WO2023131118A1 - 基于bcl-2家族蛋白配体化合物开发的蛋白降解剂及它们的应用 - Google Patents

基于bcl-2家族蛋白配体化合物开发的蛋白降解剂及它们的应用 Download PDF

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WO2023131118A1
WO2023131118A1 PCT/CN2023/070102 CN2023070102W WO2023131118A1 WO 2023131118 A1 WO2023131118 A1 WO 2023131118A1 CN 2023070102 W CN2023070102 W CN 2023070102W WO 2023131118 A1 WO2023131118 A1 WO 2023131118A1
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piperidinylene
methyl
formula
alkyl
compound
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杨小宝
姜标
谭文福
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上海科技大学
复旦大学
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Definitions

  • the present disclosure relates to protein degradation agents developed based on BCL-2 family protein ligand compounds, including compounds of formula (I) or salts thereof, enantiomers, stereoisomers, solvates, isotopically enriched analogs, pro Drugs or polymorphs, and their use in the treatment of diseases.
  • Apoptosis or programmed cell death, is a process in which cells undergo a series of programmed events leading to death. In early development, apoptosis removes unnecessary cells, and in adulthood, apoptosis is mainly responsible for removing damaged and irreparable cells in the body, thus ensuring proper development of the body. Apoptosis plays an important role in a variety of physiological processes, such as participating in normal cell renewal, the development and function of the immune system, hormone-dependent atrophy, embryonic development, and chemically induced cell death (Elmore, S., Toxicol Pathol , 2007.35(4): p.495-516.).
  • Abnormal apoptosis can lead to various diseases, including neurodegenerative diseases, cardiovascular diseases, autoimmune diseases and tumors.
  • tumors can reduce their sensitivity to anti-tumor drugs by inhibiting the apoptosis pathway during the occurrence and development of tumors (Scott, W.L. et al., Carcinogenesis, 2000.21(3): p.485-495.). Therefore, activation of apoptotic signaling in tumor tissue may be an effective antitumor strategy.
  • the BCL-2 (B cell lymphoma-2) protein family is a key regulator of cell apoptosis, which can both induce and inhibit cell apoptosis.
  • BCL-2 has four highly conserved homology (BH) domains: BH1, BH2, BH3 and BH4, which can be divided into three subtypes according to the composition of homology domains, one of which has anti-apoptosis Function, two of which have pro-apoptotic function (Daniel, N.N., Clin Cancer Res, 2007.13(24): p.7254-7263.).
  • the BH1 and BH2 homology domains of BCL-2 can form dimers with pro-apoptotic proteins, and the BH3 domain is crucial in the interaction between pro-apoptosis and anti-apoptosis, so it is contained 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 pro-apoptotic Apoptotic proteins include BAX, BAK, and BOK, composed of BH1, BH2, and BH3, and other pro-apoptotic proteins include BID, BIM, BAD, PUMA, NOXA, BMF, HRK, and BIK, composed of BH3 only (Youle, R.J. , et al., Nat Rev Mol Cell Biol, 2008.9(1): p.47-59.).
  • the level of BCL-2 family proteins maintains a dynamic balance, and cell signaling can regulate the expression of pro-apoptotic proteins or anti-apoptotic proteins by affecting the dynamic balance process, so that the balance develops towards cell survival or death.
  • the pro-apoptotic protein permeabilizes the outer mitochondrial membrane through oligomerization on the outer mitochondrial membrane, releases cytochrome c, triggers the activation of the caspase enzyme cascade reaction, and cleaves the downstream substrate Drugs cause cell death (Opferman, J.T. and A. Kothari, Cell Death Differ, 2018.25(1):p.37-45.).
  • BCL-2 family protein antagonists also known as "BH3 domain mimetics" mainly prevent it from binding to pro-apoptotic proteins BAX and BAK by inserting the BH3 domain shared by anti-apoptotic BCL-2 family proteins, Inhibit the effect of BCL-2 anti-apoptotic protein, and then induce tumor cell apoptosis.
  • ABT-199 (Venetoclax) is the only FDA-approved antineoplastic drug targeting BCL-2 family proteins, which can be used to treat certain hematological malignancies, such as chronic lymphocytic leukemia and acute myeloid leukemia (Deeks, E.D. , Drugs, 2016.76(9): p.979-87.; Carter, P.J. and G.A. Lazar, Nat Rev Drug Discov, 2018.17(3): p.197-223.).
  • BCL-2 protein since the growth of most solid tumors does not depend on BCL-2 protein, ABT-199 has no obvious therapeutic effect on solid tumors, while BCL-XL protein is significantly highly expressed in various solid tumors and blood tumor cells (Leverson, J.M.
  • BCL-XL B-cell lymphoma-extra large
  • BCL-2 B-cell lymphoma-extra large
  • It is located in the mitochondria and is a key regulator of cell apoptosis. It can also regulate the pathophysiology of various cells. Processes, such as mitochondrial ATP synthesis, protein acetylation and cell mitosis, etc. (Michels, J., et al., International Journal of Cell Biology, 2013.2013: p.1-10.).
  • 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.).
  • BCL-XL plays the most critical role, and inhibiting BCL-XL can enhance the sensitivity of chondrosarcoma cells to conventional chemotherapy (Jong, Y.D., et al., Oncogenesis, 2018.7 (9).).
  • BCL-XL Small molecule inhibitors targeting BCL-XL such as ABT-263 have significant antitumor effects, however, since BCL-XL can limit the pro-apoptotic effect of Bax and contribute to platelet survival, inhibition of BCL-XL expression causes Thrombocytopenia destroys blood coagulation function, so ABT-263 has not been approved by FDA for listing (Tse, C., et al., Cancer Research, 2008.68(9): p.3421.). BCL-XL, as one of the most important proven anti-cancer targets, has no safe and effective treatment.
  • PROTAC Proteinolysis Targeting Chimeria
  • PROTAC is a bifunctional hybrid small molecule that connects the target protein ligand to the E3 ubiquitin ligase ligand through a suitable linker chain, prompting the target protein to form a ternary complex with the E3 ligase , so that the target protein is close to the ubiquitination system, realizing the ubiquitination of the target protein, and then being recognized by the 26S subunit of the proteasome, and finally leading to the degradation of the target protein (Sun, X., et al., Sig Transduct Target Ther, 2019.4( 1): p.33.).
  • PROTACs degrade proteins similarly to catalytic reactions, and thus can work at very low doses, and they are more durable and less toxic than traditional small molecule inhibitors (Lu, J., et al. , Chem Biol, 2015.22(6): p.755-763.). More importantly, since PROTACs rely on E3 ubiquitin ligase to mediate protein degradation, even if the target protein itself is widely expressed in the body, it will still be affected by the difference in the expression of E3 ubiquitin ligase in tumor cells and normal tissues. Cell or tissue selectivity.
  • DT2216 which has entered clinical trials, uses ABT-263 as the ligand of the target protein BCL-XL, and uses the lowly expressed VHL in platelets as the E3 ubiquitin ligase ligand, which significantly improves anti-tumor activity and reduces platelet toxicity (Khan, S., et al., Nature medicine, 2019.25(4): p.1938-1947.).
  • Hh Hedgehog
  • the 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.).
  • the signal transduction of Hh in cells is a cascade form, and its key molecules include PTCH receptor with 12 transmembrane domains, SMO (Smoothened) receptor with 7 transmembrane structures, SUFU protein and nuclear transcription factor GLI protein family.
  • PTCH When there is no exogenous HH ligand, PTCH inhibits the activity of SMO, and the signaling pathway is in an inhibited state; when exogenous HH ligand binds to PTCH, it releases its inhibition of SMO, thus causing SMO to become the key to the signaling pathway Signal the central cilium, and further cause the transcription complex of SUFU-GLI to also translocate to the cilium, release the inhibitory effect of SUFU on GLI, further regulate the phosphorylation of GLI by kinases such as GSK3 and CK1, and finally make the transcriptionally active GLI enter the nucleus Initiate the transcription of downstream target genes and activate the Hh signaling pathway (Nat Rev Mol Cell Biol, 2013.14(7):p.416-29; Genes Dev,2010.24(7):p.670-82.).
  • SUFU protein contains a conserved BH3 sequence, which can bind to anti-apoptotic proteins such as BCL-XL, BCL-2, and MCL-1 in cells, thereby releasing the inhibitory effect of SUFU on GLI protein, eventually leading to Hh Pathway activation; inhibiting the binding of BCL-XL and other anti-apoptotic proteins to SUFU can effectively inhibit the activation of Hh signaling pathway (Nat Cell Biol, 2017.19(10): p.1226-1236.). Based on this, targeting BCL-2 family proteins is also a strategy to develop inhibitors targeting Hh signaling pathway.
  • an object of the present disclosure is to provide novel protein degradation agents developed based on BCL-2 family protein ligand compounds, their uses, and their methods of use.
  • the novel protein degrading agent compound or its salt (including pharmaceutically acceptable salt), stereoisomer (including enantiomer), solvate, pro Drugs or polymorphs can bind to target proteins, recruit target proteins to E3 ubiquitin ligases for ubiquitination, labeling and degradation, thereby exhibiting desired pharmacological activities.
  • the novel protein degradation agent developed based on the BCL-2 family protein ligand compound of the present disclosure can be a compound of formula (I) or a salt thereof, a stereoisomer (including an enantiomer), a solvent compounds, isotopically enriched analogs, prodrugs or polymorphs:
  • R 1 , R 2 , R 3 , and R 4 are the same or different and independently represent hydrogen, C 1-4 alkyl, halogen, or halogenated C 1-4 alkyl;
  • R 5 n represents that the benzene ring is substituted by n R 5 s, each R 5 is the same or different and independently represents halogen, C 1-6 alkyl, or halogenated C 1-6 alkyl, n represents an integer 1, 2, 3, 4 or 5;
  • R 6 m means that the piperazine ring is substituted by m R 6 , each R 6 is the same or different and each independently represents halogen, C 1-6 alkyl, or halogenated C 1-6 alkyl, m represents an integer 0 , 1, 2, 3, 4, 5, 6, 7 or 8;
  • R7 represents hydrogen or
  • R 8 represents hydrogen or -SO 2 CF 3 or -NO 2 ;
  • R represents hydrogen or C 1-4 alkyl
  • R 10 represents the following groups:
  • ring W 1 represents a 4- to 6-membered nitrogen-containing heterocyclic group
  • (R a1 ) n1 represents that ring W 1 is substituted by n1 R a1 groups, and each R a1 is the same or different and is independently C 1- 6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, cyano, halogen, or oxo, n1 represents an integer of 0-8;
  • Ring W 2 represents a 4- to 6-membered nitrogen-containing heterocyclic group, or a C 3-6 cycloalkylene group
  • n3 represents an integer 0 or 1
  • (R a2 ) n2 represents that ring W 2 is substituted by n2 R a2 groups
  • each R a2 is the same or different and is independently C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, cyano, halogen, or oxo
  • n2 represents 0- an integer of 8;
  • One or more groups R b and/or one or more groups R c or any combination of one or more groups R b and R c are inserted into its main carbon chain.
  • Chain C 2-30 alkylene wherein the group R b , R c or the combination of the group R b and R c connect the carbon-carbon between one or more pairs of adjacent carbon atoms of the main carbon chain Disconnect between bonds; each group R b is selected from O, N(R d ), C(O), C(O)O, S(O), S(O) 2 , S(O) 2 NH, NHS( O) 2 , OC(O), C(O)N(R d ), N(R d )C(O), or N(R d )C(O)N(R d ), wherein each R d is independently represents H or C 1-6 alkyl, and when two or more groups R b are inserted into the main carbon chain of the straight or branched C 2-30 alkylene, each group R b
  • R 12 represents N( Re ), O, S, C 2-6 alkynylene, or C 2-6 alkenylene, wherein R 12 represents H or C 1-6 alkyl, or R 12 represents a bond ;
  • R a t represents that the benzene ring is substituted by t R a , each R a is the same or different and independently represents bromine, and t represents an integer of 0, 1, 2 or 3;
  • X represents C(O) or CH 2 ;
  • R 7 means When, n1 represents an integer of 1-8, and each R a1 is the same or different and is independently C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, or halogen; or
  • R 8 represents -SO 2 CF 3 .
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a salt, stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorphs, and at least one pharmaceutically acceptable carrier.
  • novel protein degradation agent developed based on the BCL-2 family protein ligand compound of the present disclosure may be the following compound or its salt, stereoisomer (including enantiomer), solvate, prodrug or polymorphs:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above protein degrader compound or a salt, stereoisomer (including enantiomer), solvate, prodrug or polymorph, and at least one pharmaceutically acceptable carrier.
  • kits or kit comprising:
  • the protein degrader compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
  • the present disclosure provides a protein degrader compound of the present disclosure or a salt, stereoisomer (including enantiomer), solvate, prodrug or polymorph thereof of the present disclosure or a medicament comprising the same as an active ingredient Composition for use as a medicament.
  • the present disclosure provides a protein degrader compound of the present disclosure or a salt, stereoisomer (including enantiomer), solvate, prodrug or polymorph thereof of the present disclosure or a medicament comprising the same as an active ingredient Composition for use as a medicament.
  • the present disclosure further provides the protein degrader compound of the present disclosure or its salt, stereoisomer (including enantiomer), solvate, prodrug or polymorph, or a compound comprising it as an active ingredient.
  • a pharmaceutical composition for the treatment and/or prevention of a disease or condition selected from the group consisting of neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, myelofibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, tumors , multiple organ dysfunction syndrome (MODS), cachexia and multiple organ failure due to septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes mellitus, transplant rejection, retinopathy and acute liver function Exhausted.
  • the present disclosure also provides the protein degrader compound of the present disclosure or its salt, stereoisomer (including enantiomer), solvate, prodrug or polymorph for use in the preparation of therapeutic and/or Use of a medicament for the prevention of a disease or condition selected from the group consisting of: neurodegenerative disease, cardiovascular disease, autoimmune disease, myelofibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), cachexia and multiple organ failure due to septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes mellitus, transplant rejection, retinopathy and acute liver failure.
  • a disease or condition selected from the group consisting of: neurodegenerative disease, cardiovascular disease, autoimmune disease, myelofibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), cachexia and multiple organ failure due to septic shock, organ (including kidney, heart, lung
  • the present disclosure also provides a method for treating or preventing a disease or condition in a subject, which comprises administering to the subject a therapeutically effective amount of a protein degrader compound of the present disclosure, or a salt thereof, for Enantiomers, stereoisomers, solvates, prodrugs or polymorphs or pharmaceutical compositions comprising them, or a therapeutically effective amount of a compound of the present disclosure or a salt thereof, stereoisomers (including enantiomers conformation), solvate, prodrug or polymorph or a pharmaceutical composition comprising it as an active ingredient, wherein the disease or condition is selected from the group consisting of: neurodegenerative disease, cardiovascular disease, autoimmune disease, myelofibrosis multiple organ failure due to renal fibrosis, hepatic fibrosis, liver cirrhosis, tumors, multiple organ dysfunction syndrome (MODS), cachexia, and septic shock, organ (including kidney, heart, lung) or tissue transplant rejection reactions, diabetes mellitus, transplant rejection, retin
  • Figure 1-3 is a schematic diagram of the results of Western blot experiments, which show that the compounds of the present invention, BCL-03146, BCL-03147, BCL-03148, BCL-03149, etc. (100nM) act on Molt-4 cells for 8 hours and significantly reduce BCL-XL Protein expression, and compared with DT2216 (CAS No.: 2365172-42-3; a BCL-XL degrader reported in the literature), the protein degradation advantage is obvious.
  • the present disclosure provides a compound of formula (I) or its salt (including pharmaceutically acceptable salt), stereoisomer (including enantiomer), solvate, isotopically enriched analog, prodrug or polymorph Model:
  • R 1 , R 2 , R 3 , R 4 , (R 5 ) n , (R 6 ) m , R 7 , R 8 , R 9 , R 10 , LIN, and R 11 are as the compound of formula (I) above defined in .
  • the dashed line in the compound of formula (I) indicates the optional presence of a double bond.
  • a dotted line in a compound of formula (I) indicates the presence of a double bond.
  • the group containing the dotted line of the compound of formula (I) is as follows:
  • the dashed line in the compound of formula (I) indicates the absence of a double bond.
  • the group containing the dotted line of the compound of formula (I) is as follows:
  • R 1 , R 2 , R 3 , and R 4 of the compound of formula (I) are the same or different and independently represent hydrogen, C 1-4 alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl), halogen (such as fluorine, chlorine, bromine or iodine), or halogenated C 1-4 alkyl (such as halogenated C 1-3 alkyl, such as F 3 C- , FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 -, or CH 2 ClCH 2- ).
  • C 1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl
  • halogen such as fluorine, chlorine, bromine
  • R 1 and R 2 of the compound of formula (I) represent hydrogen, and R 3 and R 4 represent methyl.
  • R 1 and R 2 of the compound of formula (I) represent methyl, and R 3 and R 4 represent hydrogen.
  • (R 5 ) n of the compound of formula (I) represents that the benzene ring is substituted by n R 5 s, each R 5 is the same or different and each independently represents halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), or halogen Substituted C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), n represents an integer of 1, 2, 3, 4 or 5.
  • halogen such
  • (R 6 ) m of the compound of formula (I) represents that the piperazine ring is substituted by m R 6 , each R 6 is the same or different and each independently represents a halogen (such as fluorine, chlorine, bromine or iodine) , C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), or Halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), m represents an integer of 0, 1, 2, 3, 4, 5, 6, 7 or 8.
  • halogen
  • R represents hydrogen or
  • R7 represents hydrogen
  • R represents
  • R8 represents hydrogen or -SO2CF3 or -NO2 .
  • R represents hydrogen
  • R 8 represents -SO 2 CF 3 .
  • R8 represents -NO2 .
  • R represents hydrogen or C 1-4 alkyl (such as C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl ).
  • R represents hydrogen
  • R 9 represents C 1-4 alkyl (eg, C 1-3 alkyl, eg, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl).
  • R represents the following groups:
  • ring W 1 represents a 4- to 6-membered nitrogen-containing heterocyclic group
  • (R a1 ) n1 represents that ring W 1 is substituted by n1 R a1 groups
  • each R a1 is the same or different and is independently C 1- 6 Alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1- 6Alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 1-6 alkoxy (for example C 1-4 alkoxy or C 1-3 alkoxy, for
  • Ring W 2 represents a 4- to 6-membered nitrogen-containing heterocyclic group, or a C 3-6 cycloalkylene group
  • n3 represents an integer 0 or 1
  • (R a2 ) n2 represents that ring W 2 is substituted by n2 R a2 groups
  • each R a2 is the same or different and is independently C 1-6 alkyl (for example C 1-4 alkyl or C 1-3 alkyl , for example methyl, ethyl, propyl, isopropyl, butyl , sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -
  • the symbol * indicates the connection point with LIN.
  • Ring W represents a 4- to 6-membered nitrogen-containing heterocyclylene group, which includes, but is not limited to, for example, piperidinylene, piperazinylene, Morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, or thiomorpholinylene.
  • (R a1 ) n1 means that ring W 1 is substituted by n1 R a1 groups, each R a1 is the same or different and is independently C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkane Groups, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 1-6 alkoxy (such as C 1-4 alkoxy or C 1-3 alkoxy, such as methoxy, ethoxy, propoxy, iso propoxy, but
  • Ring W represents a 4- to 6-membered nitrogen-containing heterocyclylene group, which includes, but is not limited to, for example, piperidinylene, piperazinylene, Morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, or thiomorpholinylene.
  • Ring W 2 represents C 3-6 cycloalkylene
  • said 4-6 membered cycloalkylene includes, but is not limited to, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • (R a2 ) n2 means that ring W 2 is substituted by n2 R a2 groups, each R a2 is the same or different and is independently C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkane Groups, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 1-6 alkoxy (such as C 1-4 alkoxy or C 1-3 alkoxy, such as methoxy, ethoxy, propoxy, iso propoxy, but
  • n3 represents the integer 0 or 1.
  • n3 represents the integer zero.
  • n3 represents the integer 1.
  • R represents the following groups:
  • the symbol * represents the connection point with LIN.
  • R represents the following formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6 ), formula (II-7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), or the structural formula of formula (II-12):
  • R 12 represents N(R e ), O, S, C 2-6 alkynylene (such as ethynylene), or C 2-6 alkenylene (such as vinylene), wherein Re represents H or C 1 -6 alkyl (for example C 1-4 alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), or R 12 represents key;
  • X represents C(O) or CH2 ;
  • (R a ) t represents that the benzene ring is substituted by t pieces of R a , each of which is the same or different and each independently represents bromine, and t represents an integer of 0, 1, 2 or 3.
  • X represents C(O).
  • X represents CH2 .
  • R 12 represents a bond
  • t represents the integer zero.
  • t represents the integer 1, 2 or 3.
  • R 11 represents a structure of the formula:
  • n1 represents an integer of 1-8 (such as integer 1, 2, 3, 4, 5, 6, 7 or 8), and each R a1 is the same or different and is independently C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halo C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 1-6 alkoxy (such as C 1-4 alkoxy or C 1-3 alkoxy, such as methoxy, ethoxy , propoxy, is
  • the LIN represents the structure of the formula:
  • each group R b is selected from O, N(R d ), C(O), C(O)O, OC(O), S(O), S(O) 2 , S(O) 2 NH , NHS(O) 2 , C(O)N(R d ), N(R d )C(O), or N(R d )C(O)N(R d ), wherein each R d independently represents H or C 1-6 alkyl (for example C 1-4 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl); each group R is selected from Cycloalkylene (such as C 3-20 cycloalkylene), arylene (such as C 3-20 arylene), heterocyclylene (such as 4- to 20-membered heterocyclylene), heterocyclylene Aryl (such as 4- to 20-membered heteroarylene), alkynylene (such as C 2-6
  • One or more CH hydrogens of the C 1-30 alkylene group are optionally further replaced by substituents selected from the group consisting of: C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 Alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl or halo C 1-3 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkoxy (such as C 1-4 alkoxy or C 1-3 alkoxy Oxygen, such as
  • R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , and R a10 are the same or different and independently represent H, C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl Or halogenated C 1-3 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 - , CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), halogen (such as fluorine, chlorine, bromine or iodine), or
  • n4, n5, n6, n7, m1, m2, m3 are independently selected from integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
  • the symbol # indicates the point of attachment to the group R 10 .
  • the LIN represents the structure of the formula:
  • each R d independently represents H or C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec butyl or tert-butyl);
  • the cycloalkylene group (such as C 3-20 cycloalkylene group), the arylene group (such as C 3-20 arylene group), the heterocyclic group (such as 4- to 20-membered heterogeneous group) ring group) and said heteroarylene (for example 4- to 20-membered heteroarylene) independently of each other optionally further selected from C 1-6 alkyl (for example C 1-4 alkyl or C 1 -3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl or Halogenated C 1-3 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2
  • R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , and R a10 are the same or different and independently represent H, C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl Or halogenated C 1-3 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 - , CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), halogen (such as fluorine, chlorine, bromine or iodine), or
  • n4, n5, n6, n7, m1, m2, m3 are independently selected from integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15;
  • the symbol # indicates the point of attachment to the group R 10 .
  • the LIN represents the following groups:
  • the piperidinylene and the piperazinylene are independently from each other optionally further selected from C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl , ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl or halogenated C 1-3 alkyl , such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), halogen (such as fluorine, chlorine, bromine or iodine), C 1-6 alkoxy (such as C 1-4 alkoxy or C 1-3 alkoxy, such as methoxy group, e
  • Each R independently represents H or C 1-6 alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl);
  • the symbol # represents the point of attachment to the group R ;
  • n4, n5, n6, n7, m1, m2, m3 are each independently selected from integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.
  • the compound of formula (I) is also represented by the following structure of formula (I-1):
  • R 1 , R 2 , R 3 , R 4 , (R 5 ) n , (R 6 ) m , R 7 , R 8 , R 9 , R 10 , LIN, R 12 , (R a ) t and X are such as Compounds of formula (I) and embodiments thereof are defined herein.
  • the compound of formula (I) is also represented by the structure of formula (I-2) or formula (I-3):
  • R 1 , R 2 , R 3 , R 4 , (R 5 ) n , (R 6 ) m , R 8 , R 9 , R 10 , LIN, R 12 , (R a ) t and X are of the formula ( I) Compounds and various embodiments thereof as defined.
  • the compound of formula (I) is also represented by the following structure of formula (I-2-1):
  • R 10 represents the following groups:
  • ring W 1 represents a 4- to 6-membered nitrogen-containing heterocyclic group
  • (R a1 ) n1 represents that ring W 1 is substituted by n1 R a1 groups
  • each R a1 is the same or different and is independently C 1- 6 Alkyl (such as C 1-4 alkyl or C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl), halogenated C 1- 6Alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 1-6 alkoxy (for example C 1-4 alkoxy or C 1-3 alkoxy, for
  • Ring W 2 represents a 4- to 6-membered nitrogen-containing heterocyclic group, or a C 3-6 cycloalkylene group
  • n3 represents an integer 0 or 1
  • (R a2 ) n2 represents that ring W 2 is substituted by n2 R a2 groups
  • each R a2 is the same or different and is independently C 1-6 alkyl (for example C 1-4 alkyl or C 1-3 alkyl, for example methyl, ethyl, propyl, isopropyl, butyl , sec-butyl or tert-butyl), halogenated C 1-6 alkyl (such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -),
  • R 1 , R 2 , R 3 , R 4 , (R 5 ) n , (R 6 ) m , R 8 , R 9 , R 10 , LIN, R 12 and X are compounds of formula (I) herein and embodiments thereof defined in the scheme.
  • the ring W of the compound of formula (I-2-1) represents a 4- to 6-membered nitrogen-containing heterocyclylene, which includes but is not limited to, for example Piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, or Thiomorpholinyl.
  • (R a1 ) n1 of the compound of formula (I-2-1) means that ring W 1 is substituted by n1 R a1 groups, each R a1 is the same or different and each independently is a C 1-6 alkane (e.g. C 1-4 alkyl or C 1-3 alkyl, e.g.
  • halogenated C 1-6 alkane group such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 1-6 alkoxy (eg C 1-4 alkoxy or C 1-3 alkoxy, eg 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 of 1-8 (for example, an integer of 1, 2, 3, or 4
  • the ring W of the compound of formula (I-2-1) represents a 4- to 6-membered nitrogen-containing heterocyclylene, which includes but is not limited to, for example Piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oxazolidinylene, thiazolidinylene, or Thiomorpholinyl.
  • the ring W of the compound of formula (I-2-1) represents a C 3-6 cycloalkylene group
  • the 4- to 6-membered cycloalkylene group includes but is not limited to, for example, cyclopropyl, ring Butyl, cyclopentyl or cyclohexyl.
  • (R a2 ) n2 of the compound of formula (I-2-1) means that ring W 2 is substituted by n2 R a2 groups, each R a2 is the same or different and each independently is a C 1-6 alkane (e.g. C 1-4 alkyl or C 1-3 alkyl, e.g.
  • halogenated C 1-6 alkane group such as halogenated C 1-4 alkyl, such as F 3 C-, FCH 2 -, F 2 CH-, ClCH 2 -, Cl 2 CH-, CF 3 CF 2 -, CF 3 CHF-, CHF 2 CF 2 -, CHF 2 CHF-, CF 3 CH 2 - or CH 2 ClCH 2 -), C 1-6 alkoxy (eg C 1-4 alkoxy or C 1-3 alkoxy, eg 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 of 0-8 (for example, an integer of 0, 1, 2, 3,
  • n3 of the compound of formula (I-2-1) represents the integer 0 or 1.
  • n3 of the compound of formula (I-2-1) represents the integer 0.
  • n3 of the compound of formula (I-2-1) represents the integer 1.
  • R 10 of the compound of formula (I-2-1) represents the following groups:
  • the symbol * represents the connection point with LIN.
  • the compound of formula (I) is also represented by the following structure of formula (I-2-1):
  • R 8 represents -SO 2 CF 3 ;
  • R 1 , R 2 , R 3 , R 4 , (R 5 ) n , (R 6 ) m , R 9 , R 10 , LIN, R 12 and X are as described herein in compounds of formula (I) and embodiments thereof definition.
  • the compound of formula (I) is also composed of the following formula (I-2-2), formula (I-2-3), formula (I-2-4), formula (I-2-5), The structure representation of formula (I-3-1), formula (I-3-2), formula (I-3-3), or formula (I-3-4):
  • R 9 , R 10 , LIN, R 12 , (R a ) t and X are as defined herein for compounds of formula (I) and embodiments thereof.
  • hydrochloride, sulfate, citrate, maleate, sulfonate, methanesulfonate, citrate, lactate salts of compounds of formula (I) of the present disclosure tartrate, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroethylene salt, glycolate or p-toluenesulfonate.
  • the present disclosure also provides novel protein degradation agents developed based on BCL-2 family protein ligand compounds in the following Table 2, or salts thereof (including pharmaceutically acceptable salts, such as their hydrochlorides) ), stereoisomers (including enantiomers and diastereomers), solvates, isotopically enriched analogs, prodrugs or polymorphs:
  • hydrochloride, sulfate, citrate, maleate, sulfonate, methanesulfonate, citrate, lactate, tartaric acid salts of compounds of Table 2 of the present disclosure are provided Salt, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate , glycolate or p-toluenesulfonate.
  • Compounds of the present disclosure have 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 any structure in formula (I-3-4), or any structure in Table 1 or 2.
  • the compounds of the present disclosure may have a stereo configuration, and thus may exist in more than one stereoisomer form.
  • the present disclosure also relates to compounds having a stereoconfiguration that is optically enriched, such as about greater than 90% ee, such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures.
  • optically enriched means that a mixture of enantiomers consists of a significantly greater proportion of one enantiomer and can be described by enantiomeric excess (ee%).
  • Purification of isomers and separation of isomeric mixtures can be achieved by standard techniques known in the art (e.g. column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (e.g. by using chiral intermediates) and/or Or chiral resolution, etc.) to achieve.
  • salts of compounds of the present disclosure may be pharmaceutically acceptable salts, including but not limited to hydrochloride, sulfate, citrate, maleate, methanesulfonate, citrate, lactate, tartaric acid Salt, fumarate, phosphate, dihydrogen phosphate, pyrophosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, trifluoroacetate , glycolate or p-toluenesulfonate, etc.
  • the compounds of the present disclosure can exist in pharmaceutically acceptable solvents such as water, ethanol, etc. in the form of unsolvates or solvates.
  • the disclosed compounds can be prepared as prodrugs or prodrugs. Prodrugs can be converted into parent drugs in the body to play a role.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, stereoisomer ( Including enantiomers), or mixtures of stereoisomers, and at least one pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers include, but are not limited to, fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, colorants, solvents, or encapsulating materials.
  • a carrier must be "acceptable” if it is compatible with the other ingredients of the formulation, including compounds useful in the present disclosure, and not injurious to the patient.
  • compositions include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil ; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and hydroxide Aluminum; Surfactant Phosphate Buffered Saline; Polyoxyethylene, Polyvinylpyrrolidone, Polyacrylamide, Polox
  • the pharmaceutical compositions of the present disclosure further include at least one second therapeutic agent, such as an anticancer agent.
  • the second therapeutic agent can be combined with the compounds of the present disclosure (including 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 any compound of formula (I-3-4), or a compound of Table 1 or Table 2) in combination for the treatment of a disease or disorder described in the present disclosure.
  • Second therapeutic agents include, but are not limited to, chemotherapeutic agents, immunotherapeutic agents, gene therapy agents, and the like.
  • compositions can be administered according to the appropriate route of administration (including but not limited to nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, etc.) administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration and intravenous administration) are prepared in suitable formulation forms such as spray formulations, patches, tablets (such as conventional tablets, dispersible tablets, orally disintegrating tablets), capsules (such as soft capsules, hard capsules, enteric-
  • suitable formulation forms such as spray formulations, patches, tablets (such as conventional tablets, dispersible tablets, orally disintegrating tablets), capsules (such as soft capsules, hard capsules, enteric-
  • aqueous or oily suspensions solutions, emulsions or syrups
  • conventional injectable forms such as injectable solutions (e.g. using water, Ringer's solution or isotonic chloride according to methods known in the art).
  • injectable solutions e.g. using water, Ringer's solution or isotonic chloride according to methods known in the art.
  • Sodium chloride solution, etc. as a carrier or solvent for the preparation of sterile injection solutions) or lyophilized compositions.
  • the dosage of the active compound for all diseases or conditions mentioned herein is, for example, about 5 ng/kg subject body weight/day to 500 mg/kg subject body weight/day, about 10 ng/kg subject body weight/day to 300 mg/kg body weight of the subject/day, for example 0.1 to 100 mg/kg body weight of the subject/day, or 0.5 to about 25 mg/kg body weight of the subject/day.
  • Kits/packages may include packages or containers.
  • Packages 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, and the like.
  • the kit/packaging article may contain instructions for use of the product.
  • the compounds described in the present disclosure may be used in the preparation of a medicament for the prevention and/or treatment of a disease or condition selected from neurodegenerative diseases, cardiology Vascular disease, autoimmune disease, myelofibrosis, renal fibrosis, hepatic fibrosis, cirrhosis, neoplasms, multiple organ dysfunction syndrome (MODS), cachexia, and multiorgan failure due to septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes mell
  • 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 heart disease, congestive heart failure, myocardial infarction, and atherosclerosis; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulceration, Kawasaki disease, polymyositis/dermatomyositis, Sjogren's syndrome, and atopic dermatitis; myelofibrosis; renal fibrosis; liver fibrosis; cirrhosis; neoplasms, including hematologic malignancies, and solid tumors; Organ dysfunction syndrome (MODS), including multiorgan failure due to cachexia and septic shock; acute liver failure; transplant rejection, including organ (including kidney, heart,
  • the tumor includes, but is not limited to: for example, myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; myeloid disease; myeloproliferation Dysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia Leukemia, leukemia-related anemia, acute myeloid leukemia (AML); lymphoma, 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 lympho
  • 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 described in the present disclosure (including 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), any compound of formula (I-3-1), formula (I-3-2), formula (I-3-3), or formula (I-3-4), or Table 1 or Table 2 compound), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • a compound described in the present disclosure including 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), any compound of formula (I-3-1), formula (I-3-2), formula (I-3-3), or formula (I-3-4), or Table 1 or Table 2 compound
  • the disease or condition includes: neurodegenerative disease, cardiovascular disease, autoimmune disease, myelofibrosis, renal fibrosis, liver fibrosis, cirrhosis, tumor, multiple organ dysfunction syndrome (MODS), cachexia and multiple organ failure due to septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes mellitus, transplant rejection, retinopathy and acute liver failure.
  • autoimmune disease myelofibrosis
  • renal fibrosis fibrosis
  • liver fibrosis cirrhosis
  • tumor multiple organ dysfunction syndrome (MODS)
  • MODS multiple organ dysfunction syndrome
  • cachexia due to septic shock, organ (including kidney, heart, lung) or tissue transplant rejection, diabetes mellitus, transplant rejection, retinopathy and acute liver failure.
  • 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 heart disease, congestive heart failure, myocardial infarction, and atherosclerosis; autoimmune diseases, including rheumatoid arthritis, autoimmune encephalomyelitis, ankylosing spondylitis, psoriasis, systemic lupus erythematosus, multiple sclerosis, recurrent oral ulceration, Kawasaki disease, polymyositis/dermatomyositis, Sjogren's syndrome, and atopic dermatitis; myelofibrosis; renal fibrosis; liver fibrosis; cirrhosis; neoplasms, including hematologic malignancies, and solid tumors; Organ dysfunction syndrome (MODS), including multiorgan failure due to cachexia and septic shock; acute liver failure; transplant rejection, including organ (including kidney, heart,
  • the tumor includes, but is not limited to: for example, myeloma, including multiple myeloma, plasma cell myeloma, smoldering myeloma, smoldering multiple myeloma; myelofibrosis; myeloid disease; myeloproliferation Dysplastic syndrome (MDS); previously treated myelodysplastic syndrome; transplant-related cancer; neutropenia; leukemia, including acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia Leukemia, leukemia-related anemia, acute myeloid leukemia (AML); lymphoma, 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 lympho
  • Drugs, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration and intravenous administration will treat the An effective amount of the disclosed compound (including 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 a compound of any one of Formula (I-3-4), or a compound of Table 1 or Table 2), or a pharmaceutical composition of the present disclosure is administered to the subject.
  • treatment refers to administration of a compound of the present disclosure (including 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 any compound of formula (I-3-4), or Table 1 or Table 2 compound) or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, to slow down (lessen) the development of an undesired disease or condition (eg, a tumor).
  • beneficialal or desired clinical outcomes of the present disclosure include, but are not limited to, relief of symptoms, lessening of disease severity, stabilization of disease state, delay or slowing of disease progression, amelioration or palliation of disease, and remission of disease.
  • a “therapeutically effective amount" of a compound of the present disclosure depends on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, the age, sex and weight of the patient, the general medical condition of the patient, and the mode of administration. and time, rate of excretion, concomitant medications, and progression of the disease or condition in the treated patient. Based on these and other factors, one skilled in the art will be able to determine the appropriate dosage.
  • mice 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 wait.
  • mammals including but not limited to primates (such as humans), cattle, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, mice wait.
  • the phrase "...represents a bond” means that it is a linkage of bonds (ie means that it does not exist).
  • R 12 represents a bond means that R 12 is a bond linker.
  • the group LIN in the structure of formula (I) is directly connected to the benzene ring in the structure of formula (II).
  • the term used alone or in combination "inserts one or more groups R b and/or one or more groups R c or one or more groups R b and R in its main carbon chain
  • the "insertion" in "optionally substituted linear or branched C2-30 alkylene" in any combination of c has a definition known in the art, that is, it can refer to the group R b , R c or the group R b Any combination with Rc breaks carbon-carbon bonds between one or more pairs of adjacent carbon atoms of the main carbon chain.
  • examples of the above-mentioned phrase "inserting one or more” may include, but 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) a group R b as defined herein and/or a 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) group R c and/or one or more (1-30, 1-20, or 1-15, 1-10, 1-9, 1-8, 1-7, 1 - any combination of 6, 1-5, 1-4, 1-3 or 1-2, or 1) groups R b and R c , the main chain group formed thus conforms to the covalent bond theory.
  • Straight or branched C 2-30 alkylene refers to the insertion of one or more pairs of any two adjacent carbon atoms in the main carbon chain of a straight or branched C 2-30 alkylene chain
  • One or more e.g.
  • the term “optionally substituted” alone or in combination means that the indicated group may be unsubstituted or substituted with one or more substituents as defined herein.
  • the terms “optionally substituted” and “unsubstituted or substituted” are used interchangeably herein.
  • substituted generally means that one or more hydrogens in the referenced structure are replaced by the same or different specified substituents.
  • the number of substituents is in principle not subject to any restriction, either automatically by the size of the building block (ie the total number of replaceable hydrogen atoms of the building block), or as explicitly defined herein.
  • R 12 representing said group is connected to the group LIN of the compound of formula (I).
  • the hydrogen in 2 is replaced by a substituent as defined herein.
  • the term "one or more CH hydrogens” may refer to some or all of the hydrogens of the mentioned alkylene group, 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.
  • the phrase "one or more CH2 hydrogens” may refer to 1-3 of the multiple hydrogens of the referenced alkylene group. This number is in principle unlimited or automatically limited by the size of the building unit.
  • halogen atom or halogen used alone or in combination means fluorine, chlorine, bromine or iodine.
  • alkyl used alone or in combination refers to a linear or branched alkyl group.
  • Cx - Cyalkyl or " Cxyalkyl” (x and y each being an integer) refers to a straight or branched chain alkyl group containing x to y carbon atoms.
  • C 1-10 alkyl used alone or in combination in the present invention refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms.
  • C 1-10 alkyl in the present disclosure 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, and C 1-4 alkyl.
  • 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.
  • C 1-3 alkyl or "C 1 -C 3 alkyl” in the present disclosure refers to an alkyl group containing 1 to 3 carbon atoms, representative examples of which include methyl, ethyl, n-propyl and Isopropyl.
  • the "alkyl” is optionally substituted, and the substituent may be one or more selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy Substituents of radicals, trifluoromethyl groups, heterocyclic groups or combinations thereof.
  • haloalkyl used alone or in combination refers to a linear or branched alkyl group substituted by one or more halogens, wherein one or more hydrogens in the alkyl group are replaced by halogens.
  • halogenated C x -C y alkyl or “halogenated C xy alkyl” (x and y each being an integer) refers to a straight chain or branched chain alkyl.
  • halogenated C 1-10 alkyl used alone or in combination in the present disclosure refers to a straight chain or branched chain alkyl.
  • halogenated C 1-10 alkyl groups in the present disclosure include halogenated C 1-9 alkyl groups, such as halogenated C 1-8 alkyl groups, halogenated C 2-8 alkyl groups, halogenated C 1-7 alkyl groups , halogenated C 1-6 alkyl, halogenated C 1-5 alkyl, or halogenated C 1-4 alkyl.
  • Representative examples include halomethyl, haloethyl, halo-n-propyl, halo-isopropyl, halo-n-butyl, halo-isobutyl, halo-sec-butyl, halo-tert-butyl, Halopentyl, haloisopentyl, haloneopentyl, halopentyl, halohexyl, haloheptyl, halooctyl, halononyl, and halodecyl.
  • halogenated C 1-3 alkyl or "halogenated C 1 -C 3 alkyl” in the present disclosure refers to an alkyl group containing 1 to 3 carbon atoms substituted by one or more halogens, which typically Examples include halomethyl, haloethyl, halo-n-propyl and halo-isopropyl.
  • alkylene (which is used interchangeably with “alkylene chain”) alone or in combination refers to a linear or branched divalent saturated hydrocarbon group composed of carbon and hydrogen.
  • C x -C y alkylene or "C x - y alkylene” (x and y each being an integer) refers to a linear or branched chain alkylene group containing x to y carbon atoms.
  • C 1 -C 30 alkylene in the present disclosure examples include C 1 -C 30 alkylene, C 1 -C 29 alkylene, C 1 -C 28 alkylene, C 1 -C 27 alkylene, C 1 -C 26 alkylene, C 1 -C 25 alkylene, C 1 -C 24 alkylene, C 1 -C 23 alkylene, C 1 -C 22 alkylene, C 1 -C 21 Alkylene, C 1 -C 20 alkylene, C 1 -C 19 alkylene, C 1 -C 18 alkylene, C 1 -C 17 alkylene, C 1 -C 16 alkylene, C 1 -C 15 alkylene, C 1 -C 14 alkylene, C 1 -C 13 alkylene, C 1 -C 12 alkylene, C 1 -C 11 alkylene, C 1 -C 10 alkylene Alkyl, C 1 -C 9 alkylene, C 1 -C 8 alkylene, C 1 -C 7
  • Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene , Neopentylene, Pentylene, Hexylene, Heptylene, Octylene, Nonylene, Decylene, Undecylene, Dodecylene, Tridecylene, Decylene Tetraalkyl, Pentadecyl, Hexadecyl, Heptadecyl, Octadecyl, Nonadecyl, Eicosanyl, Hexadecyl, Eicosanyl Dialkyl, triacyl, tetracosyl, pentapenta, hexadecyl, heptacyl, octadecyl, nine nine Alkyl, and Triaconyl.
  • the "alkylene" is optionally substituted, and the substituents may be one or more selected from C 1 -C 3 alkyl, C 3-6 cycloalkyl, hydroxyl, amino , mercapto, halogen, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, halogenated C 1 -C 3 alkyl, amino C 1-3 alkylene, C 1-3 alkyl-NHC Substituents of (O)-, C 1-3 alkyl-C(O)NH-, cyano or any combination thereof.
  • alkoxy used alone or in combination refers to a straight-chain or branched alkoxy group whose structural formula is alkyl-O-. Alternatively, 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, pentyloxy, 2 - pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy and the like.
  • C 1 -C 3 alkoxy or "C 1-3 alkoxy” refers to a straight or branched chain alkoxy group containing 1 to 3 carbon atoms.
  • Representative examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.
  • heteroaryl used alone or in combination refers to a a) 5- to 20-membered (alternatively 5 to 15, 5 to 12, 5 to 11, 5 to 10, 5 to 9-membered, 5-8-membered, 5-7-membered, 5-6-membered, 6-15-membered or 6-9-membered) monocyclic or bicyclic or polycyclic aromatic ring groups.
  • 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 can be is a saturated, partially unsaturated or aromatic ring and may be carbocyclic or contain one or more heteroatoms independently selected from O, S and N.
  • monocyclic heteroaryl groups include, but are not limited to, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, and triazinyl.
  • bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, isoindolinyl, benzofuryl, isobenzofuryl, benzothienyl, indazolyl, benzimidazolyl, Benzoxazolyl, Benzisoxazolyl, Benzothiazolyl, Benzisothiazolyl, Benzotriazolyl, Benzo[2,1,3]oxadiazolyl, Benzo[2,1 ,3] Thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthaleinyl Azinyl, oxazolopyridyl, furopyridyl, pteridyl, purinyl, pyridopyridyl
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, and xanthenyl.
  • the heteroaryl group can be unsubstituted or substituted.
  • Substituted heteroaryl refers to a heteroaryl group substituted one or more times (eg 1-4, 1-3 times or 1-2 times) by a substituent, wherein the substituents are optionally selected from C 1 -C 3 Alkyl, C 3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, halogenated C 1 -C 3 alkyl, amino C 1 -3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano or any combination thereof.
  • heteroarylene used alone or in combination refers to a 3) 5- to 20-membered aromatic rings of heteroatoms independently selected from oxygen, nitrogen and sulfur (optionally 5 to 15, 5 to 12, 5 to 11, 5 to 10, 5-9 membered, 5-8-membered, 5-7-membered, 5-6-membered, 6-15-membered or 6-9-membered) monocyclic or bicyclic or polycyclic divalent aromatic ring groups.
  • Bicyclic or polycyclic heteroarylene includes bicyclic, tricyclic or tetracyclic heteroarylene, wherein one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other The rings can be saturated, partially unsaturated or aromatic and can be carbocyclic or contain one or more heteroatoms independently selected from O, S and N.
  • monocyclic heteroarylene groups include, but are not limited to, furylylene, oxazolylene, isoxazolylene, oxadiazolylidene, thienylene, thiazolylidene, isothiazolylene, Thiadiazolyl, pyrrolylene, imidazolyl, pyrazolylene, triazolylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, tetrazolyl, and triazolylene Azinyl.
  • bicyclic heteroarylene examples include, but are not limited to, indolylene, isoindolylene, benzofurylene, isobenzofurylene, benzothienylene, indazolyl, benzimidazole benzoxazolylene, benzoisoxazolylene, benzothiazolyl, benzoisothiazolyl, benzotriazolylene, benzo[2,1,3]oxadiazole Base, benzo[2,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnamic Linyl, quinazolinylene, quinoxalinylene, phthalazinyl, oxazolopyridinyl, furopyridinyl, apteridinyl, purinylene, pyridinopyridinyl, pyrazole A[1,5-a]pyridinylid
  • tricyclic heteroarylene examples include, but are not limited to, acridinylene, benzindolylene, carbazolylidene, dibenzofurylene, and xanthenylene.
  • the heteroarylene group can be unsubstituted or substituted.
  • Substituted heteroarylene refers to a heteroarylene group substituted one or more times (eg 1-4, 1-3 times or 1-2 times) by substituents, wherein the substituents are optionally selected from C 1 - C 3 alkyl, C 3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, halogenated C 1 -C 3 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.
  • aryl refers to a monovalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenyl or naphthyl or fluorene base.
  • the "aryl” is an optionally substituted aryl.
  • Substituted aryl refers to an aryl group substituted one or more times (for example 1-4, 1-3 times or 1-2 times) by a substituent, for example an aryl group is monosubstituted, disubstituted or trisubstituted by a substituent, Wherein the substituents are optionally selected from, for example, C 1 -C 3 alkyl, C 3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino , halogenated C 1 -C 3 alkyl, amino substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyanide groups or any combination thereof.
  • arylene refers to a divalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenylene or Naphthyl or fluorenylene.
  • the "arylene” is an optionally substituted arylene.
  • Substituted arylene refers to an arylene group substituted one or more times (for example 1-4, 1-3 times or 1-2 times) by a substituent, for example an arylene group is monosubstituted, disubstituted or Trisubstituted, wherein substituents are optionally selected from C 1 -C 3 alkyl, C 3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1 -C 3 alkoxy, C 1 -C 3 Alkylamino, halogenated C 1 -C 3 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.
  • cycloalkyl refers to a saturated or partially unsaturated (ie, having one or more double bonds, but not fully conjugated) monocyclic or bicyclic or polycyclic ring hydrocarbon group, which In some embodiments have 3 to 20 carbon atoms (ie C 3-20 cycloalkyl), or 3 to 15 carbon atoms (ie C 3-15 cycloalkyl), 3 to 12 carbon atoms (ie C 3-12 cycloalkyl), or 3 to 11 carbon atoms (ie C 3-11 cycloalkyl), or 3 to 10 carbon atoms (ie C 3-10 cycloalkyl), or 3 to 8 carbon atom (ie C 3-8 cycloalkyl), or 3 to 7 carbon atoms (ie C 3-7 cycloalkyl), or 3 to 6 carbon atoms (ie C 3-6 cycloalkyl).
  • cycloalkyl includes monocyclic, bicyclic or tricyclic cycloalkyl groups having 3 to 20 carbon atoms.
  • Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Bicyclic and tricyclic cycloalkyls include bridged cycloalkyls, fused rings and spirocycloalkyls such as but not limited to decahydronaphthyl, octahydropentalenyl, octahydro-1H-indenyl, spirocycloalkane group, adamantyl group, noradamantyl group, bornyl group, norbornyl group (IUPAC system named bicyclo[2.2.1]heptyl group).
  • 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.
  • the substituents of the substituted "cycloalkyl” are optionally one or more (for example, 1-5, 1-4, 1-3, 1-2, or 1) selected from C 1 -C 3 Alkyl, C 3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, halogenated C 1 -C 3 alkyl, amino substituted Substituents of C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C 1-3 alkyl-C(O)NH-, cyano or any combination thereof.
  • Examples of the term "C 3-6 cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl.
  • C xy spirocycloalkyl or “C xy spirocyclyl” (x and y each being an integer) used alone or in combination refers to a spirocycloalkyl group containing x to y carbon atoms.
  • C 7-11 spirocycloalkyl used alone or in combination in the present invention refers to a spirocycloalkyl group containing 7 to 11 (eg 7-10, 7-9) carbon atoms.
  • C spirocycloalkyl include, but are not limited to, spiro[3.3]heptanyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[4.4]nonyl , spiro[4.5]decyl or spiro[5.5]undecyl.
  • C 7-11 spirocycloalkyl is optionally further selected from one or more groups selected from C 1 -C 3 alkyl, C 3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1 - C 3 alkoxy, C 1 -C 3 alkylamino, halogenated C 1 -C 3 alkyl, amino substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, C Substituents of 1-3 alkyl-C(O)NH-, cyano or any combination thereof.
  • cycloalkylene used alone or in combination refers to a 7, 3-6 carbon atoms) saturated and partially unsaturated (that is, having one or more double bonds, but not fully conjugated) monocyclic or bicyclic or polycyclic ring hydrocarbon divalent groups.
  • cycloalkylene includes monocyclic, bicyclic or tricyclic hydrocarbon divalent groups having 3 to 12 carbon atoms.
  • monocyclic cycloalkylenes include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, and cyclooctylene.
  • Bicyclic and tricyclic cycloalkylenes include bridged cycloalkylenes, fused cycloalkylenes and spirocycloalkylenes such as but not limited to decahydronaphthylene, octahydropentalenylene, octahydro-1H -indenylene, 2,3-dihydro-1H-indenylene, spirocyclylene, adamantylene, noradamantylene, norbornylene (systematically named bicyclo[2.2.1]heptane Alkylene).
  • cycloalkylene is optionally monosubstituted or polysubstituted, such as but not limited to, 2,2-, 2,3-, 2,4-, 2,5- , or 2,6-disubstituted cyclohexyl.
  • the substituents of the substituted "cycloalkylene” may optionally be one or more selected from C 1 -C 3 alkyl, C 3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, halogenated C 1 -C 3 alkyl, amino substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, Substituents of C 1-3 alkyl-C(O)NH-, cyano or any combination thereof.
  • C xy spirocyclylene or “C xy spirocyclylene” (x and y each being an integer) used alone or in combination refers to a spirocyclylene containing x to y carbon atoms base.
  • C 7-11 spirocycloalkylene used alone or in combination in the present invention refers to a spirocycloalkylene containing 7 to 11 (eg, 7-10, 7-9) carbon atoms.
  • C spirocycloalkylene include, but are not limited to, spiro[3.3]heptaneylidene, spiro[2.5]octanylidene, spiro[3.5]nonanylidene, spiro[4.4 ]nonaneylidene, spiro[4.5]decaneylidene or spiro[5.5]undecaneylidene.
  • C 7-11 spirocycloalkylene is optionally further selected from one or more groups selected from C 1 -C 3 alkyl, C 3-6 cycloalkyl, hydroxyl, amino, mercapto, halogen, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, halogenated C 1 -C 3 alkyl, amino substituted C 1-3 alkylene, C 1-3 alkyl-NHC(O)-, Substituents of C 1-3 alkyl-C(O)NH-, cyano or any combination thereof.
  • heterocyclyl or “heterocycloalkyl” used alone or in combination means containing one or more (for example containing 1 to 5, 1 to 4, 1 to 3, 1 to 2 1 or 1) 3 to 20 membered monocyclic, bicyclic or tricyclic saturated or partially unsaturated (that is, having one or more double bonds, but not fully co- yoke) cycloalkyl.
  • heterocyclyl may refer to containing one or more (eg containing 1 to 5 or, 1 to 4, 1 to 3, 1 to 2 or 1) independently selected from 3 to 15 membered (alternatively 3 to 14, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7-membered, 3-6-membered, 3-5-membered or 4-9-membered) monocyclic saturated or partially unsaturated (ie, having one or more double bonds, but not fully conjugated) cyclic hydrocarbon groups.
  • monocyclic saturated or partially unsaturated ie, having one or more double bonds, but not fully conjugated
  • monocyclic heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophene base, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, azepanyl, azepine Cyclooctyl, diazepanyl (eg 1,4-diazepan-1-yl) and diazepanyl.
  • Bicyclic and tricyclic heterocyclyls include bridged, fused and spiroheterocyclyls, representative examples of which include, but are not limited to, 6-azabicyclo[3.1.1]heptan-3-yl, 2, 5-diazabicyclo[2.2.1]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-di Azabicyclo[2.2.2]octan-2-yl, and azaspirocyclyl (eg 3-azaspiro[5.5]undec-3-yl).
  • the heterocyclyl group may be unsubstituted or substituted as clearly defined (e.g. by mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxyl, amino, mercapto, nitro group, halogen, cyano, optional deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optional deuterated C 3-6 cycloalkyl, optional deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optional Deuterated C 1-6 alkyl-C(O)NH- or any combination thereof.
  • nitrogen-containing monocyclic heterocyclic group used alone or in combination means containing one nitrogen atom and optionally containing one or more (such as containing 1 to 5, 1 to 4, 1 to 3 3 to 20 (optionally 3 to 15, 3 to 14, 3 to 12, 3 to 11) independently selected from sulfur, oxygen and nitrogen heteroatoms, 1 to 2 or 1) 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 4 to 9) monocyclic saturated or partially unsaturated (that is, having one or multiple double bonds, but not fully conjugated) monovalent cyclic hydrocarbon groups.
  • one or more such as containing 1 to 5, 1 to 4, 1 to 3 3 to 20 (optionally 3 to 15, 3 to 14, 3 to 12, 3 to 11) independently selected from sulfur, oxygen and nitrogen heteroatoms, 1 to 2 or 1) 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, or 4 to 9) monocyclic saturated or partially unsaturated (that is, having one or multiple double bonds, but not fully conjugated) monovalent cyclic hydrocarbon groups.
  • nitrogen-containing monocyclic heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl , morpholinyl, thiomorpholinyl, azepanyl, azepanyl, diazepanyl (eg 1,4-diazepan-1-yl) and Diazacyclooctyl.
  • the nitrogen-containing monocyclic heterocyclyl group may be unsubstituted or substituted as clearly defined (for example by mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxyl, amino , mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, optional deuterated C 1-6 alkyl-NH-, NH 2 -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.
  • heterocyclylene or “heterocycloalkylene” used alone or in combination means containing one or more (for example containing 1 to 5, 1 to 4, 1 to 3, 1 3 to 20 membered monocyclic, bicyclic or tricyclic saturated or partially unsaturated (that is, having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon group.
  • heterocyclylene may, for example, refer to containing one or more (for example containing 1 to 5 or, 1 to 4, 1 to 3, 1 to 2 or 1) independently 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-membered, 3- to 6-, 3- to 5-, or 4- to 9-membered) monocyclic saturated or partially unsaturated (ie, having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon groups .
  • monocyclic heterocyclylenes include, but are not limited to, azetidinylene, oxetylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, tetrahydrofuranylene, tetrahydrofuranylene, tetrahydrofuranylene, Hydropyranyl, tetrahydrothiophenylene, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene , dioxanylene and diazepanylidene (such as 1,4-diazepanylidene, 4,5-diazepanylidene, 1,3-diazepanylidene Hepanylidene).
  • Bicyclic heterocyclylenes and tricyclic heterocyclylenes include bridged heterocyclylenes, fused heterocyclylenes, and spiroheterocyclylenes, representative examples of which include, but are not limited to, 6-azabicyclo[3.1.1]heptane Alkylene, 2,5-diazabicyclo[2.2.1]heptaneylidene, 3,6-diazabicyclo[3.1.1]heptaneylidene, 3-azabicyclo[3.2.1] Octane, 3,8-diazabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[ 2.2.2] Octaneylidene, and azaspirocyclyl (eg 3-azaspiro[5.5]undecylidene).
  • the heterocyclylene can be unsubstituted or substituted as defined (e.g. by mono-, di-, tri-, or polysubstituted), wherein the substituents can optionally be selected from deuterium, hydroxyl, amino, mercapto, nitro group, halogen, cyano, optional deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optional deuterated C 3-6 cycloalkyl, optional deuterated C 1-6 Alkoxy, optionally deuterated C 1-6 alkyl-NH-, NH 2 -C 1-6 alkylene, optionally deuterated C 1-6 alkyl-NHC(O)-, optional Deuterated C 1-6 alkyl-C(O)NH- or any combination thereof.
  • nitrogen-containing heterocyclylene used alone or in combination means containing one nitrogen atom and optionally containing one or more (for example containing 1 to 5, 1 to 4, 1 to 3 , 1 to 2 or 1) 3 to 20 membered (alternatively 3 to 15, 3 to 14, 3 to 12, 3 to 11) membered heteroatoms independently selected from sulfur, oxygen and nitrogen , 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 (ie, having one or more double bonds, but not fully conjugated) divalent cyclic hydrocarbon groups.
  • nitrogen-containing heterocyclylene include, but are not limited to, piperidinylene, piperazinylene, morpholinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidine group, oxazolidinyl group, thiazolidinyl group, thiomorpholinyl group, azepanylidene group, diazepanylidene group, azacyclooctylene group and diazacyclooctylene group.
  • the nitrogen-containing heterocyclylene can be unsubstituted or substituted as defined (for example by mono-, di-, tri-, or polysubstituted), wherein the substituents are optionally selected from deuterium, hydroxyl, amino, Mercapto, nitro, halogen, cyano, optionally deuterated C 1-6 alkyl, halogenated C 1-6 alkyl, optionally deuterated C 3-6 cycloalkyl, optionally deuterated C 1-6 alkoxy, optional deuterated C 1-6 alkyl-NH-, NH 2 -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.
  • alkynylene used alone or in combination refers to a group comprising 2 to 8 (eg 2 to 6, 2 to 5, 2 to 4, more preferably 2) straight-chain or branched divalent hydrocarbon groups of carbon atoms.
  • alkynylene include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.
  • alkynyl refers to a group comprising 2 to 8 (eg 2 to 2 or 1) carbon-carbon triple bonds 6, 2 to 5, 2 to 4, more preferably 2) straight-chain or branched monovalent hydrocarbon groups of carbon atoms.
  • Examples of “C 2-6 alkynyl” include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1,3-diynyl.
  • alkenylene used alone or in combination refers to a group containing 2 to 8 carbon atoms ( For example, 2 to 6, 2 to 5 carbon atoms, or 2 to 4, 2 to 3 or 2 carbon atoms) linear or branched divalent hydrocarbon groups.
  • alkenylene include, but are not limited to, ethenylene (e.g.
  • -CH CH-), 1-propenylene, allylylene, 1-butenylene, 2-butenylene, 3-butene Subunit, isobutenylidene, pentenylidene, n-pent-2,4-dienylidene, 1-methyl-but-1-enylidene, 2-methyl-but-1-enylidene , 3-methyl-but-1-enylidene, 1-methyl-but-2-enylidene, 2-methyl-but-2-enylidene, 3-methyl-but-2-ene subunit, 1-methyl-but-3-enylidene, 2-methyl-but-3-enylidene, 3-methyl-but-3-enylidene, and hexenylene.
  • alkenyl used alone or in combination refers to a compound containing 2 to 8 carbon atoms (eg, 1 to 3, 1 to 2 or 1) carbon-carbon double bond 2 to 6, 2 to 5 carbon atoms, or 2 to 4, 2 to 3 or 2 carbon atoms) linear or branched monovalent hydrocarbon groups.
  • bornyl or “bornane” (also known as 1,7,7-trimethylbicyclo[2.2.1]heptane; camphane; bornylane) has the definition known to the person skilled in the art.
  • bornyl group or “bornyl group” refers to a monovalent group of bornane, that is, a group remaining after any hydrogen in bornane is removed.
  • bornyl include, but are not limited to, 1,7,7-trimethylbicyclo[2.2.1]heptan-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,
  • bicyclo[2.2.1]heptane also known as bicyclo[2.2.1]heptane
  • norbornane has the definition known to those skilled in the art.
  • bicyclo[2.2.1]heptanyl or “norbornanyl (alkyl)” refers to the monovalent group of bicyclo[2.2.1]heptane, i.e. bicyclo[2.2.1] The group remaining after removal of any hydrogen in heptane.
  • bicyclo[2.2.1]heptanyl include, but are not limited to, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-3-yl, bicyclo[2.2.1]heptan-3-yl, [2.2.1]heptan-4-yl, bicyclo[2.2.1]heptan-5-yl or bicyclo[2.2.1]heptan-6-yl.
  • bicyclo[2.2.1]heptene also known as bicyclo[2.2.1]heptene
  • bicyclo[2.2.1]heptene has the definition known to those skilled in the art.
  • "bicyclo[2.2.1]heptenyl” refers to the monovalent group of bicyclo[2.2.1]heptene, that is, after any hydrogen in bicyclo[2.2.1]heptene is removed remaining groups.
  • 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.
  • adamantane (also known as Tricyclo[3.3.1.1 3,7 ]decane) has a definition known to those skilled in the art, and its structural formula is, for example, shown below:
  • adamantyl refers to a monovalent group of adamantane, that is, the group remaining after any hydrogen in adamantane is removed.
  • 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.
  • noradamantane also known as noradamantane
  • noradamantane has a definition known to those skilled in the art, and its structural formula is, for example, shown below:
  • noradamantane refers to a monovalent group of noradamantane, that is, the group remaining after any hydrogen in noradamantane is removed.
  • 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.
  • amantadine has the definition known to those skilled in the art, that is, it refers to an adamantane having an amino substituent, wherein an amino group can replace a hydrogen on a carbon at any position of the adamantane.
  • An example of "amantadine” may be adamantane-1-amine (its corresponding English chemical name is adamantan-1-amine or Tricyclo[3.3.1.1 3,7 ]decan-1-amine; CAS:768-94 -5), having the following structural formula
  • the compound including 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 the compound of any one in formula (I-3-4), or table 1 or table 2 compound) salt or pharmaceutically acceptable salt refer to nontoxic inorganic or organic acid and/or base addition salts.
  • Examples include: sulfate, hydrochloride, citrate, maleate, methanesulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrogen phosphate, pyro Phosphate, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, glycolate or p-toluenesulfonate, etc.
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, such as filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, the present disclosure
  • Compounds useful in are carried or transported into or administered to a patient so that they can perform their intended function. Typically, such constructs are carried or transported from one organ or part of the body to another.
  • a carrier must be “acceptable” if it is compatible with the other ingredients of the formulation, including compounds useful in the present disclosure, and not injurious to the patient.
  • 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 carboxymethylcellulose, ethyl Base cellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; surfactant phosphate buffered saline; and other nontoxic compatible substances used in pharmaceutical formulations
  • room temperature in the present disclosure refers to ambient temperature, such as a temperature of 20-30°C.
  • stereoisomers refer to compounds that have the same chemical structure but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • solvate refers to an association or complex of one or more solvent molecules and a compound of the invention.
  • solvents include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to a complex in which the solvent molecule is water.
  • chiral refers to molecules that have the property of being non-superimposable to their mirror images; whereas “achiral” refers to molecules that are superimposable to their mirror images.
  • the term “enantiomer” refers to two non-superimposable isomers of a compound that are mirror images of each other.
  • diastereomer refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting points, boiling points, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.
  • HPLC preparation used preparative grade CH 3 CN and deionized water
  • reagents various lengths of carbon chain linking unit linker (that is, the compound used to form the group represented by LIN), and other reagents and medicines, Unless otherwise specified, they can be purchased from commercial sources for direct use, or can be synthesized by adopting or following methods known in the art.
  • the compounds described in the present disclosure and/or their pharmaceutically acceptable salts can be synthesized using commercially available raw materials through synthetic techniques known in the art.
  • the synthetic schemes described below illustrate the preparation of most of the compounds.
  • the starting materials or reagents used in each scheme can be purchased from commercial sources or prepared by methods known to those skilled in the art.
  • Those skilled in the art can prepare the salt of the compound of formula (I) of the present disclosure or the salt of the compound of Table 1 or 2, its racemate, enantiomer, phosphate, sulfate, hydrochloric acid according to the conventional techniques in the art Salt and prodrug forms.
  • each scheme and its reaction substrate, reaction condition (comprising reaction consumption, temperature, time etc.), aftertreatment etc. can carry out appropriate modification and adjustment to obtain required
  • the target compound, and the obtained target compound can be further modified by substituents etc. to obtain other target compounds according to methods well known to those skilled in the art.
  • step 1
  • the raw material 2,5-dimethyl-3-bromobenzoic acid methyl ester (5.0g, 20.6mmol) was dissolved in 100mL carbon tetrachloride, and N-bromosuccinimide (8.0g, 45mmol) and Dibenzoyl 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 filtrate was distilled off under reduced pressure to remove the solvent.
  • 3-(5-(bromomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (732180) was prepared by referring to the method of Scheme 1.
  • the starting material of step 2 of scheme 2 methyl 2,4-bis(bromomethyl)benzoate (CAS number: 63112-94-7) can also be purchased through commercial channels.
  • the reaction mixture was washed with water.
  • the organic phase was separated, and distilled under reduced pressure to remove the solvent.
  • step 1
  • step 1
  • Trans product (732150) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl Base-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans Formula)-4-((R)-3-methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (732150)
  • step 1
  • step 2 of Scheme 5 prepare 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).
  • step 1
  • Example 1 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 Preparation of '-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03146)
  • the target compound (BCL-03149) was prepared from the compound (SIAIS364043) and the compound (732001) prepared according to Intermediate Example 1 as raw materials.
  • the target compound (BCL-03165) was prepared from the compound (732147) prepared according to Intermediate Example 3 and the compound (732180) prepared according to Intermediate Example 2 as raw materials.
  • the target compound (BCL-03166) was prepared from the compound (732148) prepared according to Intermediate Example 3 and the intermediate compound (732180) as raw materials.
  • the target compound (BCL-03167) was prepared from the compound (732149) prepared according to Intermediate Example 4 and the intermediate compound (732180) as raw materials.
  • Example 8 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-methyl Preparation of piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03168)
  • the target compound (BCL-03168) was prepared from the compound (732150) prepared according to Intermediate Example 4 and the intermediate compound (732180) as raw materials.
  • the target compound (BCL-03169) was prepared from the compound (732147) prepared according to Intermediate Example 3 and the intermediate compound (732001) as raw materials.
  • the target compound (BCL-03170) was prepared from the compound (732148) prepared according to Intermediate Example 3 and the intermediate compound (732001) as raw materials.
  • the target compound (BCL-03171) was prepared from the compound (732149) prepared according to Intermediate Example 3 and the intermediate compound (732001) as raw materials.
  • Example 12 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-methylpiperazine- 1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5, Preparation of 6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03172)
  • the target compound (BCL-03172) was prepared from the compound (732150) prepared according to Intermediate Example 3 and the intermediate compound (732001) as raw materials.
  • Example 13 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 Preparation of acyl)phenyl)sulfonyl)benzamide (BCL-03177)
  • Example 14 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3 ,4,5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)- 4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl )methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03179)
  • the target compound (BCL-03179) was prepared from the compound (732185) prepared according to Intermediate Example 5 and the intermediate compound (732180) as raw materials.
  • Example 15 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) Preparation of benzamide (BCL-03180)
  • the target compound (BCL-03180) was prepared from the compound (732186) prepared according to Intermediate Example 6 and the intermediate compound (732180) as raw materials.
  • Example 16 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) preparation of
  • the target compound (BCL-03181) was prepared from the compound (732187) prepared according to Intermediate Example 7 and the intermediate compound (732180) as raw materials.
  • Example 17 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3 ,4,5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)- 4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl )cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (BCL-03185)
  • Example 18 4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl) Methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl) Preparation of sulfonyl)benzamide (BCL-03186)
  • Example 19 4-(4-(4-(4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl ]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)-4-(4-((2-(2,6-dioxopiperidine -3-yl)-1,3-dioxoisoindoline-5-yl)methyl)piperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl ) Preparation of benzamide (BCL-03187)
  • Example 20 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3 ,4,5,6-Tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((trans)- 4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)piperazin-1-yl ) cyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (BCL-03188) preparation
  • Example 21 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 base) sulfonyl) phenyl) sulfonyl) benzamide (BCL-03189) preparation
  • Example 22 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3 ,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((((cis)- 4-((3S)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-3 Preparation of -methylpiperazin-1-yl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide (BCL-03190)
  • Example 23 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 Preparation of -tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide (BCL-03182)
  • the target compound (BCL-03182) was prepared from intermediate compound (732185) and intermediate compound (732001) as raw materials.
  • Example 24 N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxo Substituted isoindoline-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)piperazine- Preparation of 1-yl)benzamide (BCL-03183)
  • the target compound (BCL-03183) was prepared from intermediate compound (732186) and intermediate compound (732001) as raw materials.
  • Example 25 N-((4-((((trans)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxo Substituted isoindoline-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 ( Preparation of BCL-03184)
  • the target compound (BCL-03184) was prepared from intermediate compound (732187) and intermediate compound (732001) as raw materials.
  • Example 26 N-((4-(((2R)-4-(4-((7-bromo-2-(2,6-dioxopiperidin-3-yl)-3-oxoiso Indoline-5-yl)methyl)piperazin-1-yl)-1-(phenylsulfanyl)butane-2-yl)amino)-3-((trifluoromethyl)sulfonyl)benzene base)sulfonyl)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2- base) methyl) piperazin-1-yl) benzamide (BCL-03178) preparation
  • the target compound (BCL-03178) was prepared from intermediate compound (SIAIS360129) and intermediate compound (732001) as raw materials.
  • the BCL-XL antibody used in the experiment was purchased from Abcam, and the Tubulin antibody was purchased from Proteintech.
  • the cell lines used are RS4; 11 (human acute lymphoblastic leukemia cells), Molt-4 cells (human acute lymphoblastic leukemia cells), MV4; 11 (human myelomonocytic leukemia cells), and Light II cells.
  • RS4 human acute lymphoblastic leukemia cells
  • Molt-4 cells human acute lymphoblastic leukemia cells
  • MV4 human myelomonocytic leukemia cells
  • Light II cells Commercially available or purchased from ATCC (American Type Culture Collection), and routinely cultured according to ATCC instructions.
  • ATCC American Type Culture Collection
  • the cells used were identified as correct cells by STR cells and negative for mycoplasma by routine inspection.
  • the compounds of the present disclosure are used for preliminary evaluation of tumor cell growth inhibitory rate with single concentration or double concentration, and IC 50 determination.
  • RS4 11 cells were inoculated in 90 microliters of serum-containing RPMI 1640 medium at 3 ⁇ 10 cells/well, and at the same time, DT2216 and the compound of the present invention were added to the cell suspension according to the corresponding concentration gradient, and positive
  • the control is DT2216
  • the negative control is DMSO
  • the positive control and negative control are treated with the same treatment method as the compound of the present invention.
  • thiazolium blue solution 5 mg/mL was added at 10 microliters/well, and at 37° C., 5% CO
  • a triple solution SDS, 0.1 g/mL
  • MV4 11 cells were inoculated in 90 microliters of serum-containing IMDM medium at 2 ⁇ 10 cells/well, and at the same time, DT2216 and the compound of the present invention were added to the cell suspension according to the corresponding concentration gradient, positive
  • the control is DT2216
  • the negative control is DMSO
  • the positive control and negative control are treated with the same treatment method as the compound of the present invention.
  • Molt-4 cells are inoculated in 180 microliters of serum-containing RPMI 1640 medium at 2 ⁇ 10 cells/well, and at the same time, DT2216 and the compound of the present invention are added to the cell suspension according to the corresponding concentration gradient, positive
  • the control is DT2216
  • the negative control is DMSO
  • the positive control and negative control are treated with the same treatment method as the compound of the present invention.
  • thiazolyl blue solution (5 mg/mL) was added at 20 microliters/well, and at 37° C., 5% CO 2 In the constant temperature incubator, after incubation for 3 hours, the triple solution (SDS, 0.1 mg/mL) was added.
  • Light II cells are cloned NIH3T3 cell lines capable of stably expressing Gli-luciferase and TK-renilla reporter genes, using DMEM medium containing 10% (v/v) fetal bovine serum (FBS), and adding 0.4mg/ml G418 at the same time, 0.15mg/ml zeocin, penicillin/streptomycin, cultured in a constant temperature incubator at 37°C and 5% CO 2 .
  • Light II cells in the logarithmic growth phase were inoculated in 96-well plates at 2.5 ⁇ 10 4 cells/well, incubated for 24 hours, and then treated with SAG and different concentrations of the compound of the present invention for 36 hours to terminate the reaction. Detection was performed according to the instructions of the Dual luciferase reporter assay kit. This experiment was repeated at least three times with three replicate wells in each group. The results are shown in Table 6 below.
  • Molt-4 cells in the logarithmic growth phase were inoculated into six-well plates at 3 ⁇ 10 6 cells/well.
  • the compound of the present invention was added at the corresponding concentration to treat the cells, and the vehicle DMSO was used as the control group.
  • the cells were collected and washed once with PBS. Place the cells on ice and add IP protein lysate containing PMSF protease inhibitor to treat the cells. After centrifugation at 4°C, 10k rpm for 5 minutes, the supernatant was collected.
  • the compounds of the present invention designed and developed based on ABT-199/263 can well inhibit the proliferation of RS4;11 tumor cells (Table 3).
  • the IC 50 of DT2216 on RS4;11 cells is 81.04 ⁇ 24.89nM, and the inhibitory effect of the compounds of the present invention developed by us is significantly better than that of DT2216.
  • DT2216 (CAS No.: 2365172-42-3) is a BCL-XL degradation agent reported in the literature, and its structural formula is as follows:
  • the compound of the present invention based on ABT-199/263 that we design and develop can well inhibit myelomonocytic leukemia cell MV4; The proliferation of 11 (table 4 ).
  • the IC 50 of DT2216 on MV4;11 cells was 164.9 ⁇ 70.71 nM.
  • the inhibitory effects of the compounds of the present invention developed by us based on ABT199/263 are significantly better than those of DT2216.
  • the compound of the present invention based on ABT-199/263 that we design and develop can well inhibit the proliferation of human acute lymphoblastic leukemia cell Molt-4 (table 5 ).
  • the inhibitory effect of the compound of the present invention developed by us based on ABT199/263 is obviously better than that of DT2216.
  • the compounds of the present invention based on ABT-199/263 that we designed and developed were screened for inhibiting Hedgehog (Hh) signaling pathway activity (Table 6).
  • the half maximal inhibitory concentration IC 50 of the compounds of the present invention developed by us based on ABT-199/263 can all reach below 10nM.
  • LightII BCL-03166 Dual-luciferase assay reporter kit ⁇ 10 Light II BCL-03167 Dual-luciferase assay reporter kit ⁇ 10 Light II BCL-03168 Dual-luciferase assay reporter kit ⁇ 10 Light II BCL-03169 Dual-luciferase assay reporter kit ⁇ 10 Light II BCL-03177 Dual-luciferase assay reporter kit ⁇ 10 Light II BCL-03189 Dual-luciferase assay reporter kit ⁇ 10
  • the compound of the present invention based on ABT199/263 can effectively degrade the protein level of BCL-XL in Molt-4 cells
  • Molt-4 cells were seeded in 6-well plates at the number of 3 ⁇ 106 cells per well. The next day, the cells were treated with a drug concentration of 100nM, and the control group was DMSO and DT2216. Protein samples were collected after 8 hours, and the expression of BCL-XL protein was detected by western blot. The results show that after using the compounds of the present invention (comprising the compounds of Table 1-2 and the compounds of Examples 1-26), the expression of BCL-XL protein has been significantly reduced, such as the compounds BCL-03146, BCL-03147, BCL -03148, BCL-03149, etc. significantly degrade BCL-XL protein at a concentration of about 100 nM (as shown in Figure 1-3). Compared with DT2216, the compound of the present invention has obvious advantages in protein degradation.

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Abstract

本公开涉及基于BCL-2家族蛋白配体化合物开发的蛋白降解剂，包括式(I)的化合物或其盐、对映异构体、立体异构体、溶剂化物、前药或多晶型物，以及它们用于治疗疾病的应用。

Description

基于BCL-2家族蛋白配体化合物开发的蛋白降解剂及它们的应用 技术领域
本公开涉及基于BCL-2家族蛋白配体化合物开发的蛋白降解剂，包括式(I)的化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，以及它们用于治疗疾病的应用。
背景技术
细胞凋亡(Apoptosis)或细胞程序性死亡(programmed cell death)，是细胞经过一系列程序化的事件导致死亡的过程。早期发育中，细胞凋亡可以清除不需要的细胞，成年后，细胞凋亡主要负责清除体内已受损且无法修复的细胞，从而确保机体能够得到合适的发展。细胞凋亡在多种生理进程中发挥重要作用，如参与正常细胞更新，免疫系统的发育和功能的完善，激素依赖性萎缩，胚胎发育以及化学诱导的细胞死亡等(Elmore,S.,Toxicol Pathol,2007.35(4):p.495-516.)。而异常的细胞凋亡(过度或不足)则会导致各类疾病的产生，包括神经退行性疾病，心血管疾病，自身免疫性疾病和肿瘤。研发表现，肿瘤在发生发展进程中能够通过抑制凋亡途径从而降低其对抗肿瘤药物的敏感性(Scott,W.L.et al.,Carcinogenesis,2000.21(3):p.485-495.)。因此，激活肿瘤组织中的凋亡信号或是一种有效抗肿瘤策略。
BCL-2(B cell lymphoma-2)蛋白家族是细胞凋亡的关键调节因子，既能诱导也能抑制细胞凋亡，主要位于线粒体上，通过调节线粒体膜通透性，从而发挥“凋亡开关”的作用。BCL-2具有4个高度保守的同源(BH)结构域：BH1、BH2、BH3和BH4，依据同源结构域的不同组成情况，可分为三种亚型，其中一种具有抗凋亡功能，两种具有促凋亡功能(Daniel,N.N.,Clin Cancer Res,2007.13(24):p.7254-7263.)。BCL-2的BH1和BH2同源结构域能与促凋亡蛋白形成二聚体，BH3结构域在促凋亡和抗凋亡的相互作用中至关重要，因而在所有亚型中均包含，BH4主要包含在抗凋亡的BCL-2亚型中。抗凋亡蛋白包括BCL-2、BCL-XL、BCL-W、MCL1、A1和BCL-B，由3-4个BH结构域组成；而促凋亡蛋白又可分为两种，一种促凋亡蛋白包括BAX、BAK和BOK，由BH1、BH2和BH3组成，另一种促凋亡蛋白包括BID，BIM，BAD，PUMA，NOXA，BMF，HRK和BIK，仅由BH3组成(Youle,R.J.,et al.,Nat Rev Mol Cell Biol,2008.9(1):p.47-59.)。正常生理状态下，BCL-2家族蛋白水平维持动态平衡，而细胞信号传导可通过影响该动态平衡过程来调节促凋亡蛋白或抗凋亡蛋白的表达，从而使平衡向细胞存活或死亡发展。当平衡有利于细胞死亡时，促凋亡蛋白通过线粒体外膜上的寡聚化致使线粒体外膜透性化(permeabilization)，释放细胞色素c，触发caspase酶级联反应的激活，从而裂解下游底物导致细胞死亡(Opferman,J.T.and A.Kothari,Cell Death Differ,2018.25(1):p.37-45.)。
经过20多年的发展，已经发现了众多小分子BCL-2抑制剂，开发靶向BCL-2蛋白家族 的小分子抑制剂已经成为肿瘤领域的热点。抗凋亡BCL-2蛋白通过其疏水口袋(BH3结合口袋)与促凋亡蛋白BH3结构域结合发挥其抗细胞凋亡功能。BCL-2家族蛋白拮抗剂又称“BH3域模拟物(BH3domain mimetics)”，主要通过插入抗凋亡BCL-2家族蛋白中共有的BH3结构域，阻止其与促凋亡蛋白BAX、BAK结合，抑制BCL-2抗凋亡蛋白的作用，进而诱导肿瘤细胞凋亡。
迄今为止，ABT-199(Venetoclax)是唯一被FDA批准靶向BCL-2家族蛋白的抗肿瘤药物，可用于治疗某些血液系统恶性肿瘤，如慢性淋巴细胞白血病和急性髓系白血病(Deeks,E.D.,Drugs,2016.76(9):p.979-87.；Carter,P.J.and G.A.Lazar,Nat Rev Drug Discov,2018.17(3):p.197-223.)。然而，由于大部分实体瘤的生长不依赖于BCL-2蛋白，ABT-199对实体瘤无明显治疗效果，而BCL-XL蛋白在多种实体瘤和血液瘤细胞中显著高表达(Leverson,J.M.,et al,Sci Transl Med,2015.7(279):p.279ra40.)；另一方面，研究表明，肿瘤组织中BCL-XL表达和肿瘤耐药呈正相关(Vogler,M.,Adv Med,2014:p.943648.)，因而靶向BCL-XL是一潜在的理想的抗肿瘤分子靶点。
BCL-XL(B-cell lymphoma-extra large)是BCL-2家族抗凋亡蛋白的关键成员之一，位于线粒体中，是细胞凋亡的关键调节因子，同时也能调多种细胞的病理生理过程，如线粒体ATP合成、蛋白乙酰化和细胞有丝分裂等(Michels,J.,et al.,International Journal of Cell Biology,2013.2013:p.1-10.)。
研究发现血管细胞的老化(senescense)是导致视网膜病变，如糖尿病黄斑水肿(DME)、湿性老年黄斑变性(wAMD)的主要发病机制(Oubaha M.,et al.,Sci Transl Med.2016Oct 26,8(362):362ra144.)，而靶向抗凋亡蛋白BCL-XL能诱导老化的血管内皮细胞凋亡，从而达到治疗DME、wAMD的目的(Crespo-Garcia S.,et al.,Cell Metabolism.2021Apr 6,33(4):818-832.e7.)，靶向BCL-XL的小分子抑制剂UBX1325治疗DME、wAMD目前正处于临床二期实验阶段(clinicaltrials.gov)
还有研究表明，BCL-XL在众多肿瘤中过表达，例如肝癌、非霍奇金淋巴瘤、软骨肉瘤和结直肠癌等(Li,M.,et al.,Pharmacological Research,2019.151(4):p.104547.)。在软骨肉瘤中，与其他BCL2家族成员相比，BCL-XL发挥着最关键的作用，抑制BCL-XL能够增强软骨肉瘤细胞对常规化疗的敏感性(Jong,Y.D.,et al.,Oncogenesis,2018.7(9).)。此外，结直肠癌细胞的侵袭性与BCL-XL密切相关，在结直肠癌中BCL2蛋白家族只有BCL-XL显著上调(Liu,W.D.,et al.,Official journal of Balkan Union of Oncology,2014.19(4):p.925.；Scherr,A.L.,et al.,Cell Death&Disease,2016.7(8):p.e2342.)。靶向BCL-XL的小分子抑制剂如ABT-263具有显著的抗肿瘤作用，然而，由于BCL-XL能够限制Bax的促凋亡作用，有助于血小板存活，抑制BCL-XL的表达后引起血小板减少症，破坏了凝血功能，因而ABT-263未被FDA批准上市(Tse,C.,et al.,Cancer Research,2008.68(9):p.3421.)。BCL-XL作为经过验证的最重要的抗癌靶点之一，却没有安全有效的治疗方法。
PROTAC(Proteolysis Targeting Chimeria)是一种具有双功能的杂合小分子，通过合适 的连接链将靶蛋白配体与E3泛素连接酶配体连接，促使目的蛋白与E3连接酶形成三元复合物，从而使靶蛋白接近泛素化系统，实现靶蛋白的泛素化，随后被蛋白酶体26S亚基识别，最终导致靶蛋白降解(Sun,X.,et al.,Sig Transduct Target Ther,2019.4(1):p.33.)。PROTAC使蛋白降解的过程类似于催化反应，因而可在极低剂量下发挥作用，与传统的小分子抑制剂相比，它们的作用效力更持久，毒性更低(Lu,J.,et al.,Chem Biol,2015.22(6):p.755-763.)。更重要的是，由于PROTAC依赖于E3泛素连接酶来介导蛋白降解，即使靶蛋白本身在机体中广泛表达，利用E3泛素连接酶在肿瘤细胞和正常组织中表达量的差异，其依然具有细胞或组织选择性。如已进入临床实验的DT2216，其以ABT-263作为靶蛋白BCL-XL的配体，以血小板中低表达的VHL作为E3泛素连接酶配体，显著提高了抗肿瘤活性并减少了血小板毒性(Khan,S.,et al.,Nature medicine,2019.25(4):p.1938-1947.)。
异常激活的Hedgehog(Hh)信号通路与人体内多种肿瘤的发生发展密切相关，如基底细胞癌、髓母细胞瘤等(Nat Genet,2016.48(4):p.398-406；Cancer Cell,2014.25(3):p.393-405.)。Hh在细胞内的信号传导是一种级联形式，其关键分子包括12次跨膜结构域的PTCH受体、7次跨膜结构的SMO(Smoothened)受体、SUFU蛋白以及核转录因子GLI蛋白家族。当没有外源性HH配体时，PTCH抑制SMO活性，信号通路处于抑制状态；当外源性HH配体与PTCH结合，解除其对SMO的抑制，从而导致SMO转为至信号通路中的关键信号中枢纤毛，进一步导致SUFU-GLI的转录复合物也转位至纤毛，解除SUFU对GLI的抑制作用，进一步通过调节GSK3和CK1等激酶对GLI的磷酸化，最终使具有转录活性的GLI进入核内启动下游靶基因转录，激活Hh信号通路(Nat Rev Mol Cell Biol,2013.14(7):p.416-29；Genes Dev,2010.24(7):p.670-82.)。目前，FDA批准用于治疗基底细胞癌的药物均为以SMO为靶点(Cell,2016.164(5):p.831.)，因而对SMO突变、SUFU功能缺失性突变、GLI扩增等SMO下游关键信号分子遗传改变导致的Hh异常激活的肿瘤则无明显抑制作用。最近，有研究表明，SUFU蛋白包含一段保守的BH3序列，能和细胞内BCL-XL、BCL-2、MCL-1等抗凋亡蛋白结合，从而解除SUFU对GLI蛋白的抑制作用，最终导致Hh通路激活；抑制BCL-XL等抗凋亡蛋白与SUFU结合，能有效抑制Hh信号通路激活(Nat Cell Biol,2017.19(10):p.1226-1236.)。基于此，靶向BCL-2家族蛋白也是开发靶向Hh信号通路抑制剂的一个策略。
因此，迫切需要一系列新颖的PROTAC抑制剂，以用于治疗和/或预防BCL-2家族蛋白介导的疾病或病症、或依赖于Hedgehog信号通路的疾病或病症、或与其相关的疾病。
发明概述
鉴于以上，本公开的一个目的在于提供基于BCL-2家族蛋白配体化合物开发的新颖的蛋白降解剂，它们的用途，以及它们的使用方法。本公开的基于BCL-2家族蛋白配体化合物开发的新颖的蛋白降解剂化合物或其盐(包括药学上可接受的盐)、立体异构体(包括对映异构体)、溶剂化物、前药或多晶型物可以结合靶蛋白，将靶蛋白招募至E3泛素连接酶进行泛素化标记并降解，从而呈现出期望的药理活性。
在一些实施方案中，本公开的基于BCL-2家族蛋白配体化合物开发的新颖的蛋白降解剂可以是式(I)化合物或其盐、立体异构体(包括对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物：
Figure PCTCN2023070102-appb-000001
其中
虚线指示可选地存在双键；
R 1、R 2、R 3、R 4相同或不同且各自独立地表示氢、C 1-4烷基、卤素、或卤代C 1-4烷基；
(R 5) n表示苯环被n个R 5取代，各R 5相同或不同且各自独立地表示卤素、C 1-6烷基、或卤代C 1-6烷基，n表示整数1、2、3、4或5；
(R 6) m表示哌嗪环被m个R 6取代，各R 6相同或不同且各自独立地表示卤素、C 1-6烷基、或卤代C 1-6烷基，m表示整数0、1、2、3、4、5、6、7或8；
R 7表示氢或
Figure PCTCN2023070102-appb-000002
R 8表示氢或-SO 2CF 3或-NO 2；
R 9表示氢或C 1-4烷基；
R 10表示以下基团：
Figure PCTCN2023070102-appb-000003
其中，环W 1表示4元至6元含氮亚杂环基，(R a1) n1表示环W 1被n1个R a1基团取代，各R a1相同或不同且各自独立地为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、氰基、卤素、或氧代基，n1表示0-8的整数；
环W 2表示4元至6元含氮亚杂环基、或C 3-6亚环烷基，n3表示整数0或1，(R a2) n2表示环W 2被n2个R a2基团取代，各R a2相同或不同且各自独立地为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、氰基、卤素、或氧代基，n2表示0-8的整数；以及
符号*表示与LIN的连接点；
LIN表示
可选取代的直链或支链的C 1-30亚烷基；或
在其主碳链中插入有一或多个基团R b和/或一或多个基团R c或者一或多个基团R b与R c的任意组合的可选取代的直链或支链C 2-30亚烷基，其中所述基团R b、R c或者基团R b与R c的组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开；各基团R b选自O、 N(R d)、C(O)、C(O)O、S(O)、S(O) 2、S(O) 2NH、NHS(O) 2、OC(O)、C(O)N(R d)、N(R d)C(O)、或N(R d)C(O)N(R d)，其中各R d独立地表示H或C 1-6烷基，以及当所述直链或支链C 2-30亚烷基的主碳链中插入有两个以上基团R b时，各基团R b彼此不直接相连接；各基团R c选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合，其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、C 1-6烷氧基、或其任意组合的取代基取代；以及R 11表示以下式(II)的结构式：
Figure PCTCN2023070102-appb-000004
其中，R 12表示N(R e)、O、S、C 2-6亚炔基、或C 2-6亚烯基，其中R e表示H或C 1-6烷基，或R 12表示键；
(R a) t表示苯环被t个R a取代，各R a相同或不同且各自独立地表示溴，t表示整数0、1、2或3；以及
X表示C(O)或CH 2；
其中，在t表示整数0的情况下：
当R 7表示
Figure PCTCN2023070102-appb-000005
时，n1表示1-8的整数，且各R a1相同或不同且各自独立地为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、或卤素；或者
当R 7表示
Figure PCTCN2023070102-appb-000006
时，R 8表示-SO 2CF 3。
在另一方面，本公开提供一种药物组合物，其包含式(I)化合物或其盐、立体异构体(包括对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物，及至少一种药学上可接受的载体。
在另一方面，本公开的基于BCL-2家族蛋白配体化合物开发的新颖的蛋白降解剂可以是以下化合物或其盐、立体异构体(包括对映异构体)、溶剂化物、前药或多晶型物：
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)-1-(苯基硫基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺；
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)-1-(苯基硫基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺；
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((1r,4r)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪- 1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((1s,4s)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；或
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((1r,4r)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺。
在另一方面，本公开提供一种药物组合物，其包含上述蛋白降解剂化合物或其盐、立体异构体(包括对映异构体)、溶剂化物、前药或多晶型物，及至少一种药学上可接受的载体。
在另一方面，本公开还提供一种药盒或试剂盒，其包含：
本公开的蛋白降解剂化合物或其药学上可接受的盐或包含其的药物组合物。
在另一方面，本公开提供本公开的蛋白降解剂化合物或其盐、立体异构体(包括对映异构体)、溶剂化物、前药或多晶型物或包含其作为活性成分的药物组合物，其用作药物。
在另一方面，本公开提供本公开的蛋白降解剂化合物或其盐、立体异构体(包括对映异构体)、溶剂化物、前药或多晶型物或包含其作为活性成分的药物组合物，其用作药物。
在另一方面，本公开进一步提供本公开的蛋白降解剂化合物或其盐、立体异构体(包括对映异构体)、溶剂化物、前药或多晶型物或包含其作为活性成分的药物组合物，其用于治疗和/或预防选自以下的疾病或病症：神经退行性疾病、心血管疾病、自身免疫性疾病、骨髓纤维化、肾纤维化、肝纤维化、肝硬化、肿瘤、多器官功能障碍综合征(MODS)、恶病质和败血症休克所致的多器官功能衰竭、器官(包括肾、心脏、肺)或组织移植排斥反应、糖尿病、移植排斥反应、视网膜病变和急性肝功能衰竭。
在另一方面，本公开还提供本公开的蛋白降解剂化合物或其盐、立体异构体(包括对映异构体)、溶剂化物、前药或多晶型物用于制备治疗和/或预防选自以下的疾病或病症的药物的用途：神经退行性疾病、心血管疾病、自身免疫性疾病、骨髓纤维化、肾纤维化、肝纤维化、肝硬化、肿瘤、多器官功能障碍综合征(MODS)、恶病质和败血症休克所致的多器官功能衰竭、器官(包括肾、心脏、肺)或组织移植排斥反应、糖尿病、移植排斥反应、视网膜病变和急性肝功能衰竭。
在另一方面，本公开还提供一种治疗或预防受试者的疾病或病症的方法，其包括向所述受试者施用治疗有效量的本公开的蛋白降解剂化合物、或其盐、对映异构体、立体异构体、溶剂化物、前药或多晶型物或包含其的药物组合物，或者治疗有效量的本公开的化合物或其盐、立体异构体(包括对映异构体)、溶剂化物、前药或多晶型物或包含其作为活性成分的药物组合物，其中所述疾病或病症选自：神经退行性疾病、心血管疾病、自身免疫性疾病、骨髓纤维化、肾纤维化、肝纤维化、肝硬化、肿瘤、多器官功能障碍综合征(MODS)、恶病质和败血症休克所致的多器官功能衰竭、器官(包括肾、心脏、肺)或组织移植排斥反应、糖 尿病、移植排斥反应、视网膜病变和急性肝功能衰竭。
附图简要说明
图1-3是蛋白质免疫印迹实验结果示意图，其显示了本发明化合物BCL-03146、BCL-03147、BCL-03148、BCL-03149等(100nM)作用于Molt-4细胞8h后显著降低BCL-XL蛋白的表达，并且与DT2216(CAS号：2365172-42-3；为文献报道的BCL-XL降解剂)相比，蛋白降解优势明显。
发明详述
提供以下详细描述作为示例性具体实施方案，以帮助本领域普通技术人员理解和实施本公开内容。然而，应当认识到，这样的描述并不旨在限制本公开的范围，在不脱离本公开精神和范围的前提下，本公开描述的具体实施方案还可进行各种修饰和变化，这些变化和改进都落入要求保护的本公开范围内。
I.化合物
式(I)化合物
本公开提供一种式(I)化合物或其盐(包括药学上可接受的盐)、立体异构体(包括对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物：
Figure PCTCN2023070102-appb-000007
其中R 1、R 2、R 3、R 4、(R 5) n、(R 6) m、R 7、R 8、R 9、R 10、LIN、和R 11如上文的式(I)化合物中所定义。
在一些实施方案中，式(I)化合物的虚线指示可选地存在双键。
在一些实施方案中，式(I)化合物的虚线指示存在双键。在这种情况下，式(I)化合物的包含虚线的基团如下所示：
Figure PCTCN2023070102-appb-000008
在一些实施方案中，式(I)化合物的虚线指示不存在双键。在这种情况下，式(I)化合物的包含虚线的基团如下所示：
Figure PCTCN2023070102-appb-000009
在一些实施方案中，式(I)化合物的R 1、R 2、R 3、R 4相同或不同且各自独立地表示氢、C 1-4烷基(例如甲基、乙基、丙基、异丙基、丁基、和叔丁基)、卤素(例如氟、氯、溴或碘)、或卤代C 1-4烷基(例如卤代C 1-3烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)。
在一些实施方案中，式(I)化合物的R 1和R 2表示氢，且R 3和R 4表示甲基。
在一些实施方案中，式(I)化合物的R 1和R 2表示甲基，且R 3和R 4表示氢。
在一些实施方案中，式(I)化合物的(R 5) n表示苯环被n个R 5取代，各R 5相同或不同且各自独立地表示卤素(例如氟、氯、溴或碘)、C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、或卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)，n表示整数1、2、3、4或5。在一些实施方案中，n表示整数1，且R 5表示卤素(例如氟、氯、溴或碘)。
在一些实施方案中，式(I)化合物的(R 6) m表示哌嗪环被m个R 6取代，各R 6相同或不同且各自独立地表示卤素(例如氟、氯、溴或碘)、C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、或卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)，m表示整数0、1、2、3、4、5、6、7或8。
在一些实施方案中，R 7表示氢或
Figure PCTCN2023070102-appb-000010
在一些实施方案中，R 7表示氢。
在一些实施方案中，R 7表示
Figure PCTCN2023070102-appb-000011
在一些实施方案中，R 8表示氢或-SO 2CF 3或-NO 2。
在一些实施方案中，R 8表示氢。
在一些实施方案中，R 8表示-SO 2CF 3。
在一些实施方案中，R 8表示-NO 2。
在一些实施方案中，R 9表示氢或C 1-4烷基(例如C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)。
在一些实施方案中，R 9表示氢。
在一些实施方案中，R 9表示C 1-4烷基(例如C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)。
在一些实施方案中，R 10表示以下基团：
Figure PCTCN2023070102-appb-000012
其中，环W 1表示4元至6元含氮亚杂环基，(R a1) n1表示环W 1被n1个R a1基团取代，各R a1相同或不同且各自独立地为C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、氰基、卤素(例如氟、氯、溴或碘)、或氧代基，n1表示0-8的整数；
环W 2表示4元至6元含氮亚杂环基、或C 3-6亚环烷基，n3表示整数0或1，(R a2) n2表示环W 2被n2个R a2基团取代，各R a2相同或不同且各自独立地为C 1-6烷基(例如C 1-4烷基或C 1- 3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、氰基、卤素(例如氟、氯、溴或碘)、或氧代基，n2表示0-8的整数；以及
符号*表示与LIN的连接点。
在一些实施方案中，环W 1表示4元至6元含氮亚杂环基，所述4元至6元含氮亚杂环基包括但不限于例如亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、或亚硫代吗啉基。
在一些实施方案中，(R a1) n1表示环W 1被n1个R a1基团取代，各R a1相同或不同且各自独立地为C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、氰基、卤素(例如氟、氯、溴或碘)、或氧代基，n1表示0-8的整数(例如整数0、1、2、3、或4)。
在一些实施方案中，环W 2表示4元至6元含氮亚杂环基，所述4元至6元含氮亚杂环基包括但不限于例如亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、或亚硫代吗啉基。
在一些实施方案中，环W 2表示C 3-6亚环烷基，所述4元至6元亚环烷基包括但不限于例如环丙基、环丁基、环戊基或环己基。
在一些实施方案中，(R a2) n2表示环W 2被n2个R a2基团取代，各R a2相同或不同且各自独立地为C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基 氧基或叔丁基氧基)、氰基、卤素(例如氟、氯、溴或碘)、或氧代基，n2表示0-8的整数(例如整数0、1、2、3、或4)。
在一些实施方案中，n3表示整数0或1。
在一些实施方案中，n3表示整数0。
在一些实施方案中，n3表示整数1。
在一些实施方案中，R 10表示以下基团：
Figure PCTCN2023070102-appb-000013
其中符号*表示与LIN的连接点。
在一些实施方案中，R 11表示以下式(II-1)、式(II-2)、式(II-3)、式(II-4)、式(II-5)、式(II-6)、式(II-7)、式(II-8)、式(II-9)、式(II-10)、式(II-11)、或式(II-12)的结构式：
Figure PCTCN2023070102-appb-000014
其中
R 12表示N(R e)、O、S、C 2-6亚炔基(例如亚乙炔基)、或C 2-6亚烯基(例如亚乙烯基)，其中R e表示H或C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)，或R 12表示键；
X表示C(O)或CH 2；和
(R a) t表示苯环被t个R a取代，各R a相同或不同且各自独立地表示溴，和t表示整数0、1、2或3。
在一些实施方案中，X表示C(O)。
在一些实施方案中，X表示CH 2。
在一些实施方案中，R 12表示键。
在一些实施方案中，t表示整数0。
在一些实施方案中，t表示整数1、2或3。
在一些实施方案中，R 11表示以下式的结构：
Figure PCTCN2023070102-appb-000015
Figure PCTCN2023070102-appb-000016
在本公开中，在t表示整数0的情况下，当R 7表示
Figure PCTCN2023070102-appb-000017
时，n1表示1-8的整数(例如整数1、2、3、4、5、6、7或8)，且各R a1相同或不同且各自独立地为C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、或卤素(例如氟、氯、溴或碘)。
在本公开中，在t表示整数0的情况下，当R 7表示
Figure PCTCN2023070102-appb-000018
时，R 8表示-SO 2CF 3。
在一些实施方案中，所述LIN表示以下式的结构：
#-C 1-30亚烷基-；
#-(C(R a3)(R a4)) n4-(R b-(C(R a5)(R a6)) n5) m1-；
#-(C(R a3)(R a4)) n4-(R b-(C(R a5)(R a6)) n5) m1-(R b-(C(R a7)(R a8)) n6) m2-；
#-(C(R a3)(R a4)) n4-(R b-(C(R a5)(R a6)) n5) m1-(R b-(C(R a7)(R a8)) n6) m2-(R b-(C(R a9)(R a10)) n7) m3-；
#-(C(R a3)(R a4)) n4-(R c-(C(R a5)(R a6)) n5) m1-；
#-(C(R a3)(R a4)) n4-(R c-(C(R a5)(R a6)) n5) m1-(R c-(C(R a7)(R a8)) n6) m2-；
#-(C(R a3)(R a4)) n4-(R c-(C(R a5)(R a6)) n5) m1-(R c-(C(R a7)(R a8)) n6) m2-(R c-(C(R a9)(R a10)) n7) m3-；
#-(C(R a3)(R a4)) n4-(R b-R c-(C(R a5)(R a6)) n5) m1-；
#-(C(R a3)(R a4)) n4-(R b-(C(R a5)(R a6)) n5) m1-(R c-(C(R a7)(R a8)) n6) m2-；
#-(C(R a3)(R a4)) n4-(R c-R b-(C(R a5)(R a6)) n5) m1-；或
#-(C(R a3)(R a4)) n4-(R c-(C(R a5)(R a6)) n5) m1-(R b-(C(R a7)(R a8)) n6) m2-；
其中，各基团R b选自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)、或N(R d)C(O)N(R d)，其中各R d独立地表示H或C 1-6烷基(例如C 1-4烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)；各基团R c选自亚环烷基(例如C 3-20亚环烷基)、亚芳基(例如C 3-20亚芳基)、亚杂环基(例如4-至20-元亚杂环基)、亚杂芳基(例如4-至20-元亚杂芳基)、亚炔基(例如C 2-6亚炔基)、亚烯基(例如C 2-6亚烯基)或其任意组合，其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基或卤代C 1-3烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、卤素(例如氟、氯、溴或碘)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、或其任意组合的取代基取代；
所述C 1-30亚烷基的一或多个CH 2的氢可选地进一步被选自以下的取代基替代：C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基或卤代C 1-3烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、卤素(例如氟、氯、溴或碘)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、或其任意组合；
R a3、R a4、R a5、R a6、R a7、R a8、R a9、和R a10相同或不同且各自独立地表示H、C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基或卤代C 1-3烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、卤素(例如氟、氯、溴或碘)、或C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)；
n4、n5、n6、n7、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15；和
符号#表示与基团R 10的连接点。
在一些实施方案中，所述LIN表示以下式的结构：
#-(C(R a3)(R a4)) n4-(O-(C(R a5)(R a6)) n5) m1-；
#-(C(R a3)(R a4)) n4-(O-(C(R a5)(R a6)) n5) m1-(O-(C(R a7)(R a8)) n6) m2-；
#-(C(R a3)(R a4)) n4-(O-(C(R a5)(R a6)) n5) m1-(O-(C(R a7)(R a8)) n6) m2-(O(C(R a9)(R a10)) n7) m3-；
#-(C(R a3)(R a4)) n4-(N(R d)-(C(R a5)(R a6)) n5) m1-；
#-(C(R a3)(R a4)) n4-(N(R d)-(C(R a5)(R a6)) n5) m1-(N(R d)-(C(R a7)(R a8)) n6) m2-；
#-(C(R a3)(R a4)) n4-(N(R d)-(C(R a5)(R a6)) n5) m1-(N(R d)-(C(R a7)(R a8)) n6) m2-(N(R d)-(C(R a9)(R a10)) n7) m3-；
#-(C(R a3)(R a4)) n4-(C(O)N(R d)-(C(R a5)(R a6)) n5) m1-；
#-(C(R a3)(R a4)) n4-(C(O)N(R d)-(C(R a5)(R a6)) n5) m1-(C(O)N(R d)-(C(R a7)(R a8)) n6) m2-；
#-(C(R a3)(R a4)) n4-(C(O)N(R d)-(C(R a5)(R a6)) n5) m1-(C(O)N(R d)-(C(R a7)(R a8)) n6) m2-(C(O)N(R d)-(C(R a9)(R a10)) n7) m3-；
#-(C(R a3)(R a4)) n4-(C(O)N(R d)-(C(R a5)(R a6)) n5) m1-(O-(C(R a7)(R a8)) n6) m2-；
#-(C(R a3)(R a4)) n4-C(O)N(R d)-(C(R a5)(R a6)) n5-(O-(C(R a7)(R a8)) n6) m1-；
#-(C(R a3)(R a4)) n4-(N(R d)C(O)-(C(R a5)(R a6)) n5) m1-；
#-(C(R a3)(R a4)) n4-(N(R d)C(O)-(C(R a5)(R a6)) n5) m1-(O-(C(R a7)(R a8)) n6) m2-；
#-(C(R a3)(R a4)) n4-(N(R d)C(O)-(C(R a5)(R a6)) n5) m1-(O-(C(R a7)(R a8)) n6) m2-(O-(C(R a9)(R a10)) n7) m3-；
#-(C(R a3)(R a4)) n4-N(R d)C(O)-(C(R a5)(R a6)) n5-(O-(C(R a7)(R a8)) n6) m1-；
#-(C(R a3)(R a4)) n4-N(R d)C(O)N(R d)-(C(R a5)(R a6)) n5-；
#-(C(R a3)(R a4)) n4-C(O)-(C(R a5)(R a6)) n5-；
#-(C(R a3)(R a4)) n4-(亚芳基-(C(R a5)(R a6)) n5) m1-；
#-(C(R a3)(R a4)) n4-(亚芳基-(C(R a5)(R a6)) n5) m1-亚芳基-(C(R a7)(R a8)) n6-；
#-(C(R a3)(R a4)) n4-(亚杂环基-(C(R a5)(R a6)) n5) m1-；
#-(C(R a3)(R a4)) n4-(亚杂环基-(C(R a5)(R a6)) n5) m1-(亚杂环基-(C(R a7)(R a8)) n6) m2-；
#-(C(R a3)(R a4)) n4-(亚杂芳基-(C(R a5)(R a6)) n5) m1-；
#-(C(R a3)(R a4)) n4-(亚杂芳基-(C(R a5)(R a6)) n5) m1-(亚杂芳基-(C(R a7)(R a8)) n6) m2-；
#-(C(R a3)(R a4)) n4-(亚环烷基-(C(R a5)(R a6)) n5) m1-；或
#-(C(R a3)(R a4)) n4-(亚环烷基-(C(R a5)(R a6)) n5) m1-(亚环烷基-(C(R a7)(R a8)) n6) m2-；
其中，各R d独立地表示H或C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)；
所述亚环烷基(例如C 3-20亚环烷基)、所述亚芳基(例如C 3-20亚芳基)、所述亚杂环基(例如4-至20-元亚杂环基)和所述亚杂芳基(例如4-至20-元亚杂芳基)彼此独立地可选地进一步被选自C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基或卤代C 1-3烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、卤素(例如氟、氯、溴或碘)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、或其任意组合的取代基取代；
R a3、R a4、R a5、R a6、R a7、R a8、R a9、和R a10相同或不同且各自独立地表示H、C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基或卤代C 1-3烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、卤素(例如氟、氯、溴或碘)、或C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)；
n4、n5、n6、n7、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15；和
符号#表示与基团R 10的连接点。
在一些实施方案中，所述LIN表示以下基团：
#-CH 2-、#-(CH 2) 2-、#-(CH 2) 3-、#-(CH 2) 4-、#-(CH 2) 5-、#-(CH 2) 6-、#-(CH 2) 7-、#-(CH 2) 8-、#-(CH 2) 9-、#-(CH 2) 10-、#-(CH 2) 11-、#-(CH 2) 12-、#-(CH 2) 13-、#-(CH 2) 14-、#-(CH 2) 15-、#-(CH 2) 16-、#-(CH 2) 17-、#-(CH 2) 18-、#-(CH 2) 19-、#-(CH 2) 20-、#-(CH 2) 21-、#-(CH 2) 22-、#-(CH 2) 25-、或#-(CH 2) 30-；#-CH 2-O-CH 2-、#-CH 2-O-(CH 2) 2-、#-(CH 2) 1-O-(CH 2) 3-、#-(CH 2) 1-O-(CH 2) 4-、#-(CH 2) 1-O-(CH 2) 5-、#-(CH 2) 1-O-(CH 2) 6-、#-(CH 2) 1-O-(CH 2) 7-、#-(CH 2) 1-O-(CH 2) 8-、#-(CH 2) 1-O-(CH 2) 9-、#-(CH 2) 1-O-(CH 2) 10-、#-(CH 2) 2-O-(CH 2) 1-、#-(CH 2) 2-O-(CH 2) 2-、#-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 2-O-(CH 2) 4-、#-(CH 2) 2-O-(CH 2) 5-、#-(CH 2) 2-O-(CH 2) 6-、#-(CH 2) 2-O-(CH 2) 7-、#-(CH 2) 2-O-(CH 2) 8-、#-(CH 2) 2-O-(CH 2) 9-、#-(CH 2) 2-O-(CH 2) 10-、#-(CH 2) 2-O-(CH 2) 11-、#-(CH 2) 2-O-(CH 2) 12-、#-(CH 2) 3-O-(CH 2) 1-、#-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 3-O-(CH 2) 3-、#-(CH 2) 3-O-(CH 2) 4-、#-(CH 2) 3-O-(CH 2) 5-、#-(CH 2) 3-O-(CH 2) 6-、#-(CH 2) 3-O-(CH 2) 7-、#-(CH 2) 4-O-(CH 2) 1-、#-(CH 2) 4-O-(CH 2) 2-、#-(CH 2) 4-O-(CH 2) 3-、#-(CH 2) 4-O-(CH 2) 4-、#-(CH 2) 4-O-(CH 2) 5-、#-(CH 2) 4-O-(CH 2) 6-、#-(CH 2) 5-O-(CH 2) 1-、#-(CH 2) 5-O-(CH 2) 2-、#-(CH 2) 5-O-(CH 2) 3-、#-(CH 2) 5-O-(CH 2) 4-、#-(CH 2) 5-O-(CH 2) 5-、#-(CH 2) 6-O-(CH 2) 1-、#-(CH 2) 6-O-(CH 2) 2-、#-(CH 2) 6-O-(CH 2) 3-、#-(CH 2) 6-O-(CH 2) 4-、#-(CH 2) 7-O-(CH 2) 1-、#-(CH 2) 7-O-(CH 2) 2-、#-(CH 2) 7-O-(CH 2) 3-、#-(CH 2) 8-O-(CH 2) 1-、#-(CH 2) 8-O-(CH 2) 2-、#-CH(CH 3)-O-(CH 2) 1-、#-CH(CH 3)-O-(CH 2) 2-、#-CH(CH 3)-O-(CH 2) 3-、#-CH(CH 3)-O-(CH 2) 4-、#-CH(CH 3)-O-(CH 2) 5-、#-CH(CH 3)-O-(CH 2) 6-、#-CH(CH 3)-O-(CH 2) 7-、#-CH(CH 3)-O-(CH 2) 8-、#-CH(CH 3)-O-(CH 2) 9-、#-CH(CH 3)-O-(CH 2) 10-、#-CH 2-(O(CH 2) 2) 2-、#-CH 2-(O(CH 2) 2) 3-、#-CH 2-(O(CH 2) 2) 4-、#-CH 2-(O(CH 2) 2) 5-、#-CH 2-(O(CH 2) 2) 6-、#-CH 2-(O(CH 2) 2) 7-、#-CH 2-(O(CH 2) 2) 8-、#-CH 2-(O(CH 2) 2) 9-、#-CH 2-(O(CH 2) 2) 10-、#-CH 2-(O(CH 2) 2) 1-OCH 2-、#-CH 2-(O(CH 2) 2) 2-OCH 2-、#-CH 2-(O(CH 2) 2) 3-OCH 2-、#-CH 2-(O(CH 2) 2) 4-OCH 2-、#-CH 2-(O(CH 2) 2) 5-OCH 2-、#-CH 2-(O(CH 2) 2) 6-OCH 2-、#-CH 2-(O(CH 2) 2) 7-OCH 2-、#-CH 2-(O(CH 2) 2) 8-OCH 2-、#-CH 2-(O(CH 2) 2) 9-OCH 2-、#-CH 2-(O(CH 2) 2) 10-OCH 2-、#-(CH 2) 2-(O(CH 2) 2) 2-、#-(CH 2) 2-(O(CH 2) 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-、#-(CH 2) 2-(O(CH 2) 2) 5-、#-(CH 2) 2-(O(CH 2) 2) 6-、#-(CH 2) 2-(O(CH 2) 2) 7-、#-(CH 2) 2-(O(CH 2) 2) 8-、#-(CH 2) 2-(O(CH 2) 2) 9-、#-(CH 2) 2-(O(CH 2) 2) 10-、#-(CH 2) 3-(O(CH 2) 2) 2-、#-(CH 2) 3-(O(CH 2) 2) 3-、#-(CH 2) 3-(O(CH 2) 2) 4-、#-(CH 2) 3-(O(CH 2) 2) 5-、#-(CH 2) 3-(O(CH 2) 2) 6-、#-(CH 2) 3-(O(CH 2) 2) 7-、#-(CH 2) 3-(O(CH 2) 2) 8-、#-(CH 2) 3-(O(CH 2) 2) 9-、#-(CH 2) 3-(O(CH 2) 2) 10-、#-(CH 2) 4-(O(CH 2) 2) 2-、#-(CH 2) 4-(O(CH 2) 2) 3-、#-(CH 2) 4-(O(CH 2) 2) 4-、#-(CH 2) 4-(O(CH 2) 2) 5-、#-(CH 2) 4-(O(CH 2) 2) 6-、#-(CH 2) 4-(O(CH 2) 2) 7-、#-(CH 2) 4-(O(CH 2) 2) 8-、#-(CH 2) 4-(O(CH 2) 2) 9-、#-(CH 2) 4-(O(CH 2) 2) 10-、#-CH 2-(O(CH 2) 3) 2-、#-CH 2-(O(CH 2) 3) 3-、#-CH 2-(O(CH 2) 3) 4-、#-CH 2-(O(CH 2) 3) 5-、#-CH 2-(O(CH 2) 3) 6-、#-CH 2-(O(CH 2) 3) 7-、#-CH 2-(O(CH 2) 3) 8-、#-CH 2-(O(CH 2) 3) 9-、#-CH 2-(O(CH 2) 3) 10-、#-(CH 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 2-(O(CH 2) 3) 3-、#-(CH 2) 2-(O(CH 2) 3) 4-、#-(CH 2) 2- (O(CH 2) 3) 5-、#-(CH 2) 2-(O(CH 2) 3) 6-、#-(CH 2) 2-(O(CH 2) 3) 7-、#-(CH 2) 2-(O(CH 2) 3) 8-、#-(CH 2) 2-(O(CH 2) 3) 9-、#-(CH 2) 2-(O(CH 2) 3) 10-、#-(CH 2) 3-(O(CH 2) 3) 2-、#-(CH 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 3-(O(CH 2) 3) 4-、#-(CH 2) 3-(O(CH 2) 3) 5-、#-(CH 2) 3-(O(CH 2) 3) 6-、#-(CH 2) 3-(O(CH 2) 3) 7-、#-(CH 2) 3-(O(CH 2) 3) 8-、#-(CH 2) 3-(O(CH 2) 3) 9-、#-(CH 2) 3-(O(CH 2) 3) 10-、#-CH 2-O-(CH 2) 2-O-(CH 2) 3-、#-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-CH 2-O-(CH 2) 3-O-(CH 2) 2-、#-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-CH 2-O-(CH 2) 2-O-CH 2-、#-(CH 2) 2-O-(CH 2) 2-O-CH 2-、#-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、#-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、#-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-、#-(CH 2) 1-N(R g)-(CH 2) 1-、#-(CH 2) 1-N(R g)-(CH 2) 2-、#-(CH 2) 1-N(R g)-(CH 2) 3-、#-(CH 2) 1-N(R g)-(CH 2) 4-、#-(CH 2) 1-N(R g)-(CH 2) 5-、#-(CH 2) 1-N(R g)-(CH 2) 6-、#-(CH 2) 1-N(R g)-(CH 2) 7-、#-(CH 2) 1-N(R g)-(CH 2) 8-、#-(CH 2) 1-N(R g)-(CH 2) 9-、#-(CH 2) 1-N(R g)-(CH 2) 10-、#-(CH 2) 2-N(R g)-(CH 2) 1-、#-(CH 2) 2-N(R g)-(CH 2) 2-、#-(CH 2) 2-N(R g)-(CH 2) 3-、#-(CH 2) 2-N(R g)-(CH 2) 4-、#-(CH 2) 2-N(R g)-(CH 2) 5-、#-(CH 2) 2-N(R g)-(CH 2) 6-、#-(CH 2) 2-N(R g)-(CH 2) 7-、#-(CH 2) 2-N(R g)-(CH 2) 8-、#-(CH 2) 2-N(R g)-(CH 2) 9-、#-(CH 2) 2-N(R g)-(CH 2) 10-、#-(CH 2) 2-N(R g)-(CH 2) 11-、#-(CH 2) 2-N(R g)-(CH 2) 12-、#-(CH 2) 3-N(R g)-(CH 2) 1-、#-(CH 2) 3-N(R g)-(CH 2) 2-、#-(CH 2) 3-N(R g)-(CH 2) 3-、#-(CH 2) 4-N(R g)-(CH 2) 1-、#-(CH 2) 4-N(R g)-(CH 2) 2-、#-(CH 2) 4-N(R g)-(CH 2) 3-、#-(CH 2) 4-N(R g)-(CH 2) 4-、#-(CH 2) 5-N(R g)-(CH 2) 1-、#-(CH 2) 5-N(R g)-(CH 2) 2-、#-(CH 2) 5-N(R g)-(CH 2) 3-、#-(CH 2) 5-N(R g)-(CH 2) 4-、#-(CH 2) 5-N(R g)-(CH 2) 5-、#-(CH 2) 6-N(R g)-(CH 2) 1-、#-(CH 2) 6-N(R g)-(CH 2) 2-、#-(CH 2) 6-N(R g)-(CH 2) 3-、#-(CH 2) 7-N(R g)-(CH 2) 1-、#-(CH 2) 7-N(R g)-(CH 2) 2-、#-(CH 2) 7-N(R g)-(CH 2) 3-、#-(CH 2) 8-N(R g)-(CH 2) 1-、#-(CH 2) 8-N(R g)-(CH 2) 2-、#-(CH 2) 8-N(R g)-(CH 2) 3-、#-CH(CH 3)-N(R g)-(CH 2) 1-、#-CH(CH 3)-N(R g)-(CH 2) 2-、#-CH(CH 3)-N(R g)-(CH 2) 3-、#-CH(CH 3)-N(R g)-(CH 2) 4-、#-CH(CH 3)-N(R g)-(CH 2) 5-、#-CH(CH 3)-N(R g)-(CH 2) 6-、#-CH(CH 3)-N(R g)-(CH 2) 7-、#-CH(CH 3)-N(R g)-(CH 2) 8-、#-CH(CH 3)-N(R g)-(CH 2) 9-、#-CH(CH 3)-N(R g)-(CH 2) 10-、#-CH 2C(O)NHCH 2-、#-(CH 2) 2C(O)NH(CH 2) 2-、#-(CH 2) 2C(O)NH(CH 2) 3-、#-(CH 2) 2C(O)NH(CH 2) 4-、#-(CH 2) 2C(O)NH(CH 2) 5-、#-(CH 2) 3C(O)NH(CH 2) 3-、#- (CH 2) 3C(O)NH(CH 2) 4-、#-(CH 2) 4C(O)NH(CH 2) 4-、#-(CH 2) 5C(O)NH(CH 2) 5-、#-(CH 2) 6C(O)NH(CH 2) 7-、#-(CH 2) 6C(O)NH(CH 2) 6-、#-(CH 2) 7C(O)NH(CH 2) 7-、#-(CH 2) 8C(O)NH(CH 2) 8、U-(CH 2) 9C(O)NH(CH 2) 9-、#-(CH 2) 10C(O)NH(CH 2) 10-、#-(CH 2) 2C(O)NH(CH 2) 2-O-(CH 2) 2-、#-CH 2NHC(O)CH 2-、#-(CH 2) 2NHC(O)(CH 2) 2-、#-(CH 2) 2NHC(O)(CH 2) 3-、#-(CH 2) 2NHC(O)(CH 2) 4-、#-(CH 2) 2NHC(O)(CH 2) 5-、#-(CH 2) 3NHC(O)(CH 2) 3-、#-(CH 2) 3NHC(O)(CH 2) 4-、#-(CH 2) 4NHC(O)(CH 2) 4-、#-(CH 2) 5NHC(O)(CH 2) 5-、#-(CH 2) 6NHC(O)(CH 2) 7-、#-(CH 2) 6NHC(O)(CH 2) 6-、#-(CH 2) 7NHC(O)(CH 2) 7-、#-(CH 2) 8NHC(O)(CH 2) 8、#-(CH 2) 9NHC(O)(CH 2) 9-、#-(CH 2) 10NHC(O)(CH 2) 10-、#-(CH 2) 4NHC(O)(CH 2) 8-、#-(CH 2) 2NHC(O)(CH 2) 2-O-(CH 2) 2-、#-(CH 2) 4NHC(O)CH 2-、#-CH 2-亚哌啶基-CH 2-、#-CH 2-亚哌啶基-(CH 2) 2-、#-CH 2-亚哌啶基-(CH 2) 3-、#-CH 2-亚哌啶基-(CH 2) 4-、#-CH 2-亚哌啶基-(CH 2) 5-、#-CH 2-亚哌啶基-(CH 2) 6-、#-CH 2-亚哌啶基-(CH 2) 7-、#-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 2-亚哌啶基-(CH 2) 1-、#-(CH 2) 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 3-亚哌啶基-CH 2-、#-(CH 2) 3-亚哌啶基-(CH 2) 2-、#-(CH 2) 3-亚哌啶基-(CH 2) 3-、#-(CH 2) 3-亚哌啶基-(CH 2) 4-、#-(CH 2) 3-亚哌啶基-(CH 2) 5-、#-(CH 2) 3-亚哌啶基-(CH 2) 6-、#-(CH 2) 3-亚哌啶基-(CH 2) 7-、#-(CH 2) 3-亚哌啶基-(CH 2) 8-、#-(CH 2) 4-亚哌啶基-CH 2-、#-(CH 2) 4-亚哌啶基-(CH 2) 2-、#-(CH 2) 4-亚哌啶基-(CH 2) 3-、#-(CH 2) 4-亚哌啶基-(CH 2) 4-、#-(CH 2) 4-亚哌啶基-(CH 2) 5-、#-(CH 2) 4-亚哌啶基-(CH 2) 6-、#-(CH 2) 4-亚哌啶基-(CH 2) 7-、#-(CH 2) 4-亚哌啶基-(CH 2) 8-、#-(CH 2) 5-亚哌啶基-(CH 2) 1-、#-(CH 2) 5-亚哌啶基-(CH 2) 2-、#-(CH 2) 5-亚哌啶基-(CH 2) 3-、#-(CH 2) 5-亚哌啶基-(CH 2) 4-、#-(CH 2) 5-亚哌啶基-(CH 2) 5-、#-(CH 2) 5-亚哌啶基-(CH 2) 6-、#-(CH 2) 5-亚哌啶基-(CH 2) 7-、#-(CH 2) 5-亚哌啶基-(CH 2) 8-、#-(CH 2) 6-亚哌啶基-(CH 2) 1-、#-(CH 2) 6-亚哌啶基-(CH 2) 2-、#-(CH 2) 6-亚哌啶基-(CH 2) 3-、#-(CH 2) 6-亚哌啶基-(CH 2) 4-、#-(CH 2) 6-亚哌啶基-(CH 2) 5-、#-(CH 2) 6-亚哌啶基-(CH 2) 6-、#-(CH 2) 6-亚哌啶基-(CH 2) 7-、#-(CH 2) 6-亚哌啶基-(CH 2) 8-、#-(CH 2) 7-亚哌啶基-(CH 2) 1-、#-(CH 2) 7-亚哌啶基-(CH 2) 2-、#-(CH 2) 7-亚哌啶基-(CH 2) 3-、#-(CH 2) 7-亚哌啶基-(CH 2) 4-、#-(CH 2) 7-亚哌啶基-(CH 2) 8-、#-(CH 2) 8-亚哌啶基-CH 2-、#-(CH 2) 8-亚哌啶基-(CH 2) 2-、#-(CH 2) 8-亚哌啶基-(CH 2) 3-、#-(CH 2) 8-亚哌啶基-(CH 2) 4-、#-(CH 2) 8-亚哌啶基-(CH 2) 5-、#-(CH 2) 8-亚哌啶基-(CH 2) 6-、#-(CH 2) 8-亚哌啶基-(CH 2) 7-、#-(CH 2) 8-亚哌啶基-(CH 2) 8-、#-CH 2-N(R g)-CH 2-亚哌啶基-CH 2-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-CH 2-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 2-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 3-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 4-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 5-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 6-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 7-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 2-N(R g)-CH 2- 亚哌啶基-(CH 2) 3-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 5-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 5-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 6-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 6-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 7-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 7-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-CH 2-亚哌嗪基-CH 2-、#-CH 2-亚哌嗪基-(CH 2) 2-、#-CH 2-亚哌嗪基-(CH 2) 3-、#-CH 2-亚哌嗪基-(CH 2) 4-、#-CH 2-亚哌嗪基-(CH 2) 5-、#-CH 2-亚哌嗪基-(CH 2) 6-、#-CH 2-亚哌嗪基-(CH 2) 7-、#-CH 2-亚哌嗪基-(CH 2) 8-、#-(CH 2) 2-亚哌嗪基-(CH 2) 1-、#-(CH 2) 2-亚哌嗪基-(CH 2) 2-、#-(CH 2) 2-亚哌嗪基-(CH 2) 3-、#-(CH 2) 2-亚哌嗪基-(CH 2) 4-、#-(CH 2) 2-亚哌嗪基-(CH 2) 5-、#-(CH 2) 2-亚哌嗪基-(CH 2) 6-、#-(CH 2) 2-亚哌嗪基-(CH 2) 7-、#-(CH 2) 2-亚哌嗪基-(CH 2) 8-、#-(CH 2) 3-亚哌嗪基-CH 2-、#-(CH 2) 3-亚哌嗪基-(CH 2) 2-、#-(CH 2) 3-亚哌嗪基-(CH 2) 3-、#-(CH 2) 3-亚哌嗪基-(CH 2) 4-、#-(CH 2) 3-亚哌嗪基-(CH 2) 5-、#-(CH 2) 3-亚哌嗪基-(CH 2) 6-、#-(CH 2) 3-亚哌嗪基-(CH 2) 7-、#-(CH 2) 3-亚哌嗪基-(CH 2) 8-、#-(CH 2) 4-亚哌嗪基-CH 2-、#-(CH 2) 4-亚哌嗪基-(CH 2) 2-、#-(CH 2) 4-亚哌嗪基-(CH 2) 3-、#-(CH 2) 4-亚哌嗪基-(CH 2) 4-、#-(CH 2) 4-亚哌嗪基-(CH 2) 5-、#-(CH 2) 4-亚哌嗪基-(CH 2) 6-、#-(CH 2) 4-亚哌嗪基-(CH 2) 7-、#-(CH 2) 4-亚哌嗪基-(CH 2) 8-、#-(CH 2) 5-亚哌嗪基-(CH 2) 1-、#-(CH 2) 5-亚哌嗪基-(CH 2) 2-、#-(CH 2) 5-亚哌嗪基-(CH 2) 3-、#-(CH 2) 5-亚哌嗪基-(CH 2) 4-、#-(CH 2) 5-亚哌嗪基-(CH 2) 5-、#-(CH 2) 5-亚哌嗪基-(CH 2) 6-、#-(CH 2) 5-亚哌嗪基-(CH 2) 7-、#-(CH 2) 5-亚哌嗪基-(CH 2) 8-、#-(CH 2) 6-亚哌嗪基-(CH 2) 1-、#-(CH 2) 6-亚哌嗪基-(CH 2) 2-、#-(CH 2) 6-亚哌嗪基-(CH 2) 3-、#-(CH 2) 6-亚哌嗪基-(CH 2) 4-、#-(CH 2) 6-亚哌嗪基-(CH 2) 5-、#-(CH 2) 6-亚哌嗪基-(CH 2) 6-、#-(CH 2) 6-亚哌嗪基-(CH 2) 7-、#-(CH 2) 6-亚哌嗪基-(CH 2) 8-、#-(CH 2) 7-亚哌嗪基-(CH 2) 1-、#-(CH 2) 7-亚哌嗪基-(CH 2) 2-、#-(CH 2) 7-亚哌嗪基-(CH 2) 3-、#-(CH 2) 7-亚哌嗪基-(CH 2) 4-、#-(CH 2) 7-亚哌嗪基-(CH 2) 8-、#-(CH 2) 8-亚哌嗪基-CH 2-、#-(CH 2) 8-亚哌嗪基-(CH 2) 2-、#-(CH 2) 8-亚哌嗪基-(CH 2) 3-、#-(CH 2) 8-亚哌嗪基-(CH 2) 4-、#-(CH 2) 8-亚哌嗪基-(CH 2) 5-、#-(CH 2) 8-亚哌嗪基-(CH 2) 6-、#-(CH 2) 8-亚哌嗪基-(CH 2) 7-、或#-(CH 2) 8-亚哌嗪基-(CH 2) 8-；
其中，所述亚哌啶基和所述亚哌嗪基彼此独立地可选地进一步被选自C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基或卤代C 1-3烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、卤素(例如氟、氯、溴或碘)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧 基、仲丁基氧基或叔丁基氧基)、或其任意组合的取代基取代；
各R d独立地表示H或C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)；
符号#表示与基团R 10的连接点；和
n4、n5、n6、n7、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15。
在一些实施方案中，式(I)化合物也是由以下式(I-1)的结构表示：
Figure PCTCN2023070102-appb-000019
其中R 1、R 2、R 3、R 4、(R 5) n、(R 6) m、R 7、R 8、R 9、R 10、LIN、R 12、(R a) t和X如本文式(I)化合物及其各实施方案中所定义。
在一些实施方案中，式(I)化合物也是由以下式(I-2)或式(I-3)的结构表示：
Figure PCTCN2023070102-appb-000020
其中R 1、R 2、R 3、R 4、(R 5) n、(R 6) m、R 8、R 9、R 10、LIN、R 12、(R a) t和X如本文式(I)化合物及其各实施方案中所定义。
在一些实施方案中，式(I)化合物也是由以下式(I-2-1)的结构表示：
Figure PCTCN2023070102-appb-000021
其中
R 10表示以下基团：
Figure PCTCN2023070102-appb-000022
其中，环W 1表示4元至6元含氮亚杂环基，(R a1) n1表示环W 1被n1个R a1基团取代，各R a1相同或不同且各自独立地为C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、氰基、或卤素(例如氟、氯、溴或碘)，n1表示1-8的整数；
环W 2表示4元至6元含氮亚杂环基、或C 3-6亚环烷基，n3表示整数0或1，(R a2) n2表示环W 2被n2个R a2基团取代，各R a2相同或不同且各自独立地为C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、氰基、卤素(例如氟、氯、溴或碘)、或氧代基，n2表示0-8的整数；以及
符号*表示与LIN的连接点；以及
R 1、R 2、R 3、R 4、(R 5) n、(R 6) m、R 8、R 9、R 10、LIN、R 12和X如本文式(I)化合物及其各实施方案中所定义。
在一些实施方案中，式(I-2-1)化合物的环W 1表示4元至6元含氮亚杂环基，所述4元至6元含氮亚杂环基包括但不限于例如亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、或亚硫代吗啉基。
在一些实施方案中，式(I-2-1)化合物的(R a1) n1表示环W 1被n1个R a1基团取代，各R a1相同或不同且各自独立地为C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、氰基、卤素(例如氟、氯、溴或碘)、或氧代基，n1表示1-8的整数(例如整数1、2、3、或4)。
在一些实施方案中，式(I-2-1)化合物的环W 2表示4元至6元含氮亚杂环基，所述4元至6元含氮亚杂环基包括但不限于例如亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、或亚硫代吗啉基。
在一些实施方案中，式(I-2-1)化合物的环W 2表示C 3-6亚环烷基，所述4元至6元亚环烷基包括但不限于例如环丙基、环丁基、环戊基或环己基。
在一些实施方案中，式(I-2-1)化合物的(R a2) n2表示环W 2被n2个R a2基团取代，各R a2相同或不同且各自独立地为C 1-6烷基(例如C 1-4烷基或C 1-3烷基，例如甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基)、卤代C 1-6烷基(例如卤代C 1-4烷基，例如F 3C-、FCH 2-、F 2CH-、ClCH 2-、Cl 2CH-、CF 3CF 2-、CF 3CHF-、CHF 2CF 2-、CHF 2CHF-、CF 3CH 2-或CH 2ClCH 2-)、C 1-6烷氧基(例如C 1-4烷氧基或C 1-3烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、仲丁基氧基或叔丁基氧基)、氰基、卤素(例如氟、氯、溴或碘)、或氧代基，n2表示0-8的整数(例如整数0、1、2、3、或4)。
在一些实施方案中，式(I-2-1)化合物的n3表示整数0或1。
在一些实施方案中，式(I-2-1)化合物的n3表示整数0。
在一些实施方案中，式(I-2-1)化合物的n3表示整数1。
在一些实施方案中，式(I-2-1)化合物的R 10表示以下基团：
Figure PCTCN2023070102-appb-000023
其中符号*表示与LIN的连接点。
在一些实施方案中，式(I)化合物也是由以下式(I-2-1)的结构表示：
Figure PCTCN2023070102-appb-000024
其中
R 8表示-SO 2CF 3；以及
R 1、R 2、R 3、R 4、(R 5) n、(R 6) m、R 9、R 10、LIN、R 12和X如本文式(I)化合物及其各实施方案中所定义。
在一些实施方案中，式(I)化合物也是由以下式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)的结构表示：
Figure PCTCN2023070102-appb-000025
Figure PCTCN2023070102-appb-000026
其中R 9、R 10、LIN、R 12、(R a) t和X如本文式(I)化合物及其各实施方案中所定义。
在一些实施方案中，提供了以下表1的式(I)的具体化合物及其盐(包括药学上可接受的盐，例如它们的盐酸盐)、前药、溶剂化物、同位素富集类似物、多晶型物、立体异构体(包括对映异构体和非对映异构体)、或立体异构体的混合物：
表1本公开的化合物
Figure PCTCN2023070102-appb-000027
Figure PCTCN2023070102-appb-000028
Figure PCTCN2023070102-appb-000029
Figure PCTCN2023070102-appb-000030
Figure PCTCN2023070102-appb-000031
Figure PCTCN2023070102-appb-000032
Figure PCTCN2023070102-appb-000033
在一些实施方案中，提供了本公开的式(I)化合物的盐酸盐、硫酸盐、枸橼酸盐、马来酸盐、磺酸盐、甲磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、富马酸盐、磷酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、三氟乙酸盐、羟乙酸盐或对甲苯磺酸盐。
在另一方面，本公开还提供了以下表2中的基于BCL-2家族蛋白配体化合物开发的新颖的蛋白降解剂、或其盐(包括药学上可接受的盐，例如它们的盐酸盐)、立体异构体(包括对映异构体和非对映异构体)、溶剂化物、同位素富集类似物、前药或多晶型物：
表2本公开的化合物
Figure PCTCN2023070102-appb-000034
Figure PCTCN2023070102-appb-000035
Figure PCTCN2023070102-appb-000036
在一些实施方案中，提供了本公开表2的化合物的盐酸盐、硫酸盐、枸橼酸盐、马来酸盐、磺酸盐、甲磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、富马酸盐、磷酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、三氟乙酸盐、羟乙酸盐或对甲苯磺酸盐。
II.化合物的其它形式(包括化合物的盐、对映异构体、立体异构体、溶剂化物、前药或多晶型物)
本公开的化合物具有式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的结构，或表1或2中任一个的结构。除非另有说明，否则当提及本公开的化合物时，是指包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物以及落入这些通式范围内的具体化合物，例如表1化合物，或表2化合物。
应认识到本公开的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)可具有立体构型，因此能以一种以上的立体异构体形式存在。本公开还涉及光学富集的具有立体构型的化合物，如约大于90％ee，如约95％ee或97％ee，或大于99％ee，以及其混合物，包括外消旋混合物。本文使用的“光学富集的”意指对映异构体的混合物由显著更大比例的一种对映体组成,并且可通过对映体过量(ee％)描述。异构体的纯化和异构体混合物的分离可以通过本领域已知的标准技术(例如，柱色谱、制备型TLC、制备型HPLC、不对称合成(例如，通过使用手性中间体)和/或手性拆分等)来实现。
在一些实施方案中，还提供本公开化合物的多晶型形式或本公开化合物的盐。本公开 的化合物的盐可以是药学上可接受的盐，包括但不限于盐酸盐、硫酸盐、枸橼酸盐、马来酸盐、甲磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、富马酸盐、磷酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、三氟乙酸盐、羟乙酸盐或对甲苯磺酸盐等。本公开的化合物能以非溶剂化物或溶剂化物的形式存在于药学上可接受的溶剂如水、乙醇等中。在一些实施方案中，本公开化合物可以制备成前体药物或前药。前体药物在机体内能转化成母体药物而发挥作用。
III.药物组合物/制剂
在一些实施方案中，本公开提供一种药物组合物，其包含作为活性成分的本公开的化合物或其药学上可接受的盐、溶剂化物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物，及至少一种药学上可接受的载体。
在一些实施方案中，药学上可接受的载体包括但不限于填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、着色剂、溶剂或包封材料。载体与制剂的其他成分(包括本公开中有用的化合物)相容并且对患者无害，载体必须是“可接受的”。药学上可接受的载体的材料的一些实例包括：糖，如乳糖，葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；粉状黄蓍胶；麦芽；明胶；滑石；赋形剂，如可可脂和栓剂蜡；油，如花生油，棉籽油，红花油，芝麻油，橄榄油，玉米油和大豆油；二醇，如丙二醇；多元醇，如甘油，山梨糖醇，甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；表面活性剂磷酸盐缓冲溶液；聚氧乙烯，聚乙烯吡咯烷酮，聚丙烯酰胺，泊洛沙姆；和药物制剂中使用的其他无毒相容物质。
本公开所述的药物组合物，进一步包括至少一种第二治疗剂，例如抗癌剂。第二治疗剂可与本公开的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)联合治疗本公开所述的疾病或病症。第二治疗剂包括但不限于化疗剂、免疫治疗剂、基因治疗剂等。
本公开所述的包含作为活性成分的如本公开所述的的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)或其药学上可接受的盐的药物组合物可根据合适的给药途径(包括但不限于鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药)被制备成合适的制剂形式，例如喷雾制剂、贴剂、片剂(例如常规片剂、分散片、口腔崩解片)、胶囊(例如软胶囊、硬胶囊、肠溶胶囊)、糖衣丸、含片、散剂、颗粒剂、粉针剂、栓剂，或液体制剂(例如混悬剂(例如水性或油性混悬剂)、溶液、乳剂或糖浆剂)，或常规注射剂型例如可注射的溶液剂(例如根据本领域已知方法采用水、林格氏溶液或等渗氯化钠溶液等作为载体或溶剂来配制的无菌注射溶液) 或冻干组合物。本领域技术人员还可根据需要将本公开所述的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)制备成常规的、可分散的、可咀嚼的、口腔速崩解的或快速溶解的制剂，或缓释胶囊或控释胶囊。
作为活性成分的如本公开所述的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)被包含在药学上可接受的载体或稀释剂中，其量足以向受试者递送用于需治疗的适应症的治疗有效量，而不会在所治疗的受试者中引起严重的毒性作用。用于本文提及的所有疾病或病症的活性化合物的给药剂量为，例如约5ng/kg受试者体重/天至500mg/kg受试者体重/天，约10ng/kg受试者体重/天至300mg/kg受试者体重/天，例如0.1至100mg/kg受试者体重/天，或0.5至约25mg/kg受试者体重/天。
本公开所述的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)或其药学上可接受的盐可以任何合适的制剂形式方便地给药，合适的制剂形式的规格包括但不限于每单位剂型含有少于1mg，1mg至3000mg，或5mg至1000mg，例如5至500mg，或25至250mg活性成分。
IV.药盒(kit)/包装制品
本公开所述的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)，或其药学上可接受的盐、溶剂化物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物，其是用作药剂。本公开的药剂或本公开的药物组合物可以存在于药盒/包装制品中。药盒/包装制品可以包括包装或容器。包装或容器包括但不限于安瓶(ampoule)、泡罩包装、药用塑料瓶、小瓶、药用玻璃瓶、容器、注射器、层压软包装、共挤膜输液容器、试管和分配装置等。药盒/包装制品可以包含产品使用说明书。
V.方法和用途
本公开所述的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)，或其药学上可接受的盐、溶剂化物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物，还可以用作药剂。尤其是，本公开所述的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)，或其药学上可接受的盐、溶剂化物、多晶型物、前药、立体异构体(包括对映异构体)、或立体异构体的混合物可以用于制备用于预防及/或治疗选自以下的疾病或病症的药物：神经退行性疾病、心血管疾病、自身免疫性疾病、骨髓纤维化、肾纤维化、肝纤维化、肝硬化、肿瘤、多器官功能障碍综合征(MODS)、恶病质和败血症休克所致的多器官功能衰竭、器官(包括肾、 心脏、肺)或组织移植排斥反应、糖尿病、移植排斥反应、视网膜病变和急性肝功能衰竭。在一些实施方案中，所述疾病或病症包括但不限于：神经退行性疾病，包括帕金森病、和阿尔兹海默症；心血管疾病，包括例如冠心病、充血性心力衰竭、心肌梗塞、和动脉粥样硬化症；自身免疫性疾病，包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、和特应性皮炎；骨髓纤维化；肾纤维化；肝纤维化；肝硬化；肿瘤，包括血液系统恶性肿瘤、和实体肿瘤；多器官功能障碍综合征(MODS)，包括恶病质和败血症休克所致的多器官功能衰竭；急性肝功能衰竭；移植排斥反应，包括器官(包括肾、心脏、肺)或组织移植排斥反应；视网膜病变，包括糖尿病黄斑水肿(DME)和湿性老年黄斑变性(wAMD)；和糖尿病。在一些实施方案中，所述肿瘤包括但不限于：例如骨髓瘤，包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤；骨髓纤维化；骨髓疾病；骨髓增生异常综合征(MDS)；既往治疗的骨髓增生异常综合征；移植相关的癌症；中性粒细胞减少症；白血病，包括急性髓细胞白血病、慢性粒细胞白血病、慢性淋巴细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML)；淋巴瘤，包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、T细胞淋巴瘤(包括复发或难治性外周T细胞淋巴瘤)、小淋巴细胞淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤、淋巴浆细胞淋巴瘤、华氏巨球蛋白血症；甲状腺癌；黑色素瘤；肺癌，包括非小细胞肺癌、小细胞肺癌、肺腺癌、和肺鳞癌；炎症性肌纤维母细胞瘤；结直肠癌；脑胶质瘤；星形胶质母细胞瘤；卵巢癌；支气管癌；前列腺癌；乳腺癌，包括雌激素依赖性乳腺癌、HER2阳性乳腺癌、三阴性乳腺癌、偶发性乳腺癌和考登病；胰腺癌；神经母细胞瘤；髓外浆细胞瘤；髓母细胞瘤；浆细胞瘤；胃癌；胃肠道间质瘤；食道癌；大肠腺癌；食管鳞状细胞癌；肝癌；肾细胞癌；膀胱癌；子宫内膜癌；脑癌；口腔癌；肉瘤，包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、及平滑肌肉瘤；软骨肉瘤；尿路上皮癌；基底细胞癌；口腔鳞状细胞癌；胆管癌；骨癌；宫颈癌；和皮肤癌。
用于预防及/或治疗受试者的疾病或病症的方法，包括向所述受试者施用治疗有效量的本公开所述的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)，或其药学上可接受的盐，或本公开所述的药物组合物。在一些实施方案中，所述疾病或病症包括：神经退行性疾病、心血管疾病、自身免疫性疾病、骨髓纤维化、肾纤维化、肝纤维化、肝硬化、肿瘤、多器官功能障碍综合征(MODS)、恶病质和败血症休克所致的多器官功能衰竭、器官(包括肾、心脏、肺)或组织移植排斥反应、糖尿病、移植排斥反 应、视网膜病变和急性肝功能衰竭。在一些实施方案中，所述疾病或病症包括但不限于：神经退行性疾病，包括帕金森病、和阿尔兹海默症；心血管疾病，包括例如冠心病、充血性心力衰竭、心肌梗塞、和动脉粥样硬化症；自身免疫性疾病，包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、和特应性皮炎；骨髓纤维化；肾纤维化；肝纤维化；肝硬化；肿瘤，包括血液系统恶性肿瘤、和实体肿瘤；多器官功能障碍综合征(MODS)，包括恶病质和败血症休克所致的多器官功能衰竭；急性肝功能衰竭；移植排斥反应，包括器官(包括肾、心脏、肺)或组织移植排斥反应；视网膜病变，包括糖尿病黄斑水肿(DME)和湿性老年黄斑变性(wAMD)；和糖尿病。在一些实施方案中，所述肿瘤包括但不限于：例如骨髓瘤，包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤；骨髓纤维化；骨髓疾病；骨髓增生异常综合征(MDS)；既往治疗的骨髓增生异常综合征；移植相关的癌症；中性粒细胞减少症；白血病，包括急性髓细胞白血病、慢性粒细胞白血病、慢性淋巴细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML)；淋巴瘤，包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、T细胞淋巴瘤(包括复发或难治性外周T细胞淋巴瘤)、小淋巴细胞淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤、淋巴浆细胞淋巴瘤、华氏巨球蛋白血症；甲状腺癌；黑色素瘤；肺癌，包括非小细胞肺癌、小细胞肺癌、肺腺癌、和肺鳞癌；炎症性肌纤维母细胞瘤；结直肠癌；脑胶质瘤；星形胶质母细胞瘤；卵巢癌；支气管癌；前列腺癌；乳腺癌，包括雌激素依赖性乳腺癌、HER2阳性乳腺癌、三阴性乳腺癌、偶发性乳腺癌和考登病；胰腺癌；神经母细胞瘤；髓外浆细胞瘤；髓母细胞瘤；浆细胞瘤；胃癌；胃肠道间质瘤；食道癌；大肠腺癌；食管鳞状细胞癌；肝癌；肾细胞癌；膀胱癌；子宫内膜癌；脑癌；口腔癌；肉瘤，包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、及平滑肌肉瘤；软骨肉瘤；尿路上皮癌；基底细胞癌；口腔鳞状细胞癌；胆管癌；骨癌；宫颈癌；和皮肤癌。
在用于预防及/或治疗受试者的所述疾病或病症的方法中，通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式将治疗有效量的本公开所述的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)、或本公开所述的药物组合物施用至所述受试者。
术语“治疗”或“处理”是指向受试者施用本公开所述的化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I- 3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)或其药学上可接受的盐，或包含本公开化合物或其药学上可接受的盐的药物组合物，以减缓(减轻)不希望发生的疾病或病症(例如肿瘤)的发展。本公开的有益的或期望的临床结果包括但不限于：减轻症状，减轻疾病的严重程度，稳定疾病的状态，延迟或延缓疾病进展，改善或缓和病情，以及缓解疾病。
本公开化合物的“治疗有效量”取决于多种因素，包括所用特定化合物的活性、该化合物的代谢稳定性和作用时间长度、患者的年龄、性别和体重，患者的总体医学状况，给药方式和时间，排泄率，联合用药，以及所治疗患者的疾病或病症进展情况。本领域技术人员能够根据这些和其它因素来确定合适的剂量。
应当理解的是，使用一种或多种活性化合物和/或组合物及其剂量的选择取决于个体的基本情况(通常应该使个人情况达到最佳的效果)。给药和给药方案应该在本领域技术人员的能力范围内，并且合适的剂量取决于许多因素包括普通技术医生，兽医或研究者知识能力水平(见例如李俊主编，“临床药理学”，第4版，人民卫生出版社(2008))。
上述治疗的患者或受试者是指动物，例如哺乳动物，包括但不限于灵长类动物(如人类)、牛、绵羊、山羊、马、狗、猫、兔、豚鼠、大鼠、小鼠等。
VI.定义
除非另有说明，否则本说明书中所使用的下列词语、短语和符号通用地具有如下所述的含义。
通常，本文所用的命名法(包括IUPAC命名法)和下文描述的实验室程序(包括用于细胞培养、有机化学、分析化学和药理学等)是本领域众所周知的并且通常使用的那些。除非另有定义，否则结合本文描述的本公开内容的本文使用的所有科学和技术术语具有本领域技术人员通常理解的相同含义。另外，在权利要求书和/或说明书中，用语“一”或“一个”与术语“包含”或名词结合使用时，其含义可能是“一个”，但也与“一个或多个”，“至少一个”和“一个或多于一个”的含义一致。类似地，用语“另一个”或“其它”可以表示至少第二个或更多。
应该理解的是，每当本文用术语“包括”或“包含”描述各个方面时，还提供了其他由“由…组成”和/或“基本上由…组成”描述的类似方面。
术语“约”在本文中用于意指近似、大致、大约或在…左右。当术语“约”与数值范围联合使用时，它通过使边界延伸高于和低于阐述的数值来修饰那个范围。一般来说，术语“约”可通过向上或向下(增高或降低)变化例如10％、5％、2％或1％来修饰数值高于和低于所述的值。
在本文中，用语“……表示键”意指其是键连接体(即表示其不存在)。例如用语“R 12表示键”意指R 12是键连接体。换言之，当R 12为键时，式(I)结构的基团LIN直接连接至式(II)结构中的苯环。
如本文中所使用，单独或组合使用的用语“在其主碳链中插入有一或多个基团R b和/或一或多个基团R c或者一或多个基团R b与R c的任意组合的可选取代的直链或支链C 2-30亚烷基”中的“插入”具有本领域已知的定义，即可以指基团R b、R c或者基团R b与R c的任意组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开。在本文中，上述用语“插入有一或多个” 的示例可包括但不限于在所述主碳链中插入有一或多个(1-30、1-20、或1-15、1-10、1-9、1-8、1-7、1-6、1-5、1-4、1-3或1-2个，或1个)如本文所定义的基团R b和/或一或多个(1-30、1-20、或1-15、1-10、1-9、1-8、1-7、1-6、1-5、1-4、1-3或1-2个，或1个)基团R c和/或一或多个(1-30、1-20、或1-15、1-10、1-9、1-8、1-7、1-6、1-5、1-4、1-3或1-2个，或1个)基团R b与R c的任意组合，由此所形成的主链基团符合共价键理论。例如，表述“在其主碳链中插入有一或多个基团R b和/或一或多个基团R c或者一或多个基团R b与R c的任意组合的可选取代的直链或支链C 2-30亚烷基”是指直链或支链C 2-30亚烷基链的主碳链中的一对或多对任何两个相邻的碳原子之间插入有一或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)R b和/或R c和/或一或多个基团R b与R c的任意组合，以形成含有一个或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH 2-R b-CH 2-”片段和/或一或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH 2-R c-CH 2-”片段和/或一或多个(例如1-30、1-20、1-15、1-10、1-8、1-7、1-6、1-5、1-4、1-3、1-2或1个)“-CH 2-R b-R c-CH 2-”片段，其中各R b相同或不同，各R c相同或不同，并且如本文中所定义。
在本文中，单独或组合使用的用语“可选取代”意指指示的基团可以未被取代或被一个或多个如本文定义的取代基取代。在本文中，用语“可选地被……取代”与“未取代或取代的”可以互换使用。术语“取代的”通常表示所提及结构中的一或多个氢被相同或不同的具体取代基取代。取代基的数量原则上不受任何限制，或自动受构建单元的大小(即，构建单元的可被替换的氢原子的总数量)限制，或如本文中所明确定义。
在本文中，由波形线断裂的键显示所绘示基团与分子的其他部分的连接点。例如，下文所绘示的式(II)表示的基团
Figure PCTCN2023070102-appb-000037
表示所述基团的R 12与式(I)化合物的基团LIN连接。
在本文中，单独或组合使用的术语“所述C x-y亚烷基的一或多个CH 2的氢被…替代”表示直链或支链C x-y亚烷基中的任意一或多个CH 2中的氢被如本文中所定义的取代基替代。在本文中，“基团#-CH 2-、#-(CH 2) 2-、#-(CH 2) 3-、#-(CH 2) 4-、#-(CH 2) 5-、#-(CH 2) 6-、#-(CH 2) 7-、#-(CH 2) 8-、#-(CH 2) 9-、#-(CH 2) 10-、#-(CH 2) 11-、#-(CH 2) 12-、#-(CH 2) 13-、#-(CH 2) 14-、#-(CH 2) 15-、#-(CH 2) 16-、#-(CH 2) 17-、#-(CH 2) 18-、#-(CH 2) 19-、#-(CH 2) 20-、#-(CH 2) 21-、#-(CH 2) 22-、#-(CH 2) 25-、或#-(CH 2) 30-的一或多个CH 2的氢”中的用语“一或多个”可以是指所提及的各亚烷基基团的部分或全部的氢，包括但不限于1-60个氢。在一些实施方案中，所述用语“一或多个CH 2的氢”可以是指所提及的亚烷基的部分或全部的氢，包括但不限于1-30个，例如1-25个，1-20个，1-15个，1-10个，1-5个，1-4个，1-3个，1-2个或1个氢。在一些实施方案中，所述用语“一或多个CH 2的氢”可以是指所提及的亚烷基的多个氢中的1-3个。该数量原则上不受任何限制或自动受构建单元的大小限制。
在本文中，术语“氧代”或“氧代基”指＝O。
在本文中，单独或组合使用的术语“卤素原子”或“卤素”是指氟、氯、溴或碘。
在本文中，单独或组合使用的术语“烷基”是指直链或支链的烷基。术语“C x-C y烷基”或“C x-y烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链烷基。本发明中单独或组合使用的术语“C 1-10烷基”是指含有1至10个碳原子的直链或支链烷基。本公开的C 1-10烷基的实例包括C 1-9烷基，C 1-8烷基，C 2-8烷基，C 1-7烷基，C 1-6烷基，C 1-5烷基，和C 1-4烷基。代表性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、特戊基、己基、庚基、辛基、壬基及癸基。本公开的术语“C 1-3烷基”或“C 1-C 3烷基”是指含有1至3个碳原子的烷基，其代表性实例包括甲基、乙基、正丙基及异丙基。在本公开中，所述“烷基”是可选地经取代的，取代基可选是一或多个选自卤素、羟基、氰基、C 1-3烷基、C 1-3烷氧基、三氟甲基、杂环基或其组合的取代基。
在本文中，单独或组合使用的术语“卤代烷基”是指被一或多个卤素取代的直链或支链的烷基，其中所述烷基中的一或多个氢被卤素取代。术语“卤代C x-C y烷基”或“卤代C x-y烷基”(x及y各自为整数)是指被一或多个卤素取代的含有x至y个碳原子的直链或支链烷基。本公开中单独或组合使用的术语“卤代C 1-10烷基”是指被一或多个卤素(例如氟、氯、溴或碘)取代的含有1至10个碳原子的直链或支链烷基。本公开的卤代C 1-10烷基的实例包括卤代C 1-9烷基，例如卤代C 1-8烷基，卤代C 2-8烷基，卤代C 1-7烷基，卤代C 1-6烷基，卤代C 1-5烷基，或卤代C 1-4烷基。代表性实例包括卤代甲基、卤代乙基、卤代正丙基、卤代异丙基、卤代正丁基、卤代异丁基、卤代仲丁基、卤代叔丁基、卤代戊基、卤代异戊基、卤代新戊基、卤代特戊基、卤代己基、卤代庚基、卤代辛基、卤代壬基及卤代癸基。本公开的术语“卤代C 1-3烷基”或“卤代C 1-C 3烷基”是指被一或多个卤素取代的含有1至3个碳原子的烷基，其代表性实例包括卤代甲基、卤代乙基、卤代正丙基及卤代异丙基。
在本文中，单独或组合使用的术语“亚烷基”(其与“亚烷基链”可互换使用)是指由碳和氢组成的直链或支链的二价饱和烃基团。术语“C x-C y亚烷基”或“C x- y亚烷基”(x及y各自为整数)是指含有x至y个碳原子的直链或支链的亚烷基。本公开的C 1-C 30亚烷基的实例包括C 1-C 30亚烷基，C 1-C 29亚烷基，C 1-C 28亚烷基，C 1-C 27亚烷基，C 1-C 26亚烷基，C 1-C 25亚烷基，C 1-C 24亚烷基，C 1-C 23亚烷基，C 1-C 22亚烷基，C 1-C 21亚烷基，C 1-C 20亚烷基，C 1-C 19亚烷基，C 1-C 18亚烷基，C 1-C 17亚烷基，C 1-C 16亚烷基，C 1-C 15亚烷基，C 1-C 14亚烷基，C 1-C 13亚烷基，C 1-C 12亚烷基，C 1-C 11亚烷基，C 1-C 10亚烷基，C 1-C 9亚烷基，C 1-C 8亚烷基，C 1-C 7亚烷基，C 1-C 6亚烷基，C 1-C 5亚烷基，C 1-C 4亚烷基，C 1-C 3亚烷基，或C 1-C 2亚烷基。代表性实例包括但不限于亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚仲丁基、亚叔丁基、亚戊基、亚异戊基、亚新戊基、亚特戊基、亚己基、亚庚基、亚辛基、亚壬基、亚癸基、亚十一烷基、亚十二烷基、亚十三烷基、亚十四烷基、亚十五烷基、亚十六烷基、亚十七烷基、亚十八烷基、亚十九烷基、亚二十烷基、亚二十一烷基、亚二十二烷基、亚二十三烷基、亚二十四烷基、亚二十五烷基、亚二十六烷基、亚二十七烷基、亚二十八烷基、亚二十九烷基、 和亚三十烷基。在本公开中，所述“亚烷基”是可选地经取代的，取代基可选是一或多个选自C 1-C 3烷基、C 3-6环烷基、羟基、氨基、巯基、卤素、C 1-C 3烷氧基、C 1-C 3烷基氨基、卤代C 1-C 3烷基、氨基C 1-3亚烷基、C 1-3烷基-NHC(O)-、C 1-3烷基-C(O)NH-、氰基或其任意组合的取代基。
在本文中，单独或组合使用的术语“烷氧基”是指直链或支链烷氧基，其结构式为烷基-O-。可选地，烷氧基的烷基部分可包含1-10个碳原子。“烷氧基”的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基、3-甲基戊氧基等。术语“C 1-C 3烷氧基”或“C 1-3烷氧基”是指含有1至3个碳原子的直链或支链烷氧基。C 1-3烷氧基的代表性实例包括但不限于甲氧基、乙氧基、正丙氧基及异丙氧基。
在本发明中，单独或组合使用的术语“杂芳基”是指含有至少一个具有1个或多个(例如1至6个、或者1至5个、或者1至4个、或者1至3个)独立选自氧、氮和硫的杂原子的芳香族环的5-至20-元(可选地为5至15元、5至12元、5至11元、5至10元、5至9元、5至8元、5至7元、5至6元、6至15元或6元至9元)单环或二环或多环的芳香环基团。二环或多环杂芳基包括双环、三环或四环杂芳基，其中一个环是具有一或多个独立地选自O、S和N的杂原子的芳香族环，并且其它环可为饱和、部分不饱和或芳香族环并且可为碳环或含有一或多个独立地选自O、S和N的杂原子。单环杂芳基基团的代表性实例包括但不限于呋喃基、噁唑基、异噁唑基、噁二唑基、噻吩基、噻唑基、异噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、四唑基、和三嗪基。双环杂芳基的实例包括但不限于吲哚基、异吲哚基、异吲哚啉基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并三唑基、苯并[2,1,3]噁二唑基、苯并[2,1,3]噻二唑基、苯并[1,2,3]噻二唑基、喹啉基、异喹啉基、萘啶基、噌啉基、喹唑啉基、喹喔啉基、酞嗪基、噁唑并吡啶基、呋喃并吡啶基、喋啶基、嘌呤基、吡啶并吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-a]吡啶基、1H-吡咯并[3,2-b]吡啶基、1H-吡咯并[2,3-b]吡啶基、吡咯并[2,1-b]噻唑基和咪唑并[2,1-b]噻唑基。三环杂芳基的实例包括(但不限于)吖啶基、苯并吲哚基、咔唑基、二苯并呋喃基、和呫吨基。所述杂芳基基团可未被取代或被取代。经取代的杂芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的杂芳基，其中取代基可选地选自C 1-C 3烷基、C 3-6环烷基、羟基、氨基、巯基、卤素、C 1-C 3烷氧基、C 1-C 3烷基氨基、卤代C 1-C 3烷基、氨基C 1-3亚烷基、C 1-3烷基-NHC(O)-、C 1-3烷基-C(O)NH-、氰基或其任意组合。
在本发明中，单独或组合使用的术语“亚杂芳基”是指含有至少一个具有1个或多个(例如1至6个、或者1至5个、或者1至4个、或者1至3个)独立选自氧、氮和硫的杂原子的芳香族环的5-至20-元(可选地为5至15元、5至12元、5至11元、5至10元、5至9元、5至8元、5至7元、5至6元、6至15元或6元至9元)单环或二环或多环的二价芳香环基团。二环或多环亚杂芳基包括双环、三环或四环亚杂芳基，其中一个环是具有一或多个 独立地选自O、S和N的杂原子的芳香族环，并且其它环可为饱和、部分不饱和或芳香族环并且可为碳环或含有一或多个独立地选自O、S和N的杂原子。单环亚杂芳基基团的代表性实例包括但不限于亚呋喃基、亚噁唑基、亚异噁唑基、亚噁二唑基、亚噻吩基、亚噻唑基、亚异噻唑基、亚噻二唑基、亚吡咯基、亚咪唑基、亚吡唑基、亚三唑基、亚吡啶基、亚嘧啶基、亚哒嗪基、亚吡嗪基、亚四唑基、和亚三嗪基。双环亚杂芳基的实例包括但不限于亚吲哚基、亚异吲哚基、亚苯并呋喃基、亚异苯并呋喃基、亚苯并噻吩基、亚吲唑基、亚苯并咪唑基、亚苯并噁唑基、亚苯并异噁唑基、亚苯并噻唑基、亚苯并异噻唑基、亚苯并三唑基、亚苯并[2,1,3]噁二唑基、亚苯并[2,1,3]噻二唑基、亚苯并[1,2,3]噻二唑基、亚喹啉基、亚异喹啉基、亚萘啶基、亚噌啉基、亚喹唑啉基、亚喹喔啉基、亚酞嗪基、亚噁唑并吡啶基、亚呋喃并吡啶基、亚喋啶基、亚嘌呤基、亚吡啶并吡啶基、吡唑并[1,5-a]吡啶亚基、吡唑并[1,5-a]嘧啶亚基、咪唑并[1,2-a]吡啶亚基、1H-吡咯并[3,2-b]吡啶亚基、1H-吡咯并[2,3-b]吡啶亚基、吡咯并[2,1-b]噻唑亚基和咪唑并[2,1-b]噻唑亚基。三环亚杂芳基的实例包括(但不限于)亚吖啶基、亚苯并吲哚基、亚咔唑基、亚二苯并呋喃基、和亚呫吨基。所述亚杂芳基基团可未被取代或被取代。经取代的亚杂芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的亚杂芳基，其中取代基可选地选自C 1-C 3烷基、C 3-6环烷基、羟基、氨基、巯基、卤素、C 1-C 3烷氧基、C 1-C 3烷基氨基、卤代C 1-C 3烷基、氨基取代的C 1-3亚烷基、C 1-3烷基-NHC(O)-、C 1-3烷基-C(O)NH-、氰基或其任意组合。
在本文中，单独或组合使用的术语“芳基”是指包含5至14个碳原子并且可选地包含一个或多个稠合环的一价芳香烃基团，例如苯基或萘基或芴基。在本公开中，所述“芳基”是可选地经取代的芳基。经取代的芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的芳基，例如芳基被取代基单取代、双取代或三取代，其中取代基可选地例如选自C 1-C 3烷基、C 3- 6环烷基、羟基、氨基、巯基、卤素、C 1-C 3烷氧基、C 1-C 3烷基氨基、卤代C 1-C 3烷基、氨基取代的C 1-3亚烷基、C 1-3烷基-NHC(O)-、C 1-3烷基-C(O)NH-、氰基或其任意组合。
在本公开中，单独或组合使用的术语“亚芳基”是指包含5至14个碳原子并且可选地包含一个或多个稠合环的二价芳香烃基团，例如亚苯基或亚萘基或亚芴基。在本公开中，所述“亚芳基”是可选地经取代的亚芳基。经取代的亚芳基是指经取代基取代一或多次(例如1-4、1-3次或1-2次)的亚芳基，例如亚芳基被取代基单取代、双取代或三取代，其中取代基可选地例如选自C 1-C 3烷基、C 3-6环烷基、羟基、氨基、巯基、卤素、C 1-C 3烷氧基、C 1-C 3烷基氨基、卤代C 1-C 3烷基、氨基取代的C 1-3亚烷基、C 1-3烷基-NHC(O)-、C 1-3烷基-C(O)NH-、氰基或其任意组合。
在本文中，单独或组合使用的术语“环烷基”是指饱和或部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环或多环环烃基，其在一些实施方案中具有3至20个碳原子(即C 3-20环烷基)，或者3至15个碳原子(即C 3-15环烷基)，3至12个碳原子(即C 3-12环烷基)，或者3至11个碳原子(即C 3-11环烷基)，或者3至10个碳原子(即C 3-10环烷基)，或者3至8个碳原子(即C 3-8环烷基)，或者3至7个碳原子(即C 3-7环烷基)，或 者3至6个碳原子(即C 3-6环烷基)。术语“环烷基”包括单环、双环或三环环烷基，其具有3至20个碳原子。单环环烷基的代表性实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。双环和三环环烷基包括桥环烷基、稠环和螺环烷基，例如但不限于十氢萘基、八氢并环戊二烯基、八氢-1H-茚基、螺环烷基、金刚烷基、降金刚烷基、冰片基、降冰片烷基(IUPAC系统命名为二环[2.2.1]庚烷基)。在本文中，所述“环烷基”是可选地经单取代的或多取代的，例如但不限于，2,2-，2,3-，2,4-，2,5-，或2,6-二取代的环己基。所述经取代的“环烷基”的取代基可选地是一或多个(例如1-5、1-4、1-3、1-2、或1个)选自C 1-C 3烷基、C 3-6环烷基、羟基、氨基、巯基、卤素、C 1-C 3烷氧基、C 1-C 3烷基氨基、卤代C 1-C 3烷基、氨基取代的C 1-3亚烷基、C 1-3烷基-NHC(O)-、C 1-3烷基-C(O)NH-、氰基或其任意组合的取代基。术语“C 3-6环烷基”的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、和环己基。
在本文中，单独或组合使用的术语“C x-y螺环烷基”或“C x-y螺环基”(x及y各自为整数)是指含有x至y个碳原子的螺环烷基。本发明中单独或组合使用的术语“C 7-11螺环烷基”是指含有7至11个(例如7-10，7-9个)碳原子的螺环烷基。术语“C 7-11螺环烷基”的代表性实例包括但不限于螺[3.3]庚烷基、螺[2.5]辛烷基、螺[3.5]壬烷基、螺[4.4]壬烷基、螺[4.5]癸烷基或螺[5.5]十一烷基。所述“C 7-11螺环烷基”可选地进一步经一个或多个选自C 1-C 3烷基、C 3-6环烷基、羟基、氨基、巯基、卤素、C 1-C 3烷氧基、C 1-C 3烷基氨基、卤代C 1-C 3烷基、氨基取代的C 1-3亚烷基、C 1-3烷基-NHC(O)-、C 1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代。
在本发明中，单独或组合使用的术语“亚环烷基”是指具有3至12个碳原子(例如3-12个、3-11个、3-10个、3-8个、3-7个、3-6个碳原子)的饱和及部分不饱和(即具有一个或多个双键，但不是完全共轭)的单环或双环或多环环烃二价基团。术语“亚环烷基”包括单环、双环或三环烃二价基团，其具有3至12个碳原子。单环亚环烷基的代表性实例包括但不限于亚环丙基、亚环丁基、亚环戊基、亚环戊烯基、亚环己基、亚环己烯基、亚环庚基、和亚环辛基。双环和三环亚环烷基包括亚桥环烷基、亚稠环基和亚螺环烷基，例如但不限于亚十氢萘基、八氢并环戊二烯亚基、八氢-1H-茚亚基、2,3-二氢-1H-茚亚基、亚螺环基、亚金刚烷基、亚降金刚烷基、亚降冰片烷基(系统命名为双环[2.2.1]庚烷亚基)。在本公开中，所述“亚环烷基”是可选地经单取代的或多取代的，例如但不限于，2,2-，2,3-，2,4-，2,5-，或2,6-二取代的环己基。所述经取代的“亚环烷基”的取代基可选地是一或多个选自C 1-C 3烷基、C 3-6环烷基、羟基、氨基、巯基、卤素、C 1-C 3烷氧基、C 1-C 3烷基氨基、卤代C 1-C 3烷基、氨基取代的C 1-3亚烷基、C 1-3烷基-NHC(O)-、C 1-3烷基-C(O)NH-、氰基或其任意组合的取代基。
在本文中，单独或组合使用的术语“C x-y亚螺环烷基”或“C x-y亚螺环基”(x及y各自为整数)是指含有x至y个碳原子的亚螺环烷基。本发明中单独或组合使用的术语“C 7-11亚螺环烷基”是指含有7至11个(例如7-10，7-9个)碳原子的亚螺环烷基。术语“C 7-11亚螺环烷基”的代表性实例包括但不限于螺[3.3]庚烷亚基、螺[2.5]辛烷亚基、螺[3.5]壬烷亚基、螺[4.4]壬烷亚基、螺[4.5]癸烷亚基或螺[5.5]十一烷亚基。所述“C 7-11亚螺环烷基”可选地进一步经一个或多个选自 C 1-C 3烷基、C 3-6环烷基、羟基、氨基、巯基、卤素、C 1-C 3烷氧基、C 1-C 3烷基氨基、卤代C 1-C 3烷基、氨基取代的C 1-3亚烷基、C 1-3烷基-NHC(O)-、C 1-3烷基-C(O)NH-、氰基或其任意组合的取代基取代。
在本文中，单独或组合使用的术语“杂环基”或“杂环烷基”是指含有一个或多个(例如含有1至5个、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的3至20元单环、双环或三环的饱和或部分不饱和的(即具有一个或多个双键，但不完全共轭)环烃基。在一些实施方式中，“杂环基”可以是指含有一个或多个(例如含有1至5个或、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的3至15元(可选地为3至14元、3至12元、3至11元、3至10元、3至9元、3至8元、3至7元、3至6元、3至5元或4元至9元)单环的饱和或部分不饱和的(即具有一个或多个双键，但不完全共轭)环烃基。单环杂环基的代表性实例包括但不限于氮杂环丁基、氧杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、四氢噻喃基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、二氧杂环己基、氮杂环庚烷基、氮杂环辛烷基、二氮杂环庚烷基(例如1,4-二氮杂环庚烷-1-基)和二氮杂环辛烷基。双环和三环杂环基包括桥杂环基、稠杂环基和螺杂环基，其代表性实例包括但不限于6-氮杂双环[3.1.1]庚烷-3-基、2,5-二氮杂双环[2.2.1]庚烷-2-基、3,6-二氮杂双环[3.1.1]庚烷-3-基、3-氮杂双环[3.2.1]辛烷-8-基、3,8-二氮杂双环[3.2.1]辛烷-8-基、3,8-二氮杂双环[3.2.1]辛烷-3-基、2,5-二氮杂双环[2.2.2]辛烷-2-基、和氮杂螺环基(例如3-氮杂螺[5.5]十一烷-3-基)。所述杂环基可以是未取代的或如明确定义的取代的(例如被单-、双-、三-、或多取代)，其中取代基可选地选自氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合。
在本文中，单独或组合使用的术语“含氮单环杂环基”是指含有一个氮原子和可选地含有一或多个(例如含有1至5个、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的3至20元(可选地为3至15元、3至14元、3至12元、3至11元、3至10元、3至9元、3至8元、3至7元、3至6元、3至5元或4元至9元)单环饱和或部分不饱和的(即具有一个或多个双键，但不完全共轭)一价环烃基。含氮单环杂环基的代表性实例包括但不限于氮杂环丁基、吡咯烷基、咪唑烷基、吡唑烷基、噁唑烷基、噻唑烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氮杂环庚烷基、氮杂环辛烷基、二氮杂环庚烷基(例如1,4-二氮杂环庚烷-1-基)和二氮杂环辛烷基。所述含氮单环杂环基可以是未取代的或如明确定义的取代的(例如被单-、双-、三-、或多取代)，其中取代基可选地选自氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合。
在本文中，单独或组合使用的术语“亚杂环基”或“亚杂环烷基”是指含有一个或多个 (例如含有1至5个、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的3至20元单环、双环或三环的饱和或部分不饱和的(即具有一个或多个双键，但不完全共轭)二价环烃基。在一些实施方式中，“亚杂环基”可以例如是指含有一个或多个(例如含有1至5个或、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的3至15元(可选地为3至14元、3至12元、3至11元、3至10元、3至9元、3至8元、3至7元、3至6元、3至5元或4元至9元)单环的饱和或部分不饱和的(即具有一个或多个双键，但不完全共轭)二价环烃基。单环亚杂环基的代表性实例包括但不限于亚氮杂环丁基、亚氧杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚四氢呋喃基、亚四氢吡喃基、亚四氢噻吩基、亚四氢噻喃基、亚噁唑烷基、亚噻唑烷基、亚哌啶基、亚哌嗪基、亚吗啉基、亚硫代吗啉基、亚二氧杂环己基和二氮杂环庚烷亚基(例如1,4-二氮杂环庚烷亚基，4,5-二氮杂环庚烷亚基，1,3-二氮杂环庚烷亚基)。双环亚杂环基和三环亚杂环基包括亚桥杂环基、亚稠杂环基和亚螺杂环基，其代表性实例包括但不限于6-氮杂双环[3.1.1]庚烷亚基、2,5-二氮杂双环[2.2.1]庚烷亚基、3,6-二氮杂双环[3.1.1]庚烷亚基、3-氮杂双环[3.2.1]辛烷亚基、3,8-二氮杂双环[3.2.1]辛烷亚基、3,8-二氮杂双环[3.2.1]辛烷亚基、2,5-二氮杂双环[2.2.2]辛烷亚基、和亚氮杂螺环基(例如3-氮杂螺[5.5]十一烷亚基)。所述亚杂环基可以是未取代的或如明确定义的取代的(例如被单-、双-、三-、或多取代)，其中取代基可选选自氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合。
在本文中，单独或组合使用的术语“含氮亚杂环基”是指含有一个氮原子和可选地含有一或多个(例如含有1至5个、1至4个、1至3个、1至2个或1个)独立地选自硫、氧和氮的杂原子的3至20元(可选地为3至15元、3至14元、3至12元、3至11元、3至10元、3至9元、3至8元、3至7元、3至6元、3至5元或4元至9元)单环、双环或三环的饱和或部分不饱和的(即具有一个或多个双键，但不完全共轭)二价环烃基。含氮亚杂环基的代表性实例包括但不限于亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、亚硫代吗啉基、氮杂环庚亚基、二氮杂环庚亚基、氮杂环辛亚基和二氮杂环辛亚基。所述含氮亚杂环基可以是未取代的或如明确定义的取代的(例如被单-、双-、三-、或多取代)，其中取代基可选地选自氘、羟基、氨基、巯基、硝基、卤素、氰基、可选氘代的C 1-6烷基、卤代C 1-6烷基、可选氘代的C 3-6环烷基、可选氘代的C 1-6烷氧基、可选氘代的C 1-6烷基-NH-、NH 2-C 1-6亚烷基、可选氘代的C 1-6烷基-NHC(O)-、可选氘代的C 1-6烷基-C(O)NH-或其任意组合。
在本文中，单独或组合使用的术语“亚炔基”是指具有一个或多个(例如1至3个、1至2个或1个)碳碳叁键的包含2至8个(例如2至6个、2至5个、2至4个、较优选2个)碳原子的直链或支链二价烃基。亚炔基的实例包括但不限于亚乙炔基、1-丙炔亚基、1-丁炔亚基和1,3-二炔亚基。
在本文中，单独或组合使用的术语“炔基”是指具有一个或多个(例如1至3个、1至2个或1个)碳碳叁键的包含2至8个(例如2至6个、2至5个、2至4个、较优选2个)碳原子的直链或支链一价烃基。“C 2-6炔基”的实例包括但不限于乙炔基、1-丙炔基、1-丁炔基和1,3-二炔基。
在本文中，单独或组合使用的术语“亚烯基”是指具有一个或多个(例如1至3个、1至2个或1个)碳碳双键的包含2至8个碳原子(例如2至6个、2至5个碳原子，或2至4个、2至3个或2个碳原子)的直链或支链二价烃基。亚烯基的实例包括但不限于亚乙烯基(例如-CH＝CH-)、1-丙烯亚基、亚烯丙基、1-丁烯亚基、2-丁烯亚基、3-丁烯亚基、异丁烯亚基、戊烯亚基、正-戊-2,4-二烯亚基、1-甲基-丁-1-烯亚基、2-甲基-丁-1-烯亚基、3-甲基-丁-1-烯亚基、1-甲基-丁-2-烯亚基、2-甲基-丁-2-烯亚基、3-甲基-丁-2-烯亚基、1-甲基-丁-3-烯亚基、2-甲基-丁-3-烯亚基、3-甲基-丁-3-烯亚基、和亚己烯基。
在本文中，单独或组合使用的术语“烯基”是指具有一个或多个(例如1至3个、1至2个或1个)碳碳双键的包含2至8个碳原子(例如2至6个、2至5个碳原子，或2至4个、2至3个或2个碳原子)的直链或支链一价烃基。“C 2-6烯基”的实例包括但不限于乙烯基(例如CH 2＝CH-)、1-丙烯基、烯丙基、1-丁烯基、2-丁烯基、3-丁烯基、异丁烯基、戊烯基、正-戊-2,4-二烯基、1-甲基-丁-1-烯基、2-甲基-丁-1-烯基、3-甲基-丁-1-烯基、1-甲基-丁-2-亚基、2-甲基-丁-2-亚基、3-甲基-丁-2-亚基、1-甲基-丁-3-烯基、2-甲基-丁-3-烯基、3-甲基-丁-3-烯基、和己烯基。
在本文中，术语“冰片”或“冰片烷”(又称1,7,7-trimethylbicyclo[2.2.1]heptane；camphane；bornylane)具有本领域技术人员已知的定义。在本文中，术语“冰片烷基”或“冰片基”是指冰片烷的一价基团，即冰片烷中的任意一个氢去掉后剩余的基团。“冰片基”的代表性实例包括但不限于1,7,7-三甲基二环[2.2.1]庚烷-2-基、1,7,7-三甲基二环[2.2.1]庚烷-3-基、1,7,7-三甲基二环[2.2.1]庚烷-4-基、1,7,7-三甲基二环[2.2.1]庚烷-5-基、或1,7,7-三甲基二环[2.2.1]庚烷-6-基、
Figure PCTCN2023070102-appb-000038
在本文中，术语“二环[2.2.1]庚烷”(又称bicyclo[2.2.1]heptane)或“降冰片烷”，具有本领域技术人员已知的定义。在本文中，“二环[2.2.1]庚烷基”或“降冰片(烷)基”是指二环[2.2.1]庚烷的一价基团，即二环[2.2.1]庚烷中的任意一个氢去掉后剩余的基团。“二环[2.2.1]庚烷基”的代表性实例包括但不限于二环[2.2.1]庚烷-2-基、二环[2.2.1]庚烷-3-基、二环[2.2.1]庚烷-4-基、二环[2.2.1]庚烷-5-基或二环[2.2.1]庚烷-6-基。
在本文中，术语“二环[2.2.1]庚烯”又称bicyclo[2.2.1]heptene)，具有本领域技术人员已知的定义。在本文中，“二环[2.2.1]庚烯基”是指二环[2.2.1]庚烯的一价基团，即二环[2.2.1]庚烯中的任意一个氢去掉后剩余的基团。“二环[2.2.1]庚烯基”的代表性实例包括但不限于二环[2.2.1]庚-5-烯-2-基、二环[2.2.1]庚-5-烯-3-基、或二环[2.2.1]庚-5-烯-7-基。
在本文中，术语“金刚烷”(又称Tricyclo[3.3.1.1 3,7]decane)具有本领域技术人员已知的定义，其结构式例如如下所示：
Figure PCTCN2023070102-appb-000039
在本文中，“金刚烷基”是指金刚烷的一价基团，即金刚烷中的任意一个氢去掉后剩余的基团。“金刚烷基”的代表性实例包括但不限于1-金刚烷基、2-金刚烷基、3-金刚烷基、4-金刚烷基、5-金刚烷基、6-金刚烷基、7-金刚烷基、8-金刚烷基、9-金刚烷基或10-金刚烷基。
在本文中，术语“降金刚烷”(又称为noradamantane)具有本领域技术人员已知的定义，其结构式例如如下所示：
Figure PCTCN2023070102-appb-000040
在本文中，“降金刚烷基”是指降金刚烷的一价基团，即降金刚烷中的任意一个氢去掉后剩余的基团。“降金刚烷基”的代表性实例包括但不限于1-降金刚烷基、2-降金刚烷基、3-降金刚烷基、4-降金刚烷基、5-降金刚烷基、6-降金刚烷基、7-降金刚烷基、8-降金刚烷基或9-降金刚烷基。
在本文中，术语“金刚烷胺”具有本领域技术人员已知的定义，即是指具有氨基取代基的金刚烷，其中氨基可以取代在金刚烷任意位置的碳上的氢。“金刚烷胺”的一实施例可以是金刚烷-1-胺(其对应英文化学名称为adamantan-1-amine或Tricyclo[3.3.1.1 3,7]decan-1-amine；CAS:768-94-5)，具有以下结构式
Figure PCTCN2023070102-appb-000041
本公开所述式(I)化合物的盐、或表1或2的化合物的盐、或其药学上可接受的盐、对映异构体、立体异构体、溶剂化物、多晶型物亦涵盖于本公开范围内。
在本公开的所有实施方式中，所述化合物(包括式(I)、式(I-1)、式(I-2)、式(I-3)、式(I-2-1)、式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)中任一个的化合物，或表1或表2化合物)的盐或药学上可接受的盐是指无毒无机的或有机的酸和/或碱加成盐。示例包括：硫酸盐、盐酸盐、枸橼酸盐、马来酸盐、甲磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、富马酸盐、磷酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、羟乙酸盐或对甲苯磺酸盐等。
“药学上可接受的载体”是指药学上可接受的材料，例如填充剂、稳定剂、分散剂、悬浮剂、稀释剂、赋形剂、增稠剂、溶剂或包封材料，将本公开中有用的化合物携带或运输到患者体内或给予患者，使得其可以执行其预期功能。通常，这样的构建体从一个器官或身体的一部分携带或运输到另一个器官或身体的一部分。载体与制剂的其他成分(包括本公开中有用的化合物)相容并且对患者无害，载体必须是“可接受的”。可用作药学上可接受的载体的材料的一些实例包括：糖，如乳糖，葡萄糖和蔗糖；淀粉，如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；粉状黄蓍胶；麦芽；明胶；滑石；赋形剂，如可可脂和栓剂蜡；油，如花生油，棉籽油，红花油，芝麻油，橄榄 油，玉米油和大豆油；二醇，如丙二醇；多元醇，如甘油，山梨糖醇，甘露醇和聚乙二醇；酯类，如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，如氢氧化镁和氢氧化铝；表面活性剂磷酸盐缓冲溶液；和药物制剂中使用的其他无毒相容物质。
本公开的术语“室温”是指周围环境温度，例如20-30℃的温度。
在本文中，“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
在本文中，术语“溶剂化物”是指一种或多种溶剂分子和本发明化合物的缔合物或络合物。溶剂的实例包括水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语“水合物”是指溶剂分子是水的络合物。
在本文中，术语“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。
在本文中，术语“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
在本文中，术语“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。
实施例
在下列说明中，为了提供对本发明的彻底了解而提出许多具体细节。本发明可在不具有部分或所有这些具体细节的情况下实施。在其他情况下，为了不对本发明造成不必要的混淆，不详述众所周知的过程操作。虽然本发明将结合具体实施例来进行说明，但应当理解的是，这并非旨在将本发明限制于这些实施例。
整个说明书及实施例中使用下列缩写：
AcOH            醋酸
Boc             叔丁氧基羰基
Con.            浓度
DCM             二氯甲烷
DIEA            N,N-二异丙基乙胺
DMAP            4-二甲氨基吡啶
DMF             N,N-二甲基甲酰胺
DMSO            二甲基亚砜
DIPEA           N,N-二异丙基乙胺
DESS-MARTIN     戴斯-马丁氧化剂
EA              乙酸乙酯
EDCI             1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
ESI              电喷雾离子化
equiv            当量
EtOH             乙醇
HATU             2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐
HFIP             六氟异丙醇
HPLC             高效液相层析
HRMS             高分辨率质谱
LC-MS            液相色谱-质谱联用
LRMS             低分辨率质谱
LC               液相层析
Me               甲基
MeCN             乙腈
MeOH             甲醇
MS               质谱
NBS              N-溴代琥珀酰亚胺
1H NMR           核磁共振氢谱
PE               石油醚
(PhCOO) 2         过氧化二苯甲酰
Raney Ni         雷尼镍
rt               室温
tBu              叔丁基
TEA              三乙胺
TFA              三氟乙酸
THF              四氢呋喃
TLC              薄层层析
TMS              三甲基硅烷基
在本发明中， 1H NMR谱采用Bruker-500MHz型核磁共振仪测定，用含0.1％TMS(作为内标)的CD 3OD(δ＝3.31ppm)做溶剂；或用含0.1％TMS(作为内标)的CDCl 3(δ＝7.26ppm)做溶剂；或使用含0.03％TMS(作为内标)的DMSO-d 6(δ＝2.50ppm)做溶剂；LRMS谱在AB Triple 4600型质谱仪上测定，HPLC制备在SHIMADZU LC-20AP型仪器上测定，HPLC纯度在SHIMADZU LC-30AP或Waters 1525型仪器上测定。所有反应未作特别说明均在空气氛围下进行；反应用TLC或LC-MS跟踪。
溶剂及试剂处理如下：
反应所用溶剂DCM、DMF、无水EtOH、无水MeOH等均购自国药集团；
HPLC制备所用的是制备级CH 3CN及去离子水；
除非另有说明，否则下述实施例中所用的起始材料、试剂、各种不同长度碳链链接单元linker(即，用于形成LIN所表示的基团的化合物)、以及其他试剂和药品，如无特别说明，均可从商业途径购买来直接使用，或者可以采用或按照本领域已知的方法合成得到。
通用合成方法
本公开所述的化合物和/或其药学上可接受的盐，可以使用市售原料通过本领域已知的合成技术合成得到。下文描述的合成方案举例说明了大部分化合物的制备方法。各方案中使用的起始原料或试剂均可从商购途径购买得到或者通过本领域技术人员已知的方法制备得到。本领域技术人员可根据本领域常规技术制备本公开式(I)化合物的盐或表1或2的化合物的盐、其外消旋体、对映异构体、磷酸盐、硫酸盐、盐酸盐和前药形式。
与式(I)化合物的R 11-LIN部分对应的中间体的通用制备方法一：
Figure PCTCN2023070102-appb-000042
方案1
与式(I)化合物的R 11-LIN部分对应的中间体的通用制备方法二：
Figure PCTCN2023070102-appb-000043
方案2
参照方案1的方法，制备中间体化合物732180。
Binder中间体化合物的通用制备方法一：
Figure PCTCN2023070102-appb-000044
方案3
Binder中间体化合物的通用制备方法二：
Figure PCTCN2023070102-appb-000045
方案4
Binder中间体化合物的通用制备方法三：
Figure PCTCN2023070102-appb-000046
方案5
Binder中间体化合物的通用制备方法四：
Figure PCTCN2023070102-appb-000047
方案6
式(I)化合物的通用制备方法：
Figure PCTCN2023070102-appb-000048
方案7
在方案7中，POI显示中间体BINDER的反应基团，(R a) t和X如本文式(I)化合物中所定义。
向溴代底物(1.0equiv)的DMF溶液中加入相应的binder中间体化合物(1.0equiv)，DIEA(2.0equiv)。反应混合物在室温下反应2h，反应完全。反应混合物经C18反相柱层析(洗脱剂(v/v)：乙腈/(水+0.05％HCl)＝10％–100％)分离提纯，得到相应的目标产物。
根据目标化合物，上述各方案以及其反应底物、反应条件(包括反应用量、温度、时间等)、后处理等可通过本领域技术人员熟知的技术和方法进行适当修改和调整以获得所需 的目标化合物，并且所得的目标化合物可根据本领域技术人员熟知的方法，进一步通过取代基等进行修饰而获得其他目标化合物。
实施例
中间体实施例1：3-(4-溴-6-(溴甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(732001)的制备
Figure PCTCN2023070102-appb-000049
根据方案1，制备3-(4-溴-6-(溴甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(732001)。
步骤1：
将原料2,5-二甲基-3-溴苯甲酸甲酯(5.0g,20.6mmol)溶于100mL四氯化碳中，依次加入N-溴代琥珀酰亚胺(8.0g,45mmol)和过氧化二苯甲酰(0.31g，1.26mmol)。反应混合物在80℃回流12h，冷却至室温，并用100mL石油醚稀释。稀释所得的混合物用水洗两次，饱和食盐水洗涤一次。有机相分离并合并，经无水硫酸钠干燥，过滤，滤液减压蒸馏除去溶剂。残余物经硅胶柱层析(PE/EA＝1/0-20/1)分离，得到呈白色固体状的化合物363126(6.3g,产率：76％)。
步骤2：
将碳酸铯(16.25g,49.89mmol)加入到500mL 1,2-二氯乙烷和50mL六氟异丙醇的混合溶剂中，所得混合物在65℃搅拌15min，然后依次加入3-氨基-2,6-哌啶二酮盐酸盐(8.21g,49.89mmol)和步骤1所得的化合物363126(20g,49.89mmol)。反应混合物在65℃搅拌12h。趁热过滤反应混合物，以除去不溶物，滤液经饱和食盐水洗涤后，减压蒸馏除去有机溶剂。残留的固体用50mL二氯甲烷和200mL石油醚打浆。所得混合物过滤，过滤的固体用50mL二氯甲烷和50mL乙醚洗涤，得到呈灰色粉末状的产物732001(11g，产率：42％)。 1H NMR(500MHz,Methanol-d 4)δ7.90(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:计算值C 14H 13Br 2N 2O 3 +[M+H] +,414.9；实测值,415.1。
中间体实施例2：3-(5-(溴甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(732180)的制备
Figure PCTCN2023070102-appb-000050
根据方案2，参照方案1的方法制备3-(5-(溴甲基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(732180)。此外方案2的步骤2的起始原料2,4-二(溴甲基)苯甲酸甲酯(CAS号:63112-94-7)也可以通过市售途径购买得到。反应结束后，反应混合物用水洗。有机相分离，并减压蒸馏以除去溶剂。所得残余物经硅胶柱层析(DCM/MeOH＝1/0-10/1)分离，得到的产物用乙腈打浆进一步提纯，得到白色粉末，产率：27％。 1H NMR(500MHz,DMSO-d 6)δ11.00(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:计算值C 14H 14BrN 2O 3 +[M+H] +,337.0；实测值,337.3。
中间体实施例3：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((S)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(732147)和2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-((S)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(732148)的制备
Figure PCTCN2023070102-appb-000051
根据方案4制备2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((S)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(732147)和2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-((S)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(732148)。
步骤1：
向4-氧代环己烷甲腈(1equiv)的甲醇溶液中加入(S)-2-甲基哌嗪-1-甲酸叔丁酯(1.5equiv)和氯化锌(1.5equiv)。所得混合物在室温下搅拌15min，冷却到0℃，然后加入氰基硼氢化钠(3.0equiv)。反应过夜。向反应混合物中加入饱和氯化铵溶液，淬灭反应。所得混合物用二氯甲烷萃取3次，饱和食盐水洗涤一次。分离的有机相经加压蒸馏，除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，得到白色固体状的氰基产物，为顺式产物和反式产物的混合物，产率：80％。
步骤2：
向装有步骤1得到的氰基化合物的甲醇溶液的反应瓶中加入NH 3的甲醇溶液(7M,0.5mL)和雷尼镍。反应瓶用氢气抽换气。反应混合物加热至60℃，常压进行氢化，并反应过夜。将反应液冷却至室温，硅藻土过滤除去雷尼镍，滤液旋蒸干，得到胺的粗产物，直接投入到下一步反应中。
步骤3：
向上一步的胺产物的THF溶液中加入4-氟-3-硝基苯磺酰胺(0.9equiv)和三乙胺(1.5equiv)。反应混合物在室温下搅拌过夜。待反应完全，向反应混合物中加入饱和碳酸氢钠水溶液。所得混合物用二氯甲烷萃取3次。二氯甲烷有机相合并，用饱和食盐水洗涤。有机相分离，并减压蒸馏以除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，成功 分离得到顺式产物(732139)和反式产物(732141)。
顺式产物(732139)：(S)-2-甲基-4-((顺式)-4-(((2-硝基-4-氨基磺酰基苯基)氨基)甲基)环己基)哌嗪-1-甲酸叔丁酯
1H NMR(500MHz,DMSO-d 6)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,2H),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).
反式产物(732141)：(S)-2-甲基-4-((反式)-4-(((2-硝基-4-氨基磺酰基苯基)氨基)甲基)环己基)哌嗪-1-甲酸叔丁酯
1H NMR(500MHz,DMSO-d 6)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).
步骤4：
向2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酸(1equiv；cas:1235865-77-6)的二氯甲烷溶液中加入EDCI(1.5equiv)和DMAP(1.0equiv)。反应体系变澄清。向反应液中加入步骤3得到的顺式产物(732139)或反式产物(732141)。反应12h，原料反应完全。反应液中加入30mL二氯甲烷进行稀释。所得混合物用饱和食盐水洗涤。有机相分离，减压蒸馏以除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，得到Boc保护的产物。
向Boc保护的产物的二氯甲烷溶液中加入三氟乙酸(10equiv)。反应混合物在室温下反应30min。反应完全后，混合物减压蒸馏除去有机溶剂和三氟乙酸。残余物冻干得到呈粉末状的顺式产物(732147)和反式产物(732148)。
顺式产物(732147)：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((S)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺
1H NMR(500MHz,Methanol-d 4)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,1H),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,1H),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,2H),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).
反式产物(732148)：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-((S)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺
1H NMR(500MHz,Methanol-d 4)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,2H),1.45(d,J＝6.5Hz,3H),1.25(ddt,J＝16.2,12.9,6.2Hz,2H),1.00(s,6H).
中间体实施例4：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((R)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(732149)和2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-((R)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(732150)的制备
Figure PCTCN2023070102-appb-000052
根据方案3制备2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((R)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(732149)和2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-((R)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(732150)。
步骤1：
向4-氧代环己烷甲腈(1equiv)的甲醇溶液中加入(R)-2-甲基哌嗪-1-甲酸叔丁酯(1.5equiv)和氯化锌(1.5equiv)。所得混合物在室温下搅拌15min，冷却到0℃，然后加入氰基硼氢化钠(3.0equiv)。反应过夜。向反应混合物中加入饱和氯化铵溶液，淬灭反应。所得混合物用二氯甲烷萃取3次，饱和食盐水洗涤一次。分离的有机相经加压蒸馏，除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，得到白色固体状的氰基产物，为顺式产物和反式产物的混合物，产率：80％。
步骤2：
向装有步骤1得到的氰基化合物的甲醇溶液的反应瓶中加入NH 3的甲醇溶液(7M,0.5 mL)和雷尼镍。反应瓶用氢气抽换气。反应混合物加热至60℃，常压进行氢化，并反应过夜。将反应液冷却至室温，硅藻土过滤除去雷尼镍，滤液旋蒸干，得到胺的粗产物，直接投入到下一步反应中。
步骤3：
向上一步的胺产物的THF溶液中加入4-氟-3-硝基苯磺酰胺(0.9equiv)和三乙胺(1.5equiv)。反应混合物在室温下搅拌过夜。待反应完全，向反应混合物中加入饱和碳酸氢钠水溶液。所得混合物用二氯甲烷萃取3次。二氯甲烷有机相合并，用饱和食盐水洗涤。有机相分离，并减压蒸馏以除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，成功分离得到顺式产物(732140)和反式产物(732142)。
顺式产物(732140)：(R)-2-甲基-4-((顺式)-4-(((2-硝基-4-氨基磺酰基苯基)氨基)甲基)环己基)哌嗪-1-甲酸叔丁酯
1H NMR(500MHz,DMSO-d 6)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,2H),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).
反式产物(732142)：(R)-2-甲基-4-((反式)-4-(((2-硝基-4-氨基磺酰基苯基)氨基)甲基)环己基)哌嗪-1-甲酸叔丁酯
1H NMR(500MHz,DMSO-d 6)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).
步骤4：
向2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酸(1equiv；cas:1235865-77-6)的二氯甲烷溶液中加入EDCI(1.5equiv)和DMAP(1.0equiv)。反应体系变澄清。向反应液中加入步骤3得到的顺式产物(732140)或反式产物(732142)。反应混合物反应12h，原料反应完全。反应液中加入30mL二氯甲烷进行稀释。所得混合物用饱和食盐水洗涤。有机相分离，减压蒸馏以除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，得到Boc保护的产物。
向Boc保护的产物的二氯甲烷溶液中加入三氟乙酸(10equiv)。反应混合物在室温下反应30min。反应完全后，混合物减压蒸馏除去有机溶剂和三氟乙酸。残余物冻干得到呈粉末状的顺式产物(732149)和反式产物(732150)。
顺式产物(732149)：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6- 四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((R)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(732149)
1H NMR(500MHz,Methanol-d 4)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,1H),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,1H),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,2H),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).
反式产物(732150)：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-((R)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(732150)
1H NMR(500MHz,Methanol-d 4)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,2H),1.45(d,J＝6.5Hz,3H),1.25(ddt,J＝16.2,12.9,6.2Hz,2H),1.00(s,6H).
中间体实施例5：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(732185)的制备
Figure PCTCN2023070102-appb-000053
参照方案5制备2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(732185)。
步骤1：
向4-((反式)-4-(氨基甲基)环己基)哌嗪-1-甲酸叔丁酯(1.0equiv；CAS号：2357231-00-4)的THF溶液中加入4-氟-3-三氟甲磺酰基苯磺酰胺(1.0equiv)和三乙胺(1.5equiv)。反应混合物室温下搅拌过夜。待反应完全，向混合物中加入饱和碳酸氢钠水溶液。所得混合物用二氯甲烷萃取3次。二氯甲烷有机相合并，用饱和食盐水洗涤。有机相分离，并减压蒸馏除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，得到白色粉末状的产物4-((反式)-4-(((4-氨基磺酰基-2-((三氟甲基)磺酰基)苯基)氨基)甲基)环己基)哌嗪-1-甲酸叔丁酯 (732181)，产率98％。 1H NMR(500MHz,DMSO-d 6)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).
步骤2：
向2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酸(1equiv；cas:1235865-77-6)的二氯甲烷溶液中加入EDCI(1.5equiv)和DMAP(1.0equiv)。反应体系变澄清。向反应液中加入步骤1得到的产物4-((反式)-4-(((4-氨基磺酰基-2-((三氟甲基)磺酰基)苯基)氨基)甲基)环己基)哌嗪-1-甲酸叔丁酯(732181)。反应混合物反应12h，原料反应完全。向反应液中加入30mL二氯甲烷进行稀释。所得混合物用饱和食盐水洗涤。有机相分离，减压蒸馏以除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，得到Boc保护的产物。
向Boc保护的产物溶于二氯甲烷中的溶液中加入三氟乙酸(10equiv)。反应混合物在室温下反应30min。反应完全后，混合物减压蒸馏除去有机溶剂和三氟乙酸。残余物冻干得到呈粉末状的目标化合物(732185)的三氟乙酸盐。 1H NMR(500MHz,Methanol-d 4)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),3.66(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:计算值C 51H 61ClF 3N 8O 6S 2 +[M+H] +,1037.3791；实测值,1037.3792。
中间体实施例6：4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(732186)的制备
Figure PCTCN2023070102-appb-000054
参照方案5步骤2的方法，制备4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(732186)。
向4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酸(1equiv；CAS号:1044598-91-5)的二氯甲烷溶液中加入EDCI(1.5equiv)和DMAP(1.0equiv)。反应体系变澄清。向反应液中加入根据中间体实施例7的步骤1制备得到的化合物732181。反应混合物反应12h，原料反应完全。向反应液中加入30mL二氯甲烷稀释。所得混合物用 饱和食盐水洗涤。有机相分离，减压蒸馏以除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，得到Boc保护的产物。
向Boc保护的产物溶于二氯甲烷中的溶液中加入三氟乙酸(10equiv)。反应混合物在室温下反应30min。反应完全后，混合物减压蒸馏除去有机溶剂和三氟乙酸。残余物冻干得到呈粉末状的目标化合物(732186)的三氟乙酸盐。
1H NMR(500MHz,DMSO-d 6)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),7.13(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＝5.0Hz,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:计算值C 44H 57ClF 3N 6O 5S 2 +[M+H] +,905.3467；实测值,905.3467。
中间体实施例7：4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-((((反式)-4-(哌嗪-1-基)环己基)甲基)氨基)苯基)磺酰基)苯甲酰胺(732187)的制备
Figure PCTCN2023070102-appb-000055
参照方案6，制备4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-((((反式)-4-(哌嗪-1-基)环己基)甲基)氨基)苯基)磺酰基)苯甲酰胺(732187)。
步骤1：
向4-((反式)-4-(氨基甲基)环己基)哌嗪-1-甲酸叔丁酯(1.0equiv；CAS号：2357231-00-4)溶于THF中的溶液中加入加入4-氟-3-硝基苯磺酰胺(1.0equiv)和三乙胺(1.5equiv)。反应混合物在室温下搅拌过夜。待反应完全，向混合物中加入饱和碳酸氢钠水溶液。所得混合物用二氯甲烷萃取3次。二氯甲烷有机相合并，用饱和食盐水洗涤。有机相分离，并减压蒸馏除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，得到白色粉末状的产物4-((反式)-4-(((2-硝基-4-氨基磺酰基苯基)氨基)甲基)环己基)哌嗪-1-甲酸叔丁酯(732170)，产率95％。 1H NMR(500MHz,DMSO-d 6)δ8.56(t,J＝6.0Hz,1H),8.47(d,J＝2.3Hz,1H),7.81(dd,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).
步骤2：
向4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酸(1equiv；CAS号:1044598-91-5)溶于二氯甲烷中的溶液中加入EDCI(1.5equiv)和DMAP(1.0equiv)。反应体系变澄清。向反应液中加入步骤1制备得到的化合物732170。反应混合物反应 12h，原料反应完全。向反应液中加入30mL二氯甲烷稀释。所得混合物用饱和食盐水洗涤。有机相分离，减压蒸馏以除去溶剂。残余物经柱层析(DCM/MeOH＝1/0-10/1)分离，得到Boc保护的产物。
向Boc保护的产物溶于二氯甲烷中的溶液中加入三氟乙酸(10equiv)。反应混合物在室温下反应30min。反应完全后，混合物减压蒸馏除去有机溶剂和三氟乙酸。残余物冻干得到呈粉末状的目标化合物(732187)的三氟乙酸盐。 1H NMR(500MHz,Methanol-d 4)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:计算值C 43H 57ClN 7O 5S +[M+H] +,818.3825；实测值,818.3822。
实施例1：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((反式)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(BCL-03146)的制备
根据方案7，以中间体化合物2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-((((反式)-4-(哌嗪-1-基)环己基)甲基)氨基)苯基)磺酰基)苯甲酰胺(SIAIS364025；可参考中国专利公开号CN112707900A的中间体BINDER的制备实施例11制备，其内容通过引用方式整体并入本文中)和根据中间体实施例1制备得到的化合物(732001)为原料制备得到目标化合物(BCL-03146)。 1H NMR(500MHz,DMSO-d 6)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),2.41–2.33(m,2H),2.19–2.09(m,2H),2.05–1.97(m,3H),1.95–1.85(m,2H),1.69–1.59(m,1H),1.57–1.39(m,5H),1.32–1.21(m,2H),1.14–1.03(m,2H),0.94(s,6H).HRMS(ESI)m/z:计算值C 64H 72BrClN 11O 9S +[M+H] +,1284.4102；实测值,1284.4100。
实施例2：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(BCL-03147)的制备
根据方案7，以中间体化合物2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-((((反式)-4-(哌嗪-1-基)环己基)甲基)氨基)苯基)磺酰基)苯甲酰胺(SIAIS364025)和根据中间体实施例2制备得到的化合 物(732180)为原料制备得到目标化合物(BCL-03147)。 1H NMR(500MHz,DMSO-d 6)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＝9.3Hz,3H),1.90(d,J＝11.7Hz,2H),1.63(t,J＝11.3Hz,1H),1.49(dd,J＝12.3,3.1Hz,2H),1.44(t,J＝6.5Hz,2H),1.08(q,J＝12.1Hz,2H),0.94(s,6H).HRMS(ESI)m/z:计算值C 64H 73ClN 11O 9S +[M+H] +,1206.4996；实测值,1206.4990。
实施例3：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(BCL-03148)的制备
根据方案7，以中间体化合物2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-((((顺式)-4-(哌嗪-1-基)环己基)甲基)氨基)苯基)磺酰基)苯甲酰胺(SIAIS364043；可参考中国专利公开号CN112707900A的中间体BINDER的制备实施例12制备，其内容通过引用方式整体并入本文中)和中间体化合物(732180)为原料制备得到目标化合物(BCL-03148)。 1H NMR(500MHz,DMSO-d 6)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＝12.7,4.3Hz,1H),2.28(s,2H),2.05–1.97(m,4H),1.85(s,2H),1.78(d,J＝12.7Hz,4H),1.54(d,J＝13.0Hz,2H),1.44(t,J＝6.4Hz,2H),0.94(s,6H).HRMS(ESI)m/z:计算值C 64H 73ClN 11O 9S +[M+H] +,1206.4996；实测值,1206.4992。
实施例4：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((顺式)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(BCL-03149)的制备
根据方案7，以化合物(SIAIS364043)和根据中间体实施例1制备得到的化合物(732001)为原料制备得到目标化合物(BCL-03149)。 1H NMR(500MHz,DMSO-d 6)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:计算值C 64H 72BrClN 11O 9S +[M+H] +,1284.4102；实测值,1284.4105。
实施例5：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((3S)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(BCL-03165)的制备
根据方案7，以根据中间体实施例3制备得到的化合物(732147)和根据中间体实施例2制备得到的化合物(732180)为原料制备得到目标化合物(BCL-03165)。 1H NMR(500MHz,DMSO-d 6)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),6.72(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),3.56(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＝17.1Hz,2H),2.43(dd,J＝13.3,4.9Hz,1H),2.31(t,J＝6.5Hz,2H),2.01(d,J＝2.3Hz,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:计算值C 65H 75ClN 11O 9S +[M+H] +,1220.5153；实测值,1220.5150。
实施例6：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-((3S)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(BCL-03166)的制备
根据方案7，以根据中间体实施例3制备得到的化合物(732148)和中间体化合物(732180)为原料制备得到目标化合物(BCL-03166)。 1H NMR(500MHz,DMSO-d 6)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＝17.3Hz,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＝12.9Hz,2H),1.62(s,1H),1.54–1.40(m,6H),1.07(d,J＝11.4Hz,2H),0.94(s,6H).HRMS(ESI)m/z:计算值C 65H 75ClN 11O 9S +[M+H] +, 1220.5153；实测值,1220.5155。
实施例7：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((3R)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(BCL-03167)的制备
根据方案7，以根据中间体实施例4制备得到的化合物(732149)和中间体化合物(732180)为原料制备得到目标化合物(BCL-03167)。 1H NMR(500MHz,DMSO-d 6)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),6.72(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),3.56(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＝17.1Hz,2H),2.43(dd,J＝13.3,4.9Hz,1H),2.31(t,J＝6.5Hz,2H),2.01(d,J＝2.3Hz,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:计算值C 65H 75ClN 11O 9S +[M+H] +,1220.5153；实测值,1220.5155。
实施例8：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-((3R)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(BCL-03168)的制备
根据方案7，以根据中间体实施例4制备得到的化合物(732150)和中间体化合物(732180)为原料制备得到目标化合物(BCL-03168)。 1H NMR(500MHz,DMSO-d 6)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＝17.3Hz,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＝12.9Hz,2H),1.62(s,1H),1.54–1.40(m,6H),1.07(d,J＝11.4Hz,2H),0.94(s,6H).HRMS(ESI)m/z:计算值C 65H 75ClN 11O 9S +[M+H] +,1220.5153；实测值,1220.5154。
实施例9：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((顺式)-4-((3S)-4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(BCL-03169)的制备
根据方案7，以根据中间体实施例3制备得到的化合物(732147)和中间体化合物(732001)为原料制备得到目标化合物(BCL-03169)。 1H NMR(500MHz,DMSO-d 6)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),3.27(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＝17.2,3.4Hz,1H),2.46(dd,J＝13.2,4.8Hz,1H),2.34(t,J＝6.6Hz,2H),2.07–1.96(m,4H),1.93–1.74(m,6H),1.60–1.48(m,4H),1.44(t,J＝6.5Hz,2H),0.94(s,6H).HRMS(ESI)m/z:计算值C 65H 74BrClN 11O 9S +[M+H] +,1298.4258；实测值,1298.4260。
实施例10：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((反式)-4-((3S)-4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(BCL-03170)的制备
根据方案7，以根据中间体实施例3制备得到的化合物(732148)和中间体化合物(732001)为原料制备得到目标化合物(BCL-03170)。 1H NMR(500MHz,DMSO-d 6)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＝13.1,4.9Hz,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:计算值C 65H 74BrClN 11O 9S +[M+H] +,1298.4258；实测值,1298.4250。
实施例11：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((顺式)-4-((3R)-4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(BCL-03171)的制备
根据方案7，以根据中间体实施例3制备得到的化合物(732149)和中间体化合物(732001)为原料制备得到目标化合物(BCL-03171)。 1H NMR(500MHz,DMSO-d 6)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),3.27(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＝17.2,3.4Hz,1H),2.46(dd,J＝13.2,4.8Hz,1H),2.34(t,J＝6.6Hz,2H),2.07–1.96(m,4H),1.93–1.74(m,6H),1.60–1.48(m,4H),1.44(t,J＝6.5Hz,2H),0.94(s,6H).HRMS(ESI)m/z:计算值C 65H 74BrClN 11O 9S +[M+H] +,1298.4258；实测值,1298.4250。
实施例12：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((反式)-4-((3R)-4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(BCL-03172)的制备
根据方案7，以根据中间体实施例3制备得到的化合物(732150)和中间体化合物(732001)为原料制备得到目标化合物(BCL-03172)。 1H NMR(500MHz,DMSO-d 6)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＝13.1,4.9Hz,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:计算值C 65H 74BrClN 11O 9S +[M+H] +,1298.4258；实测值,1298.4255。
实施例13：4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)-1-(苯基硫基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(BCL-03177)的制备
根据方案7，以中间体化合物(R)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((1-(苯基硫基)-4-(哌嗪-1-基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(SIAIS360129；可参考中国专利公开号CN112707900A的中间体BINDER的制备实施例13制备，其内容通过引用方式整体并入本文中)和中间体化合物(732180)为原料制备得到目标化合物(BCL-03177)。 1H NMR(500MHz,DMSO-d 6)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),4.34(d,J＝17.1Hz,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＝4.6Hz,2H),2.61(dt,J＝ 17.2,4.2Hz,2H),2.48–2.35(m,2H),2.27(t,J＝6.8Hz,2H),2.16(s,3H),2.00(ddt,J＝7.3,5.3,2.7Hz,1H),1.46(t,J＝6.5Hz,2H),1.00(s,6H).HRMS(ESI)m/z:计算值C 61H 69ClF 3N 8O 8S 3 +[M+H] +,1229.4036；实测值,1229.4038。
实施例14：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(BCL-03179)的制备
根据方案7，以根据中间体实施例5制备得到的化合物(732185)和中间体化合物(732180)为原料制备得到目标化合物(BCL-03179)。 1H NMR(500MHz,DMSO-d 6)δ11.81(s,2H),11.74(s,1H),11.03(s,1H),10.66(s,1H),8.17(d,J＝2.6Hz,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＝8.2Hz,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＝13.3,6.5Hz,1H),2.35(s,2H),2.17–2.08(m,2H),2.01(s,3H),1.84(d,J＝11.4Hz,2H),1.65–1.55(m,1H),1.54–1.41(m,4H),1.07(t,J＝11.8Hz,2H),0.94(s,6H).HRMS(ESI)m/z:计算值C 65H 73ClF 3N 10O 9S 2 +[M+H] +,1293.4639；实测值,1293.4635。
实施例15：4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(BCL-03180)的制备
根据方案7，以根据中间体实施例6制备得到的化合物(732186)和中间体化合物(732180)为原料制备得到目标化合物(BCL-03180)。 1H NMR(500MHz,DMSO-d 6)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＝9.6Hz,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),2.62(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:计算值C 58H 69ClF 3N 8O 8S 2 +[M+H] +,1161.4315；实测值,1161.4316。
实施例16：4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(BCL-03181)的制备
根据方案7，以根据中间体实施例7制备得到的化合物(732187)和中间体化合物 (732180)为原料制备得到目标化合物(BCL-03181)。 1H NMR(500MHz,DMSO-d 6)δ12.15(s,1H),11.03(s,1H),10.69(s,1H),8.70(t,J＝6.2Hz,1H),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:计算值C 57H 69ClN 9O 8S +[M+H] +,1074.4673；实测值,1074.4673。
实施例17：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(BCL-03185)的制备
根据方案7，以根据中间体实施例5制备得到的化合物(732185)和中间体化合物5-(溴甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(732195；CAS号1312023-72-5)为原料制备得到目标化合物(BCL-03185)。 1H NMR(500MHz,DMSO-d 6)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),3.34–3.13(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:计算值C 65H 71ClF 3N 10O 10S 2 +[M+H] +,1307.4431；实测值,1307.4430。
实施例18：4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(BCL-03186)的制备
根据方案7，以根据中间体实施例6制备得到的化合物(732186)和中间体化合物5-(溴甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(732195；CAS号1312023-72-5)为原料制备得到目标化合物(BCL-03186)。 1H NMR(500MHz,DMSO-d 6)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:计算值C 58H 67ClF 3N 8O 9S 2 +[M+H] +,1175.4108；实测值,1175.4101。
实施例19：4-(4-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(BCL-03187)的制备
根据方案7，以根据中间体实施例7制备得到的化合物(732187)和中间体化合物5-(溴甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(732195；CAS号1312023-72-5)为原料制备得到目标化合物(BCL-03187)。 1H NMR(500MHz,DMSO-d 6)δ12.13(s,1H),11.15(s,1H),10.26(s,1H),8.70(t,J＝6.1Hz,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＝6.8Hz,2H),2.20–2.03(m,5H),1.90(d,J＝12.2Hz,2H),1.63(qt,J＝10.8,5.8Hz,1H),1.47(t,J＝6.6Hz,4H),1.07(q,J＝12.1,11.1Hz,2H),1.00(s,6H).HRMS(ESI)m/z:计算值C 57H 67ClN 9O 9S +[M+H] +,1088.4465；实测值,1088.4469。
实施例20：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(BCL-03188)的制备
根据方案7，以中间体化合物2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((3-硝基-4-((((反式)-4-(哌嗪-1-基)环己基)甲基)氨基)苯基)磺酰基)苯甲酰胺(SIAIS364025)和中间体化合物5-(溴甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(732195；CAS号1312023-72-5)为原料制备得到目标化合物(BCL-03188)。 1H NMR(500MHz,DMSO-d 6)δ11.76(s,1H),11.70(s,1H),11.16(s,1H),10.52(s,1H),8.64(t,J＝6.1Hz,1H),8.56(d,J＝2.4Hz,1H),8.17(s,1H),8.09–8.04(m,2H),8.00(d,J＝7.6Hz,1H),7.81(dd,J＝9.3,2.6Hz,1H),7.56(d,J＝2.7Hz,1H),7.54–7.49(m,2H),7.39(d,J＝8.4Hz,2H),7.10(dd,J＝9.2,5.3Hz,3H),6.72(dd,J＝9.0,2.4Hz,1H),6.44–6.36(m,1H),6.25(d,J＝2.4Hz,1H),5.18(dd,J＝12.8,5.5Hz,1H),4.35(s,1H),3.63(d,J＝13.9Hz,2H),3.53(d,J＝4.4Hz,5H),3.32–3.06(m,12H),2.90(ddd,J＝16.9,13.7,5.4Hz,1H),2.74(d,J＝5.0Hz,1H),2.70(t,J＝10.9Hz,2H),2.65–2.58(m,1H),2.57–2.53(m,1H),2.33(t,J＝6.6Hz,2H),2.13(d,J＝10.4Hz,2H),2.10–2.04(m,1H),2.01(s,2H),1.90(d,J＝11.6Hz,2H),1.62(dq,J＝8.1,5.5,4.0Hz,1H),1.55–1.42(m,4H),1.07(q,J＝11.5Hz,2H),0.94(s,6H).HRMS(ESI)m/z:计算值 C 64H 71ClN 11O 10S +[M+H] +,1220.4789；实测值,1220.4785。
实施例21：4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)-1-(苯基硫基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(BCL-03189)的制备
根据方案7，以中间体化合物(R)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((1-(苯基硫基)-4-(哌嗪-1-基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(SIAIS360129)和中间体化合物5-(溴甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(732195；CAS号1312023-72-5)为原料制备得到目标化合物(BCL-03189)。 1H NMR(500MHz,DMSO-d 6)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＝9.0Hz,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:计算值C 61H 67ClF 3N 8O 9S 3 +[M+H] +,1243.3828；实测值,1243.3829。
实施例22：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((3S)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺(BCL-03190)的制备
根据方案7，以根据中间体实施例3制备得到的中间体化合物(732147)和中间体化合物5-(溴甲基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(732195；CAS号1312023-72-5)为原料制备得到目标化合物(BCL-03190)。 1H NMR(500MHz,DMSO-d 6)δ11.79(s,1H),11.71(s,1H),11.17(s,1H),10.67(s,1H),8.63(t,J＝6.0Hz,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,2H),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,10H),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),2.65–2.58(m,1H),2.58–2.53(m,1H),2.35(t,J＝6.9Hz,2H),2.09(td,J＝7.6,3.7Hz,1H),2.01(s,3H),1.93–1.74(m,6H),1.66–1.47(m,5H),1.44(t,J＝6.4Hz,2H),0.94(s,6H).HRMS(ESI)m/z:计算值C 65H 73ClN 11O 10S +[M+H] +,1234.4946；实测值,1234.4940。
实施例23：2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((反式)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺 (BCL-03182)的制备
根据方案7，以中间体化合物(732185)和中间体化合物(732001)为原料制备得到目标化合物(BCL-03182)。 1H NMR(500MHz,DMSO-d 6)δ11.82(t,J＝2.4Hz,1H),11.75(s,1H),11.05(s,1H),10.80(s,1H),8.23(s,1H),8.17(d,J＝2.6Hz,1H),8.08(s,1H),8.07(d,J＝2.7Hz,1H),7.93(dd,J＝9.3,2.6Hz,1H),7.60(d,J＝2.7Hz,1H),7.55(t,J＝3.0Hz,1H),7.50(d,J＝8.9Hz,1H),7.39(d,J＝8.4Hz,2H),7.34(t,J＝6.0Hz,1H),7.10(d,J＝8.5Hz,2H),7.08(d,J＝9.8Hz,1H),6.73(dd,J＝9.0,2.4Hz,1H),6.47–6.40(m,1H),6.24(d,J＝2.3Hz,1H),5.16(dd,J＝13.2,5.1Hz,1H),4.50(s,1H),4.46(d,J＝18.0Hz,1H),4.31(d,J＝17.9Hz,1H),3.69–3.57(m,12H),3.29(dd,J＝22.6,11.6Hz,5H),3.22(t,J＝6.3Hz,3H),2.92(ddd,J＝17.4,13.4,5.2Hz,1H),2.69(d,J＝11.7Hz,2H),2.61(d,J＝17.5Hz,1H),2.46(dd,J＝13.1,4.9Hz,1H),2.36(s,2H),2.17–2.10(m,2H),2.02(d,J＝11.0Hz,3H),1.84(d,J＝11.4Hz,2H),1.59(tt,J＝7.8,3.9Hz,1H),1.49(d,J＝12.3Hz,2H),1.43(t,J＝6.4Hz,2H),1.06(d,J＝13.2Hz,2H),0.94(s,6H).HRMS(ESI)m/z:计算值C 65H 72BrClF 3N 10O 9S 2 +[M+H] +,1371.3744；实测值,1371.3740。
实施例24：N-((4-((((反式)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(BCL-03183)的制备
根据方案7，以中间体化合物(732186)和中间体化合物(732001)为原料制备得到目标化合物(BCL-03183)。 1H NMR(500MHz,DMSO-d 6)δ12.18(s,1H),11.04(s,1H),10.68(s,1H),8.22(d,J＝2.6Hz,1H),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),5.16(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(dd,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:计算值C 58H 68BrClF 3N 8O 8S 2 +[M+H] +,1239.3420；实测值,1239.3421。
实施例25：N-((4-((((反式)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(BCL-03184)的制备
根据方案7，以中间体化合物(732187)和中间体化合物(732001)为原料制备得到目标化合物(BCL-03184)。 1H NMR(500MHz,DMSO-d 6)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＝13.0Hz,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),2.17–2.09(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:计算值C 57H 68BrClN 9O 8S +[M+H] +,1152.3778；实测值,1152.3781。
实施例26：N-((4-(((2R)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)-1-(苯基硫基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(BCL-03178)的制备
根据方案7，以中间体化合物(SIAIS360129)和中间体化合物(732001)为原料制备得到目标化合物(BCL-03178)。 1H NMR(500MHz,DMSO-d 6)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＝3.5Hz,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:计算值C 61H 68BrClF 3N 8O 8S 3 +[M+H] +,1307.3141；实测值,1307.3139。
生物活性检测实验
实验试剂和材料
试剂和材料                                            供应商或来源
RPMI 1640培养基                                       HyClone公司
IMDM培养基                                            Gibco公司
DMEM培养基                                            HyClone公司
青霉素和链霉素溶液                                    Gibco公司
G418                                                  Sigma公司
博莱霉素(Zeocin)                                      Invitrogen公司
胎牛血清(FBS)                                         HyClone公司
噻唑蓝(Thiazolyl blue)                                Genview公司
十二烷基硫酸钠(SDS)                                   Genview公司
异丙醇                                                国药集团化学试剂有限公司
盐酸                                                  国药集团化学试剂有限公司
双荧光报告试剂盒(Dual luciferase assay reporter kit)  Promega公司
IP裂解液                                              上海碧云天生物技术有限公司
PMSF                                                  上海碧云天生物技术有限公司
Halt TM蛋白酶和磷酸酶抑制剂                      Thermo Fisher公司
4×LDSβ-巯基乙醇                              Thermo Fisher公司Genview公司
30％聚丙烯酰胺溶液                             北京鼎国昌盛生物技术有限责任公司
0.22μm PVDF膜                                 Millipore公司
氯化钠                                         国药集团化学试剂有限公司
三(羟甲基)氨基甲烷(Tris)                       Genview公司
吐温20(Tween-20)                               北京鼎国昌盛生物技术有限责任公司
SAG                                            Selleck公司
抗体：
实验所使用的BCL-XL抗体购自Abcam公司，Tubulin抗体购自Proteintech公司。
细胞培养
所使用的细胞株RS4；11(人急性淋巴细胞白血病细胞)、Molt-4细胞(人急性淋巴细胞白血病细胞)、MV4；11(人髓性单核细胞白血病细胞)、Light II细胞均可通过市售途径获得或购自ATCC(美国典型培养物保藏中心)，按照ATCC说明常规培养。所使用细胞经过STR细胞鉴定为正确细胞，并通过常规检查为支原体阴性。
体外对肿瘤细胞增殖抑制活性评价
本公开化合物以单浓度或双浓度进行肿瘤细胞生长抑制率初步评价，并进行IC 50测定。
化合物半抑制浓度(IC 50)测定---噻唑蓝(Thiazolyl blue)细胞增殖实验
1)基于ABT199/263的本发明化合物对于BCL-XL依赖性RS4；11细胞增殖研究
Figure PCTCN2023070102-appb-000056
具体步骤如下：RS4；11细胞按3×10 4个/孔接种于90微升含血清的RPMI 1640培养基中，同时，将DT2216和本发明化合物按相应浓度梯度加至细胞悬液中，阳性对照为DT2216，阴性对照为DMSO，阳性对照和阴性对照采用与本发明化合物相同的处理方式处理细胞。本发明化合物处理48小时后，按10微升/孔加入噻唑蓝溶液(5mg/mL)，于37℃，5％CO 2的恒温培养箱中孵育3小时后加入三联液(SDS，0.1g/mL，异丙醇，5％，盐酸，10mM)并继续于37℃，5％CO 2的恒温培养箱中孵育4-6小时。倒置生物显微镜下观察待结晶紫全部溶解后利用Epoch酶标仪(Biotek公司)于490nm处测定吸光度。本发明化合物对实验细胞的生长抑制曲线通过GraphPad Prism 8软件进行绘制并统计得出本发明化合物IC 50。本实验每组三个复孔，至少重复三次。结果如以下表3中所示。
2)基于ABT199/263的本发明化合物对于BCL-XL依赖性MV4；11细胞增殖研究
具体步骤如下：MV4；11细胞按2×10 4个细胞/孔接种于90微升含血清的IMDM培养 基中，同时，将DT2216和本发明化合物按相应浓度梯度加至细胞悬液中，阳性对照为DT2216，阴性对照为DMSO，阳性对照和阴性对照采用与本发明化合物相同的处理方式处理细胞。本发明化合物处理48小时后，按10微升/孔加入噻唑蓝溶液(5mg/mL)，于37℃，5％CO 2的恒温培养箱中孵育3小时后加入三联液(SDS，0.1mg/mL，异丙醇，5％，盐酸，10mM)并继续于37℃，5％CO 2的恒温培养箱中孵育4-6小时。倒置生物显微镜下观察待结晶紫全部溶解后，利用Epoch酶标仪(Biotek公司)于490nm处测定吸光度。本发明化合物对实验细胞的生长抑制曲线通过GraphPad Prism 8软件进行绘制并统计得出本发明化合物IC 50。本实验每组三个复孔，至少重复三次。结果如以下表4中所示。
3)基于ABT199/263的本发明化合物对于BCL-XL依赖性Molt-4细胞增殖研究
具体步骤如下：Molt-4细胞按2×10 4个/孔接种于180微升含血清的RPMI 1640培养基中，同时，将DT2216和本发明化合物按相应浓度梯度加至细胞悬液中，阳性对照为DT2216，阴性对照为DMSO，阳性对照和阴性对照采用与本发明化合物相同的处理方式处理细胞。本发明化合物处理72小时后，按20微升/孔加入噻唑蓝溶液(5mg/mL)，于37℃，5％CO 2的恒温培养箱中孵育3小时后加入三联液(SDS，0.1mg/mL，异丙醇，5％，盐酸，10mM)并继续于37℃，5％CO 2的恒温培养箱中孵育4-6小时。倒置生物显微镜下观察待结晶紫全部溶解后利用Epoch酶标仪(Biotek公司)于490nm处测定吸光度。本发明化合物对实验细胞的生长抑制曲线通过GraphPad Prism 8软件进行绘制并统计得出本发明化合物IC 50。本实验每组三个复孔，至少重复三次。结果如以下表5中所示。
化合物对hedgehog活性抑制IC 50测定---Dual-luciferase reporter assay:
Light II细胞为能稳定表达Gli-luciferase和TK-renilla报告基因的克隆NIH3T3细胞株，采用含10％(v/v)胎牛血清(FBS)的DMEM培养基，同时加入0.4mg/ml G418，0.15mg/ml博莱霉素(Zeocin)，青霉素/链霉素，置于37℃，5％CO 2的恒温培养箱中培养。取对数生长期的Light II细胞按2.5×10 4个/孔接种于96孔板中，孵育24h后加入SAG及不同浓度本发明化合物处理36h后终止反应。按照双荧光报告试剂盒(Dual luciferase reporter assay kit)的说明书进行检测。本实验每组三个复孔，至少重复三次。结果如以下表6中所示。
蛋白质免疫印迹(Western Blot)
取对数生长期的Molt-4细胞按3×10 6个/孔接种至六孔板。同时，加入相应浓度的本发明化合物处理细胞，以溶媒DMSO为对照组。药物作用10小时后，收集细胞，PBS洗一次。将细胞置于冰上，加入含有PMSF蛋白酶抑制剂的IP蛋白裂解液处理细胞。4℃，10k rpm，离心5分钟后，收集上清。将等量蛋白上清液与4×LDS蛋白上样缓冲液按体积比3:1混匀，加入5％β-巯基乙醇，涡旋混匀后，95℃金属浴10分钟，-80℃保存或者直接冰上冷却进行蛋白电泳。分离胶为10％的自制聚丙烯酰胺凝胶。电泳槽及其他相关元件购自伯公乐司(Bio-rad)，电泳条件为低电压80V 45分钟后，换为高电压120V继续电泳1小时。转膜使用PVDF膜，于冰水浴中按等流300毫安进行一小时。转膜后，5％脱脂奶粉室温封闭1小时。随后孵育一抗，4℃过夜或室温2h，1×TBST缓冲液(氯化钠，150mM，Tris，10mM，吐温20，0.1％； PH7.4)洗三次，加入二抗，室温孵育45min，1×TBST缓冲液(氯化钠，150mM，Tris，10mM，吐温20，0.1％；PH7.4)洗三次，显色。抗体稀释比参照抗体说明书。
实验结果
具体实验数据如下所示。
1基于ABT199/263的本发明化合物对于BCL-XL依赖性细胞增殖研究
我们对设计并合成的本发明化合物在RS4；11细胞里进行了剂量依赖性实验。该细胞对BCL-XL的抑制剂高度敏感。化合物以不同浓度(1000nM或100nM起始，10倍稀释梯度，7个浓度)对细胞进行处理48小时后，细胞利用噻唑蓝(THIAZOLYL BLUE)细胞增殖实验进行检测。实验重复3次以上，具体结果见表3所示。
我们设计开发的基于ABT-199/263所开发的本发明化合物(包括表1-2化合物和实施例1-26的化合物)可以很好的抑制RS4；11肿瘤细胞的增殖(表3)。DT2216对RS4；11细胞的IC 50为81.04±24.89nM，我们所开发的本发明化合物的抑制效果均显著优异于DT2216。
表3基于ABT-199/263系列的本发明化合物在RS4；11(人急性淋巴细胞白血病细胞系)中的IC 50(半数抑制浓度)
细胞系 测试化合物 试剂 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
DT2216(CAS号：2365172-42-3)为文献报道的BCL-XL降解剂，其结构式如下：
Figure PCTCN2023070102-appb-000057
我们设计开发的基于ABT-199/263的本发明化合物(包括表1-2化合物和实施例1-26的化合物)可以很好地抑制髓性单核细胞白血病细胞MV4；11的增殖(表4)。DT2216对MV4；11细胞的IC 50为164.9±70.71nM。我们基于ABT199/263所开发的本发明化合物的抑制效果均显著优于DT2216。
表4基于ABT-199/263系列的本发明化合物在髓性单核细胞白血病细胞MV4；11中的IC 50(nM，半数抑制浓度)
细胞系 测试化合物 试剂 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-03177 Thiazolyl blue <20
MV4；11 BCL-03165 Thiazolyl blue <20
MV4；11 BCL-03166 Thiazolyl blue <20
MV4；11 BCL-03167 Thiazolyl blue <20
MV4；11 BCL-03168 Thiazolyl blue <20
MV4；11 BCL-03169 Thiazolyl blue <20
MV4；11 BCL-03179 Thiazolyl blue <20
MV4；11 BCL-03185 Thiazolyl blue <20
MV4；11 BCL-03188 Thiazolyl blue <20
MV4；11 BCL-03189 Thiazolyl blue <20
MV4；11 BCL-03190 Thiazolyl blue <20
MV4；11 BCL-03182 Thiazolyl blue <20
我们设计开发的基于ABT-199/263的本发明化合物(包括表1-2化合物和实施例1-26的化合物)可以很好地抑制人急性淋巴母细胞白血病细胞Molt-4的增殖(表5)。我们基于ABT199/263所开发的本发明化合物的抑制效果明显优于DT2216。
表5基于ABT-199/263系列的本发明化合物在急性淋巴母细胞白血病细胞Molt-4中的IC 50(nM，半数抑制浓度)
细胞系 测试化合物 试剂 IC 50(nM)
Figure PCTCN2023070102-appb-000058
2基于ABT-199/263的本发明化合物抑制Hedgehog(Hh)信号通路活性抑制的IC 50：
我们设计开发的基于ABT-199/263的本发明化合物(包括表1-2化合物和实施例1-26的化合物)进行抑制Hedgehog(Hh)信号通路活性筛选(表6)。我们基于ABT-199/263所开发的本发明化合物的半数抑制浓度IC 50均能达到10nM以下。
表6.基于ABT-199/263系列的本发明化合物在Light II细胞中的IC 50(nM，半数抑制浓度)
细胞系 测试化合物 试剂 IC 50(nM)
LightII BCL-03146 Dual-luciferase assay reporter kit <10
LightII BCL-03147 Dual-luciferase assay reporter kit <10
LightII BCL-03148 Dual-luciferase assay reporter kit <10
LightII BCL-03149 Dual-luciferase assay reporter kit <10
LightII BCL-03165 Dual-luciferase assay reporter kit <10
LightII BCL-03166 Dual-luciferase assay reporter kit <10
LightII BCL-03167 Dual-luciferase assay reporter kit <10
LightII BCL-03168 Dual-luciferase assay reporter kit <10
LightII BCL-03169 Dual-luciferase assay reporter kit <10
LightII BCL-03177 Dual-luciferase assay reporter kit <10
LightII BCL-03189 Dual-luciferase assay reporter kit <10
3基于ABT199/263的本发明化合物可以有效降解Molt-4细胞内BCL-XL的蛋白水平
将Molt-4细胞以每孔3×10 6个细胞的数量接种6孔板。第二天以药物浓度100nM对细胞进行处理，对照组选用溶媒DMSO和DT2216。8小时后收集蛋白样品，采用western blot方法对BCL-XL蛋白表达进行检测。结果表明，使用本发明化合物(包括表1-2化合物和实施例1-26的化合物)后，BCL-XL蛋白表达发生了显著降低，如本发明开发的化合物BCL-03146、BCL-03147、BCL-03148、BCL-03149等在100nM左右的浓度显著降解BCL-XL蛋白(如图1-3所示)。本发明的化合物与DT2216相比，蛋白降解优势明显。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本领域技术人员应了解，本发明不受上述实施例的限制，在不脱离本发明精神和范围的前提下，本发明还可进行各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (30)

  1. 式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物：
    Figure PCTCN2023070102-appb-100001
    其中
    虚线指示可选地存在双键；
    R 1、R 2、R 3、R 4相同或不同且各自独立地表示氢、C 1-4烷基、卤素、或卤代C 1-4烷基；
    (R 5) n表示苯环被n个R 5取代，各R 5相同或不同且各自独立地表示卤素、C 1-6烷基、或卤代C 1-6烷基，n表示整数1、2、3、4或5；
    (R 6) m表示哌嗪环被m个R 6取代，各R 6相同或不同且各自独立地表示卤素、C 1-6烷基、或卤代C 1-6烷基，m表示整数0、1、2、3、4、5、6、7或8；
    R 7表示氢或
    Figure PCTCN2023070102-appb-100002
    R 8表示氢或-SO 2CF 3或-NO 2；
    R 9表示氢或C 1-4烷基；
    R 10表示以下基团：
    Figure PCTCN2023070102-appb-100003
    其中，环W 1表示4元至6元含氮亚杂环基，(R a1) n1表示环W 1被n1个R a1基团取代，各R a1相同或不同且各自独立地为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、氰基、卤素、或氧代基，n1表示0-8的整数；
    环W 2表示4元至6元含氮亚杂环基、或C 3-6亚环烷基，n3表示整数0或1，(R a2) n2表示环W 2被n2个R a2基团取代，各R a2相同或不同且各自独立地为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、氰基、卤素、或氧代基，n2表示0-8的整数；以及
    符号*表示与LIN的连接点；
    LIN表示
    可选取代的直链或支链的C 1-30亚烷基；或
    在其主碳链中插入有一或多个基团R b和/或一或多个基团R c或者一或多个基团R b与R c的任意组合的可选取代的直链或支链C 2-30亚烷基，其中所述基团R b、R c或者基团R b与 R c的组合将所述主碳链的一或多对相邻碳原子之间的碳-碳键间断开；各基团R b选自O、N(R d)、C(O)、C(O)O、S(O)、S(O) 2、S(O) 2NH、NHS(O) 2、OC(O)、C(O)N(R d)、N(R d)C(O)、或N(R d)C(O)N(R d)，其中各R d独立地表示H或C 1-6烷基，以及当所述直链或支链C 2-30亚烷基的主碳链中插入有两个以上基团R b时，各基团R b彼此不直接相连接；各基团R c选自亚环烷基、亚芳基、亚杂环基、亚杂芳基、亚炔基、亚烯基或其任意组合，其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、C 1-6烷氧基、或其任意组合的取代基取代；以及R 11表示以下式(II)的结构式：
    Figure PCTCN2023070102-appb-100004
    其中，R 12表示N(R e)、O、S、C 2-6亚炔基、或C 2-6亚烯基，其中R e表示H或C 1-6烷基，或R 12表示键；
    (R a) t表示苯环被t个R a取代，各R a相同或不同且各自独立地表示溴，t表示整数0、1、2或3；以及
    X表示C(O)或CH 2；
    其中，在t表示整数0的情况下：
    当R 7表示
    Figure PCTCN2023070102-appb-100005
    时，n1表示1-8的整数，且各R a1相同或不同且各自独立地为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、或卤素；或者
    当R 7表示
    Figure PCTCN2023070102-appb-100006
    时，R 8表示-SO 2CF 3。
  2. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其也是式(I-1)化合物：
    Figure PCTCN2023070102-appb-100007
    其中R 1、R 2、R 3、R 4、(R 5) n、(R 6) m、R 7、R 8、R 9、R 10、LIN、R 12、(R a) t和X如权利要求1中所定义。
  3. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其也是式(I-2)或式(I-3)化合物：
    Figure PCTCN2023070102-appb-100008
    其中R 1、R 2、R 3、R 4、(R 5) n、(R 6) m、R 8、R 9、R 10、LIN、R 12、(R a) t和X如权利要求1中所定义。
  4. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中t表示整数1、2或3。
  5. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中t表示整数0。
  6. 如权利要求5所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其也是式(I-2-1)化合物：
    Figure PCTCN2023070102-appb-100009
    其中
    R 10表示以下基团：
    Figure PCTCN2023070102-appb-100010
    其中，环W 1表示4元至6元含氮亚杂环基，(R a1) n1表示环W 1被n1个R a1基团取代，各R a1相同或不同且各自独立地为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、氰基、或卤素，n1表示1-8的整数；
    环W 2表示4元至6元含氮亚杂环基、或C 3-6亚环烷基，n3表示整数0或1，(R a2) n2表示环W 2被n2个R a2基团取代，各R a2相同或不同且各自独立地为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、氰基、卤素、或氧代基，n2表示0-8的整数；以及
    符号*表示与LIN的连接点；以及
    R 1、R 2、R 3、R 4、(R 5) n、(R 6) m、R 8、R 9、LIN、R 12和X如权利要求1中所定义。
  7. 如权利要求6所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中R 10表示以下基团：
    Figure PCTCN2023070102-appb-100011
    其中符号*表示与LIN的连接点。
  8. 如权利要求5所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其也是式(I-2-1)化合物：
    Figure PCTCN2023070102-appb-100012
    其中
    R 8表示-SO 2CF 3；以及
    R 1、R 2、R 3、R 4、(R 5) n、(R 6) m、R 9、R 10、LIN、R 12和X如权利要求1中所定义。
  9. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中R 10表示以下基团：
    Figure PCTCN2023070102-appb-100013
    其中，环W 1表示4元至6元含氮亚杂环基，例如亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、或亚硫代吗啉基；
    (R a1) n1表示环W 1被n1个R a1基团取代，各R a1相同或不同且各自独立地为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、氰基、卤素、或氧代基，n1表示整数0、1、2、3、或4；
    环W 2表示4元至6元含氮亚杂环基、或C 3-6亚环烷基，所述4元至6元含氮亚杂环基包括例如亚哌啶基、亚哌嗪基、亚吗啉基、亚氮杂环丁基、亚吡咯烷基、亚咪唑烷基、亚吡唑烷基、亚噁唑烷基、亚噻唑烷基、或亚硫代吗啉基，所述4元至6元亚环烷基包括例如环丙基、环丁基、环戊基或环己基；
    n3表示整数0或1，(R a2) n2表示环W 2被n2个R a2基团取代，各R a2相同或不同且各自独立地为C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、氰基、卤素、或氧代基，n2表示整数0、1、2、3、或4；以及
    符号*表示与LIN的连接点。
  10. 如权利要求1-5和8-9中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中R 10表示以下基团：
    Figure PCTCN2023070102-appb-100014
    其中符号*表示与LIN的连接点。
  11. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中R 1和R 2表示氢，且R 3和R 4表示甲基。
  12. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中R 1和R 2表示甲基，且R 3和R 4表示氢。
  13. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中R 11表示以下式(II-1)、式(II-2)、式(II-3)、式(II-4)、式(II-5)、式(II-6)、式(II-7)、式(II-8)、式(II-9)、式(II-10)、式(II-11)、或式(II-12)的结构式：
    Figure PCTCN2023070102-appb-100015
    其中
    R 12表示N(R e)、O、S、C 2-6亚炔基、或C 2-6亚烯基，其中R e表示H或C 1-6烷基，或R 12表示键；
    X表示C(O)或CH 2；和
    (R a) t表示苯环被t个R a取代，各R a相同或不同且各自独立地表示溴，和t表示整数0、1、2或3。
  14. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中R 11表示以下式的结构：
    Figure PCTCN2023070102-appb-100016
    Figure PCTCN2023070102-appb-100017
  15. 如权利要求1-14中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中所述LIN表示以下式的结构：
    #-C 1-30亚烷基-；
    #-(C(R a3)(R a4)) n4-(R b-(C(R a5)(R a6)) n5) m1-；
    #-(C(R a3)(R a4)) n4-(R b-(C(R a5)(R a6)) n5) m1-(R b-(C(R a7)(R a8)) n6) m2-；
    #-(C(R a3)(R a4)) n4-(R b-(C(R a5)(R a6)) n5) m1-(R b-(C(R a7)(R a8)) n6) m2-(R b-(C(R a9)(R a10)) n7) m3-；
    #-(C(R a3)(R a4)) n4-(R c-(C(R a5)(R a6)) n5) m1-；
    #-(C(R a3)(R a4)) n4-(R c-(C(R a5)(R a6)) n5) m1-(R c-(C(R a7)(R a8)) n6) m2-；
    #-(C(R a3)(R a4)) n4-(R c-(C(R a5)(R a6)) n5) m1-(R c-(C(R a7)(R a8)) n6) m2-(R c-(C(R a9)(R a10)) n7) m3-；
    #-(C(R a3)(R a4)) n4-(R b-R c-(C(R a5)(R a6)) n5) m1-；
    #-(C(R a3)(R a4)) n4-(R b-(C(R a5)(R a6)) n5) m1-(R c-(C(R a7)(R a8)) n6) m2-；
    #-(C(R a3)(R a4)) n4-(R c-R b-(C(R a5)(R a6)) n5) m1-；或
    #-(C(R a3)(R a4)) n4-(R c-(C(R a5)(R a6)) n5) m1-(R b-(C(R a7)(R a8)) n6) m2-；
    其中，各基团R b选自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)、或N(R d)C(O)N(R d)，其中各R d独立地表示H或C 1-6烷基；各基团R c选自亚环烷基(例如C 3-20亚环烷基)、亚芳基(例如C 3-20亚芳基)、亚杂环基(例如4-至20-元亚杂环基)、亚杂芳基(例如4-至20-元亚杂芳基)、亚炔基(例如C 2-6亚炔基)、亚烯基(例如C 2-6亚烯基)或其任意组合，其中所述亚环烷基、所述亚芳基、所述亚杂环基和所述亚杂芳基彼此独立地可选地进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、C 1-6烷氧基、或其任意组合的取代基取代；
    所述C 1-30亚烷基的一或多个CH 2的氢可选地进一步被选自以下的取代基替代：C 1-6烷基、卤代C 1-6烷基、卤素、C 1-6烷氧基、或其任意组合；
    R a3、R a4、R a5、R a6、R a7、R a8、R a9、和R a10相同或不同且各自独立地表示H、C 1-6烷基、卤代C 1-6烷基、卤素、或C 1-6烷氧基；
    n4、n5、n6、n7、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15；和
    符号#表示与基团R 10的连接点。
  16. 如权利要求1-14中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中所述LIN表示以下式的结构：
    #-(C(R a3)(R a4)) n4-(O-(C(R a5)(R a6)) n5) m1-；
    #-(C(R a3)(R a4)) n4-(O-(C(R a5)(R a6)) n5) m1-(O-(C(R a7)(R a8)) n6) m2-；
    #-(C(R a3)(R a4)) n4-(O-(C(R a5)(R a6)) n5) m1-(O-(C(R a7)(R a8)) n6) m2-(O(C(R a9)(R a10)) n7) m3-；
    #-(C(R a3)(R a4)) n4-(N(R d)-(C(R a5)(R a6)) n5) m1-；
    #-(C(R a3)(R a4)) n4-(N(R d)-(C(R a5)(R a6)) n5) m1-(N(R d)-(C(R a7)(R a8)) n6) m2-；
    #-(C(R a3)(R a4)) n4-(N(R d)-(C(R a5)(R a6)) n5) m1-(N(R d)-(C(R a7)(R a8)) n6) m2-(N(R d)-(C(R a9)(R a10)) n7) m3-；
    #-(C(R a3)(R a4)) n4-(C(O)N(R d)-(C(R a5)(R a6)) n5) m1-；
    #-(C(R a3)(R a4)) n4-(C(O)N(R d)-(C(R a5)(R a6)) n5) m1-(C(O)N(R d)-(C(R a7)(R a8)) n6) m2-；
    #-(C(R a3)(R a4)) n4-(C(O)N(R d)-(C(R a5)(R a6)) n5) m1-(C(O)N(R d)-(C(R a7)(R a8)) n6) m2-(C(O)N(R d)-(C(R a9)(R a10)) n7) m3-；
    #-(C(R a3)(R a4)) n4-(C(O)N(R d)-(C(R a5)(R a6)) n5) m1-(O-(C(R a7)(R a8)) n6) m2-；
    #-(C(R a3)(R a4)) n4-C(O)N(R d)-(C(R a5)(R a6)) n5-(O-(C(R a7)(R a8)) n6) m1-；
    #-(C(R a3)(R a4)) n4-(N(R d)C(O)-(C(R a5)(R a6)) n5) m1-；
    #-(C(R a3)(R a4)) n4-(N(R d)C(O)-(C(R a5)(R a6)) n5) m1-(O-(C(R a7)(R a8)) n6) m2-；
    #-(C(R a3)(R a4)) n4-(N(R d)C(O)-(C(R a5)(R a6)) n5) m1-(O-(C(R a7)(R a8)) n6) m2-(O-(C(R a9)(R a10)) n7) m3-；
    #-(C(R a3)(R a4)) n4-N(R d)C(O)-(C(R a5)(R a6)) n5-(O-(C(R a7)(R a8)) n6) m1-；
    #-(C(R a3)(R a4)) n4-N(R d)C(O)N(R d)-(C(R a5)(R a6)) n5-；
    #-(C(R a3)(R a4)) n4-C(O)-(C(R a5)(R a6)) n5-；
    #-(C(R a3)(R a4)) n4-(亚芳基-(C(R a5)(R a6)) n5) m1-；
    #-(C(R a3)(R a4)) n4-(亚芳基-(C(R a5)(R a6)) n5) m1-亚芳基-(C(R a7)(R a8)) n6-；
    #-(C(R a3)(R a4)) n4-(亚杂环基-(C(R a5)(R a6)) n5) m1-；
    #-(C(R a3)(R a4)) n4-(亚杂环基-(C(R a5)(R a6)) n5) m1-(亚杂环基-(C(R a7)(R a8)) n6) m2-；
    #-(C(R a3)(R a4)) n4-(亚杂芳基-(C(R a5)(R a6)) n5) m1-；
    #-(C(R a3)(R a4)) n4-(亚杂芳基-(C(R a5)(R a6)) n5) m1-(亚杂芳基-(C(R a7)(R a8)) n6) m2-；
    #-(C(R a3)(R a4)) n4-(亚环烷基-(C(R a5)(R a6)) n5) m1-；或
    #-(C(R a3)(R a4)) n4-(亚环烷基-(C(R a5)(R a6)) n5) m1-(亚环烷基-(C(R a7)(R a8)) n6) m2-；
    其中，各R d独立地表示H或C 1-6烷基；
    所述亚环烷基(例如C 3-20亚环烷基)、所述亚芳基(例如C 3-20亚芳基)、所述亚杂环基(例如4-至20-元亚杂环基)和所述亚杂芳基(例如4-至20-元亚杂芳基)彼此独立地可选地进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、C 1-6烷氧基、或其任意组合的取代基取代；
    R a3、R a4、R a5、R a6、R a7、R a8、R a9、和R a10相同或不同且各自独立地表示H、C 1-6烷基、卤代C 1-6烷基、卤素、或C 1-6烷氧基；
    n4、n5、n6、n7、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15；和
    符号#表示与基团R 10的连接点。
  17. 如权利要求1-14中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其中所述LIN表示以下基团：
    #-CH 2-、#-(CH 2) 2-、#-(CH 2) 3-、#-(CH 2) 4-、#-(CH 2) 5-、#-(CH 2) 6-、#-(CH 2) 7-、#-(CH 2) 8-、#-(CH 2) 9-、#-(CH 2) 10-、#-(CH 2) 11-、#-(CH 2) 12-、#-(CH 2) 13-、#-(CH 2) 14-、#-(CH 2) 15-、#-(CH 2) 16-、#-(CH 2) 17-、#-(CH 2) 18-、#-(CH 2) 19-、#-(CH 2) 20-、#-(CH 2) 21-、#-(CH 2) 22-、#-(CH 2) 25-、或#-(CH 2) 30-；#-CH 2-O-CH 2-、#-CH 2-O-(CH 2) 2-、#-(CH 2) 1-O-(CH 2) 3-、#-(CH 2) 1-O-(CH 2) 4-、#-(CH 2) 1-O-(CH 2) 5-、#-(CH 2) 1-O-(CH 2) 6-、#-(CH 2) 1-O-(CH 2) 7-、#-(CH 2) 1-O-(CH 2) 8-、#-(CH 2) 1-O-(CH 2) 9-、#-(CH 2) 1-O-(CH 2) 10-、#-(CH 2) 2-O-(CH 2) 1-、#-(CH 2) 2-O-(CH 2) 2-、#-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 2-O-(CH 2) 4-、#-(CH 2) 2-O-(CH 2) 5-、#-(CH 2) 2-O-(CH 2) 6-、#-(CH 2) 2-O-(CH 2) 7-、#-(CH 2) 2-O-(CH 2) 8-、#-(CH 2) 2-O-(CH 2) 9-、#-(CH 2) 2-O-(CH 2) 10-、#-(CH 2) 2-O-(CH 2) 11-、#-(CH 2) 2-O-(CH 2) 12-、#-(CH 2) 3-O-(CH 2) 1-、#-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 3-O-(CH 2) 3-、#-(CH 2) 3-O-(CH 2) 4-、#-(CH 2) 3-O-(CH 2) 5-、#-(CH 2) 3-O-(CH 2) 6-、#-(CH 2) 3-O-(CH 2) 7-、#-(CH 2) 4-O-(CH 2) 1-、#-(CH 2) 4-O-(CH 2) 2-、#-(CH 2) 4-O-(CH 2) 3-、#-(CH 2) 4-O-(CH 2) 4-、#-(CH 2) 4-O-(CH 2) 5-、#-(CH 2) 4-O-(CH 2) 6-、#-(CH 2) 5-O-(CH 2) 1-、#-(CH 2) 5-O-(CH 2) 2-、#-(CH 2) 5-O-(CH 2) 3-、#-(CH 2) 5-O-(CH 2) 4-、#-(CH 2) 5-O-(CH 2) 5-、#-(CH 2) 6-O-(CH 2) 1-、#-(CH 2) 6-O-(CH 2) 2-、#-(CH 2) 6-O-(CH 2) 3-、#-(CH 2) 6-O-(CH 2) 4-、#-(CH 2) 7-O-(CH 2) 1-、#-(CH 2) 7-O-(CH 2) 2-、#-(CH 2) 7-O-(CH 2) 3-、#-(CH 2) 8-O-(CH 2) 1-、#-(CH 2) 8-O-(CH 2) 2-、#-CH(CH 3)-O-(CH 2) 1-、#-CH(CH 3)-O-(CH 2) 2-、#-CH(CH 3)-O-(CH 2) 3-、#-CH(CH 3)-O-(CH 2) 4-、#-CH(CH 3)-O-(CH 2) 5-、#-CH(CH 3)-O-(CH 2) 6-、#-CH(CH 3)-O-(CH 2) 7-、#-CH(CH 3)-O-(CH 2) 8-、#-CH(CH 3)-O-(CH 2) 9-、#-CH(CH 3)-O-(CH 2) 10-、#-CH 2-(O(CH 2) 2) 2-、#-CH 2-(O(CH 2) 2) 3-、#-CH 2-(O(CH 2) 2) 4-、#-CH 2-(O(CH 2) 2) 5-、#-CH 2-(O(CH 2) 2) 6-、#-CH 2-(O(CH 2) 2) 7-、#-CH 2-(O(CH 2) 2) 8-、#-CH 2-(O(CH 2) 2) 9-、#-CH 2-(O(CH 2) 2) 10-、#-CH 2-(O(CH 2) 2) 1-OCH 2-、#-CH 2-(O(CH 2) 2) 2-OCH 2-、#-CH 2-(O(CH 2) 2) 3-OCH 2-、#-CH 2-(O(CH 2) 2) 4-OCH 2-、#-CH 2-(O(CH 2) 2) 5-OCH 2-、#-CH 2-(O(CH 2) 2) 6-OCH 2-、#-CH 2-(O(CH 2) 2) 7-OCH 2-、#-CH 2-(O(CH 2) 2) 8-OCH 2-、#-CH 2-(O(CH 2) 2) 9-OCH 2-、#-CH 2-(O(CH 2) 2) 10-OCH 2-、#-(CH 2) 2-(O(CH 2) 2) 2-、#-(CH 2) 2-(O(CH 2) 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-、#-(CH 2) 2-(O(CH 2) 2) 5-、#-(CH 2) 2-(O(CH 2) 2) 6-、#-(CH 2) 2-(O(CH 2) 2) 7-、#-(CH 2) 2-(O(CH 2) 2) 8-、#-(CH 2) 2-(O(CH 2) 2) 9-、#-(CH 2) 2-(O(CH 2) 2) 10-、#-(CH 2) 3-(O(CH 2) 2) 2-、#-(CH 2) 3-(O(CH 2) 2) 3-、#-(CH 2) 3-(O(CH 2) 2) 4-、#-(CH 2) 3-(O(CH 2) 2) 5-、#-(CH 2) 3-(O(CH 2) 2) 6-、#-(CH 2) 3-(O(CH 2) 2) 7-、#-(CH 2) 3-(O(CH 2) 2) 8-、#-(CH 2) 3-(O(CH 2) 2) 9-、#-(CH 2) 3-(O(CH 2) 2) 10-、#-(CH 2) 4-(O(CH 2) 2) 2-、#-(CH 2) 4-(O(CH 2) 2) 3-、#-(CH 2) 4-(O(CH 2) 2) 4-、#-(CH 2) 4-(O(CH 2) 2) 5-、#-(CH 2) 4-(O(CH 2) 2) 6-、#-(CH 2) 4-(O(CH 2) 2) 7-、#-(CH 2) 4-(O(CH 2) 2) 8-、#-(CH 2) 4-(O(CH 2) 2) 9-、#-(CH 2) 4-(O(CH 2) 2) 10-、#-CH 2-(O(CH 2) 3) 2-、#-CH 2-(O(CH 2) 3) 3-、#-CH 2-(O(CH 2) 3) 4-、#-CH 2-(O(CH 2) 3) 5-、#-CH 2-(O(CH 2) 3) 6-、#-CH 2-(O(CH 2) 3) 7-、#-CH 2-(O(CH 2) 3) 8-、#-CH 2-(O(CH 2) 3) 9-、#-CH 2-(O(CH 2) 3) 10-、#-(CH 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 2-(O(CH 2) 3) 3-、#-(CH 2) 2-(O(CH 2) 3) 4-、#-(CH 2) 2-(O(CH 2) 3) 5-、#-(CH 2) 2-(O(CH 2) 3) 6-、#-(CH 2) 2-(O(CH 2) 3) 7-、#-(CH 2) 2-(O(CH 2) 3) 8-、#-(CH 2) 2-(O(CH 2) 3) 9-、#-(CH 2) 2-(O(CH 2) 3) 10-、#-(CH 2) 3-(O(CH 2) 3) 2-、#-(CH 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 3- (O(CH 2) 3) 4-、#-(CH 2) 3-(O(CH 2) 3) 5-、#-(CH 2) 3-(O(CH 2) 3) 6-、#-(CH 2) 3-(O(CH 2) 3) 7-、#-(CH 2) 3-(O(CH 2) 3) 8-、#-(CH 2) 3-(O(CH 2) 3) 9-、#-(CH 2) 3-(O(CH 2) 3) 10-、#-CH 2-O-(CH 2) 2-O-(CH 2) 3-、#-CH 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-CH 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-CH 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-CH 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-CH 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-(CH 2) 2-O-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 2-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-(CH 2) 2-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-(CH 2) 2-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-(CH 2) 3-O-(CH 2) 2-O-(CH 2) 3-、#-(CH 2) 3-(O(CH 2) 2) 2-(O(CH 2) 3) 2-、#-(CH 2) 3-(O(CH 2) 2) 3-(O(CH 2) 3) 3-、#-(CH 2) 3-(O(CH 2) 2) 4-(O(CH 2) 3) 4-、#-(CH 2) 3-(O(CH 2) 2) 5-(O(CH 2) 3) 5-、#-(CH 2) 3-(O(CH 2) 2) 6-(O(CH 2) 3) 6-、#-CH 2-O-(CH 2) 3-O-(CH 2) 2-、#-CH 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-CH 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-CH 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-CH 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-CH 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-(CH 2) 2-O-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 2-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-(CH 2) 2-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-(CH 2) 2-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-(CH 2) 2-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-(CH 2) 2-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-(CH 2) 3-O-(CH 2) 3-O-(CH 2) 2-、#-(CH 2) 3-(O(CH 2) 3) 2-(O(CH 2) 2) 2-、#-(CH 2) 3-(O(CH 2) 3) 3-(O(CH 2) 2) 3-、#-(CH 2) 3-(O(CH 2) 3) 4-(O(CH 2) 2) 4-、#-(CH 2) 3-(O(CH 2) 3) 5-(O(CH 2) 2) 5-、#-(CH 2) 3-(O(CH 2) 3) 6-(O(CH 2) 2) 6-、#-CH 2-O-(CH 2) 2-O-CH 2-、#-(CH 2) 2-O-(CH 2) 2-O-CH 2-、#-(CH 2) 2-(O(CH 2) 2) 2-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 3-O-(CH 2) 3-、#-(CH 2) 2-(O(CH 2) 2) 4-O-(CH 2) 3-、#-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 5-、#-(CH 2) 5-(O(CH 2) 2) 2-O-(CH 2) 6-、#-(CH 2) 1-N(R g)-(CH 2) 1-、#-(CH 2) 1-N(R g)-(CH 2) 2-、#-(CH 2) 1-N(R g)-(CH 2) 3-、#-(CH 2) 1-N(R g)-(CH 2) 4-、#-(CH 2) 1-N(R g)-(CH 2) 5-、#-(CH 2) 1-N(R g)-(CH 2) 6-、#-(CH 2) 1-N(R g)-(CH 2) 7-、#-(CH 2) 1-N(R g)-(CH 2) 8-、#-(CH 2) 1-N(R g)-(CH 2) 9-、#-(CH 2) 1-N(R g)-(CH 2) 10-、#-(CH 2) 2-N(R g)-(CH 2) 1-、#-(CH 2) 2-N(R g)-(CH 2) 2-、#-(CH 2) 2-N(R g)-(CH 2) 3-、#-(CH 2) 2-N(R g)-(CH 2) 4-、#-(CH 2) 2-N(R g)-(CH 2) 5-、#-(CH 2) 2-N(R g)-(CH 2) 6-、#-(CH 2) 2-N(R g)-(CH 2) 7-、#-(CH 2) 2-N(R g)-(CH 2) 8-、#-(CH 2) 2-N(R g)-(CH 2) 9-、#-(CH 2) 2-N(R g)-(CH 2) 10-、#-(CH 2) 2-N(R g)-(CH 2) 11-、#-(CH 2) 2-N(R g)-(CH 2) 12-、#-(CH 2) 3-N(R g)-(CH 2) 1-、#-(CH 2) 3-N(R g)-(CH 2) 2-、#-(CH 2) 3-N(R g)-(CH 2) 3-、#-(CH 2) 4-N(R g)-(CH 2) 1-、#-(CH 2) 4-N(R g)-(CH 2) 2-、#-(CH 2) 4-N(R g)-(CH 2) 3-、#-(CH 2) 4-N(R g)-(CH 2) 4-、#-(CH 2) 5-N(R g)-(CH 2) 1-、#-(CH 2) 5-N(R g)-(CH 2) 2-、#-(CH 2) 5-N(R g)-(CH 2) 3-、#-(CH 2) 5-N(R g)-(CH 2) 4-、#-(CH 2) 5-N(R g)-(CH 2) 5-、#-(CH 2) 6-N(R g)-(CH 2) 1-、#-(CH 2) 6-N(R g)-(CH 2) 2-、#-(CH 2) 6-N(R g)-(CH 2) 3-、#-(CH 2) 7-N(R g)-(CH 2) 1-、#-(CH 2) 7-N(R g)-(CH 2) 2-、#-(CH 2) 7-N(R g)-(CH 2) 3-、#-(CH 2) 8-N(R g)-(CH 2) 1-、#-(CH 2) 8-N(R g)-(CH 2) 2-、#-(CH 2) 8-N(R g)-(CH 2) 3-、#-CH(CH 3)-N(R g)-(CH 2) 1-、#-CH(CH 3)-N(R g)-(CH 2) 2-、#-CH(CH 3)-N(R g)-(CH 2) 3-、#-CH(CH 3)-N(R g)-(CH 2) 4-、#-CH(CH 3)-N(R g)-(CH 2) 5-、#-CH(CH 3)-N(R g)-(CH 2) 6-、#-CH(CH 3)-N(R g)-(CH 2) 7-、#-CH(CH 3)-N(R g)-(CH 2) 8-、#-CH(CH 3)-N(R g)-(CH 2) 9-、#-CH(CH 3)-N(R g)-(CH 2) 10-、#-CH 2C(O)NHCH 2-、#-(CH 2) 2C(O)NH(CH 2) 2-、#-(CH 2) 2C(O)NH(CH 2) 3-、#-(CH 2) 2C(O)NH(CH 2) 4-、#-(CH 2) 2C(O)NH(CH 2) 5-、#-(CH 2) 3C(O)NH(CH 2) 3-、#-(CH 2) 3C(O)NH(CH 2) 4-、#-(CH 2) 4C(O)NH(CH 2) 4-、#-(CH 2) 5C(O)NH(CH 2) 5-、#-(CH 2) 6C(O)NH(CH 2) 7-、#-(CH 2) 6C(O)NH(CH 2) 6-、#-(CH 2) 7C(O)NH(CH 2) 7-、#- (CH 2) 8C(O)NH(CH 2) 8、U-(CH 2) 9C(O)NH(CH 2) 9-、#-(CH 2) 10C(O)NH(CH 2) 10-、#-(CH 2) 2C(O)NH(CH 2) 2-O-(CH 2) 2-、#-CH 2NHC(O)CH 2-、#-(CH 2) 2NHC(O)(CH 2) 2-、#-(CH 2) 2NHC(O)(CH 2) 3-、#-(CH 2) 2NHC(O)(CH 2) 4-、#-(CH 2) 2NHC(O)(CH 2) 5-、#-(CH 2) 3NHC(O)(CH 2) 3-、#-(CH 2) 3NHC(O)(CH 2) 4-、#-(CH 2) 4NHC(O)(CH 2) 4-、#-(CH 2) 5NHC(O)(CH 2) 5-、#-(CH 2) 6NHC(O)(CH 2) 7-、#-(CH 2) 6NHC(O)(CH 2) 6-、#-(CH 2) 7NHC(O)(CH 2) 7-、#-(CH 2) 8NHC(O)(CH 2) 8、#-(CH 2) 9NHC(O)(CH 2) 9-、#-(CH 2) 10NHC(O)(CH 2) 10-、#-(CH 2) 4NHC(O)(CH 2) 8-、#-(CH 2) 2NHC(O)(CH 2) 2-O-(CH 2) 2-、#-(CH 2) 4NHC(O)CH 2-、#-CH 2-亚哌啶基-CH 2-、#-CH 2-亚哌啶基-(CH 2) 2-、#-CH 2-亚哌啶基-(CH 2) 3-、#-CH 2-亚哌啶基-(CH 2) 4-、#-CH 2-亚哌啶基-(CH 2) 5-、#-CH 2-亚哌啶基-(CH 2) 6-、#-CH 2-亚哌啶基-(CH 2) 7-、#-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 2-亚哌啶基-(CH 2) 1-、#-(CH 2) 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 3-亚哌啶基-CH 2-、#-(CH 2) 3-亚哌啶基-(CH 2) 2-、#-(CH 2) 3-亚哌啶基-(CH 2) 3-、#-(CH 2) 3-亚哌啶基-(CH 2) 4-、#-(CH 2) 3-亚哌啶基-(CH 2) 5-、#-(CH 2) 3-亚哌啶基-(CH 2) 6-、#-(CH 2) 3-亚哌啶基-(CH 2) 7-、#-(CH 2) 3-亚哌啶基-(CH 2) 8-、#-(CH 2) 4-亚哌啶基-CH 2-、#-(CH 2) 4-亚哌啶基-(CH 2) 2-、#-(CH 2) 4-亚哌啶基-(CH 2) 3-、#-(CH 2) 4-亚哌啶基-(CH 2) 4-、#-(CH 2) 4-亚哌啶基-(CH 2) 5-、#-(CH 2) 4-亚哌啶基-(CH 2) 6-、#-(CH 2) 4-亚哌啶基-(CH 2) 7-、#-(CH 2) 4-亚哌啶基-(CH 2) 8-、#-(CH 2) 5-亚哌啶基-(CH 2) 1-、#-(CH 2) 5-亚哌啶基-(CH 2) 2-、#-(CH 2) 5-亚哌啶基-(CH 2) 3-、#-(CH 2) 5-亚哌啶基-(CH 2) 4-、#-(CH 2) 5-亚哌啶基-(CH 2) 5-、#-(CH 2) 5-亚哌啶基-(CH 2) 6-、#-(CH 2) 5-亚哌啶基-(CH 2) 7-、#-(CH 2) 5-亚哌啶基-(CH 2) 8-、#-(CH 2) 6-亚哌啶基-(CH 2) 1-、#-(CH 2) 6-亚哌啶基-(CH 2) 2-、#-(CH 2) 6-亚哌啶基-(CH 2) 3-、#-(CH 2) 6-亚哌啶基-(CH 2) 4-、#-(CH 2) 6-亚哌啶基-(CH 2) 5-、#-(CH 2) 6-亚哌啶基-(CH 2) 6-、#-(CH 2) 6-亚哌啶基-(CH 2) 7-、#-(CH 2) 6-亚哌啶基-(CH 2) 8-、#-(CH 2) 7-亚哌啶基-(CH 2) 1-、#-(CH 2) 7-亚哌啶基-(CH 2) 2-、#-(CH 2) 7-亚哌啶基-(CH 2) 3-、#-(CH 2) 7-亚哌啶基-(CH 2) 4-、#-(CH 2) 7-亚哌啶基-(CH 2) 8-、#-(CH 2) 8-亚哌啶基-CH 2-、#-(CH 2) 8-亚哌啶基-(CH 2) 2-、#-(CH 2) 8-亚哌啶基-(CH 2) 3-、#-(CH 2) 8-亚哌啶基-(CH 2) 4-、#-(CH 2) 8-亚哌啶基-(CH 2) 5-、#-(CH 2) 8-亚哌啶基-(CH 2) 6-、#-(CH 2) 8-亚哌啶基-(CH 2) 7-、#-(CH 2) 8-亚哌啶基-(CH 2) 8-、#-CH 2-N(R g)-CH 2-亚哌啶基-CH 2-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-CH 2-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-CH 2-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 2-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 3-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 4-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 5-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 6-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 7-、#-CH 2-N(R g)-(CH 2) 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#- (CH 2) 2-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 3-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 4-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 5-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 5-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 6-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 6-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 7-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 7-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-CH 2-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 2-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 3-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 4-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 5-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 6-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 7-、#-(CH 2) 8-N(R g)-CH 2-亚哌啶基-(CH 2) 8-、#-CH 2-亚哌嗪基-CH 2-、#-CH 2-亚哌嗪基-(CH 2) 2-、#-CH 2-亚哌嗪基-(CH 2) 3-、#-CH 2-亚哌嗪基-(CH 2) 4-、#-CH 2-亚哌嗪基-(CH 2) 5-、#-CH 2-亚哌嗪基-(CH 2) 6-、#-CH 2-亚哌嗪基-(CH 2) 7-、#-CH 2-亚哌嗪基-(CH 2) 8-、#-(CH 2) 2-亚哌嗪基-(CH 2) 1-、#-(CH 2) 2-亚哌嗪基-(CH 2) 2-、#-(CH 2) 2-亚哌嗪基-(CH 2) 3-、#-(CH 2) 2-亚哌嗪基-(CH 2) 4-、#-(CH 2) 2-亚哌嗪基-(CH 2) 5-、#-(CH 2) 2-亚哌嗪基-(CH 2) 6-、#-(CH 2) 2-亚哌嗪基-(CH 2) 7-、#-(CH 2) 2-亚哌嗪基-(CH 2) 8-、#-(CH 2) 3-亚哌嗪基-CH 2-、#-(CH 2) 3-亚哌嗪基-(CH 2) 2-、#-(CH 2) 3-亚哌嗪基-(CH 2) 3-、#-(CH 2) 3-亚哌嗪基-(CH 2) 4-、#-(CH 2) 3-亚哌嗪基-(CH 2) 5-、#-(CH 2) 3-亚哌嗪基-(CH 2) 6-、#-(CH 2) 3-亚哌嗪基-(CH 2) 7-、#-(CH 2) 3-亚哌嗪基-(CH 2) 8-、#-(CH 2) 4-亚哌嗪基-CH 2-、#-(CH 2) 4-亚哌嗪基-(CH 2) 2-、#-(CH 2) 4-亚哌嗪基-(CH 2) 3-、#-(CH 2) 4-亚哌嗪基-(CH 2) 4-、#-(CH 2) 4-亚哌嗪基-(CH 2) 5-、#-(CH 2) 4-亚哌嗪基-(CH 2) 6-、#-(CH 2) 4-亚哌嗪基-(CH 2) 7-、#-(CH 2) 4-亚哌嗪基-(CH 2) 8-、#-(CH 2) 5-亚哌嗪基-(CH 2) 1-、#-(CH 2) 5-亚哌嗪基-(CH 2) 2-、#-(CH 2) 5-亚哌嗪基-(CH 2) 3-、#-(CH 2) 5-亚哌嗪基-(CH 2) 4-、#-(CH 2) 5-亚哌嗪基-(CH 2) 5-、#-(CH 2) 5-亚哌嗪基-(CH 2) 6-、#-(CH 2) 5-亚哌嗪基-(CH 2) 7-、#-(CH 2) 5-亚哌嗪基-(CH 2) 8-、#-(CH 2) 6-亚哌嗪基-(CH 2) 1-、#-(CH 2) 6-亚哌嗪基-(CH 2) 2-、#-(CH 2) 6-亚哌嗪基-(CH 2) 3-、#-(CH 2) 6-亚哌嗪基-(CH 2) 4-、#-(CH 2) 6-亚哌嗪基-(CH 2) 5-、#-(CH 2) 6-亚哌嗪基-(CH 2) 6-、#-(CH 2) 6-亚哌嗪基-(CH 2) 7-、#-(CH 2) 6-亚哌嗪基-(CH 2) 8-、#-(CH 2) 7-亚哌嗪基-(CH 2) 1-、#-(CH 2) 7-亚哌嗪基-(CH 2) 2-、#-(CH 2) 7-亚哌嗪基-(CH 2) 3-、#-(CH 2) 7-亚哌嗪基-(CH 2) 4-、#-(CH 2) 7-亚哌嗪基-(CH 2) 8-、#-(CH 2) 8-亚哌嗪基-CH 2-、#-(CH 2) 8-亚哌嗪基-(CH 2) 2-、#-(CH 2) 8-亚哌嗪基-(CH 2) 3-、#-(CH 2) 8-亚哌嗪基-(CH 2) 4-、#-(CH 2) 8-亚哌嗪基-(CH 2) 5-、#-(CH 2) 8-亚哌嗪基-(CH 2) 6-、#-(CH 2) 8-亚哌嗪基-(CH 2) 7-、或#-(CH 2) 8-亚哌嗪基-(CH 2) 8-；
    其中，所述亚哌啶基和所述亚哌嗪基彼此独立地可选地进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、C 1-6烷氧基、或其任意组合的取代基取代；
    各R d独立地表示H或C 1-6烷基；
    符号#表示与基团R 10的连接点；和
    n4、n5、n6、n7、m1、m2、m3分别独立地选自整数1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15。
  18. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富 集类似物、前药或多晶型物，其中其也是式(I-2-2)、式(I-2-3)、式(I-2-4)、式(I-2-5)、式(I-3-1)、式(I-3-2)、式(I-3-3)、或式(I-3-4)的化合物：
    Figure PCTCN2023070102-appb-100018
    Figure PCTCN2023070102-appb-100019
    其中R 9、R 10、LIN、R 12、(R a) t和X如权利要求1中所定义。
  19. 如权利要求1所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，其选自：
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((3S)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-((3S)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((3R)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-((3R)-4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((顺式)-4-((3S)-4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((反式)-4-((3S)-4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((顺式)-4-((3R)-4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((反式)-4-((3R)-4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4- ((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-((3S)-4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)-3-甲基哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((反式)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((顺式)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺；
    4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺；
    4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；
    4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺；
    4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((反式)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺；
    N-((4-((((反式)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺；和
    N-((4-((((反式)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基) 环己基)甲基)氨基)-3-硝基苯基)磺酰基)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺。
  20. 如权利要求1至19中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其是式(I)化合物的盐酸盐、硫酸盐、枸橼酸盐、马来酸盐、甲磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、富马酸盐、磷酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、三氟乙酸盐、羟乙酸盐或对甲苯磺酸盐。
  21. 一种化合物或其盐、对映异构体、立体异构体、溶剂化物、前药或多晶型物，其选自：
    4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)-1-(苯基硫基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺；
    4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)-1-(苯基硫基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((顺式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；
    2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(4-((4'-氯-5,5-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((((反式)-4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)甲基)哌嗪-1-基)环己基)甲基)氨基)-3-硝基苯基)磺酰基)苯甲酰胺；和
    N-((4-(((2R)-4-(4-((7-溴-2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)甲基)哌嗪-1-基)-1-(苯基硫基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺。
  22. 如权利要求21所述的化合物或其盐、对映异构体、立体异构体、溶剂化物、多晶型物，其是所述化合物的盐酸盐、硫酸盐、枸橼酸盐、马来酸盐、磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、富马酸盐、磷酸盐、二氢磷酸盐、焦磷酸盐、偏磷酸盐、草酸盐、丙二酸盐、苯甲酸盐、扁桃酸盐、琥珀酸盐、三氟乙酸盐、羟乙酸盐或对甲苯磺酸盐。
  23. 药物组合物，其包含作为活性成分的如权利要求1至20中任一项所述的式(I)化合物、或其药学上可接受的盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，及至少一种药学上可接受的载体。
  24. 如权利要求23所述的药物组合物，进一步包括至少一种额外的治疗剂，例如抗癌剂。
  25. 药物组合物，其包含作为活性成分的如权利要求21或22所述的化合物或其药学上可接受 的盐、对映异构体、立体异构体、溶剂化物、前药或多晶型物，及至少一种药学上可接受的载体。
  26. 如权利要求25所述的药物组合物，进一步包括至少一种额外的治疗剂，例如抗癌剂。
  27. 一种药盒或试剂盒，其包含：
    如权利要求1至20中任一项所述的式(I)化合物或其药学上可接受的盐或如权利要求23或24所述的药物组合物；或
    如权利要求21或22所述的化合物或其药学上可接受的盐或如权利要求25或26所述的药物组合物。
  28. 如权利要求1至20中任一项所述的式(I)化合物或其盐、对映异构体、立体异构体、溶剂化物、同位素富集类似物、前药或多晶型物，或如权利要求21或22所述的化合物或其盐、对映异构体、立体异构体、溶剂化物、前药或多晶型物用于制备治疗和/或预防选自以下的疾病或病症的药物的用途：神经退行性疾病，包括帕金森病和阿尔兹海默症；心血管疾病，包括冠心病、充血性心力衰竭、心肌梗塞、和动脉粥样硬化症；自身免疫性疾病，包括类风湿性关节炎、自身免疫性脑脊髓炎、强直性脊柱炎、银屑病、系统性红斑狼疮、多发性硬化症、复发性口腔溃疡、川崎病、多发性肌炎/皮肌炎、干燥综合征、和特应性皮炎；骨髓纤维化；肾纤维化；肝纤维化；肝硬化；肿瘤，包括血液系统恶性肿瘤、和实体肿瘤；多器官功能障碍综合征(MODS)，包括恶病质和败血症休克所致的多器官功能衰竭；急性肝功能衰竭；移植排斥反应，包括器官(包括肾、心脏、肺)或组织移植排斥反应；视网膜病变，包括糖尿病黄斑水肿(DME)和湿性老年黄斑变性(wAMD)；和糖尿病。
  29. 如权利要求28所述的用途，其中所述肿瘤包括：骨髓瘤，包括多发性骨髓瘤、浆细胞骨髓瘤、阴燃骨髓瘤、闷烧多发性骨髓瘤；骨髓纤维化；骨髓疾病；骨髓增生异常综合征(MDS)；既往治疗的骨髓增生异常综合征；移植相关的癌症；中性粒细胞减少症；白血病，包括急性髓细胞白血病、慢性粒细胞白血病、慢性淋巴细胞白血病、B细胞慢性淋巴细胞白血病、与白血病相关的贫血、急性髓性白血病(AML)；淋巴瘤，包括弥漫性大B细胞淋巴瘤、非霍奇金淋巴瘤、间变性淋巴瘤、间变性大细胞淋巴瘤、CD20阳性淋巴瘤、套细胞淋巴瘤、原发性淋巴瘤、T细胞淋巴瘤(包括复发或难治性外周T细胞淋巴瘤)、小淋巴细胞淋巴瘤、B细胞淋巴瘤、复发性B细胞非霍奇金淋巴瘤、复发性弥漫性大B细胞淋巴瘤、复发性纵隔(胸腺)大B细胞淋巴瘤、原发性纵隔(胸腺)大B细胞淋巴瘤、复发性转化非霍奇金淋巴瘤、难治性B细胞非霍奇金淋巴瘤、难治性弥漫性大B细胞淋巴瘤、难治性原发性纵隔(胸腺)大B细胞淋巴瘤、难治性转化的非霍奇金淋巴瘤、淋巴浆细胞淋巴瘤、华氏巨球蛋白血症；甲状腺癌；黑色素瘤；肺癌，包括非小细胞肺癌、小细胞肺癌、肺腺癌、和肺鳞癌；炎症性肌纤维母细胞瘤；结直肠癌；脑胶质瘤；星形胶质母细胞瘤；卵巢癌；支气管癌；前列腺癌；乳腺癌，包括雌激素依赖性乳腺癌、HER2阳性乳腺癌、三阴性乳腺癌、偶发性乳腺癌和考登病；胰腺癌；神经母细胞瘤；髓外浆细胞瘤；髓母细胞瘤；浆细胞瘤；胃癌；胃肠道间质瘤；食道癌；大肠腺癌；食管鳞状细胞癌；肝 癌；肾细胞癌；膀胱癌；子宫内膜癌；脑癌；口腔癌；肉瘤，包括横纹肌肉瘤、各种脂肪源性肿瘤、尤文肉瘤/原始神经外胚层瘤(Ewing/PNETs)、及平滑肌肉瘤；软骨肉瘤；尿路上皮癌；基底细胞癌；口腔鳞状细胞癌；胆管癌；骨癌；宫颈癌；和皮肤癌。
  30. 如权利要求28或29所述的用途，其中如权利要求1至20中任一项所述的式(I)化合物或其药学上可接受的盐、或如权利要求21或22所述的化合物或其药学上可接受的盐、或所述的药物组合物被配制成通过至少一种选自鼻腔给药、吸入给药、局部给药、口服给药、口腔粘膜给药、直肠给药、胸膜腔给药、腹膜给药、阴道给药、肌内给药、皮下给药、经皮给药、硬膜外腔给药、鞘内给药和静脉给药的给药方式施用的药物。
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