Protein degraders developed based on BCL-2 family protein ligand compounds and their applications

Abstract

The present disclosure relates to a protein degrading agent, including a compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, pharmaceutical precursor or polymorph thereof, developed based on a BCL-2 family protein ligand compound, and its application for the treatment of diseases. (Formula (I)) TIFF2025503598000093.tif40110

Description

[Technical Field]

[0001] The present disclosure relates to proteolytic agents, including compounds of formula (I) or salts, enantiomers, stereoisomers, solvates, pharmaceutical precursors or polymorphs thereof, developed based on BCL-2 family protein ligand compounds, and their applications for the treatment of diseases. [Background technology]

[0002] Apoptosis, or programmed cell death, is a process in which cells undergo a series of programmed events leading to cell death. During early development, apoptosis can eliminate unnecessary cells. After adulthood, apoptosis primarily plays a role in eliminating cells that are damaged and cannot be repaired, thereby ensuring the proper development of the human body. Apoptosis plays an important role in various physiological processes, such as normal cell renewal, immune system development and function, hormone-dependent atrophy, embryonic development, and chemically induced cell death (Elmore, S., Toxicol Pathol, 2007, 35(4):pp. 495-516). Abnormal apoptosis (excessive or insufficient) can lead to various diseases, including neurodegenerative disorders, vascular and cardiac disorders, autoimmune diseases, and tumors. Research has shown that inhibiting the apoptotic pathway during tumor development can reduce the sensitivity of tumors to antitumor drugs (Scott, W. Letal., Carcinogenesis, 2000, 21(3):pp. 485-495). Therefore, activating apoptotic signals in tumor tissues may be an effective antitumor strategy.

[0003] The BCL-2 (B cell lymphoma-2) protein family is a key regulator of apoptosis, capable of both inducing and inhibiting cell apoptosis. It is primarily located on mitochondria and acts as an "apoptotic switch" by regulating mitochondrial membrane permeability. BCL-2 contains four highly conserved homeodomain (BH) domains: BH1, BH2, BH3, and BH4. Based on the different homeodomain configurations, BCL-2 can be divided into three subtypes: one with anti-apoptotic function and two with pro-apoptotic function (Daniel, NN, Clin Cancer Res, 2007.13(24):pp.7254-7263). The BH1 and BH2 homeodomains of BCL-2 can dimerize with pro-apoptotic proteins. The BH3 domain is crucial for the interaction between pro- and anti-apoptotic proteins and is therefore present in all subtypes. The BH4 domain is primarily found in the anti-apoptotic BCL-2 subtype. Anti-apoptotic proteins include BCL-2 and BCL-X. LBCL-2 family proteins, including BCL-W, MCL1, A1, and BCL-B, are composed of three to four BH domains. Proapoptotic proteins can be divided into two types: proapoptotic proteins, including BAX, BAK, and BOK, are composed of BH1, BH2, and BH3 domains; and proapoptotic proteins, including BID, BIM, BAD, PUMA, NOXA, BMF, HRK, and BIK, are composed of only BH3 domains (Youle, RJ, et al., Nat Rev Mol Cell Biol, 2008.9(1):pp.47-59). Under normal physiological conditions, the levels of BCL-2 family proteins maintain a dynamic equilibrium, and cell signaling can influence this dynamic equilibrium, regulating the expression of proapoptotic or antiapoptotic proteins, thereby shifting the balance toward cell survival or death. When the equilibrium favors cell death, pro-apoptotic proteins permeabilize the outer mitochondrial membrane by oligomerizing thereon, releasing cytochrome c and triggering the activation of a caspase enzyme cascade, which degrades downstream substrates and leads to cell death (Opferman, JT and A. Kothari, Cell Death Differ, 2018.25(1):pp.37-45.).

[0004] After more than 20 years of development, numerous small molecule BCL-2 inhibitors have been discovered, and the development of small molecule inhibitors targeting the BCL-2 protein family is in full swing. Anti-apoptotic BCL-2 proteins exert their anti-apoptotic function through the binding of their hydrophobic pocket (BH3-binding pocket) to the BH3 domains of pro-apoptotic proteins. BCL-2 family protein antagonists, also known as "BH3 domain mimetics," primarily insert the BH3 domain common to anti-apoptotic BCL-2 family proteins to block their binding to the pro-apoptotic proteins BAX and BAK, thereby inhibiting the action of BCL-2 anti-apoptotic proteins and inducing apoptosis in tumor cells.

[0005] To date, ABT-199 (Venetoclax) is the only antitumor drug approved by the FDA that targets BCL-2 family proteins and can be used to treat certain hematological malignancies (e.g., chronic lymphocytic leukemia and acute myeloid leukemia) (Deeks, ED, Drugs, 2016.76(9):pp.979-87; Carter, PJ and GALazar, Nat Rev Drug Discov, 2018.17(3):pp.197-223). However, because the growth of most solid tumors does not depend on BCL-2 proteins, ABT-199 has no clear therapeutic effect against solid tumors, and it has not been shown to target BCL-X. L The protein was significantly overexpressed in multiple types of solid tumors and hematologic tumor cells (Leverson, JM, et al., Sci Transl Med, 2015.7(279):p.279ra40). Meanwhile, studies have shown that BCL-X in tumor tissues L The expression of BCL-X was positively correlated with tumor resistance (Vogler, M., Adv Med, 2014: p. 943648). L Targeting is a potentially desirable anti-tumor molecular target.

[0006] BCL-X L (B-cell lymphoma-extra large) is a key regulator of apoptosis, located in mitochondria, and can regulate various cellular pathophysiological processes, such as mitochondrial ATP synthesis, protein acetylation, and cell mitosis (Michels, J., et al., International Journal of Cell Biology, 2013. 2013: p. 1-10.).

[0007] Research has shown that vascular senescence is a major causative factor in retinal pathologies such as diabetic macular edema (DME) and wet age-related macular degeneration (wAMD) (Oubaha M., et al., Sci Transl Med. 2016 Oct 26, 8(362):362 ra 144.). The anti-apoptotic protein BCL-X L Targeting BCL-X can induce apoptosis in senescent vascular endothelial cells and treat DME and AMD (Crespo-Garcia S., et al., Cell Metabolism. 2021 Apr 6, 33(4):818-832.e7.). L Treating DME, wAMD, with the small molecule inhibitor UBX1325, which targets is currently in Phase II clinical trials (clinicaltrials.gov).

[0008] Research also shows that BCL-X L It has been shown that BCL-X is overexpressed in many tumors, such as liver cancer, non-Hodgkin's lymphoma, chondrosarcoma, and colorectal cancer (Li, M., et al., Pharmacological Research, 2019.151(4):p. 104547.). In chondrosarcoma, BCL-X L Compared with other BCL2 family members, BCL-X plays the most important role. L Inhibiting BCL-X can enhance the sensitivity of chondrosarcoma cells to conventional chemotherapy (Jong, YD, et al., Oncogenesis, 2018.7(9)). Furthermore, the invasiveness of colorectal cancer cells is also associated with BCL-X. L The BCL2 protein family is closely related to BCL-X in colorectal cancer. L Only BCL-X was significantly elevated (Liu, WD, et al., Official Journal of Balkan Union of Oncology, 2014.19(4):p.925.; Scherr, AL, et al., Cell Death & Disease, 2016.7(8):p.e2342.). LSmall molecule inhibitors targeting BCL-X, such as ABT-263, have significant antitumor activity, but L can limit the proapoptotic effects of Bax, thus aiding platelet survival and inhibiting BCL-X L The development of ABT-263 has not been approved by the FDA because it causes thrombocytopenia and disrupts blood coagulation function after inhibiting the expression of BCL-X (Tse, C., et al., Cancer Research, 2008. 68(9):p.3421.). L is one of the most important validated anti-cancer targets, yet there is a lack of safe and effective treatments.

[0009] PROTACs (Proteolysis Targeting Chimeras) are bifunctional heteroconjugate small molecules that link a target protein ligand and an E3 ubiquitin ligase ligand via an appropriate linking chain, facilitating the formation of a ternary complex between the target protein and the E3 ligase, thereby bringing the target protein closer to the ubiquitination system and achieving ubiquitination, which is then recognized by the 26S protease subunit and ultimately leads to its degradation (Sun, X., et al., Sig Transduct Target Ther, 2019. 4(1):p.33.). Because PROTACs mimic the catalytic process of protein degradation, they can act at extremely low doses, and their efficacy is longer and less toxic than traditional small molecule inhibitors (Lu, J., et al., Chem Biol, 2015. 22(6):p.755-763.). More importantly, because PROTACs rely on E3 ubiquitin ligases to mediate protein degradation, even if the target protein itself is widely expressed in the body, it still has cell or tissue selectivity due to the difference in the expression levels of E3 ubiquitin ligases between tumor cells and normal tissues. For example, DT2216, which has entered clinical trials, targets ABT-263 by targeting the protein BCL-X. LUsing VHL, which is expressed at low levels in platelets, as an E3 ubiquitin ligase ligand significantly enhanced antitumor activity and reduced platelet toxicity (Khan, S., et al., Nature Medicine, 2019.25(4):p.1938-1947.).

[0010] Abnormally activated Hedgehog (Hh) signaling pathway is closely related to the development and occurrence of various types of human tumors (e.g., basal cell carcinoma, medulloblastoma, etc.) (Nat Genet, 2016.48(4):pp.398-406; Cancer Cell, 2014.25(3):pp.393-405). Hh signaling in cells is a cascade-like process, and key molecules involved include the 12-transmembrane domain PTCH receptor, the 7-transmembrane domain SMO (Smoothened) receptor, SUFU protein, and the nuclear transcription factor GLI protein family. In the absence of exogenous HH ligands, PTCH inhibits SMO activity, inhibiting the signaling pathway. When exogenous HH ligands bind to PTCH and release the inhibition of SMO, SMO translocates to the cilium, a crucial central location in the signaling pathway. The SUFU-GLI transcription complex also translocates to the cilium, relieving the inhibitory effect of SUFU on GLI. This then regulates the phosphorylation of GLI by kinases such as GSK3 and CK1, ultimately allowing transcriptionally active GLI to enter the nucleus and initiate transcription of downstream target genes, activating the Hh signaling pathway (Nat Rev Mol Cell Biol, 2013.14(7):p.416-29; Genes Dev, 2010.24(7):p.670-82). Currently, all FDA-approved therapeutic agents for basal cell carcinoma target SMO (Cell, 2016.164(5):p.831.), and therefore have no clear inhibitory effect on tumors in which Hh is abnormally activated due to genetic alterations of key signaling molecules downstream of SMO, such as SMO mutations, SUFU loss-of-function mutations, and GLI amplification. Recent studies have shown that the SUFU protein contains a conserved BH3 sequence and mediates intracellular BCL-X activation. LIt can bind to anti-apoptotic proteins such as BCL-2 and MCL-1, thereby relieving the inhibitory effect of SUFU on GLI proteins, ultimately leading to activation of the Hh pathway and the translocation of BCL-X. L It has been revealed that by inhibiting the binding of anti-apoptotic proteins such as SUFU to Hh signaling pathway activation can be effectively inhibited (Nat Cell Biol, 2017.19(10):pp.1226-1236). Based on this, targeting BCL-2 family proteins is also a strategy for developing inhibitors that target the Hh signaling pathway.

[0011] Therefore, there is a pressing need for a series of novel PROTAC inhibitors that can be used to treat and / or prevent diseases or conditions mediated by BCL-2 family proteins, or diseases or conditions that depend on or are associated with the Hedgehog signaling pathway. Summary of the Invention

[0012] In view of the above, the present disclosure aims to provide novel protein degraders developed based on BCL-2 family protein ligand compounds, their uses, and methods for using them. The novel protein degrader compounds developed based on the BCL-2 family protein ligand compounds disclosed herein, or salts (including pharmaceutically acceptable salts), stereoisomers (including enantiomers), solvates, pharmaceutical precursors, or polymorphs thereof, are capable of binding to target proteins and recruiting the target proteins to E3 ubiquitin ligases to tag them for ubiquitination and degradation, thereby exhibiting the desired pharmacological activity.

[0013] In some embodiments, the novel proteolytic agent developed based on the BCL-2 family protein ligand compound of the present disclosure may be a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analogue, pharmaceutical precursor, or polymorph thereof, [ka] Formula (I) where: Dotted lines indicate optional double bonds; R1, R2, R3, and R4 are the same or different and each independently represent hydrogen, C 1-4 Alkyl, halogen, or halogenated C 1-4 represents alkyl; (R5) n represents that the benzene ring is substituted with n R5, and each R5 is the same or different and independently represents halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl, and n is an integer of 1, 2, 3, 4, or 5; (R6) m represents that the piperazine ring is substituted with m R6, and each R6 is the same or different and independently represents halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl, and m is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; R7 is hydrogen or [ka] represents; R8 represents hydrogen or -SO2CF3 or -NO2; R9 is hydrogen or C 1-4 represents alkyl; R 10 is the following group: [ka] represents Here, the ring W 1 represents a 4- to 6-membered nitrogen-containing heterocyclylene, and (R a1 ) n1 Ring W 1 n1 R a1 Each R represents a substitution a1 are the same or different and each independently: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6an alkoxy, cyano, halogen, or oxo group, and n1 represents an integer of 0 to 8; Ring W 2 is a 4- to 6-membered nitrogen-containing heterocyclylene, or C 3-6 represents a cycloalkylene, n3 represents an integer of 0 or 1, (R a2 ) n2 Ring W 2 There are n2 R a2 represents a group substituted with a2 are the same or different and each independently: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 an alkoxy, cyano, halogen, or oxo group, and n2 represents an integer from 0 to 8; and The symbol * indicates the connection point with LIN; LIN is Optionally substituted straight or branched chain C 1-30 alkylene; or One or more groups R in the carbon backbone b and / or one or more groups R c or one or more groups R b and R c Optionally substituted linear or branched C inserted with any combination of 2-30 represents alkylene, wherein the group R b , R c or group R b and R c The combination of R b is O, N(R d ), C(O), C(O)O, S(O), S(O)2, S(O)2NH, NHS(O)2, OC(O), C(O)N(R d ), N(R d )C(O), or N(R d )C(O)N(R d ), wherein each R d are independently H or C 1-6 represents alkyl, and the straight or branched C 2-30 Two or more groups R in the main carbon chain of the alkylene bWhen R is inserted, each group R b are not directly connected to each other; c is selected from the group consisting of cycloalkylene, arylene, heterocyclylene, heteroarylene, alkynylene, alkenylene, or any combination thereof, wherein said cycloalkylene, said arylene, said heterocyclylene, and said heteroarylene, independently of each other, further comprise C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogen, C 1-6 Optionally substituted with a substituent selected from the group consisting of alkoxy, methyl, methyl ether, methyl methacrylate, methyl ... R 11 has the following structural formula (II): [ka] Formula (II) represents where R 12 is N(R e ), O, S, C 2-6 Alkynylene, or C 2-6 represents alkenylene, where R e is H or C 1-6 represents alkyl, or R 12 represents a bond; (R a ) t is R with t benzene rings a Each R represents a substitution a are the same or different and each independently represent bromine, and t represents an integer of 0, 1, 2, or 3; and X represents C(O) or CH2; Here, if t represents an integer equal to 0, R7 [ka] where n1 represents an integer of 1 to 8, and each R a1 are the same or different and each independently: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6alkoxy, or halogen; or R7 [ka] When R8 represents -SO2CF3.

[0014] In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a salt thereof, stereoisomer (including enantiomer), solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph, and at least one pharmaceutically acceptable carrier.

[0015] In one aspect, the novel protein degrading agent developed based on the BCL-2 family protein ligand compound of the present disclosure is the following compound: 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((2R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide; 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((2R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((1s,4s)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3)cyclohexylphenyl)sulfonyl)benzamide; or 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((1r,4r)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, or a salt, stereoisomer (including enantiomer), solvate, pharmaceutical precursor or polymorph thereof.

[0016] In one aspect, the present disclosure provides a pharmaceutical composition comprising the above-mentioned proteolytic agent compound or a salt, stereoisomer (including enantiomer), solvate, pharmaceutical precursor or polymorph thereof, and at least one pharmaceutically acceptable carrier.

[0017] In one aspect, the present disclosure further provides a pharmaceutical kit or reagent kit comprising a protein degrader compound according to the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0018] In one aspect, the present disclosure provides a proteolytic agent compound according to the present disclosure or a salt thereof, stereoisomer (including enantiomer), solvate, pharmaceutical precursor, or polymorph thereof, for use as a pharmaceutical, or a drug composition containing the same as an active ingredient.

[0019] In one aspect, the present disclosure provides a proteolytic agent compound according to the present disclosure or a salt thereof, stereoisomer (including enantiomer), solvate, pharmaceutical precursor, or polymorph thereof, for use as a pharmaceutical, or a drug composition containing the same as an active ingredient.

[0020] In one aspect, the present disclosure further provides a protein degrader compound according to the present disclosure or a salt, stereoisomer (including enantiomer), solvate, pharmaceutical precursor or polymorph thereof, or a pharmaceutical composition comprising the same as an active ingredient, for use in treating and / or preventing a disease or condition selected from the group consisting of neurodegenerative diseases, vascular heart disorders, autoimmune diseases, myelofibrosis, renal fibrosis, hepatic fibrosis, cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), multiple organ failure due to cachexia and septic shock, organ (including kidney, heart, and lung) or tissue transplant rejection, diabetes, transplant rejection, retinopathy, and acute liver failure.

[0021] In one aspect, the present disclosure further provides use of a protein degrader compound according to the present disclosure, or a salt, stereoisomer (including enantiomer), solvate, pharmaceutical precursor or polymorph thereof, in the manufacture of a medicament for treating and / or preventing a disease or condition selected from the group consisting of neurodegenerative diseases, vascular cardiac disorders, autoimmune diseases, myelofibrosis, renal fibrosis, hepatic fibrosis, cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), multiple organ failure due to cachexia and septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes, transplant rejection, retinopathy and acute liver failure.

[0022] In one aspect, the present disclosure further provides a method for treating or preventing a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a protein degrader compound according to the present disclosure, or a salt, enantiomer, stereoisomer, solvate, pharmaceutical precursor, or polymorph thereof, or a pharmaceutical composition comprising any of them, or a therapeutically effective amount of a compound according to the present disclosure, or a salt, stereoisomer (including enantiomer), solvate, pharmaceutical precursor, or polymorph thereof, or a pharmaceutical composition comprising any of them as an active ingredient, wherein the disease or condition is selected from the group consisting of neurodegenerative diseases, vascular heart disorders, autoimmune diseases, myelofibrosis, renal fibrosis, hepatic fibrosis, cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), multiple organ failure due to cachexia and septic shock, organ (including kidney, heart, and lung) or tissue transplant rejection, diabetes, transplant rejection, retinopathy, and acute liver failure. [Brief explanation of the drawings]

[0023] [Figure 1] Figures 1-3 are schematic diagrams of the results of protein Western blotting experiments, showing that compounds of the present invention, such as BCL-03146, BCL-03147, BCL-03148, and BCL-03149 (100 nM), significantly reduced BCL-XL protein expression after 8 hours of treatment in Molt-4 cells, demonstrating superior protein degradation compared to DT2216 (CAS number: 2365172-42-3; a BCL-XL degrader reported in the literature). [Figure 2] Same as above. [Figure 3] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0024] In order to facilitate understanding and implementation of the contents of the present disclosure, the following detailed description is provided as an illustrative specific embodiment. However, such description is not intended to limit the scope of the present disclosure. It should be recognized that the specific embodiments described in the present disclosure can be further modified and changed in various ways without departing from the spirit and scope of the present disclosure, and these modifications and improvements fall within the protection scope of the present disclosure. I. Compound Compounds of formula (I)

[0025] The present disclosure provides a compound of formula (I) or a salt (including a pharmaceutically acceptable salt), stereoisomer (including an enantiomer), solvate, isotopically enriched analogue, pharmaceutical precursor, or polymorph thereof, [ka] Formula (I) where R1, R2, R3, R4, (R5) n , (R6) m , R7, R8, R9, R 10 , LIN, and R 11 is as defined above for compounds of formula (I).

[0026] In some embodiments, the dotted line in compounds of Formula (I) indicates the optional presence of a double bond.

[0027] In some embodiments, the dotted line in a compound of Formula (I) indicates the presence of a bond. In this case, the group in a compound of Formula (I) that includes the dotted line has the following formula: [ka] It is expressed as:

[0028] In some embodiments, the dotted line in a compound of Formula (I) indicates an absent bond. In this case, the group in a compound of Formula (I) that includes the dotted line has the following formula: [ka] It is expressed as:

[0029] In some embodiments, R, R, R, and R of the compound of Formula (I) are the same or different and each independently represent hydrogen, C 1-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl), halogen (e.g., fluorine, chlorine, bromine, or iodine), or halogenated C 1-4 Alkyl (e.g., halogenated C 1-3 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-).

[0030] In some embodiments, R1 and R2 of the compound of Formula (I) represent hydrogen, and R3 and R4 represent methyl.

[0031] In some embodiments, R1 and R2 of the compound of Formula (I) represent methyl, and R3 and R4 represent hydrogen.

[0032] In some embodiments, (R5) of the compound of formula (I) n represents that the benzene ring is substituted with n R5, and each R5 is the same or different and independently represents halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), or halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 alkyl, e.g., F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, or CH2ClCH2-), where n represents an integer of 1, 2, 3, 4, or 5. In some embodiments, n represents an integer of 1, and R5 represents a halogen (e.g., fluorine, chlorine, bromine, or iodine).

[0033] In some embodiments, (R6) of the compound of formula (I) m represents that the piperazine ring is substituted with m R6, each R6 being the same or different and each independently selected from halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), or halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 alkyl, for example, F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), and m represents an integer of 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0034] In some embodiments, R7 is hydrogen or [ka] Represents.

[0035] In some embodiments, R7 represents hydrogen.

[0036] In some embodiments, R7 is [ka] Represents.

[0037] In some embodiments, R represents hydrogen or —SO CF or —NO ;

[0038] In some embodiments, R8 represents hydrogen.

[0039] In some embodiments, R8 represents -SO2CF3.

[0040] In some embodiments, R8 represents -NO2.

[0041] In some embodiments, R9 is hydrogen or C 1-4 Alkyl (e.g., C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl).

[0042] In some embodiments, R9 represents hydrogen.

[0043] In some embodiments, R9 is C 1-4 Alkyl (e.g., C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl).

[0044] In some embodiments, R 10 is the following group: [ka] represents Here, the ring W 1 represents a 4- to 6-membered nitrogen-containing heterocyclylene, and (R a1 ) n1 Ring W 1 n1 R a1 represents a group substituted with a1 are the same or different and each independently: C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), cyano, halogen (e.g., fluorine, chlorine, bromine, or iodine), or oxo group, and n1 represents an integer from 0 to 8; Ring W 2 is a 4- to 6-membered nitrogen-containing heterocyclylene, or C 3-6 represents a cycloalkylene, n3 represents an integer of 0 or 1, (R a2 ) n2 Ring W 2 There are n2 R a2 represents a group substituted with a2 are the same or different and each independently: C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), cyano, halogen (e.g., fluorine, chlorine, bromine, or iodine), or oxo group, and n2 represents an integer from 0 to 8; and The symbol * indicates the connection point with LIN.

[0045] In some embodiments, the ring W 1 represents a 4- to 6-membered nitrogen-containing heterocyclylene, and examples of the 4- to 6-membered nitrogen-containing heterocyclylene include, but are not limited to, piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, and thiomorpholinylene.

[0046] In some embodiments, (R a1 ) n1 Ring W 1 n1 R a1 represents a group substituted with a1 are the same or different and each independently: C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), cyano, halogen (e.g., fluorine, chlorine, bromine, or iodine), or oxo group, and n1 represents an integer of 0-8 (e.g., an integer of 0, 1, 2, 3, or 4).

[0047] In some embodiments, the ring W 2 represents a 4- to 6-membered nitrogen-containing heterocyclylene, and examples of the 4- to 6-membered nitrogen-containing heterocyclylene include, but are not limited to, piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, and thiomorpholinylene.

[0048] In some embodiments, the ring W 2 is C 3-6 It represents cycloalkylene, and the 4- to 6-membered cycloalkylene includes, but is not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0049] In some embodiments, (R a2 ) n2 Ring W 2 There are n2 R a2 represents a group substituted with a2 are the same or different and each independently: C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), cyano, halogen (e.g., fluorine, chlorine, bromine, or iodine), or oxo group, and n2 represents an integer of 0-8 (e.g., an integer of 0, 1, 2, 3, or 4).

[0050] In some embodiments, n3 represents an integer of 0 or 1.

[0051] In some embodiments, n3 represents the integer 0.

[0052] In some embodiments, n3 represents the integer 1.

[0053] In some embodiments, R 10 is the following group: [ka] represents Here, the symbol * indicates the connection point with LIN.

[0054] In some embodiments, R 11The structural formula of the compound represented by the formula (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (II-7), (II-8), (II-9), (II-10), (II-11), or (II-12): [ka] where: R 12 is N(R e ), O, S, C 2-6 Alkynylene (e.g., ethynylene), or C 2-6 represents alkenylene (e.g., vinylene), where R e is H or C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), or R 12 represents a bond; X represents C(O) or CH; and (R a ) t is R with t benzene rings a Each R represents a substitution a are the same or different and each independently represent bromine; and t represents an integer of 0, 1, 2, or 3.

[0055] In some embodiments, X represents C(O).

[0056] In some embodiments, X represents CH2.

[0057] In some embodiments, R 12 represents a bond.

[0058] In some embodiments, t represents the integer 0.

[0059] In some embodiments, t represents an integer of 1, 2, or 3.

[0060] In some embodiments, R 11 is a structure of the formula: [ka] Represents.

[0061] In the present disclosure, when t represents an integer of 0, R7 is [ka] where n1 represents an integer from 1 to 8 (e.g., an integer of 1, 2, 3, 4, 5, 6, 7, or 8), and each R a1 are the same or different and each independently: C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy, or halogen, such as fluorine, chlorine, bromine or iodine.

[0062] In the present disclosure, when t represents an integer of 0, R7 is [ka] When R8 represents -SO2CF3.

[0063] In some embodiments, the LIN has the structure of the following formula: #-C 1-30 Alkylene-; #-(C(R a3 )(Ra4 )) n4 -(R b -(C(R a5 )(R a6 )) n5 ) m1 -; #-(C(R a3 )(R a4 )) n4 -(R b -(C(R a5 )(R a6 )) n5 ) m1 -(R b -(C(R a7 )(R a8 )) n6 ) m2 -; #-(C(R a3 )(R a4 )) n4 -(R b -(C(R a5 )(R a6 )) n5 ) m1 -(R b -(C(R a7 )(R a8 )) n6 ) m2 -(R b -(C(R a9 )(R a10 )) n7 ) m3 -; #-(C(R a3 )(R a4 )) n4 -(R c -(C(R a5 )(R a6 )) n5 ) m1 -; #-(C(R a3 )(R a4 )) n4 -(R c -(C(R a5 )(R a6 )) n5 ) m1 -(R c -(C(R a7 )(R a8 )) n6 ) m2 -; #-(C(R a3 )(R a4 )) n4 -(R c -(C(R a5 )(R a6 )) n5 ) m1 -(R c -(C(R a7 )(R a8 )) n6 ) m2 -(R c -(C(R a9 )(R a10 )) n7 ) m3 -; #-(C(R a3 )(R a4 )) n4 -(R b -R c -(C(R a5 )(R a6 )) n5 ) m1 -; #-(C(R a3 )(R a4 )) n4 -(R b -(C(R<000029l>)(R a6 ))[[ID=7,2]] n5 ) m1 -(R c -(C(R a7 )(R a8 )) n6 ) m2 -; #-(C(R a3 )(R a4 )) n4 -(R c -R b -(C(R a5 I )(R a6 )) n5 ) m1 -; or #-(C(R a3 )(R a4 )) n4 I -(R c -(C(R a5 )(R a6 )) n5 ) m1 -(R b-(C(R a7 )(R a8 )) n6 ) m2 -; represents where each group R b is O, N(R d ), C(O), C(O)O, OC(O), S(O), S(O)2, S(O)2NH, NHS(O)2, C(O)N(R d ), N(R d )C(O), or N(R d )C(O)N(R d ), wherein each R d is displayed independently as H or C 1-6 Alkyl (e.g., C 1-4 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl); c is a cycloalkylene (e.g., C 3-20 cycloalkylene), arylene (e.g., C 3-20 arylene), heterocyclylene (e.g., 4- to 20-membered heterocyclylene), heteroarylene (e.g., 4- to 20-membered heteroarylene), alkynylene (e.g., C 2-6 alkynylene), alkenylene (e.g., C 2-6 alkenylene), or any combination thereof, wherein said cycloalkylene, said arylene, said heterocyclylene, and said heteroarylene, independently of each other, further comprise: 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 Alkyl or halogenated C 1-3 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), halogen (for example fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g., C1-4 Alkoxy or C 1-3 optionally substituted with a substituent selected from the group consisting of alkoxy, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), or any combination thereof; Said C 1-30 The hydrogen in one or more CH of the alkylene may further be C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 Alkyl or halogenated C 1-3 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), halogen (for example fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 optionally substituted with a substituent selected from the group consisting of alkoxy, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), or any combination thereof; R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , and R a10 are the same or different and each independently represent H, C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 Alkyl or halogenated C 1-3alkyl, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), halogen (such as fluorine, chlorine, bromine or iodine), or C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy; n4, n5, n6, n7, m1, m2, and m3 are each independently selected from the group consisting of the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and The symbol # is the group R 10 Represents the connection point with.

[0064] In some embodiments, the LIN has the structure of the following formula: #-(C(R a3 )(R a4 )) n4 -(O-(C(R a5 )(R a6 )) n5 ) m1 -; #-(C(R a3 )(R a4 )) n4 -(O-(C(R a5 )(R a6 )) n5 ) m1 -(O-(C(R a7 )(R a8 )) n6 ) m2 -; #-(C(R a3 )(R a4 )) n4 -(O-(C(R a5 )(R a6 )) n5 ) m1 -(O-(C(R a7 )(R a8 )) n6 ) m2 -(O(C(R a9 )(R a10)) n7 ) m3 -; #-(C(R a3 )(R a4 )) n4 -(N(R d )-(C(R a5 )(R a6 )) n5 ) m1 -; #-(C(R a3 )(R a4 )) n4 -(N(R d )-(C(R a5 )(R a6 )) n5 ) m1 -(N(R d )-(C(R a7 )(R a8 )) n6 ) m2 -; #-(C(R a3 )(R a4 )) n4 -(N(R d )-(C(R a5 )(R a6 )) n5 ) m1 -(N(R d )-(C(R a7 )(R a8 )) n6 ) m2 -(N(R d )-(C(R a9 )(R a10 )) n7 ) m3 -; #-(C(R a3 )(R a4 )) n4 -(C(O)N(R d )-(C(R a5 )(R a6 )) n5 ) m1 -; #-(C(R a3 )(R a4 )) n4 -(C(O)N(R d )-(C(R a5 )(R a6 ))n5 ) m1 -(C(O)N(R d )-(C(R a7 )(R a8 )) n6 ) m2 -; #-(C(R a3 )(R a4 )) n4 -(C(O)N(R d )-(C(R a5 )(R a6 )) n5 ) m1 -(C(O)N(R d )-(C(R a7 )(R a8 )) n6 ) m2 -(C(O)N(R d )-(C(R a9 )(R a10 )) n7 ) m3 -; #-(C(R a3 )(R a4 )) n4 -(C(O)N(R d )-(C(R a5 )(R a6 )) n5 ) m1 -(O-(C(R a7 )(R a8 )) n6 ) m2 -; #-(C(R a3 )(R a4 )) n4 -C(O)N(R d )-(C(R a5 )(R a6 )) n5 -(O-(C(R a7 )(R a8 )) n6 ) m1 -; #-(C(R a3 )(R a4 )) n4 -(N(R d )C(O)-(C(R a5 )(R a6 )) n5 )m1 -; #-(C(R a3 )(R a4 )) n4 -(N(R d )C(O)-(C(R a5 )(R a6 )) n5 ) m1 -(O-(C(R a7 )(R a8 )) n6 ) m2 -; #-(C(R a3 )(R a4 )) n4 -(N(R d )C(O)-(C(R a5 )(R a6 )) n5 ) m1 -(O-(C(R a7 )(R a8 )) n6 ) m2 -(O-(C(R a9 )(R a10 )) n7 ) m3 -; #-(C(R a3 )(R a4 )) n4 -N(R d )C(O)-(C(R a5 )(R a6 )) n5 -(O-(C(R a7 )(R a8 )) n6 ) m1 -; #-(C(R a3 )(R a4 )) n4 -N(R d )C(O)N(R d )-(C(R a5 )(R a6 )) n5 -; #-(C(R a3 )(R a4 )) n4 -C(O)-(C(R a5 )(R a6 )) n5 -; #-(C(R a3 )(R a4 )) n4 -(arylene-(C(R a5 )(R a6 )) n5 ) m1 -; #-(C(R a3 )(R a4 )) n4 -(arylene-(C(R a5 )(R a6 )) n5 ) m1 -Arylene-(C(R a7 )(R a8 )) n6 -; #-(C(R a3 )(R a4 )) n4 -(heterocyclylene-(C(R a5 )(R a6 )) n5 ) m1 -; #-(C(R a3 )(R a4 )) n4 -(heterocyclylene-(C(R a5 )(R a6 )) n5 ) m1 -(heterocyclylene-(C(R a7 )(R a8 )) n6 ) m2 -; #-(C(R a3 )(R a4 )) n4 -(heteroarylene-(C(R a5 )(R a6 )) n5 ) m1 -; #-(C(R a3 )(R a4 )) n4 -(heteroarylene-(C(R a5 )(R a6 )) n5 ) m1 -(heteroarylene-(C(R a7 )(R a8 )) n6 )m2 -; #-(C(R a3 )(R a4 )) n4 -(cycloalkylene-(C(R a5 )(R a6 )) n5 ) m1 -or #-(C(R a3 )(R a4 )) n4 -(cycloalkylene-(C(R a5 )(R a6 )) n5 ) m1 -(cycloalkylene-(C(R a7 )(R a8 )) n6 ) m2 - represents; Here, each R d are independently H or C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl; The cycloalkylene (e.g., C 3-20 cycloalkylene), the arylene (e.g., C 3-20 The heterocyclylene (for example, 4- to 20-membered heterocyclylene) and the heteroarylene (for example, 4- to 20-membered heteroarylene) may each independently further include C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 Alkyl or halogenated C 1-3 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), halogen (for example fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g., C 1-4Alkoxy or C 1-3 optionally substituted with a substituent selected from the group consisting of alkoxy, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), or any combination thereof; R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , and R a10 are the same or different and each independently represent H, C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 Alkyl or halogenated C 1-3 alkyl, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), halogen (such as fluorine, chlorine, bromine or iodine), or C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy; n4, n5, n6, n7, m1, m2, and m3 are each independently selected from the group consisting of the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and The symbol # is the group R 10 Represents the connection point with.

[0065] In some embodiments, the LIn is a group that is: #-CH2-, #-(CH2)2-, #-(CH2)3-, #-(CH2)4-, #-(CH2)5-, #-(CH2)6-, #-(CH2)7-, #-(CH2)8-, #-(CH2)9-, #-(CH2)10 -、 #-(CH2) 11 -、 #-(CH2) 12 -、 #-(CH2) 13 -、 #-(CH2) 14 -、 #-(CH2) 15 -、 #-(CH2) 16 -、 #-(CH2) 17 -、 #-(CH2) 18 -、 #-(CH2) 19 -、 #-(CH2) 20 -、 #-(CH2) 21 -、 #-(CH2) 22 -、 #-(CH2) 25 -、 or #-(CH2) 30 -; #-CH2-O-CH2-, #-CH2-O-(CH2)2-, #-(CH2)1-O-(CH2)3-, #-(CH2)1-O-(CH2)4-, #-(CH2)1-O-(CH2)5-, #-(CH2)1-O-(CH2)6-, #-(CH2)1-O-(CH2)7-, #-(CH2)1-O-(CH2)8-, #-(CH2)1-O-(CH2)9-, #-(CH2)1-O-(CH2) 10 -、 #-(CH2)2-O-(CH2)1-, #-(CH2)2-O-(CH2)2-, #-(CH2)2-O-(CH2)3-, #-(CH2)2-O-(CH2)4-, #-(CH2)2-O-(CH2)5-, #-(CH2)2-O-(CH2)6-, #-(CH2)2-O-(CH2)7-, #-(CH2)2-O-(CH2)8-, #-(CH2)2-O-(CH2)9-, #-(CH2)2-O-(CH2) 10 -、 #-(CH2)2-O-(CH2) 11 -、 #-(CH2)2-O-(CH2) 12-#-(CH2)3-O-(CH2)1-,#-(CH2)3-O-(CH2)2-,#-(CH2)3-O-(CH2)3-,#-(CH2)3-O-(CH2)4-,#-(CH2)3-O-(CH2)5-,#-(CH2)3-O-(CH2)6-,#-(CH2)3-O-(CH2)7-,#-(CH2)4-O-(CH2)1-,#-(CH2)4-O-(CH2)2-,#-(CH 2)4-O-(CH2)3-, #-(CH2)4-O-(CH2)4-, #-(CH2)4-O-(CH2)5-, #-(CH2)4-O-(CH2)6-, #-(CH2)5-O-(CH2)1-, #-(CH2)5-O-(CH2)2-, #-(CH2)5-O-(CH2)3-, #-(CH2)5-O-(CH2)4-, #-(CH2)5-O-(CH2)5-, #-(CH2)6-O-( CH2)1-, #-(CH2)6-O-(CH2)2-, #-(CH2)6-O-(CH2)3-, #-(CH2)6-O-(CH2)4-, #-(CH2)7-O-(CH2)1-, #-(CH2)7-O-(CH2)2-, #-(CH2)7-O-(CH2)3-, #-(CH2)8-O-(CH2)1-, #-(CH2)8-O-(CH2)2-, #-CH(CH3)-O-(CH2)1- 、#-CH(CH3)-O-(CH2)2-、#-CH(CH3)-O-(CH2)3-、#-CH(CH3)-O-(CH2)4-、#-CH(CH3)-O-(CH2)5-、#-CH(CH3)-O-(CH2)6-、#-CH(CH3)-O-(CH2)7-、#-CH(CH3)-O-(CH2)8-、#-CH(CH3)-O-(CH2)9-、#-CH(CH3)-O-(CH2) 10 -, #-CH2-(O(CH2)2)2-, #-CH2-(O(CH2)2)3-, #-CH2-(O(CH2)2)4-, #-CH2-(O(CH2)2)5-, #-CH2-(O(CH2)2)6-, #-CH2-(O(CH2)2)7-, #-CH2-(O(CH2)2)8-, #-CH2-(O(CH2)2)9-, #-CH2-(O(CH2)2) 10-、#-CH2-(O(CH2)2)1-OCH2-、#-CH2-(O(CH2)2)2-OCH2-、#-CH2-(O(CH2)2)3-OCH2-、#-CH2-(O(CH2)2)4-OCH2-、#-CH2-(O(CH2)2)5-OCH2-、#-CH2-(O(CH2)2)6-OCH2-、#-CH2-(O(CH2)2)7-OCH2-、#-CH2-(O(CH2)2)8-OCH2-、#-CH2-(O(CH2)2)9-OCH2-、#-CH2-(O(CH2)2) 10 -OCH2-、#-(CH2)2-(O(CH2)2)2-、#-(CH2)2-(O(CH2)2)3-、#-(CH2)2-(O(CH2)2)4-、#-(CH2)2-(O(CH2)2)5-、#-(CH2)2-(O(CH2)2)6-、#-(CH2)2-(O(CH2)2)7-、#-(CH2)2-(O(CH2)2)8-、#-(CH2)2-(O(CH2)2)9-、#-(CH2)2-(O(CH2)2) 10 -、#-(CH2)3-(O(CH2)2)2-、#-(CH2)3-(O(CH2)2)3-、#-(CH2)3-(O(CH2)2)4-、#-(CH2)3-(O(CH2)2)5-、#-(CH2)3-(O(CH2)2)6-、#-(CH2)3-(O(CH2)2)7-、#-(CH2)3-(O(CH2)2)8-、#-(CH2)3-(O(CH2)2)9-、#-(CH2)3-(O(CH2)2) 10 -、#-(CH2)4-(O(CH2)2)2-、#-(CH2)4-(O(CH2)2)3-、#-(CH2)4-(O(CH2)2)4-、#-(CH2)4-(O(CH2)2)5-、#-(CH2)4-(O(CH2)2)6-、#-(CH2)4-(O(CH2)2)7-、#-(CH2)4-(O(CH2)2)8-、#-(CH2)4-(O(CH2)2)9-、#-(CH2)4-(O(CH2)2) 10 -、#-CH2-(O(CH2)3)2-、#-CH2-(O(CH2)3) 3-#-CH2-(O(CH2)3) 4-#-CH2-(O(CH2)3) 5-#-CH2-(O(CH2)3) 6-#-CH2-(O(CH2)3) 7-#-CH2-(O(CH2)3) 8-#-CH2-(O(CH2)3) 9-#-CH2-(O(CH2)3) 10 -, #-(CH2)2-(O(CH2)3)2-, #-(CH2)2-(O(CH2)3)3-, #-(CH2)2-(O(CH2)3)4-, #-(CH2)2-(O(CH2)3)5-, #-(CH2)2-(O(CH2)3)6-, #-(CH2)2-(O(CH2)3)7-, #-(CH2)2-(O(CH2)3)8-, #-(CH2)2-(O(CH2)3)9-, #-(CH2)2-(O(CH2)3) 10 -, #-(CH2)3-(O(CH2)3)2-, #-(CH2)3-(O(CH2)3)3-, #-(CH2)3-(O(CH2)3)4-, #-(CH2)3-(O(CH2)3)5-, #-(CH2)3-(O(CH2)3)6-, #-(CH2)3-(O(CH2)3)7-, #-(CH2)3-(O(CH2)3)8-, #-(CH2)3-(O(CH2)3)9-, #-(CH2)3-(O(CH2)3) 10- #-CH2-O-(CH2)2-O-(CH2)3- #-CH2-(O(CH2)2)2-(O(CH2)3)2- #-CH2-(O(CH2)2)3-(O(CH2)3)3- #-CH2-(O(CH2)2)4-(O(CH2)3)4- #-CH2-(O(CH2)2)5-(O(CH2)3)5- #-CH2-(O(CH2)2)6-(O(CH2)3)6- #-(CH2)2-O-(CH2)2-O-(CH2)3- #-(CH2)2-(O(CH2)2)2-(O(CH2)3)2- #-(CH2)2-(O(CH2)2 )3-(O(CH2)3)3-、#-(CH2)2-(O(CH2)2)4-(O(CH2)3)4-、#-(CH2)2-(O(CH2)2)5-(O(CH2)3)5-、#-(CH2)2-(O(CH2)2)6-(O(CH2)3)6-、#-(CH2)3-O-(CH2)2-O-(CH2)3-、#-(CH2)3-(O(CH2)2)2-(O(CH2)3)2-、#-(CH2)3-(O(CH2)2)3-(O(CH2)3)3-、#-(CH2)3-(O(CH2)2)4-(O(CH2)3)4-、#-(CH2)3-(O(CH2 )2)5-(O(CH2)3)5-、#-(CH2)3-(O(CH2)2)6-(O(CH2)3)6-、#-CH2-O-(CH2)3-O-(CH2)2-、#-CH2-(O(CH2)3)2-(O(CH2)2)2-、#-CH2-(O(CH2)3)3-(O(CH2)2)3-、#-CH2-(O(CH2)3)4-(O(CH2)2)4-、#-CH2-(O(CH2)3)5-(O(CH2)2)5-、#-CH2-(O(CH2)3)6-(O(CH2)2)6-、#-(CH2)2-O-(CH2)3-O-(CH2)2-、#- (CH2)2-(O(CH2)3)2-(O(CH2)2)2-、#-(CH2)2-(O(CH2)3)3-(O(CH2)2)3-、#-(CH2)2-(O(CH2)3)4-(O(CH2)2)4-、#-(CH2)2-(O(CH2)3)5-(O(CH2)2)5-、#-(CH2)2-(O(CH2)3)6-(O(CH2)2)6-、#-(CH2)3-O-(CH2)3-O-(CH2)2-、#-(CH2)3-(O(CH2)3)2-(O(CH2)2)2-、#-(CH2)3-(O(CH2)3)3-(O(CH2)2)3-、#-(CH2)3-(O(CH2)3)4-(O(CH2)2)4-、#-(CH2)3-(O(CH2)3)5-(O(CH2)2)5-、#-(CH2)3-(O(CH2)3)6-(O(CH2)2)6-、#-CH2-O-(CH2)2-O-CH2-、#-(CH2)2-O-(CH2)2-O-CH2-、#-(CH2)2-(O(CH2)2)2-O-(CH2)3-、#-(CH2)2-(O(CH2)2)3-O-(CH2)3-、#-(CH2)2-(O(CH2)2)4-O-(CH2)3-、#-(CH2)5-(O(CH2)2)2-O-(CH2)5-、#-(CH2)5-(O(CH2)2)2-O-(CH2)6-、#-(CH2)1-N(R、 g )-(CH2)1-、#-(CH2)1-N(R g )-(CH2)2-、#-(CH2)1-N(R g )-(CH2)3-、#-(CH2)1-N(R g )-(CH2)4-、#-(CH2)1-N(R g )-(CH2)5-、#-(CH2)1-N(R g )-(CH2)6-、#-(CH2)1-N(R g )-(CH2)7-、#-(CH2)1-N(R g )-(CH2)8-、#-(CH2)1-N(R g )-(CH2)9-、#-(CH2)1-N(R g )-(CH2) 10 -、#-(CH2)2-N(R g )-(CH2)1-、#-(CH2)2-N(R g )-(CH2)2-、#-(CH2)2-N(R g )-(CH2)3-、#-(CH2)2-N(R g )-(CH2)4-、#-(CH2)2-N(R g )-(CH2)5-、#-(CH2)2-N(R g )-(CH2)6-、#-(CH2)2-N(R g )-(CH2)7-、#-(CH2)2-N(R g )-(CH2)8-、#-(CH2)2-N(R g )-(CH2)9-、#-(CH2) 2-N(Rg )-(CH2) 10 -、#-(CH2)2-N(R g )-(CH2) 11 -、#-(CH2)2-N(R g )-(CH2) 12 -、#-(CH2)3-N(R g )-(CH2)1-、#-(CH2)3-N(R g )-(CH2)2-、#-(CH2)3-N(R g )-(CH2)3-、#-(CH2)4-N(R g )-(CH2)1-、#-(CH2)4-N(R g )-(CH2)2-、#-(CH2)4-N(R g )-(CH2)3-、#-(CH2)4-N(R g )-(CH2)4-、#-(CH2)5-N(R g )-(CH2)1-、#-(CH2)5-N(R g )-(CH2)2-、#-(CH2)5-N(R g )-(CH2)3-、#-(CH2)5-N(R g )-(CH2)4-、#-(CH2)5-N(R g )-(CH2)5-、#-(CH2)6-N(R g )-(CH2)1-、#-(CH2)6-N(R g )-(CH2)2-、#-(CH2)6-N(R g )-(CH2)3-、#-(CH2)7-N(R g )-(CH2)1-、#-(CH2)7-N(R g )-(CH2)2-、#-(CH2)7-N(R g )-(CH2)3-、#-(CH2)8-N(R g )-(CH2)1-、#-(CH2)8-N(R g )-(CH2)2-、#-(CH2)8-N(R g )-(CH2)3-、#-CH(CH3)-N(R g )-(CH2)1-、#-CH(CH3)-N(R g )-(CH2)2-、#-CH(CH3)-N(R g )-(CH2)3-、#-CH(CH3)-N(R g)-(CH2)4-、#-CH(CH3)-N(R g )-(CH2)5-、#-CH(CH3)-N(R g )-(CH2)6-、#-CH(CH3)-N(R g )-(CH2)7-、#-CH(CH3)-N(R g )-(CH2)8-、#-CH(CH3)-N(R g )-(CH2)9-、#-CH(CH3)-N(R g )-(CH2) 10 -, #-CH2C(O)NHCH2-, #-(CH2)2C(O)NH(CH2)2-, #-(CH2)2C(O)NH(CH2)3-, #-(CH2)2C(O)NH(CH2)4-, #-(CH2)2C(O)NH(CH2)5-, #-(CH2)3C(O)NH(CH2)3-, #-(CH2)3C(O)NH(CH2)4-, #-(CH 2)4C(O)NH(CH2)4-, #-(CH2)5C(O)NH(CH2)5-, #-(CH2)6C(O)NH(CH2)7-, #-(CH2)6C(O)NH(CH2)6-, #-(CH2)7C(O)NH(CH2)7-, #-(CH2)8C(O)NH(CH2)8, U-(CH2)9C(O)NH(CH2)9-, #-(CH2) 10 C(O)NH(CH2) 10 -、#-(CH2)2C(O)NH(CH2)2-O-(CH2)2-、#-CH2NHC(O)CH2-、#-(CH2)2NHC(O)(CH2)2-、#-(CH2)2NHC(O) (CH2)3-、#-(CH2)2NHC(O)(CH2)4-、#-(CH2)2NHC(O)(CH2)5-、#-(CH2)3NHC(O)(CH2)3-、#-(CH2)3NHC (O)(CH2)4-、#-(CH2)4NHC(O)(CH2)4-、#-(CH2)5NHC(O)(CH2)5-、#-(CH2)6NHC(O)(CH2)7-、#-(CH2)6 NHC(O)(CH2)6-、#-(CH2)7NHC(O)(CH2)7-、#-(CH2)8NHC(O)(CH2)8、#-(CH2)9NHC(O)(CH2)9-、#-(CH2) 10 NHC(O)(CH2) 10-, #-(CH2)4NHC(O)(CH2)8-, #-(CH2)2NHC(O)(CH2)2-O-(CH2)2-, #-(CH2)4NHC(O)CH2-, #-CH2-piperidinylene-CH2-, #-CH2-piperidinylene-(CH2)2-, #-CH2-piperidinylene-(CH2)3-, #-CH2-piperidinylene-(CH2)4-, #-CH2-piperidinylene-(CH2)5-, #-CH2-piperidinylene-(CH2)6-, #-CH2-piperidinylene-(CH2)7-, #-CH2-piperidinylene-(CH2)8-, #-(CH2)2-piperidinylene-(CH2)1-, #-(CH2)2-piperidinylene-(CH2)2-, #-(CH2)2-piperidinylene-(CH2)3-, #-(CH2)2-piperidinylene-(CH2)4-, #-(CH2)2-piperidinylene-(CH2)5-, #-(CH2)2-piperidinylene-(CH2)6-, #-(CH2)2-piperidinylene-(CH2)7-, #-(CH2)2-piperidinylene-(CH2)8-, #-(CH2)3-piperidinylene-CH2-, #-(CH2)3-piperidinylene-(CH2)2-, # -(CH2)3-piperidinylene-(CH2)3-, #-(CH2)3-piperidinylene-(CH2)4-, #-(CH2)3-piperidinylene-(CH2)5-, #-(CH2)3-piperidinylene-(CH2)6-, #-(CH2)3-piperidinylene-(CH2)7-, #-(CH2)3-piperidinylene-(CH2)8-, #-(CH2)4-piperidinylene-CH2-, #-(CH2)4-piperidinylene-(CH2)2-, #-(CH2)4-piperidinylene-(CH2)3-, #-(CH2)4-piperidinylene-(CH2)4-, #- (CH2)4-piperidinylene-(CH2)5-, #-(CH2)4-piperidinylene-(CH2)6-, #-(CH2)4-piperidinylene-(CH2)7-, #-(CH2)4-piperidinylene-(CH2)8-, #-(CH2)5-piperidinylene-(CH2)1-, #-(CH2)5-piperidinylene-(CH2)2-, #-(CH2)5-piperidinylene-(CH2)3-, #-(CH2)5-piperidinylene-(CH2)4-, #-(CH2)5-piperidinylene-(CH2)5-, #-(CH2)5-piperidinylene-(CH2)6-,#-(CH2)5-piperidinylene-(CH2)7-, #-(CH2)5-piperidinylene-(CH2)8-, #-(CH2)6-piperidinylene-(CH2)1-, #-(CH2)6-piperidinylene-(CH2)2-, #-(CH2)6-piperidinylene-(CH2)3-, #-(CH2)6-piperidinylene-(CH2, )4-, #-(CH2)6-piperidinylene-(CH2)5-, #-(CH2)6-piperidinylene-(CH2)6-, #-(CH2)6-piperidinylene-(CH2)7-, #-(CH2)6-piperidinylene-(CH2)8-, #-(CH2)7-piperidinylene-(CH2)1-, #-(CH2)7-piperidinylene-(CH2)2-, #-(CH2)7-piperidinylene-(CH2)3-, #-(CH2)7-piperidinylene-(CH2)4-, #-(CH2)7-piperidinylene Nylene-(CH2)8-, #-(CH2)8-piperidinylene-CH2-, #-(CH2)8-piperidinylene-(CH2)2-, #-(CH2)8-piperidinylene-(CH2)3-, #-(CH2)8-piperidinylene-(CH2)4-, #-(CH2)8-piperidinylene-(CH2)5-, #-(CH2)8-piperidinylene-(CH2)6-, #-(CH2)8-piperidinylene-(CH2)7-, #-(CH2)8-piperidinylene-(CH2)8-, #-CH2-N(R g )-CH2-piperidinylene-CH2-, #-CH2-N(R g )-CH2-piperidinylene-(CH2)2-, #-CH2-N(R g )-CH2-piperidinylene-(CH2)3-, #-CH2-N(R g )-CH2-piperidinylene-(CH2)4-, #-CH2-N(R g )-CH2-piperidinylene-(CH2)5-, #-CH2-N(R g )-CH2-piperidinylene-(CH2)6-, #-CH2-N(R g )-CH2-piperidinylene-(CH2)7-, #-CH2-N(R g )-CH2-piperidinylene-(CH2)8-, #-CH2-N(R g )-(CH2)2-piperidinylene-CH2-, #-CH2-N(R g)-(CH2)2-piperidinylene-(CH2)2-, #-CH2-N(R g )-(CH2)2-piperidinylene-(CH2)3-, #-CH2-N(R g )-(CH2)2-piperidinylene-(CH2)4-, #-CH2-N(R g )-(CH2)2-piperidinylene-(CH2)5-, #-CH2-N(R g )-(CH2)2-piperidinylene-(CH2)6-, #-CH2-N(R g )-(CH2)2-piperidinylene-(CH2)7-, #-CH2-N(R g )-(CH2)2-piperidinylene-(CH2)8-, #-(CH2)2-N(R g )-CH2-piperidinylene-CH2-, #-(CH2)2-N(R g )-CH2-piperidinylene-(CH2)2-, #-(CH2)2-N(R g )-CH2-piperidinylene-(CH2)3-, #-(CH2)2-N(R g )-CH2-piperidinylene-(CH2)4-, #-(CH2)2-N(R g )-CH2-piperidinylene-(CH2)5-, #-(CH2)2-N(R g )-CH2-piperidinylene-(CH2)6-, #-(CH2)2-N(R g )-CH2-piperidinylene-(CH2)7-, #-(CH2)2-N(R g )-CH2-piperidinylene-(CH2)8-, #-(CH2)3-N(R g )-CH2-piperidinylene-CH2-, #-(CH2)3-N(R g )-CH2-piperidinylene-(CH2)2-, #-(CH2)3-N(R g )-CH2-piperidinylene-(CH2)3-, #-(CH2)3-N(R g )-CH2-piperidinylene-(CH2)8-, #-(CH2)4-N(R g )-CH2-piperidinylene-CH2-, #-(CH2)4-N(R g )-CH2-piperidinylene-(CH2)2-, #-(CH2)4-N(R g)-CH2-piperidinylene-(CH2)3-, #-(CH2)4-N(R g )-CH2-piperidinylene-(CH2)8-, #-(CH2)5-N(R g )-CH2-piperidinylene-(CH2)3-, #-(CH2)5-N(R g )-CH2-piperidinylene-(CH2)8-, #-(CH2)6-N(R g )-CH2-piperidinylene-(CH2)3-, #-(CH2)6-N(R g )-CH2-piperidinylene-(CH2)8-, #-(CH2)7-N(R g )-CH2-piperidinylene-(CH2)3-, #-(CH2)7-N(R g )-CH2-piperidinylene-(CH2)8-, #-(CH2)8-N(R g )-CH2-piperidinylene-CH2-, #-(CH2)8-N(R g )-CH2-piperidinylene-(CH2)2-, #-(CH2)8-N(R g )-CH2-piperidinylene-(CH2)3-, #-(CH2)8-N(R g )-CH2-piperidinylene-(CH2)4-, #-(CH2)8-N(R g )-CH2-piperidinylene-(CH2)5-, #-(CH2)8-N(R g )-CH2-piperidinylene-(CH2)6-, #-(CH2)8-N(R g )-CH2-piperidinylene-(CH2)7-, #-(CH2)8-N(R g)-CH2-piperidinylene-(CH2)8-, #-CH2-piperazinylene-CH2-, #-CH2-piperazinylene-(CH2)2-, #-CH2-piperazinylene-(CH2)3-, #-CH2-piperazinylene-(CH2)4-, #-CH2-piperazinylene-(CH2)5-, #-CH2-piperazinylene-(CH2)6-, #-CH2-piperazinylene-(CH2)7-, #-CH2-piperazinylene ylene-(CH2)8-, #-(CH2)2-piperazinylene-(CH2)1-, #-(CH2)2-piperazinylene-(CH2)2-, #-(CH2)2-piperazinylene-(CH2)3-, #-(CH2)2-piperazinylene-(CH2)4-, #-(CH2)2-piperazinylene-(CH2)5-, #-(CH2)2-piperazinylene-(CH2)6-, #-(CH2)2-piperazinylene-(CH2)7 -, #-(CH2)2-piperazinylene-(CH2)8-, #-(CH2)3-piperazinylene-CH2-, #-(CH2)3-piperazinylene-(CH2)2-, #-(CH2)3-piperazinylene-(CH2)3-, #-(CH2)3-piperazinylene-(CH2)4-, #-(CH2)3-piperazinylene-(CH2)5-, #-(CH2)3-piperazinylene-(CH2)6-, #-(CH2)3-piperazinylene Perazinylene-(CH2)7-, #-(CH2)3-piperazinylene-(CH2)8-, #-(CH2)4-piperazinylene-CH2-, #-(CH2)4-piperazinylene-(CH2)2-, #-(CH2)4-piperazinylene-(CH2)3-, #-(CH2)4-piperazinylene-(CH2)4-, #-(CH2)4-piperazinylene-(CH2)5-, #-(CH2)4-piperazinylene-(CH2)6 -, #-(CH2)4-piperazinylene-(CH2)7-, #-(CH2)4-piperazinylene-(CH2)8-, #-(CH2)5-piperazinylene-(CH2)1-, #-(CH2)5-piperazinylene-(CH2)2-, #-(CH2)5-piperazinylene-(CH2)3-, #-(CH2)5-piperazinylene-(CH2)4-, #-(CH2)5-piperazinylene-(CH2)5-, #-(CH2)5-piperazinylene- (CH2)6-, #-(CH2)5-piperazinylene-(CH2)7-, #-(CH2)5-piperazinylene-(CH2)8-, #-(CH2)6-piperazinylene-(CH2)1-, #-(CH2)6-piperazinylene-(CH2)2-, #-(CH2)6-piperazinylene-(CH2)3-, #-(CH2)6-piperazinylene-(CH2)4-, #-(CH2)6-piperazinylene-(CH2)5-, #-(CH2)6-pipera Dinylene-(CH2)6-, #-(CH2)6-piperazinylene-(CH2)7-, #-(CH2)6-piperazinylene-(CH2)8-, #-(CH2)7-piperazinylene-(CH2)1-, #-(CH2)7-piperazinylene-(CH2)2-, #-(CH2)7-piperazinylene-(CH2)3-, #-(CH2)7-piperazinylene-(CH2)4-, #-(CH2)7-piperazinylene-(CH2)8-, #-(CH2) 8-piperazinylene-CH2-, #-(CH2)8-piperazinylene-(CH2)2-, #-(CH2)8-piperazinylene-(CH2)3-, #-(CH2)8-piperazinylene-(CH2)4-, #-(CH2)8-piperazinylene-(CH2)5-, #-(CH2)8-piperazinylene-(CH2)6-, #-(CH2)8-piperazinylene-(CH2)7-, or #-(CH2)8-piperazinylene-(CH2)8-; wherein the piperidinylene and the piperazinylene, independently of each other, further comprise C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 Alkyl or halogenated C1-3 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), halogen (for example fluorine, chlorine, bromine or iodine), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 optionally substituted with a substituent selected from the group consisting of alkoxy, e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), or any combination thereof; Each R d are independently H or C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl; The symbol # is the group R 10 represents the connection point with; and n4, n5, n6, n7, m1, m2, and m3 are each independently selected from the group consisting of the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0066] In some embodiments, the compound of formula (I) may also be represented by the following formula (I-1): [ka] Formula (I-1) It can also be expressed by the structure where R1, R2, R3, R4, (R5) n , (R6) m , R7, R8, R9, R 10 ,LIN,R. 12 , (R a ) t and X are as defined herein for compounds of formula (I) and each embodiment thereof.

[0067] In some embodiments, the compound of formula (I) may also be represented by the following formula (I-2) or formula (I-3): [ka] Formula (I-2) [ka] Formula (I-3) It can also be expressed by the structure where R1, R2, R3, R4, (R5) n , (R6) m , R8, R9, R 10 ,LIN,R. 12 , (R a ) t and X are as defined herein for compounds of formula (I) and each embodiment thereof.

[0068] In some embodiments, the compound of formula (I) may also be represented by the following formula (I-2-1): [ka] Formula (I-2-1) It can also be expressed by the structure where: R 10 is the following group: [ka] represents Here, the ring W 1 represents a 4- to 6-membered nitrogen-containing heterocyclylene, and R a1 ) n1 Ring W 1 n1 R a1 represents a group substituted with a1 are the same or different and each independently: C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), cyano, or halogen (e.g., fluorine, chlorine, bromine, or iodine), where n1 is an integer from 1 to 8; Ring W 2 is a 4- to 6-membered nitrogen-containing heterocyclylene, or C 3-6 represents a cycloalkylene, n3 represents an integer of 0 or 1, (R a2 ) n2 Ring W 2 There are n2 R a2 represents a group substituted with a2 are the same or different and each independently: C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), cyano, halogen (e.g., fluorine, chlorine, bromine, or iodine), or oxo group, and n2 represents an integer from 0 to 8; and The symbol * indicates the connection point with LIN; and R1, R2, R3, R4, (R5) n , (R6) m , R8, R9, R 10 ,LIN,R.12 and X are as defined herein for compounds of formula (I) and each embodiment thereof.

[0069] In some embodiments, ring W of the compound of formula (I-2-1) 1 represents a 4- to 6-membered nitrogen-containing heterocyclylene, and examples of the 4- to 6-membered nitrogen-containing heterocyclylene include, but are not limited to, piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, and thiomorpholinylene.

[0070] In some embodiments, (R a1 ) n1 Ring W 1 n1 R a1 represents a group substituted with a1 are the same or different and each independently: C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), cyano, halogen (e.g., fluorine, chlorine, bromine, or iodine), or oxo group, and n1 represents an integer from 1 to 8 (e.g., an integer of 1, 2, 3, or 4).

[0071] In some embodiments, ring W of the compound of formula (I-2-1) 2represents a 4- to 6-membered nitrogen-containing heterocyclylene, and examples of the 4- to 6-membered nitrogen-containing heterocyclylene include, but are not limited to, piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, and thiomorpholinylene.

[0072] In some embodiments, ring W of the compound of formula (I-2-1) 2 is C 3-6 It represents cycloalkylene, and said 4- to 6-membered cycloalkylene includes, but is not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0073] In some embodiments, (R a2 ) n2 is a ring W 2 There are n2 R a2 represents a group substituted with a2 are the same or different and each independently: C 1-6 Alkyl (e.g., C 1-4 Alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 Alkyl (e.g., halogenated C 1-4 alkyl, for example F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy (e.g., C 1-4 Alkoxy or C 1-3 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, or tert-butoxy), cyano, halogen (e.g., fluorine, chlorine, bromine, or iodine), or oxo group, and n2 represents an integer of 0-8 (e.g., an integer of 0, 1, 2, 3, or 4).

[0074] In some embodiments, n3 of the compound of Formula (I-2-1) represents an integer of 0 or 1.

[0075] In some embodiments, n3 of the compound of Formula (I-2-1) represents the integer 0.

[0076] In some embodiments, n3 of the compound of Formula (I-2-1) represents the integer 1.

[0077] In some embodiments, R of the compound of formula (I-2-1) 10 is the following group: [ka] represents Here, the symbol * indicates the connection point with LIN.

[0078] In some embodiments, the compound of formula (I) may also be represented by the following formula (I-2-1): [ka] Formula (I-2-1) It can also be expressed by the structure where: R8 represents -SO2CF3; and R1, R2, R3, R4, (R5) n , (R6) m , R9, R 10 ,LIN,R. 12 and X are as defined herein for compounds of formula (I) and each embodiment thereof.

[0079] In some embodiments, the compound of Formula (I) may also be represented by the following formula (I-2-2), (I-2-3), (I-2-4), (I-2-5), (I-3-1), (I-3-2), (I-3-3), or (I-3-4): [ka] [ka] It can also be expressed by the structure Here, R9, R 10 ,LIN,R. 12 , (R a ) t and X are as defined herein for compounds of formula (I) and each embodiment thereof.

[0080] In some embodiments, specific compounds of Formula (I) in Table 1 below and salts (including pharmaceutically acceptable salts, e.g., hydrochloride salts thereof), pharmaceutical precursors, solvates, isotopically enriched analogues, polycrystalline forms, stereoisomers (including enantiomers and non-enantiomers), or mixtures of stereoisomers thereof are provided. Table 1. Compounds of the present disclosure [Table 1] TIFF0007825122000028.tif210140TIFF0007825122000029.tif209140TIFF0007825122000030.tif211141TIFF000 7825122000031.tif202140TIFF0007825122000032.tif211141TIFF0007825122000033.tif211141TIFF00078251220 00034.tif208141TIFF0007825122000035.tif210141TIFF0007825122000036.tif183140TIFF0007825122000037.t if210139TIFF0007825122000038.tif208141TIFF0007825122000039.tif211140TIFF0007825122000040.tif149143

[0081] In some embodiments, the present disclosure provides a hydrochloride, sulfate, citrate, maleate, sulfonate, methanesulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, hydroxyacetate, or p-toluenesulfonate salt of a compound of Formula (I).

[0082] In one aspect, the present disclosure further provides novel proteolytic agents developed based on the BCL-2 family protein ligand compounds in Table 2 below, or salts (including pharmaceutically acceptable salts, e.g., their hydrochloride salts), stereoisomers (including enantiomers and non-enantiomers), solvates, isotopically enriched analogs, pharmaceutical precursors, or polymorphs thereof. Table 2. Compounds of the present disclosure [Table 2] TIFF0007825122000042.tif210146TIFF0007825122000043.tif210146TIFF0007825122000044.tif82143

[0083] In some embodiments, the present disclosure provides a hydrochloride, sulfate, citrate, maleate, sulfonate, methanesulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, hydroxyacetate, or p-toluenesulfonate salt of a compound listed in Table 2. II. Other Aspects of the Compounds (Including Salts, Enantiomers, Stereoisomers, Solvates, Isotopically Enriched Analogues, Pharmaceutical Precursors, or Polymorphs of the Compounds)

[0084] The compounds of the present disclosure have any of the structures of formula (I), (I-1), (I-2), (I-3), (I-2-1), (I-2-2), (I-2-3), (I-2-4), (I-2-5), (I-3-1), (I-3-2), (I-3-3), or (I-3-4), or any of the structures in Table 1 or 2. Unless otherwise stated, reference to compounds of the present disclosure includes compounds of any of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-2-1), Formula (I-2-2), Formula (I-2-3), Formula (I-2-4), Formula (I-2-5), Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), or Formula (I-3-4), as well as specific compounds falling within these general formulas (e.g., compounds of Table 1 or Table 2).

[0085] It should be recognized that compounds of the present disclosure (including any of the compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-2-1), Formula (I-2-2), Formula (I-2-3), Formula (I-2-4), Formula (I-2-5), Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), or Formula (I-3-4), or compounds of Table 1 or Table 2) can have stereoisomeric configurations and therefore can exist in one or more stereoisomeric forms. The present disclosure also relates to optically enriched compounds of a stereoisomeric configuration (e.g., greater than about 90% ee, e.g., greater than about 95% ee, 97% ee, or 99% ee), and mixtures thereof (including racemates). As used herein, "optically enriched" means that a mixture of enantiomers is composed of a significantly greater proportion of one enantiomer, which can be expressed as enantiomeric excess (ee%). Purification of isomers and separation of isomeric mixtures can be achieved by standard techniques known in the art, such as column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g., synthesis using chiral intermediates), and / or chiral separation.

[0086] In some embodiments, the present disclosure also provides polymorphic forms of compounds or salts of compounds of the present disclosure. Salts of compounds of the present disclosure may be pharmaceutically acceptable salts, including, but not limited to, hydrochloride, sulfate, citrate, maleate, methanesulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, hydroxyacetate, or p-toluenesulfonate. Compounds of the present disclosure may exist in a nonsolvated or solvated form in a pharmaceutically acceptable solvent, such as water or ethanol. In some embodiments, compounds of the present disclosure can be prepared into precursor drugs or pharmaceutical precursors. The precursor drugs are converted to the parent drug in the body and function. III. Drug Compositions / Formulations

[0087] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, isotopically enriched analogue, polycrystalline form, pharmaceutical precursor, stereoisomer (including enantiomer), or mixture of stereoisomers thereof as an active ingredient, and at least one pharmaceutically acceptable carrier.

[0088] In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersing agents, suspending agents, diluents, excipients, thickeners, solvents, or sealants. Carriers must be "acceptable" in that they are compatible with the other ingredients of the formulation (including the compounds useful in the present disclosure) and are not harmful to the patient. Some examples of substances used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as coa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffers; polyethylene oxide, polyvinylpyrrolidone, polyacrylamide, poloxamer; and other non-toxic compatible substances used in drug formulations.

[0089] The pharmaceutical composition of the present disclosure further comprises at least one second therapeutic agent, for example, an anticancer agent. The second therapeutic agent can be used in combination with the compound of the present disclosure (including any one of the compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-2-1), Formula (I-2-2), Formula (I-2-3), Formula (I-2-4), Formula (I-2-5), Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), or Formula (I-3-4), or a compound in Table 1 or Table 2) to treat a disease or condition described in the present disclosure. Examples of the second therapeutic agent include, but are not limited to, chemotherapeutic agents, immunotherapeutic agents, and gene therapy agents.

[0090] The pharmaceutical compositions described in the present disclosure, which contain the compounds according to the present disclosure as an active ingredient (including any one of the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-2-1), formula (I-2-2), formula (I-2-3), formula (I-2-4), formula (I-2-5), formula (I-3-1), formula (I-3-2), formula (I-3-3), or formula (I-3-4), or the compounds of Table 1 or Table 2), or pharmaceutically acceptable salts thereof, can be administered by an appropriate administration route (including, but not limited to, nasal administration, inhalation administration, topical administration, oral administration, buccal administration, rectal administration, pleural administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration). The compound may be administered by enteral, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous route, but is not limited to such administration. The compound may be prepared in any suitable form, such as a spool, patch, tablet (e.g., regular tablet, dispersible tablet, or orally disintegrating tablet), capsule (e.g., soft capsule, hard capsule, or enteric-coated capsule), dragee, troche, powder, granule, powder injection, suppository, or liquid preparation (e.g., suspension (e.g., aqueous or oily suspension), solution, emulsion, or syrup), or in a conventional injection form, such as an injectable solution (e.g., a sterile injection solution prepared using water, Ringer's solution, isotonic sodium chloride solution, or the like as a carrier or solvent by a method known in the art) or a freeze-dried composition. Furthermore, if necessary, those skilled in the art can also prepare the compounds according to the present disclosure (including any one of the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-2-1), formula (I-2-2), formula (I-2-3), formula (I-2-4), formula (I-2-5), formula (I-3-1), formula (I-3-2), formula (I-3-3), or formula (I-3-4), or the compounds in Table 1 or Table 2) into a conventional, dispersible, chewable, orally rapidly disintegrating or rapidly dissolving formulation, or a sustained-release capsule or a controlled-release capsule.

[0091] The compounds of the present disclosure (including any one of the compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-2-1), Formula (I-2-2), Formula (I-2-3), Formula (I-2-4), Formula (I-2-5), Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), or Formula (I-3-4), or a compound in Table 1 or Table 2) as the active ingredient are contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to the subject a therapeutically effective amount for the indication requiring treatment and which does not cause serious toxic effects in the subject being treated. Dosages of active compounds for any disease or condition referred to herein are, for example, from about 5 ng / kg of subject's body weight / day to 500 mg / kg of subject's body weight / day, from about 10 ng / kg of subject's body weight / day to 300 mg / kg of subject's body weight / day, e.g., from 0.1 to 100 mg / kg of subject's body weight / day, or from 0.5 to about 25 mg / kg of subject's body weight / day.

[0092] The compounds of the present disclosure (including any one of the compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-2-1), Formula (I-2-2), Formula (I-2-3), Formula (I-2-4), Formula (I-2-5), Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), or Formula (I-3-4), or the compounds of Table 1 or Table 2) or pharmaceutically acceptable salts thereof can be conveniently administered in any suitable formulation, and specifications for suitable formulations include, but are not limited to, those having an active ingredient of less than 1 mg, 1 mg to 3000 mg, 5 mg to 1000 mg, for example, 5 to 500 mg, or 25 to 250 mg per unit dosage form. IV. Kits / Packaged Products

[0093] The compounds of the present disclosure (including any one of the compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-2-1), Formula (I-2-2), Formula (I-2-3), Formula (I-2-4), Formula (I-2-5), Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), or Formula (I-3-4), or compounds in Table 1 or Table 2), or pharmaceutically acceptable salts, solvates, polymorphs, precursors, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, are used as pharmaceuticals. The pharmaceutical agents or pharmaceutical compositions of the present disclosure can be present in kits / packaged products. The kits / packaged products can include packaging or containers. Packaging or containers include, but are not limited to, ampoules, blister packs, pharmaceutical plastic bottles, vials, pharmaceutical glass bottles, containers, syringes, laminated soft packages, co-extruded membrane infusion containers, test tubes, and dispenser devices. The kit / packaged product can include product instructions. V. Methods and Uses

[0094] The compounds of the present disclosure (including any one of the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-2-1), formula (I-2-2), formula (I-2-3), formula (I-2-4), formula (I-2-5), formula (I-3-1), formula (I-3-2), formula (I-3-3), or formula (I-3-4), or the compounds of Table 1 or Table 2), or a pharmaceutically acceptable salt, solvate, polymorph, precursor, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, can also be used as a medicine. In particular, the compounds of the present disclosure (including any one of the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-2-1), formula (I-2-2), formula (I-2-3), formula (I-2-4), formula (I-2-5), formula (I-3-1), formula (I-3-2), formula (I-3-3), or formula (I-3-4), or the compounds of Table 1 or Table 2), or pharmaceutically acceptable salts, solvates, polycrystalline forms, precursors, stereoisomers (including enantiomers) thereof, ), or a mixture of stereoisomers, can be used in the manufacture of a medicament for the prevention and / or treatment of a disease or condition selected from the group consisting of neurodegenerative diseases, vascular cardiac disorders, autoimmune diseases, myelofibrosis, renal fibrosis, hepatic fibrosis, cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), multiple organ failure due to cachexia and septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes, transplant rejection, retinopathy, and acute liver failure. In some embodiments, the disease or condition includes, but is not limited to, neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease; vascular heart disorders, including, for example, coronary heart disease, congestive heart failure, myocardial infarction, and atherosclerosis; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis / dermatomyositis, Sjogren's syndrome, and atopic dermatitis; myelofibrosis; renal fibrosis; liver fibrosis; cirrhosis; tumors, including hematological malignancies and solid tumors; multiple organ dysfunction syndrome (MODS), including multiple organ failure due to cachexia and septic shock; acute liver failure; transplant rejection, including organ (including kidney, heart, lung) or tissue transplant rejection; retinopathies, including diabetic macular edema (DME) and wet age-related macular degeneration (wAMD); and diabetes.In some embodiments, the tumor is a myeloma, including, for example, multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disorders; myelodysplastic syndromes (MDS); previously treated myelodysplastic syndromes; transplant-associated cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic granulocytic leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, leukemia-associated anemia, acute myeloid leukemia (AML); diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, undifferentiated myeloma, Refractory lymphoma, anaplastic large cell lymphoma, CD20-positive lymphoma, mantle cell lymphoma, primary lymphoma, T-cell lymphoma (including relapsed or refractory peripheral T-cell lymphoma), small lymphocytic lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma Lymphomas, including follicular lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, and Waldenstrom's macroglobulinemia; thyroid cancer; melanoma; lung cancer, including non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; brain glioma; astrocytoma; ovarian cancer; bronchogenic carcinoma; prostate cancer; estrogen-dependent breast cancer, HER2-positive breast cancer, triple-negative breast cancer, incidental breast cancer, and cancer These include, but are not limited to, breast cancer, including Uden's disease; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; medulloblastoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various lipogenic tumors, Ewing's sarcoma / primitive neuroectodermal tumors (Ewing / PNETs) and leiomyosarcoma; chondrosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct carcinoma; bone cancer; cervical cancer; and skin cancer. Therapeutically effective dose

[0095] A method for treating and / or preventing a disease or condition in a subject includes administering to the subject a therapeutically effective amount of a compound according to the present disclosure (any one of compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-2-1), Formula (I-2-2), Formula (I-2-3), Formula (I-2-4), Formula (I-2-5), Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), or Formula (I-3-4), or a compound of Table 1 or Table 2). In some embodiments, the disease or condition is a neurodegenerative disease, a vascular heart disorder, an autoimmune disease, myelofibrosis, renal fibrosis, hepatic fibrosis, cirrhosis, tumor, multiple organ dysfunction syndrome (MODS), multiple organ failure due to cachexia and septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes, transplant rejection, retinopathy, and acute myeloid leukemia. In some embodiments, the disease or condition includes, but is not limited to, neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease; vascular heart disorders, including coronary heart disease, congestive heart failure, myocardial infarction, and atherosclerosis; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis / dermatomyositis, Sjogren's syndrome, and atopic dermatitis; myelofibrosis; renal fibrosis; liver fibrosis; cirrhosis; tumors, including hematological malignancies and solid tumors; multiple organ dysfunction syndrome (MODS), including multiple organ failure due to cachexia and septic shock; acute liver failure; transplant rejection, including organ (including kidney, heart, and lung) or tissue transplant rejection; retinopathies, including diabetic macular edema (DME) and wet age-related macular degeneration (wAMD); and diabetes.In some embodiments, the tumor is a myeloma, including, for example, multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; bone marrow disorders; myelodysplastic syndromes (MDS); previously treated myelodysplastic syndromes; transplant-associated cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic granulocytic leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, leukemia-associated anemia, acute myeloid leukemia (AML); diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, anaplastic lymphoma, Lymphoma, anaplastic large cell lymphoma, CD20-positive lymphoma, mantle cell lymphoma, primary lymphoma, T-cell lymphoma (including relapsed or refractory peripheral T-cell lymphoma), small lymphocytic lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma lymphomas, including refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, and Waldenstrom's macroglobulinemia; thyroid cancer; melanoma; lung cancer, including non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; brain glioma; astrocytoma; ovarian cancer; bronchogenic carcinoma; prostate cancer; breast adenocarcinoma, comprehensive estrogen-dependent breast cancer, HER2-positive breast cancer, triple-negative breast cancer, incident breast cancer, and These include, but are not limited to, breast cancer, including Cowden's disease; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; medulloblastoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; brain cancer; oral cancer; sarcomas, including rhabdomyosarcoma, various lipogenic tumors, Ewing's sarcoma / primitive neuroectodermal tumors (Ewing / PNETs) and leiomyosarcoma; chondrosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct carcinoma; bone cancer; cervical cancer; and skin cancer.

[0096] The method for preventing and / or treating the disease or condition in a subject includes administering to the subject a therapeutically effective amount of a compound according to the present disclosure (including any one of the compounds of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-2-1), Formula (I-2-2), Formula (I-2-3), Formula (I-2-4), Formula (I-2-5), Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), or Formula (I-3-4), or a compound in Table 1 or Table 2) or a pharmaceutical composition according to the present disclosure by at least one administration route selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, buccal administration, rectal administration, pleural administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration.

[0097] The term "treatment" or "treatment" refers to the slowing (alleviation) of the progression of an unwanted disease or condition (e.g., a tumor) by administering to a subject a compound disclosed herein (including any compound of Formula (I), Formula (I-1), Formula (I-2), Formula (I-3), Formula (I-2-1), Formula (I-2-2), Formula (I-2-3), Formula (I-2-4), Formula (I-2-5), Formula (I-3-1), Formula (I-3-2), Formula (I-3-3), or Formula (I-3-4), or a compound in Table 1 or Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof. Beneficial effects or desired clinical results of the present disclosure include, but are not limited to, alleviation of symptoms, reduction in disease severity, stabilization of the disease state, delay or slowing of disease progression, improvement or palliation of the condition, and remission of the disease.

[0098] A "therapeutically effective amount" of a compound according to the present disclosure will depend on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, the age, sex, and weight of the patient, the overall medical condition of the patient, the mode and time of administration, excretion rate, concomitant medications, and the progression of the disease or condition in the patient being treated. Those skilled in the art will be able to determine the appropriate amount based on these and other factors.

[0099] It should be understood that the use of one or more active compounds and / or compositions and the selection of their dosage will vary depending on the basic condition of each individual (generally should be optimized for each individual's condition).Dosage and administration scheme should be within the scope of the ability of those skilled in the art, and the appropriate dosage depends on many factors, including the level of knowledge and ability of general technical physicians, veterinarians or researchers (see, for example, Li Jun, ed., "Clinical Pharmacology", 4th edition, People's Health Press (2008)).

[0100] The patient or subject to be treated refers to an animal, e.g., a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, mice, etc. VI. Definition

[0101] Unless otherwise specified, the following terms, phrases and symbols used in this specification generally have the following meanings:

[0102] Generally, the nomenclature used herein (e.g., IUPAC nomenclature) and the laboratory programs described below (including those used in cell culture, organic chemistry, analytical chemistry, and pharmacology) are those well known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in conjunction with the present disclosure described herein have the same meaning as commonly understood by one of ordinary skill in the art. Also, in the claims and / or specification, when the terms "a" and "an" are used in conjunction with the term "comprise" or a noun, the meaning may be "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more than one." Similarly, the term "another" or "other" can denote at least a second or more.

[0103] When embodiments are described herein using the terms "comprising" or "having," it should be understood that other embodiments similar to the statements "consisting of" and / or "consisting essentially of" are also provided.

[0104] The term "about" is used herein to mean approximately, in the region of, roughly, or on the order of... When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries to numerical values ​​greater than or less than the stated value. Generally, the term "about" can modify higher or lower than the stated value by a variance (increase or decrease) up or down, e.g., by 10%, 5%, 2%, 1%, etc.

[0105] As used herein, the term "represents a bond" refers to a bond connector (i.e., representing nothing), such as the term "R 12 represents a bond, and R 12 is a bond connective. In other words, R 12 When is a bond, the group LIN in the structure of formula (I) is directly connected to the benzene ring in the structure of formula (II).

[0106] As used herein, "a carbon backbone containing one or more groups R" used alone or in combination means a b and / or one or more groups R c or one or more groups R b and R c "Intercalated" in "intercalated with any combination of" has the definition known in the art, i.e., a group R b , R c or group R b and R c In this specification, examples of the term "inserted in one or more..." include one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) groups R as defined in the present text inserted in the carbon backbone. b and / or one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R c, and / or one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R b and R c The main chain groups formed by this are consistent with covalent bond theory. For example, "one or more groups R in the carbon main chain" can be used. b and / or one or more groups R c or one or more groups R b and R c Optionally substituted linear or branched C inserted with any combination of 2-30 "Alkylene" refers to one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) "-CH-R b -CH2-" fragment and / or one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1) "-CH2-R c -CH2-" fragment and / or one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1) "-CH2-R b -R c -CH2- fragments, 2-30 In the carbon main chain of the alkylene chain, one or more (for example, 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1) R b and / or R c and / or one or more groups R b and R c where each R b are the same or different, and each R c are the same or different and are as defined herein.

[0107] As used herein, the term "optionally substituted," alone or in combination, means that the specified group may be unsubstituted or substituted with one or more substituents as defined herein. As used herein, the terms "optionally substituted" and "unsubstituted or substituted" may be used interchangeably. The term "substituted" generally refers to the replacement of one or more hydrogen atoms in the referenced structure with the same or different specific substituents. The number of substituents is not limited in principle, nor is it automatically limited by the size of the structural unit (i.e., the total number of hydrogen atoms that may be replaced in the structural unit), or as clearly defined in the present text.

[0108] As used herein, bonds broken by wavy lines indicate the point of attachment of the depicted group to the rest of the molecule, for example, a group represented by formula (II) shown below: [ka] is the R 12 represents the connection between the group LIN of the compound of formula (I).

[0109] In the present text, the term "the above C" used alone or in combination x-y "One or more CH2 hydrogen atoms of alkylene are replaced..." refers to a straight or branched C x-y This means that one or more hydrogen atoms in CH2 in alkylene are substituted with a substituent as defined herein. In the present specification, the term "groups #-CH2-, #-(CH2)2-, #-(CH2)3-, #-(CH2)4-, #-(CH2)5-, #-(CH2)6-, #-(CH2)7-, #-(CH2)8-, #-(CH2)9-, #-(CH2) 10 -, #-(CH2) 11 -, #-(CH2) 12 -, #-(CH2) 13 -, #-(CH2) 14 -, #-(CH2) 15 -, #-(CH2) 16 -, #-(CH2) 17 -, #-(CH2) 18 -, #-(CH2) 19-, #-(CH2) 20 -, #-(CH2) 21 -, #-(CH2) 22 -, #-(CH2) 25 - or #-(CH2) 30 The term "one or more" in "one or more CH hydrogens" may refer to some or all of the hydrogens in each alkylene group referred to, including, but not limited to, 1-60 hydrogens. In some embodiments, the term "one or more CH hydrogens" may refer to some or all of the hydrogens in the alkylene group referred to, including, but not limited to, 1-30 (e.g., 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, or 1) hydrogens. In some embodiments, the term "one or more CH hydrogens" may refer to 1-3 of the hydrogens in the alkylene group referred to. The number is not limited in principle or is automatically limited by the size of the constituent unit.

[0110] As used herein, the term "oxo" or "oxo group" refers to =O.

[0111] The terms "halogen atom" or "halogen", as used herein, alone or in combination, refer to fluorine, chlorine, bromine or iodine.

[0112] As used herein, the term "alkyl," alone or in combination, refers to straight or branched chain alkyl. x -C y Alkyl" or "C x-y The term "alkyl" (x and y are each integers) refers to a straight or branched chain alkyl containing x to y carbon atoms. 1-10 "Alkyl" refers to a straight or branched chain alkyl containing 1 to 10 carbon atoms. 1-10 Examples of alkyl are C 1-9 Alkyl, C 1-8 Alkyl, C 2-8 Alkyl, C 1-7 Alkyl, C 1-6 Alkyl, C1-5 Alkyl, and C 1-4 Representative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 1-3 "Alkyl" or "C1-C3 alkyl" refers to an alkyl containing 1 to 3 carbon atoms. Representative examples include methyl, ethyl, n-propyl, and isopropyl. In this disclosure, the "alkyl" is optionally substituted, and the substituents are optionally halogen, hydroxy, cyano, C 1-3 Alkyl, C 1-3 One or more substituents selected from the group consisting of alkoxy, trifluoromethyl, heterocyclyl, or combinations thereof.

[0113] As used herein, the term "halogenated alkyl," alone or in combination, refers to a straight or branched chain alkyl substituted with one or more halogens, wherein one or more hydrogens in said alkyl are replaced with halogens. x -C y Alkyl" or "halogenated C x-y The term "alkyl" (x and y are each integers) refers to a straight or branched chain alkyl containing x to y carbon atoms substituted with one or more halogens. The term "halogenated C 1-10 "Alkyl" refers to a straight or branched chain alkyl containing 1 to 10 carbon atoms substituted with one or more halogens (e.g., fluorine, chlorine, bromine, or iodine). 1-10 Examples of alkyls include halogenated C 1-9 Alkyl, e.g., halogenated C 1-8 Alkyl, halogenated C 2-8 Alkyl, halogenated C 1-7 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-5 Alkyl or halogenated C 1-4Representative examples include methyl halides, ethyl halides, n-propyl halides, isopropyl halides, n-butyl halides, isobutyl halides, sec-butyl halides, tert-butyl halides, pentyl halides, isopentyl halides, neopentyl halides, tert-pentyl halides, hexyl halides, heptyl halides, octyl halides, nonyl halides, and decyl halides. The term "halogenated C 1-3 Alkyl" or "halogenated C 1― "C3 alkyl" refers to an alkyl containing 1 to 3 carbon atoms substituted with one or more halogens, representative examples of which include methyl halide, ethyl halide, n-propyl halide, and isopropyl halide.

[0114] As used herein, the term "alkylene" (which may be used interchangeably with "alkylene chain"), alone or in combination, refers to a straight or branched chain divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. x -C y Alkylene" or "C x - y The term "alkylene" (where x and y are each integers) refers to a straight or branched chain alkylene containing x to y carbon atoms. 30 Examples of alkylenes are C1-C 30 Alkylene, C1-C 29 Alkylene, C1-C 28 Alkylene, C1-C 27 Alkylene, C1-C 26 Alkylene, C1-C 25 Alkylene, C1-C 24 Alkylene, C1-C 23 Alkylene, C1-C 22 Alkylene, C1-C 21 Alkylene, C1-C 20 Alkylene, C1-C 19 Alkylene, C1-C 18 Alkylene, C1-C 17 Alkylene, C1-C 16 Alkylene, C1-C 15Alkylene, C1-C 14 Alkylene, C1-C 13 Alkylene, C1-C 12 Alkylene, C1-C 11 Alkylene, C1-C 10 alkylene, C1-C9 alkylene, C1-C8 alkylene, C1-C7 alkylene, C1-C6 alkylene, C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene, or C1-C2 alkylene. Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, neopentylidene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, heptacosylene, octacosylene, nonacosylene, and triacontylene. In the present disclosure, the "alkylene" is optionally substituted, and the substituents are optionally C 1-3 Alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto group, halogen, C 1-3 Alkoxy, C 1-3 Alkylamino, halogenated C 1-3 Alkyl, Amino C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 One or more substituents selected from the group consisting of alkyl-C(O)NH-, cyano group, or any combination thereof.

[0115] As used herein, the term "alkoxy," alone or in combination, refers to a straight or branched chain alkoxy and has the formula -O-alkyl. Optionally, the alkyl portion of the alkoxy may contain 1-10 carbon atoms. Representative examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like. The terms "C1-C3 alkoxy" or "C 1-3 "Alkoxy" refers to a straight or branched chain alkoxy containing 1-3 carbon atoms. 1-3 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0116] As used herein, the term "heteroaryl," used alone or in combination, refers to a 5- to 20-membered (optionally 5- to 15-, 5- to 12-, 5- to 11-, 5- to 10-, 5- to 9-, 5- to 8-, 5- to 7-, 5- to 6-, 6- to 15-, or 6- to 9-membered) monocyclic, bicyclic, or polycyclic aromatic ring group having an aromatic ring containing one or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroaryl includes bicyclic, tricyclic, or tetracyclic heteroaryl, in which one ring is an aromatic ring containing one or more heteroatoms independently selected from the group consisting of O, S, and N, and the other ring may be saturated, partially unsaturated, or aromatic, and may be carbocyclic or contain one or more heteroatoms independently selected from the group consisting of O, S, and N. Examples of monocyclic heteroaryls include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryls include indolyl, isoindolyl, isoindolinyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolyl, isoquinolyl, naphthyridinyl, and the like. Examples of tricyclic heteroaryls include, but are not limited to, phenyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, oxazolopyridyl, furopyridyl, pteridyl, purinyl, pyridopyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, pyrrolo[2,1-b]thiazolyl, and imidazo[2,1-b]thiazolyl. Examples of tricyclic heteroaryls include, but are not limited to, acridinyl, benzoindolyl, carbazolyl, dibenzofuranyl, and xanthyl.The heteroaryl may be substituted or unsubstituted. Substituted heteroaryl refers to heteroaryl substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent, where the substituent is C1-C3 alkyl, C. 3-6 Cycloalkyl, hydroxy, amino, mercapto group, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 It is optionally selected from the group consisting of alkyl-C(O)NH-, cyano group, or any combination thereof.

[0117] In the present disclosure, the term "heteroarylene," used alone or in combination, refers to a 5- to 20-membered (optionally 5- to 15-, 5- to 12-, 5- to 11-, 5- to 10-, 5- to 9-, 5- to 8-, 5- to 7-, 5- to 6-, 6- to 15-, or 6- to 9-membered) monocyclic, bicyclic, or polycyclic divalent aromatic ring group having at least one aromatic ring containing one or more (e.g., 1 to 6, 1 to 5, 1 to 4, or 1 to 3) heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroarylene includes bicyclic, tricyclic, or tetracyclic heteroarylene, in which one ring is an aromatic ring containing one or more heteroatoms independently selected from the group consisting of O, S, and N, and the other rings may be saturated, partially unsaturated, or aromatic, and may be carbocyclic or contain one or more heteroatoms independently selected from the group consisting of O, S, and N. Representative examples of monocyclic heteroarylenes include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, tetrazolylene, and triazinylene.Examples of bicyclic heteroarylenes are indolylene, isoindolinylene, isoindolinylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolylene, isoquinolylene, naphthyridinylene, and cinnamylene. Examples of heteroarylenes include, but are not limited to, phenylene, quinazolinylene, quinoxalinylene, phthalazinylene, oxazolopyridylene, furopyridylene, pteridylene, prinylene, pyridopyridylene, pyrazolo[1,5-a]pyridylene, pyrazolo[1,5-a]pyrimidinylene, imidazo[1,2-a]pyridylene, 1H-pyrrolo[3,2-b]pyridylene, 1H-pyrrolo[2,3-b]pyridylene, 4H-fluoro[3,2-b]pyrrolylene, pyrrolo[2,1-b]thiazolylene, and imidazo[2,1-b]thiazolylene. Examples of tricyclic heteroarylenes include, but are not limited to, acridinylene, benzoindolylene, carbazolylene, dibenzofuranylene, and xantylene. The heteroarylene may be unsubstituted or substituted. Substituted heteroarylene refers to heteroarylene that is substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent, wherein the substituent is C1-C3 alkyl, C. 3-6 Cycloalkyl, hydroxy, amino, mercapto group, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino-substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 It is optionally selected from the group consisting of alkyl-C(O)NH-, cyano group, or any combination thereof.

[0118] As used herein, the term "aryl," alone or in combination, refers to a monovalent aromatic hydrocarbon group (e.g., phenyl, naphthyl, or fluorenyl) containing 5 to 14 carbon atoms and optionally containing one or more fused rings. In the present disclosure, the term "aryl" refers to an optionally substituted aryl. Substituted aryl refers to an aryl substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent (e.g., an aryl mono-, di-, or tri-substituted with a substituent), where the substituent is, for example, C1-C3 alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto group, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino-substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 It is optionally selected from the group consisting of alkyl-C(O)NH-, cyano group, or any combination thereof.

[0119] In the present disclosure, the term "arylene," used alone or in combination, refers to a divalent aromatic hydrocarbon group (e.g., phenylene, naphthylene, or fluorenylene) containing 5 to 14 carbon atoms and optionally containing one or more fused rings. In the present disclosure, the term "arylene" refers to an optionally substituted arylene. Substituted arylene refers to an arylene substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) with a substituent (e.g., an arylene mono-, di-, or tri-substituted with a substituent), where the substituent is, for example, C1-C3 alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto group, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino-substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 It is optionally selected from the group consisting of alkyl-C(O)NH-, cyano group, or any combination thereof.

[0120] The term "cycloalkyl," as used herein, alone or in combination, refers to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) mono-, bi-, or polycyclic hydrocarbon group, and in some embodiments, has from 3 to 20 carbon atoms (i.e., C 3-20 cycloalkyl), or 3 to 15 carbon atoms (i.e., C 3-15 cycloalkyl), 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), or 11 carbon atoms (i.e., C 3-11 cycloalkyl), or 3 to 10 carbon atoms (i.e., C 3-10 cycloalkyl), or 3 to 8 carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 7 carbon atoms (i.e., C 3-7 cycloalkyl), or 3 to 6 carbon atoms (i.e., C 3-6 The term "cycloalkyl" includes monocyclic, bicyclic, and tricyclic cycloalkyls having 3 to 20 carbon atoms. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic and tricyclic cycloalkyls include bridged cyclic alkyls, fused rings, and spirocycloalkyls, such as, but not limited to, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, spirocycloalkyls, adamantanyl, noradamantanyl, bornyl, and norbornyl (IUPAC systematic name: biscyclo[2.2.1]heptyl). In this context, the "cycloalkyl" is optionally mono- or polysubstituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl. The substituents of the substituted "cycloalkyl" are optionally C1-C3 alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto group, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino-substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3The term "C" refers to one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from the group consisting of alkyl-C(O)NH-, cyano, or any combination thereof. 3-6 Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.

[0121] As used herein, the term "C" as used alone or in combination x-y The term "spirocycloalkyl" (where x and y are each integers) refers to a spirocycloalkyl containing x to y carbon atoms. 7-11 "Spirocycloalkyl" refers to a spirocycloalkyl containing 7 to 11 (e.g., 7-10, 7-9) carbon atoms. 7-11 Representative examples of "spirocycloalkyl" include, but are not limited to, spiro[3.3]heptyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[4.5]decyl, or spiro[5.5]undecyl. 7-11 "Spirocycloalkyl" can further include C1-C3 alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto group, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino-substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 It is optionally substituted with one or more substituents selected from the group consisting of alkyl-C(O)NH-, cyano group, or any combination thereof.

[0122] As used herein, the term "cycloalkylene," alone or in combination, refers to saturated and partially unsaturated (e.g., containing one or more double bonds but not fully conjugated) monocyclic, bicyclic, or polycyclic hydrocarbon divalent radicals having 3 to 12 carbon atoms (e.g., 3-12, 3-11, 3-10, 3-8, 3-7, 3-6 carbon atoms). The term "cycloalkylene" includes monocyclic, bicyclic, or tricyclic hydrocarbon divalent radicals having 3 to 12 carbon atoms. Representative examples of monocyclic cycloalkylenes include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, and cyclooctylene. Bicyclic and tricyclic cycloalkylenes include bridged cyclic alkylenes, fused cyclic alkylenes, and spirocyclic alkylenes, including, but not limited to, decalinylene, octahydrocyclopentalenylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, spirocycloalkylene, adamantanylene, noradamantanylene, and norbornylene (systematic name biscyclo[2.2.1]heptylene). In the present disclosure, the "cycloalkylene" is optionally mono- or polysubstituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl. The substituents of the substituted "cycloalkylene" are optionally halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 One or more substituents selected from the group consisting of alkyl (eg, trifluoromethyl), amino, hydroxy, heterocyclyl, or any combination thereof.

[0123] As used herein, the term "C" as used alone or in combination x-y The term "spirocycloalkylene" (where x and y are each integers) refers to a spirocycloalkylene containing x to y carbon atoms. 7-11 "Spirocycloalkylene" refers to a spirocycloalkylene containing 7 to 11 (e.g., 7-10, 7-9) carbon atoms.7-11 Representative examples of "spirocycloalkylene" include, but are not limited to, spiro[3.3]heptylene, spiro[2.5]octylene, spiro[3.5]nonylene, spiro[4.4]nonylene, spiro[4.5]decylene, or spiro[5.5]undecylene. 7-11 Spirocycloalkylene can further include C1-C3 alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto group, halogen, C1-C3 alkoxy, C1-C3 alkylamino, halogenated C1-C3 alkyl, amino-substituted C 1-3 Alkylene, C 1-3 Alkyl-NHC(O)-, C 1-3 It is optionally substituted with one or more substituents selected from the group consisting of alkyl-C(O)NH-, cyano group, or any combination thereof.

[0124] As used herein, the term "heterocyclyl," alone or in combination, refers to a 3- to 20-membered monocyclic, bicyclic, or tricyclic, saturated or partially unsaturated (i.e., having one or more double bonds but not completely conjugated) cyclic hydrocarbon group containing one or more (e.g., including 1 to 5, or 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. In some embodiments, "heterocyclyl" refers to a 3- to 15-membered (optionally 3- to 14-membered, 3- to 12-membered, 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 4- to 9-membered) monocyclic saturated or partially unsaturated (i.e., having one or more double bonds but not fully conjugated) cyclic hydrocarbon group containing one or more (e.g., 1-5, or 1-4, 1-3, 1-2, or 1) heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Representative examples of single-ring heterocyclyls include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azacycloheptyl, azacyclooctyl, diazacycloheptanyl (e.g., 1,4-diazacycloheptan-1-yl), and diazacyclooctyl. Bicyclic and tricyclic heterocyclyls include bridged heterocyclyls, fused heterocyclyls, and spiroheterocyclyls, and representative examples include, but are not limited to, 6-azabicyclo[3.1.1]heptan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 3,6-diazabicyclo[3.1.1]heptan-3-yl, 3-azabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, and azaspirocycloalkyl (e.g., 3-azaspiro[5.5]undecan-3-yl).The heterocyclyl may be unsubstituted or substituted as clearly defined (e.g., mono-, di-, tri- or poly-substituted), where the substituents are deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C. 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 Alkyl-NH-, NH2-C 1-6 Alkylene, optionally deuterated C 1-6 Alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH—, or any combination thereof.

[0125] As used herein, the term "nitrogen-containing monocyclic heterocyclyl," alone or in combination, refers to a 3- to 20-membered (optionally 3-15-membered, 3-14-membered, 3-12-membered, 3-11-membered, 3-10-membered, 3-9-membered, 3-8-membered, 3-7-membered, 3-6-membered, 3-5-membered, or 4-9-membered) monocyclic saturated or partially unsaturated (i.e., having one or more double bonds but not fully conjugated) monovalent cyclic hydrocarbon group containing one nitrogen atom and, optionally, one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Representative examples of nitrogen-containing monocyclic heterocyclyls include, but are not limited to, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azacycloheptyl, azacyclooctyl, diazacycloheptanyl (e.g., 1,4-diazacycloheptan-1-yl), and diazacyclooctyl. The nitrogen-containing monocyclic heterocyclyls may be unsubstituted or substituted (e.g., mono-, di-, tri-, or poly-substituted) as specifically defined, where the substituents are deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, or optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 Alkyl-NH-, NH2-C 1-6 Alkylene, optionally deuterated C 1-6 Alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH— or any combination thereof.

[0126] As used herein, the term "heterocyclylene," alone or in combination, refers to a 3- to 20-membered monocyclic, bicyclic, or tricyclic, saturated or partially unsaturated (i.e., having one or more double bonds but not completely conjugated) divalent cyclic hydrocarbon group containing one or more (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. In some embodiments, "heterocyclylene" may refer to a 3- to 15-membered (optionally 3- to 14-membered, 3- to 12-membered, 3- to 11-membered, 3- to 10-membered, 3- to 9-membered, 3- to 8-membered, 3- to 7-membered, 3- to 6-membered, 3- to 5-membered, or 4- to 9-membered) monocyclic saturated or partially unsaturated (i.e., having one or more double bonds but not fully conjugated) divalent cyclic hydrocarbon group containing one or more (e.g., containing 1 to 5, or 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Representative examples of monocyclic heterocyclylenes include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, tetrahydropyranylene, tetrahydrothienylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, dioxacyclohexylene, and diazacycloheptanylene (e.g., 1,4-diazacycloheptanylene, 4,5-diazacycloheptanylene, 1,3-diazacycloheptanylene). Bicyclic heterocyclylene and tricyclic heterocyclylene include bridged heterocyclylene, fused heterocyclylene, and spiroheterocyclylene, and representative examples include, but are not limited to, 6-azabicyclo[3.1.1]heptanylene, 2,5-diazabicyclo[2.2.1]heptanylene, 3,6-diazabicyclo[3.1.1]heptylene, 3-azabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 3,8-diazabicyclo[3.2.1]octanylene, 2,5-diazabicyclo[2.2.2]octanylene, and azaspirocycloalkylene (e.g., 3-azaspiro[5.5]undecanylene).The heterocyclylene may be unsubstituted or substituted (e.g., mono-, di-, tri- or poly-substituted) as clearly defined, where the substituents are deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, optionally deuterated C. 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 Alkyl-NH-, NH2-C 1-6 Alkylene, optionally deuterated C 1-6 Alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH— or any combination thereof.

[0127] As used herein, the term "nitrogen-containing heterocyclylene," alone or in combination, refers to a 3-20-membered (optionally 3-15-membered, 3-14-membered, 3-12-membered, 3-11-membered, 3-10-membered, 3-9-membered, 3-8-membered, 3-7-membered, 3-6-membered, 3-5-membered, or 4-9-membered), mono-, bi-, or tri-cyclic, saturated or partially unsaturated (i.e., having one or more double bonds but not fully conjugated) divalent cyclic hydrocarbon group containing one nitrogen atom and, optionally, one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) heteroatoms independently selected from the group consisting of sulfur, oxygen, and nitrogen. Representative examples of nitrogen-containing heterocyclylenes include, but are not limited to, piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, thiomorpholinylene, azacycloheptylene, diazacycloheptanylene, azacyclooctylene, and diazacyclooctylene. The nitrogen-containing heterocyclylenes may be unsubstituted or substituted as defined (e.g., mono-, di-, tri-, or poly-substituted), where the substituents are deuterium, hydroxy, amino, mercapto, nitro, halogen, cyano, or optionally deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, optionally deuterated C 3-6 Cycloalkyl, optionally deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 Alkyl-NH-, NH2-C 1-6 Alkylene, optionally deuterated C 1-6 Alkyl-NHC(O)-, optionally deuterated C 1-6 alkyl-C(O)NH— or any combination thereof.

[0128] As used herein, the term "alkynylene," alone or in combination, refers to a straight- or branched-chain divalent hydrocarbon group containing 2 to 8 (e.g., 2 to 6, 2 to 5, 2 to 4, preferably 2) carbon atoms having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon triple bonds. Examples of alkynylene include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.

[0129] As used herein, the term "alkynyl," alone or in combination, refers to a straight-chain or branched-chain monovalent hydrocarbon group containing 2 to 8 (e.g., 2 to 6, 2 to 5, 2 to 4, preferably 2) carbon atoms and having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon triple bonds. 2-6 Examples of "alkynyl" include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1,3-diynyl.

[0130] As used herein, the term "alkenylene," alone or in combination, refers to a straight-chain or branched-chain divalent hydrocarbon group containing 2 to 8 carbon atoms (e.g., 2 to 6, 2 to 5 carbon atoms, or 2 to 4, or 2 to 3, or 2 carbon atoms) having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon double bonds. Examples of alkenylene include, but are not limited to, vinylene (e.g., —CH═CH—), 1-propenylene, arylidene, 1-butenylene, 2-butenylene, 3-butenylene, isobutenylene, pentenylene, n-penta-2,4-dienylene, 1-methyl-but-1-enylene, 2-methyl-but-1-enylene, 3-methyl-but-1-enylene, 1-methyl-but-2-enylene, 2-methyl-but-2-enylene, 3-methyl-but-2-enylene, 1-methyl-but-3-enylene, 2-methyl-but-3-enylene, 3-methyl-but-3-enylene, and hexenylene.

[0131] As used herein, the term "alkenyl," alone or in combination, refers to a straight-chain or branched-chain monovalent hydrocarbon group containing 2 to 8 carbon atoms (e.g., 2 to 6, 2 to 5 carbon atoms, or 2 to 4, 2 to 3, or 2 carbon atoms) having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon double bonds. 2-6 Examples of "alkenyl" include, but are not limited to, vinyl (e.g., CH2=CH-), 1-propenyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, pentenyl, n-penta-2,4-dienyl, 1-methyl-but-1-enyl, 2-methyl-but-1-enyl, 3-methyl-but-2-enyl, 1-methyl-but-3-enyl, 2-methyl-but-2-enyl, 3-methyl-but-2-enyl, 1-methyl-but-3-enyl, 2-methyl-but-3-enyl, 3-methyl-but-3-enyl, and hexenyl.

[0132] In this specification, "bornane" (also referred to as 1,7,7-trimethylbicyclo[2.2.1]heptane; camphane; or bornylane) has the definition known to those skilled in the art. In this specification, "bornyl" refers to a monovalent radical of bornane, i.e., the radical obtained after one of the hydrogen atoms in bornane is removed. Representative examples include 1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-3-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-4-yl, 1,7,7-trimethylbicyclo[2.2.1]heptan-5-yl, or 1,7,7-trimethylbicyclo[2.2.1]heptan-6-yl. [ka] Including, but not limited to:

[0133] As used herein, "bicyclo[2.2.1]heptane" is also referred to as bicyclo[2.2.1]heptane or "norbornane," and has the definition known to those skilled in the art. As used herein, "bicyclo[2.2.1]heptyl" or "norbornyl" refers to the monovalent radical of bicyclo[2.2.1]heptane, i.e., the radical remaining after loss of one of the hydrogen atoms in bicyclo[2.2.1]heptane. Representative examples of "bicyclo[2.2.1]heptyl" include, but are not limited to, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-3-yl, bicyclo[2.2.1]heptan-4-yl, bicyclo[2.2.1]heptan-5-yl, or bicyclo[2.2.1]heptan-6-yl.

[0134] As used herein, the term "biscyclo[2.2.1]heptene" (also referred to as bicyclo[2.2.1]heptene) has the definition known to those skilled in the art. As used herein, "biscyclo[2.2.1]heptenyl" refers to a monovalent radical of biscyclo[2.2.1]heptene, i.e., the radical remaining after loss of one of the hydrogen atoms in biscyclo[2.2.1]heptene. Representative examples of "biscyclo[2.2.1]heptenyl" include, but are not limited to, biscyclo[2.2.1]hept-5-en-2-yl, biscyclo[2.2.1]hept-5-en-3-yl, or biscyclo[2.2.1]hept-5-en-7-yl.

[0135] In the text, "adamantane" (Tricyclo[3.3.1.1 3,7 ]decane) has a definition known to those skilled in the art, and its structural formula is, for example, [ka] As used herein, "adamantanyl" refers to a monovalent radical of adamantane, i.e., the radical remaining after one of the hydrogen atoms in adamantane is removed. Representative examples of "adamantanyl" include, but are not limited to, 1-adamantanyl, 2-adamantanyl, 3-adamantanyl, 4-adamantanyl, 5-adamantanyl, 6-adamantanyl, 7-adamantanyl, 8-adamantanyl, 9-adamantanyl, or 10-adamantanyl.

[0136] In this document, "noradamantane" (also referred to as noradamantane) has the definition known to those skilled in the art, and its structural formula is, e.g., [ka] As used herein, "noradamantanyl" refers to a monovalent radical of noradamantane, i.e., the radical remaining after any hydrogen atom in noradamantane is removed. As used herein, representative examples of "noradamantanyl" include, but are not limited to, 1-noradamantanyl, 2-noradamantanyl, 3-noradamantanyl, 4-noradamantanyl, 5-noradamantanyl, 6-noradamantanyl, 7-noradamantanyl, 8-noradamantanyl, and 9-noradamantanyl.

[0137] As used herein, "adamantanamine" has the definition known to those skilled in the art, i.e., refers to an adamantane bearing an amino substituent, where amino can replace a hydrogen on any carbon of the adamantane. One example of an "adamantanamine" is adamantan-1-amine (the corresponding English name is adamantan-1-amine or Tricyclo[3.3.1.1]), having the following structural formula: 3,7 ]decan-1-amine; CAS: 768-94-5), which has the following structural formula: [ka] It has.

[0138] Also included within the scope of this disclosure are salts of the compounds of formula (I) or of the compounds of Table 1 or 2 according to this disclosure, or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, and polymorphs thereof.

[0139] In all embodiments of the present disclosure, the salt or pharmaceutically acceptable salt of the compound ((including any one of the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-2-1), formula (I-2-2), formula (I-2-3), formula (I-2-4), formula (I-2-5), formula (I-3-1), formula (I-3-2), formula (I-3-3), or formula (I-3-4), or a compound of Table 1 or Table 2) means It refers to non-toxic inorganic or organic acid and / or base addition salts, such as sulfate, hydrochloride, citrate, maleate, methanesulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, hydroxyacetate, or p-toluenesulfonate.

[0140] A "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or sealant, that can carry or deliver the compounds useful in the present disclosure into the body of a patient to perform its desired function. Generally, such constructs are carried or delivered from one organ or part of the body to another organ or part. A carrier must be "acceptable" in that it is compatible with the other ingredients of the formulation (including the compounds useful in the present disclosure) and is not harmful to the patient. Some examples of substances used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants, phosphate buffers; and other non-toxic compatible substances used in drug formulations.

[0141] In the present disclosure, the term "room temperature" refers to an ambient temperature, for example, a temperature of 20 to 30°C.

[0142] As used herein, "stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, non-enantiomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, etc.

[0143] As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acrylate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex where the solvent molecule is water.

[0144] As used herein, the term "chiral" refers to a molecule that has the property of not being superimposable on its mirror image, and "non-chiral" refers to a molecule that is superimposable on its mirror image.

[0145] As used herein, the term "enantiomers" refers to two isomers of a compound that are non-superimposable mirror images of one another.

[0146] As used herein, the term "non-enantiomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of one another. Non-enantiomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of non-enantiomers can be separated by high-resolution analytical procedures, such as electrophoresis and chromatography, e.g., HPLC. Example

[0147] In the following description, numerous specific details are set forth to provide a thorough understanding of the present disclosure. The present disclosure may be practiced without some or all of these specific details. In other instances, well-known process operations will not be described in detail so as not to unnecessarily obscure the present disclosure. While the present disclosure will be described with reference to specific examples, it should be understood that the present disclosure is not intended to be limited by these examples.

[0148] In all descriptions and examples, the following abbreviations are used: TIFF0007825122000050.tif205122TIFF0007825122000051.tif7590

[0149] In the present invention, 1The H NMR spectrum was measured using a Bruker 500 MHz nuclear magnetic resonance spectrometer. When CD3OD containing 0.1% TMS was used as the solvent, CD3OD (δ=3.31 ppm) was used as the internal standard, or when CDCl3 containing 0.1% TMS was used as the solvent, 1 H NMR spectra were obtained using CDCl3 (δ = 7.26 ppm) as an internal standard or DMSO-d6 containing 0.03% TMS as the solvent. 1 1 H NMR spectra were measured using DMSO-d6 (δ = 2.50 ppm) as an internal standard. LEMS spectra were measured using an AB Triple 4600 mass spectrometer, preparative HPLC was measured using a SHIMADZU LC-20AP, and HPLC purity was measured using a SHIMADZU LC-30AP or a Waters 1525. Unless otherwise specified, all reactions were carried out in an air atmosphere and followed by TLC or LC-MS.

[0150] The solvents and reagents are as follows: The solvents used in the reaction, DCM, DMF, anhydrous EtOH, and anhydrous MeOH, were all purchased from Chinese Sinopharm Group. Preparative grade CH3CN and deionized water were used for preparative HPLC. Unless otherwise specified, the starting materials, reagents, various carbon chain linkers (i.e., compounds for forming the group represented by LIN) of different lengths, and other reagents and pharmaceuticals used in the following examples can be purchased from manufacturers and used as is, or can be synthesized by methods known in the art.

[0151] Common synthesis methods

[0152] The compounds and / or pharmaceutically acceptable salts thereof according to the present disclosure can be synthesized using commercially available raw materials by synthetic techniques known in the art. The synthesis schemes described below illustrate the methods for preparing most of the compounds by way of example. The starting materials or reagents used in each scheme are all commercially available or can be prepared by methods known to those skilled in the art. Those skilled in the art can use ordinary skills in the art to prepare salts of the compounds of formula (I) of the present disclosure or salts of the compounds of Table 1 or 2, including their racemates, enantiomers, phosphates, sulfates, hydrochlorides, and pharmaceutical precursors.

[0153] R of the compound of formula (I) 11 - Common preparation method of intermediate corresponding to LIN moiety 1: [ka] Scheme 1

[0154] R of the compound of formula (I) 11 - Common preparation method 2 of the intermediate corresponding to the LIN moiety: [ka] Scheme 2

[0155] Intermediate compound 732180 was prepared with reference to the method in Scheme 1.

[0156] Common preparation method of binder intermediate compound 1: [ka] Scheme 3

[0157] Common preparation method 2 of binder intermediate compound: [ka] Scheme 4

[0158] Common preparation method 3 of binder intermediate compound: [ka] Scheme 5

[0159] Common preparation method 4 of binder intermediate compound: [ka] Scheme 6

[0160] Common methods for preparing compounds of formula (I): [ka] Scheme 7

[0161] In Scheme 7, POI represents the reactive group of the intermediate BINDER, and (R a ) t and X is as defined herein for compounds of formula (I).

[0162] To a DMF solution of the bromo substrate (1.0 equiv) was added the corresponding binder intermediate compound (1.0 equiv) and DIEA (2.0 equiv). The reaction mixture was allowed to react at room temperature for 2 h, and then the reaction was completed. The reaction mixture was separated and purified by C18 reverse-phase column chromatography (eluent (v / v): acetonitrile / (water + 0.05% HCl) = 10%-100%) to obtain the corresponding target product.

[0163] Depending on the target compound, the required target compound can be obtained by appropriately modifying and adjusting the above schemes and their reaction substrates, reaction conditions (including reaction volume, temperature, time, etc.), post-treatment, etc. using techniques and methods well known to those skilled in the art. In addition, the obtained target compound can be further modified with substituents, etc. using methods well known to those skilled in the art to obtain other target compounds.

[0164] Example

[0165] Intermediate Example 1: Preparation of 3-(4-bromo-6-(bromomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (732001) [ka]

[0166] 3-(4-bromo-6-(bromomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (732001) was prepared according to Scheme 1.

[0167] Step 1:

[0168] The starting material, methyl 3-bromo-2-methylbenzoate (5.0 g, 20.6 mmol), was dissolved in 100 mL of carbon tetrachloride, and N-bromosuccinimide (8.0 g, 45 mmol) and dibenzoyl peroxide (0.31 g, 1.26 mmol) were added, in that order. The reaction mixture was refluxed at 80 °C for 12 h, cooled to room temperature, and diluted with 100 mL of petroleum ether. The diluted mixture was washed twice with water and once with saturated brine. The organic phases were separated, combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0-20 / 1) to give compound 363126 (6.3 g, yield: 76%) as a white solid.

[0169] Step 2:

[0170] Cesium carbonate (16.25 g, 49.89 mmol) was added to a mixture of 500 mL of 1,2-dichloroethane and 50 mL of hexafluoroisopropanol. The resulting mixture was stirred at 65 °C for 15 min, followed by the addition of 3-amino-2,6-piperidinedione hydrochloride (8.21 g, 49.89 mmol) and compound 363126 (20 g, 49.89 mmol) obtained in step 1. The reaction mixture was stirred at 65 °C for 12 h. The hot reaction mixture was filtered to remove insoluble material, and the filtrate was washed with saturated brine and then evaporated under reduced pressure to remove the organic solvent. The remaining solid was slurried in 50 mL of dichloromethane and 200 mL of petroleum ether. The resulting mixture was filtered, and the solid was washed with 50 mL of dichloromethane and 50 mL of ethyl ether to give product 732001 (11 g, 42% yield) as a gray powder. 1 H NMR (500 MHz, Methanol-d4) δ 7.90 (d, J = 1.5 Hz, 1H), 7.84 (d, J = 1.5 Hz, 1H), 5.17 (dd, J = 13.4, 5.2 Hz, 1H), 4.68 (s, 2H), 4.45 (q, J = 17.6 Hz, 2H), 2.91 (ddd, J = 17.6, 13.6, 5.4 Hz, 1H), 2.79 (ddd, J = 17.6, 4.6, 2.4 Hz, 1H), 2.53 (qd, J = 13.4, 4.7 Hz, 1H), 2.19 (dtd, J = 13.0, 5.4, 2.4 Hz, 1H). MS (ESI) m / z: Calculated value C 14 H 13 Br2N2O3 + [M+H] + , 414.9; actual value, 415.1.

[0171] Intermediate Example 2: Preparation of 3-(5-(bromomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (732180) [ka]

[0172] According to Scheme 2, 3-(5-(bromomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (732180) was prepared by referring to the method of Scheme 1. Alternatively, the starting material for Step 2 of Scheme 2, methyl 2,4-bis(bromomethyl)benzoate (CAS number: 63112-94-7), can be purchased commercially. After the reaction was completed, the reaction mixture was washed with water. The organic layer was separated and the solvent was removed by distillation under reduced pressure. The resulting residue was separated by silica gel column chromatography (DCM / MeOH = 1 / 0-10 / 1), and the resulting product was further purified by slurrying with acetonitrile to give a white powder (yield: 27%). 1 H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.78 - 7.66 (m, 2H), 7.59 (dd, J = 7.9, 1.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.83 (s, 2H), 4.47 (d, J = 17.3 Hz, 1H), 4.34 (d, J = 17.4 Hz, 1H), 2.91 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.68 - 2.55 (m, 1H), 2.39 (qd, J = 13.3, 4.5 Hz, 1H), 2.01 (dtd, J = 12.7, 5.3, 4.7, 1.9 Hz, 1H). MS (ESI) m / z: Calculated value C 14 H 14 BrN2O3 + [M+H] + , 337.0; actual value, 337.3.

[0173] Intermediate Example 3: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732147), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732148) [ka]

[0174] According to Scheme 4, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732147), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732148) were prepared.

[0175] Step 1:

[0176] To a solution of 4-oxocyclohexanecarbonitrile (1 equiv) in methanol was added tert-butyl (S)-2-methylpiperazine-1-carboxylate (1.5 equiv) and zinc chloride (1.5 equiv). The resulting mixture was stirred at room temperature for 15 min, cooled to 0 °C, and then sodium cyanoborohydride (3.0 equiv) was added. The reaction was allowed to proceed overnight. The reaction mixture was quenched by the addition of saturated ammonium chloride solution. The resulting mixture was extracted three times with dichloromethane and washed once with saturated brine. The separated organic phase was evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to obtain the cyano product as a white solid (yield: 80%), which was a mixture of cis- and trans-products.

[0177] Step 2:

[0178] A solution of NH3 in methanol (7 M, 0.5 mL) and Raney nickel were added to a reaction bottle containing the methanol solution of the cyano compound obtained in Step 1. The reaction bottle was purged with hydrogen gas. The reaction mixture was heated to 60 °C and hydrogenated at atmospheric pressure overnight. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth to remove the Raney nickel. The eluate was rotary evaporated to obtain the crude amine, which was used directly in the next step.

[0179] Step 3:

[0180] To a solution of the amine product from the previous step in THF was added 4-fluoro-3-nitrobenzenesulfonamide (0.9 equiv) and triethylamine (1.5 equiv). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The resulting mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine. The organic phases were separated and evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to separate the cis product (732139) and the trans product (732141). Cis product (732139): tert-butyl (S)-2-methyl-4-((cis)-4-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylate 1 H NMR (500 MHz, DMSO-d6) δ 8.54 (dt, J = 7.0, 5.1 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 9.1, 2.3 Hz, 1H), 7.33 (s, 2H), 7.26 (d, J = 9.3 Hz, 1H), 4.07 (s, 1H), 3.68 (d, J = 12.7 Hz, 1H), 3.38 (d, J = 6.5 Hz, 2H), 2.99 - 2.83 (m, 2H), 2.77 (d, J = 11.3 Hz, 1H), 2.13 (s, 1H), 2.00 (d, J = 10.9 Hz, 1H), 1.86 (d, J = 9.9 Hz, 2H), 1.81 - 1.66 (m, 2H), 1.53 (d, J = 7.0 Hz, 2H), 1.48 - 1.42 (m, 3H), 1.39 (s, 9H), 1.14 (d, J = 6.7 Hz, 3H). Trans product (732141): tert-butyl (S)-2-methyl-4-((trans)-4-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylate 1H NMR (500 MHz, DMSO-d6) δ 8.56 (t, J = 5.9 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 9.1, 2.3 Hz, 1H), 7.33 (s, 2H), 7.25 (d, J = 9.3 Hz, 1H), 4.04 (s, 1H), 3.63 (d, J = 12.7 Hz, 1H), 3.29 (t, J = 6.4 Hz, 2H), 2.88 (t, J = 12.1 Hz, 1H), 2.71 (d, J = 10.9 Hz, 1H), 2.60 (d, J = 11.1 Hz, 1H), 2.25 (ddt, J = 15.6, 11.0, 5.9 Hz, 2H), 2.12 (td, J = 11.4, 3.3 Hz, 1H), 1.86 - 1.70 (m, 4H), 1.57 (dt, J = 7.7, 3.6 Hz, 1H), 1.38 (s, 9H), 1.18 (ddd, J = 25.3, 13.9, 7.4 Hz, 2H), 1.10 (d, J = 6.7 Hz, 3H), 1.07 - 0.96 (m, 2H).

[0181] ステップ4:

[0182] To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1 equiv; cas: 1235865-77-6) in dichloromethane was added EDCI (1.5 equiv) and DMAP (1.0 equiv). The reaction mixture became clear. To the reaction mixture was added the cis product (732139) or trans product (732141) obtained in Step 3. The reaction was allowed to proceed for 12 h until the reaction of the raw materials was complete. The reaction mixture was diluted with 30 mL of dichloromethane. The resulting mixture was washed with saturated brine. The organic phase was separated and evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to give the Boc-protected product.

[0183] To a solution of the Boc-protected product in dichloromethane was added trifluoroacetic acid (10 equiv). The reaction mixture was allowed to react at room temperature for 30 min. After the reaction was complete, the mixture was evaporated under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to give the cis product (732147) and the trans product (732148) as powders. Cis product (732147): 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 1H NMR (500 MHz, Methanol-d4) δ 8.66 (d, J = 2.3 Hz, 1H), 8.06 - 7.96 (m, 1H), 7.86 (dd, J = 9.2, 2.3 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.47 (d, J = 3.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 9.4 Hz, 1H), 6.76 (dd, J = 8.9, 2.4 Hz, 1H), 6.43 (d, J = 3.5 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 3.99 - 3.84 (m, 3H), 3.80 - 3.60 (d, J = 29.2 Hz, 6H), 3.50 - 3.35 (m, 6H), 3.27 - 3.09 (m, 3H), 2.79 (s, 2H), 2.33 - 2.26 (m, 2H), 2.10 (s, 3H), 1.96 (dt, J = 31.7, 9.6 Hz, 7H), 1.72 (ddd, J = 15.0, 10.4, 4.7 Hz, 2H), 1.56 (t, J = 6.4 Hz, 2H), 1.45 (d, J = 6.5 Hz, 3H), 1.00 (s, 6H). Trans product (732148): 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-((S)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide 1H NMR (500 MHz, Methanol-d4) δ 8.66 (d, J = 2.3 Hz, 1H), 8.00 (s, 1H), 7.85 (dd, J = 9.3, 2.3 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.47 (d, J = 3.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 9.3 Hz, 1H), 6.76 (dd, J = 9.0, 2.4 Hz, 1H), 6.43 (d, J = 3.4 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 3.90 - 3.78 (m, 3H), 3.77 - 3.57 (m, 7H), 3.51 - 3.35 (m, 5H), 3.28 (d, J = 6.7 Hz, 3H), 3.17 (d, J = 15.8 Hz, 2H), 2.79 (s, 2H), 2.33 - 2.24 (m, 4H), 2.10 (s, 2H), 2.06 (d, J = 12.0 Hz, 2H), 1.81 - 1.71 (m, 1H), 1.70 - 1.59 (m, 2H), 1.56 (t, J = 6.4 Hz, 2H), 1.45 (d, J = 6.5 Hz, 3H), 1.25 (ddt, J = 16.2, 12.9, 6.2 Hz, 2H), 1.00 (s, 6H).

[0184] Intermediate Example 4: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((R)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732149), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-((R)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732150) [ka]

[0185] According to Scheme 3, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((R)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732149), and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-((R)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732150) were prepared.

[0186] Step 1:

[0187] To a solution of 4-oxocyclohexanecarbonitrile (1 equiv) in methanol was added tert-butyl (R)-2-methylpiperazine-1-carboxylate (1.5 equiv) and zinc chloride (1.5 equiv). The resulting mixture was stirred at room temperature for 15 min, cooled to 0 °C, and then sodium cyanoborohydride (3.0 equiv) was added. The reaction was allowed to proceed overnight. The reaction mixture was quenched by adding saturated ammonium chloride solution. The resulting mixture was extracted three times with dichloromethane and washed once with saturated brine. The separated organic phase was distilled under pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to obtain the cyano product (yield: 80%) as a white solid, which was a mixture of cis- and trans-products.

[0188] Step 2:

[0189] To a reaction bottle containing the methanol solution of the cyano compound obtained in Step 1, a methanol solution of NH3 (7 M, 0.5 mL) and Raney nickel were added. The reaction bottle was purged with hydrogen gas. The reaction mixture was heated to 60 °C, hydrogenated at atmospheric pressure, and reacted overnight. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth to remove the Raney nickel. The filtrate was rotary evaporated to obtain the crude amine, which was used directly in the next step.

[0190] Step 3:

[0191] To a solution of the amine product from the previous step in THF was added 4-fluoro-3-nitrobenzenesulfonamide (0.9 equiv) and triethylamine (1.5 equiv). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The resulting mixture was extracted three times with dichloromethane. The combined dichloromethane organic phase was washed with saturated brine. The organic phase was separated and evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to successfully separate and obtain the cis product (732140) and the trans product (732142). Cis product (732140): tert-butyl (R)-2-methyl-4-((cis)-4-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylate 1 H NMR (500 MHz, DMSO-d6) δ 8.54 (dt, J = 7.0, 5.1 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 7.82 (dd, J = 9.1, 2.3 Hz, 1H), 7.33 (s, 2H), 7.26 (d, J = 9.3 Hz, 1H), 4.07 (s, 1H), 3.68 (d, J = 12.7 Hz, 1H), 3.38 (d, J = 6.5 Hz, 2H), 2.99 - 2.83 (m, 2H), 2.77 (d, J = 11.3 Hz, 1H), 2.13 (s, 1H), 2.00 (d, J = 10.9 Hz, 1H), 1.86 (d, J = 9.9 Hz, 2H), 1.81 - 1.66 (m, 2H), 1.53 (d, J = 7.0 Hz, 2H), 1.48 - 1.42 (m, 3H), 1.39 (s, 9H), 1.14 (d, J = 6.7 Hz, 3H). Trans product (732142): tert-butyl (R)-2-methyl-4-((trans)-4-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylate 1 H NMR (500 MHz, DMSO-d6) δ 8.56 (t, J = 5.9 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 9.1, 2.3 Hz, 1H), 7.33 (s, 2H), 7.25 (d, J = 9.3 Hz, 1H), 4.04 (s, 1H), 3.63 (d, J = 12.7 Hz, 1H), 3.29 (t, J = 6.4 Hz, 2H), 2.88 (t, J = 12.1 Hz, 1H), 2.71 (d, J = 10.9 Hz, 1H), 2.60 (d, J = 11.1 Hz, 1H), 2.25 (ddt, J = 15.6, 11.0, 5.9 Hz, 2H), 2.12 (td, J = 11.4, 3.3 Hz, 1H), 1.86 - 1.70 (m, 4H), 1.57 (dt, J = 7.7, 3.6 Hz, 1H), 1.38 (s, 9H), 1.18 (ddd, J = 25.3, 13.9, 7.4 Hz, 2H), 1.10 (d, J = 6.7 Hz, 3H), 1.07 - 0.96 (m, 2H).

[0192] ステップ4:

[0193] To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1 equiv; cas: 1235865-77-6) in dichloromethane was added EDCI (1.5 equiv) and DMAP (1.0 equiv). The reaction mixture became clear. To the reaction mixture was added the cis product (732140) or trans product (732142) obtained in Step 3. The reaction mixture was allowed to react for 12 h to allow the reaction of the raw materials to complete. The reaction mixture was diluted with 30 mL of dichloromethane. The resulting mixture was washed with saturated brine. The organic phase was separated and evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH=1 / 0-10 / 1) to give the Boc-protected product.

[0194] To a solution of the Boc-protected product in dichloromethane was added trifluoroacetic acid (10 equiv). The reaction mixture was allowed to react at room temperature for 30 min. After the reaction was complete, the mixture was evaporated under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to give the cis product (732149) and the trans product (732150) as powders. Cis product (732149): 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((R)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732149) 1H NMR (500 MHz, Methanol-d4) δ 8.66 (d, J = 2.3 Hz, 1H), 8.06 - 7.96 (m, 1H), 7.86 (dd, J = 9.2, 2.3 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.47 (d, J = 3.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 9.4 Hz, 1H), 6.76 (dd, J = 8.9, 2.4 Hz, 1H), 6.43 (d, J = 3.5 Hz, 1H), 6.34 (d, J = 2.3 Hz, 1H), 3.99 - 3.84 (m, 3H), 3.80 - 3.60 (d, J = 29.2 Hz, 6H), 3.50 - 3.35 (m, 6H), 3.27 - 3.09 (m, 3H), 2.79 (s, 2H), 2.33 - 2.26 (m, 2H), 2.10 (s, 3H), 1.96 (dt, J = 31.7, 9.6 Hz, 7H), 1.72 (ddd, J = 15.0, 10.4, 4.7 Hz, 2H), 1.56 (t, J = 6.4 Hz, 2H), 1.45 (d, J = 6.5 Hz, 3H), 1.00 (s, 6H). Trans product (732150): 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-((R)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732150) 1H NMR (500 MHz, Methanol-d4) δ 8.66 (d, J = 2.3 Hz, 1H), 8.00 (s, 1H), 7.85 (dd, J = 9.3, 2.3 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.47 (d, J = 3.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 9.3 Hz, 1H), 6.76 (dd, J = 9.0, 2.4 Hz, 1H), 6.43 (d, J = 3.4 Hz, 1H), 6.33 (d, J = 2.4 Hz, 1H), 3.90 - 3.78 (m, 3H), 3.77 - 3.57 (m, 7H), 3.51 - 3.35 (m, 5H), 3.28 (d, J = 6.7 Hz, 3H), 3.17 (d, J = 15.8 Hz, 2H), 2.79 (s, 2H), 2.33 - 2.24 (m, 4H), 2.10 (s, 2H), 2.06 (d, J = 12.0 Hz, 2H), 1.81 - 1.71 (m, 1H), 1.70 - 1.59 (m, 2H), 1.56 (t, J = 6.4 Hz, 2H), 1.45 (d, J = 6.5 Hz, 3H), 1.25 (ddt, J = 16.2, 12.9, 6.2 Hz, 2H), 1.00 (s, 6H).

[0195] Intermediate Example 5 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (732185) [ka]

[0196] Referring to Scheme 5, 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (732185) was prepared.

[0197] Step 1:

[0198] To a solution of tert-butyl 4-((trans)-4-(aminomethyl)cyclohexyl)piperazine-1-carboxylate (1.0 equiv; CAS number: 2357231-00-4) in THF, 4-fluoro-3-trifluoromethylsulfonylbenzenesulfonamide (1.0 equiv) and triethylamine (1.5 equiv) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to the mixture. The resulting mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine. The organic phase was separated and evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to give the product tert-butyl 4-((trans)-4-(((4-aminosulfonyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylate (732181) as a white powder (yield 98%). 1H NMR (500 MHz, DMSO-d6) δ 8.01 (d, J = 2.3 Hz, 1H), 7.93 (dd, J = 9.2, 2.4 Hz, 1H), 7.39 (s, 2H), 7.21 (d, J = 9.3 Hz, 1H), 7.16 (t, J = 5.8 Hz, 1H), 3.23 (dd, J = 13.3, 6.9 Hz, 6H), 2.41 (t, J = 5.2 Hz, 4H), 2.22 (t, J = 12.0 Hz, 1H), 1.85 - 1.70 (m, 4H), 1.60 - 1.47 (m, 1H), 1.38 (s, 9H), 1.19 (q, J = 12.2 Hz, 2H), 1.04 - 0.93 (m, 2H).

[0199] Step 2:

[0200] To a solution of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1 equiv; cas: 1235865-77-6) in dichloromethane was added EDCI (1.5 equiv) and DMAP (1.0 equiv). The reaction mixture became clear. To the reaction mixture was added the product obtained in Step 1, tert-butyl 4-((trans)-4-(((4-aminosulfonyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylate (732181). The reaction mixture was allowed to react for 12 h to allow the reaction of the raw materials to complete. The reaction mixture was diluted with 30 mL of dichloromethane. The resulting mixture was washed with saturated brine. The organic phase was separated and evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to give the Boc-protected product.

[0201] To a solution of the Boc-protected product in dichloromethane was added trifluoroacetic acid (10 equiv). The reaction mixture was allowed to react at room temperature for 30 minutes. After the reaction was complete, the mixture was evaporated under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to obtain the trifluoroacetic acid salt of the target compound (732185) as a powder. 1 H NMR (500 MHz, Methanol-d4) δ 8.30 (d, J = 2.3 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.97 (dd, J = 9.3, 2.3 Hz, 1H), 7.65 - 7.60 (m, 2H), 7.49 (d, J = 3.5 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 9.4 Hz, 1H), 6.75 (d, J = 8.9 Hz, 1H), 6.47 (d, J = 3.5 Hz, 1H), 6.30 (d, J = 2.4 Hz, 1H), 3.66 (s, 3H), 3.59 (s, 10H), 3.20 (d, J = 6.8 Hz, 3H), 3.06 (s, 2H), 2.96 - 2.66 (m, 2H), 2.25 (tt, J = 6.4, 2.4 Hz, 3H), 2.20 (d, J = 10.8 Hz, 2H), 2.11 (d, J = 8.2 Hz, 3H), 2.01 (d, J = 11.8 Hz, 2H), 1.69 (tdd, J = 11.2, 7.7, 4.8 Hz, 1H), 1.64 - 1.52 (m, 5H), 1.25 - 1.15 (m, 2H), 0.99 (s, 6H). HRMS (ESI) m / z: Calculated value C 51 H 61 ClF3N8O6S2 + [M+H] + , 1037.3791; measured value, 1037.3792.

[0202] Intermediate Example 6: Preparation of 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (732186) [ka]

[0203] By referring to the method of Scheme 5, Step 2, 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (732186) was prepared.

[0204] To a solution of 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1 equiv; CAS number: 1044598-91-5) in dichloromethane, EDCI (1.5 equiv) and DMAP (1.0 equiv) were added. The reaction mixture became clear. Compound 732181 prepared according to Step 1 of Intermediate Example 7 was added to the reaction mixture. The reaction mixture was allowed to react for 2 hours to allow the reaction of the raw materials to complete. The reaction mixture was diluted with 30 mL of dichloromethane. The resulting mixture was washed with saturated brine. The organic phase was separated and evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to obtain the Boc-protected product.

[0205] To a solution of the Boc-protected product in dichloromethane was added trifluoroacetic acid (10 equiv). The reaction mixture was allowed to react at room temperature for 30 minutes. After the reaction was complete, the mixture was evaporated under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to obtain the trifluoroacetic acid salt of the target compound (732186) as a powder. 1 H NMR (500 MHz, DMSO-d6) δ 8.05 (d, J = 2.1 Hz, 1H), 8.01 (dd, J = 9.0, 2.2 Hz, 1H), 7.71 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 9.2 Hz, 1H), 6.85 (t, J = 5.7 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 3.16 (t, J = 6.3 Hz, 3H), 3.12 (t, J = 5.0Hz, 4H), 2.97 - 2.91 (m, 4H), 2.74 (s, 2H), 2.62 (t, J = 5.0 Hz, 4H), 2.24 (dt, J = 20.9, 5.4 Hz, 7H), 1.99 (s, 2H), 1.78 (dt, J = 9.1, 4.3 Hz, 4H), 1.58 - 1.47 (m, 1H), 1.43 (t, J = 6.5 Hz, 2H), 1.26 - 1.15 (m, 3H), 1.03 - 0.99 (m, 1H), 0.97 (s, 6H). HRMS (ESI) m / z: Calculated value,C 44 H 57 ClF3N6O5S2 + [M+H] + , 905.3467; Actual value, 905.3467.

[0206] Intermediate Example 7: Preparation of 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((((trans)-4-(piperazin-1-yl)cyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide (732187) [ka]

[0207] Referring to Scheme 6, 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((((trans)-4-(piperazin-1-yl)cyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide (732187) was prepared.

[0208] Step 1:

[0209] To a solution of tert-butyl 4-((trans)-4-(aminomethyl)cyclohexyl)piperazine-1-carboxylate (1.0 equiv; CAS number: 2357231-00-4) in THF was added 4-fluoro-3-nitrobenzenesulfonamide (1.0 equiv) and triethylamine (1.5 equiv). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, saturated aqueous sodium bicarbonate solution was added to the mixture. The resulting mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated brine. The organic phase was separated and evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to give the product tert-butyl 4-((trans)-4-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylate (732170) as a white powder (yield 95%). 1H NMR (500 MHz, DMSO-d6) δ 8.56 (t, J = 6.0 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 9.1, 2.3 Hz, 1H), 7.33 (s, 2H), 7.26 (d, J = 9.3 Hz, 1H), 3.27 (dt, J = 14.8, 5.7 Hz, 6H), 2.41 (t, J = 5.1 Hz, 4H), 2.25 (t, J = 11.6 Hz, 1H), 1.88 - 1.74 (m, 4H), 1.57 (dt, J = 7.7, 3.5 Hz, 1H), 1.38 (s, 9H), 1.25 - 1.13 (m, 2H), 1.09 - 0.87 (m, 2H).

[0210] Step 2:

[0211] To a solution of 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1 equiv; CAS number: 1044598-91-5) in dichloromethane was added EDCI (1.5 equiv) and DMAP (1.0 equiv). The reaction mixture became clear. Compound 732170 prepared in Step 1 was added to the reaction mixture. The reaction mixture was reacted for 12 h to allow the reaction of the raw materials to complete. The reaction mixture was diluted with 30 mL of dichloromethane. The resulting mixture was washed with saturated brine. The organic phase was separated and evaporated under reduced pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to obtain the Boc-protected product.

[0212] To a solution of the Boc-protected product in dichloromethane was added trifluoroacetic acid (10 equiv). The reaction mixture was allowed to react at room temperature for 30 minutes. After the reaction was complete, the mixture was evaporated under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to obtain the trifluoroacetic acid salt of the target compound (732187) as a powder. 1H NMR (500 MHz, Methanol-d4) δ 8.82 (d, J = 2.3 Hz, 1H), 8.03 (dd, J = 9.3, 2.3 Hz, 1H), 7.72 (d, J = 9.1 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.16 (t, J = 8.5 Hz, 3H), 6.95 (d, J = 9.1 Hz, 2H), 3.89 (s, 1H), 3.70 (s, 2H), 3.59 (s, 10H), 3.34 (dd, J = 7.5, 5.5 Hz, 3H), 3.22 (s, 2H), 2.89 (s, 2H), 2.40 (t, J = 6.5 Hz, 2H), 2.20 (d, J = 10.8 Hz, 2H), 2.11 - 2.04 (m, 4H), 1.78 (dqd, J = 14.5, 8.4, 6.8, 3.4 Hz, 1H), 1.64 - 1.55 (m, 4H), 1.31 - 1.18 (m, 3H), 1.06 (s, 6H). HRMS (ESI) m / z: Calculated value C 43 H 57 ClN7O5S + [M+H] + , 818.3825; measured value, 818.3822.

[0213] Example 1 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03146)

[0214] According to Scheme 7, the intermediate compound 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((((trans)-4-(piperazin-1-yl)cyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide (SIAIS364025; can be prepared by referring to Preparation Example 11 of Intermediate BINDER in Chinese Patent Publication No. CN112707900A, the entire contents of which are incorporated herein by reference), and the compound (732001) prepared according to Intermediate Example 1 were used as starting materials to prepare the target compound (BCL-03146). 11H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 11.71 (s, 1H), 11.05 (s, 1H), 10.78 (s, 1H), 8.64 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.7 Hz, 1H), 8.22 (s, 1H), 8.07 (s, 1H), 8.05 (d, J = 2.9 Hz, 1H), 7.81 (dd, J = 9.2, 2.6 Hz, 1H), 7.57 (d, J = 3.1 Hz, 1H), 7.56 - 7.49 (m, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.15 - 7.06 (m, 3H), 6.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.46 - 6.37 (m, 1H), 6.26 (d, J = 2.3 Hz, 1H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.46 (d, J = 18.0 Hz, 3H), 4.31 (d, J = 17.9 Hz, 1H), 3.72 - 3.53 (m, 8H), 3.28 (dd, J = 12.3, 6.5 Hz, 9H), 2.92 (ddd, J = 17.9, 13.5, 5.6 Hz, 1H), 2.75 - 2.57 (m, 3H), 2.41 - 2.33 (m, 2H), 2.19 - 2.09 (m, 2H), 2.05 - 1.97 (m, 3H), 1.95 - 1.85 (m, 2H), 1.69 - 1.59 (m, 1H), 1.57 - 1.39 (m, 5H), 1.32 - 1.21 (m, 2H), 1.14 - 1.03 (m, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 64 H 72 BrClN 11 O9S + [M+H] + , 1284.4102; Observed, 1284.4100。

[0215] Example 2 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03147)

[0216] According to Scheme 7, the target compound (BCL-03147) was prepared using the intermediate compound 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((((trans)-4-(piperazin-1-yl)cyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide (SIAIS364025) and the compound (732180) prepared according to Intermediate Example 2 as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 11.71 (s, 1H), 11.03 (s, 1H), 10.67 (s, 1H), 8.64 (t, J = 6.1 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 3.1 Hz, 1H), 7.90 (s, 1H), 7.80 (t, J = 5.8 Hz, 3H), 7.57 (d, J = 2.9 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.14 - 7.07 (m, 3H), 6.72 (d, J = 9.2 Hz, 1H), 6.45 - 6.40 (m, 1H), 6.26 (s, 1H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.50 (d, J = 17.7 Hz, 3H), 4.37 (d, J = 17.7 Hz, 1H), 3.70 - 3.52 (m, 11H), 3.26 (d, J = 10.1 Hz, 8H), 2.92 (td, J = 13.0, 6.6 Hz, 1H), 2.76 - 2.57 (m, 3H), 2.43 (dt, J = 13.3, 6.6 Hz, 1H), 2.35 (s, 2H), 2.18 - 2.08 (m, 2H), 2.02 (d, J = 9.3 Hz, 3H), 1.90 (d, J = 11.7 Hz, 2H), 1.63 (t, J = 11.3 Hz, 1H), 1.49 (dd, J = 12.3, 3.1 Hz, 2H), 1.44 (t, J = 6.5 Hz, 2H), 1.08 (q, J = 12.1 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 64 H 73 ClN 11 O9S + [M+H] + , 1206.4996; Found, 1206.4990。

[0217] Example 3 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03148)

[0218] According to Scheme 7, the intermediate compound 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((((cis)-4-(piperazin-1-yl)cyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide (SIAIS364043; can be prepared by referring to Preparation Example 12 of intermediate BINDER of Chinese Patent Publication No. CN112707900A, the entire contents of which are incorporated herein by reference) and intermediate compound (732180) as starting materials to prepare the target compound (BCL-03148). 11H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 11.70 (s, 1H), 11.02 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.91 - 7.69 (m, 4H), 7.56 (d, J = 2.7 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.72 (dd, J = 9.0, 2.4 Hz, 1H), 6.44 - 6.37 (m, 1H), 6.25 (d, J = 2.3 Hz, 1H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.55 - 4.29 (m, 4H), 3.63 (d, J = 11.3 Hz, 5H), 3.54 (s, 3H), 3.30 - 3.16 (m, 6H), 2.93 (ddd, J = 17.5, 13.7, 5.6 Hz, 1H), 2.70 (d, J = 10.7 Hz, 2H), 2.62 (d, J = 17.4 Hz, 1H), 2.43 (qd, J = 12.7, 4.3 Hz, 1H), 2.28 (s, 2H), 2.05 - 1.97 (m, 4H), 1.85 (s, 2H), 1.78 (d, J = 12.7 Hz, 4H), 1.54 (d, J = 13.0 Hz, 2H), 1.44 (t, J = 6.4 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 64 H 73 ClN 11 O9S + [M+H] + , 1206.4996; Observed, 1206.4992。

[0219] Example 4 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((cis)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03149)

[0220] According to Scheme 7, the target compound (BCL-03149) was produced using the compound (SIAIS364043) and the compound (732001) produced according to Intermediate Example 1 as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 11.70 (s, 1H), 11.04 (s, 1H), 10.47 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 8.05 (d, J = 2.6 Hz, 1H), 8.02 (s, 1H), 7.82 (dd, J = 9.2, 2.4 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.42 - 7.38 (m, 2H), 7.15 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.72 (dd, J = 9.1, 2.5 Hz, 1H), 6.42 - 6.38 (m, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.16 (dd, J = 13.2, 5.1 Hz, 1H), 4.38 (dd, J = 78.7, 17.9 Hz, 4H), 3.63 (d, J = 13.9 Hz, 5H), 3.53 (s, 4H), 3.31 - 3.09 (m, 9H), 2.92 (ddd, J = 17.4, 13.6, 5.4 Hz, 1H), 2.69 (q, J = 13.3, 12.1 Hz, 2H), 2.61 (d, J = 17.1 Hz, 1H), 2.46 (dd, J = 13.0, 4.8 Hz, 1H), 2.32 (s, 2H), 2.07 - 1.96 (m, 4H), 1.85 (s, 2H), 1.78 (d, J = 11.1 Hz, 4H), 1.58 - 1.48 (m, 2H), 1.44 (t, J = 6.4 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 64 H 72 BrClN 11 O9S + [M+H] + , 1284.4102; Observed, 1284.4105。

[0221] Example 5 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((3S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03165)

[0222] According to Scheme 7, the target compound (BCL-03165) was produced using the compound (732147) produced according to Intermediate Example 3 and the compound (732180) produced according to Intermediate Example 2 as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 11.70 (s, 1H), 11.02 (s, 1H), 10.32 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.05 (s, 1H), 7.85 - 7.78 (m, 3H), 7.56 (d, J = 2.6 Hz, 1H), 7.53 - 7.50 (m, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 9.5 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.41 (dd, J = 3.6, 1.9 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.49 (t, J = 17.1 Hz, 1H), 4.36 (t, J = 17.5 Hz, 1H), 3.63 (d, J = 13.4 Hz, 4H), 3.56 (d, J = 18.2 Hz, 4H), 3.30 - 3.15 (m, 8H), 2.98 - 2.88 (m, 1H), 2.70 (d, J = 10.5 Hz, 2H), 2.61 (d, J = 17.1 Hz, 2H), 2.43 (dd, J = 13.3, 4.9 Hz, 1H), 2.31 (t, J = 6.5 Hz, 2H), 2.01 (d, J = 2.3 Hz, 5H), 1.90 - 1.73 (m, 7H), 1.59 - 1.47 (m, 4H), 1.47 - 1.42 (m, 3H), 0.95 (s, 6H). HRMS (ESI) m / z: Calculated for C 65 H 75 ClN 11 O9S + [M+H] + , 1220.5153; Found, 1220.5150。

[0223] Example 6 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-((3S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03166)

[0224] According to Scheme 7, the target compound (BCL-03166) was prepared using the compound (732148) prepared in accordance with Intermediate Example 3 and the intermediate compound (732180) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 11.69 (s, 1H), 11.02 (s, 1H), 10.32 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.56 (d, J = 2.6 Hz, 1H), 8.04 (d, J = 2.9 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.69 (s, 1H), 7.55 (d, J = 2.9 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.10 (dd, J = 8.7, 5.5 Hz, 3H), 6.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.43 - 6.37 (m, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.13 (dd, J = 13.4, 5.2 Hz, 1H), 4.55 - 4.43 (m, 1H), 4.35 (t, J = {16.3} Hz, 1H), 3.63 (d, J = 12.1 Hz, 3H), 3.54 (s, 3H), 3.30 - 3.10 (m, 11H), 2.92 (ddd, J = 18.0, 13.6, 5.6 Hz, 2H), 2.70 (d, J = 10.2 Hz, 2H), 2.61 (d, J = 17.3 Hz, 2H), 2.47 - 2.35 (m, 2H), 2.31 (s, 2H), 2.19 - 2.08 (m, 2H), 2.01 (s, 3H), 1.90 (d, J = 12.9 Hz, 2H), 1.62 (s, 1H), 1.54 - 1.40 (m, 6H), 1.07 (d, J = 11.4 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 65 H 75 ClN 11 O9S + [M+H] + , 1220.5153; Found, 1220.5155。 并保留 、

[0225] 、 原样。

[0225] 需注意,原文中“4.35 (t, J = {16.3} Hz, 1H)”这里的{16.3}推测可能是格式问题,翻译时保留原样。Example 7 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((3R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03167)

[0226] According to Scheme 7, the target compound (BCL-03167) was obtained using the compound (732149) prepared in accordance with Intermediate Example 4 and the intermediate compound (732180) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 11.70 (s, 1H), 11.02 (s, 1H), 10.32 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.05 (s, 1H), 7.85 - 7.78 (m, 3H), 7.56 (d, J = 2.6 Hz, 1H), 7.53 - 7.50 (m, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 9.5 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.41 (dd, J = 3.6, 1.9 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.49 (t, J = 17.1 Hz, 1H), 4.36 (t, J = 17.5 Hz, 1H), 3.63 (d, J = 13.4 Hz, 4H), 3.56 (d, J = 18.2 Hz, 4H), 3.30 - 3.15 (m, 8H), 2.98 - 2.88 (m, 1H), 2.70 (d, J = 10.5 Hz, 2H), 2.61 (d, J = 17.1 Hz, 2H), 2.43 (dd, J = 13.3, 4.9 Hz, 1H), 2.31 (t, J = 6.5 Hz, 2H), 2.01 (d, J = 2.3 Hz, 5H), 1.90 - 1.73 (m, 7H), 1.59 - 1.47 (m, 4H), 1.47 - 1.42 (m, 3H), 0.95 (s, 6H). HRMS (ESI) m / z: Calculated for C 65 H 75 ClN 11 O9S + [M+H] + , 1220.5153; Found, 1220.5155。

[0227] Example 8 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-((3R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03168)

[0228] According to Scheme 7, the target compound (BCL-03168) was prepared using the compound (732150) prepared according to Intermediate Example 4 and the intermediate compound (732180) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 11.69 (s, 1H), 11.02 (s, 1H), 10.32 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.56 (d, J = 2.6 Hz, 1H), 8.04 (d, J = 2.9 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.69 (s, 1H), 7.55 (d, J = 2.9 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.10 (dd, J = 8.7, 5.5 Hz, 3H), 6.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.43 - 6.37 (m, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.13 (dd, J = 13.4, 5.2 Hz, 1H), 4.55 - 4.43 (m, 1H), 4.35 (t, J = 16.3 Hz, 1H), 3.63 (d, J = 12.1 Hz, 3H), 3.54 (s, 3H), 3.30 - 3.10 (m, 11H), 2.92 (ddd, J = 18.0, 13.6, 5.6 Hz, 2H), 2.70 (d, J = 10.2 Hz, 2H), 2.61 (d, J = 17.3 Hz, 2H), 2.47 - 2.35 (m, 2H), 2.31 (s, 2H), 2.19 - 2.08 (m, 2H), 2.01 (s, 3H), 1.90 (d, J = 12.9 Hz, 2H), 1.62 (s, 1H), 1.54 - 1.40 (m, 6H), 1.07 (d, J = 11.4 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 65 H 75 ClN 11 O9S + [M+H] + , 1220.5153; Observed, 1220.5154。

[0229] Example 9 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((cis)-4-((3S)-4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03169)

[0230] According to Scheme 7, the target compound (BCL-03169) was prepared using the compound (732147) prepared in accordance with Intermediate Example 3 and the intermediate compound (732001) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.76 (s, 1H), 11.71 (s, 1H), 11.05 (s, 1H), 10.58 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 9.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.72 (dd, J = 9.1, 2.5 Hz, 1H), 6.45 - 6.39 (m, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.16 (dd, J = 13.2, 5.1 Hz, 1H), 4.46 (d, J = 17.9 Hz, 1H), 4.30 (d, J = 20.0 Hz, 1H), 3.63 (d, J = 11.1 Hz, 4H), 3.53 (s, 5H), 3.27 (d, J = 13.0 Hz, 8H), 2.92 (ddd, J = 18.0, 13.5, 5.4 Hz, 1H), 2.75 - 2.66 (m, 2H), 2.61 (dt, J = 17.2, 3.4 Hz, 1H), 2.46 (dd, J = 13.2, 4.8 Hz, 1H), 2.34 (t, J = 6.6 Hz, 2H), 2.07 - 1.96 (m, 4H), 1.93 - 1.74 (m, 6H), 1.60 - 1.48 (m, 4H), 1.44 (t, J = 6.5 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 65 H 74 BrClN 11 O9S + [M+H] + , 1298.4258; Found, 1298.4260。

[0231] Example 10 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((trans)-4-((3S)-4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03170)

[0232] According to Scheme 7, the target compound (BCL-03170) was prepared using the compound (732148) prepared in accordance with Intermediate Example 3 and the intermediate compound (732001) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 11.70 (s, 1H), 11.04 (s, 1H), 10.59 (s, 1H), 8.64 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.98 (s, 1H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.56 (d, J = 2.9 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.10 (dd, J = 8.9, 3.1 Hz, 3H), 6.72 (dd, J = 9.1, 2.5 Hz, 1H), 6.46 - 6.39 (m, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.15 (dd, J = 13.3, 5.2 Hz, 1H), 4.70 (s, 1H), 4.45 (d, J = 17.9 Hz, 1H), 4.30 (d, J = 17.5 Hz, 1H), 3.63 (d, J = 12.7 Hz, 4H), 3.53 (s, 4H), 3.32 - 3.04 (m, 10H), 2.92 (ddd, J = 18.0, 13.4, 5.6 Hz, 1H), 2.74 - 2.66 (m, 2H), 2.65 - 2.57 (m, 1H), 2.46 (dd, J = 13.1, 4.9 Hz, 1H), 2.34 (t, J = 6.6 Hz, 2H), 2.19 - 2.08 (m, 2H), 2.06 - 1.97 (m, 3H), 1.90 (d, J = 12.4 Hz, 2H), 1.63 (tq, J = 7.9, 4.2 Hz, 1H), 1.55 - 1.39 (m, 6H), 1.07 (q, J = 12.5, 11.7 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated value C 65 H 74 BrClN 11 O9S + [M+H] +, 1298.4258; measured value, 1298.4250.

[0233] Example 11 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((cis)-4-((3R)-4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03171)

[0234] According to Scheme 7, the target compound (BCL-03171) was produced using the compound (732149) produced in accordance with Intermediate Example 3 and the intermediate compound (732001) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.76 (s, 1H), 11.71 (s, 1H), 11.05 (s, 1H), 10.58 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 9.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.72 (dd, J = 9.1, 2.5 Hz, 1H), 6.45 - 6.39 (m, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.16 (dd, J = 13.2, 5.1 Hz, 1H), 4.46 (d, J = 17.9 Hz, 1H), 4.30 (d, J = 20.0 Hz, 1H), 3.63 (d, J = 11.1 Hz, 4H), 3.53 (s, 5H), 3.27 (d, J = 13.0 Hz, 8H), 2.92 (ddd, J = 18.0, 13.5, 5.4 Hz, 1H), 2.75 - 2.66 (m, 2H), 2.61 (dt, J = 17.2, 3.4 Hz, 1H), 2.46 (dd, J = 13.2, 4.8 Hz, 1H), 2.34 (t, J = 6.6 Hz, 2H), 2.07 - 1.96 (m, 4H), 1.93 - 1.74 (m, 6H), 1.60 - 1.48 (m, 4H), 1.44 (t, J = 6.5 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 65 H 74 BrClN 11 O9S + [M+H] + , 1298.4258; Observed, 1298.4250。

[0235] Example 12 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((trans)-4-((3R)-4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03172)

[0236] According to Scheme 7, the target compound (BCL-03172) was produced using the compound (732150) produced in accordance with Intermediate Example 3 and the intermediate compound (732001) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.75 (s, 1H), 11.70 (s, 1H), 11.04 (s, 1H), 10.59 (s, 1H), 8.64 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.4 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.98 (s, 1H), 7.81 (dd, J = 9.2, 2.7 Hz, 1H), 7.56 (d, J = 2.9 Hz, 1H), 7.54 - 7.50 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.10 (dd, J = 8.9, 3.1 Hz, 3H), 6.72 (dd, J = 9.1, 2.5 Hz, 1H), 6.46 - 6.39 (m, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.15 (dd, J = 13.3, 5.2 Hz, 1H), 4.70 (s, 1H), 4.45 (d, J = 17.9 Hz, 1H), 4.30 (d, J = 17.5 Hz, 1H), 3.63 (d, J = 12.7 Hz, 4H), 3.53 (s, 4H), 3.32 - 3.04 (m, 10H), 2.92 (ddd, J = 18.0, 13.4, 5.6 Hz, 1H), 2.74 - 2.66 (m, 2H), 2.65 - 2.57 (m, 1H), 2.46 (dd, J = 13.1, 4.9 Hz, 1H), 2.34 (t, J = 6.6 Hz, 2H), 2.19 - 2.08 (m, 2H), 2.06 - 1.97 (m, 3H), 1.90 (d, J = 12.4 Hz, 2H), 1.63 (tq, J = 7.9, 4.2 Hz, 1H), 1.55 - 1.39 (m, 6H), 1.07 (q, J = 12.5, 11.7 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 65 H 74 BrClN 11 O9S + [M+H] +, 1298.4258; measured value, 1298.4255.

[0237] Example 13 Preparation of 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((2R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03177)

[0238] According to Scheme 7, the target compound (BCL-03177) was prepared using the intermediate compound (R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (SIAIS360129; can be prepared by referring to Preparation Example 13 of Intermediate BINDER in Chinese Patent Publication No. CN112707900A, the entire contents of which are incorporated herein by reference) and intermediate compound (732180) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.76 (dd, J = 9.1, 1.9 Hz, 3H), 7.57 (s, 2H), 7.43 - 7.39 (m, 2H), 7.32 - 7.28 (m, 2H), 7.26 - 7.21 (m, 2H), 7.20 - 7.13 (m, 4H), 6.95 (dd, J = 13.6, 9.0 Hz, 3H), 5.13 (dd, J = 13.3, 5.2 Hz, 1H), 4.46 (d, J = 17.5 Hz, 1H), 4.34 (d, J = 17.1 Hz, 1H), 4.18 (s, 1H), 3.90 - 3.62 (m, 3H), 3.50 - 3.10 (m, 14H), 2.99 - 2.85 (m, 4H), 2.73 (d, J = 4.6 Hz, 2H), 2.61 (dt, J = 17.2, 4.2 Hz, 2H), 2.48 - 2.35 (m, 2H), 2.27 (t, J = 6.8 Hz, 2H), 2.16 (s, 3H), 2.00 (ddt, J = 7.3, 5.3, 2.7 Hz, 1H), 1.46 (t, J = 6.5 Hz, 2H), 1.00 (s, 6H). HRMS (ESI) m / z: Calculated for C 61 H 69 ClF3N8O8S3 + [M+H] + , 1229.4036; Observed, 1229.4038.

[0239] Example 14 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03179)

[0240] According to Scheme 7, the target compound (BCL-03179) was prepared using the compound (732185) prepared according to Intermediate Example 5 and the intermediate compound (732180) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.81 (s, 2H), 11.74 (s, 1H), 11.03 (s, 1H), 10.66 (s, 1H), 8.17 (d, J = 2.6 Hz, 1H), 8.07 (d, J = 3.1 Hz, 1H), 7.97 - 7.89 (m, 2H), 7.81 (s, 2H), 7.60 (d, J = 3.2 Hz, 1H), 7.55 (t, J = 3.3 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.35 (t, J = 5.9 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 9.3 Hz, 1H), 6.76 - 6.70 (m, 1H), 6.47 - 6.41 (m, 1H), 6.28 - 6.21 (m, 1H), 5.15 (dd, J = 13.3, 5.2 Hz, 1H), 4.50 (d, J = 17.7 Hz, 3H), 4.37 (d, J = 17.7 Hz, 1H), 3.61 (s, 9H), 3.33 - 3.11 (m, 9H), 2.93 (ddd, J = 17.5, 13.3, 5.3 Hz, 1H), 2.71 (dd, J = 20.1, 7.3 Hz, 2H), 2.61 (d, J = 17.9 Hz, 1H), 2.45 (tt, J = 13.3, 6.5 Hz, 1H), 2.35 (s, 2H), 2.17 - 2.08 (m, 2H), 2.01 (s, 3H), 1.84 (d, J = 11.4 Hz, 2H), 1.65 - 1.55 (m, 1H), 1.54 - 1.41 (m, 4H), 1.07 (t, J = 11.8 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 65 H 73 ClF3N 10 O9S2 + [M+H] + , 1293.4639; Measured, 1293.4635.

[0241] Example 15 Preparation of 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03180)

[0242] According to Scheme 7, the target compound (BCL-03180) was prepared using the compound (732186) prepared in accordance with Intermediate Example 6 and the intermediate compound (732180) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 12.16 (s, 1H), 11.02 (s, 1H), 10.25 (s, 1H), 8.22 (s, 1H), 8.05 (dd, J = 9.2, 2.2 Hz, 1H), 7.77 (t, J = 9.6 Hz, 4H), 7.70 (s, 1H), 7.42 (d, J = 8.2 Hz, 3H), 7.24 (d, J = 9.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.48 (d, J = 17.7 Hz, 1H), 4.36 (d, J = 17.5 Hz, 2H), 3.89 (d, J = 13.9 Hz, 2H), 3.58 (s, 3H), 3.51 (s, 2H), 3.30 - 3.00 (m, 12H), 2.93 (ddd, J = 17.9, 13.4, 5.4 Hz, 1H), 2.78 (q, J = 14.2, 12.4 Hz, 2H), 2.62 (d, J = 14.4 Hz, 1H), 2.41 (ddd, J = 18.6, 11.7, 5.1 Hz, 2H), 2.29 (t, J = 6.9 Hz, 2H), 2.16 (s, 2H), 2.15 - 2.07 (m, 2H), 2.02 (q, J = 5.8, 5.3 Hz, 1H), 1.84 (d, J = 11.1 Hz, 2H), 1.60 (t, J = 11.3 Hz, 1H), 1.48 (p, J = 7.5, 6.3 Hz, 4H), 1.05 (d, J = 12.7 Hz, 2H), 1.01 (s, 6H). HRMS (ESI) m / z: Calculated for C 58 H 69 ClF3N8O8S2 + [M+H] + , 1161.4315; Observed, 1161.4316。

[0243] Example 16 Preparation of 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03181)

[0244] According to Scheme 7, the target compound (BCL-03181) was prepared using the compound (732187) prepared according to Intermediate Example 7 and the intermediate compound (732180) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 12.15 (s, 1H), 11.03 (s, 1H), 10.69 (s, 1H), 8.70 (t, J = 6.2 Hz, 1H), 8.64 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 9.2, 2.6 Hz, 1H), 7.88 (s, 1H), 7.82 - 7.73 (m, 4H), 7.41 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 9.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 9.3 Hz, 2H), 5.14 (dd, J = 13.3, 5.0 Hz, 1H), 4.54 - 4.31 (m, 4H), 3.87 (d, J = 13.6 Hz, 2H), 3.56 (s, 6H), 3.40 - 3.11 (m, 11H), 2.93 (ddd, J = 17.7, 13.6, 5.5 Hz, 1H), 2.83 - 2.69 (m, 2H), 2.66 - 2.58 (m, 1H), 2.42 (tt, J = 13.1, 6.5 Hz, 1H), 2.27 (t, J = 6.9 Hz, 2H), 2.21 (s, 2H), 2.18 - 2.08 (m, 2H), 2.02 (dq, J = 7.5, 3.6, 2.3 Hz, 1H), 1.95 - 1.87 (m, 2H), 1.64 (dd, J = 7.2, 3.6 Hz, 1H), 1.46 (q, J = 8.2, 6.7 Hz, 4H), 1.15 - 1.04 (m, 2H), 0.99 (s, 6H). HRMS (ESI) m / z: Calculated for C 57 H 69 ClN9O8S + [M+H] + , 1074.4673; Found, 1074.4673。

[0245] Example 17 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03185)

[0246] According to Scheme 7, the target compound (BCL-03185) was prepared using the compound (732185) prepared according to Intermediate Example 5 and the intermediate compound 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (732195; CAS number 1312023-72-5) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.84 (s, 1H), 11.75 (s, 1H), 11.17 (s, 1H), 10.77 (s, 1H), 8.28 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.15 (s, 1H), 8.07 (d, J = 2.7 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.93 (dd, J = 9.3, 2.6 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.55 (t, J = 3.1 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 5.9 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 9.5 Hz, 1H), 6.73 (dd, J = 9.0, 2.4 Hz, 1H), 6.48 - 6.42 (m, 1H), 6.25 (d, J = 2.3 Hz, 1H), 5.19 (dd, J = 12.8, 5.5 Hz, 1H), 4.57 (s, 2H), 3.75 - 3.40 (m, 11H), 3.34 - 3.13 (m, 8H), 2.91 (ddd, J = 16.8, 13.6, 5.4 Hz, 1H), 2.75 - 2.66 (m, 2H), 2.65 - 2.53 (m, 2H), 2.36 (t, J = 6.6 Hz, 2H), 2.18 - 2.05 (m, 3H), 2.01 (s, 2H), 1.83 (d, J = 11.1 Hz, 2H), 1.59 (tt, J = 8.2, 4.2 Hz, 1H), 1.50 (d, J = 8.7 Hz, 2H), 1.44 (t, J = 6.4 Hz, 2H), 1.07 (t, J = 12.7 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated value C 65 H 71 ClF3N 10 O 10 S2 + [M+H] +, 1307.4431; measured value, 1307.4430.

[0247] Example 18 Preparation of 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03186)

[0248] According to Scheme 7, the target compound (BCL-03186) was prepared using the compound (732186) prepared according to Intermediate Example 6 and the intermediate compound 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (732195; CAS number 1312023-72-5) as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 12.17 (s, 1H), 11.61 (s, 1H), 11.16 (s, 1H), 10.58 (s, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 8.05 (dd, J = 9.3, 2.6 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 9.0 Hz, 2H), 7.41 (td, J = 7.3, 6.8, 3.6 Hz, 3H), 7.24 (d, J = 9.6 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 9.3 Hz, 2H), 5.18 (dd, J = 12.9, 5.4 Hz, 1H), 4.36 (s, 1H), 3.88 (d, J = 13.3 Hz, 2H), 3.65 - 3.13 (m, 18H), 2.91 (ddd, J = 16.9, 13.8, 5.5 Hz, 1H), 2.76 (q, J = 10.0, 9.2 Hz, 2H), 2.67 - 2.58 (m, 1H), 2.57 - 2.53 (m, 1H), 2.28 (t, J = 6.8 Hz, 2H), 2.20 (s, 2H), 2.13 (d, J = 10.5 Hz, 2H), 2.11 - 2.04 (m, 1H), 1.84 (d, J = 11.0 Hz, 2H), 1.60 (tdq, J = 11.0, 7.2, 4.3, 3.7 Hz, 1H), 1.47 (q, J = 6.3 Hz, 4H), 1.07 (t, J = 12.1 Hz, 2H), 1.00 (s, 6H). HRMS (ESI) m / z: Calculated value C 58 H 67 ClF3N8O9S2 + [M+H] + , 1175.4108; measured value, 1175.4101.

[0249] Example 19: 4Preparation of -(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03187)

[0250] According to Scheme 7, the target compound (BCL-03187) was prepared using the compound (732187) prepared according to Intermediate Example 7 and the intermediate compound 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (732195; CAS number 1312023-72-5) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 12.13 (s, 1H), 11.15 (s, 1H), 10.26 (s, 1H), 8.70 (t, J = 6.1 Hz, 1H), 8.64 (d, J = 2.3 Hz, 1H), 8.10 (s, 1H), 7.98 (s, 2H), 7.93 (dd, J = 9.2, 2.5 Hz, 1H), 7.76 (d, J = 9.0 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 9.5 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 9.3 Hz, 2H), 5.17 (dd, J = 12.8, 5.5 Hz, 1H), 4.22 (s, 1H), 3.88 (d, J = 14.2 Hz, 2H), 3.57 (s, 2H), 3.55 - 3.10 (m, 15H), 2.90 (ddd, J = 16.9, 13.8, 5.5 Hz, 1H), 2.81 - 2.72 (m, 3H), 2.65 - 2.58 (m, 1H), 2.55 (d, J = 5.2 Hz, 1H), 2.28 (t, J = 6.8 Hz, 2H), 2.20 - 2.03 (m, 5H), 1.90 (d, J = 12.2 Hz, 2H), 1.63 (qt, J = 10.8, 5.8 Hz, 1H), 1.47 (t, J = 6.6 Hz, 4H), 1.07 (q, J = 12.1, 11.1 Hz, 2H), 1.00 (s, 6H). HRMS (ESI) m / z: Calculated for C 57 H 67 ClN9O9S + [M+H] + , 1088.4 (465); Observed, 1088.4469.

[0251] Note: There seems to be a formatting issue in the original text where "計算値C " might be incomplete or incorrect. Also, the "1088.4 (465)" in the translation of might need further clarification as it's not clear what the "465" represents in the context. The translation is done as accurately as possible based on the provided rules.Example 20 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03188)

[0252] According to Scheme 7, the intermediate compound 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((((trans)-4-(piperazin-1-yl)cyclohexyl)methyl)amino)phenyl)sulfonyl)benzamide (SIAIS364025) and the intermediate compound 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (732195; CAS number 1312023-72-5) were used as starting materials to produce the target compound (BCL-03188). 11H NMR (500 MHz, DMSO-d6) δ 11.76 (s, 1H), 11.70 (s, 1H), 11.16 (s, 1H), 10.52 (s, 1H), 8.64 (t, J = 6.1 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.09 - 8.04 (m, 2H), 8.00 (d, J = 7.6 Hz, 1H), 7.81 (dd, J = 9.3, 2.6 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.10 (dd, J = 9.2, 5.3 Hz, 3H), 6.72 (dd, J = 9.0, 2.4 Hz, 1H), 6.44 - 6.36 (m, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.18 (dd, J = 12.8, 5.5 Hz, 1H), 4.35 (s, 1H), 3.63 (d, J = 13.9 Hz, 2H), 3.53 (d, J = 4.4 Hz, 5H), 3.32 - 3.06 (m, 12H), 2.90 (ddd, J = 16.9, 13.7, 5.4 Hz, 1H), 2.74 (d, J = 5.0 Hz, 1H), 2.70 (t, J = 10.9 Hz, 2H), 2.65 - 2.58 (m, 1H), 2.57 - 2.53 (m, 1H), 2.33 (t, J = 6.6 Hz, 2H), 2.13 (d, J = 10.4 Hz, 2H), 2.10 - 2.04 (m, 1H), 2.01 (s, 2H), 1.90 (d, J = 11.6 Hz, 2H), 1.62 (dq, J = 8.1, 5.5, 4.0 Hz, 1H), 1.55 - 1.42 (m, 4H), 1.07 (q, J = 11.5 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 64 H 71 ClN 11 O 10 S + [M+H] +, 1220.4789; measured value, 1220.4785.

[0253] Example 21 Preparation of 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((2R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03189)

[0254] According to Scheme 7, the intermediate compound (R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((1-(phenylthio)-4-(piperazin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (SIAIS360129) and the intermediate compound 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (732195; CAS number 1312023-72-5) were used as starting materials to produce the target compound (BCL-03189). 11H NMR (500 MHz, DMSO-d6) δ 12.18 (s, 1H), 11.15 (s, 1H), 10.08 (s, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 9.3, 2.4 Hz, 1H), 7.92 (s, 2H), 7.84 (s, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.44 - 7.39 (m, 2H), 7.31 - 7.27 (m, 2H), 7.22 (t, J = 7.6 Hz, 3H), 7.17 (d, J = 8.7 Hz, 3H), 7.15 - 7.13 (m, 1H), 6.97 (t, J = 10.1 Hz, 3H), 5.16 (dd, J = 12.9, 5.4 Hz, 1H), 4.18 (s, 1H), 3.95 - 3.84 (m, 2H), 3.79 (s, 1H), 3.58 (s, 2H), 3.40 - 3.25 (m, 7H), 3.17 (s, 1H), 3.00 (s, 3H), 2.90 (ddd, J = 17.1, 14.2, 5.4 Hz, 3H), 2.76 (dd, J = 19.2, 6.9 Hz, 2H), 2.65 - 2.58 (m, 2H), 2.56 - 2.54 (m, 1H), 2.28 (t, J = 6.5 Hz, 2H), 2.14 (s, 4H), 2.10 - 2.03 (m, 1H), 1.47 (t, J = 6.6 Hz, 2H), 1.00 (s, 6H). HRMS (ESI) m / z: Calculated for C 61 H 67 ClF3N8O9S3 + [M+H] + , 1243.3828; Observed, 1243.3829。

[0255] Example 22 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((3S)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03190)

[0256] According to Scheme 7, the target compound (BCL-03190) was prepared using the intermediate compound (732147) prepared according to Intermediate Example 3 and the intermediate compound 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (732195; CAS number 1312023-72-5) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.79 (s, 1H), 11.71 (s, 1H), 11.17 (s, 1H), 10.67 (s, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.57 (d, J = 2.6 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 8.06 (d, J = 2.9 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.82 (dd, J = 9.2, 2.7 Hz, 1H), 7.58 (d, J = 2.9 Hz, 1H), 7.56 - 7.48 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 9.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.72 (dd, J = 9.1, 2.5 Hz, 1H), 6.45 - 6.36 (m, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.19 (dd, J = 12.8, 5.5 Hz, 1H), 4.88 (s, 1H), 4.30 (s, 1H), 3.97 - 3.50 (m, 10H), 3.27 (d, J = 11.7 Hz, 8H), 2.91 (ddd, J = 17.4, 13.6, 5.5 Hz, 1H), 2.69 (q, J = 10.9, 9.5 Hz, 2H), 2.65 - 2.58 (m, 1H), 2.58 - 2.53 (m, 1H), 2.35 (t, J = 6.9 Hz, 2H), 2.09 (td, J = 7.6, 3.7 Hz, 1H), 2.01 (s, 3H), 1.93 - 1.74 (m, 6H), 1.66 - 1.47 (m, 5H), 1.44 (t, J = 6.4 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: Calculated for C 65 H 73 ClN 11 O 10 S + [M+H] + , 1234.4946; Found, 1234.4940。

[0257] Example 23 Preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03182)

[0258] According to Scheme 7, the target compound (BCL-03182) was produced using the intermediate compound (732185) and the intermediate compound (732001) as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 11.82 (t, J = 2.4 Hz, 1H), 11.75 (s, 1H), 11.05 (s, 1H), 10.80 (s, 1H), 8.23 (s, 1H), 8.17 (d, J = 2.6 Hz, 1H), 8.08 (s, 1H), 8.07 (d, J = 2.7 Hz, 1H), 7.93 (dd, J = 9.3, 2.6 Hz, 1H), 7.60 (d, J = 2.7 Hz, 1H), 7.55 (t, J = 3.0 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 6.0 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 9.8 Hz, 1H), 6.73 (dd, J = 9.0, 2.4 Hz, 1H), 6.47 - 6.40 (m, 1H), 6.24 (d, J = 2.3 Hz, 1H), 5.16 (dd, J = 13.2, 5.1 Hz, 1H), 4.50 (s, 1H), 4.46 (d, J = 18.0 Hz, 1H), 4.31 (d, J = 17.9 Hz, 1H), 3.69 - 3.57 (m, 12H), 3.29 (dd, J = 22.6, 11.6 Hz, 5H), 3.22 (t, J = 6.3 Hz, 3H), 2.92 (ddd, J = 17.4, 13.4, 5.2 Hz, 1H), 2.69 (d, J = 11.7 Hz, 2H), 2.61 (d, J = 17.5 Hz, 1H), 2.46 (dd, J = 13.1, 4.9 Hz, 1H), 2.36 (s, 2H), 2.17 - 2.10 (m, 2H), 2.02 (d, J = 11.0 Hz, 3H), 1.84 (d, J = 11.4 Hz, 2H), 1.59 (tt, J = 7.8, 3.9 Hz, 1H), 1.49 (d, J = 12.3 Hz, 2H), 1.43 (t, J = 6.4 Hz, 2H), 1.06 (d, J = 13.2 Hz, 2H), 0.94 (s, 6H).HRMS (ESI) m / z: Calculated value C. 65 H 72 BrClF3N 10 O9S2 + [M+H] + , 1371.3744; measured value, 1371.3740.

[0259] Example 24 Preparation of N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03183)

[0260] According to Scheme 7, the target compound (BCL-03183) was produced using the intermediate compound (732186) and the intermediate compound (732001) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 12.18 (s, 1H), 11.04 (s, 1H), 10.68 (s, 1H), 8.22 (d, J = 2.6 Hz, 1H), 8.16 (s, 1H), 8.05 (dd, J = 9.2, 2.5 Hz, 1H), 8.02 (s, 1H), 7.76 (d, J = 9.0 Hz, 2H), 7.44 - 7.38 (m, 3H), 7.24 (d, J = 9.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.37 (dd, J = 76.8, 17.9 Hz, 4H), 3.88 (d, J = 13.3 Hz, 2H), 3.56 (s, 6H), 3.36 - 3.07 (m, 11H), 2.92 (ddd, J = 17.5, 13.5, 5.2 Hz, 1H), 2.77 (s, 2H), 2.61 (dd, J = 13.9, 3.5 Hz, 1H), 2.46 (dd, J = 13.1, 4.9 Hz, 1H), 2.27 (s, 2H), 2.21 (s, 2H), 2.12 (s, 2H), 2.03 (td, J = 7.6, 3.8 Hz, 1H), 1.84 (d, J = 11.4 Hz, 2H), 1.60 (td, J = 9.5, 7.9, 5.8 Hz, 1H), 1.47 (q, J = 7.4, 6.7 Hz, 4H), 1.11 - 1.02 (m, 2H), 1.00 (s, 6H). HRMS (ESI) m / z: Calculated for C 58 H 68 BrClF3N8O8S2 + [M+H] + , 1239.3420; Observed, 1239.3421。

[0261] Example 25 Preparation of N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03184)

[0262] According to Scheme 7, the target compound (BCL-03184) was produced using the intermediate compound (732187) and the intermediate compound (732001) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 12.14 (s, 1H), 11.04 (s, 1H), 10.63 (s, 1H), 8.70 (t, J = 6.1 Hz, 1H), 8.64 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.94 (dd, J = 9.2, 2.5 Hz, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 9.6 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.37 (dd, J = 77.3, 17.8 Hz, 4H), 3.88 (d, J = 13.0 Hz, 2H), 3.56 (s, 5H), 3.37 - 3.13 (m, 12H), 2.96 - 2.86 (m, 1H), 2.81 - 2.70 (m, 2H), 2.61 (d, J = 17.3 Hz, 1H), 2.47 (dd, J = 13.4, 8.2 Hz, 1H), 2.28 (t, J = 6.8 Hz, 2H), 2.21 (s, 2H), 2.17 - 2.09 (m, 2H), 2.07 - 2.00 (m, 1H), 1.91 (d, J = 11.3 Hz, 2H), 1.64 (tdd, J = 14.8, 7.0, 3.4 Hz, 1H), 1.47 (q, J = 7.5, 6.7 Hz, 4H), 1.08 (q, J = 12.5, 11.3 Hz, 2H), 1.00 (s, 6H). HRMS (ESI) m / z: Calculated for C 57 H 68 BrClN9O8S + [M+H] + , 1152.3778; Observed, 1152.3781。

[0263] Example 26: Preparation of N-((4-(((2R)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03178)

[0264] According to Scheme 7, the target compound (BCL-03178) was produced using the intermediate compound (SIAIS360129) and the intermediate compound (732001) as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 11.04 (s, 1H), 10.49 (s, 1H), 8.18 (d, J = 2.6 Hz, 1H), 8.05 (s, 1H), 7.98 (dd, J = 9.3, 2.4 Hz, 1H), 7.94 (s, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 7.22 (t, J = 7.7 Hz, 3H), 7.20 - 7.12 (m, 3H), 6.99 (d, J = 8.9 Hz, 1H), 6.96 (d, J = 9.2 Hz, 2H), 5.15 (dd, J = 13.3, 5.2 Hz, 1H), 4.44 (d, J = 17.9 Hz, 1H), 4.28 (d, J = 17.7 Hz, 1H), 4.20 (s, 2H), 3.89 (d, J = 12.7 Hz, 2H), 3.57 (s, 2H), 3.50 - 3.00 (m, 15H), 2.97 - 2.86 (m, 2H), 2.77 (d, J = 11.3 Hz, 2H), 2.62 (d, J = 3.5 Hz, 1H), 2.59 (s, 1H), 2.46 (dd, J = 13.2, 4.8 Hz, 1H), 2.28 (t, J = 6.9 Hz, 2H), 2.21 - 2.07 (m, 4H), 2.06 - 1.97 (m, 1H), 1.47 (t, J = 6.5 Hz, 2H), 1.00 (s, 6H). HRMS (ESI) m / z: Calculated value C 61 H 68 BrClF3N8O8S3 + [M+H] + , 1307.3141; measured value, 1307.3139. Biological activity test

[0265] Experimental recipes and materials TIFF0007825122000066.tif206145

[0266] Antibody:

[0267] BCL-X used in the experiment L Antibodies were purchased from Abcam, and Tubulin antibody was purchased from Proteintech.

[0268] cell culture

[0269] The cell lines used, RS4;11 (human acute lymphoblastic leukemia cells), Molt-4 cells (human acute lymphoblastic leukemia cells), MV4;11 (human myelomonocytic leukemia cells), and Light II cells, were all commercially available or purchased from the American Type Culture Collection (ATCC) and cultured according to the ATCC instructions. The cells were identified as correct cells by STR before the experiment and were detected as mycoplasma-negative using a mycoplasma detection kit.

[0270] Assessment of tumor cell growth inhibitory activity in vitro

[0271] The compounds according to the present disclosure were subjected to a preliminary evaluation of tumor cell growth inhibition rate at a single concentration and at two concentrations, and the IC 50 Measurements were taken.

[0272] The half maximal inhibitory concentration (IC 50 ) Measurement - Thiazolyl blue cell proliferation experiment

[0273] 1) BCL-X L Study of the compounds of the present invention based on ABT199 / 263 on the proliferation of β-dependent RS4;11 cells [ka]

[0274] The specific steps are as follows: 1. Incubate 3 x 10 RS4;11 cells in 90 μl of serum-containing RPMI 1640 medium. 4Cells were seeded at 1000 cells / well, and DT2216 and the compounds of the present invention were added to the cell suspension at a concentration gradient. DT2216 was used as the positive control, and DMSO was used as the negative control. The positive and negative control cells were treated with the same treatment regimen as the compounds of the present invention. After 48 hours of treatment with the compounds of the present invention, 10 μl / well of thiazolyl blue solution (5 mg / mL) was added and the cells were incubated in an incubator at 37°C with 5% CO2 for 3 hours. A triple solution (0.1 g / mL SDS, 5% isopropyl alcohol, 10 mM hydrochloric acid) was then added and the cells were incubated in an incubator at 37°C with 5% CO2 for 4-6 hours. After complete dissolution of crystal violet was observed under an inverted microscope, the absorbance was measured at 490 nm using an Epoch microplate reader (Biotek). Growth inhibition curves for the experimental cells of the compounds of the present invention were plotted using GraphPad Prism 8 software, and the IC values ​​of the compounds of the present invention were statistically determined. 50 The experiment had 3 wells per group and was repeated at least 3 times. The results are shown in Table 3 below.

[0275] 2) BCL-X L Study of the compounds of the present invention based on ABT199 / 263 on MV4;11 cell proliferation

[0276] The specific steps are as follows: MV4;11 cells were cultured at 2 × 10 in 90 μl of serum-containing IMDM medium. 4Cells were seeded at 1000 cells / well, and DT2216 and the compounds of the present invention were added to the cell suspension at a concentration gradient. DT2216 was used as the positive control, and DMSO was used as the negative control. The positive and negative control cells were treated with the same treatment regimen as the compounds of the present invention. After 48 hours of treatment with the compounds of the present invention, 10 μl / well of thiazolyl blue solution (5 mg / mL) was added and the cells were incubated in an incubator at 37°C with 5% CO2 for 3 hours. A triple solution (0.1 g / mL SDS, 5% isopropyl alcohol, 10 mM hydrochloric acid) was then added and the cells were incubated in an incubator at 37°C with 5% CO2 for 4-6 hours. After observing the complete dissolution of crystal violet under an inverted microscope, the absorbance was measured at 490 nm using an Epoch microplate reader (Biotek). Growth inhibition curves for the experimental cells of the compounds of the present invention were plotted using GraphPad Prism 8 software, and the IC values ​​of the compounds of the present invention were statistically determined. 50 The experiment had 3 wells per group and was repeated at least 3 times. The results are shown in Table 4 below.

[0277] 3) BCL-X L Study of the compounds of the present invention based on ABT199 / 263 on the proliferation of β-lactam-dependent Molt-4 cells

[0278] The specific steps are as follows: Molt-4 cells were cultured at 2 × 10 in 180 μl of serum-containing RPMI 1640 medium. 4Cells were seeded at 1000 cells / well, and DT2216 and the compounds of the present invention were added to the cell suspension at a concentration gradient. DT2216 was used as the positive control, and DMSO was used as the negative control. The positive and negative control cells were treated with the same treatment regimen as the compounds of the present invention. After 72 hours of treatment with the compounds of the present invention, 20 μl / well of thiazolyl blue solution (5 mg / mL) was added and the cells were incubated in an incubator at 37°C with 5% CO2 for 3 hours. A triple solution (0.1 g / mL SDS, 5% isopropyl alcohol, 10 mM hydrochloric acid) was then added and the cells were incubated in an incubator at 37°C with 5% CO2 for 4-6 hours. After observing the complete dissolution of crystal violet under an inverted microscope, the absorbance was measured at 490 nm using an Epoch microplate reader (Biotek). Growth inhibition curves for the experimental cells of the compounds of the present invention were plotted using GraphPad Prism 8 software, and the IC values ​​of the compounds of the present invention were statistically determined. 50 The experiment had three wells per group and was repeated at least three times. The results are shown in Table 5 below.

[0279] IC of compounds that inhibit hedgehog activity 50 Measurement - Dual-luciferase reporter assay:

[0280] Light II cells are a clonal NIH3T3 cell line capable of stably expressing Gli-luciferase and TK-renilla reporter genes. They were cultured in DMEM medium containing 10% (v / v) fetal bovine serum (FBS), 0.4 mg / ml G418, 0.15 mg / ml bleomycin (Zeocin), and penicillin / streptomycin in an incubator at 37°C with 5% CO2. 2.5 × 10 Light II cells in the logarithmic growth phase were cultured. 4The cells were seeded at 1000 cells / well in a 96-well plate and incubated for 24 hours. After incubation, SAG and various concentrations of the compounds of the present invention were added and the reaction was terminated after 36 hours of treatment. Detection was performed according to the instructions of the Dual luciferase reporter assay kit. This experiment had three wells per group and was repeated at least three times. The results are shown in Table 6 below.

[0281] Protein Western Blot

[0282] Molt-4 cells in logarithmic growth phase were plated in a 6-well plate at 3 × 10 6Cells were seeded at 1000 cells / well. The corresponding concentrations of the compounds of the present invention were then added and treated. DMSO was used as a control. After 10 hours of drug treatment, the cells were harvested and washed once with PBS. The cells were placed on ice and treated with IP protein lysis buffer containing PMSF protease inhibitor. After centrifugation at 10 krpm at 4°C for 5 minutes, the supernatant was collected. Equal amounts of the protein supernatant and 4x LDS protein loading buffer were mixed to homogeneity at a volume ratio of 3:1, 5% β-mercaptoethanol was added, and the mixture was vortexed. The mixture was then heated in a metal bath at 95°C for 10 minutes, stored at -80°C, or cooled directly on ice for protein electrophoresis. A 10% homemade polyacrylamide gel was used as the separation gel. The electrophoresis tank and related components were purchased from Bio-Rad. Electrophoresis was performed at a low voltage of 80V for 45 minutes, followed by a high voltage of 120V for 1 hour. PVDF membranes were used for transfer, and a constant current of 300mA was used in an ice-water bath for 1 hour. After transfer, the membranes were blocked with 5% skim milk at room temperature for 1 hour. The primary antibody was then incubated overnight at 4°C or for 2 hours at room temperature, followed by three washes with 1x TBST buffer (150mM sodium chloride, 10mM Tris, 0.1% Tween® 20, pH 7.4). The secondary antibody was then added, incubated for 45 minutes at room temperature, and washed three times with 1x TBST buffer (150mmol sodium chloride, 10mM Tris, 0.1% Tween® 20, pH 7.4) for color development. The antibody dilution ratio was determined by referring to the antibody manufacturer's instructions.

[0283] Experimental results

[0284] The specific experimental data is as follows:

[0285] 1 BCL-X L Study of the compounds of the present invention based on ABT199 / 263 on dependent cell proliferation

[0286] We performed a dose-response experiment on the compounds designed and synthesized according to the present invention in RS4;11 cells. L The cells were highly sensitive to the inhibitors of thiazolyl blue. After treating the cells with different concentrations of the compounds (starting at 1000 nM or 100 nM, followed by seven concentrations diluted 10-fold), for 48 hours, the cells were measured by thiazolyl blue cell proliferation assay. The experiment was repeated three times. The specific results are shown in Table 3.

[0287] The compounds of the present invention based on ABT-199 / 263 (including the compounds in Tables 1-2 and Examples 1-26) designed and developed by us were able to effectively inhibit the proliferation of RS4;11 tumor cells (Table 3). The IC value of DT2216 against RS4;11 cells was 0.01. 50 The inhibitory effect of the compound of the present invention developed by us was significantly superior to that of DT2216. Table 3. IC of compounds according to the present invention based on the ABT-199 / 263 series in RS4;11 (human acute lymphoblastic leukemia cell line) 50 (half maximal inhibitory concentration) [Table 3] DT2216 (CAS number: 2365172-42-3) is a BCL-X inhibitor reported in the literature. L It is a decomposing agent and its structural formula is as follows: [ka]

[0288] The compounds of the present invention based on ABT-199 / 263 (including the compounds in Tables 1-2 and Examples 1-26) designed and developed by us can effectively inhibit the proliferation of myelomonocytic leukemia cells MV4;11 (Table 4), and the IC of DT2216 against MV4;11 cells was significantly higher than that of DT2216. 50 The inhibitory effects of the compounds according to the present invention, which were developed based on ABT-199 / 263, were all significantly superior to those of DT2216. Table 4. IC of compounds of the present invention based on the ABT-199 / 263 series in myelomonocytic leukemia cells MV4;11 50 (nM, half-maximal inhibitory concentration) [Table 4]

[0289] The compounds of the present invention based on ABT-199 / 263 (including the compounds in Tables 1-2 and Examples 1-26) designed and developed by us were able to effectively inhibit the proliferation of human lymphocytic leukemia cells Molt-4 (Table 5). The inhibitory effects of the compounds of the present invention developed based on ABT-199 / 263 were all significantly superior to those of DT2216. Table 5. IC of compounds according to the present invention based on the ABT-199 / 263 series in lymphoid leukemia cells Molt-4 50 (nM, half-maximal inhibitory concentration) [Table 5]

[0290] 2. IC for compounds of the present invention based on ABT-199 / 263 that inhibit Hedgehog (Hh) signaling pathway activity 50 :

[0291] The compounds of the present invention based on ABT-199 / 263 that we designed and developed (including the compounds in Tables 1-2 and Examples 1-26) were able to inhibit the selection of Hedgehog (Hh) signaling pathway activity (Table 6). The half-maximal inhibitory concentration (IC) of the compounds of the present invention developed based on ABT-199 / 263 was 0.01. 50 All of these concentrations reached 10 nM or less. Table 6. IC of compounds of the present invention based on the ABT-199 / 263 series in Light II cells 50 (nM, half-maximal inhibitory concentration) [Table 6]

[0292] 3. The compounds of the present invention, developed based on ABT-199 / 263, inhibit BCL-X in Molt-4 cells. L The levels of proteins can be efficiently reduced.

[0293] Molt-4 cells were cultured at 3 × 10 cells per well. 6 Cells were seeded in 6-well plates at 100 nM each. The next day, cells were treated with 100 nM of the drug. Control groups included DMSO and DT2216. After 8 hours, protein samples were collected and analyzed by Western blot analysis for BCL-X. L The protein expression was measured. As a result, the compounds according to the present invention (including the compounds in Tables 1-2 and Examples 1-26) were used to inhibit BCL-X L Protein expression was significantly reduced. For example, compounds developed by the present invention, such as BCL-03146, BCL-03147, BCL-03148, and BCL-03149, reduced BCL-X expression at concentrations around 100 nM. L It was shown that the compounds of the present invention significantly decompose proteins (as shown in Figures 1 to 3). The compounds of the present invention were clearly superior to DT2216 in terms of protein degradation.

[0294] The above has described the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above-mentioned practice and can make various modifications and improvements to the present invention without departing from the spirit and scope of the present invention, and these modifications and improvements fall within the scope of the present invention claimed for protection. The scope of protection claimed for the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof, 【Chemistry 1】 Formula (I) where: Dotted lines indicate the presence of double bonds; (R ５ ) ｎ R has n benzene rings ５ and each R ５ are the same or different and each independently represent a halogen, and n represents an integer of 1 or 2; (R ６ ) ｍ R has m piperazine rings ６ and each R ６ are the same or different and each independently represent halogen or C1-3 alkyl, and m is an integer of 0; R ７ is hydrogen or 【Chemistry 2】 represents; R ８ is hydrogen or -SO ２ CF ３ or -NO ２ represents; R ９ represents hydrogen or C1-3 alkyl; R １０ is the following group: 【Transformation 3】 represents Here, ring W １ represents a 4- to 6-membered nitrogen-containing heterocyclylene, and (R ａ１ ) ｎ１ Is Ring W １ There are n1 R ａ１ represents a group substituted with ａ１ are the same or different and each independently represent a C1-3 alkyl, a halogenated C1-4 alkyl, a halogen, or an oxo group, and n1 represents an integer of 0, 1, 2, or 3; Ring W ２ is C ３－６ represents a cycloalkylene, n3 represents an integer of 0 or 1, (R ａ２ ) ｎ２ Is Ring W ２ There are n2 R ａ２ represents a group substituted with ａ２ are the same or different and each independently represent a C1-3 alkyl, a halogenated C1-4 alkyl, a halogen, or an oxo group, and n2 represents an integer of 0, 1, 2, or 3; and The symbol * indicates the connection point with LIN; LIN is, C 1 alkylene, the hydrogen atoms of which are optionally substituted with a substituent selected from the group consisting of C 1-3 alkyl, halogenated C 1-3 alkyl, or halogen; １ represents alkylene; and R １１ is represented by the following structural formula (II-2) or (II-3): 【Chemistry 4】 Formula (II-2), Formula (II-3) represents Here, R １２ represents a bond; (R ａ ) ｔ R has t benzene rings ａ and each R ａ are the same or different and each independently represent bromine, and t represents an integer of 0, 1, 2, or 3; and X is C(O) or CH ２ represents; wherein R 1 and R 2 represent hydrogen and R 3 and R 4 represent methyl, or R 1 and R 2 represent methyl and R 3 and R 4 represent hydrogen; Here, when t represents an integer of 0, R ７ but 【Transformation 5】 When n1 represents an integer of 1, 2, or 3, and each R ａ１ are the same or different and each independently represent C1-3 alkyl, halogenated C1-3 alkyl, or halogen; or R ７ but 【Transformation 6】 When R ８ Ha-SO ２ CF ３ or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof, of formula (I),

2. (R ５ ) ｎ represents that the benzene ring is substituted with n R5s, each R5 being the same or different and each independently representing a halogen, and n represents 1; or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof of the compound of formula (I) according to claim 1 .

3. Here, (R ５ ) ｎ represents that the benzene ring is substituted with n R5s, each R5 being the same or different and each independently representing chlorine, bromine, or fluorine, and n represents 1; or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof of the compound of formula (I) according to claim 1 .

4. (i) t represents an integer of 1, 2, or 3; and / or (ii) R １ and R ２ represents hydrogen, and R ３ and R ４ represents methyl; or (iii) R １ and R ２ represents methyl, and R ３ and R ４ represents hydrogen; or (iv) R １１ is represented by the following structural formula (II-6), (II-7), (II-10), or (II-11): 【Chemistry 10】 Formula (II-6), Formula (II-7), Formula (II-10), Formula (II-11) where: R １２ represents a bond; X is C(O) or CH ２ represents; and (R ａ ) ｔ R has t benzene rings ａ and each R ａ are the same or different and each independently represent bromine, and t represents an integer of 0, 1, 2, or 3, or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof according to claim 1 .

5. (i) t represents the integer 0; and / or (ii) R １１ is a structure of the formula: 【Chemistry 11】 2. The compound of formula (I) according to claim 1, wherein:

6. R １０ is the following group: 【Chemistry 13】 represents Here, ring W １ represents a 6-membered nitrogen-containing heterocyclylene, (R ａ１ ) ｎ１ Is Ring W １ There are n1 R ａ１ represents a group substituted with ａ１ are the same or different and each independently represent C1-3 alkyl, halogenated C1-4 alkyl, or halogen, and n1 represents an integer of 0, 1, 2, or 3; Ring W ２ represents a C6 cycloalkylene, n3 represents an integer of 0 or 1, (R ａ２ ) ｎ２ Is Ring W ２ There are n2 R ａ２ represents being substituted with a group, R ａ２ are the same or different and each independently represent a C1-3 alkyl, a halogenated C1-4 alkyl, a halogen, or an oxo group, and n2 represents an integer of 0, 1, 2, or 3; and The symbol * denotes the connection point with LIN; and / or (ii) the LIN is: #-CH ２ represents -, where: The symbol # represents the group R １０ 2. A compound of formula (I) according to claim 1, or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof, which represents a connection point with

7. R １０ is the following group: 【Chemistry 14】 represents; 2. A compound of formula (I) according to claim 1, or a salt, enantiomer, stereoisomer, solvate or polymorph thereof, wherein the symbol * represents the point of attachment to LIN.

8. R １０ is the following group: 【Chemistry 16】 represents Here, ring W １ represents piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, or thiomorpholinylene; (R ａ１ ) ｎ１ Is Ring W １ There are n1 R ａ１ represents a group substituted with ａ１ are the same or different and each independently represent a C1-3 alkyl, a halogenated C1-4 alkyl, a halogen, or an oxo group, and n1 represents an integer of 0, 1, 2, or 3; Ring W ２ includes cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene; n3 represents an integer of 0 or 1, (R ａ２ ) ｎ２ Is Ring W ２ There are n2 R ａ２ represents a group substituted with ａ２ are the same or different and each independently represent a C1-3 alkyl, a halogenated C1-4 alkyl, a halogen, or an oxo group, and n2 represents an integer of 0, 1, 2, or 3; and 2. A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate or polymorph thereof according to claim 1, wherein the symbol * represents the point of attachment to LIN.

9. R １０ is the following group: 【Chemistry 17】 represents 2. A compound of formula (I) according to claim 1, or a salt, enantiomer, stereoisomer, solvate or polymorph thereof, wherein the symbol * represents the point of attachment to LIN.

10. 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((3S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-((3S)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((3R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-((3R)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((cis)-4-((3S)-4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((trans)-4-((3S)-4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((cis)-4-((3R)-4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((trans)-4-((3R)-4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-((3S)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((cis)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide; 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide; 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide; 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide; N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide; and 2. The compound of formula (I) according to claim 1, or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof, selected from the group consisting of N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide.

11. 11. The compound of formula (I) or a salt, enantiomer, stereoisomer, solvate or polymorph thereof according to any one of claims 1 to 10, which is the hydrochloride, sulfate, citrate, maleate, methanesulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, hydroxyacetate or p-toluenesulfonate salt of the compound of formula (I).

12. A compound or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof, 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((2R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide; 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((2R)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; and N-((4-(((2R)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide, or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof.

13. 13. The compound of claim 12, or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof, which is a hydrochloride, sulfate, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, hydroxyacetate, or p-toluenesulfonate salt of the compound.

14. 11. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10 as an active ingredient, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof, and at least one pharmaceutically acceptable carrier, and optionally at least one additional therapeutic agent, such as an anti-cancer agent.

15. 14. A pharmaceutical composition comprising the compound of claim 12 or 13 as an active ingredient or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof, and at least one pharmaceutically acceptable carrier, and optionally at least one additional therapeutic agent, such as an anti-cancer agent.

16. A compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14; or A compound according to claim 12 or 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15. A pharmaceutical kit or reagent kit comprising:

17. 15. The pharmaceutical composition of claim 14, for use in treating and / or preventing a disease or condition selected from the group consisting of neurodegenerative diseases including Parkinson's disease and Alzheimer's disease; vascular heart disorders including coronary heart disease, congestive heart failure, myocardial infarction, and atherosclerosis; autoimmune diseases including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis / dermatomyositis, Sjogren's syndrome, and atopic dermatitis; myelofibrosis; renal fibrosis; liver fibrosis; cirrhosis; tumors including hematological malignancies and solid tumors; multiple organ dysfunction syndrome (MODS) including multiple organ failure due to cachexia and septic shock; acute liver failure; transplant rejection including organ (including kidney, heart, lung) or tissue transplant rejection; retinopathies including diabetic macular edema (DME) and wet age-related macular degeneration (wAMD); and diabetes.

18. The tumors include myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, and smoldering multiple myeloma; myelofibrosis; bone marrow disorders; myelodysplastic syndromes (MDS); previously treated myelodysplastic syndromes; transplant-associated cancers; neutropenia; leukemia, including acute myeloid leukemia, chronic granulocytic leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, leukemia-associated anemia, and acute myeloid leukemia (AML); diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, anaplastic lymphoma, and anaplastic large cell lymphoma. lymphoma, CD20-positive lymphoma, mantle cell lymphoma, primary lymphoma, T-cell lymphoma (including relapsed or refractory peripheral T-cell lymphoma), small lymphocytic lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma, refractory rheumatoid arthritis lymphomas, including primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, and Waldenstrom's macroglobulinemia; thyroid cancer; melanoma; lung cancer, including non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; brain glioma; astrocytoma; ovarian cancer; bronchogenic carcinoma; prostate cancer; estrogen-dependent breast cancer, HER2-positive breast cancer, triple-negative breast cancer, incidental breast cancer, and Cowden's disease 18. The pharmaceutical composition of claim 17, comprising breast cancer; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; medulloblastoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; brain cancer; oral cancer; sarcomas including rhabdomyosarcoma, various lipogenic tumors, Ewing's sarcoma / primitive neuroectodermal tumors (Ewing / PNETs) and leiomyosarcoma; chondrosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct carcinoma; bone cancer; cervical cancer; and skin cancer.

19. 18. The pharmaceutical composition of claim 17, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 is prepared into a drug to be administered by at least one administration form selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration and intravenous administration.

20. Neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease; vascular heart disorders, including coronary heart disease, congestive heart failure, myocardial infarction, and atherosclerosis; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis / dermatomyositis, Sjogren's syndrome, and atopic dermatitis; myelofibrosis; renal fibrosis; liver fibrosis; liver cirrhosis; hematologic malignancies, and tumors, including solid tumors; and multiple organ failure, including multiple organ failure due to cachexia and septic shock.

14. A compound of formula (I) according to any one of claims 1 to 10 or a salt, enantiomer, stereoisomer, solvate or polymorph thereof, or a compound according to claim 12 or 13 or a salt, enantiomer, stereoisomer, solvate or polymorph thereof, for use in treating and / or preventing a disease or condition selected from the group consisting of Modified Optic Syndrome (MODS); acute liver failure; transplant rejection including organ (including kidney, heart, lung) or tissue transplant rejection; retinopathies including diabetic macular edema (DME) and wet age-related macular degeneration (wAMD); and diabetes.

21. The tumors include myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, and smoldering multiple myeloma; myelofibrosis; bone marrow disorders; myelodysplastic syndromes (MDS); previously treated myelodysplastic syndromes; transplant-associated cancers; neutropenia; leukemia, including acute myeloid leukemia, chronic granulocytic leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, leukemia-associated anemia, and acute myeloid leukemia (AML); diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, and CD2 O-positive lymphoma, mantle cell lymphoma, primary lymphoma, T-cell lymphoma (including relapsed or refractory peripheral T-cell lymphoma), small lymphocytic lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma Lymphomas, including myeloid cell lymphoma, refractory transformed non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, and Waldenstrom's macroglobulinemia; thyroid cancer; melanoma; lung cancer, including non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; brain glioma; astrocytoma; ovarian cancer; bronchogenic carcinoma; prostate cancer; breast cancer, including estrogen-dependent breast cancer, HER2-positive breast cancer, triple-negative breast cancer, incidental breast cancer, and Cowden's disease; pancreatic cancer; neuroblastoma; extramedullary plasma cell 21. The compound of claim 20 or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof, including tumors; medulloblastoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; brain cancer; oral cancer; sarcomas including rhabdomyosarcoma, various lipogenic tumors, Ewing's sarcoma / primitive neuroectodermal tumors (Ewing / PNETs) and leiomyosarcoma; chondrosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct carcinoma; bone cancer; cervical cancer; and skin cancer.

22. 21. The compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or the compound of claim 12 or 13 or a pharmaceutically acceptable salt thereof, is manufactured into a medicament to be administered by at least one administration form selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration and intravenous administration, or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof according to claim 20.

23. 16. The pharmaceutical composition of claim 15, for use in treating and / or preventing a disease or condition selected from the group consisting of neurodegenerative diseases including Parkinson's disease and Alzheimer's disease; vascular heart disorders including coronary heart disease, congestive heart failure, myocardial infarction, and atherosclerosis; autoimmune diseases including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis / dermatomyositis, Sjogren's syndrome, and atopic dermatitis; myelofibrosis; renal fibrosis; liver fibrosis; cirrhosis; tumors including hematological malignancies and solid tumors; multiple organ dysfunction syndrome (MODS) including multiple organ failure due to cachexia and septic shock; acute liver failure; transplant rejection including organ (including kidney, heart, lung) or tissue transplant rejection; retinopathies including diabetic macular edema (DME) and wet age-related macular degeneration (wAMD); and diabetes.

24. The tumor is a myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, and smoldering multiple myeloma; myelofibrosis; bone marrow disease; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-associated cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic granulocytic leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, leukemia-associated anemia, and acute myeloid leukemia (AML); diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, anaplastic lymphoma, and anaplastic large cell lymphoma. lymphoma, CD20-positive lymphoma, mantle cell lymphoma, primary lymphoma, T-cell lymphoma (including relapsed or refractory peripheral T-cell lymphoma), small lymphocytic lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin's lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal (thymic) large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, relapsed transformed non-Hodgkin's lymphoma, refractory B-cell non-Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma, refractory rheumatoid arthritis lymphomas, including primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, and Waldenstrom's macroglobulinemia; thyroid cancer; melanoma; lung cancer, including non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma; inflammatory myofibroblastic tumor; colorectal cancer; brain glioma; astrocytoma; ovarian cancer; bronchogenic carcinoma; prostate cancer; estrogen-dependent breast cancer, HER2-positive breast cancer, triple-negative breast cancer, incidental breast cancer, and Cowden's disease 24. The pharmaceutical composition of claim 23, comprising breast cancer; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; medulloblastoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; brain cancer; oral cancer; sarcomas including rhabdomyosarcoma, various lipogenic tumors, Ewing's sarcoma / primitive neuroectodermal tumors (Ewing / PNETs) and leiomyosarcoma; chondrosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct carcinoma; bone cancer; cervical cancer; and skin cancer.

25. The pharmaceutical composition of claim 23, wherein the compound or pharmaceutically acceptable salt thereof according to claim 12 or 13 is manufactured into a drug to be administered by at least one administration form selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration and intravenous administration.

Images