Protein degraders developed on basis of bcl-2 family proteins ligand compounds and uses thereof

Abstract

This disclosure relates to protein degraders developed based on BCL-2 family protein ligand compounds, including compounds of formula (I) or salts thereof, enantiomers, stereoisomers, solvates, prodrugs or polymorphs, and their use in treating diseases.

Description

Technical Field

[0001] This disclosure relates to protein degraders developed based on BCL-2 family protein ligand compounds, including compounds of formula (I) or salts thereof, enantiomers, stereoisomers, solvates, isotope-enriched analogs, prodrugs or polymorphs, and their use in treating diseases. Background Technology

[0002] Apoptosis, or programmed cell death, is the process by which cells die through a series of programmed events. In early development, apoptosis can eliminate unwanted cells. In adulthood, apoptosis is mainly responsible for eliminating damaged and irreparable cells in the body, thereby ensuring proper development of the body. Apoptosis plays an important role in various physiological processes, such as participating in normal cell renewal, the development and improvement of the immune system, hormone-dependent atrophy, embryonic development, and chemically induced cell death (Elmore, S., Toxicol Pathol, 2007. 35(4): p. 495-516.). Abnormal apoptosis (excessive or insufficient) can lead to various diseases, including neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and tumors. Research shows that tumors can reduce their sensitivity to anti-tumor drugs by inhibiting the apoptosis pathway during their development (Scott, W. Letal., Carcinogenesis, 2000. 21(3): p. 485-495.). Therefore, activating apoptosis signals in tumor tissue may be an effective anti-tumor strategy.

[0003] The BCL-2 (B cell lymphoma-2) protein family is a key regulator of apoptosis, capable of both inducing and inhibiting it. Primarily located in mitochondria, it acts as an "apoptotic switch" by regulating mitochondrial membrane permeability. BCL-2 possesses four highly conserved homologous (BH) domains: BH1, BH2, BH3, and BH4. Based on the different compositions of these homologous domains, it can be divided into three subtypes, one of which has anti-apoptotic function, and the other two have pro-apoptotic function (Daniel, NN, Clin Cancer Res, 2007.13(24):p.7254-7263.). The BH1 and BH2 homologous domains of BCL-2 can form dimers with pro-apoptotic proteins. The BH3 domain is crucial in the interaction between pro-apoptotic and anti-apoptotic proteins and is therefore included in all subtypes. BH4 is mainly contained in the anti-apoptotic BCL-2 subtype. Anti-apoptotic proteins include BCL-2, BCL-XL, BCL-W, MCL1, A1, and BCL-B, which are composed of 3-4 BH domains. Pro-apoptotic proteins can be divided into two types: one type includes BAX, BAK, and BOK, which are composed of BH1, BH2, and BH3; the other type 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 levels of BCL-2 family proteins maintain a dynamic balance. Cell signaling can regulate the expression of pro-apoptotic or anti-apoptotic proteins by affecting this dynamic balance, thereby shifting the balance towards cell survival or death. When the balance favors cell death, pro-apoptotic proteins cause permeabilization of the mitochondrial outer membrane through oligomerization on the outer membrane, releasing cytochrome c and triggering the activation of the caspase cascade, which in turn cleaves downstream substrates, leading to cell death (Opferman, J.T. and A. Kothari, Cell Death Differ, 2018.25(1):p.37-45.).

[0004] Over the past 20 years, numerous small-molecule BCL-2 inhibitors have been discovered, and developing small-molecule inhibitors targeting the BCL-2 protein family has become a hot topic in the field of oncology. Anti-apoptotic BCL-2 proteins exert their anti-apoptotic function by binding to the BH3 domain of pro-apoptotic proteins through their hydrophobic pocket (BH3 binding pocket). BCL-2 family protein antagonists, also known as "BH3 domain mimetics," primarily work by inserting into the common BH3 domain of anti-apoptotic BCL-2 family proteins, preventing their binding to pro-apoptotic proteins BAX and BAK, thereby inhibiting the anti-apoptotic effects of BCL-2 and inducing tumor cell apoptosis.

[0005] To date, ABT-199 (Venetoclax) is the only FDA-approved anti-tumor drug targeting BCL-2 family proteins, which can be used to treat certain hematologic malignancies, such as chronic lymphocytic leukemia and acute myeloid leukemia (Deeks, ED, Drugs, 2016.76(9):p.979-87.; Carter, PJ and GALazar, Nat Rev DrugDiscov, 2018.17(3):p.197-223.). However, since the growth of most solid tumors does not depend on BCL-2 protein, ABT-199 has no significant therapeutic effect on solid tumors, while BCL-XL protein is significantly highly expressed in various solid tumors and hematologic malignancies (Leverson, JM, et al, Sci Transl Med, 2015.7(279):p.279ra40.). On the other hand, studies have shown that BCL-XL expression in tumor tissues is positively correlated with tumor drug resistance (Vogler, M., Adv Med, 2014:p.943648.). Therefore, targeting BCL-XL is a potentially ideal anti-tumor molecular target.

[0006] BCL-XL (B-cell lymphoma-extra large) is a key member of the BCL-2 family of anti-apoptotic proteins. Located in mitochondria, it is a key regulator of apoptosis and can also 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: p. 1-10.).

[0007] Studies have found that senescence of vascular cells is a major pathogenesis leading to retinal diseases 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): 362ra144.). Targeting the anti-apoptotic protein BCL-XL can induce apoptosis in senescent vascular endothelial cells, thereby achieving the goal of treating DME and wAMD (Crespo-Garcia S., et al., Cell Metabolism. 2021 Apr 6, 33(4): 818-832.e7.). The small molecule inhibitor UBX1325, which targets BCL-XL, is currently in phase II clinical trials for the treatment of DME and wAMD (clinicaltrials.gov).

[0008] Studies have also shown that BCL-XL is overexpressed in many tumors, such as liver cancer, non-Hodgkin's lymphoma, chondrosarcoma, and colorectal cancer (Li, M., et al., Pharmacological Research, 2019. 151(4): p. 104547.). In chondrosarcoma, BCL-XL plays the most crucial role compared to other members of the BCL2 family, and inhibiting BCL-XL can enhance the sensitivity of chondrosarcoma cells to conventional chemotherapy (Jong, YD, et al., Oncogenesis, 2018. 7(9).). Furthermore, the invasiveness of colorectal cancer cells is closely related to BCL-XL. In colorectal cancer, only BCL-XL of the BCL2 protein family is significantly upregulated (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.). Small molecule inhibitors targeting BCL-XL, such as ABT-263, have significant anti-tumor effects. However, because BCL-XL can limit the pro-apoptotic effect of Bax, which helps platelet survival, inhibiting BCL-XL expression causes thrombocytopenia and disrupts coagulation function. Therefore, ABT-263 has not been approved by the FDA (Tse, C., et al., Cancer Research, 2008.68(9):p.3421.). BCL-XL is one of the most important validated anti-cancer targets, but there is no safe and effective treatment.

[0009] PROTAC (Proteolysis Targeting Chimeria) is a bifunctional hybrid small molecule that links a target protein ligand to an E3 ubiquitin ligase ligand via a suitable linker chain. This promotes the formation of a ternary complex between the target protein and the E3 ligase, bringing the target protein into the ubiquitination system and achieving ubiquitination. Subsequently, the target protein is recognized by the 26S subunit of the proteasome, ultimately leading to its degradation (Sun, X., et al., Sig Transduct Target Ther, 2019.4(1):p.33.). The protein degradation process of PROTAC is similar to a catalytic reaction, thus it can work at very low doses. Compared with traditional small molecule inhibitors, they have a longer duration of action and lower toxicity (Lu, J., et al., Chem Biol, 2015.22(6):p.755-763.). More importantly, because PROTAC relies on E3 ubiquitin ligases to mediate protein degradation, even if the target protein itself is widely expressed in the body, it still exhibits cell or tissue selectivity by utilizing the difference in the expression levels of E3 ubiquitin ligases in tumor cells and normal tissues. For example, DT2216, which has entered clinical trials, uses ABT-263 as a ligand for the target protein BCL-XL and VHL, which is low in platelets, as a ligand for E3 ubiquitin ligase, which significantly improves antitumor activity and reduces platelet toxicity (Khan, S., et al., Nature Medicine, 2019.25(4):p.1938-1947.).

[0010] Abnormally activated Hedgehog (Hh) signaling pathway is closely related to the occurrence and development of various tumors in the human body, such as basal cell carcinoma and medulloblastoma (Nat Genet, 2016, 48(4): p.398-406; Cancer Cell, 2014, 25(3): p.393-405.). Hh signal transduction in cells is a cascade, and its key molecules include the PTCH receptor with 12 transmembrane domains, the SMO (Smoothed) receptor with 7 transmembrane domains, SUFU protein, and the GLI family of nuclear transcription factors. When there is no exogenous HH ligand, PTCH inhibits SMO activity, and the signaling pathway is in an inhibited state. When the exogenous HH ligand binds to PTCH, it relieves the inhibition of SMO, which causes SMO to be transferred to the cilia, the key signaling center in the signaling pathway. This further causes the SUFU-GLI transcription complex to also translocate to the cilia, relieving the inhibitory effect of SUFU on GLI. Furthermore, by regulating the phosphorylation of GLI by kinases such as GSK3 and CK1, the transcriptionally active GLI enters the nucleus to initiate the transcription of downstream target genes, thus 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 the treatment of basal cell carcinoma target SMO (Cell, 2016.164(5):p.831.), and therefore have no significant inhibitory effect on tumors with abnormal Hh activation caused by genetic alterations in key downstream signaling molecules of SMO, such as SMO mutations, loss-of-function mutations of SUFU, and GLI amplification. Recently, studies have shown that the SUFU protein contains a conserved BH3 sequence that can bind to intracellular anti-apoptotic proteins such as BCL-XL, BCL-2, and MCL-1, thereby relieving the inhibitory effect of SUFU on GLI proteins and ultimately leading to Hh pathway activation; inhibiting the binding of anti-apoptotic proteins such as BCL-XL to SUFU can effectively inhibit Hh signaling pathway activation (Nat Cell Biol, 2017.19(10):p.1226-1236.). Based on this, targeting BCL-2 family proteins is also a strategy for developing inhibitors targeting the Hh signaling pathway.

[0011] Therefore, there is an urgent need for a series of novel PROTAC inhibitors for the treatment and / or prevention of diseases or conditions mediated by BCL-2 family proteins, or diseases or conditions dependent on the Hedgehog signaling pathway, or related diseases. Invention Overview

[0012] In view of the above, one object of this disclosure is to provide novel protein degraders developed based on BCL-2 family protein ligand compounds, their uses, and methods of use. The novel protein degraders developed based on BCL-2 family protein ligand compounds of this disclosure, or their salts (including pharmaceutically acceptable salts), stereoisomers (including enantiomers), solvates, prodrugs, or polymorphs, can bind to target proteins, recruit the target proteins to E3 ubiquitin ligases for ubiquitination labeling and degradation, thereby exhibiting the desired pharmacological activity.

[0013] In some embodiments, the novel protein degraders developed based on BCL-2 family protein ligand compounds disclosed herein may be compounds of formula (I) or salts thereof, stereoisomers (including enantiomers), solvates, isotope-enriched analogs, prodrugs, or polymorphs:

[0014]

[0015] in

[0016] The dashed line indicates that a double bond may be present.

[0017] R1, R2, R3, and R4 may be the same or different and each independently represents hydrogen and C. 1-4 Alkyl, halogen, or halogenated C 1-4 alkyl;

[0018] (R5) n This indicates that the benzene ring is replaced by n R5 groups, each R5 group being the same or different and independently representing a halogen or carbon. 1-6 Alkyl or halogenated C 1-6 Alkyl group, where n represents an integer 1, 2, 3, 4, or 5;

[0019] (R6) m This indicates that the piperazine ring is replaced by m R6 molecules, each R6 molecule being the same or different and independently representing a halogen or carbon. 1-6 Alkyl or halogenated C 1-6 Alkyl group, where m represents an integer 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0020] R7 indicates hydrogen or

[0021] R8 represents hydrogen or -SO2CF3 or -NO2;

[0022] R9 represents hydrogen or C. 1-4 alkyl;

[0023] R 10 Represents the following groups:

[0024]

[0025] Among them, ring W 1 Indicates a 4- to 6-membered nitrogen-containing heterocyclic group, (R a1 ) n1 Represents ring W 1 by n1 R a1 Group substitution, each R a1 The same or different and each independently is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl, cyano, halogen, or oxo group, n1 represents an integer from 0 to 8;

[0026] Ring W 2 Indicates a 4- to 6-membered nitrogen-containing heterocyclic group, or C 3-6 cycloalkylene, n3 represents the integer 0 or 1, (R a2 ) n2 Represents ring W 2 by n2 R a2 Group substitution, each R a2 The same or different and each independently is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl, cyano, halogen, or oxo group, n2 represents an integer from 0 to 8; and

[0027] The symbol * indicates a connection point with LIN;

[0028] LIN means

[0029] Optional replacement of straight or branched C 1-30 alkylene; or

[0030] One or more R groups are inserted into its main carbon chain. b and / or one or more groups R c Or one or more groups R b and

[0031] R c Any combination of optional substitutions for straight or branched C 2-30 alkylene, wherein the group R b R c Or group R b With R c The combination breaks the carbon-carbon bonds between one or more pairs of adjacent carbon atoms in the main carbon chain; each group R b Selected from 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 ),

[0032] N(R d C(O), or N(R) d )C(O)N(R d ), where each R d Independently represent H or C 1-6 Alkyl groups, and when the straight-chain or branched C... 2-30 Two or more R groups are inserted into the main carbon chain of the alkylene group. b At that time, each group R b They are not directly connected to each other; each group R c Selected from cycloalkylene, arylene, heterocyclic, heteroarylene, ynylene, alkenylene, or any combination thereof, wherein the cycloalkylene, arylene, heterocyclic, and heteroarylene are optionally further selected independently from C1. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, C 1-6 Alkoxy groups, or any combination thereof, are substituents; and

[0033] R 11 The structural formula for the following equation (II) is:

[0034]

[0035] Among them, R 12 N(R) e ), O, S, C 2-6 etyne group, or C 2-6 alkenyl, wherein R e Indicates H or C 1-6 Alkyl, or R 12 Indicates key;

[0036] (R a ) t This indicates that the benzene ring is divided by t R a Replace, each R a The same or different and independent representations of bromine, where t represents the integer 0, 1, 2 or 3; and

[0037] X represents C(O) or CH2;

[0038] Where t represents the integer 0:

[0039] When R7 represents When n1 represents an integer from 1 to 8, and each R a1 The same or different and each independently is C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogen; or

[0040] When R7 represents In this case, R8 represents -SO2CF3.

[0041] In another aspect, this disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a salt thereof, a stereoisomer (including an enantiomer), a solvate, an isotope-enriched analog, a prodrug or polymorph, and at least one pharmaceutically acceptable carrier.

[0042] On the other hand, the novel protein degrading agents developed based on BCL-2 family protein ligand compounds disclosed herein can be the following compounds or their salts, stereoisomers (including enantiomers), solvates, prodrugs, or polymorphs:

[0043] 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-oxoisoindoline-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butane-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;

[0044] 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-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butane-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;

[0045] 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-oxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

[0046] 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-oxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; or

[0047] 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-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide.

[0048] In another aspect, this disclosure provides a pharmaceutical composition comprising the aforementioned protein degrading compound or a salt thereof, a stereoisomer (including enantiomers), a solvate, a prodrug or polymorph, and at least one pharmaceutically acceptable carrier.

[0049] In another aspect, this disclosure also provides a kit or reagent kit comprising:

[0050] The present disclosure includes protein degrading compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof.

[0051] On the other hand, this disclosure provides protein degrading compounds of the present disclosure or their salts, stereoisomers (including enantiomers), solvates, prodrugs or polymorphs or pharmaceutical compositions containing them as active ingredients, which are used as pharmaceuticals.

[0052] On the other hand, this disclosure provides protein degrading compounds of the present disclosure or their salts, stereoisomers (including enantiomers), solvates, prodrugs or polymorphs or pharmaceutical compositions containing them as active ingredients, which are used as pharmaceuticals.

[0053] In another aspect, this disclosure further provides protein degrading compounds of the present disclosure or their salts, stereoisomers (including enantiomers), solvates, prodrugs or polymorphs, or pharmaceutical compositions containing them as active ingredients, for the treatment and / or prevention of diseases or conditions selected from: neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, myelofibrosis, renal fibrosis, liver fibrosis, cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), multiple organ failure due to cachexia and septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes, transplant rejection, retinopathy, and acute liver failure.

[0054] On the other hand, this disclosure also provides the use of the protein degrading compound of the disclosure or its salts, stereoisomers (including enantiomers), solvates, prodrugs or polymorphs for the preparation of medicaments for the treatment and / or prevention of diseases or conditions selected from: neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, myelofibrosis, renal fibrosis, liver fibrosis, cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), multiple organ failure due to cachexia and septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes, transplant rejection, retinopathy and acute liver failure.

[0055] In another aspect, this disclosure also provides a method for treating or preventing a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of the protein-degrading compound of this disclosure, or a salt thereof, enantiomer, stereoisomer, solvate, prodrug, or polymorph thereof, or a pharmaceutical composition comprising thereunder, or a therapeutically effective amount of the compound of this disclosure, or a salt thereof, stereoisomer (including enantiomer), solvate, prodrug, or polymorph thereof, or a pharmaceutical composition comprising thereunder as an active ingredient, wherein the disease or condition is selected from: neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, myelofibrosis, renal fibrosis, liver fibrosis, cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), cachexia and septic shock-induced multiple organ failure, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes, transplant rejection, retinopathy, and acute liver failure. Brief description of the attached figures

[0056] Figures 1-3This is a schematic diagram of the results of a protein immunoblotting experiment, which shows that the compounds BCL-03146, BCL-03147, BCL-03148, BCL-03149 (100 nM) of this invention significantly reduced the expression of BCL-XL protein after 8 h of treatment in Molt-4 cells, and showed a clear advantage in protein degradation compared with DT2216 (CAS No.: 2365172-42-3; a BCL-XL degrading agent reported in the literature). Invention Details

[0057] The following detailed description is provided as exemplary embodiments to assist those skilled in the art in understanding and implementing the present disclosure. However, it should be understood that such description is not intended to limit the scope of the disclosure, and various modifications and variations may be made to the specific embodiments described herein without departing from the spirit and scope of the disclosure, all of which fall within the claimed scope of the disclosure.

[0058] I. Compounds

[0059] Compound of formula (I)

[0060] This disclosure provides a compound of formula (I) or a salt thereof (including pharmaceutically acceptable salts), a stereoisomer (including enantiomers), a solvate, an isotope-enriched analog, a prodrug, or a polymorph:

[0061]

[0062] Where R1, R2, R3, R4, (R5) n (R6) m R7, R8, R9, R 10 LIN and R 11 As defined in compound (I) above.

[0063] In some embodiments, the dashed line in the compound of formula (I) indicates the optional presence of a double bond.

[0064] In some embodiments, the dashed lines in the compound of formula (I) indicate the presence of a double bond. In this case, the groups containing the dashed lines in the compound of formula (I) are as follows:

[0065]

[0066] In some embodiments, the dashed lines in the compound of formula (I) indicate the absence of double bonds. In this case, the groups containing the dashed lines in the compound of formula (I) are as follows:

[0067]

[0068] In some embodiments, R1, R2, R3, and R4 of compound (I) may be the same or different and each independently represents hydrogen, C, and C. 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl), halogens (e.g., fluorine, chlorine, bromine, or iodine), or halogenated C groups 1-4 Alkyl groups (e.g., halogenated C) 1-3 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, or CH2ClCH2-.

[0069] In some embodiments, R1 and R2 of the compound of formula (I) represent hydrogen, and R3 and R4 represent methyl groups.

[0070] In some embodiments, R1 and R2 of compound (I) represent methyl groups, and R3 and R4 represent hydrogen groups.

[0071] In some embodiments, compound (I) has (R5). n This indicates that the benzene ring is substituted by n R5 groups, each R5 group being the same or different and independently representing a halogen (e.g., fluorine, chlorine, bromine, or iodine), C. 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups (such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), or halogenated C 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2-, or CH2ClCH2-, where n represents an integer 1, 2, 3, 4, or 5. In some embodiments, n represents an integer 1, and R5 represents a halogen (e.g., fluorine, chlorine, bromine, or iodine).

[0072] In some implementations, compound (I) has (R6). m This indicates that the piperazine ring is substituted by m R6 atoms, each R6 being the same or different and independently representing a halogen (e.g., fluorine, chlorine, bromine, or iodine), C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups (such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl), or halogenated C 1-6 Alkyl groups (e.g., halogenated C) 1-4Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-, where m represents an integer 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0073] In some implementations, R7 represents hydrogen or

[0074] In some implementations, R7 represents hydrogen.

[0075] In some implementations, R7 indicates

[0076] In some implementations, R8 represents hydrogen or -SO2CF3 or -NO2.

[0077] In some implementations, R8 represents hydrogen.

[0078] In some implementations, R8 stands for -SO2CF3.

[0079] In some implementations, R8 represents -NO2.

[0080] In some implementations, R9 represents hydrogen or C. 1-4 Alkyl (e.g., C10) 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.

[0081] In some implementations, R9 represents hydrogen.

[0082] In some implementations, R9 represents C 1-4 Alkyl (e.g., C10) 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl.

[0083] In some implementation schemes, R 10 Represents the following groups:

[0084]

[0085] Among them, ring W 1 Indicates a 4- to 6-membered nitrogen-containing heterocyclic group, (R a1 ) n1 Represents ring W 1 by n1 R a1 Group substitution, each R a1 The same or different and each independently is C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkyl groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), cyano, halogen (such as fluorine, chlorine, bromine or iodine), or oxo groups, where n1 represents an integer from 0 to 8;

[0086] Ring W 2 Indicates a 4- to 6-membered nitrogen-containing heterocyclic group, or C 3-6 cycloalkylene, n3 represents the integer 0 or 1, (R a2 ) n2 Represents ring W 2 by n2 R a2 Group substitution, each R a2 The same or different and each independently is C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), cyano groups, halogens (e.g., fluorine, chlorine, bromine, or iodine), or oxo groups, where n2 represents an integer from 0 to 8; and

[0087] The symbol * indicates a connection point with LIN.

[0088] In some implementation schemes, ring W 1 The term refers to a 4- to 6-membered nitrogen-containing heterocyclic group, which includes, but is not limited to, for example, piperidinyl, piperazineyl, morpholinyl, aziridine, pyrrolidine, imidazoalkyl, pyrazolidine, oxazolidine, thiazoalkyl, or thiomorpholinyl.

[0089] In some implementation schemes, (R a1 ) n1 Represents ring W 1 by n1 R a1 Group substitution, each R a1 The same or different and each independently is C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), cyano, halogen (such as fluorine, chlorine, bromine or iodine), or oxo, n1 represents an integer from 0 to 8 (such as integers 0, 1, 2, 3 or 4).

[0090] In some implementation schemes, ring W 2 The term refers to a 4- to 6-membered nitrogen-containing heterocyclic group, which includes, but is not limited to, for example, piperidinyl, piperazineyl, morpholinyl, aziridine, pyrrolidine, imidazoalkyl, pyrazolidine, oxazolidine, thiazoalkyl, or thiomorpholinyl.

[0091] In some implementation schemes, ring W 2 C represents 3-6 Cycloalkylene compounds, including but not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0092] In some implementation schemes, (R a2 ) n2 Represents ring W 2 by n2 R a2 Group substitution, each R a2 The same or different and each independently is C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), cyano, halogen (such as fluorine, chlorine, bromine or iodine), or oxo, n2 represents an integer from 0 to 8 (such as integers 0, 1, 2, 3 or 4).

[0093] In some implementations, n3 represents the integer 0 or 1.

[0094] In some implementations, n3 represents the integer 0.

[0095] In some implementations, n3 represents the integer 1.

[0096] In some implementation schemes, R 10 Represents the following groups:

[0097]

[0098] The symbol * indicates the connection point with LIN.

[0099] In some implementation schemes, R 11 The structural formulas representing the following equations (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) are as follows:

[0100]

[0101] in

[0102] R 12 N(R) e ), O, S, C 2-6 alkyne (e.g., ethynylene), or C 2-6 alkenyl (e.g., vinylene), where R e Indicates H or C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl, or R 12 Indicates key;

[0103] X represents C(O) or CH2; and

[0104] (R a ) t This indicates that the benzene ring is divided by t R a Replace, each R a The same or different and independent of each other represent bromine, and t represents the integer 0, 1, 2 or 3.

[0105] In some implementations, X represents C(O).

[0106] In some implementations, X represents CH2.

[0107] In some implementation schemes, R 12 Indicates a key.

[0108] In some implementations, t represents the integer 0.

[0109] In some implementations, t represents the integer 1, 2, or 3.

[0110] In some implementation schemes, R 11 The structure of the following expression is represented as:

[0111]

[0112]

[0113] In this disclosure, when t represents the integer 0, R7 represents When n1 represents an integer from 1 to 8 (e.g., integers 1, 2, 3, 4, 5, 6, 7, or 8), and each R a1 The same or different and each independently is C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy, or halogens (such as fluorine, chlorine, bromine, or iodine).

[0114] In this disclosure, when t represents the integer 0, R7 represents In this case, R8 represents -SO2CF3.

[0115] In some implementations, the LIN represents the structure of the following formula:

[0116] #-C 1-30 alkylene-;

[0117] #-(C(R a3 (R) a4 )) n4 -(R b -(C(R a5 (R) a6 )) n5 ) m1 -;

[0118] #-(C(R a3 (R) a4 )) n4 -(R b -(C(R a5 (R) a6 )) n5 ) m1 -(R b -(C(R a7 (R) a8 )) n6 ) m2 -;

[0119] #-(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 -;

[0120] #-(C(R a3 (R) a4 )) n4 -(R c -(C(R a5 (R) a6 )) n5 ) m1 -;

[0121] #-(C(Ra3 )(R a4 )) n4 -(R c -(C(R a5 )(R a6 )) n5 ) m1 -(R c -(C(R a7 )(R a8 )) n6 ) m2 -;

[0122] #-(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 -;

[0123] #-(C(R a3 )(R a4 )) n4 -(R b -R c -(C(R a5 )(R a6 )) n5 ) m1 -;

[0124] #-(C(R a3 )(R a4 )) n4 -(R b -(C(R a5 )(R a6 )) n5 ) m1 -(R c -(C(R a7 )(R a8 )) n6 ) m2 -;

[0125] #-(C(R a3 )(R a4 )) n4-(R c -R b -(C(R a5 (R) a6 )) n5 ) m1 -;or

[0126] #-(C(R a3 (R) a4 )) n4 -(R c -(C(R a5 (R) a6 )) n5 ) m1 -(R b -(C(R a7 (R) a8 )) n6 ) m2 -;

[0127] Among them, each group R b Selected from 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 ), where each R d Independently represent H or C 1-6 Alkyl (e.g., C10) 1-4 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; each group R c Selected from cyclohexane (e.g., C10) 3-20 Cycloalkylene, arylene (e.g., C164-) 3-20 arylene), heterocyclic (e.g., 4- to 20-membered heterocyclic), heteroarylene (e.g., 4- to 20-membered heteroarylene), ynylene (e.g., C... 2-6 (e.g., C-ynyl), (e.g., C-yl) 2-6 (alkenyl) or any combination thereof, wherein the cycloalkylene, the arylene, the heterocyclic and the heteroarylene are optionally further selected independently from C10. 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl or halogenated C 1-3Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-; halogens (such as fluorine, chlorine, bromine or iodine); C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkoxy groups (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), or any combination thereof, are substituted with substituents.

[0128] The C 1-30 One or more hydrogen atoms of the CH2 group of the alkylene group may optionally be further substituted by substituents selected from the following: C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl or halogenated C 1-3 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-; halogens (such as fluorine, chlorine, bromine or iodine); C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy, or any combination thereof;

[0129] R a3 R a4 R a5 R a6 R a7 R a8 R a9 and R a10 The same or different and each independently represents H and C. 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl or halogenated C 1-3Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-, halogens (such as fluorine, chlorine, bromine or iodine), or C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkyl groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy.

[0130] n4, n5, n6, n7, m1, m2, m3 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and

[0131] The symbol # indicates the group R 10 The connection point.

[0132] In some implementations, the LIN represents the structure of the following formula:

[0133] #-(C(R a3 (R) a4 )) n4 -(O-(C(R a5 (R) a6 )) n5 ) m1 -;

[0134] #-(C(R a3 (R) a4 )) n4 -(O-(C(R a5 (R) a6 )) n5 ) m1 -(O-(C(R a7 (R) a8 )) n6 ) m2 -;

[0135] #-(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 -;

[0136] #-(C(R a3 )(R a4 )) n4 -(N(R d )-(C(R a5 )(R a6 )) n5 ) m1 -;

[0137] #-(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 -;

[0138] #-(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 -;

[0139] #-(C(R a3 )(R a4 )) n4 -(C(O)N(R d )-(C(R a5 )(R a6 )) n5 ) m1 -;

[0140] #-(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 -;

[0141] #-(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 -;

[0142] #-(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 -;

[0143] #-(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 -;

[0144] #-(C(R a3)(R a4 )) n4 -(N(R d )C(O)-(C(R a5 )(R a6 )) n5 ) m1 -;

[0145] #-(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 -;

[0146] #-(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 -;

[0147] #-(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 -;

[0148] #-(C(R a3 )(R a4 )) n4 -N(R d )C(O)N(R d )-(C(R a5 )(Ra6 )) n5 -;

[0149] #-(C(R a3 (R) a4 )) n4 -C(O)-(C(R a5 (R) a6 )) n5 -;

[0150] #-(C(R a3 (R) a4 )) n4 -(Asaryl-(C(R) a5 (R) a6 )) n5 ) m1 -;

[0151] #-(C(R a3 (R) a4 )) n4 -(Asaryl-(C(R) a5 (R) a6 )) n5 ) m1 -Asaryl-(C(R) a7 (R) a8 )) n6 -;

[0152] #-(C(R a3 (R) a4 )) n4 -(heterocyclic group-(C(R) a5 (R) a6 )) n5 ) m1 -;

[0153] #-(C(R a3 (R) a4 )) n4 -(heterocyclic group-(C(R) a5 (R) a6 )) n5 ) m1 -(heterocyclic group-(C(R) a7 (R) a8 )) n6 ) m2 -;

[0154] #-(C(R a3 (R) a4 )) n4 -(hybridyl-(C(R) a5 (R) a6 )) n5 )m1 -;

[0155] #-(C(R a3 (R) a4 )) n4 -(hybridyl-(C(R) a5 (R) a6 )) n5 ) m1 -(hybridyl-(C(R) a7 (R) a8 )) n6 ) m2 -;

[0156] #-(C(R a3 (R) a4 )) n4 -(cycloalkylene-(C(R) a5 (R) a6 )) n5 ) m1 -;or

[0157] #-(C(R a3 (R) a4 )) n4 -(cycloalkylene-(C(R) a5 (R) a6 )) n5 ) m1 -(cycloalkylene-(C(R) a7 (R) a8 )) n6 ) m2 -;

[0158] Among them, each R d Independently represent H or C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl;

[0159] The cycloalkylene (e.g., C) 3-20 cycloalkylene), said arylene (e.g., C10) 3-20 The arylene group, the heterocyclic group (e.g., 4- to 20-membered heterocyclic group), and the heteroarylene group (e.g., 4- to 20-membered heteroarylene group) are optionally further selected independently from C. 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl or halogenated C 1-3Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-; halogens (such as fluorine, chlorine, bromine or iodine); C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkoxy groups (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), or any combination thereof, are substituted with substituents.

[0160] R a3 R a4 R a5 R a6 R a7 R a8 R a9 and R a10 The same or different and each independently represents H and C. 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl or halogenated C 1-3 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-, halogens (such as fluorine, chlorine, bromine or iodine), or C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkyl groups, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy.

[0161] n4, n5, n6, n7, m1, m2, m3 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and

[0162] The symbol # indicates the group R 10 The connection point.

[0163] In some implementations, LIN represents the following groups:

[0164] #-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(R g)-(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-piperidinyl-CH2-、#-CH2-piperidinyl-(CH2)2-、#-CH2-piperidinyl-(CH2)3-、#-CH2-piperidinyl-(CH2)4-、#-CH2-piperidinyl-(CH2)5-、#-CH2-piperidinyl-(CH2)6-、#-CH2-piperidinyl-(CH2)7-、#-CH2-piperidinyl-(CH2)8-、#-(CH2)2-piperidinyl-(CH2)1-、# -(CH2)2-piperidinyl-(CH2)2-, #-(CH2)2-piperidinyl-(CH2)3-, #-(CH2)2-piperidinyl-(CH2)4-, #-(CH2)2-piperidinyl-(CH2)5-, #-(CH2)2-piperidinyl-(CH2)6-, #-(CH2)2-piperidinyl-(CH2)7-, #-(CH2)2-piperidinyl-(CH2)8-, #-(CH2)3-piperidinyl-CH2-, #-(CH2)3-piperidinyl-(CH2)2-, #-(CH2)3-piperidinyl-(CH2)3-, #-(CH2)3-piperidinyl-(CH2)4-, #-(CH2)3- Piperidinyl-(CH2)5-, #-(CH2)3-piperidinyl-(CH2)6-, #-(CH2)3-piperidinyl-(CH2)7-, #-(CH2)3-piperidinyl-(CH2)8-, #-(CH2)4-piperidinyl-CH2-, #-(CH2)4-piperidinyl-(CH2)2-, #-(CH2)4-piperidinyl-(CH2)3-, #-(CH2)4-piperidinyl-(CH2)4-, #-(CH2)4-piperidinyl-(CH2)5-, #-(CH2)4-piperidinyl-(CH2)6-, #-(CH2)4-piperidinyl-(CH2)7 ...5-, #-(CH2)4-piperidinyl-(CH2)6-, #-(CH2)4-piperidinyl-(CH2)5-, #-(CH2)4-piperidinyl-(CH2)6-, #-(CH2)4-piperidinyl-(CH2)6-, #-(CH2)4-piperidinyl-(CH2)6-, #-(CH2)4-piperidinyl-(CH2)6-, #-(CH2)4-piperidinyl-(CH2)6-, #-(CH2)4-piperidinyl-(CH2) 2) 8-, #-(CH2)5-piperidinyl-(CH2)1-, #-(CH2)5-piperidinyl-(CH2)2-, #-(CH2)5-piperidinyl-(CH2)3-, #-(CH2)5-piperidinyl-(CH2)4-, #-(CH2)5-piperidinyl-(CH2)5-, #-(CH2)5-piperidinyl-(CH2)6-, #-(CH2)5-piperidinyl-(CH2)7-, #-(CH2)5-piperidinyl-(CH2)8-, #-(CH2)6-piperidinyl-(CH2)1-, #-(CH2)6-piperidinyl-(CH2)2-, #-(CH2)6-piperidinyl-(CH2)3-,#-(CH2)6-piperidinyl-(CH2)4-, #-(CH2)6-piperidinyl-(CH2)5-, #-(CH2)6-piperidinyl-(CH2)6-, #-(CH2)6-piperidinyl-(CH2)7-, #-(CH2)6-piperidinyl-(CH2)8-, #-(CH2)7-piperidinyl-(CH2)1-, #-(CH2)7-piperidinyl-(CH2)2-, #-(CH2)7-piperidinyl-(CH2)3-, #-(CH2)7-piperidinyl-(CH2)4-, #-( CH2)7-piperidinyl-(CH2)8-, #-(CH2)8-piperidinyl-CH2-, #-(CH2)8-piperidinyl-(CH2)2-, #-(CH2)8-piperidinyl-(CH2)3-, #-(CH2)8-piperidinyl-(CH2)4-, #-(CH2)8-piperidinyl-(CH2)5-, #-(CH2)8-piperidinyl-(CH2)6-, #-(CH2)8-piperidinyl-(CH2)7-, #-(CH2)8-piperidinyl-(CH2)8-, #-CH2-N(R, g )-CH2-piperidine-CH2-, #-CH2-N(R g )-CH2-piperidine-(CH2)2-、#-CH2-N(R g )-CH2-piperidine-(CH2)3-、#-CH2-N(R g )-CH2-piperidine-(CH2)4-、#-CH2-N(R g )-CH2-piperidine-(CH2)5-、#-CH2-N(R g )-CH2-piperidine-(CH2)6-、#-CH2-N(R g )-CH2-piperidine-(CH2)7-、#-CH2-N(R g )-CH2-piperidine-(CH2)8-、#-CH2-N(R g )-(CH2)2-piperidine-CH2-, #-CH2-N(R g )-(CH2)2-piperidine-(CH2)2-、#-CH2-N(R g )-(CH2)2-piperidine-(CH2)3-、#-CH2-N(R g )-(CH2)2-piperidine-(CH2)4-、#-CH2-N(R g )-(CH2)2-piperidine-(CH2)5-、#-CH2-N(R g )-(CH2)2-piperidine-(CH2)6-、#-CH2-N(R g)-(CH2)2-piperidine-(CH2)7-、#-CH2-N(R g )-(CH2)2-piperidine-(CH2)8-、#-(CH2)2-N(R g )-CH2-piperidine-CH2-、#-(CH2)2-N(R g )-CH2-piperidine-(CH2)2-、#-(CH2)2-N(R g )-CH2-piperidine-(CH2)3-、#-(CH2)2-N(R g )-CH2-piperidine-(CH2)4-、#-(CH2)2-N(R g )-CH2-piperidine-(CH2)5-、#-(CH2)2-N(R g )-CH2-piperidine-(CH2)6-、#-(CH2)2-N(R g )-CH2-piperidine-(CH2)7-、#-(CH2)2-N(R g )-CH2-piperidine-(CH2)8-、#-(CH2)3-N(R g )-CH2-piperidine-CH2-、#-(CH2)3-N(R g )-CH2-piperidine-(CH2)2-、#-(CH2)3-N(R g )-CH2-piperidine-(CH2)3-、#-(CH2)3-N(R g )-CH2-piperidinyl-(CH2)8-、#-(CH2)4-N(R g )-CH2-piperidine-CH2-、#-(CH2)4-N(R g )-CH2-piperidinyl-(CH2)2-、#-(CH2)4-N(R g )-CH2-piperidine-(CH2)3-、#-(CH2)4-N(R g )-CH2-piperidinyl-(CH2)8-、#-(CH2)5-N(R g )-CH2-piperidine-(CH2)3-、#-(CH2)5-N(R g )-CH2-piperidine-(CH2)8-、#-(CH2)6-N(R g )-CH2-piperidine-(CH2)3-、#-(CH2)6-N(R g )-CH2-piperidine-(CH2)8-、#-(CH2)7-N(R g )-CH2-piperidine-(CH2)3-、#-(CH2)7-N(Rg )-CH2-piperidinyl-(CH2)8-、#-(CH2)8-N(R g )-CH2-piperidine-CH2-、#-(CH2)8-N(R g )-CH2-piperidine-(CH2)2-、#-(CH2)8-N(R g )-CH2-piperidine-(CH2)3-、#-(CH2)8-N(R g )-CH2-piperidinyl-(CH2)4-、#-(CH2)8-N(R g )-CH2-piperidinyl-(CH2)5-、#-(CH2)8-N(R g )-CH2-piperidine-(CH2)6-、#-(CH2)8-N(R g )-CH2-piperidine-(CH2)7-、#-(CH2)8-N(R g#-CH2-piperazinyl-(CH2)8-, #-CH2-piperazinyl-CH2-, #-CH2-piperazinyl-(CH2)2-, #-CH2-piperazinyl-(CH2)3-, #-CH2-piperazinyl-(CH2)4-, #-CH2-piperazinyl-(CH2)5-, #-CH2-piperazinyl-(CH2)6-, #-CH2-piperazinyl-(CH2)7-, #-CH2-piperazinyl-(CH2)8-, #-(CH2)2-piperazinyl-(CH2)1-, #-(CH2)2-piperazinyl-(CH2)2-, #-(CH2)2-piperazinyl-(CH2)3-, #-(CH2)2-piperazinyl-( CH2)4-, #-(CH2)2-piperazinyl-(CH2)5-, #-(CH2)2-piperazinyl-(CH2)6-, #-(CH2)2-piperazinyl-(CH2)7-, #-(CH2)2-piperazinyl-(CH2)8-, #-(CH2)3-piperazinyl-CH2-, #-(CH2)3-piperazinyl-(CH2)2-, #-(CH2)3-piperazinyl-(CH2)3-, #-(CH2)3-piperazinyl-(CH2)4-, #-(CH2)3-piperazinyl-(CH2)5-, #-(CH2)3-piperazinyl-(CH2)6-, #-(CH2)3-piperazinyl-(CH2)7-, #-(C H2)3-piperazinyl-(CH2)8-, #-(CH2)4-piperazinyl-CH2-, #-(CH2)4-piperazinyl-(CH2)2-, #-(CH2)4-piperazinyl-(CH2)3-, #-(CH2)4-piperazinyl-(CH2)4-, #-(CH2)4-piperazinyl-(CH2)5-, #-(CH2)4-piperazinyl-(CH2)6-, #-(CH2)4-piperazinyl-(CH2)7-, #-(CH2)4-piperazinyl-(CH2)8-, #-(CH2)5-piperazinyl-(CH2)1-, #-(CH2)5-piperazinyl-(CH2)2-, #-(CH2)5-piperazinyl- (CH2)3-, #-(CH2)5-piperazinyl-(CH2)4-, #-(CH2)5-piperazinyl-(CH2)5-, #-(CH2)5-piperazinyl-(CH2)6-, #-(CH2)5-piperazinyl-(CH2)7-, #-(CH2)5-piperazinyl-(CH2)8-, #-(CH2)6-piperazinyl-(CH2)1-, #-(CH2)6-piperazinyl-(CH2)2-, #-(CH2)6-piperazinyl-(CH2)3-, #-(CH2)6-piperazinyl-(CH2)4-, #-(CH2)6-piperazinyl-(CH2)5-, #-(CH2)6-piperazinyl-(CH2)6-#-(CH2)6-piperazinyl-(CH2)7-, #-(CH2)6-piperazinyl-(CH2)8-, #-(CH2)7-piperazinyl-(CH2)1-, #-(CH2)7-piperazinyl-(CH2)2-, #-(CH2)7-piperazinyl-(CH2)3-, #-(CH2)7-piperazinyl-(CH2)4-, #-(CH2)7-piperazinyl-(CH2)8-, #-(CH2)8-piperazinyl-(CH2)8- Piperazinyl-CH2-, #-(CH2)8-piperazinyl-(CH2)2-, #-(CH2)8-piperazinyl-(CH2)3-, #-(CH2)8-piperazinyl-(CH2)4-, #-(CH2)8-piperazinyl-(CH2)5-, #-(CH2)8-piperazinyl-(CH2)6-, #-(CH2)8-piperazinyl-(CH2)7-, or #-(CH2)8-piperazinyl-(CH2)8-;

[0165] Wherein, the piperidinyl group and the piperazine group are optionally further selected independently from C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl or halogenated C 1-3 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-; halogens (such as fluorine, chlorine, bromine or iodine); C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkoxy groups (such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), or any combination thereof, are substituted with substituents.

[0166] Each R d Independently represent H or C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl;

[0167] The symbol # indicates the group R 10 The connection point; and

[0168] n4, n5, n6, n7, m1, m2, m3 are each independently selected from the integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0169] In some embodiments, the compound of formula (I) is also represented by the structure of formula (I-1):

[0170]

[0171] Where R1, R2, R3, R4, (R5) n (R6) m R7, R8, R9, R 10 LIN, R 12 、(R a ) t And X is as defined in this paper as in the compound of formula (I) and its various embodiments.

[0172] In some embodiments, the compound of formula (I) is also represented by the structure of formula (I-2) or formula (I-3):

[0173]

[0174] Where R1, R2, R3, R4, (R5) n (R6) m R8, R9, R 10 LIN, R 12 、(R a ) t And X is as defined in this paper as in the compound of formula (I) and its various embodiments.

[0175] In some embodiments, the compound of formula (I) is also represented by the structure of formula (I-2-1):

[0176]

[0177] in

[0178] R 10 Represents the following groups:

[0179]

[0180] Among them, ring W 1 Indicates a 4- to 6-membered nitrogen-containing heterocyclic group, (R a1 ) n1 Represents ring W 1 by n1 R a1 Group substitution, each R a1 The same or different and each independently is C 1-6 Alkyl (e.g., C10)1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl groups, such as F3C-,

[0181] FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), cyano, or halogen (such as fluorine, chlorine, bromine or iodine), n1 represents an integer from 1 to 8;

[0182] Ring W 2 Indicates a 4- to 6-membered nitrogen-containing heterocyclic group, or C 3-6 cycloalkylene, n3 represents the integer 0 or 1, (R a2 ) n2 Represents ring W 2 by n2 R a2 Group substitution, each R a2 The same or different and each independently is C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-,

[0183] CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkyl groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy, or tert-butyloxy), cyano groups, halogens (e.g., fluorine, chlorine, bromine, or iodine), or oxo groups, where n2 represents an integer from 0 to 8; and

[0184] The symbol * indicates a connection point with LIN; and

[0185] R1, R2, R3, R4, (R5) n (R6) m R8, R9, R10 LIN, R 12 And X is as defined in this paper as in the compound of formula (I) and its various embodiments.

[0186] In some embodiments, the ring W of the compound of formula (I-2-1) 1 The term refers to a 4- to 6-membered nitrogen-containing heterocyclic group, which includes, but is not limited to, for example, piperidinyl, piperazineyl, morpholinyl, aziridine, pyrrolidine, imidazoalkyl, pyrazolidine, oxazolidine, thiazoalkyl, or thiomorpholinyl.

[0187] In some embodiments, the (R) of the compound of formula (I-2-1) a1 ) n1 Represents ring W 1 by n1 R a1 Group substitution, each R a1 The same or different and each independently is C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkyl group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), cyano, halogen (such as fluorine, chlorine, bromine or iodine), or oxo group, n1 represents an integer from 1 to 8 (such as integers 1, 2, 3 or 4).

[0188] In some embodiments, the ring W of the compound of formula (I-2-1) 2 The term refers to a 4- to 6-membered nitrogen-containing heterocyclic group, which includes, but is not limited to, for example, piperidinyl, piperazineyl, morpholinyl, aziridine, pyrrolidine, imidazoalkyl, pyrazolidine, oxazolidine, thiazoalkyl, or thiomorpholinyl.

[0189] In some embodiments, the ring W of the compound of formula (I-2-1) 2 C represents 3-6 Cycloalkylene compounds, including but not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0190] In some embodiments, the (R) of the compound of formula (I-2-1) a2 ) n2 Represents ring W 2 by n2 R a2 Group substitution, each R a2 The same or different and each independently is C 1-6 Alkyl (e.g., C10) 1-4 Alkyl or C 1-3 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl; and halogenated C groups. 1-6 Alkyl groups (e.g., halogenated C) 1-4 Alkyl groups, such as F3C-, FCH2-, F2CH-, ClCH2-, Cl2CH-, CF3CF2-, CF3CHF-, CHF2CF2-, CHF2CHF-, CF3CH2- or CH2ClCH2-), C 1-6 Alkoxy groups (e.g., C) 1-4 Alkoxy or C 1-3 Alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butyloxy or tert-butyloxy), cyano, halogen (such as fluorine, chlorine, bromine or iodine), or oxo, n2 represents an integer from 0 to 8 (such as integers 0, 1, 2, 3 or 4).

[0191] In some implementations, n3 in the compound of formula (I-2-1) represents the integer 0 or 1.

[0192] In some implementations, n3 in the compound of formula (I-2-1) represents the integer 0.

[0193] In some implementations, n3 in the compound of formula (I-2-1) represents the integer 1.

[0194] In some embodiments, the R of the compound of formula (I-2-1) 10 Represents the following groups:

[0195]

[0196] The symbol * indicates the connection point with LIN.

[0197] In some embodiments, the compound of formula (I) is also represented by the structure of formula (I-2-1):

[0198]

[0199] in

[0200] R8 represents -SO2CF3; and

[0201] R1, R2, R3, R4, (R5) n(R6) m R9, R 10 LIN, R 12 And X is as defined in this paper as in the compound of formula (I) and its various embodiments.

[0202] In some embodiments, the compound of formula (I) is also represented by the following structures: (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):

[0203]

[0204]

[0205] Among them, R9, R 10 LIN, R 12 、(R a ) t And X is as defined in this paper as in the compound of formula (I) and its various embodiments.

[0206] In some embodiments, specific compounds of formula (I) in Table 1 below, and their salts (including pharmaceutically acceptable salts, such as their hydrochlorides), prodrugs, solvates, isotope-enriched analogs, polymorphs, stereoisomers (including enantiomers and diastereomers), or mixtures of stereoisomers are provided:

[0207] Table 1. Compounds disclosed herein

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215] In some embodiments, hydrochloride, sulfate, citrate, maleate, sulfonate, methanesulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrophosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, hydroxyacetate, or p-toluenesulfonate of the compounds of formula (I) of this disclosure are provided.

[0216] On the other hand, this disclosure also provides novel protein degraders, or salts thereof (including pharmaceutically acceptable salts, such as their hydrochlorides), stereoisomers (including enantiomers and diastereomers), solvates, isotope-enriched analogs, prodrugs, or polymorphs developed based on BCL-2 family protein ligand compounds, as listed in Table 2 below:

[0217] Table 2. Compounds disclosed herein

[0218]

[0219]

[0220]

[0221] In some embodiments, hydrochloride, sulfate, citrate, maleate, sulfonate, methanesulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrophosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, hydroxyacetate, or p-toluenesulfonate of the compounds listed in Table 2 of this disclosure are provided.

[0222] II. Other forms of the compound (including salts, enantiomers, stereoisomers, solvates, prodrugs, or polymorphs of the compound).

[0223] The compounds disclosed herein have the structure of any one 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 structure of any one of the formulas in Table 1 or 2. Unless otherwise stated, reference to compounds of this disclosure means compounds comprising any one of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-2-1), formula (I-2-2), formula (I-2-3), formula (I-2-4), formula (I-2-5), formula (I-3-1), formula (I-3-2), formula (I-3-3), or formula (I-3-4), as well as specific compounds falling within the scope of these general formulas, such as the compounds in Table 1 or Table 2.

[0224] It should be recognized that the compounds of this disclosure (including compounds of any one 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 the compounds in Table 1 or Table 2) may have stereoconfigurations and therefore can exist in more than one stereoisomer. This disclosure also relates to optically enriched compounds of stereoconfiguration, such as about 90% ee, such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures. As used herein, "optically enriched" means that a mixture of enantiomers consists of a significantly larger proportion of one enantiomer and can be described by an enantiomer excess (ee%). Purification of isomers and separation of mixtures of isomers can be achieved using standard techniques known in the art (e.g., column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g., by using chiral intermediates) and / or chiral resolution, etc.).

[0225] In some embodiments, polymorphic forms of the disclosed compounds or salts of the disclosed compounds are also provided. Salts of the disclosed compounds can be pharmaceutically acceptable salts, including but not limited to hydrochlorides, sulfates, citrates, maleates, mesylates, citrates, lactates, tartrates, fumarates, phosphates, dihydrophosphates, pyrophosphates, metaphosphates, oxalates, malonates, benzoates, mandelates, succinates, trifluoroacetates, glycolate, or p-toluenesulfonates. The disclosed compounds can be present in pharmaceutically acceptable solvents such as water and ethanol in either a solvated or solvent form. In some embodiments, the disclosed compounds can be prepared as prodrugs or prodrugs. The prodrug can be converted into the parent drug in the body to exert its effect.

[0226] III. Pharmaceutical Compositions / Formulations

[0227] In some embodiments, this disclosure provides a pharmaceutical composition comprising, as an active ingredient, a compound of the disclosure or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, stereoisomer (including enantiomers), or mixture of stereoisomers, and at least one pharmaceutically acceptable carrier.

[0228] In some embodiments, pharmaceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, colorants, solvents, or encapsulating materials. The carrier must be compatible with other components of the formulation (including compounds useful in this disclosure) and harmless to the patient; the carrier must be "acceptable." Some examples of pharmaceutically acceptable carrier materials include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; 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 such as phosphate buffer solutions; polyoxyethylene, polyvinylpyrrolidone, polyacrylamide, poloxamer; and other non-toxic and compatible substances used in pharmaceutical formulations.

[0229] The pharmaceutical compositions described in this disclosure further include at least one second therapeutic agent, such as an anticancer agent. The second therapeutic agent may be used in combination with any one of the compounds of this disclosure (including compounds 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 compounds in Table 1 or Table 2) to treat the diseases or conditions described in this disclosure. The second therapeutic agent includes, but is not limited to, chemotherapeutic agents, immunotherapeutic agents, gene therapy agents, etc.

[0230] The pharmaceutical compositions comprising, as active ingredients, any one of the compounds described herein (including compounds 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 the compounds in Table 1 or Table 2) or pharmaceutically acceptable salts thereof, may be administered via a suitable route of administration (including, but not limited to, nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, intrapleural administration, peritoneal administration, etc.) according to a suitable route of administration (including, but not limited to, intranasal administration, inhalation administration, local administration, oral administration, oral mucosal administration, rectal administration, intrapleural administration, peritoneal administration, etc.). The drug is prepared in a suitable formulation form, such as a spray, patch, tablet (e.g., conventional tablets, dispersible tablets, orally disintegrating tablets), capsule (e.g., soft capsules, hard capsules, enteric-coated capsules), sugar-coated pills, lozenges, powders, granules, powder for injection, suppositories, or liquid formulations (e.g., suspensions (e.g., aqueous or oily suspensions), solutions, emulsions, or syrups), or conventional injectable formulations such as injectable solutions (e.g., sterile injectable solutions formulated according to methods known in the art using water, Ringer's solution, or isotonic sodium chloride solution as a carrier or solvent) or lyophilized compositions. Those skilled in the art can also prepare the compounds described in this disclosure (including any one of the compounds of formula (I), formula (I-1), formula (I-2), formula (I-3), formula (I-2-1), formula (I-2-2), formula (I-2-3), formula (I-2-4), formula (I-2-5), formula (I-3-1), formula (I-3-2), formula (I-3-3), or formula (I-3-4), or the compounds in Table 1 or Table 2) into conventional, dispersible, chewable, or orally disintegrating or rapidly dissolving formulations, or sustained-release capsules or controlled-release capsules, as needed.

[0231] The active ingredient of the compound as described in this disclosure (including any one 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 the compounds in Table 1 or Table 2) is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a subject a therapeutically effective amount for the indication to be treated without causing serious toxicity in the treated subject. The dosage of the active compound used for all diseases or conditions mentioned herein is, for example, from about 5 ng / kg subject body weight / day to 500 mg / kg subject body weight / day, from about 10 ng / kg subject body weight / day to 300 mg / kg subject body weight / day, for example, from 0.1 to 100 mg / kg subject body weight / day, or from 0.5 to about 25 mg / kg subject body weight / day.

[0232] The compounds described in this disclosure (including compounds of any one 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 the compounds in Table 1 or Table 2) or pharmaceutically acceptable salts thereof may be conveniently administered in any suitable formulation, the specifications of which include, but are not limited to, less than 1 mg, 1 mg to 3000 mg, or 5 mg to 1000 mg per unit dosage form, for example 5 to 500 mg, or 25 to 250 mg of active ingredient.

[0233] IV. Medicine kits / packaging products

[0234] The compounds described in this disclosure (including compounds of any one of formulas (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 the compounds in Tables 1 or 2), or pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, are intended for use as pharmaceutical agents. The pharmaceutical agents or pharmaceutical compositions of this disclosure may be present in a cassette / packaging article. The cassette / packaging article may include packaging or containers. Packaging or containers include, but are not limited to, ampoules, blister packs, pharmaceutical plastic bottles, vials, pharmaceutical glass bottles, containers, syringes, laminated flexible packaging, co-extruded film infusion containers, test tubes, and dispensing devices, etc. Medicine boxes / packaging products may include product instructions.

[0235] V. Methods and Applications

[0236] The compounds described in this disclosure (including compounds of any one 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 the compounds in Table 1 or Table 2), or pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, stereoisomers (including enantiomers), or mixtures of stereoisomers thereof, may also be used as pharmaceutical agents. In particular, the compounds described in this disclosure (including compounds of any one 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 the compounds in Table 1 or Table 2), or their pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, stereoisomers (including...) Enantiomers (or mixtures of stereoisomers) can be used to prepare medicines for the prevention and / or treatment of diseases or conditions selected from the following: neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, myelofibrosis, renal fibrosis, liver fibrosis, cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), multiple organ failure due to cachexia and septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes, transplant rejection, retinopathy, and acute liver failure. In some implementations, the diseases or conditions include, but are not limited to: neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease; cardiovascular diseases, including, for example, coronary artery 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, Sjögren's syndrome, and atopic dermatitis; myelofibrosis; renal fibrosis; liver fibrosis; cirrhosis; tumors, including hematologic 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; retinopathy, including diabetic macular edema (DME) and wet age-related macular degeneration (wAMD); and diabetes.In some implementations, the tumor includes, but is not limited to: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, and smoldering multiple myeloma; myelofibrosis; bone marrow diseases; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancers; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, leukemia-associated anemia, and acute myeloid leukemia (AML); lymphoma; and other related conditions. Tumors, including diffuse large B-cell lymphoma, non-Hodgkin 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 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 lymphoma, and refractory B-cell non-Hodgkin lymphoma. Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, Waldenström 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; glioma; glioblastoma; ovarian cancer; bronchial cancer; prostate cancer; breast cancer, including estrogen-dependent breast cancer, HER2-positive breast cancer, triple-negative breast cancer. Incidental breast cancer and Cowden's disease; pancreatic cancer; neuroblastoma; extramedullary 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 adipose-derived 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.

[0237] A method for preventing and / or treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure (including any one 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 compounds of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, the disease or condition includes: neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, myelofibrosis, renal fibrosis, liver fibrosis, cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), cachexia and septic shock leading to multiple organ failure, including kidney, heart, and lung transplant rejection, diabetes, transplant rejection, retinopathy, and acute liver failure. In some implementations, the diseases or conditions include, but are not limited to: neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease; cardiovascular diseases, including, for example, coronary artery 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, Sjögren's syndrome, and atopic dermatitis; myelofibrosis; renal fibrosis; liver fibrosis; cirrhosis; tumors, including hematologic 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; retinopathy, including diabetic macular edema (DME) and wet age-related macular degeneration (wAMD); and diabetes.In some implementations, the tumor includes, but is not limited to: myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, and smoldering multiple myeloma; myelofibrosis; bone marrow diseases; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancers; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, leukemia-associated anemia, and acute myeloid leukemia (AML); lymphoma; and other related conditions. Tumors, including diffuse large B-cell lymphoma, non-Hodgkin 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 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 lymphoma, and refractory B-cell non-Hodgkin lymphoma. Hodgkin's lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal (thymic) large B-cell lymphoma, refractory transformed non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, Waldenström 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; glioma; glioblastoma; ovarian cancer; bronchial cancer; prostate cancer; breast cancer, including estrogen-dependent breast cancer, HER2-positive breast cancer, triple-negative breast cancer. Incidental breast cancer and Cowden's disease; pancreatic cancer; neuroblastoma; extramedullary 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 adipose-derived 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.

[0238] In a method for preventing and / or treating the disease or condition of a subject, a therapeutically effective amount of the compound of this disclosure (including any one of the compounds 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 the compounds in Table 1 or Table 2) or the pharmaceutical composition of this disclosure is administered to the subject via at least one administration route selected from nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, intrapleural administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration, and intravenous administration)

[0239] The terms “treatment” or “treatment” refer to the administration to a subject of a compound described in this disclosure (including any one 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 compounds in Table 1 or Table 2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of this disclosure or a pharmaceutically acceptable salt thereof, to slow (alleviate) the development of an undesirable disease or condition (e.g., tumor). Beneficial or desired clinical outcomes of this disclosure include, but are not limited to: relief of symptoms, reduction of disease severity, stabilization of disease status, delay or slowing of disease progression, improvement or mitigation of the condition, and remission of the disease.

[0240] The "therapeutic effective amount" of the disclosed compounds depends on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, the patient's age, sex and weight, the patient's overall medical condition, the route and timing of administration, the excretion rate, concomitant medication, and the disease or disease progression of the patient being treated. Those skilled in the art can determine the appropriate dosage based on these and other factors.

[0241] It should be understood that the choice of use of one or more active compounds and / or combinations and their dosage depends on the individual’s basic condition (generally, the individual condition should be optimized for the best effect). Dosing and dosing regimens should be within the competence of those skilled in the art, and appropriate dosage depends on many factors including the knowledge and competence level of a general technical physician, veterinarian, or researcher (see, for example, Li Jun, ed., “Clinical Pharmacology”, 4th edition, People’s Medical Publishing House (2008)).

[0242] The patients or subjects of the above treatment refer to animals, such as mammals, including but not limited to primates (such as humans), cattle, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, mice, etc.

[0243] VI. Definition

[0244] Unless otherwise stated, the following words, phrases and symbols used in this specification generally have the meanings described below.

[0245] Generally, the nomenclature used herein (including IUPAC nomenclature) and the laboratory procedures described below (including those for cell culture, organic chemistry, analytical chemistry, and pharmacology) are those well-known and commonly used in the art. Unless otherwise defined, all scientific and technical terms used herein in conjunction with the disclosure described herein have the same meaning as commonly understood by one of ordinary skill in the art. Additionally, in the claims and / or description, the term “a” or “an” used in conjunction with the term “comprising” or a noun may mean “one,” but also is consistent with the meanings of “one or more,” “at least one,” and “one or more.” Similarly, the term “another” or “other” may mean at least a second or more.

[0246] It should be understood that whenever this document uses the terms “comprising” or “including” to describe a particular aspect, other similar aspects described by “consisting of” and / or “substantially consisting of” are also provided.

[0247] The term “about” is used herein to mean approximately, roughly, about, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical value. Generally, the term “about” can modify numerical values ​​above and below the stated value by varying upward or downward (increasing or decreasing) for example, by 10%, 5%, 2%, or 1%.

[0248] In this article, the phrase "... denotes a key" means that it is a key-connected entity (i.e., it indicates that it does not exist). For example, the phrase "R..." 12 "Key" means R 12 It is a bond connector. In other words, when R 12 When the bond is LIN, the group LIN in the structure of formula (I) is directly attached to the benzene ring in the structure of formula (II).

[0249] As used herein, the term "insertion of one or more groups R into its main carbon chain" or "intercalation of one or more groups R" is used alone or in combination. b and / or one or more groups R c Or one or more groups R b With R c Any combination of optional substitutions for straight or branched C 2-30The term "insertion" in "alkylene" has a definition known in the art, namely, it can refer to the group R. b R c Or group R b With R c Any combination thereof breaks one or more pairs of carbon-carbon bonds between adjacent carbon atoms in the main carbon chain. In this document, examples of the above term "inserting one or more" may include, but are not limited to, inserting one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2, or 1) groups R as defined herein into the main carbon chain. b And / or one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R c And / or one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R b With R c Any combination of these groups results in a main chain group that conforms to the covalent bond theory. For example, the statement "one or more groups R are inserted into its main carbon chain" is valid. b and / or one or more groups R c Or one or more groups R b With R c Any combination of optional substitutions for straight or branched C 2-30 "alkylene" refers to straight-chain or branched C 2-30 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 are inserted between any two adjacent carbon atoms in one or more pairs of the main carbon chain of the alkylene chain. b and / or R c and / or one or more groups R b With R c Any combination of these to form a structure containing one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) "-CH2-R b -CH2-" segments and / or one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1) "-CH2-R c-CH2-" segments and / or one or more (e.g., 1-30, 1-20, 1-15, 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2 or 1) "-CH2-R b -R c -CH2-” fragment, where each R b Whether the R values ​​are the same or different, each R value c Same or different, and as defined in this article.

[0250] In this document, the term “optionally substituted” used alone or in combination means that the indicated group may be unsubstituted or substituted with one or more substituents as defined herein. In this document, the terms “optionally substituted” and “unsubstituted or substituted” are used interchangeably. The term “substituted” generally indicates that one or more hydrogens in the mentioned structure are substituted with the same or different specific substituents. The number of substituents is not limited in principle, or is automatically limited by the size of the building unit (i.e., the total number of substituted hydrogen atoms in the building unit), or as expressly defined herein.

[0251] In this paper, the broken bonds indicated by the wavy lines show the connection points between the illustrated groups and other parts of the molecule. For example, the group represented by formula (II) illustrated below.

[0252]

[0253] R represents the group 12 It is attached to the LIN group of the compound of formula (I).

[0254] In this document, the term "the C" is used alone or in combination. x-y "One or more hydrogen atoms of CH2 in an alkylene group are replaced by..." indicates a straight-chain or branched C-chain. x-y The hydrogen atoms in any one or more of the CH2 groups in the alkylene group are replaced by substituents as defined herein. In this document, "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 hydrogens of CH2" in "one or more hydrogens of CH2" can refer to some or all of the hydrogens of the mentioned alkylene groups, including but not limited to 1-60 hydrogens. In some embodiments, the term "one or more hydrogens of CH2" can refer to some or all of the hydrogens of the mentioned alkylene groups, including but not limited to 1-30, such as 1-25, 1-20, 1-15, 1-10, 1-5, 1-4, 1-3, 1-2, or 1 hydrogen. In some embodiments, the term "one or more hydrogens of CH2" can refer to 1-3 of the multiple hydrogens of the mentioned alkylene groups. This number is not limited in principle or is automatically limited by the size of the building blocks.

[0255] In this article, the term "oxo" or "oxo group" refers to =O.

[0256] In this document, the terms “halogen atom” or “halogen” used alone or in combination refer to fluorine, chlorine, bromine, or iodine.

[0257] In this document, the term "alkyl" as used alone or in combination refers to a straight-chain or branched alkyl group. The term "C" x -C y Alkyl or C x-y Alkyl group (where x and y are integers) refers to a straight-chain or branched alkyl group containing x to y carbon atoms. The term "C" used alone or in combination in this invention... 1-10 "Alkyl" refers to a straight-chain or branched alkyl group containing 1 to 10 carbon atoms. The C10 of this disclosure... 1-10 Examples of alkyl groups include C 1-9 Alkyl, C 1-8 Alkyl, C 2-8 Alkyl, C 1-7 Alkyl, C 1-6 Alkyl, C 1-5 Alkyl groups, and C 1-4 Alkyl groups. Representative examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, p-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. The term "C" in this disclosure... 1-3 "Alkyl" or "C1-C3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms, with representative examples including methyl, ethyl, n-propyl, and isopropyl. In this disclosure, the "alkyl" may be optionally substituted, with the substituent being one or more selected from halogens, hydroxyl groups, cyano groups, C1-C3 groups, etc. 1-3 Alkyl, C1-3 Substituents of alkoxy, trifluoromethyl, heterocyclic, or combinations thereof.

[0258] In this document, the term "halogenated alkyl" as used alone or in combination refers to a straight-chain or branched alkyl group substituted with one or more halogens, wherein one or more hydrogen atoms in the alkyl group are substituted with halogens. The term "halogenated C" x -C y Alkyl or halogenated C x-y Alkyl group (where x and y are integers) refers to a straight-chain or branched alkyl group containing x to y carbon atoms that has been substituted with one or more halogens. The term "halogenated C" is used alone or in combination in this disclosure. 1-10 "Alkyl" refers to a straight-chain or branched alkyl group containing 1 to 10 carbon atoms that has been substituted with one or more halogens (e.g., fluorine, chlorine, bromine, or iodine). The halogenated C-type alkyl groups disclosed herein... 1-10 Examples of alkyl groups include halogenated C4 groups. 1-9 Alkyl groups, such as 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 1-4 Alkyl groups. Representative examples include halogenated methyl, halogenated ethyl, halogenated n-propyl, halogenated isopropyl, halogenated n-butyl, halogenated isobutyl, halogenated sec-butyl, halogenated tert-butyl, halogenated pentyl, halogenated isopentyl, halogenated neopentyl, halogenated tert-pentyl, halogenated hexyl, halogenated heptyl, halogenated octyl, halogenated nonyl, and halogenated decyl. The term "halogenated C" in this disclosure... 1-3 "Alkyl" or "halogenated C1-C3 alkyl" refers to an alkyl group containing 1 to 3 carbon atoms that has been substituted with one or more halogens. Representative examples include halogenated methyl, halogenated ethyl, halogenated n-propyl, and halogenated isopropyl.

[0259] In this document, the term "alkylene" (which is used alone or in combination and is interchangeable with "alkylene chain") refers to a straight-chain or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen. The term "C..." x -C y "alkylene" or "C" x-y "alkylene" (where x and y are integers) refers to a straight-chain or branched alkylene containing x to y carbon atoms. The C1-C of this disclosure... 30 Examples of alkylene groups include 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 24Alkylene, 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 15 Alkylene, 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, pentylene, isopentylene, neopentylene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecanylene, octadecylene, nonadecanylene, eicosylene, icosylene, icosylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecanylene, octadecylene, nonadecanylene, and triacontylene. In this disclosure, the "alkylene" is optionally substituted, and the substituent may be one or more selected from C1-C3 alkyl groups, C4-C5 alkyl groups, C6 ... 3-6 Cycloalkyl, hydroxyl, 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 Alkyl-C(O)NH-, cyano, or any combination thereof are substituents.

[0260] In this document, the term "alkoxy" as used alone or in combination refers to a straight-chain or branched alkoxy group with the structural formula alkyl-O-. Optionally, the alkyl portion of the alkoxy group 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, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. The terms "C1-C3 alkoxy" or "C 1-3"Alkoxy" refers to a straight-chain or branched alkoxy group containing 1 to 3 carbon atoms. 1-3 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0261] In this invention, the term "heteroaryl," used alone or in combination, refers to an aromatic ring group containing at least one 5- to 20-membered (optionally 5- to 15-membered, 5- to 12-membered, 5- to 11-membered, 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 6- to 15-membered, or 6- to 9-membered) monocyclic, bicyclic, or polycyclic aromatic ring having one or more (e.g., 1 to 6, 1 to 5, 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroaryl groups include bicyclic, tricyclic, or tetracyclic heteroaryl groups, wherein one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated, or aromatic rings and may be carbocyclic or contain one or more heteroatoms independently selected from O, S, and N. Representative examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, isoyindolyl, isoyindolinyl, benzofuranyl, isobenzofuranyl, benzothiopheneyl, inazolyl, benzimidazolyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, naphridinyl, and zolinyl. Examples of tricyclic heteroaryl groups include (but are not limited to) acrylonitrile, quinoxalonitrile, phthalazinyl, oxazolopyridyl, furanopyridyl, pteridinyl, purine, 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 heteroaryl groups include (but are not limited to) acrylonitrile, benzoindolyl, carbazole, dibenzofuranyl, and xanthonyl. The heteroaryl groups may be unsubstituted or substituted. Substituted heteroaryl refers to a heteroaryl group that has been substituted one or more times (e.g., 1-4, 1-3, or 1-2 times), wherein the substituents are optionally selected from C1-C3 alkyl groups, ... 3-6 Cycloalkyl, hydroxyl, 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 1-3Alkyl-C(O)NH-, cyano, or any combination thereof.

[0262] In this invention, the term "hybrid aryl" used alone or in combination refers to a divalent aromatic ring group containing at least one 5- to 20-membered (optionally 5- to 15-membered, 5- to 12-membered, 5- to 11-membered, 5- to 10-membered, 5- to 9-membered, 5- to 8-membered, 5- to 7-membered, 5- to 6-membered, 6- to 15-membered, or 6- to 9-membered) monocyclic, bicyclic, or polycyclic aromatic ring having one or more (e.g., 1 to 6, 1 to 5, 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Bicyclic or polycyclic heteroaryl groups include bicyclic, tricyclic, or tetracyclic heteroaryl groups, wherein one ring is an aromatic ring having one or more heteroatoms independently selected from O, S, and N, and the other rings may be saturated, partially unsaturated, or aromatic rings and may be carbocyclic or contain one or more heteroatoms independently selected from O, S, and N. Representative examples of monocyclic heteroaryl groups include, but are not limited to, iminofuranyl, iminozolyl, iminozolyl, iminodiazolyl, iminophenyl, iminozolyl, iminozolyl, iminodiazolyl, iminopyrroleyl, iminozolyl, iminopyrazolyl, iminotriazolyl, iminopyridyl, iminopyridinyl, iminopyrazinyl, iminotetrazoleyl, and iminotriazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, isoyindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazoleyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisoxazolyl, benzothiazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxetazolyl, benzotriazolyl, benzo[2,1,3]oxadiazolyl, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, naphthidyl, and zolinyl. Examples of tricyclic heteroaryl groups include (but are not limited to) acrylonitrile, quinoxalonitrile, phthalazinyl, oxazolopyridyl, furanopyridyl, pteridinyl, purine, pyridinopyridyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,1-b]thiazole, and imidazo[2,1-b]thiazole. Examples of tricyclic heteroaryl groups include (but are not limited to) acrylonitrile, benzoindolyl, carbazoyl, dibenzofuranyl, and xanthonyl. The heteroaryl groups may be unsubstituted or substituted. Substituted heteroaryl refers to a heteroaryl group that has been substituted one or more times (e.g., 1-4, 1-3, or 1-2 times), wherein the substituents are optionally selected from C1-C3 alkyl groups, ... 3-6 Cycloalkyl, hydroxyl, 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)-, C1-3 Alkyl-C(O)NH-, cyano, or any combination thereof.

[0263] In this document, the term "aryl" as used alone or in combination refers to a monovalent aromatic hydrocarbon group comprising 5 to 14 carbon atoms and optionally comprising one or more fused rings, such as phenyl, naphthyl, or fluorenyl. In this disclosure, "aryl" refers to an optionally substituted aryl group. A substituted aryl group is an aryl group that is substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) by a substituent, such as a monosubstituted, disubstituted, or trisubstituted aryl group, wherein the substituent is optionally selected, for example, from C1-C3 alkyl, C2-C4 alkyl, C3 ... 3-6 Cycloalkyl, hydroxyl, 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 Alkyl-C(O)NH-, cyano, or any combination thereof.

[0264] In this disclosure, the term "arylene" as used alone or in combination refers to a divalent aromatic hydrocarbon group comprising 5 to 14 carbon atoms and optionally comprising one or more fused rings, such as phenylene, naphthylene, or fluorene. In this disclosure, the "arylene" is an optionally substituted arylene. A substituted arylene refers to an arylene that has been substituted one or more times (e.g., 1-4, 1-3, or 1-2 times) by a substituent, such as a mono-, di-, or tri-substituted arylene, wherein the substituent is optionally selected, for example, from C1-C3 alkyl, C2-C4 alkyl, C3 ... 3-6 Cycloalkyl, hydroxyl, 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 Alkyl-C(O)NH-, cyano, or any combination thereof.

[0265] In this document, the term "cycloalkyl" as used alone or in combination refers to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) monocyclic, bicyclic, or polycyclic cyclic hydrocarbon group having 3 to 20 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 3-20 cycloalkyl groups, or 3 to 15 carbon atoms (i.e., C14-C15). 3-15 cycloalkyl groups, 3 to 12 carbon atoms (i.e., C64) 3-12 cycloalkyl groups, or 3 to 11 carbon atoms (i.e., C164-C ... 3-11 cycloalkyl groups, or 3 to 10 carbon atoms (i.e., C14-C15). 3-10 cycloalkyl groups, or 3 to 8 carbon atoms (i.e., C646-C ... 3-8cycloalkyl groups, or 3 to 7 carbon atoms (i.e., C64-C75 ... 3-7 cycloalkyl groups, or 3 to 6 carbon atoms (i.e., C64-C ... 3-6 Cycloalkyl. The term “cycloalkyl” includes monocyclic, bicyclic, or tricyclic cycloalkyl groups having 3 to 20 carbon atoms. Representative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic and tricyclic cycloalkyl groups include bridged cycloalkyl, fused cycloalkyl, and spirocycloalkyl groups, such as, but not limited to, decahydronaphthyl, octahydrocyclopentadienyl, octahydro-1H-indenyl, spirocycloalkyl, adamantyl, noradamantyl, borneol, norborneolyl (IUPAC system name: bicyclo[2.2.1]heptyl). In this document, “cycloalkyl” is optionally monosubstituted or polysubstituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups. The substituted "cycloalkyl" may optionally have one or more (e.g., 1-5, 1-4, 1-3, 1-2, or 1) substituents selected from C1-C3 alkyl, C1-C2 ... 3-6 Cycloalkyl, hydroxyl, 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 Alkyl-C(O)NH-, cyano, or any combination thereof are substituents. The term "C" is used to indicate the presence of substituents. 3-6 Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.

[0266] In this document, the term "C" is used alone or in combination. x-y "spirocycloalkyl" or "C" x-y "Spirocycloalkyl" (where x and y are integers) refers to a spirocycloalkyl group containing x to y carbon atoms. The term "C" used alone or in combination in this invention... 7-11 "Spirocycloalkyl" refers to a spirocycloalkyl group containing 7 to 11 (e.g., 7-10, 7-9) carbon atoms. The term "C"... 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. The "C" 7-11 The "spirocycloalkyl" may optionally be further derived from one or more alkyl groups selected from C1-C3 alkyl groups. 3-6 Cycloalkyl, hydroxyl, 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)-, C1-3 Substitution by alkyl-C(O)NH-, cyano, or any combination thereof.

[0267] In this invention, the term "cycloalkylene" used alone or in combination refers to a monocyclic, bicyclic, or polycyclic hydrocarbon divalent group having 3 to 12 carbon atoms (e.g., 3-12, 3-11, 3-10, 3-8, 3-7, 3-6 carbon atoms) that is saturated or partially unsaturated (i.e., has one or more double bonds, but is not fully conjugated). The term "cycloalkylene" includes monocyclic, bicyclic, or tricyclic hydrocarbon divalent groups having 3 to 12 carbon atoms. Representative examples of monocyclic cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, and cyclooctylene. Bicyclic and tricyclic cycloalkylene groups include bridged cycloalkylene, fused cycloalkylene, and spirocycloalkylene, such as, but not limited to, decahydronaphthylene, octahydrocyclopentadienylene, octahydro-1H-indenylene, 2,3-dihydro-1H-indenylene, spirocycloalkylene, adamantylene, norbornenylene (systematically named bicyclic [2.2.1]heptaneylene). In this disclosure, the “cycloalkylene” is optionally monosubstituted or polysubstituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexylene. The substituents of the substituted “cycloalkylene” are optionally one or more selected from C1-C3 alkylene, C2-C4-alkylene, C3-C4-alkylene, C4 ...C4-alkylene, C4-C4-C4-alkylene, C4-C4-C4-alkylene, C4-C4-C4-C4-alkylene, C 3-6 Cycloalkyl, hydroxyl, 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 Alkyl-C(O)NH-, cyano, or any combination thereof are substituents.

[0268] In this document, the term "C" is used alone or in combination. x-y "Hydrocycloalkyl" or "C" x-y "Hydrocycloalkyl group" (where x and y are integers) refers to a cycloalkyl group containing x to y carbon atoms. The term "C" used alone or in combination in this invention... 7-11 "Spirocycloalkyl" refers to a spirocycloalkyl group containing 7 to 11 (e.g., 7-10, 7-9) carbon atoms. The term "C"... 7-11 Representative examples of "spirocycloalkyl" include, but are not limited to, spiro[3.3]heptanediol, spiro[2.5]octanediol, spiro[3.5]nonanediol, spiro[4.4]nonanediol, spiro[4.5]decanediol, or spiro[5.5]undecanediol. The "C" 7-11 "Spirocycloalkyl" may optionally be further derived from one or more alkyl groups selected from C1-C3 alkyl groups. 3-6Cycloalkyl, hydroxyl, 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 Substitution by alkyl-C(O)NH-, cyano, or any combination thereof.

[0269] In this document, the terms “heterocyclic” or “heterocyclic alkyl” as used alone or in combination refer to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cyclic hydrocarbon group comprising one or more (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen, of a 3 to 20-membered monocyclic, bicyclic, or tricyclic ring. In some embodiments, “heterocyclic” may refer to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) cyclic hydrocarbon group comprising one or more (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen, of a 3 to 15-membered (optionally 3 to 14, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 4 to 9) monocyclic ring. Representative examples of monocyclic heterocyclic groups include, but are not limited to, azirrobutyl, oxacyclobutyl, pyrrolidinyl, imidazoalkyl, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiaranyl, oxazolyl, thiazoalkyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxacyclohexyl, azirroheptyl, azirrooctyl, diazacycloheptyl (e.g., 1,4-diazacycloheptane-1-yl), and diazacyclooctyl. Bicyclic and tricyclic heterocyclic groups include bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups, with representative examples including but not limited to 6-azabicyclo[3.1.1]heptane-3-yl, 2,5-diazabicyclo[2.2.1]heptane-2-yl, 3,6-diazabicyclo[3.1.1]heptane-3-yl, 3-azabicyclo[3.2.1]octane-8-yl, 3,8-diazabicyclo[3.2.1]octane-8-yl, 3,8-diazabicyclo[3.2.1]octane-3-yl, 2,5-diazabicyclo[2.2.2]octane-2-yl, and azaspirocyclic groups (e.g., 3-azaspiro[5.5]undecane-3-yl). The heterocyclic group may be unsubstituted or substituted as defined (e.g., mono-, di-, tri-, or poly-substituted), wherein the substituent is optionally selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, and optionally deuterated C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, optional deuterated C 3-6 cycloalkyl, optional deuterated C 1-6 Alkoxy, optional deuterated C 1-6Alkyl-NH-, NH2-C 1-6 Alkylene, optional deuterated C 1-6 Alkyl-NHC(O)-, optionally deuterated C 1-6 Alkyl-C(O)NH- or any combination thereof.

[0270] In this document, the term “nitrogen-containing monocyclic heterocyclic group” used alone or in combination refers to a monocyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) monocyclic cyclic hydrocarbon group containing one nitrogen atom and optionally one or more (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) heteroatoms independently selected from sulfur, oxygen and nitrogen, consisting of a 3 to 20-membered (optionally 3 to 15-membered, 3 to 14-membered, 3 to 12-membered, 3 to 11-membered, 3 to 10-membered, 3 to 9-membered, 3 to 8-membered, 3 to 7-membered, 3 to 6-membered, 3 to 5-membered or 4 to 9-membered) monocyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) hydrocarbon group. Representative examples of nitrogen-containing monocyclic heterocyclic groups include, but are not limited to, aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, oxazolyl, thiazoalkyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridine-heptyl, aziridine-octyl, diazacycloheptyl (e.g., 1,4-diazacycloheptane-1-yl), and diazacyclooctyl. The nitrogen-containing monocyclic heterocyclic group may be unsubstituted or substituted as defined (e.g., mono-, di-, tri-, or poly-substituted), wherein the substituent is optionally selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, and optionally deuterated C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, optional deuterated C 3-6 cycloalkyl, optional deuterated C 1-6 Alkoxy, optional deuterated C 1-6 Alkyl-NH-, NH2-C 1-6 Alkylene, optional deuterated C 1-6 Alkyl-NHC(O)-, optionally deuterated C 1-6 Alkyl-C(O)NH- or any combination thereof.

[0271] In this document, the terms “heterocyclic group” or “heterocyclic alkyl group” used alone or in combination refer to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen, of a 3 to 20-membered monocyclic, bicyclic, or tricyclic ring. In some embodiments, “heterocyclic group” may, for example, refer to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one or more (e.g., containing 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen, of a 3 to 15-membered (optionally 3 to 14, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 4 to 9) monocyclic ring. Representative examples of monocyclic heterocyclic groups include, but are not limited to, azapyrocyclobutyl, oxazolidinyl, pyrrolidine, imidazoalkyl, pyrazolidine, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiaranyl, oxazolidinyl, thiazoalkyl, piperidinyl, piperazineyl, morpholinyl, thiomorpholinyl, dioxazolidinyl, and diazacycloheptanediol (e.g., 1,4-diazacycloheptanediol, 4,5-diazacycloheptanediol, 1,3-diazacycloheptanediol). Bicyclic and tricyclic heterocyclic groups include bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups, with representative examples including, but not limited to, 6-azabicyclo[3.1.1]heptane group, 2,5-diazabicyclo[2.2.1]heptane group, 3,6-diazabicyclo[3.1.1]heptane group, 3-azabicyclo[3.2.1]octane group, 3,8-diazabicyclo[3.2.1]octane group, 3,8-diazabicyclo[3.2.1]octane group, 2,5-diazabicyclo[2.2.2]octane group, and azaspirocyclic groups (e.g., 3-azaspiro[5.5]undecane group). The heterocyclic group may be unsubstituted or substituted as defined (e.g., mono-, di-, tri-, or poly-substituted), wherein the substituent may be selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, or optionally deuterated C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, optional deuterated C 3-6 cycloalkyl, optional deuterated C 1-6 Alkoxy, optional deuterated C 1-6 Alkyl-NH-, NH2-C 1-6 Alkylene, optional deuterated C 1-6 Alkyl-NHC(O)-, optionally deuterated C 1-6 Alkyl-C(O)NH- or any combination thereof.

[0272] In this document, the term “nitrogen-containing subheterocyclic group” used alone or in combination refers to a 3 to 20-membered (optionally 3 to 15, 3 to 14, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 4 to 9) monocyclic, bicyclic, or tricyclic saturated or partially unsaturated (i.e. having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group containing one nitrogen atom and optionally one or more (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms independently selected from sulfur, oxygen, and nitrogen. Representative examples of nitrogen-containing heterocyclic groups include, but are not limited to, piperidinyl, piperazineyl, morpholinyl, azeticyclic butyl, pyrrolidine, imidazoalkyl, pyrazolidine, oxazolidine, thiazoalkyl, thiomorpholinyl, azeticyclic heptyl, diazeticyclic heptyl, azeticyclic octyl, and diazeticyclic octyl. The nitrogen-containing heterocyclic group may be unsubstituted or substituted as defined (e.g., mono-, di-, tri-, or poly-substituted), wherein the substituent is optionally selected from deuterium, hydroxyl, amino, mercapto, nitro, halogen, cyano, and optionally deuterated C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, optional deuterated C 3-6 cycloalkyl, optional deuterated C 1-6 Alkoxy, optional deuterated C 1-6 Alkyl-NH-, NH2-C 1-6 Alkylene, optional deuterated C 1-6 Alkyl-NHC(O)-, optionally deuterated C 1-6 Alkyl-C(O)NH- or any combination thereof.

[0273] In this document, the term "ynynyl" as used alone or in combination refers to a straight-chain or branched divalent hydrocarbon group having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon triple bonds and comprising 2 to 8 (e.g., 2 to 6, 2 to 5, 2 to 4, preferably 2) carbon atoms. Examples of ynynyl groups include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.

[0274] In this document, the term "alkynyl" as used alone or in combination refers to a straight-chain or branched monovalent hydrocarbon group having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon triple bonds and comprising 2 to 8 (e.g., 2 to 6, 2 to 5, 2 to 4, preferably 2) carbon atoms. 2-6 Examples of "alkynyl" include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl and 1,3-diynyl.

[0275] In this document, the term “alkenyl” as used alone or in combination refers to a straight-chain or branched divalent hydrocarbon group having one or more (e.g., 1 to 3, 1 to 2 or 1) carbon-carbon double bonds and containing 2 to 8 carbon atoms (e.g., 2 to 6, 2 to 5, or 2 to 4, 2 to 3 or 2 carbon atoms). Examples of alkenyl groups include, but are not limited to, vinylidene (e.g., -CH=CH-), 1-propenyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, pentenyl, n-pent-2,4-dieneyl, 1-methyl-but-1-eneyl, 2-methyl-but-1-eneyl, 3-methyl-but-1-eneyl, 1-methyl-but-2-eneyl, 2-methyl-but-2-eneyl, 3-methyl-but-2-eneyl, 1-methyl-but-3-eneyl, 2-methyl-but-3-eneyl, 3-methyl-but-3-eneyl, and hexenyl.

[0276] In this document, the term "alkenyl" as used alone or in combination refers to a straight-chain or branched monovalent hydrocarbon group having one or more (e.g., 1 to 3, 1 to 2, or 1) carbon-carbon double bonds and containing 2 to 8 carbon atoms (e.g., 2 to 6, 2 to 5, or 2 to 4, 2 to 3, or 2 carbon atoms). "C 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-pent-2,4-dienyl, 1-methyl-but-1-enyl, 2-methyl-but-1-enyl, 3-methyl-but-1-enyl, 1-methyl-but-2-ene, 2-methyl-but-2-ene, 3-methyl-but-2-ene, 1-methyl-but-3-enyl, 2-methyl-but-3-enyl, 3-methyl-but-3-enyl, and hexenyl.

[0277] In this document, the terms "borneol" or "borneylane" (also known as 1,7,7-trimethylbicyclo[2.2.1]heptane; camphane; bornylane) have definitions known to those skilled in the art. In this document, the terms "borneyl group" or "borneyl group" refer to the monovalent group of borneol, i.e., the group remaining after removing any one of the hydrogen atoms from borneol. Representative examples of "borneyl group" include, but are not limited to, 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,

[0278] In this document, the term “bicyclo[2.2.1]heptane” or “norbornane” has a definition known to those skilled in the art. In this document, “bicyclo[2.2.1]heptyl” or “norbornyl” refers to the monovalent group of bicyclo[2.2.1]heptane, i.e., the group remaining after removing any one of the hydrogen atoms from bicyclo[2.2.1]heptane. Representative examples of “bicyclo[2.2.1]heptyl” include, but are not limited to, bicyclo[2.2.1]heptane-2-yl, bicyclo[2.2.1]heptane-3-yl, bicyclo[2.2.1]heptane-4-yl, bicyclo[2.2.1]heptane-5-yl, or bicyclo[2.2.1]heptane-6-yl.

[0279] In this document, the term "bicyclo[2.2.1]heptene" (also known as bicyclo[2.2.1]heptene) has a definition known to those skilled in the art. In this document, "bicyclo[2.2.1]heptenyl" refers to the monovalent group of bicyclo[2.2.1]heptene, that is, the group remaining after removing any one of the hydrogen atoms from bicyclo[2.2.1]heptene. Representative examples of "bicyclo[2.2.1]heptenyl" include, but are not limited to, bicyclo[2.2.1]hept-5-en-2-yl, bicyclo[2.2.1]hept-5-en-3-yl, or bicyclo[2.2.1]hept-5-en-7-yl.

[0280] In this article, the term "adamantane" (also known as Tricyclo[3.3.1.1]) is used. 3,7 ]decane) has a definition known to those skilled in the art, and its structure is as follows: In this article, "adamantyl" refers to the monovalent group of adamantane, that is, the group remaining after removing any one of the hydrogen atoms in adamantane. Representative examples of "adamantyl" include, but are not limited to, 1-adamantyl, 2-adamantyl, 3-adamantyl, 4-adamantyl, 5-adamantyl, 6-adamantyl, 7-adamantyl, 8-adamantyl, 9-adamantyl, or 10-adamantyl.

[0281] In this document, the term "noradamantane" has a definition known to those skilled in the art, and its structural formula is shown below for example: In this article, "noradamantyl" refers to the monovalent group of noradamantane, that is, the group remaining after removing any one of the hydrogen atoms in noradamantane. Representative examples of "noradamantyl" include, but are not limited to, 1-noradamantyl, 2-noradamantyl, 3-noradamantyl, 4-noradamantyl, 5-noradamantyl, 6-noradamantyl, 7-noradamantyl, 8-noradamantyl, or 9-noradamantyl.

[0282] In this document, the term "adamantanamine" has a definition known to those skilled in the art, namely, an adamantane having an amino substituent, wherein the amino group may replace a hydrogen atom at any position on the carbon atom of the adamantane. An example of "adamantanamine" may be adamantane-1-amine (its corresponding English chemical name is adamantane-1-amine or Tricyclo[3.3.1.1]). 3,7 [decan-1-amine; CAS: 768-94-5] has the following structural formula

[0283]

[0284] Salts of compounds of formula (I) described in this disclosure, or salts of compounds in Table 1 or 2, or pharmaceutically acceptable salts thereof, enantiomers, stereoisomers, solvates, and polymorphs are also included within the scope of this disclosure.

[0285] In all embodiments of this disclosure, the salts or pharmaceutically acceptable salts of the compounds (including compounds of any one of formulas (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 the compounds in Tables 1 or 2) refer to non-toxic inorganic or organic acid and / or base addition salts. Examples include: sulfates, hydrochlorides, citrates, maleates, methanesulfonates, citrates, lactates, tartrates, fumarates, phosphates, dihydrophosphates, pyrophosphates, metaphosphates, oxalates, malonates, benzoates, mandelates, succinates, hydroxyacetates, or p-toluenesulfonates, etc.

[0286] A "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, such as a filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that carries or transports the useful compounds of this disclosure into or to a patient so that the compound can perform its intended function. Typically, such constructs carry or transport from one organ or part of the body to another organ or part of the body. The carrier must be compatible with other components of the formulation (including the useful compounds of this disclosure) and harmless to the patient; the carrier must be "acceptable." Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; 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; surfactant phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations.

[0287] The term “room temperature” in this disclosure refers to the ambient temperature, such as a temperature of 20-30°C.

[0288] In this article, "stereoisomers" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, and hindered isomers, etc.

[0289] In this document, the term "solvent" refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0290] In this paper, the term "chirality" refers to a molecule that has the property that it cannot be superimposed on its mirror image; while "achirality" refers to a molecule that can be superimposed on its mirror image.

[0291] In this paper, the term "enantiomer" refers to two non-overlapping but mirror-image isomers of a compound.

[0292] In this paper, the term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC. Example

[0293] In the following description, numerous specific details are set forth to provide a thorough understanding of the invention. The invention may be practiced without some or all of these specific details. In other instances, well-known processes are not described in detail to avoid unnecessarily obscuring the invention. While the invention will be described in conjunction with specific embodiments, it should be understood that this is not intended to limit the invention to these embodiments.

[0294] The following abbreviations are used throughout the instruction manual and examples:

[0295] AcOH (acetic acid)

[0296] Boc tert-butoxycarbonyl

[0297] Concentration

[0298] DCM dichloromethane

[0299] DIEA N,N-Diisopropylethylamine

[0300] DMAP 4-Dimethylaminopyridine

[0301] DMF N,N-dimethylformamide

[0302] DMSO (dimethyl sulfoxide)

[0303] DIPEA N,N-Diisopropylethylamine

[0304] DESS-MARTIN Oxidizing Agent

[0305] EA (ethyl acetate)

[0306] EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0307] ESI Electrospray Ionization

[0308] equivalent

[0309] EtOH (ethanol)

[0310] HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0311] HFIP (Hexafluoroisopropanol)

[0312] HPLC (High Performance Liquid Chromatography)

[0313] HRMS high-resolution mass spectrometry

[0314] LC-MS (Liquid Chromatography-Mass Spectrometry)

[0315] LRMS low-resolution mass spectrometry

[0316] LC liquid chromatography

[0317] Me methyl

[0318] MeCN Acetonitrile

[0319] MeOH (methanol)

[0320] MS mass spectrometry

[0321] NBS N-bromosuccinimide

[0322] 1 1H NMR nuclear magnetic resonance spectroscopy

[0323] PE petroleum ether (PhCOO)2 benzoyl peroxide

[0324] Raney Ni

[0325] rt room temperature

[0326] tBu tert-butyl

[0327] TEA Triethylamine

[0328] TFA (trifluoroacetic acid)

[0329] THF Tetrahydrofuran

[0330] TLC (Thin Layer Chromatography)

[0331] TMS trimethylsilyl

[0332] In this invention, 1¹H NMR spectra were determined using a Bruker 500MHz NMR spectrometer, with CD₃OD (δ = 3.31 ppm) containing 0.1% TMS (as internal standard) as the solvent; or CDCl₃ (δ = 7.26 ppm) containing 0.1% TMS (as internal standard) as the solvent; or DMSO-d₆ (δ = 2.50 ppm) containing 0.03% TMS (as internal standard) as the solvent. LRMS spectra were determined using an ABTriple 4600 mass spectrometer. HPLC preparation was performed using a SHIMADZU LC-20AP instrument, and HPLC purity was determined using a SHIMADZU LC-30AP or Waters 1525 instrument. All reactions were carried out in air unless otherwise specified; the reactions were monitored by TLC or LC-MS.

[0333] Solvent and reagent treatment is as follows:

[0334] The solvents used in the reaction, including DCM, DMF, anhydrous EtOH, and anhydrous MeOH, were all purchased from Sinopharm Group.

[0335] The HPLC preparation used preparative grade CH3CN and deionized water;

[0336] Unless otherwise stated, the starting materials, reagents, linkers of various carbon chain lengths (i.e., compounds used to form the group represented by LIN), and other reagents and pharmaceuticals used in the following examples may be commercially available or synthesized using methods known in the art.

[0337] General Synthesis Method

[0338] The compounds described herein and / or their pharmaceutically acceptable salts can be synthesized using commercially available raw materials using synthetic techniques known in the art. The synthetic schemes described below illustrate methods for preparing most of the compounds. The starting materials or reagents used in each scheme are commercially available or prepared using methods known to those skilled in the art. Those skilled in the art can prepare salts of the compounds of formula (I) of this disclosure, or salts, racemates, enantiomers, phosphates, sulfates, hydrochlorides, and prodrug forms of the compounds in Tables 1 or 2, using conventional techniques in the art.

[0339] R of compound (I) 11 -General preparation method for intermediates corresponding to the LIN part:

[0340]

[0341] Option 1

[0342] R of compound (I)11 -General preparation method 2 for intermediates corresponding to the LIN part:

[0343]

[0344] Option 2

[0345] The intermediate compound 732180 was prepared according to the method in Scheme 1.

[0346] General preparation method for Binder intermediate compounds:

[0347]

[0348] Option 3

[0349] General preparation method for Binder intermediate compounds, Part 2:

[0350]

[0351] Option 4

[0352] General preparation method three for Binder intermediate compounds:

[0353]

[0354] Option 5

[0355] General preparation method for Binder intermediate compounds, part four:

[0356]

[0357] Option 6

[0358] General preparation method for compounds of formula (I):

[0359]

[0360] Option 7

[0361] In scheme 7, POI shows the reactive group of the intermediate BINDER, (R a ) t And X is as defined in the compound of formula (I) in this paper.

[0362] The corresponding binder intermediate compound (1.0 equiv) and DIEA (2.0 equiv) were added to a DMF solution of the brominated substrate (1.0 equiv). The reaction mixture was reacted at room temperature for 2 h until complete. The reaction mixture was purified by C18 reversed-phase column chromatography (eluent (v / v): acetonitrile / (water + 0.05% HCl) = 10%–100%) to obtain the target product.

[0363] Based on the target compound, the above-mentioned schemes, as well as 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 desired target compound. Furthermore, the obtained target compound can be further modified by substituents, etc., using methods well known to those skilled in the art to obtain other target compounds.

[0364] Example

[0365] Intermediate Example 1: Preparation of 3-(4-bromo-6-(bromomethyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (732001)

[0366]

[0367] According to Scheme 1, 3-(4-bromo-6-(bromomethyl)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (732001) was prepared.

[0368] Step 1:

[0369] Methyl 2,5-dimethyl-3-bromobenzoate (5.0 g, 20.6 mmol) was dissolved in 100 mL of carbon tetrachloride, followed by the addition of N-bromosuccinimide (8.0 g, 45 mmol) and benzoyl peroxide (0.31 g, 1.26 mmol). 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 solvent was removed by vacuum distillation of the filtrate. The residue was separated by silica gel column chromatography (PE / EA = 1 / 0-20 / 1) to give compound 363126 (6.3 g, yield: 76%) as a white solid.

[0370] Step 2:

[0371] Cesium carbonate (16.25 g, 49.89 mmol) was added to a mixed solvent of 500 mL of 1,2-dichloroethane and 50 mL of hexafluoroisopropanol. The resulting mixture was stirred at 65 °C for 15 min. Then, 3-amino-2,6-piperidinidone hydrochloride (8.21 g, 49.89 mmol) and compound 363126 obtained in step 1 (20 g, 49.89 mmol) were added sequentially. The reaction mixture was stirred at 65 °C for 12 h. The reaction mixture was filtered while hot to remove insoluble matter. The filtrate was washed with saturated brine and the organic solvent was removed by vacuum distillation. The remaining solid was slurried with 50 mL of dichloromethane and 200 mL of petroleum ether. The resulting mixture was filtered, and the filtered solid was washed with 50 mL of dichloromethane and 50 mL of diethyl ether to give product 732001 (11 g, yield: 42%) as a gray powder. 1 ¹H NMR (500MHz, Methanol-d⁴) δ 7.90 (d, J = 1.5Hz, 1H), 7.84 (d, J = 1.5Hz, 1H), 5.17 (dd, J = 13.4, 5.2Hz, 1H), 4.68 (s, 2H), 4.45 (q, J = 17.6Hz, 2H), 2.91 (ddd, J = 17.6, 13.6, 5.4Hz, 1H), 2.79 (ddd, J = 17.6, 4.6, 2.4Hz, 1H), 2.53 (qd, J = 13.4, 4.7Hz, 1H), 2.19 (dtd, J = 13.0, 5.4, 2.4Hz, 1H). MS (ESI) m / z: calculated value C 14 H 13 Br2N2O3 + [M+H] + ,414.9; measured value,415.1.

[0372] Intermediate Example 2: Preparation of 3-(5-(bromomethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (732180)

[0373] According to Scheme 2, 3-(5-(bromomethyl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (732180) was prepared using the method described in Scheme 1. Furthermore, the starting material methyl 2,4-di(bromomethyl)benzoate (CAS No.: 63112-94-7) for step 2 of Scheme 2 can also be obtained commercially. After the reaction was completed, the reaction mixture was washed with water. The organic phase was separated and the solvent was removed by vacuum distillation. The resulting residue was separated by silica gel column chromatography (DCM / MeOH = 1 / 0-10 / 1), and the product was further purified by acetonitrile slurry to obtain a white powder, yield: 27%. 1¹H NMR (500MHz, DMSO-d⁶) δ 11.00 (s, 1H), 7.78–7.66 (m, 2H), 7.59 (dd, J = 7.9, 1.5Hz, 1H), 5.11 (dd, J = 13.3, 5.1Hz, 1H), 4.83 (s, 2H), 4.47 (d, J = 17.3Hz, 1H), 4.34 (d, J = 17.4Hz, 1H), 2.91 (ddd, J = 17.3, 13.6, 5.4Hz, 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, 1.9Hz, 1H). MS (ESI) m / z: calculated value C 14 H 14 BrN2O3 + [M+H] + ,337.0; measured value,337.3.

[0374] 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 (73214) 7) and the 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-((S)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732148)

[0375]

[0376] 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 (7321) was prepared according to scheme 4. 47) 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).

[0377] Step 1:

[0378] To a methanol solution of 4-oxocyclohexanecarboxynitrile (1 equiv), tert-butyl (S)-2-methylpiperazine-1-carboxylate (1.5 equiv) and zinc chloride (1.5 equiv) were added. The resulting mixture was stirred at room temperature for 15 min, cooled to 0 °C, and then sodium cyanoborohydride (3.0 equiv) was added. The reaction was allowed to proceed overnight. The reaction mixture was quenched by adding a saturated ammonium chloride solution. The resulting mixture was extracted three times with dichloromethane and washed once with saturated brine. The separated organic phase was distilled under pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to give a white solid cyano product, a mixture of cis and trans products, in 80% yield.

[0379] Step 2:

[0380] Add a methanol solution of NH3 (7M, 0.5 mL) and Raney nickel to a reaction flask containing a methanol solution of the cyano compound obtained in step 1. Purge the reaction flask with hydrogen. Heat the reaction mixture to 60°C and hydrogenate at atmospheric pressure overnight. Cool the reaction solution to room temperature, remove Raney nickel by diatomaceous earth filtration, and evaporate the filtrate to dryness to obtain the crude amine product, which is directly added to the next reaction step.

[0381] Step 3:

[0382] 4-Fluoro-3-nitrobenzenesulfonamide (0.9 equiv) and triethylamine (1.5 equiv) were added to the THF solution of the amine product from the previous step. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The resulting mixture was extracted three times with dichloromethane. The dichloromethane organic phases were combined and washed with saturated brine. The organic phases were separated and the solvent was removed by vacuum distillation. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1), successfully yielding the cis product (732139) and the trans product (732141).

[0383] cis product (732139): (S)-2-methyl-4-((cis)-4-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester

[0384] 1 H NMR(500MHz,DMSO-d6)δ8.54(dt,J=7.0,5.1Hz,1H),8.47(d,J=2.3Hz,1H),7.82(dd,J=9.1,2.3Hz, 1H),7.33(s,2H),7.26(d,J=9.3Hz,1H),4.07(s,1H),3.68(d,J=12.7Hz,1H),3.38(d,J=6.5Hz,2H), 2.99–2.83(m,2H),2.77(d,J=11.3Hz,1H),2.13(s,1H),2.00(d,J=10.9Hz,1H),1.86(d,J=9.9Hz,2 H),1.81–1.66(m,2H),1.53(d,J=7.0Hz,2H),1.48–1.42(m,3H),1.39(s,9H),1.14(d,J=6.7Hz,3H).

[0385] Trans product (732141): (S)-2-methyl-4-((trans)-4-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester

[0386] 1H NMR (500MHz, DMSO-d6) δ8.56(t,J=5.9Hz,1H),8.47(d,J=2.3Hz,1H),7.81(dd,J=9.1,2.3Hz,1H),7.33(s,2H),7.25( d,J=9.3Hz,1H),4.04(s,1H),3.63(d,J=12.7Hz,1H),3.29(t,J=6.4Hz,2H),2.88(t,J=12.1Hz,1H),2.71(d,J=10.9Hz ,1H),2.60(d,J=11.1Hz,1H),2.25(ddt,J=15.6,11.0,5.9Hz,2H),2.12(td,J=11.4,3.3Hz,1H),1.86–1.70(m,4H),1. 57(dt,J=7.7,3.6Hz,1H),1.38(s,9H),1.18(ddd,J=25.3,13.9,7.4Hz,2H),1.10(d,J=6.7Hz,3H),1.07–0.96(m,2H).

[0387] Step 4:

[0388] Add EDCI (1.5 equiv) and DMAP (1.0 equiv) to a dichloromethane 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). The reaction system becomes clear. Add the cis product (732139) or trans product (732141) obtained in step 3 to the reaction solution. React for 12 h until the reactants are completely reacted. Dilute the reaction solution with 30 mL of dichloromethane. Wash the resulting mixture with saturated brine. Separate the organic phase and remove the solvent by vacuum distillation. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to obtain the Boc-protected product.

[0389] Trifluoroacetic acid (10 equiv) was added to a dichloromethane solution of the Boc-protected product. The reaction mixture was reacted at room temperature for 30 min. After the reaction was complete, the mixture was distilled under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to give the cis product (732147) and trans product (732148) as powders.

[0390] 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

[0391] 1 H NMR (500MHz, Methanol-d4) δ8.66(d,J=2.3Hz,1H),8.06–7.96(m,1H),7.86(dd,J=9.2,2.3Hz,1H),7.62(d,J=8.9Hz,1H),7.57(d,J=2.5Hz,1 H),7.47(d,J=3.4Hz,1H),7.35(d,J=8.4Hz,2H),7.08(d,J=8.4Hz,2H),7.01(d,J=9.4Hz,1H),6.76(dd,J=8.9,2.4Hz,1H),6.43(d,J=3.5Hz,1 H),6.34(d,J=2.3Hz,1H),3.99–3.84(m,3H),3.80-3.60(d,J=29.2Hz, 6H),3.50-3.35(m,6H),3.27–3.09(m,3H),2.79(s,2H),2.33–2.26(m,2 H), 2.10 (s, 3H), 1.96 (dt, J = 31.7, 9.6Hz, 7H), 1.72 (ddd, J = 15.0, 10.4, 4.7Hz, 2H), 1.56 (t, J = 6.4Hz, 2H), 1.45 (d, J = 6.5Hz, 3H), 1.00 (s, 6H).

[0392] 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

[0393] 1H NMR (500MHz, Methanol-d4) δ8.66(d,J=2.3Hz,1H),8.00(s,1H),7.85(dd,J=9.3,2.3Hz,1H),7.62(d,J=8.9Hz,1H),7.57(d,J=2.5Hz,1H),7.47(d,J=3. 4Hz,1H),7.35(d,J=8.4Hz,2H),7.08(d,J=8.4Hz,2H),6.95(d,J=9.3Hz,1H) ,6.76(dd,J=9.0,2.4Hz,1H),6.43(d,J=3.4Hz,1H),6.33(d,J=2.4Hz,1H),3 .90–3.78(m,3H),3.77–3.57(m,7H),3.51–3.35(m,5H),3.28(d,J=6.7Hz,3H ),3.17(d,J=15.8Hz,2H),2.79(s,2H),2.33–2.24(m,4H),2.10(s,2H),2.06 (d,J=12.0Hz,2H),1.81–1.71(m,1H),1.70–1.59(m,2H),1.56(t,J=6.4Hz,2 H),1.45(d,J=6.5Hz,3H),1.25(ddt,J=16.2,12.9,6.2Hz,2H),1.00(s,6H).

[0394] 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 (73214) 9) and the 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-((R)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732150)

[0395]

[0396] 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 (7321) was prepared according to scheme 3. 49) 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).

[0397] Step 1:

[0398] To a methanol solution of 4-oxocyclohexanecarboxynitrile (1 equiv), tert-butyl (R)-2-methylpiperazine-1-carboxylate (1.5 equiv) and zinc chloride (1.5 equiv) were added. The resulting mixture was stirred at room temperature for 15 min, cooled to 0 °C, and then sodium cyanoborohydride (3.0 equiv) was added. The reaction was allowed to proceed overnight. A saturated ammonium chloride solution was added to the reaction mixture to quench the reaction. The resulting mixture was extracted three times with dichloromethane and washed once with saturated brine. The separated organic phase was distilled under pressure to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to give a white solid cyano product, a mixture of cis and trans products, in 80% yield.

[0399] Step 2:

[0400] Add a methanol solution of NH3 (7M, 0.5 mL) and Raney nickel to a reaction flask containing a methanol solution of the cyano compound obtained in step 1. Purge the reaction flask with hydrogen. Heat the reaction mixture to 60°C and hydrogenate at atmospheric pressure overnight. Cool the reaction solution to room temperature, remove Raney nickel by diatomaceous earth filtration, and evaporate the filtrate to dryness to obtain the crude amine product, which is directly added to the next reaction step.

[0401] Step 3:

[0402] 4-Fluoro-3-nitrobenzenesulfonamide (0.9 equiv) and triethylamine (1.5 equiv) were added to the THF solution of the amine product from the previous step. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. The resulting mixture was extracted three times with dichloromethane. The dichloromethane organic phases were combined and washed with saturated brine. The organic phases were separated and the solvent was removed by vacuum distillation. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1), successfully yielding the cis product (732140) and the trans product (732142).

[0403] cis product (732140): (R)-2-methyl-4-((cis)-4-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester

[0404] 1 H NMR(500MHz,DMSO-d6)δ8.54(dt,J=7.0,5.1Hz,1H),8.47(d,J=2.3Hz,1H),7.82(dd,J=9.1,2.3Hz, 1H),7.33(s,2H),7.26(d,J=9.3Hz,1H),4.07(s,1H),3.68(d,J=12.7Hz,1H),3.38(d,J=6.5Hz,2H), 2.99–2.83(m,2H),2.77(d,J=11.3Hz,1H),2.13(s,1H),2.00(d,J=10.9Hz,1H),1.86(d,J=9.9Hz,2 H),1.81–1.66(m,2H),1.53(d,J=7.0Hz,2H),1.48–1.42(m,3H),1.39(s,9H),1.14(d,J=6.7Hz,3H).

[0405] Trans product (732142): (R)-2-methyl-4-((trans)-4-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester

[0406] 1H NMR (500MHz, DMSO-d6) δ8.56(t,J=5.9Hz,1H),8.47(d,J=2.3Hz,1H),7.81(dd,J=9.1,2.3Hz,1H),7.33(s,2H),7.25( d,J=9.3Hz,1H),4.04(s,1H),3.63(d,J=12.7Hz,1H),3.29(t,J=6.4Hz,2H),2.88(t,J=12.1Hz,1H),2.71(d,J=10.9Hz ,1H),2.60(d,J=11.1Hz,1H),2.25(ddt,J=15.6,11.0,5.9Hz,2H),2.12(td,J=11.4,3.3Hz,1H),1.86–1.70(m,4H),1. 57(dt,J=7.7,3.6Hz,1H),1.38(s,9H),1.18(ddd,J=25.3,13.9,7.4Hz,2H),1.10(d,J=6.7Hz,3H),1.07–0.96(m,2H).

[0407] Step 4:

[0408] Add EDCI (1.5 equiv) and DMAP (1.0 equiv) to a dichloromethane 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). The reaction mixture becomes clear. Add the cis product (732140) or trans product (732142) obtained in step 3 to the reaction solution. Let the reaction mixture react for 12 h until the reactants are completely reacted. Dilute the reaction solution with 30 mL of dichloromethane. Wash the resulting mixture with saturated brine. Separate the organic phase and remove the solvent by vacuum distillation. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to obtain the Boc-protected product.

[0409] Trifluoroacetic acid (10 equiv) was added to a dichloromethane solution of the Boc-protected product. The reaction mixture was reacted at room temperature for 30 min. After the reaction was complete, the mixture was distilled under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to give the cis product (732149) and trans product (732150) as powders.

[0410] 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)

[0411] 1 H NMR (500MHz, Methanol-d4) δ8.66(d,J=2.3Hz,1H),8.06–7.96(m,1H),7.86(dd,J=9.2,2.3Hz,1H),7.62(d,J=8.9Hz,1H),7.57(d,J=2.5Hz,1 H),7.47(d,J=3.4Hz,1H),7.35(d,J=8.4Hz,2H),7.08(d,J=8.4Hz,2H),7.01(d,J=9.4Hz,1H),6.76(dd,J=8.9,2.4Hz,1H),6.43(d,J=3.5Hz,1 H),6.34(d,J=2.3Hz,1H),3.99–3.84(m,3H),3.80-3.60(d,J=29.2Hz, 6H),3.50-3.35(m,6H),3.27–3.09(m,3H),2.79(s,2H),2.33–2.26(m,2 H), 2.10 (s, 3H), 1.96 (dt, J = 31.7, 9.6Hz, 7H), 1.72 (ddd, J = 15.0, 10.4, 4.7Hz, 2H), 1.56 (t, J = 6.4Hz, 2H), 1.45 (d, J = 6.5Hz, 3H), 1.00 (s, 6H).

[0412] 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)

[0413] 1H NMR (500MHz, Methanol-d4) δ8.66(d,J=2.3Hz,1H),8.00(s,1H),7.85(dd,J=9.3,2.3Hz,1H),7.62(d,J=8.9Hz,1H),7.57(d,J=2.5Hz,1H),7.47(d,J=3. 4Hz,1H),7.35(d,J=8.4Hz,2H),7.08(d,J=8.4Hz,2H),6.95(d,J=9.3Hz,1H) ,6.76(dd,J=9.0,2.4Hz,1H),6.43(d,J=3.4Hz,1H),6.33(d,J=2.4Hz,1H),3 .90–3.78(m,3H),3.77–3.57(m,7H),3.51–3.35(m,5H),3.28(d,J=6.7Hz,3H ),3.17(d,J=15.8Hz,2H),2.79(s,2H),2.33–2.24(m,4H),2.10(s,2H),2.06 (d,J=12.0Hz,2H),1.81–1.71(m,1H),1.70–1.59(m,2H),1.56(t,J=6.4Hz,2 H),1.45(d,J=6.5Hz,3H),1.25(ddt,J=16.2,12.9,6.2Hz,2H),1.00(s,6H).

[0414] 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)

[0415]

[0416] 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 according to Scheme 5.

[0417] Step 1:

[0418] To a THF solution of 4-((trans)-4-(aminomethyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (1.0 equiv; CAS No.: 2357231-00-4), 4-fluoro-3-trifluoromethanesulfonylbenzenesulfonamide (1.0 equiv) and triethylamine (1.5 equiv) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, a saturated aqueous solution of sodium bicarbonate was added to the mixture. The resulting mixture was extracted three times with dichloromethane. The dichloromethane organic phases were combined and washed with saturated brine. The organic phases were separated and the solvent was removed by vacuum distillation. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to give a white powder product 4-((trans)-4-(((4-aminosulfonyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylic acid tert-butyl ester (732181), with a yield of 98%. 1 H NMR (500MHz, DMSO-d6) δ8.01(d,J=2.3Hz,1H),7.93(dd,J=9.2,2.4Hz,1H),7.39(s,2H),7.21(d,J=9.3Hz,1H),7.16(t,J=5.8Hz,1H),3.23(dd,J=13.3, 6.9Hz,6H),2.41(t,J=5.2Hz,4H),2.22(t,J=12.0Hz,1H),1.85–1.70(m,4H) ,1.60–1.47(m,1H),1.38(s,9H),1.19(q,J=12.2Hz,2H),1.04–0.93(m,2H).

[0419] Step 2:

[0420] EDCI (1.5 equiv) and DMAP (1.0 equiv) were added to a dichloromethane 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). The reaction mixture became clear. The product obtained in step 1, 4-((trans)-4-(((4-aminosulfonyl-2-((trifluoromethyl)sulfonyl)phenyl)amino)methyl)cyclohexyl)piperazin-1-carboxylic acid tert-butyl ester (732181), was added to the reaction mixture. The reaction mixture was allowed to react for 12 h until the reactants were completely reacted. 30 mL of dichloromethane was added to dilute the reaction mixture. The resulting mixture was washed with saturated brine. Organic phase separation was performed, followed by vacuum distillation to remove the solvent. The residue was then separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to obtain the Boc-protected product.

[0421] Trifluoroacetic acid (10 equiv) was added to a solution of the Boc-protected product dissolved in dichloromethane. The reaction mixture was reacted at room temperature for 30 min. After the reaction was complete, the mixture was distilled under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to give the trifluoroacetate of the target compound (732185) as a powder. 1 H NMR (500MHz, Methanol-d4) δ8.30(d,J=2.3Hz,1H),8.03(d,J=2.6Hz,1H),7.97(dd,J=9.3,2.3Hz,1H),7.65–7.60(m,2H),7.49(d,J=3.5Hz,1H ),7.35(d,J=8.2Hz,2H),7.07(d,J=8.4Hz,2H),6.89(d,J=9.4Hz,1H),6.75(d,J=8.9Hz,1H),6.47(d,J=3.5Hz,1H),6.30(d,J=2.4Hz,1H),3.6 6(s,3H), 3.59(s,10H), 3.20(d,J=6.8Hz,3H), 3.06(s,2H), 2.96–2.66(m,2H), 2.25(tt,J=6.4,2.4Hz,3H), 2.20(d,J=10.8Hz,2H), 2.11(d,J=8.2Hz,3H), 2.01(d,J=11.8Hz,2H), 1.69(tdd,J=11.2,7.7,4.8Hz,1H), 1.64–1.52(m,5H), 1.25–1.15(m,2H), 0.99(s,6H). HRMS(ESI) m / z: Calculated value C 51 H 61 ClF3N8O6S2 + [M+H] + ,1037.3791; measured value,1037.3792.

[0422] 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)

[0423]

[0424] Following the method in step 2 of scheme 5, 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.

[0425] 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 No.: 1044598-91-5). The reaction mixture became clear. Compound 732181, prepared according to step 1 of intermediate Example 7, was added to the reaction solution. The reaction mixture was allowed to react for 12 h until the reactants were fully reacted. 30 mL of dichloromethane was added to dilute the reaction solution. The resulting mixture was washed with saturated brine. The organic phase was separated by vacuum distillation to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to give the Boc-protected product.

[0426] Trifluoroacetic acid (10 equiv) was added to a solution of the Boc-protected product dissolved in dichloromethane. The reaction mixture was reacted at room temperature for 30 min. After the reaction was complete, the mixture was distilled under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to give the trifluoroacetate salt of the target compound (732186) as a powder.

[0427] 1H NMR (500MHz, DMSO-d6) δ8.05(d,J=2.1Hz,1H),8.01(dd,J=9.0,2.2Hz,1H),7.71(d,J=8.7Hz,2H),7.38(d,J=8.5Hz,2H),7.1 3(d,J=8.4Hz,2H),6.99(d,J=9.2Hz,1H),6.85(t,J=5.7Hz,1H),6.77(d,J=8.8Hz,2H),3.16(t,J=6.3Hz,3H),3.12(t,J=5.0 Hz, 4H), 2.97–2.91(m, 4H), 2.74(s, 2H), 2.62(t, J = 5.0Hz, 4H), 2.24(dt, J = 20.9, 5.4Hz, 7H), 1.99(s, 2H), 1.78(dt, J = 9.1, 4.3Hz, 4H), 1.58–1.47(m, 1H), 1.43(t, J = 6.5Hz, 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; Measured value,905.3467.

[0428] 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)

[0429]

[0430] 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.

[0431] Step 1:

[0432] To a solution of 4-((trans)-4-(aminomethyl)cyclohexyl)piperazine-1-carboxylate tert-butyl ester (1.0 equiv; CAS No.: 2357231-00-4) dissolved in THF, 4-fluoro-3-nitrobenzenesulfonamide (1.0 equiv) and triethylamine (1.5 equiv) were added. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, a saturated aqueous solution of sodium bicarbonate was added to the mixture. The resulting mixture was extracted three times with dichloromethane. The dichloromethane organic phases were combined and washed with saturated brine. The organic phases were separated and the solvent was removed by vacuum distillation. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to give a white powder of 4-((trans)-4-(((2-nitro-4-aminosulfonylphenyl)amino)methyl)cyclohexyl)piperazine-1-carboxylate tert-butyl ester (732170), yield 95%. 1 H NMR(500MHz,DMSO-d6)δ8.56(t,J=6.0Hz,1H),8.47(d,J=2.3Hz,1H),7.81(d d,J=9.1,2.3Hz,1H),7.33(s,2H),7.26(d,J=9.3Hz,1H),3.27(dt,J=14.8,5. 7Hz,6H),2.41(t,J=5.1Hz,4H),2.25(t,J=11.6Hz,1H),1.88–1.74(m,4H),1. 57(dt,J=7.7,3.5Hz,1H),1.38(s,9H),1.25–1.13(m,2H),1.09–0.87(m,2H).

[0433] Step 2:

[0434] EDCI (1.5 equiv) and DMAP (1.0 equiv) were added to a solution of 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (1 equiv; CAS No.: 1044598-91-5) dissolved in dichloromethane. The reaction mixture became clear. Compound 732170 prepared in step 1 was added to the reaction solution. The reaction mixture was allowed to react for 12 h until the reactants were completely reacted. 30 mL of dichloromethane was added to dilute the reaction solution. The resulting mixture was washed with saturated brine. The organic phase was separated by vacuum distillation to remove the solvent. The residue was separated by column chromatography (DCM / MeOH = 1 / 0-10 / 1) to give the Boc-protected product.

[0435] Trifluoroacetic acid (10 equiv) was added to a solution of the Boc-protected product dissolved in dichloromethane. The reaction mixture was reacted at room temperature for 30 min. After the reaction was complete, the mixture was distilled under reduced pressure to remove the organic solvent and trifluoroacetic acid. The residue was lyophilized to give the trifluoroacetate of the target compound (732187) as a powder. 1 H NMR (500MHz, Methanol-d4) δ8.82(d,J=2.3Hz,1H),8.03(dd,J=9.3,2.3Hz,1H),7.72(d,J=9.1Hz,2H),7.38(d, J=8.4Hz,2H),7.16(t,J=8.5Hz,3H),6.95(d,J=9.1Hz,2H),3.89(s,1H),3.70(s,2H),3.59(s,10H),3.34(dd,J =7.5,5.5Hz,3H), 3.22(s,2H), 2.89(s,2H), 2.40(t,J=6.5Hz,2H), 2.20(d,J=10.8Hz,2H), 2.11–2.04(m,4H), 1.78(dqd,J=14.5,8.4,6.8,3.4Hz,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.

[0436] 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-oxoisoindoline-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)

[0437] According to Scheme 7, the target compound (BCL-03146) was prepared from 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; see Example 11 of the preparation of intermediate BINDER in Chinese Patent Publication No. CN112707900 A, the contents of which are incorporated herein by reference in their entirety) and the compound (732001) prepared according to intermediate Example 1. 1 HNMR(500MHz,DMSO-d6)δ11.78(s,1H),11.71(s,1H),11.05(s,1H),10.78(s,1H),8.64(t, J=6.0Hz,1H),8.57(d,J=2.7Hz,1H),8.22(s,1H),8.07(s,1H),8.05(d,J=2.9Hz,1H),7.81 (dd,J=9.2,2.6Hz,1H),7.57(d,J=3.1Hz,1H),7.56–7.49(m,2H),7.39(d,J=8.2Hz,2H),7. 15–7.06(m,3H),6.72(dd,J=9.1,2.4Hz,1H),6.46–6.37(m,1H),6.26(d,J=2.3Hz,1H),5.16 (dd,J=13.3,5.2Hz,1H),4.46(d,J=18.0Hz,3H),4.31(d,J=17.9Hz,1H),3.72–3.53(m,8H) ,3.28(dd,J=12.3,6.5Hz,9H),2.92(ddd,J=17.9,13.5,5.6Hz,1H),2.75–2.57(m,3H),2.4 1–2.33(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 value C 64 H 72 BrClN 11 O9S + [M+H] + ,1284.4102; measured value,1284.4100.

[0438] 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-oxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03147)

[0439] According to Scheme 7, the target compound (BCL-03147) was prepared from 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. 1H NMR (500MHz, DMSO-d6) δ11.77(s,1H),11.71(s,1H),11.03(s,1H),10.67(s,1H),8.64(t,J= 6.1Hz,1H),8.56(d,J=2.0Hz,1H),8.05(d,J=3.1Hz,1H),7.90(s,1H),7.80(t,J=5.8Hz,3H) ,7.57(d,J=2.9Hz,1H),7.55–7.48(m,2H),7.39(d,J=8.2Hz,2H),7.14–7.07(m,3H),6.72(d ,J=9.2Hz,1H),6.45–6.40(m,1H),6.26(s,1H),5.14(dd,J=13.3,5.2Hz,1H),4.50(d,J=17. 7Hz,3H),4.37(d,J=17.7Hz,1H),3.70–3.52(m,11H),3.26(d,J=10.1Hz,8H),2.92(td,J=13 .0,6.6Hz,1H),2.76–2.57(m,3H),2.43(dt,J=13.3,6.6Hz,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 value C 64 H 73 ClN 11 O9S + [M+H] + ,1206.4996; measured value,1206.4990.

[0440] 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-oxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03148)

[0441] According to Scheme 7, the target compound (BCL-03148) was prepared from 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; see Example 12 of the preparation of intermediate BINDER in Chinese Patent Publication No. CN112707900 A, the contents of which are incorporated herein by reference in their entirety) and intermediate compound (732180). 1 H NMR(500MHz,DMSO-d6)δ11.75(s,1H),11.70(s,1H),11.02(s,1H),8.63(t,J=6.0Hz,1H ),8.57(d,J=2.4Hz,1H),8.05(d,J=2.6Hz,1H),7.91–7.69(m,4H),7.56(d,J=2.7Hz,1H) ,7.54–7.49(m,2H),7.39(d,J=8.5Hz,2H),7.15(d,J=9.6Hz,1H),7.09(d,J=8.4Hz,2H) ,6.72(dd,J=9.0,2.4Hz,1H),6.44–6.37(m,1H),6.25(d,J=2.3Hz,1H),5.14(dd,J=13.3 ,5.2Hz,1H),4.55–4.29(m,4H),3.63(d,J=11.3Hz,5H),3.54(s,3H),3.30–3.16(m,6H) ,2.93(ddd,J=17.5,13.7,5.6Hz,1H),2.70(d,J=10.7Hz,2H),2.62(d,J=17.4Hz,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 value C 64 H 73 ClN 11 O9S + [M+H] + ,1206.4996; measured value,1206.4992.

[0442] 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-oxoisoindoline-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)

[0443] According to Scheme 7, the target compound (BCL-03149) was prepared from compound (SIAIS364043) and compound (732001) prepared according to intermediate Example 1. 1 H NMR (500MHz, DMSO-d6) δ11.75(s,1H),11.70(s,1H),11.04(s,1H),10.47(s,1H),8.63(t,J=6. 0Hz,1H),8.57(d,J=2.3Hz,1H),8.15(s,1H),8.05(d,J=2.6Hz,1H),8.02(s,1H),7.82(dd,J=9. 2,2.4Hz,1H),7.56(d,J=2.7Hz,1H),7.54–7.49(m,2H),7.42–7.38(m,2H),7.15(d,J=9.6Hz,1H ),7.09(d,J=8.4Hz,2H),6.72(dd,J=9.1,2.5Hz,1H),6.42–6.38(m,1H),6.25(d,J=2.4Hz,1H), 5.16(dd,J=13.2,5.1Hz,1H),4.38(dd,J=78.7,17.9Hz,4H),3.63(d,J=13.9Hz,5H),3.53(s,4H ),3.31–3.09(m,9H),2.92(ddd,J=17.4,13.6,5.4Hz,1H),2.69(q,J=13.3,12.1Hz,2H),2.61(d ,J=17.1Hz,1H), 2.46(dd,J=13.0,4.8Hz,1H), 2.32(s,2H), 2.07–1.96(m,4H), 1.85(s,2H), 1.78(d,J=11.1Hz,4H), 1.58–1.48(m,2H), 1.44(t,J=6.4Hz,2H), 0.94(s,6H).HRMS(ESI)m / z: Calculated value C 64 H 72 BrClN 11 O9S+ [M+H] + ,1284.4102; measured value,1284.4105.

[0444] 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-oxoisoindoline-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03165)

[0445] According to Scheme 7, the target compound (BCL-03165) was prepared using the compound (732147) prepared according to intermediate Example 3 and the compound (732180) prepared according to intermediate Example 2 as raw materials. 1H NMR(500MHz,DMSO-d6)δ11.74(s,1H),11.70(s,1H),11.02(s,1H),10.32(s,1H),8.63(t,J =6.0Hz,1H),8.57(d,J=2.3Hz,1H),8.05(s,1H),7.85–7.78(m,3H),7.56(d,J=2.6Hz,1H), 7.53–7.50(m,2H),7.39(d,J=8.5Hz,2H),7.15(d,J=9.5Hz,1H),7.09(d,J=8.4Hz,2H),6.7 2(dd,J=9.1,2.4Hz,1H),6.41(dd,J=3.6,1.9Hz,1H),6.25(d,J=2.4Hz,1H),5.14(dd,J=13 .3,5.2Hz,1H),4.49(t,J=17.1Hz,1H),4.36(t,J=17.5Hz,1H),3.63(d,J=13.4Hz,4H),3.5 6(d,J=18.2Hz,4H),3.30–3.15(m,8H),2.98–2.88(m,1H),2.70(d,J=10.5Hz,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 value C 65 H 75 ClN 11 O9S + [M+H] + ,1220.5153; measured value,1220.5150.

[0446] 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-dioxopiperazin-3-yl)-1-oxoisoindoline-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03166)

[0447] According to Scheme 7, the target compound (BCL-03166) was prepared using the compound (732148) prepared according to intermediate Example 3 and the intermediate compound (732180) as raw materials. 1 H NMR (500MHz, DMSO-d6) δ11.74(s,1H),11.69(s,1H),11.02(s,1H),10.32(s,1H),8.63(t,J= 6.0Hz,1H),8.56(d,J=2.6Hz,1H),8.04(d,J=2.9Hz,1H),7.83–7.77(m,2H),7.69(s,1H),7. 55(d,J=2.9Hz,1H),7.54–7.50(m,2H),7.39(d,J=8.4Hz,2H),7.10(dd,J=8.7,5.5Hz,3H),6 .72(dd,J=9.1,2.4Hz,1H),6.43–6.37(m,1H),6.25(d,J=2.4Hz,1H),5.13(dd,J=13.4,5.2Hz ,1H),4.55–4.43(m,1H),4.35(t,J=16.3Hz,1H),3.63(d,J=12.1Hz,3H),3.54(s,3H),3.30– 3.10(m,11H),2.92(ddd,J=18.0,13.6,5.6Hz,2H),2.70(d,J=10.2Hz,2H),2.61(d,J=17.3H z, 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 value C 65 H 75 ClN 11 O9S + [M+H] + ,1220.5153; measured value,1220.5155.

[0448] 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-oxoisoindoline-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03167)

[0449] According to Scheme 7, the target compound (BCL-03167) was prepared using the compound (732149) prepared according to intermediate Example 4 and the intermediate compound (732180) as raw materials. 1 H NMR(500MHz,DMSO-d6)δ11.74(s,1H),11.70(s,1H),11.02(s,1H),10.32(s,1H),8.63(t,J =6.0Hz,1H),8.57(d,J=2.3Hz,1H),8.05(s,1H),7.85–7.78(m,3H),7.56(d,J=2.6Hz,1H), 7.53–7.50(m,2H),7.39(d,J=8.5Hz,2H),7.15(d,J=9.5Hz,1H),7.09(d,J=8.4Hz,2H),6.7 2(dd,J=9.1,2.4Hz,1H),6.41(dd,J=3.6,1.9Hz,1H),6.25(d,J=2.4Hz,1H),5.14(dd,J=13 .3,5.2Hz,1H),4.49(t,J=17.1Hz,1H),4.36(t,J=17.5Hz,1H),3.63(d,J=13.4Hz,4H),3.5 6(d,J=18.2Hz,4H),3.30–3.15(m,8H),2.98–2.88(m,1H),2.70(d,J=10.5Hz,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 value C 65 H 75 ClN 11 O9S + [M+H] +,1220.5153; measured value,1220.5155.

[0450] 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-dioxopiperazin-3-yl)-1-oxoisoindoline-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03168)

[0451] According to Scheme 7, the target compound (BCL-03168) was prepared using the compound (732150) prepared according to intermediate Example 4 and intermediate compound (732180) as raw materials. 1 H NMR (500MHz, DMSO-d6) δ11.74(s,1H),11.69(s,1H),11.02(s,1H),10.32(s,1H),8.63(t,J= 6.0Hz,1H),8.56(d,J=2.6Hz,1H),8.04(d,J=2.9Hz,1H),7.83–7.77(m,2H),7.69(s,1H),7. 55(d,J=2.9Hz,1H),7.54–7.50(m,2H),7.39(d,J=8.4Hz,2H),7.10(dd,J=8.7,5.5Hz,3H),6 .72(dd,J=9.1,2.4Hz,1H),6.43–6.37(m,1H),6.25(d,J=2.4Hz,1H),5.13(dd,J=13.4,5.2Hz ,1H),4.55–4.43(m,1H),4.35(t,J=16.3Hz,1H),3.63(d,J=12.1Hz,3H),3.54(s,3H),3.30– 3.10(m,11H),2.92(ddd,J=18.0,13.6,5.6Hz,2H),2.70(d,J=10.2Hz,2H),2.61(d,J=17.3H z, 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 value C 65 H75 ClN 11 O9S + [M+H] + ,1220.5153; measured value,1220.5154.

[0452] 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-oxoisoindoline-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)

[0453] According to Scheme 7, the target compound (BCL-03169) was prepared using the compound (732147) prepared according to intermediate Example 3 and the intermediate compound (732001) as raw materials. 1H NMR(500MHz,DMSO-d6)δ11.76(s,1H),11.71(s,1H),11.05(s,1H),10.58(s,1H),8.63(t, J=6.0Hz,1H),8.57(d,J=2.3Hz,1H),8.15(s,1H),8.01(s,1H),7.56(d,J=2.7Hz,1H),7.54 –7.50(m,2H),7.39(d,J=8.4Hz,2H),7.15(d,J=9.6Hz,1H),7.10(d,J=8.4Hz,2H),6.72(dd ,J=9.1,2.5Hz,1H),6.45–6.39(m,1H),6.25(d,J=2.4Hz,1H),5.16(dd,J=13.2,5.1Hz,1H) ,4.46(d,J=17.9Hz,1H),4.30(d,J=20.0Hz,1H),3.63(d,J=11.1Hz,4H),3.53(s,5H),3.2 7(d,J=13.0Hz,8H),2.92(ddd,J=18.0,13.5,5.4Hz,1H),2.75–2.66(m,2H),2.61(dt,J=17 2.2, 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 value C 65 H 74 BrClN 11 O9S + [M+H] + ,1298.4258; measured value,1298.4260.

[0454] 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-oxoisoindoline-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)

[0455] According to Scheme 7, the target compound (BCL-03170) was prepared using the compound (732148) prepared according to intermediate Example 3 and the intermediate compound (732001) as raw materials. 1 H NMR(500MHz,DMSO-d6)δ11.75(s,1H),11.70(s,1H),11.04(s,1H),10.59(s,1H),8.64(t,J=6.0Hz,1H ),8.57(d,J=2.4Hz,1H),8.13(s,1H),8.05(d,J=2.7Hz,1H),7.98(s,1H),7.81(dd,J=9.2,2.7Hz,1H), 7.56(d,J=2.9Hz,1H),7.54–7.50(m,2H),7.39(d,J=8.4Hz,2H),7.10(dd,J=8.9,3.1Hz,3H),6.72(dd ,J=9.1,2.5Hz,1H),6.46–6.39(m,1H),6.26(d,J=2.4Hz,1H),5.15(dd,J=13.3,5.2Hz,1H),4.70(s,1H ),4.45(d,J=17.9Hz,1H),4.30(d,J=17.5Hz,1H),3.63(d,J=12.7Hz,4H),3.53(s,4H),3.32–3.04(m, 10H),2.92(ddd,J=18.0,13.4,5.6Hz,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 = 6.6Hz, 2H), 2.19–2.08(m, 2H), 2.06–1.97(m, 3H), 1.90(d, J = 12.4Hz, 2H), 1.63(tq, J = 7.9, 4.2Hz, 1H), 1.55–1.39(m, 6H), 1.07(q, J = 12.5, 11.7Hz, 2H), 0.94(s, 6H). HRMS(ESI) m / z: Calculated value C 65 H 74 BrClN 11 O9S + [M+H] + ,1298.4258; measured value,1298.4250.

[0456] 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-oxoisoindoline-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)

[0457] According to Scheme 7, the target compound (BCL-03171) was prepared using the compound (732149) prepared according to intermediate Example 3 and the intermediate compound (732001) as raw materials. 1 H NMR(500MHz,DMSO-d6)δ11.76(s,1H),11.71(s,1H),11.05(s,1H),10.58(s,1H),8.63(t, J=6.0Hz,1H),8.57(d,J=2.3Hz,1H),8.15(s,1H),8.01(s,1H),7.56(d,J=2.7Hz,1H),7.54 –7.50(m,2H),7.39(d,J=8.4Hz,2H),7.15(d,J=9.6Hz,1H),7.10(d,J=8.4Hz,2H),6.72(dd ,J=9.1,2.5Hz,1H),6.45–6.39(m,1H),6.25(d,J=2.4Hz,1H),5.16(dd,J=13.2,5.1Hz,1H) ,4.46(d,J=17.9Hz,1H),4.30(d,J=20.0Hz,1H),3.63(d,J=11.1Hz,4H),3.53(s,5H),3.2 7(d,J=13.0Hz,8H),2.92(ddd,J=18.0,13.5,5.4Hz,1H),2.75–2.66(m,2H),2.61(dt,J=17 2.2, 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 value C 65 H 74 BrClN 11 O9S + [M+H]+ ,1298.4258; measured value,1298.4250.

[0458] 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-oxoisoindoline-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)

[0459] According to Scheme 7, the target compound (BCL-03172) was prepared using the compound (732150) prepared according to intermediate Example 3 and intermediate compound (732001) as raw materials. 1H NMR(500MHz,DMSO-d6)δ11.75(s,1H),11.70(s,1H),11.04(s,1H),10.59(s,1H),8.64(t,J=6.0Hz,1H ),8.57(d,J=2.4Hz,1H),8.13(s,1H),8.05(d,J=2.7Hz,1H),7.98(s,1H),7.81(dd,J=9.2,2.7Hz,1H), 7.56(d,J=2.9Hz,1H),7.54–7.50(m,2H),7.39(d,J=8.4Hz,2H),7.10(dd,J=8.9,3.1Hz,3H),6.72(dd ,J=9.1,2.5Hz,1H),6.46–6.39(m,1H),6.26(d,J=2.4Hz,1H),5.15(dd,J=13.3,5.2Hz,1H),4.70(s,1H ),4.45(d,J=17.9Hz,1H),4.30(d,J=17.5Hz,1H),3.63(d,J=12.7Hz,4H),3.53(s,4H),3.32–3.04(m, 10H),2.92(ddd,J=18.0,13.4,5.6Hz,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 = 6.6Hz, 2H), 2.19–2.08(m, 2H), 2.06–1.97(m, 3H), 1.90(d, J = 12.4Hz, 2H), 1.63(tq, J = 7.9, 4.2Hz, 1H), 1.55–1.39(m, 6H), 1.07(q, J = 12.5, 11.7Hz, 2H), 0.94(s, 6H). HRMS(ESI) m / z: Calculated value C 65 H 74 BrClN 11 O9S + [M+H] + ,1298.4258; measured value,1298.4255.

[0460] 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-oxoisoindoline-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butane-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03177)

[0461] According to Scheme 7, the target compound (BCL-03177) was prepared from 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)butane-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (SIAIS360129; see Example 13 of the preparation of intermediate BINDER in Chinese Patent Publication No. CN112707900 A, the contents of which are incorporated herein by reference in their entirety) and intermediate compound (732180). 1 H NMR (500MHz, DMSO-d6) δ11.02(s,1H),8.17(d,J=2.4Hz,1H),7.99(d,J=8.6Hz,1H),7.76(dd,J=9.1,1.9Hz,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 .6,9.0Hz,3H),5.13(dd,J=13.3,5.2Hz,1H),4.46(d,J=17.5Hz,1H),4.3 4 (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 value C 61 H 69 ClF3N8O8S3 + [M+H] + ,1229.4036; measured value,1229.4038.

[0462] 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-oxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03179)

[0463] According to Scheme 7, the target compound (BCL-03179) was prepared using the compound (732185) prepared according to intermediate Example 5 and the intermediate compound (732180) as raw materials. 1 H NMR(500MHz,DMSO-d6)δ11.81(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=3.1Hz,1H),7.97–7.89(m,2H),7.81(s,2H),7.60(d,J=3.2Hz,1H),7.55(t,J= 3.3Hz,1H),7.50(d,J=8.9Hz,1H),7.40(d,J=8.2Hz,2H),7.35(t,J=5.9Hz,1H),7.10(d,J=8.2H z,2H),7.08(d,J=9.3Hz,1H),6.76–6.70(m,1H),6.47–6.41(m,1H),6.28–6.21(m,1H),5.15(dd, J=13.3,5.2Hz,1H),4.50(d,J=17.7Hz,3H),4.37(d,J=17.7Hz,1H),3.61(s,9H),3.33–3.11(m, 9H),2.93(ddd,J=17.5,13.3,5.3Hz,1H),2.71(dd,J=20.1,7.3Hz,2H),2.61(d,J=17.9Hz,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 value C 65 H 73 ClF3N10 O9S2 + [M+H] + ,1293.4639; measured value,1293.4635.

[0464] 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-oxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03180)

[0465] According to Scheme 7, the target compound (BCL-03180) was prepared using the compound (732186) prepared according to intermediate Example 6 and the intermediate compound (732180) as raw materials. 1 H NMR(500MHz,DMSO-d6)δ12.16(s,1H),11.02(s,1H),10.25(s,1H),8.22(s,1H),8.05(dd,J =9.2,2.2Hz,1H),7.77(t,J=9.6Hz,4H),7.70(s,1H),7.42(d,J=8.2Hz,3H),7.24(d,J=9.6 Hz,1H),7.18(d,J=8.4Hz,2H),6.96(d,J=9.0Hz,2H),5.14(dd,J=13.3,5.2Hz,1H),4.48(d ,J=17.7Hz,1H),4.36(d,J=17.5Hz,2H),3.89(d,J=13.9Hz,2H),3.58(s,3H),3.51(s,2H), 3.30–3.00(m,12H),2.93(ddd,J=17.9,13.4,5.4Hz,1H),2.78(q,J=14.2,12.4Hz,2H),2.6 2(d,J=14.4Hz,1H),2.41(ddd,J=18.6,11.7,5.1Hz,2H),2.29(t,J=6.9Hz,2H),2.16(s,2H ), 2.15–2.07(m,2H), 2.02(q,J=5.8,5.3Hz,1H), 1.84(d,J=11.1Hz,2H), 1.60(t,J=11.3Hz,1H), 1.48(p,J=7.5,6.3Hz,4H), 1.05(d,J=12.7Hz,2H), 1.01(s,6H). HRMS(ESI) m / z: calculated value C58 H 69 ClF3N8O8S2 + [M+H] + ,1161.4315; measured value,1161.4316.

[0466] 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-oxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03181)

[0467] According to Scheme 7, the target compound (BCL-03181) was prepared using the compound (732187) prepared according to intermediate Example 7 and the intermediate compound (732180) as raw materials. 1 H NMR(500MHz,DMSO-d6)δ12.15(s,1H),11.03(s,1H),10.69(s,1H),8.70(t,J=6.2Hz,1 H),8.64(d,J=2.4Hz,1H),7.94(dd,J=9.2,2.6Hz,1H),7.88(s,1H),7.82–7.73(m,4H) ,7.41(d,J=8.4Hz,2H),7.28(d,J=9.6Hz,1H),7.18(d,J=8.4Hz,2H),6.95(d,J=9.3Hz ,2H),5.14(dd,J=13.3,5.0Hz,1H),4.54–4.31(m,4H),3.87(d,J=13.6Hz,2H),3.56(s, 6H),3.40–3.11(m,11H),2.93(ddd,J=17.7,13.6,5.5Hz,1H),2.83–2.69(m,2H),2.66 –2.58(m,1H),2.42(tt,J=13.1,6.5Hz,1H),2.27(t,J=6.9Hz,2H),2.21(s,2H),2.18–2 .08(m,2H), 2.02(dq,J=7.5,3.6,2.3Hz,1H), 1.95–1.87(m,2H), 1.64(dd,J=7.2,3.6Hz,1H), 1.46(q,J=8.2,6.7Hz,4H), 1.15–1.04(m,2H), 0.99(s,6H). HRMS(ESI) m / z: Calculated value C 57 H 69ClN9O8S + [M+H] + ,1074.4673; Measured value,1074.4673.

[0468] 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-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03185)

[0469] According to Scheme 7, the target compound (BCL-03185) was prepared from 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 No. 1312023-72-5). 1H NMR(500MHz,DMSO-d6)δ11.84(s,1H),11.75(s,1H),11.17(s,1H),10.77(s,1H),8.28(s,1H),8.17 (d,J=2.4Hz,1H),8.15(s,1H),8.07(d,J=2.7Hz,1H),8.02(d,J=7.8Hz,1H),7.93(dd,J=9.3,2.6Hz, 1H),7.62(d,J=2.7Hz,1H),7.55(t,J=3.1Hz,1H),7.50(d,J=8.9Hz,1H),7.39(d,J=8.5Hz,2H),7.34 (t,J=5.9Hz,1H),7.10(d,J=8.5Hz,2H),7.08(d,J=9.5Hz,1H),6.73(dd,J=9.0,2.4Hz,1H),6.48–6. 42(m,1H),6.25(d,J=2.3Hz,1H),5.19(dd,J=12.8,5.5Hz,1H),4.57(s,2H),3.75-3.40(m,11H),3.3 4–3.13(m,8H),2.91(ddd,J=16.8,13.6,5.4Hz,1H),2.75–2.66(m,2H),2.65–2.53(m,2H),2.36(t,J =6.6Hz, 2H), 2.18–2.05(m, 3H), 2.01(s, 2H), 1.83(d, J = 11.1Hz, 2H), 1.59(tt, J = 8.2, 4.2Hz, 1H), 1.50(d, J = 8.7Hz, 2H), 1.44(t, J = 6.4Hz, 2H), 1.07(t, J = 12.7Hz, 2H), 0.94(s, 6H). HRMS(ESI) m / z: Calculated value C 65 H 71 ClF3N 10 O 10 S2 + [M+H] + ,1307.4431; measured value,1307.4430.

[0470] 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-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03186)

[0471] According to Scheme 7, the target compound (BCL-03186) was prepared from 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 No. 1312023-72-5). 1 H NMR(500MHz,DMSO-d6)δ12.17(s,1H),11.61(s,1H),11.16(s,1H),10.58(s,1H),8.22(d, J=2.4Hz,1H),8.18(s,1H),8.09(s,1H),8.05(dd,J=9.3,2.6Hz,1H),7.99(d,J=7.6Hz,1H ),7.76(d,J=9.0Hz,2H),7.41(td,J=7.3,6.8,3.6Hz,3H),7.24(d,J=9.6Hz,1H),7.18(d, J=8.5Hz,2H),6.96(d,J=9.3Hz,2H),5.18(dd,J=12.9,5.4Hz,1H),4.36(s,1H),3.88(d,J= 13.3Hz,2H),3.65–3.13(m,18H),2.91(ddd,J=16.9,13.8,5.5Hz,1H),2.76(q,J=10.0,9. 2Hz,2H),2.67–2.58(m,1H),2.57–2.53(m,1H),2.28(t,J=6.8Hz,2H),2.20(s,2H),2.13(d ,J=10.5Hz,2H), 2.11–2.04(m,1H), 1.84(d,J=11.0Hz,2H), 1.60(tdq,J=11.0,7.2,4.3,3.7Hz,1H), 1.47(q,J=6.3Hz,4H), 1.07(t,J=12.1Hz,2H), 1.00(s,6H).HRMS(ESI)m / z: calculated value C 58 H 67 ClF3N8O9S2 + [M+H] + ,1175.4108; measured value,1175.4101.

[0472] Example 19: Preparation of 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-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03187)

[0473] According to Scheme 7, the target compound (BCL-03187) was prepared from 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 No. 1312023-72-5). 1 H NMR(500MHz,DMSO-d6)δ12.13(s,1H),11.15(s,1H),10.26(s,1H),8.70(t,J=6.1H z,1H),8.64(d,J=2.3Hz,1H),8.10(s,1H),7.98(s,2H),7.93(dd,J=9.2,2.5Hz,1H ),7.76(d,J=9.0Hz,2H),7.42(d,J=8.4Hz,2H),7.28(d,J=9.5Hz,1H),7.17(d,J=8 .5Hz,2H),6.95(d,J=9.3Hz,2H),5.17(dd,J=12.8,5.5Hz,1H),4.22(s,1H),3.88( d,J=14.2Hz,2H),3.57(s,2H),3.55-3.10(m,15H),2.90(ddd,J=16.9,13.8,5.5Hz ,1H),2.81–2.72(m,3H),2.65–2.58(m,1H),2.55(d,J=5.2Hz,1H),2.28(t,J=6.8H z, 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 value C 57 H 67 ClN9O9S + [M+H] + ,1088.4465; measured value,1088.4469.

[0474] 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-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03188)

[0475] According to Scheme 7, the target compound (BCL-03188) was prepared from 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 intermediate compound 5-(bromomethyl)-2-(2,6-dioxopiperazin-3-yl)isoindoline-1,3-dione (732195; CAS No. 1312023-72-5). 11H NMR (500 MHz, DMSO-d6) δ 11.76 (s, 1H), 11.70 (s, 1H), 11.16 (s, 1H), 10.52 (s, 1H), 8.64 (t, J = 6.1 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.09–8.04 (m, 2H), 8.00 (d, J = 7.6 Hz, 1H), 7.81 (dd, J = 9.3, 2.6 Hz, 1H), 7.56 (d, J = 2.7 Hz, 1H), 7.54–7.49 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.10 (dd, J = 9.2, 5.3 Hz, 3H), 6.72 (dd, J = 9.0, 2.4 Hz, 1H), 6.44–6.36 (m, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.18 (dd, J = 12.8, 5.5 Hz, 1H), 4.35 (s, 1H), 3.63 (d, J = 13.9 Hz, 2H), 3.53 (d, J = 4.4 Hz, 5H), 3.32–3.06 (m, 12H), 2.90 (ddd, J = 16.9, 13.7, 5.4 Hz, 1H), 2.74 (d, J = 5.0 Hz, 1H), 2.70 (t, J = 10.9 Hz, 2H), 2.65–2.58 (m, 1H), 2.57–2.53 (m, 1H), 2.33 (t, J = 6.6 Hz, 2H), 2.13 (d, J = 10.4 Hz, 2H), 2.10–2.04 (m, 1H), 2.01 (s, 2H), 1.90 (d, J = 11.6 Hz, 2H), 1.62 (dq, J = 8.1, 5.5, 4.0 Hz, 1H), 1.55–1.42 (m, 4H), 1.07 (q, J = 11.5 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) m / z: calculated for C 64 H 71 ClN 11 O 10 S + [M + H] + , 1220.4789; found, 1220.4785.

[0476] 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-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butane-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03189)

[0477] According to Scheme 7, the target compound (BCL-03189) was prepared from 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)butane-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (SIAIS360129) and intermediate compound 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (732195; CAS No. 1312023-72-5). 1HNMR(500MHz,DMSO-d6)δ12.18(s,1H),11.15(s,1H),10.08(s,1H),8.17(d,J=2 .4Hz,1H),7.99(dd,J=9.3,2.4Hz,1H),7.92(s,2H),7.84(s,1H),7.77(d,J=9.0H z,2H),7.44–7.39(m,2H),7.31–7.27(m,2H),7.22(t,J=7.6Hz,3H),7.17(d,J=8 .7Hz,3H),7.15–7.13(m,1H),6.97(t,J=10.1Hz,3H),5.16(dd,J=12.9,5.4Hz,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=17.1,14.2,5.4Hz,3H), 2.76(dd,J=19.2,6.9Hz,2H), 2.65–2.58(m,2H), 2.56–2.54(m,1H), 2.28(t,J=6.5Hz,2H), 2.14(s,4H), 2.10–2.03(m,1H), 1.47(t,J=6.6Hz,2H), 1.00(s,6H). HRMS(ESI) m / z: Calculated value C 61 H 67 ClF3N8O9S3 + [M+H] + ,1243.3828; measured value,1243.3829.

[0478] 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-dioxoisoindoline-5-yl)methyl)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03190)

[0479] According to Scheme 7, the target compound (BCL-03190) was prepared from intermediate compound (732147) prepared according to intermediate example 3 and intermediate compound 5-(bromomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (732195; CAS No. 1312023-72-5). 1 H NMR(500MHz,DMSO-d6)δ11.79(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=2.6Hz,1H),8.27(s,1H),8.15(s,1H),8.06(d,J=2.9Hz,1H),8.02(d,J=7.6Hz ,1H),7.82(dd,J=9.2,2.7Hz,1H),7.58(d,J=2.9Hz,1H),7.56–7.48(m,2H),7.39(d,J=8.4Hz,2 H),7.16(d,J=9.6Hz,1H),7.10(d,J=8.4Hz,2H),6.72(dd,J=9.1,2.5Hz,1H),6.45–6.36(m,1H), 6.26(d,J=2.4Hz,1H),5.19(dd,J=12.8,5.5Hz,1H),4.88(s,1H),4.30(s,1H),3.97–3.50(m,10 H),3.27(d,J=11.7Hz,8H),2.91(ddd,J=17.4,13.6,5.5Hz,1H),2.69(q,J=10.9,9.5Hz,2H),2.6 5–2.58(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 value C 65 H 73 ClN 11 O 10 S + [M+H] + ,1234.4946; measured value,1234.4940.

[0480] 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-oxoisoindoline-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)

[0481] According to Scheme 7, the target compound (BCL-03182) was prepared using intermediate compound (732185) and intermediate compound (732001) as raw materials. 11H 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 for C 65 H 72 BrClF3N 10 O9S2 + [M + H] + , 1371.3744; found, 1371.3740.

[0482] Example 24: Preparation of N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-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)

[0483] According to Scheme 7, the target compound (BCL-03183) was prepared using intermediate compound (732186) and intermediate compound (732001) as raw materials. 1 H NMR(500MHz,DMSO-d6)δ12.18(s,1H),11.04(s,1H),10.68(s,1H),8.22(d,J=2.6Hz,1 H),8.16(s,1H),8.05(dd,J=9.2,2.5Hz,1H),8.02(s,1H),7.76(d,J=9.0Hz,2H),7.44 –7.38(m,3H),7.24(d,J=9.6Hz,1H),7.18(d,J=8.4Hz,2H),6.95(d,J=9.2Hz,2H),5.1 6(dd,J=13.3,5.2Hz,1H),4.37(dd,J=76.8,17.9Hz,4H),3.88(d,J=13.3Hz,2H),3.56 (s,6H),3.36–3.07(m,11H),2.92(ddd,J=17.5,13.5,5.2Hz,1H),2.77(s,2H),2.61(d d,J=13.9,3.5Hz,1H),2.46(dd,J=13.1,4.9Hz,1H),2.27(s,2H),2.21(s,2H),2.12(s ,2H), 2.03(td,J=7.6,3.8Hz,1H), 1.84(d,J=11.4Hz,2H), 1.60(td,J=9.5,7.9,5.8Hz,1H), 1.47(q,J=7.4,6.7Hz,4H), 1.11–1.02(m,2H), 1.00(s,6H).HRMS(ESI)m / z: Calculated value C 58 H 68 BrClF3N8O8S2 + [M+H] + ,1239.3420; measured value,1239.3421.

[0484] Example 25: Preparation of N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-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)

[0485] According to Scheme 7, the target compound (BCL-03184) was prepared from intermediate compound (732187) and intermediate compound (732001) as raw materials. 1 H NMR (500MHz, DMSO-d6) δ12.14(s,1H),11.04(s,1H),10.63(s,1H),8.70(t,J=6.1Hz,1H) ,8.64(d,J=2.3Hz,1H),8.15(s,1H),8.01(s,1H),7.94(dd,J=9.2,2.5Hz,1H),7.77(d,J= 9.0Hz,2H),7.42(d,J=8.5Hz,2H),7.28(d,J=9.6Hz,1H),7.18(d,J=8.5Hz,2H),6.95(d,J =9.2Hz,2H),5.16(dd,J=13.3,5.2Hz,1H),4.37(dd,J=77.3,17.8Hz,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 =17.3Hz,1H),2.47(dd,J=13.4,8.2Hz,1H),2.28(t,J=6.8Hz,2H),2.21(s,2H),2.17–2.0 9(m,2H), 2.07–2.00(m,1H), 1.91(d,J=11.3Hz,2H), 1.64(tdd,J=14.8,7.0,3.4Hz,1H), 1.47(q,J=7.5,6.7Hz,4H), 1.08(q,J=12.5,11.3Hz,2H), 1.00(s,6H). HRMS(ESI) m / z: Calculated value C 57 H 68 BrClN9O8S + [M+H] + ,1152.3778; measured value,1152.3781.

[0486] Example 26: Preparation of N-((4-(((2R)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butane-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)

[0487] According to Scheme 7, the target compound (BCL-03178) was prepared from intermediate compound (SIAIS360129) and intermediate compound (732001) as raw materials. 1 H NMR(500MHz,DMSO-d6)δ12.19(s,1H),11.04(s,1H),10.49(s,1H),8.18(d,J=2.6Hz ,1H),8.05(s,1H),7.98(dd,J=9.3,2.4Hz,1H),7.94(s,1H),7.77(d,J=9.0Hz,2H),7 .41(d,J=8.5Hz,2H),7.29(d,J=7.6Hz,2H),7.22(t,J=7.7Hz,3H),7.20–7.12(m,3H ),6.99(d,J=8.9Hz,1H),6.96(d,J=9.2Hz,2H),5.15(dd,J=13.3,5.2Hz,1H),4.44(d ,J=17.9Hz,1H),4.28(d,J=17.7Hz,1H),4.20(s,2H),3.89(d,J=12.7Hz,2H),3.57( s,2H),3.50-3.00(m,15H),2.97–2.86(m,2H),2.77(d,J=11.3Hz,2H),2.62(d,J=3.5 Hz, 1H), 2.59(s, 1H), 2.46(dd, J = 13.2, 4.8Hz, 1H), 2.28(t, J = 6.9Hz, 2H), 2.21–2.07(m, 4H), 2.06–1.97(m, 1H), 1.47(t, J = 6.5Hz, 2H), 1.00(s, 6H). HRMS(ESI) m / z: Calculated value C 61 H 68 BrClF3N8O8S3 + [M+H] + ,1307.3141; measured value,1307.3139.

[0488] Bioactivity detection experiment

[0489] Experimental reagents and materials

[0490]

[0491]

[0492] Antibody:

[0493] The BCL-XL antibody used in the experiment was purchased from Abcam, and the Tubulin antibody was purchased from Proteintech.

[0494] Cell culture

[0495] The cell lines used—RS4;11 (human acute lymphoblastic leukemia cells), Molt-4 cells (human acute lymphoblastic leukemia cells), MV4;11 (human myeloid monocytic leukemia cells), and Light II cells—were all commercially available or purchased from the American Type Culture Collection (ATCC) and cultured according to ATCC instructions. All cells were identified as correct by STR cell line testing and were negative for mycoplasma through routine examination.

[0496] Evaluation of in vitro inhibitory activity against tumor cell proliferation

[0497] The disclosed compounds were initially evaluated for their tumor cell growth inhibition rate at single or dual concentrations, and IC50 was performed. 50 Measurement.

[0498] Compound half-inhibitory concentration (IC50) 50 Assay for Thiazolyl Blue Cell Proliferation

[0499] 1) The compounds of this invention based on ABT199 / 263 showed BCL-XL-dependent RS4;11 cell proliferation studies.

[0500]

[0501] The specific steps are as follows: RS4; 11 cells were injected at 3×10 4Cells were seeded per well in 90 μL of serum-containing RPMI 1640 medium. Simultaneously, DT2216 and the compound of the present invention were added to the cell suspension at corresponding concentration gradients. DT2216 was used as a positive control, and DMSO as a negative control. Both positive and negative controls were treated using the same method as the compound of the present invention. After 48 hours of treatment with the compound of the present invention, 10 μL of thiazolyl blue solution (5 mg / mL) was added to each well, and the cells were incubated at 37°C with 5% CO2 for 3 hours. Then, a triplet solution (SDS, 0.1 g / mL, isopropanol, 5%, hydrochloric acid, 10 mM) was added, and the cells were incubated at 37°C with 5% CO2 for another 4-6 hours. The absorbance was measured at 490 nm using an Epoch microplate reader (Biotek) after the crystal violet had completely dissolved, observed under an inverted biological microscope. The growth inhibition curves of the compound of the present invention on the experimental cells were plotted using GraphPad Prism 8 software, and the IC50 of the compound of the present invention was statistically determined. 50 Each group in this experiment had three replicates, and the experiment was repeated at least three times. The results are shown in Table 3 below.

[0502] 2) Study on the proliferation of BCL-XL-dependent MV4-11 cells based on the compounds of this invention, ABT199 / 263.

[0503] The specific steps are as follows: MV4;11 cells were injected at 2×10 4 Cells / well were seeded in 90 μL of serum-containing IMDM medium. Simultaneously, DT2216 and the compound of the present invention were added to the cell suspension at corresponding concentration gradients. DT2216 was used as a positive control, and DMSO as a negative control. Both positive and negative controls were treated with the same method as the compound of the present invention. After 48 hours of treatment with the compound of the present invention, 10 μL / well of thiazolyl blue solution (5 mg / mL) was added, and the cells were incubated for 3 hours at 37°C and 5% CO2. Then, a triple solution (SDS, 0.1 mg / mL, isopropanol, 5%, hydrochloric acid, 10 mM) was added, and the cells were incubated for another 4-6 hours at 37°C and 5% CO2. The absorbance was measured at 490 nm using an Epoch microplate reader (Biotek) after the crystal violet had completely dissolved, observed under an inverted biological microscope. The growth inhibition curves of the compound of the present invention on the experimental cells were plotted using GraphPad Prism 8 software, and the IC50 of the compound of the present invention was statistically determined. 50 Each group in this experiment had three replicates, and the experiment was repeated at least three times. The results are shown in Table 4 below.

[0504] 3) Study on the proliferation of BCL-XL-dependent Molt-4 cells based on the compounds of this invention, ABT199 / 263.

[0505] The specific steps are as follows: Molt-4 cells were injected at a rate of 2 × 10⁻⁶. 4 Cells were seeded per well in 180 μL of serum-containing RPMI 1640 medium. Simultaneously, DT2216 and the compound of the present invention were added to the cell suspension at corresponding concentration gradients. DT2216 was used as a positive control, and DMSO as a negative control. Both positive and negative controls were treated using the same method as the compound of the present invention. After treatment with the compound of the present invention for 72 hours, 20 μL of thiazolyl blue solution (5 mg / mL) was added to each well, and the cells were incubated at 37°C with 5% CO2 for 3 hours. Then, a triple solution (SDS, 0.1 mg / mL, isopropanol, 5%, hydrochloric acid, 10 mM) was added, and the cells were incubated at 37°C with 5% CO2 for another 4-6 hours. The absorbance was measured at 490 nm using an Epoch microplate reader (Biotek) after the crystal violet had completely dissolved, observed under an inverted biological microscope. The growth inhibition curves of the compound of the present invention on the experimental cells were plotted using GraphPad Prism 8 software, and the IC50 of the compound of the present invention was statistically determined. 50 Each group in this experiment had three replicates, and the experiment was repeated at least three times. The results are shown in Table 5 below.

[0506] Compound inhibits hedgehog activity IC 50 Measurement---Dual-luciferase reporter assay:

[0507] Light II cells were a cloned NIH3T3 cell line stably expressing Gli-luciferase and TK-renilla reporter genes. They were cultured in DMEM medium containing 10% (v / v) fetal bovine serum (FBS), with the addition of 0.4 mg / ml G418, 0.15 mg / ml bleomycin (Zeocin), and penicillin / streptomycin. The cells were incubated at 37°C in a 5% CO2 incubator. Light II cells in the logarithmic growth phase were harvested at 2.5 × 10⁻⁶ cells / year. 4 Each well was seeded with one sample of the compound and incubated for 24 hours. SAG and different concentrations of the compound of this invention were then added and treated for 36 hours before the reaction was terminated. Detection was performed according to the instructions of the Dual Luciferase Reporter Assay Kit. Each group was tested in triplicate, with at least three replicates. The results are shown in Table 6 below.

[0508] Western blotting of proteins

[0509] Molt-4 cells in logarithmic growth phase were collected at a dose of 3 × 10⁻⁶. 6Cells were seeded per well in a six-well plate. Simultaneously, cells were treated with the appropriate concentration of the compound of this invention, with DMSO as the control. After 10 hours of drug treatment, cells were collected and washed once with PBS. Cells were placed on ice and treated with IP protein lysis buffer containing a PMSF protease inhibitor. After centrifugation at 10 krpm for 5 minutes at 4°C, the supernatant was collected. An equal volume of protein supernatant was mixed with 4×LDS protein loading buffer at a volume ratio of 3:1, and 5% β-mercaptoethanol was added. After vortexing, the mixture was incubated in a 95°C metal bath for 10 minutes and stored at -80°C or directly cooled on ice for protein electrophoresis. The separating gel was a 10% self-made polyacrylamide gel. The electrophoresis tank and other related components were purchased from Bio-rad. Electrophoresis conditions were: low voltage 80V for 45 minutes, then high voltage 120V for 1 hour. PVDF membranes were used for transfer, and the transfer was performed at an isocurrent of 300 mA in an ice-water bath for one hour. After transfer, block with 5% skim milk powder at room temperature for 1 hour. Then incubate with primary antibody overnight at 4°C or 2 hours at room temperature. Wash three times with 1×TBST buffer (sodium chloride, 150 mM, Tris, 10 mM, Tween 20, 0.1%; pH 7.4), add secondary antibody, incubate at room temperature for 45 minutes, wash three times with 1×TBST buffer (sodium chloride, 150 mM, Tris, 10 mM, Tween 20, 0.1%; pH 7.4), and develop color. Antibody dilution ratios should follow the antibody manufacturer's instructions.

[0510] Experimental results

[0511] The specific experimental data are shown below.

[0512] 1. Study on the effect of the compound of the present invention based on ABT199 / 263 on BCL-XL-dependent cell proliferation

[0513] We conducted dose-dependent experiments on the designed and synthesized compounds of this invention in RS4;11 cells. These cells were highly sensitive to inhibitors of BCL-XL. After treating cells with different concentrations of the compounds (starting at 1000 nM or 100 nM, in 10-fold dilution gradients, 7 concentrations) for 48 hours, cell proliferation was detected using a thiazolyl blue (THIAZOLYL BLUE) assay. The experiments were repeated at least three times; the specific results are shown in Table 3.

[0514] The compounds of this invention (including compounds in Tables 1-2 and Examples 1-26) based on ABT-199 / 263, which we designed and developed, can effectively inhibit the proliferation of RS4;11 tumor cells (Table 3). DT2216's IC50 for RS4;11 cells... 50 The inhibitory effect of the compounds we developed in this invention is 81.04 ± 24.89 nM, which is significantly better than that of DT2216.

[0515] Table 3 shows the IC50 values ​​of the compounds of the present invention based on the ABT-199 / 263 series in RS4;11 (human acute lymphoblastic leukemia cell line). 50 (Hardest inhibitory concentration)

[0516] Cell line Test compound Reagent <![CDATA[IC 50 (nM)]]> RS4;11 DT2216 Thiazolyl blue 81.04±24.89 RS4;11 BCL-03146 Thiazolyl blue <20 RS4;11 BCL-03149 Thiazolyl blue <20 RS4;11 BCL-03165 Thiazolyl blue <20 RS4;11 BCL-03166 Thiazolyl blue <20 RS4;11 BCL-03167 Thiazolyl blue <20 RS4;11 BCL-03168 Thiazolyl blue <20 RS4;11 BCL-03169 Thiazolyl blue <20 RS4;11 BCL-03177 Thiazolyl blue <20 RS4;11 BCL-03179 Thiazolyl blue <20 RS4;11 BCL-03180 Thiazolyl blue <20 RS4;11 BCL-03181 Thiazolyl blue <20 RS4;11 BCL-03185 Thiazolyl blue <20 RS4;11 BCL-03188 Thiazolyl blue <20 RS4;11 BCL-03189 Thiazolyl blue <20 RS4;11 BCL-03190 Thiazolyl blue <20 RS4;11 BCL-03147 Thiazolyl blue <20 RS4;11 BCL-03148 Thiazolyl blue <20 RS4;11 BCL-03182 Thiazolyl blue <20

[0517] DT2216 (CAS No.: 2365172-42-3) is a BCL-XL degrading agent reported in the literature, and its structural formula is as follows:

[0518]

[0519] The compounds of this invention based on ABT-199 / 263 (including compounds in Tables 1-2 and Examples 1-26) that we designed and developed can effectively inhibit the proliferation of myeloid monocytic leukemia cells MV4;11 (Table 4). DT2216 has an IC50 effect on MV4;11 cells. 50 The value was 164.9 ± 70.71 nM. The inhibitory effects of the compounds of this invention, developed based on ABT199 / 263, were significantly better than those of DT2216.

[0520] Table 4 shows the IC50 values ​​of the compounds of this invention based on the ABT-199 / 263 series in myeloid monocytic leukemia cells MV4;11. 50 (nM, half-maximal inhibitory concentration)

[0521] Cell line Test compound Reagent <![CDATA[IC 50 (nM)]]> MV4;11 DT2216 Thiazolyl blue 164.9±70.71 MV4;11 BCL-03146 Thiazolyl blue <20 MV4;11 BCL-03147 Thiazolyl blue <20 MV4;11 BCL-03148 Thiazolyl blue <20 MV4;11 BCL-03149 Thiazolyl blue <20 MV4;11 BCL- ​ <20 ​ ​ ​ <20 ​ ​ ​ <20 ​ ​ ​ <20 ​ ​ ​ <20 ​ ​ ​ <20 ​ ​ ​ <20 ​ ​ ​ <20 ​ ​ ​ <20 ​ ​ Thiazolyl blue <20 MV4; 11 BCL-03190 Thiazolyl blue <20 MV4; 11 BCL-03182 Thiazolyl blue <20

[0522] The compounds of this invention based on ABT-199 / 263 (including the compounds in Tables 1-2 and Examples 1-26) designed and developed by us can effectively inhibit the proliferation of human acute lymphoblastic leukemia cells Molt-4 (Table 5). The inhibitory effect of the compounds of this invention based on ABT199 / 263 is significantly better than that of DT2216.

[0523] Table 5 shows the IC50 values ​​of the compounds of this invention based on the ABT-199 / 263 series in Molt-4 acute lymphoblastic leukemia cells. 50 (nM, half-maximal inhibitory concentration)

[0524]

[0525]

[0526] 2. IC Inhibition of Hedgehog (Hh) Signaling Pathway Activity Based on ABT-199 / 263 Compounds of the Present Invention 50 :

[0527] We designed and developed compounds of this invention based on ABT-199 / 263 (including compounds in Tables 1-2 and Examples 1-26) for screening their activity against the Hedgehog (Hh) signaling pathway (Table 6). The half-maximal inhibitory concentration (IC50) of the compounds of this invention developed based on ABT-199 / 263 was determined. 50 All can reach below 10nM.

[0528] Table 6. IC50 of the compounds of the present invention based on the ABT-199 / 263 series in Light II cells. 50 (nM, half-maximal inhibitory concentration)

[0529]

[0530]

[0531] 3. The compounds of this invention based on ABT199 / 263 can effectively degrade the protein level of BCL-XL in Molt-4 cells.

[0532] Molt-4 cells were spaced at 3 × 10⁶ cells per well. 6 Cells were seeded in 6-well plates. The next day, cells were treated with a drug concentration of 100 nM. The control group used DMSO and DT2216 as solvents. Protein samples were collected after 8 hours, and BCL-XL protein expression was detected by Western blot. The results showed that BCL-XL protein expression was significantly reduced after using the compounds of this invention (including the compounds in Tables 1-2 and Examples 1-26). For example, compounds BCL-03146, BCL-03147, BCL-03148, and BCL-03149 developed in this invention significantly degraded BCL-XL protein at concentrations around 100 nM (e.g., ...). Figure 1-3 (As shown). The compounds of this invention exhibit significant advantages in protein degradation compared to DT2216.

[0533] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments, and various changes and modifications can be made without departing from the spirit and scope of the invention; all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. Compounds of formula (I) or their salts, enantiomers or stereoisomers: Formula (I) in The dashed line indicates the presence of a double bond; (R5) n This indicates that the benzene ring is replaced by n R5 groups, each R5 group being the same or different and independently representing a halogen or carbon. 1-3 Alkyl or halogenated C 1-3 Alkyl group, where n represents the integer 1 or 2; (R6) m This indicates that the piperazine ring is replaced by m R6 molecules, each R6 molecule being the same or different and independently representing a halogen or carbon. 1-3 Alkyl or halogenated C 1-3 Alkyl group, where m represents the integer 0 or 1; R7 indicates hydrogen or ; R8 represents hydrogen or -SO2CF3 or -NO2; R9 represents hydrogen or C. 1-3 alkyl; R 10 Represents the following groups: in, Ring W 1 Indicates a 4- to 6-membered nitrogen-containing heterocyclic group, (R a1 ) n1 Represents ring W 1 by n1 R a1 Group substitution, each R a1 The same or different and each independently is C 1-3 Alkyl, Halogenated C 1-4 Alkyl, halogen, or oxo group, n1 represents the integer 0, 1, 2, or 3; Ring W 2 Indicate C 3-6 cycloalkylene, n3 represents an integer 0 or 1, (R a2 ) n2 Represents ring W 2 by n2 R a2 Group substitution, each R a2 The same or different and each independently is C 1-3 Alkyl, Halogenated C 1-4 Alkyl, halogen, or oxo group, n2 represents the integer 0, 1, 2, or 3; and The symbol * indicates a connection point with LIN; LIN means: C1 alkylene, wherein the hydrogen atoms of the C1 alkylene are optionally replaced by substituents selected from the following: C 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogen; and R 11 The structural formula for the following expression is: or Where R 12 Indicates key; (R a ) t This indicates that the benzene ring is divided by t R a Replace, each R a The same or different and independent representations of bromine, where t represents the integer 0, 1, 2 or 3; and X represents C(O) or CH2; and Where R1 and R2 represent hydrogen, and R3 and R4 represent methyl; or R1 and R2 represent methyl, and R3 and R4 represent hydrogen; Where t represents the integer 0: When R7 represents When n1 represents an integer 1, 2, or 3, and each R a1 The same or different and each independently is C 1-3 Alkyl, Halogenated C 1-3 Alkyl or halogen; or When R7 represents In this case, R8 represents -SO2CF3.

2. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer, or stereoisomer thereof, wherein (R5) n This indicates that the benzene ring is replaced by n R5s, each R5 being the same or different and each independently representing a halogen, where n represents an integer 1.

3. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer, or stereoisomer thereof, wherein (R5) n This indicates that the benzene ring is replaced by n R5s, each R5 being the same or different and independently representing chlorine, bromine, or fluorine, where n represents the integer 1.

4. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer or stereoisomer thereof, wherein t represents an integer 1, 2 or 3.

5. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer or stereoisomer thereof, wherein t represents an integer 0.

6. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer, or stereoisomer thereof, wherein R 10 Represents the following groups: in, Ring W 1 This indicates a 6-membered nitrogen-containing heterocyclic group, (R a1 ) n1 Represents ring W 1 by n1 R a1 Group substitution, each R a1 The same or different and each independently is C 1-3 Alkyl, Halogenated C 1-4 Alkyl or halogen, n1 represents the integer 0, 1, 2 or 3; Ring W 2 Indicates C6 cycloalkylene, n3 represents the integer 0 or 1, (R a2 ) n2 Represents ring W 2 by n2 R a2 Group substitution, each R a2 The same or different and each independently is C 1-3 Alkyl, Halogenated C 1-4 Alkyl, halogen, or oxo group, n2 represents the integer 0, 1, 2, or 3; and The symbol * indicates a connection point with LIN.

7. The compound of formula (I) as claimed in claim 1 or 6, or a salt, enantiomer, or stereoisomer thereof, wherein R 10 Represents the following groups: or .

8. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer, or stereoisomer thereof, wherein R 10 Represents the following groups: in, Ring W 1 It represents piperidinyl, piperazinyl, imomorpholinyl, zazonyl, pyrrolidine, imidazoalkyl, imidazoalkyl, imidazoalkyl, imidazoalkyl, or thiomorpholinyl; (R a1 ) n1 Represents ring W 1 by n1 R a1 Group substitution, each R a1 The same or different and each independently is C 1-3 Alkyl, Halogenated C 1-4 Alkyl, halogen, or oxo group, n1 represents the integer 0, 1, 2, or 3; Ring W 2 This indicates cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; n3 represents the integer 0 or 1, (R) a2 ) n2 Represents ring W 2 by n2 R a2 Group substitution, each R a2 The same or different and each independently is C 1-3 Alkyl, Halogenated C 1-4 Alkyl, halogen, or oxo group, n2 represents the integer 0, 1, 2, or 3; and The symbol * indicates a connection point with LIN.

9. The compound of formula (I) as claimed in any one of claims 1-5, or a salt, enantiomer, or stereoisomer thereof, wherein R 10 Represents the following groups: ； The symbol * indicates the connection point with LIN.

10. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer or stereoisomer thereof, wherein R1 and R2 represent hydrogen, and R3 and R4 represent methyl.

11. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer or stereoisomer thereof, wherein R1 and R2 represent methyl groups and R3 and R4 represent hydrogen groups.

12. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer, or stereoisomer thereof, wherein R 11 Represent the structural formulas of the following equations (II-6), (II-7), (II-10), or (II-11): ； in R 12 Indicates key; X represents C(O) or CH2; and (R a ) t This indicates that the benzene ring is divided by t R a Replace, each R a The same or different and independent of each other represent bromine, and t represents the integer 0, 1, 2 or 3.

13. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer, or stereoisomer thereof, wherein R 11 The structure of the following expression is represented as: 。 14. The compound of formula (I) or a salt, enantiomer, or stereoisomer thereof as described in any one of claims 1-6, 8, and 10-13, wherein the LIN represents the following group: #-CH2-; The symbol # represents the group R. 10 The connection point.

15. The compound of formula (I) as claimed in claim 1, or a salt, enantiomer, or stereoisomer thereof, selected from: 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-oxoisoindoline-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-oxoisoindoline-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-oxoisoindoline-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-oxoisoindoline-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-oxoisoindoline-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-oxoisoindoline-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-oxoisoindoline-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-oxoisoindoline-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-dioxoisoindoline-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-oxoisoindoline-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-oxoisoindoline-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-oxoisoindoline-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-dioxoisoindoline-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-oxoisoindoline-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-oxoisoindoline-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-dioxoisoindoline-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-dioxoisoindoline-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-oxoisoindoline-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-oxoisoindololin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide; and N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-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.

16. The compound of formula (I) or a salt, enantiomer or stereoisomer thereof as claimed in any one of claims 1-6, 8, 10-13 and 15, wherein the compound is a hydrochloride, sulfate, citrate, maleate, methanesulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrophosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, glycolate or p-toluenesulfonate.

17. A compound or its salt, enantiomer, or stereoisomer, selected from: 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-oxoisoindoline-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butane-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-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butane-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-oxoisoindoline-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-oxoisoindoline-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-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; and N-((4-(((2R)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-5-yl)methyl)piperazin-1-yl)-1-(phenylthio)butane-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.

18. The compound of claim 17 or a salt, enantiomer, or stereoisomer thereof, wherein the compound is a hydrochloride, sulfate, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrophosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate, glycolate, or p-toluenesulfonate.

19. A pharmaceutical composition comprising, as an active ingredient, a compound of formula (I) as described in any one of claims 1 to 16, or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19, further comprising at least one additional therapeutic agent.

21. The pharmaceutical composition of claim 20, wherein the therapeutic agent is an anticancer agent.

22. A pharmaceutical composition comprising, as an active ingredient, a compound as described in claim 17 or 18, or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22, further comprising at least one additional therapeutic agent.

24. The pharmaceutical composition of claim 23, wherein the therapeutic agent is an anticancer agent.

25. A medicine box or reagent kit comprising: The compound of formula (I) as claimed in any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in any one of claims 19-21; or The compound of claim 17 or 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 22-24.

26. The use of a compound of formula (I) as claimed in any one of claims 1 to 16, or a salt, enantiomer, or stereoisomer thereof, or a compound as claimed in claim 17 or 18, or a salt, enantiomer, or stereoisomer thereof, or a pharmaceutical composition as claimed in any one of claims 19-24, for the preparation of a medicament for the treatment and / or prevention of diseases or conditions selected from: neurodegenerative diseases; cardiovascular diseases; autoimmune diseases; bone marrow diseases; renal fibrosis; liver fibrosis; cirrhosis; tumors; leukemia-associated anemia; multiple organ dysfunction syndrome; acute liver failure; transplant rejection; retinopathy; and diabetes.

27. The use as described in claim 26, wherein the disease or condition is selected from: Parkinson's disease and Alzheimer's disease; coronary heart disease, congestive heart failure, myocardial infarction, and atherosclerosis; rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulcers, Kawasaki disease, polymyositis / dermatomyositis, Sjögren's syndrome, and atopic dermatitis; myelofibrosis; myelodysplastic syndrome (MDS); previously treated myelodysplastic syndrome; neutropenia; renal fibrosis; liver fibrosis; cirrhosis; hematologic malignancies and solid tumors; multiple organ dysfunction syndrome due to cachexia and septic shock; acute liver failure; organ or tissue transplant rejection; diabetic macular edema and wet age-related macular degeneration; and diabetes.

28. The use as claimed in claim 26, wherein the disease or condition is selected from: kidney, heart, lung, or tissue transplant rejection.

29. The use as described in claim 26, wherein the tumor is selected from: multiple myeloma; transplant-related cancers; leukemia; lymphoma; thyroid cancer; melanoma; lung cancer; inflammatory myofibroblastoma; colorectal cancer; glioma; astroblastoma; ovarian cancer; bronchial cancer; prostate cancer; breast cancer; pancreatic cancer; neuroblastoma; extramedullary plasmacytoma; medulloblastoma; plasmacytoma; gastric cancer; gastrointestinal stromal tumor; esophageal cancer; colorectal adenocarcinoma; esophageal squamous cell carcinoma; liver cancer; renal cell carcinoma; bladder cancer; endometrial cancer; brain cancer; oral cancer; sarcoma; chondrosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct carcinoma; bone cancer; cervical cancer; and skin cancer.

30. The use as described in claim 26, wherein the tumor is selected from: multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; transplant-related cancers; acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, acute myeloid leukemia; diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, anaplastic lymphoma, anaplastic large cell lymphoma, CD20 positive... Mantle cell lymphoma, primary lymphoma, T-cell lymphoma, small lymphocytic lymphoma, B-cell lymphoma, relapsed B-cell non-Hodgkin lymphoma, relapsed diffuse large B-cell lymphoma, relapsed mediastinal large B-cell lymphoma, primary mediastinal large B-cell lymphoma, relapsed transformed non-Hodgkin lymphoma, refractory B-cell non-Hodgkin lymphoma, refractory diffuse large B-cell lymphoma, refractory primary mediastinal large B-cell lymphoma Refractory-transforming non-Hodgkin's lymphoma, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia; thyroid cancer; melanoma; non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, and squamous cell carcinoma of the lung; inflammatory myofibroblastic tumor; colorectal cancer; glioma; glioblastoma; ovarian cancer; bronchial cancer; prostate cancer; estrogen-dependent breast cancer, HER2-positive breast cancer, triple-negative breast cancer, incidental breast cancer, and Cowden's disease; pancreatic cancer; neurological cancer. Medulloblastoma; 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; rhabdomyosarcoma; various adipose-derived tumors; Ewing sarcoma / primitive neuroectodermal tumor; and leiomyosarcoma; chondrosarcoma; urothelial carcinoma; basal cell carcinoma; oral squamous cell carcinoma; bile duct carcinoma; bone cancer; cervical cancer; and skin cancer.

31. The use as described in claim 26, wherein the tumor is selected from relapsed or refractory peripheral T-cell lymphoma.

32. The use according to any one of claims 26-31, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 16, or the compound or a pharmaceutically acceptable salt thereof as claimed in claims 17 or 18, or the pharmaceutical composition as claimed in any one of claims 19-24, is formulated as a medicament administered by at least one route of administration selected from nasal administration, inhalation 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.

33. The use as described in any one of claims 26-31, wherein the compound of formula (I) as described in any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or the compound as described in claims 17 or 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described in any one of claims 19-24, is formulated as a medicament to be administered via a topical route.

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