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 protein degraders, 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 the process by which cells undergo a series of programmed events leading to death. During early development, apoptosis can eliminate unnecessary cells, and after adulthood, apoptosis mainly plays a role in eliminating cells that are damaged and cannot be repaired in the body, thereby ensuring the proper development of the human body. Apoptosis plays an important role in various physiological processes, such as normal cell renewal, improving the development and function of the immune system, hormone-dependent atrophy, embryonic development, and chemically induced cell death (Elmore, S., Toxicol Pathol, 2007.35(4):p. 495-516.). Meanwhile, abnormal apoptosis (excessive or insufficient) can cause the development of various diseases, including neurodegenerative diseases, vascular heart disorders, autoimmune diseases, and tumors. Research has shown that tumors can be made less sensitive to antitumor drugs by inhibiting the apoptotic pathway during development and development (Scott, W Letal., Carcinogenesis, 2000.21(3):p.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 crucial regulator of apoptosis, which can both induce and inhibit cell apoptosis. It is mainly located on mitochondria and plays the role of "apoptosis switch" by regulating the permeability of the mitochondrial membrane. BCL-2 has four highly conserved homeodomain (BH) domains, BH1, BH2, BH3 and BH4, and can be divided into three subtypes according to the different compositional conditions of the homeodomain, one of which has anti-apoptotic function and two of which have pro-apoptotic function (Daniel, NN, Clin Cancer Res, 2007.13(24):p.7254-7263.). The BH1 and BH2 homeodomains of BCL-2 can form dimers with pro-apoptotic proteins, and the BH3 domain is crucial in the interaction between pro-apoptotic and anti-apoptotic, so it is also included in all subtypes, and BH4 is mainly included in the anti-apoptotic BCL-2 subtype. Anti-apoptotic proteins include BCL-2, BCL-X, and BCL-X. L, BCL-W, MCL1, A1 and BCL-B, which are composed of 3-4 BH domains. Meanwhile, pro-apoptotic proteins can be divided into two types, one type of pro-apoptotic protein includes BAX, BAK and BOK, which are composed of BH1, BH2 and BH3, and the other type of pro-apoptotic protein includes BID, BIM, BAD, PUMA, NOXA, BMF, HRK and BIK, which are composed of only BH3 (Youle, RJ, et al., Nat Rev Mol Cell Biol, 2008.9(1):p.47-59.). Under normal physiological conditions, the level of BCL-2 family proteins maintains a dynamic equilibrium, and cell signaling can regulate the expression of pro-apoptotic or anti-apoptotic proteins by influencing this dynamic equilibrium process, which can lead to the development of the equilibrium into cell survival or death. When the equilibrium favors cell death, pro-apoptotic proteins permeabilize the outer mitochondrial membrane by oligomerization on the membrane, releasing cytochrome c and triggering activation of the caspase enzyme cascade, which degrades downstream substrates and causes cell death (Opferman, JT and A. Kothari, Cell Death Differ, 2018.25(1):p.37-45.).

[0004] After more than 20 years of development, many 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) with pro-apoptotic protein BH3 domains. BCL-2 family protein antagonists, also called "BH3 domain mimetics", mainly insert the BH3 domain common to anti-apoptotic BCL-2 family proteins to block their binding with pro-apoptotic proteins BAX and BAK, inhibit the action of BCL-2 anti-apoptotic proteins, and further induce apoptosis of 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):p.979-87.; Carter, PJ and GALazar, Nat Rev Drug Discov, 2018.17(3):p.197-223.). However, ABT-199 has no clear therapeutic effect against solid tumors, as the growth of most solid tumors does not depend on BCL-2 protein, and it has not been shown to be effective against BCL-X. L The protein was significantly overexpressed in multiple types of solid tumors and blood 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 antitumor molecular target.

[0006] BCL-X L (B-cell lymphoma-extra large), as a crucial regulator of apoptosis, is located in the mitochondria and is a key regulator of apoptosis, which 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 cell senescence is a major pathogenesis of 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.). Anti-apoptotic protein BCL-X L Targeting BCL-X can induce apoptosis of senescent endothelial cells and achieve the purpose of treating DME and wAMD (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 has also shown 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.). 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).). In addition, the invasiveness of colorectal cancer cells is increased by inhibiting BCL-X. L In colorectal cancer, the BCL2 protein family is closely related to BCL-X. L Only BCL-X was significantly increased (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 destroys 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 safe and effective treatments are lacking.

[0009] PROTAC (Proteolysis Targeting Chimeria) is a bifunctional heterojunction small molecule that links the target protein ligand and the E3 ubiquitin ligase ligand by a suitable link chain, and promotes the formation of a ternary complex between the target protein and E3 ligase, thereby bringing the target protein closer to the ubiquitination system, realizing the ubiquitination of the target protein, which is then recognized by the protease 26 S subunit, and finally resulting in the degradation of the target protein (Sun, X., et al., Sig Transduct Target Ther, 2019. 4(1): p. 33.). PROTACs make the process of protein degradation similar to catalytic reactions, so they can act at extremely low doses, and compared with traditional small molecule inhibitors, their efficacy is longer and their toxicity is lower (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 in tumor cells and normal tissues. For example, DT2216, which has entered clinical trials, targets ABT-263 by targeting the protein BCL-X. LBy using VHL, which is lowly expressed in platelets, as an E3 ubiquitin ligase ligand, the antitumor activity was significantly enhanced and platelet toxicity was reduced (Khan, S., et al., Nature medicine, 2019.25(4):p.1938-1947.).

[0010] Abnormally activated Hedgehog (Hh) signaling pathway is closely related to the occurrence and development of various types of tumors in the human body (e.g., basal cell carcinoma, medulloblastoma, etc.) (Nat Genet, 2016.48(4):p.398-406; Cancer Cell, 2014.25(3):p.393-405.). Hh signaling in cells is a cascade type, and its key molecules include the 12-transmembrane domain PTCH receptor, the 7-transmembrane structure SMO (Smoothened) receptor, SUFU protein, and the nuclear transcription factor GLI protein family. In the absence of exogenous HH ligand, PTCH inhibits SMO activity and the signaling pathway is in an inhibited state. When exogenous HH ligand binds to PTCH and releases its inhibition of SMO, SMO translocates to the cilium, which is the key signal center in the signaling pathway, and the SUFU-GLI transcription complex also translocates to the cilium, releasing the inhibitory effect of SUFU on GLI and further regulating the phosphorylation of GLI by kinases such as GSK3 and CK1, ultimately allowing transcriptionally active GLI to enter the nucleus and initiate the 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 drugs for basal cell carcinoma target SMO (Cell, 2016.164(5):p.831.), and therefore have no obvious inhibitory effect on tumors in which Hh is abnormally activated due to genetic alterations of key signal 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 the activation of intracellular BCL-X. LIt can bind to apoptosis-resistant proteins such as BCL-2 and MCL-1, thereby relieving the inhibitory effect of SUFU on GLI proteins, ultimately leading to the activation of the Hh pathway and the translocation of BCL-X. L It has been revealed that it can inhibit the binding of anti-apoptotic proteins such as SUFU to effectively inhibit the activation of the Hh signal pathway (Nat Cell Biol, 2017.19(10):p.1226-1236.). Based on this, targeting BCL-2 family proteins is also a strategy to develop inhibitors that target the Hh signal pathway.

[0011] Therefore, there is a strong 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 related to the Hedgehog signaling pathway. Summary of the Invention

[0012] In view of the above, the present disclosure aims to provide a novel protein degrader developed based on a BCL-2 family protein ligand compound, its uses, and its methods of use. The novel protein degrader compound developed based on the BCL-2 family protein ligand compound according to the present disclosure, or its salt (including pharma- ceutically acceptable salt), stereoisomer (including enantiomer), solvate, pharmaceutical precursor, or polymorph can bind to a target protein, and recruit the target protein to E3 ubiquitin ligase for ubiquitination tagging and degradation, thereby exhibiting the desired pharmacological activity.

[0013] In some embodiments, the novel protein degrading 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: The dotted lines indicate the optional presence of double bonds; R1, R2, R3, and R4 are the same or different and each independently represents 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, each R5 being the same or different and each independently being halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl, where n is an integer of 1, 2, 3, 4, or 5; (R6) m represents that the piperazine ring is substituted with m R6, each R6 being the same or different and each independently being 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; (R a1 ) n1 Ring W 1 There are 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 Each R a2 are the same or different and each independently: C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkoxy, cyano, halogen, or oxo group, and n2 represents an integer of 0-8; and The symbol * indicates the connection point with LIN; LIN is, Optionally substituted linear or branched 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 2-30 alkylene, where 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 an alkyl group, and 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 the cycloalkylene, the arylene, the heterocyclylene, and the 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, aryl, aryloxy ... R 11 has the following structural formula (II): [ka] Formula (II) represents Here, R 12 is N(R e ), O, S, C 2-6 Alkynylene or C 2-6 alkenylene, where R e is H or C 1-6 Represents alkyl, or R 12 represents a bond; (R a ) t R has t benzene rings. a Each R represents a substitution. a are the same or different and each independently represent bromine, t represents an integer of 0, 1, 2, or 3; and X represents C(O) or CH2; Here, if t is an integer equal to 0, R7 [ka] where n1 represents an integer from 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 disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, and at least one pharma- ceutically 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 comprises 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 protein degrader compound or a salt, stereoisomer (including enantiomer), solvate, pharmaceutical precursor or polymorph thereof, and at least one pharma- ceutically acceptable carrier.

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

[0018] In one aspect, the present disclosure provides a protein decomposing 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 them as an active ingredient.

[0019] In one aspect, the present disclosure provides a protein decomposing 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 them 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, liver 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.

[0021] In one aspect, the present disclosure further provides the use of a protein degrader compound of 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 heart disorders, autoimmune diseases, myelofibrosis, renal fibrosis, hepatic fibrosis, liver cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), cachexia and multiple organ failure due to 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 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 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, liver cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), cachexia and multiple organ failure due to septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes, transplant rejection, retinopathy and acute liver failure. [Brief description of the drawings]

[0023] [Figure 1] Figures 1-3 are schematic diagrams of protein Western blotting experiment results, which show that the compounds of the present invention, BCL-03146, BCL-03147, BCL-03148, BCL-03149, etc. (100 nM), significantly reduced the expression of BCL-XL protein after acting on Molt-4 cells for 8 hours, and showed clear superiority in protein degradation compared to DT2216 (CAS number: 2365172-42-3; a BCL-XL degrading agent reported in the literature). [Diagram 2] Same as above. [Diagram 3] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] In order to facilitate the 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, and 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 pharma- ceutically acceptable salt), stereoisomer (including an enantiomer), solvate, isotopically enriched analogue, pharmaceutical precursor, or polymorph thereof, [ka] Formula (I) Here, 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 a compound 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 contains 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 absence of a bond. In this case, the group in a compound of Formula (I) that contains 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 selected from 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, each R5 being the same or different and each independently being 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 a 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, R8 represents hydrogen or -SO2CF3 or -NO2;

[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, R 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, R 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; (R a1 ) n1 Ring W 1 There are n1 R a1 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 1-3alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy), cyano, halogen, such as fluorine, chlorine, bromine or iodine, or an oxo group, where 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 Each R 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, where 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 the 4- to 6-membered nitrogen-containing heterocyclylene includes, but is not limited to, for example, piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, or thiomorpholinylene.

[0046] In some embodiments, (R a1 ) n1 Ring W 1 There are n1 R a1 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), cyano, halogen, such as fluorine, chlorine, bromine or iodine, or an oxo group, and n1 represents an integer from 0 to 8, such as an integer 0, 1, 2, 3, or 4.

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

[0048] In some embodiments, the ring W 2 is C 3-6 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 Each R 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, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy), cyano, halogen, such as fluorine, chlorine, bromine or iodine, or an oxo group; and n2 represents an integer from 0 to 8, such as an integer 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 compound represented by the following structural 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 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 CH2; and (R a ) t R has 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, R [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, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy, or halogen, for example fluorine, chlorine, bromine or iodine.

[0062] In the present disclosure, when t represents an integer of 0, R [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 a5 )(R a6 )) n5 ) m1 -(R c -(C(R a7 )(R a8 )) n6 ) m2 -; #-(C(R a3 )(R a4 )) n4 -(R c -R b -(C(R a5 )(R a6 )) n5 ) m1 -; or #-(C(R a3 )(R a4 )) n4 -(R c -(C(R a5 )(R a6 )) n5 ) m1 -(R b-(C(R a7 )(R a8 )) n6 ) m2 -; represents Here, 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 the cycloalkylene, the arylene, the heterocyclylene, and the 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, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), halogen (such as 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 CH2 of the alkylene is further represented by 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), 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 integers of 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 - stands for; 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 (e.g., 4- to 20-membered heterocyclylene) and the heteroarylene (e.g., 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, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), halogen (such as 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 integers of 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: #-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 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 #-(CH2)2-piperazinylene-(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-(CH2) 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 are each independently further selected from the group consisting of 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, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), halogen (such as 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 integers of 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 represented by the structure Here, R1, R2, R3, R4, (R5) n , (R6) m , R7, R8, R9, R 10 , L.I.N., 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 represented by the structure Here, R1, R2, R3, R4, (R5) n , (R6) m , R8, R9, R 10 , L.I.N., 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 represented 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; R a1 ) n1 Ring W 1 There are n1 R a1 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 1-4alkyl, 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 represents 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 Each R 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, where 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 , L.I.N., R.12 and X are as defined herein for compounds of formula (I) and each embodiment thereof.

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

[0070] In some embodiments, (R a1 ) n1 Ring W 1 There are n1 R a1 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), cyano, halogen, such as fluorine, chlorine, bromine or iodine, or an oxo group, and n1 represents an integer from 1 to 8, such as an integer of 1, 2, 3, or 4.

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

[0072] In some embodiments, the ring W of the compound of formula (I-2-1) 2 is C 3-6 The 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 Each R 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, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy), cyano, halogen, such as fluorine, chlorine, bromine or iodine, or an oxo group; and n2 represents an integer from 0 to 8, such as an integer 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 represented by the structure Where: R8 represents -SO2CF3; and R1, R2, R3, R4, (R5) n , (R6) m , R9, R 10 , L.I.N., 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 represented by the structure Here, R9, R 10 , L.I.N., 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 pharma- ceutically 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] TIFF2025503598000029.tif210140TIFF2025503598000030.tif209140TIFF2025503598000031.tif211141TIFF202 5503598000032.tif202140TIFF2025503598000033.tif211141TIFF2025503598000034.tif211141TIFF20255035980 00035.tif208141TIFF2025503598000036.tif210141TIFF2025503598000037.tif183140TIFF2025503598000038.t if210139TIFF2025503598000039.tif208141TIFF2025503598000040.tif211140TIFF2025503598000041.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 protein degrading agents developed based on the BCL-2 family protein ligand compounds in Table 2 below, or salts (including pharma- ceutically 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] TIFF2025503598000043.tif210146TIFF2025503598000044.tif210146TIFF2025503598000045.tif82143

[0083] In some embodiments, the 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 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 a compound of the present disclosure includes any compound 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), as well as specific compounds falling within the scope of these general formulas (e.g., the compounds of Table 1, or the compounds of Table 2).

[0085] It should be recognized that the 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 the compounds of Table 1 or Table 2) can have spatial configurations and therefore can exist in one or more stereoisomeric forms. The present disclosure also relates to optically enriched compounds having a spatial configuration (e.g., greater than about 90% ee, such as greater than about 95% ee or 97% ee, or greater than 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 an 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, for example, column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g., synthesis by using chiral intermediates) and / or chiral separation.

[0086] In some embodiments, the present disclosure further provides polymorphic forms of the compounds or salts of the compounds of the present disclosure. The salts of the compounds of the present disclosure may be pharma- ceutically 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. The compounds of the present disclosure may be in a nonsolvated or solvated form in a pharma-ceutically acceptable solvent, such as water, ethanol, etc. In some embodiments, the compounds of the present disclosure may be prepared into precursor drugs or pharmaceutical precursors. The precursor drugs are converted to the parent drugs in the body to 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 pharma- ceutically acceptable salt, solvate, isotopically enriched analogue, polymorph, pharmaceutical precursor, stereoisomer (including enantiomer), or mixture of stereoisomers thereof as an active ingredient, and at least one pharma- ceutically acceptable carrier.

[0088] In some embodiments, pharma- ceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersing agents, suspending agents, diluents, excipients, thickeners, solvents, or sealants. A carrier must be "acceptable" in that it is compatible with the other ingredients of the formulation (including the compound useful in the present disclosure) and is not harmful to the patient. Some examples of substances used as pharma- ceutically 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, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as core 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 of Table 1 or Table 2) to treat a disease or condition described in the present disclosure. The second therapeutic agent includes, but is not limited to, a chemotherapeutic agent, an immunotherapeutic agent, and a gene therapy agent.

[0090] The pharmaceutical composition comprising the compound 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 a compound of Table 1 or Table 2), or a pharma- ceutically acceptable salt thereof, can be administered by an appropriate administration route (including, but not limited to, nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration) through an appropriate administration route (including, but not limited to, nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration). The composition may be administered by any of the following routes (including, but not limited to, enteral, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous) in the form of an appropriate formulation, such as a spool formulation, 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 a regular injection form, such as an injectable solution (e.g., a sterile injection solution prepared using water, Ringer's solution, or isotonic sodium chloride solution as a carrier or solvent by a method known in the art) or a lyophilized composition. In addition, 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 of Table 1 or Table 2) into a normal, dispersible, chewable, intraoral fast disintegrating or fast dissolving formulation, or a sustained release capsule or a controlled release capsule, if necessary.

[0091] The compounds according to the present disclosure as active ingredients (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 of Table 1 or Table 2) are contained in a pharma- ceutically 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. The dosage of active compound for any disease or condition mentioned herein is, 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, for example, 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 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 of Table 1 or Table 2) or pharma- ceutically acceptable salts thereof can be conveniently administered in any suitable formulation, and the specifications of the suitable formulation include, but are not limited to, less than 1 mg, 1 mg to 3000 mg, 5 mg to 1000 mg, for example, 5 to 500 mg, 25 to 250 mg of active ingredient 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 any one of the compounds of Table 1 or Table 2), or a pharma- ceutically acceptable salt, solvate, polymorph, prodrug, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, are for use as a medicament. The medicament of the present disclosure or the pharmaceutical composition of the present disclosure can be present in a kit / packaged product. The kit / packaged product can include a package or container. The packages 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 pharma- ceutically acceptable salt, solvate, polymorph, precursor, stereoisomer (including enantiomer), or mixture of stereoisomers thereof, can further be used as a medicament. In particular, the present disclosure relates to a 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), or a pharma- ceutically acceptable salt, solvate, polymorph, precursor, or stereoisomer (including enantiomer) thereof. ), or a mixture of stereoisomers, may 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 heart disorders, autoimmune diseases, myelofibrosis, renal fibrosis, hepatic fibrosis, liver 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, anemia associated with leukemia, acute myeloid leukemia (AML); diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, undifferentiated lymphoma, Refractory or recurrent peripheral T-cell 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, 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, incident breast cancer, and cystic ovarian cancer. These include, but are not limited to, breast cancer, including Wooden's disease; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; medulloblastoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumors; 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 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] The 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, a 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, 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; liver 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, anemia associated with leukemia, 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 Lymphoma, including refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, 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 tumors; 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 of Table 1 or Table 2), or a pharmaceutical composition according to the present disclosure, 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 cavity 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 slowing (alleviating) the development of an unwanted disease or condition (e.g., a tumor) by administering to a subject 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 of Table 1 or Table 2), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to the present disclosure or a pharma- ceutically acceptable salt thereof. Beneficial effects or desired clinical results of the present disclosure include, but are not limited to, alleviation of symptoms, reduction in severity of disease, stabilization of the disease state, delay or slowing of disease progression, improvement or alleviation of the condition, and alleviation 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, co-administered 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 the amount of use will vary according to the basic condition of the individual (generally should be optimally effective for the individual's condition).The administration and administration scheme should be within the scope of the ability of a person skilled in the art, and the appropriate dosage depends on many factors, including the knowledge and ability level of the general technical physician, veterinarian or researcher (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 animals, e.g., mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, mice, and the like. VI. Definition

[0101] Unless otherwise stated, 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, etc.) are those well known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in accordance with the content of the present disclosure described herein have the same meaning as commonly understood by those of ordinary skill in the art. Also, in the claims and / or specification, when the terms "a" and "one" are used in combination with the term "comprise" or a noun, the meaning may be "one", but it is also consistent with the meaning of "one or more", "at least one" and "one or more than one". Similarly, the term "another" or "other" can represent at least a second or more.

[0103] Whenever an embodiment is described herein with 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 numerical value. Generally, the term "about" can be modified higher or lower than the stated value by a shift 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, 12 is a bond connector. 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, "one or more groups R in the carbon backbone" used alone or in combination means b and / or one or more groups R c or one or more groups R b and R c "Inserted with any combination of" has the definition known in the art, i.e., the group R b , R c or group R b and R c In the present 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 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 cand / 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 thereby are consistent with covalent bond theory. For example, "one or more groups R 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 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 -CH-" 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) "-CH-R c -CH-" 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) "-CH-R b -R c Linear or branched C to form and contain -CH2- fragments 2-30 In the carbon main chain of the alkylene chain, 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) R is present between any pair or pairs of adjacent carbon atoms. 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 one or more hydrogens in the referenced structure being replaced with the same or different specific substituents. The number of substituents is not limited in principle to any one or is automatically limited to the size of the constitutional unit (i.e., the total number of hydrogen atoms that may be replaced in the constitutional unit) or as clearly defined in the present text.

[0108] In this specification, 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 R of the group 12 represents the connection between the groups LIN of a compound of formula (I).

[0109] In the present text, the term "C" used alone or in combination x-y "One or more hydrogen atoms of the CH2 of the alkylene are replaced..." refers to a straight or branched C x-y It means that one or more hydrogen atoms in CH2 in alkylene are replaced by a substituent defined in the present text. In the present text, "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 CH2 hydrogens" may refer to some or all of the hydrogens of each alkylene group mentioned, including but not limited to 1-60 hydrogens. In some embodiments, the term "one or more CH2 hydrogens" may refer to some or all of the hydrogens of the alkylene mentioned, 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 CH2 hydrogens" may refer to 1-3 of the hydrogens of the alkylene mentioned. The amount is not limited in principle or is automatically limited by the size of the structural 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" (where 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 groups 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 the present disclosure, the "alkyl" is optionally substituted, and the substituents are optionally selected from 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] The term "halogenated alkyl" as used herein alone or in combination refers to a straight or branched chain alkyl substituted with one or more halogens, where 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 alkyl containing x to y carbon atoms substituted with one or more halogens. 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 alkyl halides include 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 group 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 linear or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. x -C y Alkylene" or "C x - y "Alkylene" (x and y are each integers) refers to a straight or branched chain alkylene containing x to y carbon atoms. 30 Examples of alkylene 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, 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 having 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 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] In the present invention, the term "heteroaryl", used alone or in combination, refers to a 5-20 membered (optionally 5-15 membered, 5-12 membered, 5-11 membered, 5-10 membered, 5-9 membered, 5-8 membered, 5-7 membered, 5-6 membered, 6-15 membered or 6-9 membered) monocyclic, bicyclic or polycyclic aromatic ring group having an aromatic ring containing one or more (e.g. 1-6, or 1-5, or 1-4, or 1-3) 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 may 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, nyl, 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, 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 arbitrarily selected from the group consisting of alkyl-C(O)NH-, cyano group, or any combination thereof.

[0117] In the present disclosure, the term "heteroarylene," alone or in combination, refers to a 5-20 membered (optionally 5-15 membered, 5-12 membered, 5-11 membered, 5-10 membered, 5-9 membered, 5-8 membered, 5-7 membered, 5-6 membered, 6-15 membered, or 6-9 membered) monocyclic, bicyclic, or polycyclic divalent aromatic ring group having at least one aromatic ring containing one or more (e.g., 1-6, 1-5, 1-4, or 1-3) 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 may contain one or more heteroatoms independently selected from the group consisting of O, S, and N. Representative examples of single-ring 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, isoindolylene, isoindolinylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzoisoxazolylene, benzothiazolylene, benzoisothiazolylene, benzotriazolylene, benzo[2,1,3]oxadiazolylene, benzo[2,1,3]thiadiazolylene, benzo[1,2,3]thiadiazolylene, quinolylene, isoquinolylene, naphthyridinylene, cinnamylene, and cinnamylene. Examples of heteroarylene include, but are not limited to, 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 heteroarylene include, but are not limited to, acridinylene, benzoindolylene, carbazolylene, dibenzofuranylene and xantylene. Said 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, where the substituent is C1-C3 alkyl, C. 3-6 Cycloalkyl, hydroxy, amino, mercapto, 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 arbitrarily 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 radical containing 5 to 14 carbon atoms and optionally containing one or more fused rings (e.g., phenyl, or naphthyl or fluorenyl). 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, C1-C3 aryl, C2-C3 aryl ... 3-6 Cycloalkyl, hydroxy, amino, mercapto, 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 arbitrarily selected from the group consisting of alkyl-C(O)NH-, cyano group, or any combination thereof.

[0119] In the present disclosure, the term "arylene", alone or in combination, refers to a divalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally containing one or more fused rings (e.g., phenylene or naphthylene or fluorenylene). 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, 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 arbitrarily 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, having 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, or tricyclic cycloalkyl having 3 to 20 carbon atoms. Representative examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic and tricyclic cycloalkyl include bridged cyclic alkyl, fused ring, and spirocycloalkyl, such as, but not limited to, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, spirocycloalkyl, adamantanyl, noradamantanyl, bornyl, and norbornyl (IUPAC systematic name is 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, 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 x-y The term "spirocycloalkyl" (where x and y are each an integer) 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, 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] In the present invention, the term "cycloalkylene", alone or in combination, refers to a saturated and partially unsaturated (e.g., containing one or more double bonds but not fully conjugated) monocyclic, bicyclic or polycyclic hydrocarbon divalent radical 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 x-y The term "spirocycloalkylene" (where x and y are each an integer) 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 be further defined as C1-C3 alkyl, C 3-6 Cycloalkyl, hydroxy, amino, mercapto, 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 3-20 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 3-15 membered (optionally 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) 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, representative examples of which 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 azaspirocycloalkyls (e.g., 3-azaspiro[5.5]undecan-3-yl).The heterocyclyl may be unsubstituted or substituted (e.g., mono-, di-, tri- or polysubstituted) 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.

[0125] The term "nitrogen-containing monocyclic heterocyclyl", as used herein, 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) monocyclic saturated or partially unsaturated (i.e., having one or more double bonds, but which are not fully conjugated) monovalent cyclic hydrocarbon radical containing one nitrogen atom and optionally containing one or more (e.g., containing 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 clearly defined, where the substituents are deuterium, hydroxy, amino, mercapto groups, nitro, halogen, cyano groups, 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 3-20 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 3-15 membered (optionally 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) divalent cyclic hydrocarbon group containing one or more (e.g., containing 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 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 and tricyclic heterocyclylenes include bridged, fused and spiroheterocyclylenes, representative examples of which 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 azaspirocycloalkylenes (e.g., 3-azaspiro[5.5]undecanylene).The heterocyclylene may be unsubstituted or substituted (e.g., mono-, di-, tri- or polysubstituted) as clearly defined, where the substituents are deuterium, hydroxy, amino, mercapto groups, nitro, halogen, cyano groups, 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] The term "nitrogen-containing heterocyclylene", as used herein, 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), monocyclic, bicyclic, or tricyclic, saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated), divalent cyclic hydrocarbon radical containing one nitrogen atom and optionally containing one or more (e.g., containing 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 (e.g., mono-, di-, tri- or poly-substituted) as clearly defined, where the substituents are deuterium, hydroxy, amino, mercapto groups, nitro, halogen, cyano groups, 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 linear or branched monovalent 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. 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 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 linear or branched 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 the present specification, "bornane" (also called 1,7,7-trimethylbicyclo[2.2.1]heptane; camphane; bornylane) has the definition known to those skilled in the art. In the present specification, "bornyl" refers to a monovalent radical of bornane, i.e., a radical obtained after one of the hydrogen atoms in bornane is removed. Representative examples include 1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl, 1,7,7-trimethylbicyclo[2.2.1]heptane-3-yl, 1,7,7-trimethylbicyclo[2.2.1]heptane-4-yl, 1,7,7-trimethylbicyclo[2.2.1]heptane-5-yl, or 1,7,7-trimethylbicyclo[2.2.1]heptane-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 any hydrogen in bicyclo[2.2.1]heptane is removed. 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 any hydrogen in biscyclo[2.2.1]heptene is removed. 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 any hydrogen 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 group of noradamantane, i.e., a group 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, or 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 adamantane-1-amine having the following structural formula (the corresponding English name is adamantan-1-amine or Tricyclo[3.3.1.1 3,7 ]decan-1-amine; CAS: 768-94-5), which has the following structural formula: [ka] has.

[0138] Also included within the scope of the present disclosure are salts of the compounds of formula (I) or of the compounds of Tables 1 or 2 according to the present disclosure, or pharma- ceutically acceptable salts, enantiomers, stereoisomers, solvates, and polymorphic forms thereof.

[0139] In all embodiments of the present disclosure, the salt or pharma- ceutically 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, examples of which include sulfates, hydrochlorides, citrates, maleates, methanesulfonates, citrates, lactates, tartrates, fumarates, phosphates, dihydrogen phosphates, pyrophosphates, metaphosphates, oxalates, malonates, benzoates, mandelates, succinates, hydroxyacetates, or p-toluenesulfonates.

[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 a desired function. Generally, such constructs are carried or delivered from one organ or part of the body to another organ or part of the body. A carrier must be compatible with the other ingredients of the formulation (including the compounds useful in the present disclosure) and not harmful to the patient, making it "acceptable." Some examples of substances used as pharma- ceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, 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 the 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, and the like.

[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 can be superimposed on its mirror image.

[0145] As used herein, the term "enantiomers" refers to two isomers of a compound which 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. Working Example

[0147] In the following description, many specific details are given in order to provide a thorough understanding of the present disclosure. The present disclosure may be implemented without some or all of these specific details. In other instances, well-known process operations are not described in detail so as not to unnecessarily obscure the present disclosure. Although the present disclosure is described by 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: TIFF2025503598000051.tif205122TIFF2025503598000052.tif7590

[0149] In the present invention, 1H NMR spectra were 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 the internal standard or DMSO-d6 containing 0.03% TMS as the solvent. 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 Waters 1525. Unless otherwise stated, all reactions were carried out in an air atmosphere and were 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. For preparative HPLC, preparative grade CH3CN and deionized water were used. Unless otherwise specified, the starting materials, reagents, various carbon chain linkers (i.e., compounds for forming a group represented by LIN) of different lengths, and other reagents and pharmaceuticals used in the following examples can all 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 pharma- ceutically acceptable salts of the present disclosure can be obtained by synthesis using commercially available raw materials and synthesis techniques known in the art. The synthesis schemes described below will explain the methods for preparing most of the compounds by way of examples. 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 Tables 1 or 2, in the form of their racemates, enantiomers, phosphates, sulfates, hydrochlorides and pharmaceutical precursors.

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

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

[0155] Intermediate compound 732180 was prepared with reference to the methods 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 a reactive group of the intermediate BINDER, (R a ) t and X are as defined herein for compounds of formula (I).

[0162] To a DMF solution of the bromo substrate (1.0 equiv), the corresponding binder intermediate compound (1.0 equiv) and DIEA (2.0 equiv) were added. The reaction mixture was reacted at room temperature for 2 h, and the reaction was terminated. 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 above-mentioned schemes and their reaction substrates, reaction conditions (including reaction amount, temperature, time, etc.), post-treatment, etc. can be appropriately modified and adjusted using techniques and methods well known to those skilled in the art to obtain the required target compound, and 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] Working 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 raw 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 and combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated by silica gel column chromatography (PE / EA=1 / 0-20 / 1) to obtain 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 mixture was stirred at 65 °C for 15 min, and then 3-amino-2,6-piperidinedione hydrochloride (8.21 g, 49.89 mmol) and compound 363126 (20 g, 49.89 mmol) obtained in step 1 were added in that order. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was filtered while hot to remove insoluble matter, and the filtrate was washed with saturated saline and then distilled 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 mixture was filtered, and the filtered solid was washed with 50 mL of dichloromethane and 50 mL of ethyl ether to give product 732001 (11 g, yield: 42%) 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. In addition, the starting material 2,4-bis(bromomethyl)methylbenzoate (CAS number: 63112-94-7) of step 2 of scheme 2 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 obtained residue was separated by silica gel column chromatography (DCM / MeOH=1 / 0-10 / 1), and the obtained product was further purified by slurrying with acetonitrile to obtain 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, 4.5Hz, 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 mixture was stirred at room temperature for 15 min, cooled to 0° C., and 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 mixture was extracted three times with dichloromethane and washed once with saturated brine. The separated organic phase was evaporated under pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH =1 / 0-10 / 1) to give 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 the reaction bottle containing the methanol solution of the cyano compound obtained in step 1. The reaction bottle was gassed with hydrogen gas. The reaction mixture was heated to 60°C and hydrogenated at atmospheric pressure, and reacted overnight. The reaction solution was cooled to room temperature and filtered through diatomaceous earth to remove the Raney nickel, and the eluate was rotary evaporated to obtain the crude amine product, 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 at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate was added to the reaction mixture. The resulting mixture was extracted three times with dichloromethane. The combined organic phases of dichloromethane 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] EDCI (1.5 equiv) and DMAP (1.0 equiv) were added 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. The reaction mixture became clear. The cis product (732139) or trans product (732141) obtained in step 3 was added to the reaction mixture. 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 mixture was washed with saturated saline. The organic phase was separated and the solvent was removed by evaporation under reduced pressure. 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 mixture was stirred at room temperature for 15 min, cooled to 0°C, and 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 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 as a white solid (yield: 80%), which was a mixture of cis and trans products.

[0188] Step 2:

[0189] To the reaction bottle containing the methanolic solution of the cyano compound obtained in step 1, a methanolic solution of NH3 (7 M, 0.5 mL) and Raney nickel were added. The reaction bottle was gassed with hydrogen gas. The reaction mixture was heated to 60°C, hydrogenated at atmospheric pressure, and reacted overnight. The reaction solution was cooled to room temperature and filtered through diatomaceous earth to remove the Raney nickel, and 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, 4-fluoro-3-nitrobenzenesulfonamide (0.9 equiv) and triethylamine (1.5 equiv) were added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate 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 isolate 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, EDCI (1.5 equiv) and DMAP (1.0 equiv) were added. The reaction mixture became clear. The cis product (732140) or trans product (732142) obtained in step 3 was added to the reaction mixture. The reaction mixture was allowed to react for 12 h to ensure that 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 saline. The organic phase was separated and the solvent was removed by evaporation under reduced pressure. 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 was added 4-fluoro-3-trifluoromethylsulfonylbenzenesulfonamide (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 was added to the mixture. The resulting mixture was extracted three times with dichloromethane. The combined organic phases of dichloromethane 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) (yield 98%) as a white powder. 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, EDCI (1.5 equiv) and DMAP (1.0 equiv) were added. The reaction mixture became clear. The product obtained in step 1, tert-butyl 4-((trans)-4-(((4-aminosulfonyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylate (732181), was added. The reaction mixture was allowed to react for 12 h to allow the reaction of the raw materials to reach completion. The reaction mixture was diluted with 30 mL of dichloromethane. The mixture was washed with saturated saline. 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] Trifluoroacetic acid (10 equiv) was added to a solution of the Boc-protected product in dichloromethane. 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 obtain the trifluoroacetate salt of the target compound (732185) in powder form. 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; actual 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] 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] EDCI (1.5 equiv) and DMAP (1.0 equiv) were added to a dichloromethane 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). The reaction system became clear. Compound 732181 prepared according to step 1 of intermediate example 7 was added to the reaction solution. The reaction mixture was reacted for 2 h to ensure that the reaction of the raw material was completed. The reaction solution was diluted by adding 30 mL of dichloromethane. The resulting mixture was washed with saturated saline. 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] Trifluoroacetic acid (10 equiv) was added to a solution of the Boc-protected product in dichloromethane. The reaction mixture was allowed to react at room temperature for 30 min. After the reaction was completed, the mixture was evaporated under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to obtain the trifluoroacetate salt of the target compound (732186) in powder form. 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 was added to the mixture. The resulting mixture was extracted three times with dichloromethane. The combined organic phases of dichloromethane 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] 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) was dissolved in dichloromethane, and EDCI (1.5 equiv) and DMAP (1.0 equiv) were added to the solution. The reaction system became clear. Compound 732170 prepared in step 1 was added to the reaction solution. The reaction mixture was reacted for 12 h to ensure that the reaction of the raw materials was completed. The reaction solution was diluted with 30 mL of dichloromethane. The resulting mixture was washed with saturated saline. 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] Trifluoroacetic acid (10 equiv) was added to a solution of the Boc-protected product in dichloromethane. The reaction mixture was allowed to react at room temperature for 30 min. After the reaction was completed, the mixture was evaporated under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to obtain the trifluoroacetate salt of the target compound (732187) in powder form. 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, 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 of Chinese patent publication number CN112707900A, the entire contents of which are incorporated herein by reference), and the compound (732001) prepared according to intermediate example 1 were used as raw 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; Found, 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 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 were used as starting materials to prepare the target compound (BCL-03147). 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, 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 raw materials to prepare 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; Found, 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; Found, 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 produced using the compound (732148) produced according to 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。

[0225] 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 according to Intermediate Example 4 and the intermediate compound (732180) as starting materials. 11H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 11.70 (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 produced using the compound (732150) produced 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; Found, 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 produced using the compound (732147) produced according to 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 produced using the compound (732148) produced according to 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; actual 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 according to 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, 1298.4250。

[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 according to 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; actual 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, 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 of Chinese Patent Publication No. CN112707900A, the entire contents of which are incorporated herein by reference) and intermediate compound (732180) as raw materials to prepare the target compound (BCL-03177). 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; Found, 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 produced using the compound (732185) produced 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; Found, 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 produced using the compound (732186) produced according to 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; found, 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 produced using the compound (732187) produced 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 raw 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 for C 65 H 71 ClF3N 10 O 10 S2 + [M+H] +, 1307.4431; actual 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 raw materials. 11H 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 for C 58 H 67 ClF3N8O9S2 + [M+H] + , 1175.4108; Found, 1175.4101.

[0249] Example 19: Preparation of 4-(4-(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 (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 raw 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] + , 1088.4465; Found, 1088.4469。

[0251] 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 raw 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 value C 64 H 71 ClN 11 O 10 S + [M+H] +, 1220.4789; actual 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 raw 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; Found, 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 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) were used as raw materials to prepare the target compound (BCL-03190). 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 valueC. 65 H 72 BrClF3N 10 O9S2 + [M+H] + , 1371.3744; actual 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; Found, 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; Found, 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 raw 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: calcd. 61 H 68 BrClF3N8O8S3 + [M+H] + , 1307.3141; measured value, 1307.3139. Biological activity test

[0265] Experimental recipes and materials TIFF2025503598000067.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 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 used are all commercially available or purchased from ATCC (American Type Culture Collection), and can be cultured according to the ATCC instructions. The cells used were identified as correct cells by STR before the experiment, and were detected as mycoplasma negative by a mycoplasma detection reagent kit.

[0270] Assessment of tumor cell proliferation 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 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 .ALPHA.-dependent RS4;11 cells [ka]

[0274] The specific steps are as follows: RS4;11 cells were cultured at 3 × 10 in 90 μl of serum-containing RPMI 1640 medium. 4Cells were seeded at 1000 / well, and DT2216 and the compound according to the present invention were added to the cell suspension in a concentration gradient. The positive control was DT2216, and the negative control was DMSO. The positive and negative controls were treated with the same treatment method as the compound according to the present invention. After 48 hours of treatment with the compound according to the present invention, 10 μl / well of thiazolyl blue solution (5 mg / mL) was added and the cells were cultured in an incubator at 37°C and 5% CO2 for 3 hours, and then triple solution (SDS, 0.1 g / mL, isopropyl alcohol, 5%, hydrochloric acid, 10 mM) was added and the cells were cultured in an incubator at 37°C and 5% CO2 for 4 to 6 hours. After the total dissolution of crystal violet was observed under an inverted microscope, the absorbance was measured at 490 nm using an Epoch microplate reader (Biotek). The growth inhibition curves of the compound according to the present invention against the experimental cells were plotted using GraphPad Prism 8 software, and the IC value of the compound according to the present invention was statistically calculated. 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 according to the present invention based on ABT199 / 263 on MV4;11 cell proliferation

[0276] The specific steps are as follows: MV4;11 cells were cultured in 90 μl of serum-containing IMDM medium at 2 × 10 4Cells were seeded at 1000 cells / well, and DT2216 and the compound according to the present invention were added to the cell suspension in a concentration gradient. The positive control was DT2216, and the negative control was DMSO. The positive and negative controls were treated with the same treatment method as the compound according to the present invention. After 48 hours of treatment with the compound according to the present invention, 10 μl / well of thiazolyl blue solution (5 mg / mL) was added and the cells were cultured in an incubator at 37°C and 5% CO2 for 3 hours, and then triple solution (SDS, 0.1 g / mL, isopropyl alcohol, 5%, hydrochloric acid, 10 mM) was added and the cells were cultured in an incubator at 37°C and 5% CO2 for 4 to 6 hours. After observing the total dissolution of crystal violet under an inverted microscope, the absorbance was measured at 490 nm using an Epoch microplate reader (Biotek). The growth inhibition curves of the compound according to the present invention against the experimental cells were plotted using GraphPad Prism 8 software, and the IC value of the compound according to the present invention was statistically calculated. 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 α-dependent Molt-4 cell proliferation

[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 / well, and DT2216 and the compound according to the present invention were added to the cell suspension in a concentration gradient. The positive control was DT 2216, and the negative control was DMSO. The positive and negative controls were treated with the same treatment method as the compound according to the present invention. After 72 hours of treatment with the compound according to the present invention, 20 μl / well of thiazolyl blue solution (5 mg / mL) was added and the cells were cultured in an incubator at 37°C and 5% CO2 for 3 hours, and then triple solution (SDS, 0.1 g / mL, isopropyl alcohol, 5%, hydrochloric acid, 10 mM) was added and the cells were cultured in an incubator at 37°C and 5% CO2 for 4 to 6 hours. After observing the total dissolution of crystal violet under an inverted microscope, the absorbance was measured at 490 nm using an Epoch microplate reader (Biotek). The growth inhibition curves of the compound according to the present invention against the experimental cells were plotted using GraphPad Prism 8 software, and the IC value of the compound according to the present invention was statistically calculated. 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 cloned 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 a 37°C, 5% CO2 incubator. 2.5 × 10 Light II cells in logarithmic growth phase 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 a 37°C, 5% CO2 incubator. 4The cells were seeded in a 96-well plate at 1000 / well, incubated for 24 hours, and then SAG and different concentrations of the compounds according to the present invention were added for 36 hours, after which the reaction was terminated. Detection was performed according to the instruction manual of the Dual luciferase reporter assay kit. This experiment had 3 wells per group and was repeated at least 3 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 6The cells were seeded at 1000 / well. The corresponding concentration of the compound according to the present invention was added to treat the cells. The solvent DMSO was used as the control group. After 10 hours of drug exposure, 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 4°C, 10krpm, 5 minutes, the supernatant was collected. An equal amount of protein supernatant and 4×LDS protein loading buffer were mixed uniformly at a volume ratio of 3:1, 5% β-mercaptoethanol was added, mixed with a vortex mixer, and then subjected to a metal bath at 95°C for 10 minutes, stored at -80°C, or directly cooled on ice for protein electrophoresis. The separation gel was a 10% homemade polyacrylamide gel. The electrophoresis tank and related components were purchased from Bio-Rad. The electrophoresis conditions were a low voltage of 80v for 45 minutes, followed by a high voltage of 120V for 1 hour. The membrane transfer was performed using a PVDF membrane and at a constant flow of 300mA in an ice-water bath for 1 hour. After the membrane transfer, the membrane was blocked with 5% skim milk at room temperature for 1 hour. The first antibody was then incubated overnight at 4°C or incubated at room temperature for 2 hours, washed three times with 1xTBST buffer (sodium chloride, 150mM, Tris, 10mM, Tween (registered trademark) 20, 0.1%, PH7.4), and then the second antibody was added, incubated at room temperature for 45 minutes, washed three times with 1xTBST buffer (sodium chloride, 150mmol, Tris, 10mM, Tween (registered trademark) 20, 0.1%, PH7.4), and allowed to develop. The antibody dilution ratio was determined by referring to the antibody instruction manual.

[0283] Experimental Results

[0284] The specific experimental data is as follows:

[0285] 1 BCL-X L Study of the compounds according to the present invention based on ABT199 / 263 against 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 . After treating the cells with different concentrations of the compounds (starting from 1000nM or 100nM, seven concentrations were obtained with a 10-fold dilution gradient) for 48 hours, the cells were measured by thiazolyl blue cell proliferation experiment. The experiment was repeated three times or more. The specific results are shown in Table 3.

[0287] 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) could effectively inhibit the proliferation of RS4;11 tumor cells (Table 3). The IC of DT2216 against RS4;11 cells 50 The inhibitory effect of the compound according to the present invention developed by us was significantly superior to that of DT2216. Table 3. IC of compounds according to the invention based on the ABT-199 / 263 series in RS4;11 (human acute lymphoblastic leukemia cell line) 50 (50% inhibitory concentration) [Table 3] DT2216 (CAS number: 2365172-42-3) is a BCL-X inhibitor reported in the literature. L It is a decomposition 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 the compounds in Examples 1-26) designed and developed by us can effectively inhibit the proliferation of myelomonocytic leukemia cells MV4;11 (Table 4), and the IC 50 The inhibitory effect of the compounds according to the present invention, which were developed based on ABT-199 / 263, was significantly superior to that of DT2216. Table 4. IC of compounds according to the present invention based on the ABT-199 / 263 series in myelomonocytic leukemia cells MV4;11 50 (nM, half inhibitory concentration) [Table 4]

[0289] The compounds according to the present invention based on ABT-199 / 263 that we designed and developed (including the compounds in Tables 1-2 and the compounds in Examples 1-26) were able to effectively inhibit the proliferation of human lymphocytic leukemia cells Molt-4 (Table 5). The inhibitory effects of the compounds according to 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 lymphocytic leukemia cells Molt-4 50 (nM, half inhibitory concentration) [Table 5]

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

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

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

[0294] The above text describes the basic principle, 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 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 are within the scope of the present invention that is 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, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, comprising: 【Chemistry 1】 Formula (I) Where: The dotted line indicates the optional presence of a double bond; R １ , R ２ , R ３ , R ４ are the same or different and each independently represent hydrogen, C １－４ Alkyl, halogen, or halogenated C １－４ represents alkyl; (R ５ ) ｎ R has n benzene rings. ５ Each R ５ are the same or different and each independently represents a halogen, C １－６ Alkyl or halogenated C １－６ alkyl, n is an integer of 1, 2, 3, 4, or 5; (R ６ ) ｍ R has m piperazine rings. ６ Each R ６ are the same or different and each independently represents a halogen, C １－６ Alkyl or halogenated C １－６ alkyl, m is an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8; R ７ is hydrogen or 【Chemistry 2】 represents; R ８ is hydrogen or -SO ２ CF ３ OR - NO ２ represents; R ９ is hydrogen or C １－４ represents alkyl; R １０ is the following group: 【Chemistry 3】 represents Here, the ring W １ represents a 4- to 6-membered nitrogen-containing heterocyclylene; ａ１ ) ｎ１ Is Ring W １ There are n1 R ａ１ Each R ａ１ are the same or different and each independently represent C １－６ Alkyl, halogenated C １－６ Alkyl, C １－６ an 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 Is Ring W ２ There are n2 R ａ２ Each R ａ２ are the same or different and each independently represent C １－６ Alkyl, halogenated C １－６ Alkyl, C １－６ an alkoxy, cyano, halogen, or oxo group, and n2 represents an integer of 0-8; and The symbol * indicates the connection point with LIN; LIN is, Optionally substituted linear or branched C １－３０ represents alkylene; or One or more groups R ｂ and / or one or more groups R ｃ or one or more groups R ｂ YR ｃ Optionally substituted linear or branched C ２－３０ alkylene, where 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) ２ NH, 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 an alkyl group, and ２－３０ Two or more groups R ｂ When 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 the cycloalkylene, the arylene, the heterocyclylene, and the 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, aryl, aryloxy ... R １１ has the following structural formula (II): 【Chemistry 4】 Formula (II) represents Here, R １２ is N(R ｅ ), O.S., C. ２－６ Alkynylene, or C ２－６ alkenylene, where R ｅ is H or C １－６ represents alkyl, or R １２ represents a bond; (R ａ ) ｔ R has t benzene rings. ａ Each R ａ are the same or different and each independently represent bromine, t represents an integer of 0, 1, 2, or 3; and X is C(O) or CH ２ represents; Here, when t represents an integer equal to 0, R ７ but 【Chemistry 5】 When n1 represents an integer of 1 to 8, and each R ａ１ are the same or different and each independently represent C １－６ Alkyl, halogenated C １－６ Alkyl, C １－６ alkoxy, or halogen; or R ７ but 【Chemistry 6】 When R ８ Ha-SO ２ CF ３ or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, of formula (I) which represents:

2. It is also a compound of formula (I-1), 【Chemistry 7】 Formula (I-1) Here, R １ , R ２ , R ３ , R ４ , (R ５ ) ｎ , (R ６ ) ｍ , R ７ , R ８ , R ９ , R １０ , L.I.N., R. １２ , (R ａ ) ｔ and X is as defined in claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof.

3. It is also a compound of formula (I-2) or formula (I-3), 【Chemistry 8】 Formula (I-2) 【Chemistry 9】 Formula (I-3) Here, R １ , R ２ , R ３ , R ４ , (R ５ ) ｎ , (R ６ ) ｍ , R ８ , R ９ , R １０ , L.I.N., R. １２ , (R ａ ) ｔ and X is as defined in claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof.

4. 2. The compound of formula (I) according to claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, wherein t represents an integer of 1, 2 or 3.

5. 2. The compound of formula (I) according to claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, wherein t represents an integer equal to 0.

6. It is also a compound of formula (I-2-1): 【Chemistry 12】 Formula (I-2-1) Where: R １０ is the following group: 【Chemistry 13】 represents Here, the ring W １ represents a 4- to 6-membered nitrogen-containing heterocyclylene; ａ１ ) ｎ１ Is Ring W １ There are n1 R ａ１ group, each R ａ１ are the same or different and each independently represent C １－６ Alkyl, halogenated C １－６ Alkyl, C １－６ alkoxy, cyano, or halogen, and n1 represents an integer of 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 Is Ring W ２ There are n2 R ａ２ R represents a group substituted with ａ２ are the same or different and each independently represent C １－６ Alkyl, halogenated C １－６ Alkyl, C １－６ an alkoxy, cyano, halogen, or oxo group, and n2 represents an integer of 0-8; and The symbol * represents the connection point with LIN; and R １ , R ２ , R ３ , R ４ , (R ５ ) ｎ , (R ６ ) ｍ , R ８ , R ９ , L.I.N., R. １２ and X is as defined in claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof.

7. R １０ is the following group: 【Chemistry 14】 represents; 7. A compound of formula (I) according to claim 6, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, wherein the symbol * represents the point of attachment to LIN.

8. It is also a compound of formula (I-2-1): 【Chemistry 15】 Formula (I-2-1) Where: R ８ Ha-SO ２ CF ３ represents; and R １ , R ２ , R ３ , R ４ , (R ５ ) ｎ , (R ６ ) ｍ , R ９ , R １０ , L.I.N., R. １２ and X is as defined in claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof.

9. R １０ is the following group: 【Chemistry 16】 represents Here, the ring W １ represents a 4- to 6-membered nitrogen-containing heterocyclylene, such as piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, or thiomorpholinylene; (R ａ１ ) ｎ１ Is Ring W １ There are n1 R ａ１ group, each R ａ１ are the same or different and each independently represent C １－６ Alkyl, halogenated C １－６ Alkyl, C １－６ alkoxy, cyano, halogen, or oxo group, and n1 represents an integer of 0, 1, 2, 3, or 4; Ring W ２ is a 4- to 6-membered nitrogen-containing heterocyclylene, or C ３－６ represents cycloalkylene, said 4- to 6-membered nitrogen-containing heterocyclylene including, for example, piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, or thiomorpholinylene, said 4- to 6-membered cycloalkylene including, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; n3 represents an integer of 0 or 1; (R ａ２ ) ｎ２ Is Ring W ２ There are n2 R ａ２ group, each R ａ２ are the same or different and each independently represent C １－６ Alkyl, halogenated C １－６ Alkyl, C １－６ alkoxy, cyano, halogen, or oxo group, and n2 represents an integer of 0, 1, 2, 3, or 4; and 2. A compound of formula (I) according to claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, wherein the symbol * represents the point of attachment to LIN.

10. R １０ is the following group: 【Chemistry 17】 represents A compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof according to any one of claims 1-5 and 8-9, wherein the symbol * represents the connection point with LIN.

11. R １ and R ２ represents hydrogen, and R ３ and R ４ 2. The compound of formula (I) according to claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, wherein represents methyl.

12. R １ and R ２ represents methyl, and R ３ and R ４ 2. The compound of formula (I) according to claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, wherein represents hydrogen.

13. R １１ is represented by the following structural 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): 【Chemistry 10】 where: R １２ is N(R ｅ ), O.S., C. ２－６ Alkynylene, or C ２－６ alkenylene, where R ｅ is H or C １－６ represents alkyl, or R １２ represents a bond; X is C(O) or CH ２ represents; and (R ａ ) ｔ R has t benzene rings. ａ 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, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, of formula (I) according to claim 1 .

14. R １１ is a structure of the formula: 【Chemistry 11】 2. A compound of formula (I) according to claim 1, which represents:

15. The LIN has the structure: #-C １－３０ Alkylene-; #-(C(R ａ３ )(R ａ４ )) 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 ａ５ )(R ａ６ )) ｎ５ ) ｍ１ -(R ｃ -(C(R ａ７ )(R ａ８ )) ｎ６ ) ｍ２ -; #-(C(R ａ３ ) (R ａ４ )) ｎ４ - (R ｃ -R ｂ -(C(R ａ５ ) (R ａ６ )) ｎ５ ) ｍ１ - or #-(C(R ａ３ ) (R ａ４ )) ｎ４ - (R ｃ -(C(R ａ５ ) (R ａ６ )) ｎ５ ) ｍ１ - (R ｂ -(C(R ａ７ ) (R ａ８ )) ｎ６ ) ｍ２ - represents Here, each group R ｂ is O, N (R ｄ ), C(O), C(O)O, OC(O), S(O), S(O) ２ , S(O) ２ NH, 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 are independently H or C １－６ each group R 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 the cycloalkylene, the arylene, the heterocyclylene, and the heteroarylene, independently of each other, further comprise: １－６ Alkyl, halogenated C １－６ Alkyl, halogen, C １－６ Optionally substituted with a substituent selected from the group consisting of alkoxy, aryl, aryloxy ... Said C １－３０ One or more CH of alkylene ２ The hydrogen of is further １－６ Alkyl, halogenated C １－６ Alkyl, halogen, C １－６ alkoxy, 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, halogenated C １－６ Alkyl, halogen, or C １－６ represents alkoxy; n4, n5, n6, n7, m1, m2, and m3 are each independently selected from the group consisting of integers of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and The symbol # is the group R １０ 15. A compound of formula (I) according to any one of claims 1-14, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, which represents a junction point with

16. The LIN has the structure: #-(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 represents alkyl; The cycloalkylene (e.g., C ３－２０ cycloalkylene), the arylene (e.g., C ３－２０ arylene), the heterocyclylene (e.g., 4- to 20-membered heterocyclylene) and the heteroarylene (e.g., 4- to 20-membered 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, aryl, aryloxy ... 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, halogenated C １－６ Alkyl, halogen, or C １－６ represents alkoxy; n4, n5, n6, n7, m1, m2, and m3 are each independently selected from the group consisting of integers of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and The symbol # is the group R １０ 15. A compound of formula (I) according to any one of claims 1-14, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, which represents a junction point with

17. wherein LIN is a group as follows: #-CH ２ -, #-(CH ２ ) ２ -, #-(CH ２ ) ３ -, #-(CH ２ ) ４ -, #-(CH ２ ) ５ -, #-(CH ２ ) ６ -, #-(CH ２ ) ７ -, #-(CH ２ ) ８ -, #-(CH ２ ) ９ -, #-(CH ２ ) １０ -, #-(CH ２ ) １１ -, #-(CH ２ ) １２ -, #-(CH ２ ) １３ -, #-(CH ２ ) １４ -, #-(CH ２ ) １５ -, #-(CH ２ ) １６ -, #-(CH ２ ) １７ -, #-(CH ２ ) １８ -, #-(CH ２ ) １９ -, #-(CH ２ ) ２０ -, #-(CH ２ ) ２１ -, #-(CH ２ ) ２２ -, #-(CH ２ ) ２５ -, or #-(CH ２ ) ３０ -; #-CH ２ -O-CH ２ -, #-CH ２ -O-(CH ２ ) ２ -, #-(CH ２ ) １ -O-(CH ２ ) ３ -, #-(CH ２ ) １ -O-(CH ２ ) ４ -、#-(CH ２ ) １ -O-(CH ２ ) ５ -、#-(CH ２ ) １ -O-(CH ２ ) ６ -、#-(CH ２ ) １ -O-(CH ２ ) ７ -、#-(CH ２ ) １ -O-(CH ２ ) ８ -、#-(CH ２ ) １ -O-(CH ２ ) ９ -、#-(CH ２ ) １ -O-(CH ２ ) １０ -、#-(CH ２ ) ２ -O-(CH ２ ) １ -、#-(CH ２ ) ２ -O-(CH ２ ) ２ -、#-(CH ２ ) ２ -O-(CH ２ ) ３ -、#-(CH ２ ) ２ -O-(CH ２ ) ４ -、#-(CH ２ ) ２ -O-(CH ２ ) ５ -、#-(CH ２ ) ２ -O-(CH ２ ) ６ -、#-(CH ２ ) ２ -O-(CH ２ ) ７ -、#-(CH ２ ) ２ -O-(CH ２ ) ８ -、#-(CH ２ ) ２ -O-(CH ２ ) ９ -、#-(CH ２ ) ２ -O-(CH ２ ) １０ -、#-(CH ２ ) ２ -O-(CH ２ ) １１ -、#-(CH ２ ) ２ -O-(CH ２ ) １２ -、#-(CH ２ ) ３ -O-(CH ２ ) １ -、#-(CH ２ ) ３ -O-(CH ２ ) ２ -、#-(CH ２ ) ３ -O-(CH ２ ) ３ -、#-(CH ２ ) ３ -O-(CH ２ ) ４ -、#-(CH ２ ) ３ -O-(CH ２ ) ５ -、#-(CH ２ ) ３ -O-(CH ２ ) ６ -、#-(CH ２ ) ３ -O-(CH ２ ) ７ -、#-(CH ２ ) ４ -O-(CH ２ ) １ -、#-(CH ２ ) ４ -O-(CH ２ ) ２ -、#-(CH ２ ) ４ -O-(CH ２ ) ３ -、#-(CH ２ ) ４ -O-(CH ２ ) ４ -、#-(CH ２ ) ４ -O-(CH ２ ) ５ -、#-(CH ２ ) ４ -O-(CH ２ ) ６ -、#-(CH ２ ) ５ -O-(CH ２ ) １ -、#-(CH ２ ) ５ -O-(CH ２ ) ２ -、#-(CH ２ ) ５ -O-(CH ２ ) ３ -、#-(CH ２ ) ５ -O-(CH ２ ) ４ -、#-(CH ２ ) ５ -O-(CH ２ ) ５ -、#-(CH ２ ) ６ -O-(CH ２ ) １ -、#-(CH ２ ) ６ -O-(CH ２ ) ２ -、#-(CH ２ ) ６ -O-(CH ２ ) ３ -、#-(CH ２ ) ６ -O-(CH ２ ) ４ -、#-(CH ２ ) ７ -O-(CH ２ ) １ -、#-(CH ２ ) ７ -O-(CH ２ ) ２ -、#-(CH ２ ) ７ -O-(CH ２ ) ３ -、#-(CH ２ ) ８ -O-(CH ２ ) １ -、#-(CH ２ ) ８ -O-(CH ２ ) ２ -、#-CH(CH ３ )-O-(CH ２ ) １ -、#-CH(CH ３ )-O-(CH ２ ) ２ -、#-CH(CH ３ )-O-(CH ２ ) ３ -、#-CH(CH ３ )-O-(CH ２ ) ４ -、#-CH(CH ３ )-O-(CH ２ ) ５ -、#-CH(CH ３ )-O-(CH ２ ) ６ -、#-CH(CH ３ )-O-(CH ２ ) ７ -、#-CH(CH ３ )-O-(CH ２ ) ８ -、#-CH(CH ３ )-O-(CH ２ ) ９ -、#-CH(CH ３ )-O-(CH ２ ) １０ -、#-CH ２ -(O(CH ２ ) ２ ) ２ -、#-CH ２ -(O(CH ２ ) ２ ) ３ -、#-CH ２ -(O(CH ２ ) ２ ) ４ -、#-CH ２ -(O(CH ２ ) ２ ) ５ -、#-CH ２ -(O(CH ２ ) ２ ) ６ -、#-CH ２ -(O(CH ２ ) ２ ) ７ -、#-H ２ -(O(CH ２ ) ２ ) ８ -、#-H ２ -(O(CH ２ ) ２ ) ９ -、#-H ２ -(O(CH ２ ) ２ ) １０ -、#-H ２ -(O(CH ２ ) ２ ) １ -OCH ２ -、#-H ２ -(O(CH ２ ) ２ ) ２ -OCH ２ -、#-H ２ -(O(CH ２ ) ２ ) ３ -OCH ２ -、#-H ２ -(O(CH ２ ) ２ ) ４ -OCH ２ -、#-H ２ -(O(CH ２ ) ２ ) ５ -OCH ２ -、#-H ２ -(O(CH ２ ) ２ ) ６ -OCH ２ -、#-H ２ -(O(CH ２ ) ２ ) ７ -OCH ２ -、#-H ２ -(O(CH ２ ) ２ ) ８ -OCH ２ -、#-H ２ -(O(CH ２ ) ２ ) ９ -OCH ２ -、#-H ２ -(O(CH ２ ) ２ ) １０ -OCH ２ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ２ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ３ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ４ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ５ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ６ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ７ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ８ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ９ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) １０ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ２ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ３ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ４ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ５ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ６ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ７ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ８ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ９ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) １０ -、#-(CH ２ ) ４ -(O(CH ２ ) ２ ) ２ -、#-(CH ２ ) ４ -(O(CH ２ ) ２ ) ３ -、#-(CH ２ ) ４ -(O(CH ２ ) ２ ) ４ -、#-(CH ２ ) ４ -(O(CH ２ ) ２ ) ５ -、#-(CH ２ ) ４ -(O(CH ２ ) ２ ) ６ -、#-(CH ２ ) ４ -(O(CH ２ ) ２ ) ７ -、#-(CH ２ ) ４ -(O(CH ２ ) ２ ) ８ -、#-(CH ２ ) ４ -(O(CH ２ ) ２ ) ９ -、#-(CH ２ ) ４ -(O(CH ２ ) ２ ) １０ -、#-CH ２ -(O(CH ２ ) ３ ) ２ -、#-CH ２ -(O(CH ２ ) ３ ) ３ -、#-CH ２ -(O(CH ２ ) ３ ) ４ -、#-CH ２ -(O(CH ２ ) ３ ) ５ -、#-CH ２ -(O(CH ２ ) ３ ) ６ -、#-CH ２ -(O(CH ２ ) ３ ) ７ -、#-CH ２ -(O(CH ２ ) ３ ) ８ -、#-CH ２ -(O(CH ２ ) ３ ) ９ -、#-CH ２ -(O(CH ２ ) ３ ) １０ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ２ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ３ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ４ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ５ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ６ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ７ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ８ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ９ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) １０ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ２ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ３ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ４ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ５ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ６ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ７ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ８ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ９ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) １０ -、#-CH ２ -O-(CH ２ ) ２ -O-(CH ２ ) ３ -、#-CH ２ -(O(CH ２ ) ２ ) ２ -(O(CH ２ ) ３ ) ２ -、#-CH ２ -(O(CH ２ ) ２ ) ３ -(O(CH ２ ) ３ ) ３ -、#-CH ２ -(O(CH ２ ) ２ ) ４ -(O(CH ２ ) ３ ) ４ -、#-CH ２ -(O(CH ２ ) ２ ) ５ -(O(CH ２ ) ３ ) ５ -、#-CH ２ -(O(CH ２ ) ２ ) ６ -(O(CH ２ ) ３ ) ６ -、#-(CH ２ ) ２ -O-(CH ２ ) ２ -O-(CH ２ ) ３ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ２ -(O(CH ２ ) ３ ) ２ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ３ -(O(CH ２ ) ３ ) ３ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ４ -(O(CH ２ ) ３ ) ４ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ５ -(O(CH ２ ) ３ ) ５ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ６ -(O(CH ２ ) ３ ) ６ -、#-(CH ２ ) ３ -O-(CH ２ ) ２ -O-(CH ２ ) ３ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ２ -(O(CH ２ ) ３ ) ２ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ３ -(O(CH ２ ) ３ ) ３ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ４ -(O(CH ２ ) ３ ) ４ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ５ -(O(CH ２ ) ３ ) ５ -、#-(CH ２ ) ３ -(O(CH ２ ) ２ ) ６ -(O(CH ２ ) ３ ) ６ -、#-CH ２ -O-(CH ２ ) ３ -O-(CH ２ ) ２ -、#-CH ２ -(O(CH ２ ) ３ ) ２ -(O(CH ２ ) ２ ) ２ -、#-CH ２ -(O(CH ２ ) ３ ) ３ -(O(CH ２ ) ２ ) ３ -、#-CH ２ -(O(CH ２ ) ３ ) ４ -(O(CH ２ ) ２ ) ４ -、#-CH ２ -(O(CH ２ ) ３ ) ５ -(O(CH ２ ) ２ ) ５ -、#-CH ２ -(O(CH ２ ) ３ ) ６ -(O(CH ２ ) ２ ) ６ -、#-(CH ２ ) ２ -O-(CH ２ ) ３ -O-(CH ２ ) ２ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ２ -(O(CH ２ ) ２ ) ２ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ３ -(O(CH ２ ) ２ ) ３ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ４ -(O(CH ２ ) ２ ) ４ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ５ -(O(CH ２ ) ２ ) ５ -、#-(CH ２ ) ２ -(O(CH ２ ) ３ ) ６ -(O(CH ２ ) ２ ) ６ -、#-(CH ２ ) ３ -O-(CH ２ ) ３ -O-(CH ２ ) ２ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ２ -(O(CH ２ ) ２ ) ２ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ３ -(O(CH ２ ) ２ ) ３ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ４ -(O(CH ２ ) ２ ) ４ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ５ -(O(CH ２ ) ２ ) ５ -、#-(CH ２ ) ３ -(O(CH ２ ) ３ ) ６ -(O(CH ２ ) ２ ) ６ -、#-CH ２ -O-(CH ２ ) ２ -O-CH ２ -、#-(CH ２ ) ２ -O-(CH ２ ) ２ -O-CH ２ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ２ -O-(CH ２ ) ３ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ３ -O-(CH ２ ) ３ -、#-(CH ２ ) ２ -(O(CH ２ ) ２ ) ４ -O-(CH ２ ) ３ -、#-(CH ２ ) ５ -(O(CH ２ ) ２ ) ２ -O-(CH ２ ) ５ -、#-(CH ２ ) ５ -(O(CH ２ ) ２ ) ２ -O-(CH ２ ) ６ -、#-(CH ２ ) １ -N(R ｇ )-(CH ２ ) １ -、#-(CH ２ ) １ -N(R ｇ )-(CH ２ ) ２ -、#-(CH ２ ) １ -N(R ｇ )-(CH ２ ) ３ -、#-(CH ２ ) １ -N(R ｇ )-(CH ２ ) ４ -、#-(CH ２ ) １ -N(R ｇ )-(CH ２ ) ５ -、#-(CH ２ ) １ -N(R ｇ )-(CH ２ ) ６ -、#-(CH ２ ) １ -N(R ｇ )-(CH ２ ) ７ -、#-(CH ２ ) １ -N(R ｇ )-(CH ２ ) ８ -、#-(CH ２ ) １ -N(R ｇ )-(CH ２ ) ９ -、#-(CH ２ ) １ -N(R ｇ )-(CH ２ ) １０ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) １ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) ２ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) ３ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) ４ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) ５ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) ６ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) ７ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) ８ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) ９ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) １０ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) １１ -、#-(CH ２ ) ２ -N(R ｇ )-(CH ２ ) １２ -、#-(CH ２ ) ３ -N(R ｇ )-(CH ２ ) １ -、#-(CH ２ ) ３ -N(R ｇ )-(CH ２ ) ２ -、#-(CH ２ ) ３ -N(R ｇ )-(CH ２ ) ３ -、#-(CH ２ ) ４ -N(R ｇ )-(CH ２ ) １ -、#-(CH ２ ) ４ -N(R ｇ )-(CH ２ ) ２ -、#-(CH ２ ) ４ -N(R ｇ )-(CH ２ ) ３ -、#-(CH ２ ) ４ -N(R ｇ )-(CH ２ ) ４ -、#-(CH ２ ) ５ -N(R ｇ )-(CH ２ ) １ -、#-(CH ２ ) ５ -N(R ｇ )-(CH ２ ) ２ -、#-(CH ２ ) ５ -N(R ｇ )-(CH ２ ) ３ -、#-(CH ２ ) ５ -N(R ｇ )-(CH ２ ) ４ -、#-(CH ２ ) ５ -N(R ｇ )-(CH ２ ) ５ -、#-(CH ２ ) ６ -N(R ｇ )-(CH ２ ) １ -、#-(CH ２ ) ６ -N(R ｇ )-(CH ２ ) ２ -、#-(CH ２ ) ６ -N(R ｇ )-(CH ２ ) ３ -、#-(CH ２ ) ７ -N(R ｇ )-(CH ２ ) １ -、#-(CH ２ ) ７ -N(R ｇ )-(CH ２ ) ２ -、#-(CH ２ ) ７ -N(R ｇ )-(CH ２ ) ３ -、#-(CH ２ ) ８ -N(R ｇ )-(CH ２ ) １ -、#-(CH ２ ) ８ -N(R ｇ )-(CH ２ ) ２ -、#-(CH ２ ) ８ -N(R ｇ )-(CH ２ ) ３ -、#-CH(CH ３ )-N(R ｇ )-(CH ２ ) １ -、#-CH(CH ３ )-N(R ｇ )-(CH ２ ) ２ -、#-CH(CH ３ )-N(R ｇ )-(CH ２ ) ３ -、#-CH(CH ３ )-N(R ｇ )-(CH ２ ) ４ -、#-CH(CH ３ )-N(R ｇ )-(CH ２ ) ５ -、#-CH(CH ３ )-N(R ｇ )-(CH ２ ) ６ -、#-CH(CH ３ )-N(R ｇ )-(CH ２ ) ７ -、#-CH(CH ３ )-N(R ｇ )-(CH ２ ) ８ -、#-CH(CH ３ )-N(R ｇ )-(CH ２ ) ９ -、#-CH(CH ３ )-N(R ｇ )-(CH ２ ) １０ -、#-CH ２ C(O)NHCH ２ -、#-(CH ２ ) ２ C(O)NH(CH ２ ) ２ -、#-(CH ２ ) ２ C(O)NH(CH ２ ) ３ -、#-(CH ２ ) ２ C(O)NH(CH ２ ) ４ -、#-(CH ２ ) ２ C(O)NH(CH ２ ) ５ -、#-(CH ２ ) ３ P.S. ２ ) ３ -、#-(CH ２ ) ３ P.S. ２ ) ４ -、#-(CH ２ ) ４ P.S. ２ ) ４ -、#-(CH ２ ) ５ P.S. ２ ) ５ -、#-(CH ２ ) ６ P.S. ２ ) ７ -、#-(CH ２ ) ６ P.S. ２ ) ６ -、#-(CH ２ ) ７ P.S. ２ ) ７ -、#-(CH ２ ) ８ P.S. ２ ) ８ (CH) ２ ) ９ P.S. ２ ) ９ -、#-(CH ２ ) １０ P.S. ２ ) １０ -、#-(CH ２ ) ２ P.S. ２ ) ２ -O-(CH ２ ) ２ -、#-CH ２ I'm sorry ２ -、#-(CH ２ ) ２ I'm sorry ２ ) ２ -、#-(CH ２ ) ２ I'm sorry ２ ) ３ -、#-(CH ２ ) ２ I'm sorry ２ ) ４ -、#-(CH ２ ) ２ I'm sorry ２ ) ５ -、#-(CH ２ ) ３ I'm sorry ２ ) ３ -、#-(CH ２ ) ３ I'm sorry ２ ) ４ -、#-(CH ２ ) ４ I'm sorry ２ ) ４ -、#-(CH ２ ) ５ I'm sorry ２ ) ５ -、#-(CH ２ ) ６ I'm sorry ２ ) ７ -、#-(CH ２ ) ６ I'm sorry ２ ) ６ -、#-(CH ２ ) ７ I'm sorry ２ ) ７ -、#-(CH ２ ) ８ I'm sorry ２ ) ８ #-(CH ２ ) ９ I'm sorry ２ ) ９ -、#-(CH ２ ) １０ I'm sorry ２ ) １０ -、#-(CH ２ ) ４ I'm sorry ２ ) ８ -、#-(CH ２ ) ２ I'm sorry ２ ) ２ -O-(CH ２ ) ２ -, #- (CH ２ ) ４ NHC(O)CH ２ -, #-CH ２ -piperidinylene-CH ２ -, #-CH ２ -piperidinylene-(CH ２ ) ２ -, #-CH ２ -piperidinylene-(CH ２ ) ３ -, #-CH ２ -piperidinylene-(CH ２ ) ４ -, #-CH ２ -piperidinylene-(CH ２ ) ５ -, #-CH ２ -piperidinylene-(CH ２ ) ６ -, #-CH ２ -piperidinylene-(CH ２ ) ７ -, #-CH ２ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ２ -piperidinylene-(CH ２ ) １ -, #- (CH ２ ) ２ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ２ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ２ -piperidinylene-(CH ２ ) ４ -, #- (CH ２ ) ２ -piperidinylene-(CH ２ ) ５ -, #- (CH ２ ) ２ -piperidinylene-(CH ２ ) ６ -, #- (CH ２ ) ２ -piperidinylene-(CH ２ ) ７ -, #- (CH ２ ) ２ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ３ -piperidinylene-CH ２ -, #- (CH ２ ) ３ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ３ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ３ -piperidinylene-(CH ２ ) ４ -, #- (CH ２ ) ３ -piperidinylene-(CH ２ ) ５ -, #- (CH ２ ) ３ -piperidinylene-(CH ２ ) ６ -, #- (CH ２ ) ３ -piperidinylene-(CH ２ ) ７ -, #- (CH ２ ) ３ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ４ -piperidinylene-CH ２ -, #- (CH ２ ) ４ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ４ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ４ -piperidinylene-(CH ２ ) ４ -, #- (CH ２ ) ４ -piperidinylene-(CH ２ ) ５ -, #- (CH ２ ) ４ -piperidinylene-(CH ２ ) ６ -, #- (CH ２ ) ４ -piperidinylene-(CH ２ ) ７ -, #- (CH ２ ) ４ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ５ -piperidinylene-(CH ２ ) １ -, #- (CH ２ ) ５ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ５ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ５ -piperidinylene-(CH ２ ) ４ -, #- (CH ２ ) ５ -piperidinylene-(CH ２ ) ５ -, #- (CH ２ ) ５ -piperidinylene-(CH ２ ) ６ -, #- (CH ２ ) ５ -piperidinylene-(CH ２ ) ７ -, #- (CH ２ ) ５ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ６ -piperidinylene-(CH ２ ) １ -, #- (CH ２ ) ６ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ６ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ６ -piperidinylene-(CH ２ ) ４ -, #- (CH ２ ) ６ -piperidinylene-(CH ２ ) ５ -, #- (CH ２ ) ６ -piperidinylene-(CH ２ ) ６ -, #- (CH ２ ) ６ -piperidinylene-(CH ２ ) ７ -, #- (CH ２ ) ６ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ７ -piperidinylene-(CH ２ ) １ -, #- (CH ２ ) ７ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ７ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ７ -piperidinylene-(CH ２ ) ４ -, #- (CH ２ ) ７ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ８ -piperidinylene-CH ２ -, #- (CH ２ ) ８ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ８ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ８ -piperidinylene-(CH ２ ) ４ -, #- (CH ２ ) ８ -piperidinylene-(CH ２ ) ５ -, #- (CH ２ ) ８ -piperidinylene-(CH ２ ) ６ -, #- (CH ２ ) ８ -piperidinylene-(CH ２ ) ７ -, #- (CH ２ ) ８ -piperidinylene-(CH ２ ) ８ -, #-CH ２ -N(R ｇ )-CH ２ -piperidinylene-CH ２ -, #-CH ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ２ -, #-CH ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ３ -, #-CH ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ４ -, #-CH ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ５ -, #-CH ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ６ -, #-CH ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ７ -, #-CH ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ８ -, #-CH ２ -N(R ｇ )-(CH ２ ) ２ -piperidinylene-CH ２ -, #-CH ２ -N(R ｇ )-(CH ２ ) ２ -piperidinylene-(CH ２ ) ２ -, #-CH ２ -N(R ｇ )-(CH ２ ) ２ -piperidinylene-(CH ２ ) ３ -, #-CH ２ -N(R ｇ )-(CH ２ ) ２ -piperidinylene-(CH ２ ) ４ -, #-CH ２ -N(R ｇ )-(CH ２ ) ２ -piperidinylene-(CH ２ ) ５ -, #-CH ２ -N(R ｇ )-(CH ２ ) ２ -piperidinylene-(CH ２ ) ６ -, #-CH ２ -N(R ｇ )-(CH ２ ) ２ -piperidinylene-(CH ２ ) ７ -, #-CH ２ -N(R ｇ )-(CH ２ ) ２ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ２ -N(R ｇ )-CH ２ -piperidinylene-CH ２ -, #- (CH ２ ) ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ４ -, #- (CH ２ ) ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ５ -, #- (CH ２ ) ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ６ -, #- (CH ２ ) ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ７ -, #- (CH ２ ) ２ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ３ -N(R ｇ )-CH ２ -piperidinylene-CH ２ -, #- (CH ２ ) ３ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ３ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ３ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ４ -N(R ｇ )-CH ２ -piperidinylene-CH ２ -, #- (CH ２ ) ４ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ４ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ４ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ５ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ５ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ６ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ６ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ７ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ７ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ８ -, #- (CH ２ ) ８ -N(R ｇ )-CH ２ -piperidinylene-CH ２ -, #- (CH ２ ) ８ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ２ -, #- (CH ２ ) ８ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ３ -, #- (CH ２ ) ８ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ４ -, #- (CH ２ ) ８ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ５ -, #- (CH ２ ) ８ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ６ -, #- (CH ２ ) ８ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ７ -, #- (CH ２ ) ８ -N(R ｇ )-CH ２ -piperidinylene-(CH ２ ) ８ -, #-CH ２ -piperazinylene-CH ２ -, #-CH ２ -Piperazinylene-(CH ２ ) ２ -, #-CH ２ -Piperazinylene-(CH ２ ) ３ -, #-CH ２ -Piperazinylene-(CH ２ ) ４ -, #-CH ２ -Piperazinylene-(CH ２ ) ５ -, #-CH ２ -Piperazinylene-(CH ２ ) ６ -, #-CH ２ -Piperazinylene-(CH ２ ) ７ -, #-CH ２ -Piperazinylene-(CH ２ ) ８ -, #- (CH ２ ) ２ -Piperazinylene-(CH ２ ) １ -, #- (CH ２ ) ２ -Piperazinylene-(CH ２ ) ２ -, #- (CH ２ ) ２ -Piperazinylene-(CH ２ ) ３ -, #- (CH ２ ) ２ -Piperazinylene-(CH ２ ) ４ -, #- (CH ２ ) ２ -Piperazinylene-(CH ２ ) ５ -, #- (CH ２ ) ２ -Piperazinylene-(CH ２ ) ６ -, #- (CH ２ ) ２ -Piperazinylene-(CH ２ ) ７ -, #- (CH ２ ) ２ -Piperazinylene-(CH ２ ) ８ -, #- (CH ２ ) ３ -piperazinylene-CH ２ -, #- (CH ２ ) ３ -Piperazinylene-(CH ２ ) ２ -, #- (CH ２ ) ３ -Piperazinylene-(CH ２ ) ３ -, #- (CH ２ ) ３ -Piperazinylene-(CH ２ ) ４ -, #- (CH ２ ) ３ -Piperazinylene-(CH ２ ) ５ -, #- (CH ２ ) ３ -Piperazinylene-(CH ２ ) ６ -, #- (CH ２ ) ３ -Piperazinylene-(CH ２ ) ７ -, #- (CH ２ ) ３ -Piperazinylene-(CH ２ ) ８ -, #- (CH ２ ) ４ -piperazinylene-CH ２ -, #- (CH ２ ) ４ -Piperazinylene-(CH ２ ) ２ -, #- (CH ２ ) ４ -Piperazinylene-(CH ２ ) ３ -, #- (CH ２ ) ４ -Piperazinylene-(CH ２ ) ４ -, #- (CH ２ ) ４ -Piperazinylene-(CH ２ ) ５ -, #- (CH ２ ) ４ -Piperazinylene-(CH ２ ) ６ -, #- (CH ２ ) ４ -Piperazinylene-(CH ２ ) ７ -, #- (CH ２ ) ４ -Piperazinylene-(CH ２ ) ８ -, #- (CH ２ ) ５ -Piperazinylene-(CH ２ ) １ -, #- (CH ２ ) ５ -Piperazinylene-(CH ２ ) ２ -, #- (CH ２ ) ５ -Piperazinylene-(CH ２ ) ３ -, #- (CH ２ ) ５ -Piperazinylene-(CH ２ ) ４ -, #- (CH ２ ) ５ -Piperazinylene-(CH ２ ) ５ -, #- (CH ２ ) ５ -Piperazinylene-(CH ２ ) ６ -, #- (CH ２ ) ５ -Piperazinylene-(CH ２ ) ７ -, #- (CH ２ ) ５ -Piperazinylene-(CH ２ ) ８ -, #- (CH ２ ) ６ -Piperazinylene-(CH ２ ) １ -, #- (CH ２ ) ６ -Piperazinylene-(CH ２ ) ２ -, #- (CH ２ ) ６ -Piperazinylene-(CH ２ ) ３ -, #- (CH ２ ) ６ -Piperazinylene-(CH ２ ) ４ -, #- (CH ２ ) ６ -Piperazinylene-(CH ２ ) ５ -, #- (CH ２ ) ６ -Piperazinylene-(CH ２ ) ６ -, #- (CH ２ ) ６ -Piperazinylene-(CH ２ ) ７ -, #- (CH ２ ) ６ -Piperazinylene-(CH ２ ) ８ -, #- (CH ２ ) ７ -Piperazinylene-(CH ２ ) １ -, #- (CH ２ ) ７ -Piperazinylene-(CH ２ ) ２ -, #- (CH ２ ) ７ -Piperazinylene-(CH ２ ) ３ -, #- (CH ２ ) ７ -Piperazinylene-(CH ２ ) ４ -, #- (CH ２ ) ７ -Piperazinylene-(CH ２ ) ８ -, #- (CH ２ ) ８ -piperazinylene-CH ２ -, #- (CH ２ ) ８ -Piperazinylene-(CH ２ ) ２ -, #- (CH ２ ) ８ -Piperazinylene-(CH ２ ) ３ -, #- (CH ２ ) ８ -Piperazinylene-(CH ２ ) ４ -, #- (CH ２ ) ８ -Piperazinylene-(CH ２ ) ５ -, #- (CH ２ ) ８ -Piperazinylene-(CH ２ ) ６ -, #- (CH ２ ) ８ -Piperazinylene-(CH ２ ) ７ - or #- (CH ２ ) ８ -Piperazinylene-(CH ２ ) ８ - represents wherein the piperidinylene and the piperazinylene are each independently further selected from the group consisting of 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, aryl, aryloxy ... Each R ｄ are independently H or C １－６ represents alkyl; The symbol # is the group R １０ represents a connection point with; and The compound of formula (I) according to any one of claims 1-14, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, wherein 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.

18. It is also a compound of 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), 【Chemistry 18】 【Chemistry 19】 Here, R ９ , R １０ , L.I.N., R. １２ , (R ａ ) ｔ and X is as defined in claim 1, or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof.

19. 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; 2. The compound of formula (I) according to claim 1, 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 or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof.

20. The compound of formula (I) or a salt thereof, enantiomer, stereoisomer, solvate, or polymorph thereof according to any one of claims 1 to 19, which is a 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).

21. A compound or a salt, enantiomer, stereoisomer, solvate, pharmaceutical precursor, 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 or a salt, enantiomer, stereoisomer, solvate, pharmaceutical precursor, or polymorph thereof selected from the group consisting 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.

22. 22. The compound of claim 21, 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.

23. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 20 as an active ingredient, or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, and at least one pharma- ceutically acceptable carrier.

24. 24. The pharmaceutical composition of claim 23, further comprising at least one additional therapeutic agent, such as an anti-cancer agent.

25. 23. A pharmaceutical composition comprising a compound according to claim 21 or 22 as an active ingredient or a pharma- ceutically acceptable salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, and at least one pharma- ceutically acceptable carrier.

26. 26. The pharmaceutical composition of claim 25, further comprising at least one additional therapeutic agent, such as an anti-cancer agent.

27. A compound of formula (I) according to any one of claims 1 to 20 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23 or 24; or A compound according to claim 21 or 22 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25 or 26. A pharmaceutical kit or reagent kit comprising:

28. 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; hepatic fibrosis; liver cirrhosis; tumors including hematological malignancies and solid tumors; multiple organ dysfunction syndrome (MODS) including multiple organ failure due to cachexia and septic shock; acute 23. Use of a compound of formula (I) according to any one of claims 1 to 20 or a salt, enantiomer, stereoisomer, solvate, isotopically enriched analogue, pharmaceutical precursor or polymorph thereof, or a compound according to claim 21 or 22 or a salt, enantiomer, stereoisomer, solvate, pharmaceutical precursor or polymorph thereof, in the manufacture of a medicament for the treatment and / or prevention of a disease or condition selected from the group consisting of: 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.

29. The tumors include myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, 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, acute myeloid leukemia (AML); diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, anaplastic 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, refractory lymphomas, including primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, 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, incident breast cancer, and Cowden's disease.

29. The use of claim 28, including breast cancer, including 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.

30. The use according to claim 28 or 29, wherein the compound of formula (I) according to any one of claims 1 to 20 or a pharma- ceutically acceptable salt thereof, or the compound according to claim 21 or 22 or a pharma- ceutically acceptable salt thereof, or said pharmaceutical composition 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.

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