, or 2; s4 is 0 or 1; Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; the ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; the ring is substituted with at least one substituent R 3 and s3 is 0, 1, 2, 3, 4, or 5; R 1 R 2 and R 3 are each independently hydrogen, halogen, -C1-C8 alkyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12Aryl, 5- to 12-membered heteroaryl, oxo(=O), -CN, -OR 1a , -C(O)R 1a , -CO2R 1a , -C(O)NR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , or -NR 1a CO2R 1b ; -C1-C8 alkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or each of 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R 1c ; or when adjacent, two Rs 1 , two Rs 2 , or two Rs 3 together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent R 1c ; R 1a and R 1b are each independently hydrogen, -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or 5- to 12-membered heteroaryl; -C1-C8 alkyl, -C1-C8 haloalkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-C 12 aryl, or each of 5- to 12-membered heteroaryl is halogen, -OH, -CN, oxo(=O), -C1-C8 alkyl, -C1-C8 alkyl-OH, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12Optionally substituted with at least one substituent selected from aryl or 5- to 12-membered heteroaryl; R 1c is, independently for each occurrence, halogen, -OH, -CN, oxo (=O), -C1-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5- to 12-membered heteroaryl; R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d are each independently absent, oxo, hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -C 3-8 cycloalkyl; each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -C 3-8 cycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -CN; or R 11a and R 12a together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -CN; and / or R 11b and R 12b together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -CN; and / or R 11c and R 12c together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -CN; and / or R 11d and R 12d together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 1-8 alkoxy, or -CN; Each occurrence of L 1 is independently selected from -O-, -NR a -, -C(O)NR a -, -C(O)O-,

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[0011] Aspect 2. A compound of formula (I),

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[0012] Aspect 3. A compound of formula (I’),

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[0013] Aspect 4. The compound is selected from formula (IIa), (IIa’), (IIb), (IIb’), (IIc), (IIc’), (IId), (IId’), (IIe), and (IIe’),

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[0014] Embodiment 5. 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’), [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] In the formula, R 1 , R 2 , R 3 , R 11a , R 11b , R11c , 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, Degron are as defined in embodiment 1, the compound according to embodiment 1.

[0015] 4. The compound is selected from formula (IVa), (Iva'), (IVb), (IVb'), (IVc), and (IVc'),

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[0016] 5. The compound is selected from formula (Va) or (Va'),

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[0017] Embodiment 6. The compound is selected from formula (VIa) or (Via’),

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[0018] Embodiment 7.Y 1 , Y 2 , and Y 3 at least one of which is N; preferably, Y 1 is N, Y 2 and Y 3 are C; or Y 2 is N, Y 1 and Y 3 are C; or Y 3 is N, Y 1 and Y 2 are C, the compound according to any one of the preceding embodiments.

[0019] Embodiment 8. Cy1 is pyridinyl or pyridinonyl, the compound according to any one of the preceding embodiments.

[0020] Embodiment 9.

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[0021] Embodiment 10.

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[0022] Aspect 11. Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring is substituted with at least one substituent R 3 and In one embodiment, Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring, each of the 5- and 6-membered aromatic rings is a monocyclic ring, each of the 8-, 9-, or 10-membered aromatic rings is a bicyclic ring, and the 7-membered aromatic ring is a monocyclic or bicyclic ring. Preferably, Cy3 is a 5- or 9-membered aromatic ring; said ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen; said ring is substituted with at least one substituent R 3 and Even more preferably

Chem.

[0023] Aspect 12.R 1 , R 2 , and R 3 are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, 5- to 12-membered heteroaryl, oxo(=O), -CN, -OR 1a , -C(O)R 1a , -CO2R 1a , -C(O)NR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , or -NR 1a CO2R 1band; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R 1c and is optionally substituted with R 1a and R 1b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C1-C8 haloalkyl (preferably, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3), -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C1-C8 haloalkyl (preferably, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3), -C2-C8 alkenyl, -C2-C8 alkynyl, C1-C8 alkoxy-C1-C8 alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH2OH, -C2H4OH, -C3H6OH, -C4H8OH, -C5H 10 OH, -C6H 12 OH, -C7H 14 OH, -C8H 16 OH, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; and is optionally substituted with at least one substituent selected from R 1c is, for each occurrence, independently, -F, -Cl, -Br, -I, -OH, -CN, oxo(=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, a compound according to any one of the preceding aspects.

[0024] Aspect 13. R 1 , R 2 , and R 3 are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, oxo(=O), -CN, -OR 1a or -C(O)NR 1a R 1b , -NR 1a R 1b ; and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3- to 8-membered heterocyclyl is optionally substituted with at least one substituent R 1c ; R 1a and R 1b are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH2OH, -C2H4OH, -C3H6OH, -C4H8OH, -C5H 10 OH, -C6H 12 OH, -C7H14 OH, -C8H 16 Each of OH, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, -OH, -CN, oxo(=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; R 1c is, independently for each occurrence, -F, -Cl, -Br, -I, -OH; Preferably, R 1 , R 2 and R 3 are each independently H, -F, -Cl, -Br, -I, -CH3, -CH2CH3, -CF3, -CF2CH3, -CH2CF3, -CH(CH3)2, -C(CH3)3, -NHCH3, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH3)2, -CHF2, oxo(=O), -CN, cyclopropyl, -CONH2, -OMe, -OEt, -OCH2CH2CH3, -OCH(CH3)2,

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[0025] Aspect 14. Two Rs 3 together with the atom to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent R 1c ; R 1c is, each occurrence independently, -F, -Cl, -Br, -I, -OH, -CN, oxo(=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, two Rs 3 together with the atom to which they are attached form a 3-, 4-, 5-, or 6-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from oxygen; said ring is optionally substituted with at least one substituent R 1c ; R 1c is, each occurrence independently, -F, -Cl, -Br, -I, -OH, -CN, oxo(=O), methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl, the compound according to any one of the preceding aspects.

[0026] Aspect 15. R 11a , R11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12d is, independently of one another, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; and each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, or -CN; or (R 11a and R 12a ), (R 11b and R 12b ), (R 11c and R 12c ), or (R 11d and R 12d ) together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8A compound according to any one of the preceding aspects, optionally substituted with at least one substituent selected from alkynyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, or -CN.

[0027] Aspect 16.

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[0028] Aspect 17.

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[0029] Aspect 18.R 11a , R 11b , R 11c , R 11d , R 12a , R 12b , R 12c , and R 12dis, independently of one another, 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 is, independently of one another, 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 is, independently of one another, hydrogen or methyl; or (R 11a and R 12a ), (R 11b and R 12b ), (R 11c and R 12c ), or (R 11d and R 12d ) together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; preferably, (R 11a and R 12a ), (R 11b and R 12b ), (R 11c and R 12c ), or (R 11d and R 12d ) together with the carbon atom to which they are attached form a 3-, 4-, or 5-membered cycloalkyl ring, a compound according to any one of the preceding aspects.

[0030] Aspect 19.L 1 is -O-, -N(Ra )-, [Chem.] selected from; said [Chem.] each of which is optionally substituted with at least one R L1c ; each of said R L1c is independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; and each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is optionally substituted with at least one R Lca ; R Lca is independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or two R L1ctogether with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent of F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; R a is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted with at least one substituent of halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, a compound according to any one of the preceding aspects.

[0031] Aspect 20.L 1 is -O-, -N(CH3)-,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0032] Aspect 21.L 2 is -O-, -N(R a ), [Chemical formula] selected from; said [Chemical formula] each of which is optionally substituted with at least one R L2c ; each of said R L2c is independently oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is optionally substituted with at least one R Lca ; R Lcais, independently, oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or Two Rs L2c together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent of F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; R a is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted with at least one substituent of halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, a compound according to any one of the preceding aspects.

[0033] Aspect 22.L2 is -O-, -N(CH3)-,

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[0034] Aspect 23.

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[0035] Aspect 24.L 3 is -O-, -N(Ra )-, [Chemical formula] is selected from; said [Chemical formula] each of which is optionally substituted with at least one R L3c ; each of said R L3c is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is optionally substituted with at least one R Lca ; R Lca is independently oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or two R'sL3c together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; R a is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, a compound according to any one of the preceding aspects.

[0036] Aspect 25.L 3 is -O-, -N(CH3)-, -NH-,

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Chemical formula

Chemical formula

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[0037] Aspect 26.

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[0038] Aspect 27.L 4 is, independently, a single bond, -O-, -NR a -, -(CR a R b ) n8 -, -O(CR a R b ) n8 -, -NR a (CR a R b ) n8 -, or -C(O)-; Each time it appears, R a and R bis independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, and each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl or a 5- to 12-membered heteroaryl, a compound according to any one of the preceding aspects.

[0039] Aspect 28.L 4 is independently selected from a single bond or -NH-, a compound according to any one of the preceding aspects.

[0040] Aspect 29.X 7 is independently -CR a or N; R ais independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, a compound according to any one of the preceding aspects.

[0041] Aspect 30.X 7 is independently selected from -CH, -C(CH3), or N; preferably, X 7 is independently selected from -CH, a compound according to any one of the preceding aspects.

[0042] Aspect 31.X 8 is independently -NR a -, -O-, -S-, and -CR a R b - is selected from; for each occurrence, R a and Rb is independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, the compound according to any one of the preceding aspects.

[0043] Aspect 32.X 8 is independently selected from -NH- and -CH2-; preferably, X 8 is independently selected from -CH2-, the compound according to any one of the preceding aspects.

[0044] Aspect 33.

Chemical formula

Chemical formula

[0045] Aspect 34.Z 1 , Z 2 , and Z 3 wherein at most one of them is N, a compound according to any one of the preceding aspects.

[0046] Aspect 35.Z 1 , Z 2 , and Z 3 are each independently CR z a compound according to any one of the preceding aspects.

[0047] Aspect 36.R Z is, each time it appears, independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR Za R Zb , -OR Za , -SR Za, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, or CN; each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or 3- to 8-membered heterocyclyl is optionally substituted with at least one R Zc ; R Za and R Zb are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Zd ; R Zc and R Zd are each independently -F, -Cl, -Br, -I, hydroxy, 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 heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, a compound according to any one of the preceding aspects.

[0048] Aspect 37. R zis a compound according to any one of the preceding aspects, selected from H, -CH3, -C2H5, F, -CH2F, -CHF2, -CF3, -OCH3, -OC2H5, -C3H7, -OCH2F, -OCHF2, -OCH2CF3, -OCF3, -SCF3, -CF3, or -CH(OH)CH3.

[0049] Aspect 38.R 13 and R 14 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3- to 8-membered heterocyclyl, -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 selected from; 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 heterocyclyl, -C6-C 12Each of aryl, 5- to 12-membered heteroaryl is optionally substituted 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 heterocyclyl, -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 ; and is optionally substituted with R 13a , R 13b , R 13c , and R 13d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3- to 8-membered heterocyclyl, -C6-C 12 aryl, or 5- to 12-membered heteroaryl, a compound according to any one of the preceding aspects.

[0050] Aspect 39.R 13 and R 14is, independently of one another, a compound according to any one of the preceding aspects 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.

[0051] Aspect 40.

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Chemical formula

[0052] Aspect 41.L 5 and L 6 are, independently of one another, a single bond, -O-, -NR a -, -(CR a R b ) n8 -, -O(CR a R b ) n8 -, -NR a (CR a R b ) n8 -, or -C(O)-; X 8 is -CR a R b -; Each occurrence, R a and R bis, independently of each other, hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C2-C8 alkenyl, -C2-C8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, a compound according to any one of the preceding aspects.

[0053] Aspect 42.L 5 and L 6 is, independently of each other, a single bond,

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[0054] Aspect 43. R 13 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, cyclooctyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3- to 8-membered heterocyclyl, -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 selected from; 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 heterocyclyl, -C6-C 12Each of aryl and 5- to 12-membered heteroaryl is optionally substituted 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 heterocyclyl, -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 and is optionally substituted; each occurrence of R 13a , R 13b , R 13c , and R 13d 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 heterocyclyl, -C6-C 12 aryl, or 5- to 12-membered heteroaryl, a compound according to any one of the preceding aspects.

[0055] Aspect 44.R 13 is independently selected from hydrogen, F, Cl, Br, I, CN, -C1-C8 alkyl, or -C1-C8 alkoxy; preferably, R 13is independently selected from hydrogen, F, Cl, Br, I, CN, -Me, -Et, -C3H7, -C4H9, -OMe, -OEt, -OC3H7, or -OC4H9; The compound according to any one of the preceding aspects, wherein n7 is 0, 1, or 2.

[0056] Aspect 45.

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[0057] Aspect 46. The compound according to any one of the preceding aspects, wherein the compound is selected from the following:

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Chem.

Chem.

[0058] Aspect 47. A pharmaceutical composition comprising the compound according to any one of Aspects 1 to 45 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, together with a pharmaceutically acceptable excipient.

[0059] Aspect 48. A method for treating a disease that can be affected by IRAK4 regulation, the method comprising administering to a subject in need of treatment for a disease that can be affected by IRAK4 regulation an effective amount of the compound according to any one of Aspects 1 to 45, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof.

[0060] Aspect 49. The method according to Aspect 47, wherein the disease is selected from autoimmune diseases and inflammatory disorders, preferably systemic lupus, hidradenitis suppurativa, rheumatoid arthritis, arthritis, gout, multiple sclerosis, psoriasis, and cancer, preferably acute myeloid leukemia cancer, lymphoma, B-cell myelodysplasia.

[0061] Aspect 50. Use of the compound according to any one of Aspects 1 to 45, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in the preparation of a medicament for treating a disease that can be affected by IRAK4 regulation.

[0062] Aspect 51. The use according to Aspect 49, wherein the disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer.

[0063] The inventors of the present invention have surprisingly found that a linker-like moiety between the IRAK4 binder moiety and the E3 ligase ligand moiety

Chemical formula

[0064] In a preferred linker, m1, m2, m3, and m4 are each independently 0, 1, or 2; m5 and m7 are each independently 0 or 1; m6 is 0, 1, or 2; preferably, m1 and m2 are 0; m3 and m4 are each independently 0, 1, or 2; m5 and m7 are each independently 1; m6 is 1 or 2. More preferably,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0065] Even more preferably, [Chemical formula] the moiety is [Chemical formula] ; More preferably, [Chemical formula] The part is

Chem.

Chem.

DETAILED DESCRIPTION OF THE INVENTION

[0066] The following terms have the meanings set forth throughout this specification.

[0067] As used herein, including the appended aspects, singular terms such as "a," "an," and "the" include references to their corresponding plurals unless the context clearly dictates otherwise.

[0068] The term "or" means "and / or" and is used interchangeably unless the context clearly indicates otherwise.

[0069] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched-chain saturated hydrocarbon groups containing 1 to 18 carbon atoms, such as 1 to 12 carbon atoms, more specifically 1 to 10 carbon atoms, even more specifically 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Alkyl containing 1 to 6 carbon atoms (i.e., C 1-6Examples of the (alkyl) group include 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 s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-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, but are not limited thereto.

[0070] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups including monocyclic groups and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spirocycloalkyl. In one embodiment, the aforementioned "cycloalkyl" is any one of "-C3-C8 cycloalkyl", "-C3-C 12 cycloalkyl", "cyclopropyl", "cyclobutyl", "cyclopentyl", "cyclohexyl", "cycloheptyl" or "cyclooctyl" as described herein or in the claims.

[0071] The term "aryl", used alone or in combination with other terms, refers to a group selected from: 5- and 6-membered carbocyclic aromatic rings, e.g., phenyl; bicyclic ring systems such as 7- to 12-membered bicyclic ring systems in which at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl; and tricyclic ring systems such as 10- to 15-membered tricyclic ring systems in which at least one ring is carbocyclic and aromatic, e.g., fluorenyl.

[0072] In one embodiment, the aforementioned "aryl" is any one of "C6-C 12 aryl" described in this specification or the claims.

[0073] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure of this specification. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalen-1-yl, naphthalen-2-yl, anthracenyl, phenanthrenyl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalen-1-yl or naphthalen-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0074] The term "aryl-alkyl-" refers to an alkyl group as defined above, which is further substituted with an aryl group. Examples of aryl-alkyl groups include aryl-C 1-8 alkyl such as phenylethyl or phenylmethyl (benzyl).

[0075] The term "heteroaryl" refers to a group selected from: a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1 to 4, or in some embodiments 1 to 3, or in some embodiments 1 to 2 heteroatoms, with the remaining ring atoms being carbon, a 7- to 12-membered bicyclic ring containing at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, with the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being present in the aromatic ring, and An 11- to 14-membered tricyclic ring containing at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments, 1 to 3, or in other embodiments, 1 or 2 heteroatoms, with the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being present in an aromatic ring.

[0076] In one embodiment, the foregoing "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 herein or in the claims.

[0077] When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less. When the heteroaryl group contains two or more heteroatom ring members, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group may be oxidized to form N-oxides. As used herein, the term "C-bonded heteroaryl" means that the heteroaryl group is connected to the core molecule by a bond derived from a C atom of the heteroaryl ring. The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably throughout the disclosure of this specification. In some embodiments, the monocyclic or bicyclic aromatic heterocycle independently has 5, 6, 7, 8, 9, or 10 ring-forming members including 1, 2, 3, or 4 heteroatom ring members selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is independently a monocyclic or bicyclic ring including 1 or 2 heteroatom ring members selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is monocyclic and is a 5- to 6-membered heteroaryl ring independently having 1 or 2 heteroatom ring members selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is bicyclic and is an 8- to 10-membered heteroaryl ring independently having 1 or 2 heteroatom ring members selected from nitrogen, sulfur, and oxygen.

[0078] "Heterocyclyl", "heterocycle", or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro rings, i.e., including monocyclic, heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups. As used herein, the term "optionally oxidized sulfur" refers to S, SO, or SO2.

[0079] The compounds disclosed herein may contain asymmetric centers and, accordingly, may exist as enantiomers.

[0080] "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they may further exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. It is intended that all such possible stereoisomers are included as substantially pure isolated enantiomers, their racemic mixtures, and even mixtures of diastereomers. It is intended that all stereoisomers of the compounds and / or their pharmaceutically acceptable salts disclosed herein are included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. When the composition of the isomers is not specified, all possible isomers are always included.

[0081] As used herein, the term "substantially pure" means that the target stereoisomer contains 35% by weight or less, such as 30% by weight or less, more particularly such as 25% by weight or less, and even more particularly such as 20% by weight or less of any other stereoisomer(s). In some embodiments, the term "substantially pure" means that the target stereoisomer contains 10% by weight or less, such as 5% by weight or less, such as 1% by weight or less of any other stereoisomer(s).

[0082] When the compounds disclosed in this specification contain double bonds of olefins, unless otherwise specified, such double bonds are meant to include both E geometric isomers and Z geometric isomers.

[0083] When the compounds disclosed in this specification contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring may adopt the cis and trans forms. The cis form means that the arrangements of the two substituents at the carbon are both found on the upper side, while the trans form, on the contrary, means that the arrangements of the two substituents are on the opposite sides respectively.

[0084] It may be advantageous to separate the reaction products from each other and / or from the starting materials.

[0085] The desired product of each step or series of steps may be separated and / or purified (hereinafter “separated”) to the desired degree of uniformity by techniques common in the art. Typically, such separation will involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include, for example, reverse and normal phase, size exclusion, ion exchange, high, medium, and low pressure liquid chromatography methods and apparatus, small scale analysis, simulated moving bed (“SMB”) and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques, and various other methods. One of ordinary skill in the art will apply the technique most likely to achieve the desired separation. “Diastereomers” refers to stereoisomers of a compound having two or more chiral centers that are not mirror images of each other. A mixture of diastereomers can be separated into the individual diastereomers based on their physicochemical differences by methods well known to those of ordinary skill in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride) to convert the enantiomeric mixture to a diastereomeric mixture, separating the diastereomers, and converting the individual diastereoisomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by use of a chiral HPLC column. “Pharmaceutically acceptable salts” refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately, by reacting the free base functional group with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0086] In addition, when the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, the free base can be dissolved in a suitable organic solvent and / or water and the solution treated with an acid to yield an addition salt (such as a pharmaceutically acceptable addition salt) according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize the various synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0087] As defined herein, "its pharmaceutically acceptable salts" include salts of at least one compound of formula (I), and salts of stereoisomers of the compounds of formula (I), e.g., salts of enantiomers, and / or salts of diastereomers.

[0088] As used herein, the terms "administer", "administering", "treat" and "treatment", when applied to an animal, human, subject, cell, tissue, organ, or body fluid, mean contacting an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or body fluid. Treatment of cells includes contacting the cells with a reagent, as well as contacting a reagent with a fluid when the fluid is in contact with the cells. The terms "administer" and "treatment" also mean treatment of cells by a reagent, diagnostic, binding compound, or another cell, e.g., in vitro and ex vivo. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0089] The terms "effective amount" or "therapeutically effective amount" refer to an amount of an active ingredient (such as a compound) sufficient to have an impact on the treatment of such a disease, disorder, or symptom when administered to a subject for treating at least one of a disease, or clinical symptoms of a disease or disorder. The "therapeutically effective amount" can vary depending on the compound, the disease, the disorder, and / or the symptoms of the disease or disorder, the severity of the disease, the disorder, and / or the symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case may be apparent to one of ordinary skill in the art or may be determined by routine experimentation. In some embodiments, the "therapeutically effective amount" is an amount of at least one compound and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, disclosed herein that is effective for the "treatment" of a disease or disorder in a subject as defined above. In the case of combination therapy, the "therapeutically effective amount" refers to the total amount of the combination being administered to effectively treat a disease, disorder, or medical condition.

[0090] The pharmaceutical composition comprising the compounds disclosed herein can be administered to a subject in need thereof by oral, inhalation, rectal, parenteral or topical administration. With respect to oral administration, the pharmaceutical composition can be a conventional solid preparation such as tablets, powders, granules, capsules and the like, a liquid preparation such as an aqueous or oily suspension, or other liquid preparations such as syrups, solutions, suspensions or the like. With respect to parenteral administration, the pharmaceutical composition can be a solution, an aqueous solution, an oily suspension concentrate, a lyophilized powder or the like. Preferably, the dosage form of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal drops or injections, more preferably tablets or capsules. The pharmaceutical composition can be administered in single units of precise dosages. In addition, the pharmaceutical composition can further contain additional active ingredients.

[0091] All formulations of the pharmaceutical compositions disclosed herein can be manufactured by conventional methods in the pharmaceutical art. For example, the active ingredient can be mixed with one or more excipients to produce the desired formulation. The term "pharmaceutically acceptable excipient" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles such as water and various organic solvents, fillers such as starch and sucrose, cellulose derivatives, alginates, gelatin, and binders such as polyvinylpyrrolidone (PVP); wetting agents such as glycerol; disintegrants such as agar, calcium carbonate, and sodium bicarbonate; absorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorption carriers such as kaolin and soap clay; lubricants such as talc, calcium stearate, magnesium stearate, and polyethylene glycol. In addition, the pharmaceutical composition further comprises other pharmaceutically acceptable excipients such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners, and dyes.

[0092] The term "disease" refers to any disease, discomfort, illness, symptom or sign and is interchangeable with the terms "disorder" or "condition".

[0093] Throughout this specification and the entire aspects in accordance therewith, unless the context requires otherwise, the term "comprise", and variations such as "comprises" and "comprising", are intended to specify the presence of the subsequent features, but not to exclude the presence or addition of one or more other features. As used herein, the term "comprising" may be replaced by the terms "containing", "including", or in some cases "having".

[0094] Throughout this specification and the entire aspects in accordance therewith, the term "C n-m " refers to a range including the endpoints, where n and m are integers and indicate the number of carbon atoms. As an example, C 1-8 、C 1-6and the like.

[0095] Unless otherwise defined in other parts of this specification, all other technical and scientific terms used in this specification have the meanings commonly understood by those skilled in the technical field to which the present invention pertains. [Table 1-1] [Table 1-2] [Examples]

[0096] The following examples are merely intended to illustrate and should not be construed as limiting in any way. Although efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), some experimental errors and deviations should be accounted for. Unless otherwise indicated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, Pharmablock, Bidepharm, or TCI and used without further purification unless otherwise indicated. Unless otherwise indicated, the reactions described below were carried out under a positive pressure of nitrogen or argon or in an anhydrous solvent using a drying tube, and the reaction flask was equipped with a rubber septum for the introduction of substrates and reagents via a syringe. Glassware was oven-dried and / or heat-dried.

[0097] 1 The 1H NMR spectra were recorded on an Agilent instrument operating at 400 MHz or 500 MHz. 11H 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 solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05) as reference standards. When peak multiplicities are reported, the abbreviations s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets) are used. When coupling constants are given, they are reported in Hertz (Hz).

[0098] LCMS-1: LC-MS spectrometer (Agilent 1260 Infinity), detector: MWD (190 - 400 nm), mass detector: 6120 SQ, mobile phase: A: 0.1% aqueous formic acid solution, B: 0.1% formic acid acetonitrile solution, column: Poroshell 120 EC-C18, 4.6×50 mm, 2.7 pm Gradient method: Flow rate: 1.8 mL / min Time (min) A (%) B (%)

Table 2

[0099] LCMS, LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II), detector: MWD (190 - 400 nm), mass detector: G6125C SQ, mobile phase: A: 0.1% aqueous formic acid solution, B: 0.1% formic acid acetonitrile solution, column: Poroshell 120 EC-C18, 4.6×50 mm, 2.7 pm Gradient method: Flow rate: 1.8 mL / min Time (min) A (%) B (%)

Table 3

[0100] LCMS-2: LC-MS spectrometer (Agilent 1290 Infinity II), detector: MWD (190 - 400 nm), mass detector: G6125C SQ, mobile phase: A: 0.1% aqueous formic acid solution, B: 0.1% formic acid acetonitrile solution, column: Poroshell 120 EC-C18, 4.6×50 mm, 2.7 µm Gradient method: flow rate: 1.2 mL / min Time (min) A (%) B (%)

Table 4

[0101] Preparative HPLC was performed using a column (150×21.2 mm ID, 5 µm, Gemini NXC18) at a flow rate of 20 ml / min, an injection volume of 2 ml, at room temperature, and UV detection was carried out at 214 nm and 254 nm.

[0102] Common intermediate A: 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbaldehyde

[0103] Step 1: 4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl trifluoromethanesulfonate

Chemical formula

[0104] Step 2: 1-(4-(3-(hydroxymethyl)azetidin-1-yl)phenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione

Chemical Structure

[0105] Step 3: 1-(4-(2,4-Dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbaldehyde

Chemical formula

[0106] Common intermediate B: 1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylic acid

[0107] Step 1: tert-Butyl 1-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylate

Chem.

[0108] Step 2: 1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carboxylic acid

Chem.

[0109] Common Intermediate C: tert-Butyl 4-((trans)-4-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate

[0110] Step 1: (cis)-4-(4-Benzylpiperazin-1-yl)cyclohexan-1-ol

Chemical Structure

[0111] Step 2: (cis)-4-(Piperazin-1-yl)cyclohexan-1-ol (Intermediate 3)

Chem.

[0112] Step 3: tert-Butyl (cis)-4-(4-Hydroxycyclohexyl)piperazine-1-carboxylate

Chem.

[0113] Step 4: (cis)-4-[4-(Methanesulfonyloxy)cyclohexyl]piperazine-1-carboxylic acid tert-butyl

Chem.

[0114] Step 5: 4-((trans)-4-(3-Carbamoyl-4-nitro-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl

Chem.

[0115] Step 6: tert-Butyl 4-((trans)-4-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate

Chemical Structure

[0116] Common intermediate D: tert-Butyl 4-((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate

[0117] Step 1: 1-Benzyl-1H-pyrazole-3-carbaldehyde [Chemical formula] To a DMF solution (500 mL) of 1H-pyrazole-3-carbaldehyde (50.0 g, 0.52 mol) and benzyl bromide (93.5 g, 0.546 mol), cesium carbonate (423.9 g, 1.30 mol) was added. After stirring at 25 °C for 1 hour, the mixture was added to water (2.0 L) and extracted with ethyl acetate (300 mL × 2). The combined organic layers were washed with brine (2.0 L), dried over Na2SO4, filtered, concentrated under reduced pressure to obtain a crude compound, which was purified by silica gel column chromatography (PE:EtOAc = 20:1) to obtain the product (65 g, 64%). 1 H NMR (300 MHz, CDCl3) δ 10.00 (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.

[0118] Step 2: 1-Benzyl-3-(difluoromethyl)-1H-pyrazole [Chemical formula] To a solution of 1-benzyl-1H-pyrazole-3-carbaldehyde (65 g, 0.335 mol) in dichloromethane (500 mL) was added diethylaminosulfur trifluoride (216.1 g, 1.34 mol) at 0 °C. After stirring at 20 °C for 16 h, ice water (1.0 L) was added to the mixture, and the mixture was extracted with dichloromethane (300 mL × 2). The combined organic layers were washed with brine (1.0 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude compound, which was purified by silica gel column chromatography (PE:EtOAc = 40:1) to give the product (48.5 g, 70%). 1 H NMR (300 MHz, CDCl3) δ 7.38 - 7.34 (m, 4H), 7.26 - 7.21 (m, 2H), 6.89 - 6.50 (m, 2H), 5.32 (s, 2H). [M+H] + =209.1

[0119] Step 3: 3-(Difluoromethyl)-1H-pyrazole

Chemical formula

[0120] Step 4: 3-(Difluoromethyl)-4-nitro-1H-pyrazole

Chemical formula

[0121] Step 5: tert-Butyl 4-((trans)-4-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate

Chemical formula

[0122] Step 6: tert-Butyl 4-((trans)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate

Chemical formula

[0123] Common Intermediate E: (R)-3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione

[0124] Step 1: 2,6-bis(benzyloxy)-3-(4-(3-(benzyloxy)azetidin-1-yl)-2,6-difluorophenyl)pyridine

Chemical Structure

[0125] Step 2: 3-(2,6-Difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione

Chemical Structure

[0126] Step 3: (R)-3-(2,6-Difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione [Chemical formula] For crude 3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (76 g), chiral separation was carried out for purification under the following conditions (CHIRALPAK IF (10 cm × 25 cm, 10 um), MtBE (0.1% DEA):(MeOH:DCM = 1:1) = 50:50, 250 mL / min) to obtain (R)-3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (35.83 g, 47.14%, ee = 99.54%). [M+H] + = 297.27.

[0127] Step 4: (R)-3-(2,6-Difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione [Chemical formula] To a solution of (R)-3-(2,6-difluoro-4-(3-hydroxyazetidin-1-yl)phenyl)piperidine-2,6-dione (106 g, 357.78 mmol) in DCM (2 L), Dess-Martin reagent (455.24 g, 1073.34 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 0 °C for 3 hours. Then, the reaction was diluted with DCM (3 L) and filtered. The filter cake was washed with DCM (300 mL) and collected. The filtrate was washed with saturated aqueous sodium bicarbonate solution (2 L × 2) and brine (2 L × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The solution was concentrated in vacuo. The residue was combined with the collected filter cake and dried under reduced pressure to obtain (R)-3-(2,6-difluoro-4-(3-oxoazetidin-1-yl)phenyl)piperidine-2,6-dione (91 g, 86.43%). [M+H] + = 295.27.

[0128] Example 1: N-(3-(Difluoromethyl)-1-((1R,4r)-4-((4-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0129] Step 1: tert-Butyl (4-bromopyridin-2-yl)(2,2,2-trifluoroethyl)carbamate

Chem.

[0130] Step 2: Ethyl 2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylate

Chem.

[0131] Step 3: 2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid

Chemical formula

[0132] Step 4: 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

Chemical formula

[0133] Step 5: tert-Butyl (4-(4-((3-(difluoromethyl)-1-((1r,4r)-4-formylcyclohexyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate

Chemical Structure

[0134] Step 6: tert-Butyl 4-(((1r,4r)-4-(4-(2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)methyl)piperazine-1-carboxylate

Chem.

[0135] Step 7: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(piperazin-1-ylmethyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0136] Step 8: N-(3-(Difluoromethyl)-1-((1R,4R)-4-((4-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chemical formula

[0137] Example 2: N-(3-(Difluoromethyl)-1-((1r,4r)-4-((4-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chemical Structure

[0138] Example 3: N-(3-(Difluoromethyl)-1-((1r,4r)-4-((4-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide [Chemical Structure] The title compound (5.0 mg, yield 32.1%) was prepared by a method similar to the method described in Example 1. 11H NMR (500 MHz, DMSO) δ 10.25 (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 = 10.0 Hz, 2H), 4.26 - 4.21 (m, 3H), 3.90 (t, J = 5.0 Hz, 2H), 3.67 (t, J = 5.0 Hz, 2H), 3.57 (t, J = 5.0 Hz, 2H), 3.25 - 3.22 (m, 2H), 2.67 (t, J = 5.0 Hz, 2H), 2.43 - 2.25 (m, 7H), 2.12 (d, J = 10.0 Hz, 2H), 2.04 (d, J = 10.0 Hz, 2H), 1.90 (d, J = 10.0 Hz, 2H), 1.77 - 1.74 (m, 2H), 1.65 - 1.55 (m, 1H), 1.05 - 1.03 (m, 2H). [M + H] + = 826.6。

[0139] Example 4: N-(3-(Difluoromethyl)-1-((1r,4r)-4-((4-(1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0140] Example 5: N-(2-((1r,4r)-4-((4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

Chemical Structure

[0141] Example 6: N-(2-((1R,4r)-4-((4-((1r,4R)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0142] Step 1: tert-Butyl 4-((1s,4s)-4-hydroxycyclohexane-1-carbonyl)piperazine-1-carboxylate

Chemical Structure

[0143] Step 2: tert-Butyl 4-(((1s,4s)-4-hydroxycyclohexyl)methyl)piperazine-1-carboxylate

Chemical formula

[0144] Step 3: tert-Butyl 4-(((1s,4s)-4-((methylsulfonyl)oxy)cyclohexyl)methyl)piperazine-1-carboxylate

Chemical Structure

[0145] Step 4: tert-Butyl 4-(((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)methyl)piperazine-1-carboxylate

Chemical Structure

[0146] Step 5: N-(6-methoxy-2-((1r,4r)-4-(piperazin-1-ylmethyl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide, TFA salt

Chemical Structure

[0147] Step 6: N-(2-((1R,4r)-4-((4-((1r,4R)-4-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)phenoxy)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

Chemical Structure

[0148] Step 7: N-(2-((1R,4r)-4-((4-((1r,4R)-4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

Chemical formula

[0149] Example 7: N-(2-((1r,4r)-4-((4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidine-4-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide [Chemical formula] The title compound was prepared by the same method as described in Example 6. 1 H NMR (500 MHz, DMSO) δ 10.50 (s, 1H), 10.25 (s, 1H), 8.69 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.41 (t, J = 7.7 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.17 - 7.10 (m, 3H), 6.93 (d, J = 8.8 Hz, 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.

[0150] Example 12: N-(3-carbamoyl-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazine-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0151] Step 1: tert-Butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide)-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate [Chemical formula] To a DMF solution (5 mL) of tert-butyl 4-((trans)-4-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (1.0 g, 2.54 mmol), 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid (1.2 g, 3.048 mmol), DIEA (518 mg, 5.08 mmol) and HATU (1.45 g, 5.08 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was purified by CombiFlash eluting with DCM:MeOH = 1~0 to 1:10 to give the product (1.8 g, 93%). [M+H] + = 761.8。

[0152] Step 2: N-(3-carbamoyl-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0153] Step 3: N-(3-carbamoyl-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chemical Structure

[0154] Example 13: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0155] Step 1: tert-Butyl 4-((1r,4r)-4-(4-(2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate

Chemical Structure

[0156] Step 2: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide [Chemical formula] To a DCM solution (10 mL) of tert-butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate (1.8 g, 2.34 mmol), TFA (5 mL) was added. The mixture was stirred at room temperature overnight. The solvent was removed under vacuum. The residue was basified to pH 10 with Na2CO3 (aqueous solution) and extracted with DCM (50 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product (1.2 g, 90%).

[0157] Step 3: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0158] Example 14: N-(3-(Difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0159] Example 15: N-(3-(Difluoromethyl)-1-((1S,4r)-4-(4-((S)-1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chemical Structure

[0160] Example 16: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chemical Structure

[0161] Example 17: N-(3-(Difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chemical Structure

[0162] Example 18: N-(3-(Difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)-4,4-dimethylpyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0163] Example 19: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-((1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0164] Example 20: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-((1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chemical Structure

[0165] Example 21: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidin-3-yl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide [Chemical Structure Diagram] The title compound was prepared by a method similar to the method described in Example 13. 11H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 9.71 (s, 1H), 8.95 (s, 1H), 8.24 (d, J = 5.0 Hz, 1H), 8.18 (s, 1H), 7.62 - 7.59 (m, 1H), 7.27 - 7.05 (m, 5H), 6.52 (d, J = 10.0 Hz, 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), 2.54 (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。

[0166] Example 175: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,6-Dioxopiperidin-3-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0167] Example 22: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1S,4R)-4-(4-((S)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Chemical Structure

[0168] Example 23: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Chemical Structure

[0169] Example 24: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Chem.

[0170] Example 25: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0171]

Chem.

[0172] Example 26: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Chemical Structure

[0173] Example 27: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-((1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Chemical Structure

[0174] Example 85: N-(3-(Difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-isopropylpyridin-4-yl)oxazole-4-carboxamide

Chem.

[0175] Example 86: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-isopropylpyridin-4-yl)oxazole-4-carboxamide

Chemical Structure

[0176] Example 170: 2-(2-(sec-Butyl)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide [Chemical Structure] The title compound was prepared by a method similar to the method described in Example 13. 11H NMR (500 MHz, DMSO) δ 10.84 (s, 1H), 9.85 (s, 1H), 8.99 (s, 1H), 8.75 (d, J = 5.0 Hz, 1H), 8.15 (s, 1H), 7.86 - 7.73 (m, 2H), 7.15 (t, J = 54.4 Hz, 1H), 6.22 (d, J = 12.2 Hz, 2H), 4.22 (brs, 1H), 4.02 (dd, J = 12.5, 4.8 Hz, 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 = 7.4 Hz, 3H). [M+H] + = 848.6

[0177] Example 28: N-(3-carbamoyl-1-(6-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chemical Structure

[0178] Example 8: N-(3-carbamoyl-1-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0179] Example 11: N-(3-carbamoyl-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0180] Step 1: Methyl 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylate

Chemical formula

[0181] Step 2: 1-(4-(2,6-bis(benzyloxy)pyridin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid

Chemical formula

[0182] Step 3: (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid

Chemical formula

[0183] Step 4: N-(3-carbamoyl-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0184] Example 9: N-(3-carbamoyl-1-((1r,4r)-4-(4-(3-(4-(((R)-2,6-dioxopiperidin-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chemical Structure

[0185] Example 10: N-(3-carbamoyl-1-((1r,4r)-4-(4-(3-(4-(((S)-2,6-dioxopiperidin-3-yl)amino)phenyl)cyclobutyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chemical Structure

[0186] Example 76: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0187] Example 100: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-2-oxopiperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

[0188] Step 1: tert-Butyl 4-((1r,4r)-4-(4-(2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)-3-oxopiperazine-1-carboxylate

Chem.

[0189] Step 2: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(2-oxopiperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Chem.

[0190] Step 3: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4R)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-2-oxopiperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Chemical Structure

[0191] Example 101: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-2-oxopiperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Chemical Structure

[0192] Example 166: N-(3-carbamoyl-1-(6-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

[0193] Step 1: (6-(4-(tert-Butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)boronic acid

Chemical formula

[0194] Step 2: tert-Butyl 4-(5-(3-(ethoxycarbonyl)-4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-carboxylate

Chemical formula

[0195] Step 3: tert-Butyl 4-(5-(3-carbamoyl-4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-carboxylate

Chemical formula

[0196] Step 4: tert-Butyl 4-(5-(4-amino-3-carbamoyl-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-carboxylate

Chemical formula

[0197] Step 5: tert-Butyl 4-(5-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-carbamoyl-1H-pyrazol-1-yl)pyridin-2-yl)piperazine-1-carboxylate

Chemical formula

[0198] Step 6: N-(3-carbamoyl-1-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide hydrochloride

Chemical formula

[0199] Step 7: N-(3-carbamoyl-1-(6-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

Chem.

[0200] Example 30: N-(3-Carbamoyl-1-(6-(4-((R)-1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Chemical formula

[0201] Example 31: N-(3-Carbamoyl-1-(6-(4-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Chemical formula

[0202] Example 51: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamide

[0203] Step 1: 2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxylic acid

Chem.

[0204] Step 2: tert-Butyl 4-((1r,4r)-4-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexyl)piperazine-1-carboxylate

Chemical Structure

[0205] Step 3: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamide

Chemical formula

[0206] Step 4: N-(3-(Difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamide

Chemical formula

[0207] Example 52: N-(3-(Difluoromethyl)-1-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-Trifluoroethyl)amino)pyridin-4-yl)-2H-1,2,3-triazole-4-carboxamide [Chemical Structure] The title compound was prepared by a method similar to the method described in Example 51. 1 H NMR (500 MHz, DMSO) δ 10.77 (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 = 10.0 Hz, 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.

[0208] Example 61: 2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(3-(difluoromethyl)-1-((1r,4r)-4-(4-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-1H-pyrazol-4-yl)-2H-1,2,3-triazole-4-carboxamide [Chemical Structure] The title compound was prepared by a method similar to the method described in Example 51. 11H NMR (500 MHz, DMSO) δ 10.50 (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 = 10.0 Hz, 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 = 5.0 Hz, 2H), 3.51 - 3.45 (m, 3H), 3.20 (t, J = 5.0 Hz, 2H), 2.68 (t, J = 5.0 Hz, 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。

[0209] 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-triazole-4-carboxamide

Chemical Structure

[0210] Example 130: N-Cyclopropyl-2-(trans)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamide)-2H-indazole-6-carboxamide

[0211] Step 1: (cis)-4-(4-Benzylpiperazin-1-yl)cyclohexan-1-ol

Chemical Structure

[0212] Step 2: (cis)-4-(Piperazin-1-yl)cyclohexan-1-ol

Chem.

[0213] Step 3: tert-Butyl 4-((cis)-4-hydroxycyclohexyl)piperazine-1-carboxylate

Chem.

[0214] Step 4: Methyl 2-((trans)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate

Chemical Structure

[0215] Step 5: Methyl 5-amino-2-((trans)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

Chem.

[0216] Step 6: Methyl 2-((trans)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolylamide)-2H-indazole-6-carboxylate

Chem.

[0217] Step 7: 2-((trans)-4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolylamide)-2H-indazole-6-carboxylic acid

Chemical Structure

[0218] Step 8: tert-Butyl 4-((trans)-4-(6-(cyclopropylcarbamoyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chem.

[0219] Step 9: N-Cyclopropyl-2-(trans)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide hydrochloride

Chem.

[0220] Step 10: N-Cyclopropyl-2-(trans)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxamide [Chemical formula] HATU (18 mg, 0.046 mmol) was added to a solution of (R)-1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carboxylic acid (14 mg, 0.042 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 10 min. Then, N-cyclopropyl-2-(trans)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolinamido)-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. The reaction was stirred at room temperature for 4 h. The solvent was removed under reduced pressure. The residue was washed with water (15 mL), extracted with dichloromethane (3×20 mL), and washed with brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (elution with a gradient of DCM:MeOH from 100:0 to 10:1) to give the product (5 mg, 14%). [M+H] + =862.6 1 1H NMR (500 MHz, DMSO) δ 12.39 (s, 1H), 10.86 (s, 1H), 8.88 (s, 1H), 8.79 (d, J = 4.3 Hz, 1H), 8.49 (s, 1H), 8.43 (d, J = 7.9 Hz, 1H), 8.37 (t, J = 7.8 Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H), 8.00 (s, 1H), 6.17 (d, J = 11.1 Hz, 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, 8.6 Hz, 1H), 0.75 - 0.70 (m, 2H), 0.65 - 0.58 (m, 2H).

[0221] Example 129: N - Cyclopropyl - 2 - ((1R,4r) - 4 - (4 - ((R) - 1 - (4 - ((R) - 2,6 - dioxopiperidin - 3 - yl) - 3,5 - difluorophenyl)pyrrolidine - 3 - carbonyl)piperazin - 1 - yl)cyclohexyl) - 5 - (6 - (trifluoromethyl)picolinamide) - 2H - indazole - 6 - carboxamide

Chemical formula

[0222] Example 168: 2 - ((1R,4R) - 4 - (4 - ((R) - 1 - (4 - ((R) - 2,6 - dioxopiperidin - 3 - yl) - 3,5 - difluorophenyl)pyrrolidine - 3 - carbonyl)piperazin - 1 - yl)cyclohexyl) - N - ((1r,3R) - 3 - (hydroxymethyl)cyclobutyl) - 5 - (6 - (trifluoromethyl)picolinamide) - 2H - indazole - 6 - carboxamide

[0223] Step 1: tert - butyl 4 - ((1R,4r) - 4 - (6 - ((((1r,3R) - 3 - (hydroxymethyl)cyclobutyl)carbamoyl) - 5 - (6 - (trifluoromethyl)picolinamide) - 2H - indazol - 2 - yl)cyclohexyl)piperazine - 1 - carboxylate

Chem.

[0224] Step 2: N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-2-((1r,4R)-4-(piperazin-1-yl)cyclohexyl)-5-(6-(trifluoromethyl)picolylamide)-2H-indazole-6-carboxamide hydrochloride

Chemical formula

[0225] Step 3: 2-((1R,4R)-4-(4-((R)-1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-N-((1r,3R)-3-(hydroxymethyl)cyclobutyl)-5-(6-(trifluoromethyl)picolylamide)-2H-indazole-6-carboxamide

Chem.

[0226] Example 167: 2 - ((1r,4R) - 4 - (4 - (1 - (4 - ((R) - 2,6 - dioxopiperidin - 3 - yl) - 3,5 - difluorophenyl)azetidine - 3 - carbonyl)piperazin - 1 - yl)cyclohexyl) - N - ((1r,3R) - 3 - (hydroxymethyl)cyclobutyl) - 5 - (6 - (trifluoromethyl)picolylamide) - 2H - indazole - 6 - carboxamide

Chemical formula

[0227] Example 35: N-(2-(1-((1r,4r)-4-(4-(2,6-Dioxopiperidin-3-yl)phenoxy)cyclohexane-1-carbonyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

Chemical formula

[0228] Example 36: N-(2-((1R,4r)-4-((4-((R)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)methyl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

Chemical Structure

[0229] Example 32: N-(2-((1r,4r)-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamido)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0230] Step 1: (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate

Chemical Structure

[0231] Step 2: tert-Butyl ((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)carbamate

Chemical formula

[0232] Step 3: N-(2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide hydrochloride

Chemical Structure

[0233] Step 4: N-(2-((1r,4r)-4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamido)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

Chem.

[0234] Example 41: (R)-N-(2-(1-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)azetidine-3-yl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0235] Step 1: N-(6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

Chemical formula

[0236] Step 2: tert-Butyl 4-(6-methoxy-5-(6-(trifluoromethyl)picolylamide)-2H-indazol-2-yl)piperidine-1-carboxylate

Chemical formula

[0237] Step 3: N-(6-Methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide hydrochloride

Chemical formula

[0238] Step 4: tert-Butyl 3-(4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)piperidin-1-yl)azetidine-1-carboxylate

Chemical formula

[0239] Step 5: N-(2-(1-(azetidin-3-yl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamine trifluoroacetate

Chemical formula

[0240] Step 6: (R)-N-(2-(1-(1-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)azetidine-3-yl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamine

Chemical formula

[0241] Example 42: N-(2-(1-(1-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)azetidin-3-yl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide [Chem.] The title compound was prepared in the same manner as the method described in Example 41. 1 H NMR (500 MHz, DMSO) δ 10.77 (s, 1H), 10.44 (s, 1H), 8.63 (s, 1H), 8.40 (d, J = 7.8 Hz, 1H), 8.37 - 8.30 (m, 2H), 8.15 (d, J = 7.7 Hz, 1H), 7.10 (s, 1H), 6.17 (dd, J = 12.0, 8.5 Hz, 2H), 4.43 - 4.33 (m, 1H), 4.27 - 4.17 (m, 1H), 4.09 - 4.00 (m, 1H), 3.99 - 3.90 (m, 4H), 3.86 (dt, J = 14.9, 4.2 Hz, 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.

[0242] Example 43: N-(2-(1'-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-[1,4'-bipiperidin]-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide [Chem.] The title compound was prepared in the same manner as the method described in Example 41. 11H NMR (500 MHz, DMSO) δ 10.84 (s, 1H), 10.52 (s, 1H), 8.72 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 8.40 (dd, J = 15.8, 7.9 Hz, 2H), 8.23 (d, J = 7.7 Hz, 1H), 7.16 (s, 1H), 6.23 (d, J = 12.8 Hz, 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), 2.85 - 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。

[0243] Example 44: N-(2-(1'-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)azetidine-3-carbonyl)-[1,4'-bipiperidin]-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

Chemical Structure

[0244] Example 45: (R)-N-(2-(1'-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-[1,4'-bipiperidin]-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

Chemical formula

[0245] Example 102: 1-Cyclopropyl-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0246] Step 1: Methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

Chemical Structure

[0247] Step 2: Methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

Chemical formula

[0248] Step 3: Methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate

Chemical formula

[0249] Step 4: Methyl 5-amino-2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

Chemical formula

[0250] Step 5: tert-Butyl 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chemical formula

[0251] Step 6: tert-Butyl 4-((1r,4r)-4-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chemical Structure

[0252] Step 7: 1-Cyclopropyl-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chem.

[0253] Step 8: 1-Cyclopropyl-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chem.

[0254] Example 103: 1-Cyclopropyl-N-(2-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide [Chemical formula] To a solution of 1-cyclopropyl-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (20.72 mg, 0.04 mmol) and (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (13.52 mg, 0.04 mmol) in DCM (5 mL) were added DIPEA (15.48 mg, 0.12 mmol) and T3P (50% in EtOAc, 50.78 mg, 0.08 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. 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 (0.1% FA aqueous solution: acetonitrile = 90:10 to 60:40 gradient elution)) to give the desired product (9.75 mg, 30.4%). [M+H] + = 839.4 11H NMR (500 MHz, DMSO) δ 12.05 (s, 1H), 10.85 (s, 1H), 9.65 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 8.31 (s, 1H), 8.18 (s, 1H), 7.93 (d, J = 5.0 Hz, 1H), 7.58 (s, 1H), 6.47 (t, J = 10.0 Hz, 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 = 10.0 Hz, 5.0 Hz, 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).

[0255] Example 117: (R)-1-Cyclopropyl-N-(2-(1'-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-[1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0256] Step 1: Methyl 2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidin]-4-yl)-5-(1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-2H-indazole-6-carboxylate

Chem.

[0257] Step 2: tert-Butyl 4-(5-(1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)-[1,4'-bipiperidine]-1'-carboxylate

Chemical formula

[0258] Step 3: N-(2-([1,4’-Bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide

Chem.

[0259] Step 4: (R)-1-Cyclopropyl-N-(2-(1’-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-[1,4’-bipiperidine]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

Chem.

[0260] Example 118: 1-Cyclopropyl-N-(2-(1’-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidin-3-carbonyl)-[1,4’-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide [Chemical formula] To a solution of N-(2-([1,4’-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-1-cyclopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (41 mg, 0.08 mmol) and (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (27 mg, 0.08 mmol) in DCM (5 mL) were added DIPEA (31 mg, 0.24 mmol) and T3P (50% in EtOAc, 102 mg, 0.16 mmol) at room temperature. The resulting mixture was stirred at room temperature 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 (0.1% aqueous FA: acetonitrile = 90:10 to 60:40 gradient elution)) to give the desired product (20.81 mg, 31%). [M+H] + = 839.4 11H NMR (500 MHz, DMSO) δ 12.04 (s, 1H), 10.84 (s, 1H), 8.38 (d, J = 5.0 Hz, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 7.92 (d, J = 5.0 Hz, 1H), 7.58 (s, 1H), 6.46 (t, J = 10.0 Hz, 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).

[0261] Example 160: (R)-N-(2-(1'-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-[1,4'-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0262] Step 1: tert-Butyl 4-(6-bromo-2H-indazol-2-yl)-[1,4'-bipiperidin]-1'-carboxylate

Chem.

[0263] Step 2: Methyl 2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidine]-4-yl)-2H-indazole-6-carboxylate

Chem.

[0264] Step 3: Methyl 2-([1,4'-bipiperidine]-4-yl)-5-nitro-2H-indazole-6-carboxylate

Chem.

[0265] Step 4: Methyl 2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidin]-4-yl)-5-nitro-2H-indazole-6-carboxylate

Chemical formula

[0266] Step 5: Methyl 5-amino-2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidin]-4-yl)-2H-indazole-6-carboxylate

Chemical formula

[0267] Step 6: Methyl 2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidin]-4-yl)-5-(6-(trifluoromethyl)picolylamide)-2H-indazole-6-carboxylate

Chemical formula

[0268] Step 7: tert-Butyl 4-(6-(2-hydroxypropan-2-yl)-5-(6-(trifluoromethyl)picolylamide)-2H-indazol-2-yl)-[1,4'-bipiperidin]-1'-carboxylate [Chem.] A solution of methyl 2-(1'-(tert-butoxycarbonyl)-[1,4'-bipiperidin]-4-yl)-5-(6-(trifluoromethyl)picolinamide)-2H-indazole-6-carboxylate (0.4 g, 0.635 mmol) and LiCl (0.135 g, 3.175 mmol) in THF (10 mL) was added dropwise with MeMgBr (1 M in THF, 6.4 mL, 6.4 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The mixture was quenched with saturated NH4Cl solution and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated 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

[0269] Step 8: N-(2-([1,4'-Bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide [Chem.] TFA (2 mL) was added to a solution of tert-butyl 4-(6-(2-hydroxypropan-2-yl)-5-(6-(trifluoromethyl)picolinamide)-2H-indazol-2-yl)-[1,4'-bipiperidin]-1'-carboxylate (0.24 g, 0.381 mmol) in DCM (10 mL) at room temperature. The resulting mixture was stirred at room temperature 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

[0270] Step 9: (R)-N-(2-(1’-(1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-[1,4’-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

Chem.

[0271] Example 161: N-(2-(1’-((R)-1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-[1,4’-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide [Chemical formula] A solution of N-(2-([1,4’-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (42 mg, 0.08 mmol) and (R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (27 mg, 0.08 mmol) in DCM (5 mL) was added with DIPEA (31 mg, 0.24 mmol) and T3P (50% in EtOAc, 102 mg, 0.16 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. 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 (0.1% aqueous FA: acetonitrile = 90:10 - 60:40 gradient elution)) to give the desired product (27 mg, 39%). [M+H] + =851.4 1 H NMR (500 MHz, DMSO) δ 12.37 (s, 1H), 10.84 (s, 1H), 8.72 (s, 1H), 8.45 (d, J = 10.0 Hz, 1H), 8.40 (s, 1H), 8.37 (t, J = 5.0 Hz, 1H), 8.16 (d, J = 10.0 Hz, 1H), 7.57 (s, 1H), 6.23 (t, J = 10.0 Hz, 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), 2.44 - 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).

[0272] Example 162: (R)-N-(2-(1’-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-[1,4’-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide [Chemical formula] To a solution of N-(2-([1,4’-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide (42 mg, 0.08 mmol) and (R)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carboxylic acid (obtained in the same manner as common intermediate B) (24 mg, 0.08 mmol) in DCM (5 mL) were added DIPEA (31 mg, 0.24 mmol) and T3P (50% in EtOAc, 102 mg, 0.16 mmol) at room temperature. The resulting mixture was stirred at room temperature 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 (0.1% aqueous FA: acetonitrile = 90:10 to 60:40 gradient elution)) to give the desired product (25.18 mg, 39%). [M+H] + =816.4 11H NMR (500 MHz, DMSO) δ 12.37 (s, 1H), 10.21 (s, 1H), 8.72 (s, 1H), 8.45 (d, J = 10.0 Hz, 1H), 8.40 (s, 1H), 8.37 (t, J = 5.0 Hz, 1H), 8.16 (d, J = 10.0 Hz, 1H), 7.58 (s, 1H), 7.10 (d, J = 10.0 Hz, 2H), 6.54 (t, J = 10.0 Hz, 2H), 5.94 (s, 1H), 4.44 - 4.38 (m, 2H), 4.14 - 4.05 (m, 1H), 3.67 (t, J = 10.0 Hz, 2H), 3.58 - 3.42 (m, 2H), 3.29 - 3.23 (m, 2H), 3.11 - 2.98 (m, 3H), 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).

[0273] Example 163: (S)-N-(2-(1’-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-[1,4’-bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide [Chemical Structure] A solution of N-(2-([1,4’-Bipiperidin]-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (42 mg, 0.08 mmol) and (S)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carboxylic acid (obtained in the same manner as common intermediate B) (24 mg, 0.08 mmol) in DCM (5 mL) was added with DIPEA (31 mg, 0.24 mmol) and T3P (50% in EtOAc, 102 mg, 0.16 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The residue was purified by preparative HPLC (C-18 column chromatography (0.1% aqueous FA:acetonitrile = 90:10 to 60:40 gradient elution)) to give the desired product (32.95 mg, 51%). [M+H] + =816.4 1 H NMR (500 MHz, DMSO) δ 12.37 (s, 1H), 10.21 (s, 1H), 8.72 (s, 1H), 8.45 (d, J = 10.0 Hz, 1H), 8.40 (s, 1H), 8.37 (t, J = 5.0 Hz, 1H), 8.16 (d, J = 10.0 Hz, 1H), 7.58 (s, 1H), 7.10 (d, J = 10.0 Hz, 2H), 6.54 (t, J = 10.0 Hz, 2H), 5.94 (s, 1H), 4.44 - 4.38 (m, 2H), 4.14 - 4.05 (m, 1H), 3.67 (t, J = 10.0 Hz, 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).

[0274] Example 178: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

[0275] Step 1: Potassium 3,3-diethoxy-2-formylpropanenitrile

Chemical formula

[0276] Step 2: Pyrrolo[1,2-b]pyridazine-3-carbonitrile

Chemical formula

[0277] Step 3: 7 - Bromopyrrolo[1,2 - b]pyridazine - 3 - carbonitrile

Chemical formula

[0278] Step 4: 3 - Cyanopyrrolo[1,2 - b]pyridazine - 7 - carboxylic acid

Chemical formula

[0279] Step 5: tert-Butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chemical Structure

[0280] Step 6: 3-Cyano-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

Chemical Structure

[0281] Step 7: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

Chem.

[0282] Example 105: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

Chemical formula

[0283] Example 110: 3 - Cyano - N - (2 - ((1R,4r) - 4 - (4 - (1 - (4 - ((R) - 2,6 - dioxopiperidin - 3 - yl) - 3,5 - difluorophenyl)azetidin - 3 - yl)piperazin - 1 - yl)cyclohexyl) - 6 - (2 - hydroxypropan - 2 - yl) - 2H - indazol - 5 - yl)pyrrolo[1,2 - b]pyridazine - 7 - carboxamide

Chemical Structure

[0284] This compound can also be synthesized by another method.

[0285] Step 1: Methyl 2 - ((1r,4r)-4-(4-(tert - butoxycarbonyl)piperazin - 1 - yl)cyclohexyl)-2H - indazole - 6 - carboxylate

Chemical formula

[0286] Step 2: Methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

Chem.

[0287] Step 3: Methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate

Chem.

[0288] Step 4: Methyl 5-amino-2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

Chem.

[0289] Step 5: Methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(2,2,2-trifluoroacetamido)-2H-indazole-6-carboxylate

Chem.

[0290] Step 6: tert-Butyl 4-((1r,4r)-4-(6-(2-hydroxypropan-2-yl)-5-(2,2,2-trifluoroacetamido)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chem.

[0291] Step 7: tert-Butyl 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chem.

[0292] Step 8: tert-Butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chemical Structure

[0293] Step 9: 3-Cyano-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

Chem.

[0294] Step 10: 3-Cyano-N-(2-((1R,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

Chem.

[0295] Example 181: 3-Cyano-N-(2-((1R,4r)-4-(4-((R)-1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

Chemical formula

[0296] Example 182: 3 - Cyano - N-(2 - ((1R,4r)-4-(4-(4 - ((R)-2,6 - dioxopiperidin - 3 - yl)-3,5 - difluorophenethyl)piperazin - 1 - yl)cyclohexyl)-6-(2 - hydroxypropan - 2 - yl)-2H - indazol - 5 - yl)pyrrolo[1,2 - b]pyridazine - 7 - carboxamide

Chem.

[0297] This compound can also be synthesized by another method.

[0298] Step 1: Methyl 2 - ((1r,4r)-4-(4-(tert - butoxycarbonyl)piperazin - 1 - yl)cyclohexyl)-2H - indazole - 6 - carboxylate

Chemical Structure

[0299] Step 2: Methyl 5-nitro-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

Chem.

[0300] Step 3: Methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-nitro-2H-indazole-6-carboxylate

Chem.

[0301] Step 4: Methyl 5-amino-2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-2H-indazole-6-carboxylate

Chem.

[0302] Step 5: Methyl 2-((1r,4r)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)cyclohexyl)-5-(2,2,2-trifluoroacetamido)-2H-indazole-6-carboxylate

Chem.

[0303] Step 6: tert-Butyl 4-((1r,4r)-4-(6-(2-hydroxypropan-2-yl)-5-(2,2,2-trifluoroacetamido)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chem.

[0304] Step 7: tert-Butyl 4-((1r,4r)-4-(5-amino-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chem.

[0305] Step 8: tert-Butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chemical Structure

[0306] Step 9: 3-Cyano-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide [Chemical formula] To a stirred solution of tert-butyl 4-((1r,4r)-4-(5-(3-cyanopyrrolo[1,2-b]pyridazine-7-carboxamido)-6-(2-hydroxypropan-2-yl)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate (90 g, 143.77 mmol) in MeOH (600 mL) was added concentrated HCl (36%, 300 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The solid was collected by filtration. The solid was dissolved in water (500 mL), then adjusted to pH 8 with saturated NaHCO3 solution and extracted with DCM / MeOH (V / V = 10 / 1, 5 × 2000 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The residue was slurried with petroleum ether (1000 mL) and filtered. The solid was filtered and dried under vacuum to give the product (70 g, 92.45%). [M+H] + = 527.4

[0307] Step 10: 3-Cyano-N-(2-((1R,4r)-4-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide [Chemical formula] 3-Cyano-N-(6-(2-hydroxypropan-2-yl)-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide (4.9 g, 9.30 mmol) and (R)-2-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)acetaldehyde (3.23 g, 12.09 mmol) (CAS: 2758533-79-6, obtained by the same method as described in WO2022012622A1) in a stirred solution of DCE (100 mL) were added AcOH (0.542 g, 9.30 mmol) and NaBH(OAc)3 (2.96 g, 13.95 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with MeOH (30 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give an impure product. The impure product was then slurried in MeOH (30 mL) and filtered. The filter cake was collected and dried under pressure to give the product (3.8 g, 52.53%). 1 H NMR (500 MHz, DMSO) δ 12.02 (s, 1H), 10.95 (s, 1H), 8.93 (d, J = 2.2 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 7.09 (d, J = 4.8 Hz, 1H), 7.03 (d, J = 10.0 Hz, 2H), 5.72 (s, 1H), 4.47 - 4.39 (m, 1H), 4.20 (dd, J = 12.6, 5.0 Hz, 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

[0308] Example 193: 3-Cyano-N-(2-((1R,4r)-4-(4-((4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)glycyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

Chem.

[0309] Example 194: 3-Cyano-N-(2-((1R,4r)-4-(4-(2-((4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)amino)ethyl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

Chem.

[0310] Example 195: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

Chemical Structure

[0311] Example 196: 3-Cyano-N-(2-((1r,4r)-4-(4-(1-(4-((R)-2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)piperazin-1-yl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)pyrrolo[1,2-b]pyridazine-7-carboxamide

Chem.

[0312] Example 128: (S)-N-(2-(1’-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-[1,4’-bipiperidin]-4-yl)-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)picolylamide

[0313] Step 1: Methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-nitroimidazo[1,2-a]pyridine-7-carboxylate

Chem.

[0314] Step 2: Methyl 6-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)imidazo[1,2-a]pyridine-7-carboxylate

Chem.

[0315] Step 3: Methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-6-(6-(trifluoromethyl)picolylamide)imidazo[1,2-a]pyridine-7-carboxylate

Chem.

[0316] Step 4: tert-Butyl 4-(7-(2-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)picolylamide)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate

Chem.

[0317] Step 5: N-(7-(2-Hydroxypropan-2-yl)-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)picolinamide hydrochloride

Chemical Structure

[0318] Step 6: tert-Butyl 4-(7-(2-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)picolinamido)imidazo[1,2-a]pyridin-2-yl)-[1,4’-bipiperidine]-1’-carboxylate

Chem.

[0319] Step 7: N-(2-([1,4’-Bipiperidin]-4-yl)-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)picolylamide hydrochloride

Chem.

[0320] Step 8: (S)-N-(2-(1’-(1-(4-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)-[1,4’-bipiperidin]-4-yl)-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)picolylamide

Chem.

[0321] Example 127: N-(2-(1’-((R)-1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)-[1,4’-bipiperidin]-4-yl)-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)picolylamide

Chemical Structure

[0322] Example 126: (R)-N-(2-(1'-(1-(4-(2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidine-3-carbonyl)-[1,4'-bipiperidin]-4-yl)-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)picolylamide

Chemical Structure

[0323] Example 50: N-(2-(1-(1-((R)-1-(4-((R)-2,6-Dioxopiperidin-3-yl)-3,5-difluorophenyl)pyrrolidine-3-carbonyl)azetidin-3-yl)piperidin-4-yl)-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)picolylamide

Chem.

[0324] Example 164: N-(2-((1R,4r)-4-(4-((R)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0325] Step 1: Benzyl 4-(1,4-dioxaspiro[4.5]dec-8-yl)piperazine-1-carboxylate

Chemical Structure

[0326] Step 2: Benzyl 4-(4-oxocyclohexyl)piperazine-1-carboxylate

Chemical formula

[0327] Step 3: Benzyl 4-((1s,4s)-4-hydroxycyclohexyl)piperazine-1-carboxylate

Chem.

[0328] Step 4: Benzyl 4-((1s,4s)-4-((methylsulfonyl)oxy)cyclohexyl)piperazine-1-carboxylate

Chem.

[0329] Step 5: Benzyl 4-((1r,4r)-4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)cyclohexyl)piperazine-1-carboxylate

Chemical Structure

[0330] Step 6: N-(6-Methoxy-2-((1r,4r)-4-(piperazin-1-yl)cyclohexyl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamid

Chemical Structure

[0331] Step 7: N-(2-((1R,4r)-4-(4-((R)-1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)pyrrolidine-3-carbonyl)piperazin-1-yl)cyclohexyl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

Chemical Structure

Claims

1. A compound of formula (X), 【Chemical 1】 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analogue thereof, or a prodrug thereof, wherein in the formula, L ｘ is either ＊Ｌｘ -CONH- ＊＊Ｌｘ or ＊Ｌｘ -NHCO- ＊＊Ｌｘ and ＊Ｌｘ refers to the position of attachment to the Cy2 moiety ＊＊Ｌｘ and refers to the position of attachment to the Cy3 moiety; Cy1 is a 6-membered partially or fully unsaturated ring; said ring is substituted with at least one substituent R １ and is substituted with; Y １ , Y ２ , and Y ３ is, independently of one another, C or N; s1 is 0, 1, 2, 3, 4, or 5; Cy2 is a 5-, 6-, 7-, 8-, 9-, or 10-membered partially or fully unsaturated ring (aromatic ring); said ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring is substituted with at least one substituent R ２ and is substituted with; s2 is 0, 1, or 2; s4 is 0 or 1; Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring contains from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring is substituted with at least one substituent R ３ and is substituted with; s3 is 0, 1, 2, 3, 4, or 5; R １ 、R ２ 、and R ３ are each independently hydrogen, halogen, -C １ -C ８ alkyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, 5- to 12-membered heteroaryl, oxo(=O), -CN, -OR １ａ 、-C(O)R １ａ 、-CO ２ R １ａ 、-C(O)NR １ａ R １ｂ 、-NR １ａ R １ｂ 、-NR １ａ COR １ｂ 、or -NR １ａ CO ２ R １ｂ ; -C １ -C ８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or each of 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R １ｃ ; or When adjacent, two Rs １ two Rs ２ or two Rs ３ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent R １ｃ ; R １ａ and R １ｂ each independently represents hydrogen, -C １ -C ８ alkyl, -C １ -C ８ haloalkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C １ -C ８ alkoxy-C １ -C ８ alkyl-, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; -C １ -C ８ alkyl, -C １ -C ８ haloalkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C １ -C ８ alkoxy-C １ -C ８ alkyl-, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, each of which is optionally substituted with at least one substituent selected from halogen, -OH, -CN, oxo(=O), -C １ -C ８ alkyl, -C １ -C ８ alkyl-OH, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R １ｃ is, each time it appears, independently, halogen, -OH, -CN, oxo (=O), -C １ -C ８ alkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R １１ａ 、R １１ｂ 、R １１ｃ 、R １１ｄ 、R １２ａ 、R １２ｂ 、R １２ｃ 、and R １２ｄ are each independently absent, oxo, hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -C ３－８ cycloalkyl; said -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -C ３－８ cycloalkyl is each optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; or R １１ａ and R １２ａ together with the carbon atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; and / or R １１ｂ and R １２ｂ together with the carbon atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; and / or R １１ｃ and R １２ｃ together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; and / or R １１ｄ and R １２ｄ together with the carbon atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; Upon each occurrence, L １ is independently —O—, —NR ａ —, —C(O)NR ａ —, —C(O)O—, 【Chemical 2】 selected from, referring to the position of attachment to the said 【Chemical Formula 3】 Each of which is optionally substituted with at least one R Ｌ１ｃ ; and In the formula, ＊Ｌ１ is 【Chemical Formula 4】 refers to the position to be coupled to the portion and ＊＊Ｌ１ is 【Chemical Formula 5】 moiety; Upon each occurrence, L ２ is independently, -O-, -NR ａ -, -CONR ａ -, -C(O)O-, ​ selected from; in the formula, referring to the position of attachment to the said 【Chemical Formula 7】 Each of which is optionally substituted with at least one R Ｌ２ｃ ; and In the formula, ＊Ｌ２ is 【Chemical 8】 Refers to the position of joining to the part and ＊＊Ｌ２ is 【Chemical Formula 9】 moiety; Upon each occurrence, L ３ is independently, -O-, -NR ａ -, -CONR ａ -, -C(O)O-, 【Chemical Formula 10】 selected from; in the formula, referring to the position of attachment to the said 【Chemical 11】 Each of which is optionally replaced with at least one R Ｌ３ｃ ; and In the formula, ＊Ｌ３ is 【Chemical Formula 12】 Refers to the position to be coupled to the part and ＊＊Ｌ３ is 【Chemical 13】 moiety; said R Ｌ１ｃ 、R Ｌ２ｃ 、and R Ｌ３ｃ each of which is independently absent, oxo (=O), halogen, hydroxy, -CN, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; said -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, and 5- to 12-membered heteroaryl each is optionally substituted with at least one R Ｌｃａ ; R Ｌｃａ is, independently, absent, oxo(=O), halogen, hydroxy, -CN, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; or Two Rs Ｌ１ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ optionally substituted with at least one substituent of alkyl; Two Rs Ｌ２ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ alkyl; Two Rs Ｌ３ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ optionally substituted with at least one substituent of alkyl; 【Chemical 14】 is 【Chemical Formula 15】 selected from; Z １ 、Z ２ 、and Z ３ are each independently N or CR ｚ wherein, however, Z １ 、Z ２ 、and Z ３ will not simultaneously become N; R ｚ is, for each occurrence, independently absent, hydrogen, halogen, -C １－８ alkyl, -NR Ｚａ R Ｚｂ , -OR Ｚａ , -SR Ｚａ , C ３ , -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, or CN, and -C １－８ alkyl, C ３ , -C ８ cycloalkyl, 3- to 8-membered heterocyclyl are each optionally substituted with at least one R Ｚｃ ; 【Chemical Formula 16】 the moiety is 【Chemical 17】 Partially, Z １ , Z ２ , or Z ３ (CR ｚ and there is no R ｚ ) is coupled through any one of them; R Ｚａ and R Ｚｂ are each independently absent, hydrogen, -C １ -C ８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, and each of said -C １－８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Ｚｄ ; R Ｚｃ and R Ｚｄ each independently represents a halogen, hydroxy, -C １ -C ８ alkyl, -C １－８ alkoxy, C ３ -C ８ cycloalkyl, a 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or a 5- to 12-membered heteroaryl; R １３ and R １４ are each independently absent, hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, 5- to 12-membered heteroaryl, -CN, -SO ２ R １３ａ , -SO ２ NR １３ａ R １３ｂ , -COR １３ａ , -CO ２ R １３ａ , -CONR １３ａ R １３ｂ , -NR １３ａ R １３ｂ , -NR １３ａ COR １３ｂ , -NR １３ａ CO ２ R １３ｂ , or -NR １３ａ SO ２ R １３ｂ selected from; -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, 5- to 12-membered heteroaryl each is halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR １３ｃ , -SO ２ R １３ｃ , -SO ２ NR １３ｃ R １３ｄ 、 - COR １３ｃ 、 - CO ２ R １３ｃ 、 - CONR １３ｃ R １３ｄ 、 - NR １３ｃ R １３ｄ 、 - NR １３ｃ COR １３ｄ 、 - NR １３ｃ CO ２ R １３ｄ 、 or - NR １３ｃ SO ２ R １３ｄ is optionally replaced by; Each occurrence, R １３ａ , R １３ｂ , R １３ｃ , and R １３ｄ is, independently of one another, absent, hydrogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; L ４ 、 L ５ 、 and L ６ are each independently absent, a single bond, -O-, -NR ａ -, -(CR ａ R ｂ ), ｎ８ -O(CR ａ R ｂ ), ｎ８ -NR ａ (CR ａ R ｂ ), ｎ８ - or -C(O)-; Upon each occurrence, X １ , X ２ , and X ７ is independently selected from -CR ａ or N; Upon each occurrence, X ３ , X ４ , and X ８ are each independently selected from -NR ａ -, -O-, -S-, and -CR ａ R ｂ -; Upon each occurrence, X ５ and X ６ are each independently selected from absent, single bond, -C(O)-, -NR ａ -, and -O-; Q １ , Q ２ , Q ３ , and Q ４ are each independently selected from CR ａ or N; Upon each occurrence, R ａ and R ｂ is each independently selected from hydrogen, hydroxy, halogen, CN, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, and each of said -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from halogen, hydroxy, halogen, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; or R ａ and R ｂ together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ alkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; m1, m2, m3, and m4 are each independently 0, 1, or 2; m5 and m7 are each independently 0 or 1; m6 is 0, 1, or 2, and when m6 is 2, the two L2s are the same or different; n1, n2, n3, n4, and n5 are each independently 0, 1, 2, or 3; n6, n7, and n8 are each independently 0, 1, 2, 3, or 4, said compound, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analogue thereof, or a prodrug thereof.

2. A compound of formula (I), 【Chemical 18】 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analogue thereof, or a prodrug thereof, wherein in the formula, Cy1 is a 6-membered partially or fully unsaturated ring; said ring is substituted with at least one substituent R １ and is substituted with; Y １ , Y ２ , and Y ３ are each independently C or N; s1 is 0, 1, 2, 3, 4, or 5; Cy2 is a 5-, 6-, 7-, 8-, 9-, or 10-membered partially or fully unsaturated ring (aromatic ring); said ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring is substituted with at least one substituent R ２ and is substituted with; s2 is 0, 1, or 2; s4 is 0 or 1; Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring contains from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring is substituted with at least one substituent R ３ and is substituted with; s3 is 0, 1, 2, 3, 4, or 5; R １ 、 R ２ 、 and R ３ are each independently hydrogen, halogen, -C １ -C ８ alkyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, 5- to 12-membered heteroaryl, oxo(=O), -CN, -OR １ａ , -C(O)R １ａ , -CO ２ R １ａ , -C(O)NR １ａ R １ｂ , -NR １ａ R １ｂ , -NR １ａ COR １ｂ , or -NR １ａ CO ２ R １ｂ ; -C １ -C ８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or each of 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R １ｃ ; or When adjacent, two Rs １ , two Rs ２ , or two Rs ３ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent R １ｃ ; R １ａ and R １ｂ are each independently hydrogen, -C １ -C ８ alkyl, -C １ -C ８ haloalkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C １ -C ８ alkoxy-C １ -C ８ alkyl-, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; -C １ -C ８ alkyl, -C １ -C ８ haloalkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C １ -C ８ alkoxy-C １ -C ８ alkyl-, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl is each optionally substituted with at least one substituent selected from halogen, -OH, -CN, oxo(=O), -C １ -C ８ alkyl, -C １ -C ８ alkyl-OH, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R １ｃ is, independently for each occurrence, halogen, -OH, -CN, oxo(=O), -C １ -C ８ alkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R １１ａ 、 R １１ｂ 、 R １１ｃ 、 R １１ｄ 、 R １２ａ 、 R １２ｂ 、 R １２ｃ 、 and R １２ｄ are each independently absent, oxo, hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -C ３－８ cycloalkyl; said -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -C ３－８ cycloalkyl is each optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; or R １１ａ and R １２ａ together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; and / or R １１ｂ and R １２ｂ together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; and / or R １１ｃ and R １２ｃ together with the carbon atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; and / or R １１ｄ and R １２ｄ together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; Upon each occurrence, L １ is independently —O—, —NR ａ —, —C(O)NR ａ —, —C(O)O—, 【Chemical Formula 19】 selected from, referring to the position of attachment to the said 【Chemical 20】 Each of which is optionally substituted with at least one R Ｌ１ｃ ; In the formula, ＊Ｌ１ is 【Chemical 21】 refers to the position of attachment to the part and ＊＊Ｌ１ is 【Chemical 22】 moiety; Each occurrence, L ２ independently is -O-, -NR ａ -, -CONR ａ -, -C(O)O- 【Chemical 23】 selected from; in the formula, referring to the position of attachment to the said 【Chemical 24】 Each of which is optionally substituted with at least one R Ｌ２ｃ ; and In the formula, ＊Ｌ２ is 【Chemical 25】 refers to the position of attachment to the part and ＊＊Ｌ２ is 【Chemical 26】 moiety; Each occurrence, L ３ is independently, -O-, -NR ａ -, -CONR ａ -, -C(O)O-, 【Chemical 27】 selected from; in the formula, referring to the position of attachment to the said 【Chemical 28】 Each of which is optionally substituted with at least one R Ｌ３ｃ ; and In the formula, ＊Ｌ３ is ​ Refers to the position of attachment to the part, and ＊＊Ｌ３ is 【Chemical 30】 moiety; said R Ｌ１ｃ 、R Ｌ２ｃ 、and R Ｌ３ｃ each of which is independently absent, oxo(=O), halogen, hydroxy, -CN, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; said -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, and 5- to 12-membered heteroaryl are each optionally substituted with at least one R Ｌｃａ ; R Ｌｃａ is, independently, absent, oxo(=O), halogen, hydroxy, -CN, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; or Two Rs Ｌ１ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ alkyl; Two Rs Ｌ２ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ alkyl; Two Rs Ｌ３ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ alkyl; 【Chemical 31】 is 【Chemical 32】 selected from; Z １ 、Z ２ 、and Z ３ are each independently N or CR ｚ wherein, however, Z １ 、Z ２ 、and Z ３ will not simultaneously become N; R ｚ is, for each occurrence, independently absent, hydrogen, halogen, -C １－８ alkyl, -NR Ｚａ R Ｚｂ -, -OR Ｚａ -, -SR Ｚａ C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, or CN, and -C １－８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl are each optionally substituted with at least one R Ｚｃ ; 【Chemical 33】 the moiety is 【Chemical 34】 Partially, Z １ , Z ２ , or Z ３ (CR ｚ and there is no R ｚ ) is coupled through any one of them; R Ｚａ and R Ｚｂ are each independently absent, hydrogen, -C １ -C ８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, and each of said -C １－８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Ｚｄ ; R Ｚｃ and R Ｚｄ each independently represents halogen, hydroxy, -C １ -C ８ alkyl, -C １－８ alkoxy, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R １３ and R １４ are each independently absent, hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, 5- to 12-membered heteroaryl, -CN, -SO ２ R １３ａ , -SO ２ NR １３ａ R １３ｂ , -COR １３ａ , -CO ２ R １３ａ , -CONR １３ａ R １３ｂ , -NR １３ａ R １３ｂ , -NR １３ａ COR １３ｂ , -NR １３ａ CO ２ R １３ｂ , or -NR １３ａ SO ２ R １３ｂ selected from; -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, each of which is halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR １３ｃ , -SO ２ R １３ｃ , -SO ２ NR １３ｃ R １３ｄ 、 - COR １３ｃ 、 - CO ２ R １３ｃ 、 - CONR １３ｃ R １３ｄ 、 - NR １３ｃ R １３ｄ 、 - NR １３ｃ COR １３ｄ 、 - NR １３ｃ CO ２ R １３ｄ 、 or - NR １３ｃ SO ２ R １３ｄ is optionally replaced by; Upon each occurrence, R １３ａ , R １３ｂ , R １３ｃ , and R １３ｄ are each independently absent, hydrogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; L ４ 、 L ５ 、 and L ６ are each independently absent, a single bond, -O-, -NR ａ -, -(CR ａ R ｂ ) ｎ８ -, -O(CR ａ R ｂ ) ｎ８ -, -NR ａ (CR ａ R ｂ ) ｎ８ -, or -C(O)-; Upon each occurrence, X １ , X ２ , and X ７ is independently selected from -CR ａ or N; Upon each occurrence, X ３ , X ４ , and X ８ are each independently selected from -NR ａ -, -O-, -S-, and -CR ａ R ｂ -; Upon each occurrence, X ５ and X ６ are each independently selected from absent, single bond, -C(O)-, -NR ａ -, and -O-; Q １ , Q ２ , Q ３ , and Q ４ are each independently selected from CR ａ or N; Each occurrence, R ａ and R ｂ is independently selected from hydrogen, hydroxy, halogen, CN, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, wherein the -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl is each optionally substituted with at least one substituent selected from halogen, hydroxy, halogen, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; or R ａ and R ｂ together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring is optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ alkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; m1, m2, m3, and m4 are each independently 0, 1, or 2; m5 and m7 are each independently 0 or 1; m6 is 0, 1, or 2, and when m6 is 2, the two L2s are the same or different; n1, n2, n3, n4, and n5 are each independently 0, 1, 2, or 3; n6, n7, and n8 are each independently 0, 1, 2, 3, or 4, said compound, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analogue thereof, or a prodrug thereof.

3. A compound of formula (I'), 【Chemical 35】 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof, wherein in the formula,[[]]END]] Cy1 is a 6-membered partially or fully unsaturated ring; said ring is substituted with at least one substituent R １ and is substituted with; Y １ , Y ２ , and Y ３ is, independently of one another, C or N; s1 is 0, 1, 2, 3, 4, or 5; Cy2 is a 5-, 6-, 7-, 8-, 9-, or 10-membered partially or fully unsaturated ring (aromatic ring); said ring contains 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring is substituted with at least one substituent R ２ and is substituted with; s2 is 0, 1, or 2; s4 is 0 or 1; Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring contains from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring is substituted with at least one substituent R ３ and is substituted with; s3 is 0, 1, 2, 3, 4, or 5; R １ 、 R ２ 、 and R ３ are each independently hydrogen, halogen, -C １ -C ８ alkyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, 5- to 12-membered heteroaryl, oxo(=O), -CN, -OR １ａ 、 -C(O)R １ａ 、 -CO ２ R １ａ 、 -C(O)NR １ａ R １ｂ 、 -NR １ａ R １ｂ 、 -NR １ａ COR １ｂ 、 or -NR １ａ CO ２ R １ｂ ; -C １ -C ８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or each of 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R １ｃ ; or When adjacent, two Rs １ , two Rs ２ , or two Rs ３ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent R １ｃ ; R １ａ and R １ｂ each independently is hydrogen, -C １ -C ８ alkyl, -C １ -C ８ haloalkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C １ -C ８ alkoxy-C １ -C ８ alkyl-, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; -C １ -C ８ alkyl, -C １ -C ８ haloalkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C １ -C ８ alkoxy-C １ -C ８ alkyl-, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl each is optionally substituted with at least one substituent selected from halogen, -OH, -CN, oxo(=O), -C １ -C ８ alkyl, -C １ -C ８ alkyl-OH, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R １ｃ is, for each occurrence, independently, halogen, -OH, -CN, oxo(=O), -C １ -C ８ alkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R １１ａ 、R １１ｂ 、R １１ｃ 、R １１ｄ 、R １２ａ 、R １２ｂ 、R １２ｃ 、and R １２ｄ are each independently absent, oxo, hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -C ３－８ cycloalkyl; wherein each of said -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -C ３－８ cycloalkyl is optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; or R １１ａ and R １２ａ together with the carbon atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; and / or R １１ｂ and R １２ｂ together with the carbon atom to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; and / or R １１ｃ and R １２ｃ together with the carbon atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; and / or R １１ｄ and R １２ｄ together with the carbon atoms to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, or -CN; Each occurrence, L １ is independently, -O-, -NR ａ -, -C(O)NR ａ -, -C(O)O-, 【Chemical Formula 36】 selected from, referring to the position of attachment to the said 【Chemical 37】 Each of which is optionally substituted with at least one R Ｌ１ｃ ; In the formula, ＊Ｌ１ is 【Chemical Formula 38】 Refers to the position to be coupled to the part and ＊＊Ｌ１ is 【Chemical 39】 moiety; Upon each occurrence, L ２ independently represents -O-, -NR ａ -, -CONR ａ -, -C(O)O-, 【Chemical 40】 selected from; in the formula, referring to the position of attachment to the said 【Chemical 41】 Each of which has at least one R Ｌ２ｃ is optionally replaced by; In the formula, ＊Ｌ２ is 【Chemical 42】 Refers to the position of attachment to the part and ＊＊Ｌ２ is 【Chemical Formula 43】 moiety; Upon each occurrence, L ３ is independently, -O-, -NR ａ -, -CONR ａ -, -C(O)O-, 【Chemical 44】 selected from; in the formula, referring to the position of attachment to the said 【Chemical 45】 Each of which is optionally substituted with at least one R Ｌ３ｃ ; and In the formula, ＊Ｌ３ is 【Chemical 46】 Refers to the position of joining to the part, and ＊＊Ｌ３ is 【Chemical 47】 moiety; Said R Ｌ１ｃ , R Ｌ２ｃ , and R Ｌ３ｃ each is independently absent, oxo (=O), halogen, hydroxy, -CN, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; said -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, and 5- to 12-membered heteroaryl each is optionally substituted with at least one R Ｌｃａ ; R Ｌｃａ is, independently, absent, oxo(=O), halogen, hydroxy, -CN, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; or Two Rs Ｌ１ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ alkyl; Two Rs Ｌ２ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ optionally substituted with at least one substituent of alkyl; Two Rs Ｌ３ｃ together with the atoms to which they are attached form a 3- to 12-membered ring, said ring containing from 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent of halogen, hydroxy, -C １ -C ８ optionally substituted with at least one substituent of alkyl; 【Chemical 48】 is 【Chemical 49】 selected from; Z １ 、Z ２ 、and Z ３ are each independently N or CR ｚ wherein, however, Z １ 、Z ２ 、and Z ３ will not simultaneously be N; R ｚ is, independently for each occurrence, absent, hydrogen, halogen, -C １－８ alkyl, -NR Ｚａ R Ｚｂ -, -OR Ｚａ -, -SR Ｚａ C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, or CN, -C １－８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl each is optionally substituted with at least one R Ｚｃ ; 【Chemical 50】 the moiety is 【Chemical 51】 In the part, Z １ , Z ２ , or Z ３ (CR ｚ and there is no R ｚ ) is coupled through any one of them; R Ｚａ and R Ｚｂ are each independently absent, hydrogen, -C １ -C ８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, and each of said -C １－８ alkyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Ｚｄ ; R Ｚｃ and R Ｚｄ each independently represents halogen, hydroxy, -C １ -C ８ alkyl, -C １－８ alkoxy, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; R １３ and R １４ are each independently absent, hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, 5- to 12-membered heteroaryl, -CN, -SO ２ R １３ａ , -SO ２ NR １３ａ R １３ｂ , -COR １３ａ , -CO ２ R １３ａ , -CONR １３ａ R １３ｂ , -NR １３ａ R １３ｂ , -NR １３ａ COR １３ｂ , -NR １３ａ CO ２ R １３ｂ , or -NR １３ａ SO ２ R １３ｂ selected from; -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C １－８ alkoxy, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, 5- to 12-membered heteroaryl each is halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR １３ｃ , -SO ２ R １３ｃ , -SO ２ NR １３ｃ R １３ｄ , -COR １３ｃ , -CO ２ R １３ｃ , -CONR １３ｃ R １３ｄ , -NR １３ｃ R １３ｄ , -NR １３ｃ COR １３ｄ , -NR １３ｃ CO ２ R １３ｄ , or -NR １３ｃ SO ２ R １３ｄ is optionally replaced by; Upon each occurrence, R １３ａ , R １３ｂ , R １３ｃ , and R １３ｄ are each independently absent, hydrogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; L ４ 、 L ５ 、 and L ６ are each independently absent, a single bond, -O-, -NR ａ -, -(CR ａ R ｂ ), ｎ８ -O(CR ａ R ｂ ), ｎ８ -NR ａ (CR ａ R ｂ ), ｎ８ - or -C(O)-; Upon each occurrence, X １ , X ２ , and X ７ are each independently selected from -CR ａ or N; Upon each occurrence, X ３ , X ４ , and X ８ are each independently selected from -NR ａ -, -O-, -S-, and -CR ａ R ｂ -; Upon each occurrence, X ５ and X ６ are each independently selected from absent, single bond, -C(O)-, -NR ａ -, and -O-; Q １ , Q ２ , Q ３ , and Q ４ are each independently selected from CR ａ or N; Upon each occurrence, R ａ and R ｂ is each independently selected from hydrogen, hydroxy, halogen, CN, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl, wherein each of said -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from halogen, hydroxy, halogen, -C １ -C ８ alkyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; or R ａ and R ｂ together with the carbon atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from halogen, hydroxy, -C １ -C ８ alkyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, -C １ -C ８ alkoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C ３ -C ８ cycloalkyl, 3- to 8-membered heterocyclyl, C ６ -C １２ aryl, or 5- to 12-membered heteroaryl; m1, m2, m3, and m4 are each independently 0, 1, or 2; m5 and m7 are each independently 0 or 1; m6 is 0, 1, or 2, and when m6 is 2, the two L2s are the same or different; n1, n2, n3, n4, and n5 are each independently 0, 1, 2, or 3; n6, n7, and n8 are each independently 0, 1, 2, 3, or 4, the said compound, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated analog thereof, or a prodrug thereof.

4. The said compound is selected from formula (IIa), (IIa'), (IIb), (IIb'), (IIc), (IIc'), (IId), (IId'), (IIe), and (IIe'), 【Chemical Formula 52-1】 【Chemical Formula 52-2】 【Chemical Formula 52-3】 wherein 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, Degron are as defined in claim 1, the compound according to claim 1.

5. The said 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'), 【Chemical Formula 53-1】 【Chemical Formula 53-2】 【Chemical Formula 53-3】 【Chemical Formula 53-4】 【Chemical Formula 53-5】 wherein, R １ , R ２ , R ３ , R １１ａ , R １１ｂ , R １１ｃ , R １１ｄ , R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , Y １ , Y ２ , Y ３ , L １ , L ２ , L ３ , s1, s2, s3, m1, m2, m3, m4, m5, m6, m7, Cy1, Cy3, Degron are as defined in claim 1, the compound according to claim 1.

6. The said compound is selected from formula (IVa), (Iva'), (IVb), (IVb'), (IVc), and (IVc'), 【Chemical Formula 54-1】 【Chemical Formula 54-2】 wherein 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 Degron are as defined in claim 1, a compound according to claim 1.

7. The said compound is selected from formula (Va) or (Va'), 【Chemical Formula 55】 Preferably, the said compound is selected from formula (Vb), (Vb'), (Vc), and (Vc'), 【Chemical 56】 More preferably, the said compound is selected from formula (Vd), (Vd'), (Ve), and (Ve'). 【Chemical 57】 More preferably, the compound is selected from the formulas (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'), 【Chemical Formula 58-1】 【Chemical Formula 58-2】 【Chemical Formula 58-3】 【Chemical Formula 58-4】 Even more preferably, the compound is selected from the formulas (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'), 【Chemical Formula 59-1】 【Chemical Formula 59-2】 【Chemical Formula 59-3】 【Chemical Formula 59-4】 wherein, Y ４ Y ７ Y ８ Y ９ Y １０ Y １１ Y １２ Y １３ Y １４ Y １５ Y １６ and Y １７ are each independently selected from C or N; Y ５ and Y ６ are each independently selected from C, N, O, or S; provided that 【Chemical Formula 60】 is an aromatic ring; wherein, 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 Degron are as defined in claim 1, a compound according to claim 1. Claim 8 The compound is selected from the formulas (VIa) or (Via'). 【Chemical Formula 61】 Preferably, the compound is selected from (Vlb) or (Vlb). 【Chemical Formula 62】 wherein 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 Degron are as defined in claim 1, a compound according to claim 1. Claim 9 Y １ , Y ２ , and Y ３ at least one of which is N; preferably, Y １ is N, Y ２ and Y ３ are C; or Y ２ is N, Y １ and Y ３ are C; or Y ３ is N, Y １ and Y ２ are C, a compound according to any one of the preceding claims. Claim 10 The compound according to any one of the preceding claims, wherein Cy1 is pyridinyl or pyridinonyl.

11. 【Fig. 63】 The moiety is 【Chemical Formula 64】 ; preferably, 【Chemical Formula 65】 The moiety is 【Chemical Formula 66】 The compound according to any one of the preceding claims.

12. 【Fig. 67】 The moiety is 【Chemical Formula 68-1】 【Chemical Formula 68-2】 and wherein; in the formula, ＊Ｃｙ２ is 【Chemical Formula 69】 Refers to the position for coupling to the part, and ＊＊Ｃｙ２ is 【Chemical 70】 refers to the position where it is attached to the moiety; Preferably, 【Chemical 71】 The moiety is 【Chemical Formula 72】 The compound according to any one of the preceding claims. Claim 13 Cy3 is a 5-, 6-, 7-, 8-, 9-, or 10-membered aromatic ring; said ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur; said ring is substituted with at least one substituent R ３ and is substituted with; Preferably, Cy3 is a 5- or 9-membered aromatic ring; said ring contains 0, 1, 2, or 3 heteroatoms independently selected from nitrogen; said ring is substituted with at least one substituent R ３ and is substituted with; Even more preferably, 【Chemical 73】 is 【Chemical 74】 ; In the formula, ＊Ｃｙ３ is 【Chemical 75】 refers to the position of attachment to the part and ＊＊Ｃｙ３ is 【Chemical Formula 76】 refers to the position where it is attached to the moiety; Even more preferably, 【Chemical 77】 is 【Chemical Formula 78】 The compound according to any one of the preceding claims. Claim 14 R １ 、 R ２ 、 and R ３ are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, a 5- to 12-membered heteroaryl, oxo(=O), -CN, -OR １ａ 、 -C(O)R １ａ 、 -CO ２ R １ａ 、 -C(O)NR １ａ R １ｂ 、 -NR １ａ R １ｂ 、 -NR １ａ COR １ｂ 、 or -NR １ａ CO ２ R １ｂ ; and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R １ｃ ; R １ａ and R １ｂ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C １ -C ８ haloalkyl (preferably -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ ), -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C １ -C ８ alkoxy-C １ -C ８ alkyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C １ -C ８ haloalkyl (preferably -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ ), -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, C １ -C ８ alkoxy-C １ -C ８ Each of alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from -F, -Cl, -Br, -I, -OH, -CN, oxo(=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH ２ OH, -C ２ H ４ OH, -C ３ H ６ OH, -C ４ H ８ OH, -C ５ H １０ OH, -C ６ H １２ OH, -C ７ H １４ OH, -C ８ H １６ OH, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; R １ｃ is, for each occurrence, independently, -F, -Cl, -Br, -I, -OH, -CN, oxo(=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, a compound according to any one of the preceding claims. Claim 15 R １ 、R ２ 、and R ３ are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, oxo(=O), -CN, -OR １ａ or -C(O)NR １ａ R １ｂ 、-NR １ａ R １ｂ ; and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a 3- to 8-membered heterocyclyl is optionally substituted with at least one substituent R １ｃ ; R １ａ and R １ｂ are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -CH ２ OH, -C ２ H ４ OH, -C ３ H ６ OH, -C ４ H ８ OH, -C ５ H １０ OH, -C ６ H １２ OH, -C ７ H １４ OH, -C ８ H １６ OH, -CH ２ F, -CHF ２ , -CF ３ , -CH ２ CH ２ F, -CH ２ CHF ２ , -CH ２ CF ３ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl each is -F, -Cl, -Br, -I, -OH, -CN, oxo(=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２ -C ８ alkenyl, -C ２ -C ８ Optionally substituted with at least one substituent selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; R １ｃ is, independently for each occurrence, -F, -Cl, -Br, -I, -OH; Preferably, R １ , R ２ , and R ３ are each independently H, -F, -Cl, -Br, -I, -CH ３ , -CH ２ CH ３ , -CF ３ , -CF ２ CH ３ , -CH ２ CF ３ , -CH(CH ３ ) ２ , -C(CH ３ ) ３ , -NHCH ３ , -NHCH ２ CH ３ , -N(CH ３ )CH ２ CH ３ , -N(CH ３ ) ２ , -CHF ２ , oxo(=O), -CN, cyclopropyl, -CONH ２ , -OMe, -OEt, -OCH ２ CH ２ CH ３ , -OCH(CH ３ ) ２ , 【Chemical Formula 79】 is; More preferably, R １ is H, -CH ３ , -CH ２ CH ３ , -CF ３ , -CF ２ CH ３ , -CH(CH ３ ), ２ , -C(CH ３ ), ３ , -NHCH ３ , -NHCH ２ CH ３ , -N(CH ３ )CH ２ CH ３ , -N(CH ３ ), ２ oxo(=O), cyclopropyl, 【Chemical 80】 is; R ２ is H, -CF ３ , cyclopropyl, oxo(=O), -F, -Cl, -Br, -I, or -CN; R ３ is H, -CH ３ , oxo(=O), -CHF ２ , -CONH ２ , -OMe, -OCD ３ , -OEt, -OCH ２ CH ２ CH ３ , -OCH(CH ３ ) ２ , 【Chemical Formula 81】 The compound according to any one of the preceding claims. Claim 16 Two Rs ３ together with the atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent R １ｃ ; R １ｃ is, for each occurrence, independently, -F, -Cl, -Br, -I, -OH, -CN, oxo(=O), methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; Preferably, the two Rs ３ together with the atoms to which they are attached form a 3-, 4-, 5- or 6-membered ring, said ring containing 0, 1, 2 or 3 heteroatoms independently selected from oxygen; said ring being optionally substituted with at least one substituent R １ｃ ; R １ｃ is, for each occurrence, independently, a compound according to any one of the preceding claims, which is -F, -Cl, -Br, -I, -OH, -CN, oxo (=O), methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl. Claim 17 R １１ａ 、R １１ｂ 、R １１ｃ 、R １１ｄ 、R １２ａ 、R １２ｂ 、R １２ｃ 、and R １２ｄ is, independently of one another, hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, or -CN; or (R １１ａ and R １２ａ ), (R １１ｂ and R １２ｂ ), (R １１ｃ and R １２ｃ ), or (R １１ｄ and R １２ｄ ) together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent selected from hydrogen, halogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, or -CN, a compound according to any one of the preceding claims.

18. 【Fig. 82】 The moiety is 【Chemical 83】 The compound according to any one of the preceding claims.

19. 【Fig. 84】 The moiety is 【Chemical Figure 85-1】 【Chemical Figure 85-2】 【Chemical Figure 85-3】 ; Preferably, 【Chemical 86】 The moiety is 【Chemical 87】 The compound according to any one of the preceding claims. Claim 20 R １１ａ 、R １１ｂ 、R １１ｃ 、R １１ｄ 、R １２ａ 、R １２ｂ 、R １２ｃ 、and R １２ｄ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, 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 are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, or propyl; more preferably, R １１ａ 、R １１ｂ 、R １１ｃ 、R １１ｄ 、R １２ａ 、R １２ｂ 、R １２ｃ 、and R １２ｄ are each independently hydrogen or methyl; or (R １１ａ and R １２ａ ), (R １１ｂ and R １２ｂ ), (R １１ｃ and R １２ｃ ), or (R １１ｄ and R １２ｄ ) together with the carbon atom to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; preferably, (R １１ａ and R １２ａ ), (R １１ｂ and R １２ｂ ), (R １１ｃ and R １２ｃ ), or (R １１ｄ and R １２ｄ ) together with the carbon atom to which they are attached form a 3-, 4-, or 5-membered cycloalkyl ring, a compound according to any one of the preceding claims. Claim 21 L １ is -O-, -N(R ａ )-, 【Chemical 88】 selected from; The said 【Chemical 89】 Each of which is optionally substituted with at least one R Ｌ１ｃ ; and Said R Ｌ１ｃ each independently is oxo (=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, and a 5- to 12-membered heteroaryl is each optionally substituted with at least one R Ｌｃａ and R Ｌｃａ is, independently, oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or Two Rs Ｌ１ｃ together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent of F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; R ａ is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and is a compound according to any one of the preceding claims. Claim 22 L １ is —O—, —N(CH ３ )—, 【Chemical Formula 90-1】 【Chemical Formula 90-2】 【Chemical Formula 90-3】 【Chemical Formula 90-4】 【Chemical Formula 90-5】 The compound according to any one of the preceding claims, selected from. Claim 23 L ２ is -O-, -N(R ａ )-, 【Chemical Formula 91】 selected from; The said 【Chemical 92】 Each of which is optionally replaced with at least one R Ｌ２ｃ ; and Said R Ｌ２ｃ each independently is oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is each optionally substituted with at least one R Ｌｃａ and R Ｌｃａ is, independently, oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or Two Rs Ｌ２ｃ together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring containing 0, 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; said ring being optionally substituted with at least one substituent of F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; R ａ is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, the compound according to any one of the preceding claims. Claim 24 L ２ is -O-, -N(CH ３ )-, 【Chemical Formula 93-1】 [Chemical Formula 93-2] 【Chemical Formula 93-3】 【Chemical Formula 93-4】 The compound according to any one of the preceding claims, selected from.

25. 【Fig. 94】 The moiety is 【Chemical Formula 95】 ; Preferably, 【Chemical Formula 96】 The moiety is 【Chemical Formula 97】 ; More preferably, 【Chemical Formula 98】 The moiety is 【Chemical Formula 99-1】 【Chemical Formula 99-2】 The compound according to any one of the preceding claims. Claim 26 L ３ is —O—, —N(R ａ )—, 【Chemical Formula 100】 selected from; The said 【Chemical 101】 Each of which has at least one R Ｌ３ｃ is optionally replaced by; Said R Ｌ３ｃ each independently is oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, and 5- to 12-membered heteroaryl is each optionally substituted with at least one R Ｌｃａ and R Ｌｃａ is, independently, oxo(=O), F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl; or Two Rs Ｌ３ｃ together with the carbon atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, said ring containing 0, 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; said ring being optionally substituted with at least one substituent of F, Cl, Br, I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; R ａ is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, and the compound according to any one of the preceding claims. Claim 27 L ３ is —O—, —N(CH ３ )—, —NH—, 【Chemical 102-1】 【Chemical 102-2】 【Chemical 102-3】 【Chemical 102-4】 【Chemical 102-5】 The compound according to any one of the preceding claims, selected from.

28. 【Fig. 103】 The moiety is 【Chemical Formula 104-1】 【Chemical 104-2】 【Chemical 104-3】 【Chemical 104-4】 【Chemical 104-5】 【Chemical 104-6】 【Chemical 104-7】 【Chemical 104-8】 selected from, Preferably, 【Chemical 105】 The moiety is 【Chemical 106-1】 【Chemical 106-2】 【Chemical 106-3】 【Chemical 106-4】 【Chemical 106-5】 A compound according to any one of the preceding claims, selected from

29. L ４ is independently selected from a single bond, -O-, -NR ａ -, -(CR ａ R ｂ ) ｎ８ -, -O(CR ａ R ｂ ) ｎ８ -, -NR ａ (CR ａ R ｂ ) ｎ８ -, or -C(O)-; Upon each occurrence, R ａ and R ｂ are each independently hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl are each optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, a compound according to any one of the preceding claims.

30. L ４ is, independently, a single bond or -NH-, a compound according to any one of the preceding claims.

31. X ７ is independently selected from -CR ａ or N; R ａ is independently hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, wherein said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, each of which is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, and is a compound according to any one of the preceding claims, optionally substituted with at least one substituent of

32. X ７ is independently selected from -CH, -C(CH ３ ), or N; preferably, X ７ is independently selected from -CH, and is a compound according to any one of the preceding claims.

33. X ８ independently represents -NR ａ -, -O-, -S-, and -CR ａ R ｂ - and is selected from; Each occurrence, R ａ and R ｂ is independently hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl, and the compound according to any one of the preceding claims.

34. X ８ is independently selected from -NH- and -CH ２ -; preferably, X ８ is independently selected from -CH ２ -; a compound according to any one of the preceding claims.

35. 【Fig. 107】 is selected from 【Chemical 108】 ; preferably, 【Chemical 109】 is 【Chemical 110】 selected from more preferably, 【Chemical 111】 is 【Chemical 112】 A compound according to any one of the preceding claims, selected from

36. Z １ , Z ２ , and Z ３ The compound according to any one of the preceding claims, wherein at most one of Z

37. Z １ , Z ２ , and Z ３ is, independently of one another, CR ｚ is a compound according to any one of the preceding claims.

38. R Ｚ is, for each occurrence, independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -NR Ｚａ R Ｚｂ , -OR Ｚａ , -SR Ｚａ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, or CN; and each of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a 3- to 8-membered heterocyclyl is optionally substituted with at least one R Ｚｃ ; R Ｚａ and R Ｚｂ are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, and each of said hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl is optionally substituted with at least one substituent R Ｚｄ ; R Ｚｃ and R Ｚｄ is, independently of one another, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a 3- to 8-membered heterocyclyl, phenyl, or a 5- to 12-membered heteroaryl, a compound according to any one of the preceding claims.

39. R ｚ is selected from H, -CH ３ , -C ２ H ５ , F, -CH ２ F, -CHF ２ , -CF ３ , -OCH ３ , -OC ２ H ５ , -C ３ H ７ , -OCH ２ F, -OCHF ２ , -OCH ２ CF ３ , -OCF ３ , -SCF ３ , -CF ３ , or -CH(OH)CH ３ and is a compound according to any one of the preceding claims.

40. R １３ and R １４ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ alkenyl, -C ２－８ alkynyl, a 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, a 5- to 12-membered heteroaryl, -CN, -SO ２ R １３ａ , -SO ２ NR １３ａ R １３ｂ , -COR １３ａ , -CO ２ R １３ａ , -CONR １３ａ R １３ｂ , -NR １３ａ R １３ｂ , -NR １３ａ COR １３ｂ , -NR １３ａ CO ２ R １３ｂ , or -NR １３ａ SO ２ R １３ｂ selected from; 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, a 3- to 8-membered heterocyclyl, -C ６ -C １２ Each of aryl and 5- to 12-membered heteroaryl is optionally substituted 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 heterocyclyl, -C ６ -C １２ aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR １３ｃ , -SO ２ R １３ｃ , -SO ２ NR １３ｃ R １３ｄ , -COR １３ｃ , -CO ２ R １３ｃ , -CONR １３ｃ R １３ｄ , -NR １３ｃ R １３ｄ , -NR １３ｃ COR １３ｄ , -NR １３ｃ CO ２ R １３ｄ , or -NR １３ｃ SO ２ R １３ｄ and is optionally substituted with; R １３ａ 、 R １３ｂ 、 R １３ｃ 、 and R １３ｄ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ alkenyl, -C ２－８ alkynyl, a 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or a 5- to 12-membered heteroaryl, the compound according to any one of the preceding claims.

41. R １３ and R １４ are each independently hydrogen, F, Cl, Br, I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -CN, -CH ２ F, -CHF ２ , -CF ３ , -OCH ２ F, -OCHF ２ , -OCH ２ CF ３ , -OCF ３ , -SCF ３ or phenyl, a compound according to any one of the preceding claims.

42. 【Fig. 113】 is 【Chemical 114】 A compound according to any one of the preceding claims, which is

43. L ５ and L ６ each independently represents a single bond, -O-, -NR ａ -, -(CR ａ R ｂ ), ｎ８ -O(CR ａ R ｂ ), ｎ８ -NR ａ (CR ａ R ｂ ), ｎ８ or -C(O)-; X ８ is -CR ａ R ｂ -; Upon each occurrence, R ａ and R ｂ is independently selected from hydrogen, hydroxy, -F, -Cl, -Br, -I, -CN, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl, and each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 12-membered heteroaryl is optionally substituted with at least one substituent selected from halogen, hydroxy, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octyloxy, -C ２ -C ８ alkenyl, -C ２ -C ８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 3- to 8-membered heterocyclyl, phenyl or 5- to 12-membered heteroaryl; a compound according to any one of the preceding claims.

44. L ５ and L ６ each independently represents a single bond, 【Chemical 115】 -O-, -NH-, -NMe-, -N(CH ２ CH ３ ), -CH ２ -, -CHF-, -CF ２ -, -C(CH ３ )([[]] ２ -), or -CO- (preferably, L ５ is -CO- or -CH ２ -, and L ６ is It should be noted that there may be some inaccuracies in the original text's chemical structure representation, and the translation is based on the literal meaning as much as possible. If it is for a more accurate chemical-related translation, it may need to be further adjusted according to the specific chemical context. 【Chemical 116】 -O-, -NH-, -NMe-, -N(CH ２ CH ３ ), -CH ２ -, -CHF-, -CF ２ -, -C(CH ３ ), ２ -, or -CO-); X ８ is CH ２ and; and n6 is 0 or 1, a compound according to any one of the preceding claims.

45. R １３ 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, cyclooctyl, -C ２－８ alkenyl, -C ２－８ alkynyl, a 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, a 5- to 12-membered heteroaryl, -CN, -SO ２ R １３ａ -, -SO ２ NR １３ａ R １３ｂ -, -COR １３ａ -, -CO ２ R １３ａ -, -CONR １３ａ R １３ｂ -, -NR １３ａ R １３ｂ -, -NR １３ａ COR １３ｂ -, -NR １３ａ CO ２ R １３ｂ -, or -NR １３ａ SO ２ R １３ｂ is selected from; 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, a 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, each of the 5- to 12-membered heteroaryls is 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 heterocyclyl, -C ６ -C １２ Aryl, 5- to 12-membered heteroaryl, oxo, -CN, -OR １３ｃ , -SO ２ R １３ｃ , -SO ２ NR １３ｃ R １３ｄ , -COR １３ｃ , -CO ２ R １３ｃ , -CONR １３ｃ R １３ｄ , -NR １３ｃ R １３ｄ , -NR １３ｃ COR １３ｄ , -NR １３ｃ CO ２ R １３ｄ , or -NR １３ｃ SO ２ R １３ｄ and is optionally substituted with; Upon each occurrence, R １３ａ , R １３ｂ , R １３ｃ , and R １３ｄ is, independently of one another, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -C ２－８ alkenyl, -C ２－８ alkynyl, a 3- to 8-membered heterocyclyl, -C ６ -C １２ aryl, or a 5- to 12-membered heteroaryl, a compound according to any one of the preceding claims.

46. R １３ is independently selected from hydrogen, F, Cl, Br, I, CN, -C １ -C ８ alkyl, or -C １ -C ８ alkoxy; preferably, R １３ is independently selected from hydrogen, F, Cl, Br, I, CN, -Me, -Et, -C ３ H ７ -C ４ H ９ -OMe, -OEt, -OC ３ H ７ or -OC ４ H ９ ; n ７ The compound according to any one of the preceding claims, wherein n is 0, 1, or 2.

47. 【Fig. 117】 is 【Chemical 118-1】 【Chemical 118-2】 【Chemical 118-3】 A compound according to any one of the preceding claims, which is

48. The said compounds are Compound Numbers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274The compound according to any one of the preceding claims, selected from 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, or 441.,

49. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, together with a pharmaceutically acceptable excipient.

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

51. The disease is selected from autoimmune diseases and inflammatory diseases, preferably systemic lupus, hidradenitis suppurativa, rheumatoid arthritis, arthritis, gout, multiple sclerosis, psoriasis, and cancer, preferably acute myeloid leukemia cancer, lymphoma, B-cell myelodysplasia, according to claim 50.

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

53. The disease is cancer, preferably pancreatic cancer, breast cancer, glioblastoma multiforme, head and neck cancer, or non-small cell lung cancer, according to claim 52.

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