WO2021078301A1 - Agent de dégradation de protéine et son utilisation dans le traitement de maladies - Google Patents

Agent de dégradation de protéine et son utilisation dans le traitement de maladies Download PDF

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WO2021078301A1
WO2021078301A1 PCT/CN2020/123731 CN2020123731W WO2021078301A1 WO 2021078301 A1 WO2021078301 A1 WO 2021078301A1 CN 2020123731 W CN2020123731 W CN 2020123731W WO 2021078301 A1 WO2021078301 A1 WO 2021078301A1
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methyl
amino
oxy
piperazin
tetrahydro
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Chinese (zh)
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杨小宝
姜标
谭文福
徐中黎
骆佳
王娟
杨君
张绍卿
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上海科技大学
复旦大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present disclosure relates to compounds of formula (I) and formula (II) or their salts, enantiomers, stereoisomers, solvates, polymorphs, and their use in the treatment of diseases.
  • Apoptosis (programmed cell death) is a form in which cells undergo a series of programmed events to cause cell death, eliminate aging, unnecessary or unhealthy cells, and develop and maintain the health of the body. Play a vital role. Apoptosis is considered to be an important part of various processes, including normal cell renewal, immune system development and function, embryonic development and chemically induced cell death (Elmore, S., Toxicol Pathol, 2007.35(4): p. 495-516.). When cell apoptosis is abnormal, the cells that should be eliminated can escape apoptosis and continue to exist, such as cancer and leukemia; when cell apoptosis is excessive, it will kill too many cells and cause serious tissue damage, such as neurodegeneration Sexual diseases.
  • the BCL-2 (B cell lymphoma-2) protein family is a key regulator of programmed cell death or apoptosis. They are mainly located on the mitochondria and regulate the release of cytochrome c. Structurally, the BCL-2 family is characterized by an evolutionarily conserved BCL-2 homology (BH) domain, which is mainly divided into two subgroups, namely anti-apoptotic proteins and pro-apoptotic proteins.
  • BH BCL-2 homology
  • BCL-2 anti-apoptotic proteins such as BCL-2, BCL-XL, MCL-1, BFL-1, BCL-W and BCL2L10, have four conserved regions: BH1, BH2, BH3 and BH4, which promote apoptosis by inhibiting Members to maintain the integrity of the outer mitochondrial membrane (Ivanova, H., et al., Oncotarget, 2016.7(34): p.55704-55720; Chang, BS, et al., Mol Cell Biol, 1999.19(10): p. 6673-81.).
  • Pro-apoptotic proteins are effector proteins with multiple BH domains, such as BAK, BAX and BOK; or a large number of proteins containing only conserved BH3 (BH3-only) domains, such as BIM, PUMA, NOXA, and BID.
  • BCL-2 family protein levels maintain a dynamic balance, and cell signal transduction can affect the dynamic balance process to regulate the expression of pro-apoptotic proteins or anti-apoptotic proteins, thereby tilting the balance toward cell survival or death.
  • the oligomerization of the pro-apoptotic effector protein on the outer mitochondrial membrane leads to permeabilization of the outer mitochondrial membrane and release of cytochrome c, triggers the activation of the caspase enzyme cascade, and cleaves downstream substrates Cause cell death (Opferman, JT and A. Kothari, Cell Death Differ, 2018.25(1): p.37-45.).
  • the anti-apoptotic BCL-2 protein uses the BH3 domain containing the hydrophobic groove to chelate the pro-apoptotic protein BAK/BAX to exert its anti-apoptotic function.
  • BCL-2 family protein antagonists also known as "BH3 domain mimetics" are mainly used to prevent the binding of BH3 domains shared by the anti-apoptotic BCL-2 family proteins to the pro-apoptotic proteins BAX and BAK , Inhibit the effect of BCL-2 anti-apoptotic protein, and then induce tumor cell apoptosis.
  • ABT-199 is the only BCL-2 inhibitor approved by the FDA for the clinical treatment of chronic myeloid leukemia and acute lymphoblastic leukemia (Carter, PJand GALazar, Nat Rev Drug Discov, 2018.17(3): p. 197-223.).
  • BCL-2 protein is effective in many leukemia cells and entities.
  • MCL-1 Myeloid cell leukemia-1
  • Myeloid cell leukemia-1 is one of the key members of the anti-apoptotic protein of the BCL-2 protein family. It is mainly located in the mitochondria of the cell. It is inserted into the mitochondrial membrane through a hydrophobic tail and is a key regulator of mitochondrial homeostasis Factors (Perciavalle, RM and JTOpferman, Trends Cell Biol, 2013.23(1): p.22-9.).
  • the anti-apoptotic function of MCL-1 is essential for cell survival and homeostasis, and for promoting early embryonic development and neuron development and maintenance.
  • breast cancer especially triple-negative breast cancer, is characterized by the amplification ( ⁇ 20%) of the MCL-1 locus (Balko, JM, et al., Cancer Discov, 2014.4(2): p.232-45 .).
  • MCL-1 is an intrinsic and acquired resistance factor, which limits the efficacy of various anti-tumor agents, including paclitaxel, cisplatin, erlotinib and other standard anti-cancer drugs, while down-regulating the expression of MCL-1 can increase
  • the sensitivity of cancer cells to drug therapy Wertz, IE, et al., Nature, 2011.471(7336): p.110-4.; Wei, SH, et al., Cancer Chemother Pharmacol, 2008.62(6): p. 1055-64.
  • knockdown of MCL-1 in neuroblastoma cell lines increases its sensitivity to etoposide, doxorubicin, and ABT-737 by 2-300 times.
  • MCL-1 can reverse the chemoresistance of osteosarcoma cell lines in vitro and xenograft tumors in vivo to cisplatin and adriamycin (Lestini, BJ, et al., Cancer Biol Ther, 2009.8(16): p.1587 -95.).
  • MCL-1 is often overexpressed in human cancers and has been identified as a key to cancer drug resistance in multiple tumor types, making it an attractive therapeutic target. This emphasizes the necessity of developing MCL-1 inhibitors.
  • MCL-1 inhibitors are mainly focused on BH3-mimics. Now several small molecules with high MCL-1 affinity and selectivity have been discovered. However, most MCL-1 inhibitors are still in the pre-clinical or early clinical development stage. Therefore, exploring novel small molecule drugs that can degrade MCL-1 protein has important clinical significance. We use protein degradation targeting drugs (Proteolysis Targeting Drugs).
  • PROTAD technology platform developed MCL-1 protein degradation agent can effectively remove pathogenic proteins and used in the development of anti-tumor drugs (Neklesa, TK, JD Winkler, and CMCrews,. Pharmacol Ther, 2017.174: p.138-144 .; Xiang, W., CYYang, and L. Bai, Onco Targets Ther, 2018.11: p.7301-7314.).
  • Hh Hedgehog
  • the abnormally activated Hedgehog (Hh) signaling pathway is closely related to the occurrence and development of many human tumors, such as basal cell carcinoma, medulloblastoma, etc. (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 form of cascade. Its key molecules include PTCH receptor with 12 transmembrane domains, SMO (Smoothened) receptor with 7 transmembrane structure, SUFU protein and nuclear transcription factor GLI protein. family.
  • PTCH In the absence of exogenous HH ligand, PTCH inhibits SMO activity and the signal pathway is in an inhibited state; when exogenous HH ligand binds to PTCH, the inhibition of SMO is released, and activated SMO promotes the dissociation of inhibitory protein SUFU and GLI, GLI enters the nucleus to initiate 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).
  • the drugs approved by the FDA for the treatment of basal cell carcinoma all target SMO (Cell, 2016.164(5): p.831).
  • an object of the present disclosure is to provide a compound of formula (I):
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • a 2 does not exist or represents a carbonyl group
  • R 2 represents the structural formula of formula (I-1) or formula (I-2):
  • X represents CH 2 or CO
  • R 3 is absent or represents N(R 4 ), S, ethynylene or vinylene
  • R 4 represents H or C 1-3 alkyl
  • LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more selected from oxygen, optionally substituted heterocyclylene, or any combination thereof
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof;
  • a 2 does not exist or represents a carbonyl group
  • R 2 represents the structural formula of formula (I-1) or formula (I-2):
  • R 3 is absent or represents N(R 4 ), and R 4 represents H.
  • R 1 represents:
  • a 1 does not exist or represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group
  • R 2 represents the structural formula of formula (I-1):
  • X represents CH 2 or CO
  • R 3 is absent or represents N(R 4 ), wherein R 4 represents H or C 1-3 alkyl
  • a 2 represents a carbonyl group
  • R 2 represents the structural formula of formula (I-2):
  • Another object of the present disclosure is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • Another object of the present disclosure is to provide the compound of formula (I), or a pharmaceutically acceptable salt thereof, which is used in the preparation for the prevention and/or treatment of BCL-2 family proteins or Hedgehog signaling pathway.
  • Drugs for diseases including but not limited to tumors and non-neoplastic diseases such as liver cirrhosis, renal fibrosis, liver fibrosis, bone marrow fibrosis, etc.:
  • Another object of the present disclosure is to provide the compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament:
  • the compound of formula (I) described in the present disclosure is used for the prevention and/or treatment of diseases related to BCL-2 family proteins or Hedgehog signaling pathway (including but not limited to tumors and diseases).
  • Tumor diseases such as liver cirrhosis, renal fibrosis, liver fibrosis, bone marrow fibrosis, etc.).
  • the tumor is a tumor that depends on BCL-2 family proteins (for example, BCL-2 and/or MCL-1 and/or BCL-XL), or a tumor that depends on the Hedgehog signaling pathway.
  • BCL-2 family proteins for example, BCL-2 and/or MCL-1 and/or BCL-XL
  • Hedgehog signaling pathway for example, BCL-2 and/or MCL-1 and/or BCL-XL
  • the diseases related to BCL-2 family proteins or Hedgehog signaling pathway include tumors and non-neoplastic diseases, including but not limited to myeloma, including multiple myeloma (MM); leukemia, including chronic lymphocytic leukemia (CLL) , Acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML); lymphoma, including non-Hodgkin’s lymphoma, anaplastic large cell lymphoma, diffuse large B cell lymphoma; myelodysplastic syndrome; bone marrow Fibrosis, renal fibrosis, liver fibrosis; breast cancer; lung cancer, including non-small cell lung cancer and small cell lung cancer; melanoma; mesothelioma; neuroblastoma; osteosarcoma; ovarian cancer; prostate cancer; medulloblasts Tumor; Basal cell carcinoma; Goering syndrome; Esophageal cancer; Colorectal cancer; Medulloblastoma;
  • Another object of the present disclosure is to provide a method for preventing and/or treating diseases related to BCL-2 family proteins or Hedgehog signaling pathway, which comprises administering a therapeutically effective amount of the formula (I) to a subject in need thereof
  • the compound, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprises administering a therapeutically effective amount of the formula (I) to a subject in need thereof.
  • an object of the present disclosure is to provide a compound of formula (II):
  • R 12 means:
  • R x means
  • connection point with NH and the symbol ** represents the connection point with A 12
  • n represents an integer of 1-3
  • R b1 , R b2 , R b3 and R b4 are the same or different and are independently H Or oxo group
  • R b5 represents H or C 1-3 alkyl
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist or represents a carbonyl group
  • R 22 represents an optionally substituted adamantyl group, or the structural formula of formula (II-1) or formula (II-2):
  • R c does not exist or represents N(R c1 ), O, S, ethynylene, vinylene, or five- or six-membered heterocyclylene, where R c1 and R c2 are independent of each other ⁇ represents H or C 1-3 alkyl, and R d represents H or methyl;
  • LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 1-15, 1-10, 1- 9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) selected from oxygen, optionally substituted heterocyclylene or any
  • the group consisting of the combination is interrupted, wherein when LIN is not present, one of A 12 and A 22 is not present and the other represents a carbonyl group or both A 12 and A 22 are not present, and R 22 represents optionally A substituted adamantyl group, or R 22 represents the structural formula of formula (II-1), wherein R c does not exist or represents an ethynylene group, a vinylene group, or a five- or six-membered heterocyclylene;
  • R x means The symbol * indicates the connection point with NH, and the symbol ** indicates the connection point with A 12,
  • R 22 represents an optionally substituted adamantyl group, or the structural formula of formula (II-1), wherein X represents CH 2 or CO, and R c represents a five-membered or six-membered heterocyclylene, and R c2 represents H or C 1-3 alkyl, and LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 1- 15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) selected from oxygen, optional substitution
  • the group consisting of the heterocyclylene or any combination thereof is interrupted, wherein in the absence of LIN, one of A 12 and A 22 does not exist and the other represents a carbonyl group or both A 12 and A 22 Does not exist, or
  • R 22 represents the structural formula of formula (II-1) wherein X represents CH 2 or CO.'S, and R c represents O, and R c2 represents H or C 1- 3 alkyl, LIN, and a substituted or unsubstituted straight or Branched alkylene, or
  • R 22 represents the structural formula of formula (II-2), wherein R d represents a methyl group, and A 22 is not present, and LIN represents a substituted or unsubstituted linear or branched alkylene group;
  • R x means
  • R 22 represents an optionally substituted adamantyl group, or the structural formula of formula (II-1), wherein X represents CH 2 or CO, and R c represents a five-membered or six-membered heterocyclylene or O, and R c2 represents H or C 1-3 alkyl, and LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) selected from oxygen, can
  • the group consisting of optionally substituted heterocyclylene or any combination thereof is interrupted, wherein in the absence of LIN, one of A 12 and A 22 does not exist and the other represents a carbonyl group or both A 12 and A 22 Neither is present, and R 22 represents an optionally substituted adamantyl group, or R 22 represents the structural
  • R 22 represents the structural formula of formula (II-1), where X represents CH 2 or CO, and R c represents vinylene or ethynylene, and R c2 represents C 1-3 alkyl, and LIN does not exist or represents substitution Or an unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof Interrupt, or
  • R 22 represents the structural formula of formula (II-2), wherein R d represents a methyl group, and LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (E.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1 A) interrupted by a group selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof.
  • R d represents a methyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (E.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1 A) interrupted by a group selected from the group consisting of oxygen, optionally substituted heterocyclylene or any
  • Another object of the present disclosure is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (II) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • Another object of the present disclosure is to provide the compound of formula (II), or a pharmaceutically acceptable salt thereof, which is used in the preparation for the prevention and/or treatment of BCL-2 family proteins or Hedgehog signaling pathway.
  • Another object of the present disclosure is to provide the compound of formula (II), or a pharmaceutically acceptable salt thereof, for use as a medicament:
  • the compound of formula (II) described in the present disclosure is used to prevent and/or treat diseases related to BCL-2 family proteins or Hedgehog signaling pathway (including tumors and non-neoplastic diseases) , Such as bone marrow fibrosis, renal fibrosis, liver fibrosis, liver cirrhosis, etc.).
  • the tumor is a tumor that depends on the BCL-2 family protein (for example, BCL-2 and/or MCL-1 and/or BCL-XL) oncogene, or a tumor that depends on the Hedgehog signaling pathway.
  • the tumor includes hematological tumors and solid tumors, including but not limited to myeloma, including multiple myeloma (MM); leukemia, including chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML); lymphoma, including non-Hodgkin’s lymphoma, anaplastic large cell lymphoma, diffuse large B cell lymphoma; myelodysplastic syndrome; bone marrow fibrosis, renal fibrosis , Liver fibrosis; breast cancer; lung cancer, including non-small cell lung cancer and small cell lung cancer; melanoma; mesothelioma; neuroblastoma;
  • myeloma
  • Another object of the present disclosure is to provide prevention and/or treatment of diseases related to BCL-2 family proteins or Hedgehog signaling pathway (including tumor and non-neoplastic diseases, such as myelofibrosis, renal fibrosis, liver fibrosis, and cirrhosis).
  • Etc. which comprises administering a therapeutically effective amount of the compound of formula (II), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject in need thereof.
  • Figure 1 is a schematic diagram of the results of Western blotting experiments, which shows that the PROTAD drug of the present invention can significantly degrade MCL-1 protein compared with ABT-199.
  • Figure 2 is a schematic diagram of the results of Western blotting experiments, which shows that the PROTAD drug of the present invention can significantly degrade MCL-1 protein compared with ABT-199.
  • Figure 3 is a schematic diagram of the results of western blot experiments, which show that compounds SAIS361022 and SIAIS361023 can significantly degrade MCL-1 and BCL-XL proteins; SAIS361043, SAIS361044, SAIS361048, and SAIS361049 can significantly degrade BCL-XL proteins.
  • Figure 4 is a schematic diagram of the results of Western blot experiments, which show that compounds SIAIS363021, SIAIS363022, SIAIS363025, SIAIS363026, SIAIS363037, SIAIS363038, SIAIS364048, SIAIS364049, SIAIS364051, SIAIS364056, and SIAIS364057 can significantly degrade BCL-XL.
  • Figure 5 is a schematic diagram of the results of Western blot experiments, which shows that the compounds of the present invention SIAIS346014, SIAIS268027, SIAIS292113, SIAIS255134 can significantly degrade MCL-1 and BCL-XL proteins in Molt-4 cells, MV4; 11 cells, and NIH-3T3 cells .
  • PROTAD Protein degradation targeting drug
  • BCL-2 family proteins Including BCL-2, MCL-1 protein and/or BCL-XL protein
  • PROTAD uses a specially designed bispecific protein regulator to "degrade" the BCL-2 family proteins (including BCL-2, MCL-1 protein and/or BCL-XL protein), and activate the protein degradation inside the cell.
  • the pathway targeted degradation of BCL-2 family proteins including BCL-2, MCL-1 protein and/or BCL-XL protein).
  • the targeted protein modulator small molecule developed by the PROTAD technology platform can induce the degradation of the target protein, and is essentially different from the traditional small molecule inhibitor in the mechanism. Therefore, we use the protein degradation technology platform to develop small molecule degradation agents that can degrade BCL-2 family proteins (including BCL-2, MCL-1 protein and/or BCL-XL protein), and apply them to the treatment of related diseases .
  • BCL-2 family proteins including BCL-2, MCL-1 protein and/or BCL-XL protein
  • a series of compounds designed and synthesized in the present disclosure have a wide range of pharmacological activities, and have the function of degrading BCL-2 family proteins (including BCL-2, MCL-1 protein and/or BCL-XL protein)/inhibiting BCL-2 family proteins (including The function of BCL-2, MCL-1 protein and/or BCL-XL protein) activity can be used in the treatment of related diseases including tumors.
  • one aspect of the present disclosure provides a compound of formula (I) or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof,
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • a 2 does not exist or represents a carbonyl group
  • R 2 represents the structural formula of formula (I-1) or formula (I-2):
  • X represents CH 2 or CO
  • R 3 is absent or represents N(R 4 ), S, ethynylene or vinylene
  • R 4 represents H or C 1-3 alkyl
  • LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 1-15, 1-10, 1- 9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) selected from oxygen, optionally substituted heterocyclylene or any
  • the group consisting of the combination is interrupted, wherein when LIN is not present, one of A 1 and A 2 is not present and the other represents a carbonyl group, and R 2 represents the structural formula of formula (I-1), wherein the R 3 group Represents ethynylene or vinylene;
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof;
  • a 2 does not exist or represents a carbonyl group
  • R 2 represents the structural formula of formula (I-1) or formula (I-2):
  • R 3 is absent or represents N(R 4 ), and R 4 represents H.
  • the alkylene group when LIN represents a substituted or unsubstituted linear or branched alkylene group, the alkylene group is optionally substituted by one or more (e.g., 1-20, 1 -15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) selected from oxygen, optional
  • the group consisting of the substituted heterocyclylene or any combination thereof is interrupted.
  • either one of the two ends of the alkylene group may be connected to the group A 1 , and the other end is connected to the group A 2 .
  • X represents CH 2 or CO
  • R 3 is absent or represents N(R 4 ), S, ethynylene or vinylene
  • R 4 represents H or C 1-3 alkyl.
  • the expression "the alkylene group is interrupted by one or more... groups” means that one or more (for example 1- 10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) groups as defined herein, That is, any one or more pairs of two adjacent carbon atoms in the carbon chain main chain structure of the linear or branched alkylene are covalently connected through the group.
  • the expression "the alkylene group is interrupted by one or more oxygens” means that one or more carbon atoms are interspersed between any two adjacent carbon atoms in the carbon chain main chain structure of the linear or branched alkylene group.
  • the formation contains one or more (e.g. 1-10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1 A) the oxaalkylene group of the "-CH 2 -O-CH 2 -" fragment.
  • the compound of formula (I) further does not include the following compounds (that is, the following compounds are excluded from the scope of the present invention):
  • R 1 represents:
  • a 1 does not exist or represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group
  • R 2 represents the structural formula of formula (I-1):
  • X represents CH 2 or CO
  • R 3 is absent or represents N(R 4 ), wherein R 4 represents H or C 1-3 alkyl
  • a 2 represents a carbonyl group
  • R 2 represents the structural formula of formula (I-2):
  • R 2 represents:
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 2 is not present.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 2 is not present.
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof interrupted; and
  • a 2 represents a carbonyl group.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof interrupted; and
  • a 2 represents a carbonyl group.
  • LIN does not exist
  • one of A 1 and A 2 does not exist and the other represents a carbonyl group
  • R 2 represents the structural formula of formula (I-1) , Wherein the R 3 group represents an ethynylene group or a vinylene group.
  • LIN represents a substituted or unsubstituted linear or branched C 1-30 alkylene group
  • the substituent is selected from a C 1 -C 3 alkyl group , Hydroxy, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g. C 1-6 alkoxy), alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g. C 1-3 haloalkyl, e.g. trifluoromethyl), cyano or any combination thereof, wherein the number of substituents can be one or more (e.g., 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or more (e.g., 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group may Selected by one or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted, wherein the substituents of the C 2-30 alkylene and heterocyclylene are independently Is selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl (e.g.
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkane
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be One or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -,-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -, or -(CR a5 R a6 ) n1 -(O (CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -, where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a7 , R a7 , R a7 , R a7 ,
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino such as C 1-6 alkylamino
  • R a1 , R a2 , R a3 , R a4 , or R a5 , R a6 , R a7 , R a8 , R a9 , and R a10 are not H at the same time;
  • n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents the following substituted or unsubstituted groups:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group may Selected by one or more (e.g.
  • an optionally substituted heterocyclylene especially a five-membered or six-membered heterocyclylene having a heteroatom selected from O, N and S interrupted, wherein the substituent is selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl (for example C 5-14 aryl, especially C 6-10 aryl), alkoxy (for example C 1-6 alkoxy), alkyl Alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g.
  • LIN represents -(CH 2 ) n7 -heterocyclylene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and the heterocyclylene is unsubstituted or It is substituted with a substituent selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano or any combination thereof.
  • heterocyclylene examples include, but are not limited to, azetidinyl, oxetanylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, Imidazolylidene, pyrazolidine, pyrazolylidene, pyridinylene, triazolylidene, tetrahydrofuranylene, furanylene, tetrahydropyranylene, tetrahydrothienylene, thienylene, Tetrahydrothiopyranyl, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazole, Piperidinylene, piperazinylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene,
  • LIN represents -(CH 2 ) n7 -piperidinylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • LIN represents -CH 2 -piperidinylene-CH 2 -, -(CH 2 ) 2 -piperidinylene-CH 2 -,- CH 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-(CH 2 ) 3 -, -(CH 2 ) 3 -piperidinylene -(CH 2 ) 2 -, -(CH 2 ) 3 -piperidinylene -(CH 2 ) 3 -, -(CH 2 ) 3 -piperidinide Ridinyl -(CH 2 ) 4 -, or -(CH 2 ) 4 -piperidinyl-(CH 2 ) 3 -.
  • LIN represents -(CH 2 ) n7 -piperazinylidene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents - (CH 2) 2 - piperazinyl alkylene -CH 2 -, - CH 2 - piperazinyl alkylene -CH 2 -, - CH 2 -piperazinyl-(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-(CH 2 ) 3 -, -(CH 2 ) 3 -piperazinyl -(CH 2 ) 2 -, -(CH 2 ) 3 -piperazinyl -(CH 2 ) 3 -, -(CH 2 ) 3 -piperazine Azinyl-(CH 2 ) 4 -, or -(CH 2 ) 4 -piperazinyl-(CH 2 ) 3 -, or -(CH 2 )
  • LIN represents -(CH 2 ) n7 -triazolylidene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents -CH 2 - triazolyl alkylene -CH 2 -, - CH 2 - triazolyl alkylene - (CH 2) 2 -, - CH 2 -triazolylidene-(CH 2 ) 3 -, -CH 2 -triazolylidene-(CH 2 ) 4 -, -(CH 2 ) 2 -triazolylidene-CH 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 4 -, -(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -, -(CH
  • LIN represents -(CH 2 ) n7 -imidazolylidene-(CH 2 ) n8 -, where n7 and n8 independently represent integers 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents -CH 2 - imidazolyl alkylene -CH 2 -, - CH 2 - imidazolyl alkylene - (CH 2) 2 -, - CH 2 -Imidazolylidene-(CH 2 ) 3 -, -CH 2 -imidazolylidene-(CH 2 ) 4 -, -(CH 2 ) 2 -imidazolylidene-CH 2 -, -(CH 2 ) 2- Imidazolyl -(CH 2 ) 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 4 -, -(CH 2 ) 3 -imidazolylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -imidazolylidene-(CH 2 ) 2
  • LIN represents -(CH 2 ) n7 -pyrazolylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents -CH 2 - pyrazolyl alkylene -CH 2 -, - CH 2 - pyrazol-alkylene group - (CH 2) 2 -, - CH 2 -Pyrazolylene-(CH 2 ) 3 -, -CH 2 -Pyrazolylene-(CH 2 ) 4 -, -(CH 2 ) 2 -Pyrazolylene-CH 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 3 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 4 -, -(CH 2 ) 3 -Pyrazolylene -(CH 2 ) 2 -, -(CH 2 ) 3 -Pyrazolylene-(CH 2 ) 2 -,
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • a 2 does not exist or represents a carbonyl group
  • R 2 represents the structural formula of formula (I-1):
  • X represents CH 2 or CO
  • R 3 represents S, ethynylene or vinylene
  • LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (eg 1-20, 1-15, 1-10, 1- 9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) selected from oxygen, optionally substituted heterocyclylene or any
  • the group consisting of the combination is interrupted, wherein when LIN is not present, one of A 1 and A 2 is not present and the other represents a carbonyl group, and R 2 represents the structural formula of formula (I-1), wherein the R 3 group Represents ethynylene or vinylene.
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 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 selected from the group consisting of oxygen, (having a heteroatom selected from O, N and S) optionally substituted heterocyclylene or any combination thereof interrupted; and A 2 does not exist.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 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 selected from the group consisting of oxygen, (having a heteroatom selected from O, N and S) optionally substituted heterocyclylene or any combination thereof interrupted; and A 2 does not exist.
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 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 selected from the group consisting of oxygen, (having a heteroatom selected from O, N and S) optionally substituted heterocyclylene or any combination thereof; and
  • a 2 represents Carbonyl.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 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 selected from the group consisting of oxygen, (having a heteroatom selected from O, N and S) optionally substituted heterocyclylene or any combination thereof; and A 2 represents Carbonyl.
  • LIN does not exist
  • one of A 1 and A 2 does not exist and the other represents a carbonyl group
  • R 2 represents formula (I-1 ), wherein the R 3 group represents an ethynylene group or a vinylene group.
  • R 2 represents:
  • LIN represents a substituted or unsubstituted linear or branched C 1-30 alkylene group, and the substituent is selected from C 1 -C 3 Alkyl, hydroxyl, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g.
  • C 1-6 alkoxy C 1-6 alkoxy
  • alkylamino For example, C 1-6 alkylamino
  • haloalkyl e.g., C 1-3 haloalkyl, such as trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group
  • the alkyl group is optionally substituted by one or more (e.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1- 3 or 1-2, or 1) interrupted by a group selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof, wherein the substituent is selected from C 1 -C 3 alkyl, hydroxyl, Amino, mercapto, halogen, aryl (e.g.
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 Alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(O (CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -,-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -, or- (CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -, where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7
  • n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group The alkyl group is optionally substituted by one or more (e.g.
  • heterocyclylene especially five-membered or six-membered heterocyclylene having heteroatoms selected from O, N and S interrupt, wherein the substituents are selected from From C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g. C 1-6 alkoxy) ), alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g.
  • LIN represents -(CH 2 ) n1 -heterocyclylene -(CH 2 ) n2 -, wherein n1 and n2 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and the heterocyclylene is not Substituted or substituted by a substituent selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano or any combination thereof .
  • heterocyclylene examples include, but are not limited to, azetidinyl, oxetanylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, Imidazolylidene, pyrazolidine, pyrazolylidene, pyridinylene, triazolylidene, tetrahydrofuranylene, furanylene, tetrahydropyranylene, tetrahydrothienylene, thienylene, Tetrahydrothiopyranyl, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazole, Piperidinylene, piperazinylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene,
  • LIN represents -(CH 2 ) n7 -piperidinylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • LIN represents -CH 2 -piperidinylene-CH 2 -, -(CH 2 ) 2 -piperidinylene-CH 2 -, -CH 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-( CH 2 ) 3 -, -(CH 2 ) 3 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 3 -piperidinylene-(CH 2 ) 3 -, -(CH 2 ) 3 -Piperidinylene-(CH 2 ) 4 -or -(CH 2 ) 4 -piperidinylene-(CH 2 ) 3 -.
  • LIN represents -(CH 2 ) n7 -piperazinylidene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • in the compound of formula (I) in the LIN represents - (CH 2) 2 - piperazinyl alkylene -CH 2 -, - CH 2 - -CH 2 alkylene piperazinyl -, -CH 2 -piperazinyl -(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-( CH 2 ) 3 -, -(CH 2 ) 3 -piperazinylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -piperazinylidene-(CH 2 ) 3 -, -(CH 2 ) 3 -Piperazinyl-(CH 2 ) 4 -, or-(CH 2 ) 4 -Piperazinyl-(CH 2 ) 3 -, or-(CH 2 ) 4 -Piperazinyl
  • LIN represents -(CH 2 ) n7 -triazolylidene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • in the compound of formula (I) in the LIN represents -CH 2 - triazolyl alkylene -CH 2 -, - CH 2 - triazolyl alkylene - (CH 2) 2 -, -CH 2 -triazolylidene -(CH 2 ) 3 -, -CH 2 -triazolylidene -(CH 2 ) 4 -, -(CH 2 ) 2 -triazolylidene -CH 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -triazolylidene- (CH 2 ) 4 -, -(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -,
  • LIN represents -(CH 2 ) n7 -imidazolylidene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • a sub ii) embodiment, in the compound of formula (I) in the LIN represents -CH 2 - imidazolyl alkylene -CH 2 -, - CH 2 - imidazolyl alkylene - (CH 2) 2 -, -CH 2 -imidazolylidene -(CH 2 ) 3 -, -CH 2 -imidazolylidene -(CH 2 ) 4 -, -(CH 2 ) 2 -imidazolylidene -CH 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 4 -,- (CH 2 ) 3 -imidazolylidene-(CH 2 ) 2 -, -(CH 2 ) 3
  • LIN represents -(CH 2 ) n7 -pyrazolylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • in the compound of formula (I) in the LIN represents -CH 2 - pyrazolyl alkylene -CH 2 -, - CH 2 - pyrazol-alkylene group - (CH 2) 2 -, -CH 2 -Pyrazolylene -(CH 2 ) 3 -, -CH 2 -Pyrazolylene -(CH 2 ) 4 -, -(CH 2 ) 2 -Pyrazolylene -CH 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 3 -, -(CH 2 ) 2 -Pyrazolylene- (CH 2 ) 4 -, -(CH 2 ) 3 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 3 -Pyrazolylene-(CH 2 ) 2
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group
  • R 2 represents the structural formula of formula (I-1):
  • X represents CH 2 or CO
  • R 3 is absent or represents N(R 4 ), wherein R 4 represents H or C 1-3 alkyl
  • R 2 represents the structural formula of formula (I-2):
  • R 2 represents the structural formula of formula (I-1), and A 1 does not exist;
  • LIN represents a substituted or unsubstituted linear or branched chain ⁇ alkylene; and A 2 does not exist.
  • R 2 represents the structural formula of formula (I-1), A 1 represents a carbonyl group; LIN represents a substituted or unsubstituted linear or branched chain ⁇ alkylene; and A 2 does not exist.
  • R 2 represents the structural formula of formula (I-1), and A 1 does not exist; LIN represents a substituted or unsubstituted linear or branched chain And A 2 represents a carbonyl group.
  • R 2 represents the structural formula of formula (I-1), A 1 represents a carbonyl group; LIN represents a substituted or unsubstituted linear or branched chain And A 2 represents a carbonyl group.
  • R 2 represents the structural formula of formula (I-2), A 1 does not exist; and A 2 does not exist.
  • R 2 represents the structural formula of formula (I-2), A 1 represents a carbonyl group; and A 2 does not exist.
  • LIN represents a substituted or unsubstituted linear or branched C 1-30 alkylene group, and the substituent is selected from C 1 -C 3 Alkyl, hydroxyl, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g.
  • C 1-6 alkoxy C 1-6 alkoxy
  • alkylamino For example, C 1-6 alkylamino
  • haloalkyl e.g., C 1-3 haloalkyl, such as trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • a 2 does not exist or represents a carbonyl group
  • R 2 represents the structural formula of formula (I-1) or formula (I-2):
  • X represents CH 2 or CO
  • R 3 is absent or represents N(R 4 ), S, ethynylene or vinylene
  • R 4 represents H or C 1-3 alkyl
  • LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (eg 1-20, 1-15, 1-10, 1- 9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) selected from oxygen, optionally substituted heterocyclylene or any
  • the group consisting of the combination is interrupted, wherein when LIN is not present, one of A 1 and A 2 is not present and the other represents a carbonyl group, and R 2 represents the structural formula of formula (I-1), wherein the R 3 group Represents ethynylene or vinylene.
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is One or more (e.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2 , Or 1) oxygen interruption; and
  • a 2 does not exist.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 2 is not present.
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof interrupted; and
  • a 2 represents a carbonyl group.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof interrupted; and
  • a 2 represents a carbonyl group.
  • R 2 represents:
  • LIN represents a substituted or unsubstituted linear or branched C 1-30 alkylene group, and the substituent is selected from C 1 -C 3 Alkyl, hydroxyl, amino, mercapto, halogen, aryl (such as C 5-14 aryl, especially C 6-10 aryl), alkoxy (such as C 1-6 alkoxy), alkylamino (E.g. C 1-6 alkylamino), haloalkyl (e.g.
  • C 1-3 haloalkyl such as trifluoromethyl
  • cyano or any combination thereof, wherein the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or more (e.g., 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group
  • the base is optionally divided by one or more (e.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 Or 1-2, or 1) oxygen interruption, wherein the substituent is selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl (such as C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g.
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, such as trifluoromethyl Group
  • cyano group or any combination thereof can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20).
  • LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(O (CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -,-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -, or -(CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -, where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a6 , R a5 , R a6 , R a6 , R a
  • n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group
  • the alkyl group is optionally substituted by one or more (e.g.
  • heterocyclylene especially five-membered or six-membered heterocyclylene having heteroatoms selected from O, N and S interrupt, wherein the substituents are selected from From C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g. C 1-6 alkoxy) ), alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g.
  • LIN represents -(CH 2 ) n1 -heterocyclylene -(CH 2 ) n2 -, wherein n1 and n2 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and the heterocyclylene is not Substituted or substituted by a substituent selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano or any combination thereof .
  • heterocyclylene examples include, but are not limited to, azetidinyl, oxetanylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, Imidazolylidene, pyrazolidine, pyrazolylidene, pyridinylene, triazolylidene, tetrahydrofuranylene, furanylene, tetrahydropyranylene, tetrahydrothienylene, thienylene, Tetrahydrothiopyranyl, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazole, Piperidinylene, piperazinylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene,
  • LIN represents -(CH 2 ) n7 -piperidinylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • LIN represents -CH 2 -piperidinylene-CH 2 -, -(CH 2 ) 2 -piperidinylene-CH 2 -, -CH 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-( CH 2 ) 3 -, -(CH 2 ) 3 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 3 -piperidinylene-(CH 2 ) 3 -, -(CH 2 ) 3 -Piperidinylene-(CH 2 ) 4 -or -(CH 2 ) 4 -piperidinylene-(CH 2 ) 3 -.
  • LIN represents -(CH 2 ) n7 -piperazinylidene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents - (CH 2) 2 - piperazinyl alkylene -CH 2 -, - CH 2 - -CH 2 alkylene piperazinyl -, -CH 2 -piperazinyl -(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-( CH 2 ) 3 -, -(CH 2 ) 3 -piperazinylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -piperazinylidene-(CH 2 ) 3 -, -(CH 2 ) 3 -Piperazinyl-(CH 2 ) 4 -, or-(CH 2 ) 4 -Piperazinyl-(CH 2 ) 3 -,
  • LIN represents -(CH 2 ) n7 -triazolylidene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents -CH 2 - triazolyl alkylene -CH 2 -, - CH 2 - triazolyl alkylene - (CH 2) 2 -, -CH 2 -triazolylidene -(CH 2 ) 3 -, -CH 2 -triazolylidene -(CH 2 ) 4 -, -(CH 2 ) 2 -triazolylidene -CH 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -triazolylidene- (CH 2 ) 4 -, -(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -,
  • LIN represents -(CH 2 ) n7 -imidazolylidene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents -CH 2 - imidazolyl alkylene -CH 2 -, - CH 2 - imidazolyl alkylene - (CH 2) 2 -, -CH 2 -imidazolylidene -(CH 2 ) 3 -, -CH 2 -imidazolylidene -(CH 2 ) 4 -, -(CH 2 ) 2 -imidazolylidene -CH 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 4 -,- (CH 2 ) 3 -imidazolylidene-(CH 2 ) 2 -,
  • LIN represents -(CH 2 ) n7 -pyrazolylidene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents -CH 2 - pyrazolyl alkylene -CH 2 -, - CH 2 - pyrazol-alkylene group - (CH 2) 2 -, -CH 2 -Pyrazolylene -(CH 2 ) 3 -, -CH 2 -Pyrazolylene -(CH 2 ) 4 -, -(CH 2 ) 2 -Pyrazolylene -CH 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 3 -, -(CH 2 ) 2 -Pyrazolylene- (CH 2 ) 4 -, -(CH 2 ) 3 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 4 -, -(CH 2 ) 3 -Pyraz
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • R 2 represents the structural formula of formula (I-1):
  • X represents CH 2 or CO
  • R 3 represents S, ethynylene or vinylene
  • LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more selected from oxygen, optionally substituted heterocyclylene, or any combination thereof
  • the groups of the composition group are interrupted, where when LIN is not present, one of A 1 and A 2 is not present and the other represents a carbonyl group, and the R 3 group represents an ethynylene group or a vinylene group.
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1 -2, or 1) the group selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 2 is not present.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1 -2, or 1) the group selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 2 is not present.
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and
  • a 2 represents a carbonyl group.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and
  • a 2 represents a carbonyl group.
  • LIN is absent, one of A 1 and A 2 is absent and the other represents a carbonyl group, and the R 3 group represents an ethynylene group Or vinylidene.
  • R 2 represents:
  • LIN represents a substituted or unsubstituted linear or branched C 1-30 alkylene group, and the substituent is selected from C 1 -C 3 Alkyl, hydroxyl, amino, mercapto, halogen, aryl (such as C 5-14 aryl, especially C 6-10 aryl), alkoxy (such as C 1-6 alkoxy), alkylamino (E.g. C 1-6 alkylamino), haloalkyl (e.g.
  • C 1-3 haloalkyl such as trifluoromethyl
  • cyano or any combination thereof, wherein the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or more (e.g., 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group
  • the alkyl group is optionally substituted by one or more (e.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1- 3 or 1-2, or 1) interrupted by a group selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof, wherein the substituent is selected from C 1 -C 3 alkyl, hydroxyl, Amino, mercapto, halogen, aryl (e.g.
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 Alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(O (CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -,-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -, or -(CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -, where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7
  • n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents the following substituted or unsubstituted groups:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group The alkyl group is optionally substituted by one or more (e.g.
  • heterocyclylene especially five-membered or six-membered heterocyclylene having heteroatoms selected from O, N and S interrupt, wherein the substituents are selected from From C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g. C 1-6 alkoxy) ), alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g.
  • LIN represents -(CH 2 ) n1 -heterocyclylene -(CH 2 ) n2 -, wherein n1 and n2 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and the heterocyclylene is not Substituted or substituted by a substituent selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano or any combination thereof .
  • heterocyclylene examples include, but are not limited to, azetidinyl, oxetanylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, Imidazolylidene, pyrazolidine, pyrazolylidene, pyridinylene, triazolylidene, tetrahydrofuranylene, furanylene, tetrahydropyranylene, tetrahydrothienylene, thienylene, Tetrahydrothiopyranyl, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazole, Piperidinylene, piperazinylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene,
  • LIN represents -(CH 2 ) n7 -piperidinylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • LIN represents -CH 2 -piperidinylene-CH 2 -, -(CH 2 ) 2 -piperidinylene-CH 2 -, -CH 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-( CH 2 ) 3 -, -(CH 2 ) 3 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 3 -piperidinylene-(CH 2 ) 3 -, -(CH 2 ) 3 -Piperidinylene-(CH 2 ) 4 -or -(CH 2 ) 4 -piperidinylene-(CH 2 ) 3 -.
  • LIN represents -(CH 2 ) n7 -piperazinylidene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents - (CH 2) 2 - piperazinyl alkylene -CH 2 -, - CH 2 - -CH 2 alkylene piperazinyl -, -CH 2 -piperazinyl -(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-( CH 2 ) 3 -, -(CH 2 ) 3 -piperazinylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -piperazinylidene-(CH 2 ) 3 -, -(CH 2 ) 3 -Piperazinyl-(CH 2 ) 4 -, or-(CH 2 ) 4 -Piperazinyl-(CH 2 ) 3 -, or
  • LIN represents -(CH 2 ) n7 -triazolylidene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents -CH 2 - triazolyl alkylene -CH 2 -, - CH 2 - triazolyl alkylene - (CH 2) 2 -, -CH 2 -triazolylidene -(CH 2 ) 3 -, -CH 2 -triazolylidene -(CH 2 ) 4 -, -(CH 2 ) 2 -triazolylidene -CH 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -triazolylidene- (CH 2 ) 4 -, -(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -,
  • LIN represents -(CH 2 ) n7 -imidazolylidene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents -CH 2 - imidazolyl alkylene -CH 2 -, - CH 2 - imidazolyl alkylene - (CH 2) 2 -, -CH 2 -imidazolylidene-(CH 2 ) 3 -, -CH 2 -imidazolylidene-(CH 2 ) 4 -, -(CH 2 ) 2 -imidazolylidene-CH 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 4 -,- (CH 2 ) 3 -imidazolylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -imidazolylidene-(CH 2
  • LIN represents -(CH 2 ) n7 -pyrazolylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound of formula (I) in the LIN represents -CH 2 - pyrazolyl alkylene -CH 2 -, - CH 2 - pyrazol-alkylene group - (CH 2) 2 -, -CH 2 -Pyrazolylene -(CH 2 ) 3 -, -CH 2 -Pyrazolylene -(CH 2 ) 4 -, -(CH 2 ) 2 -Pyrazolylene -CH 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 3 -, -(CH 2 ) 2 -Pyrazolylene- (CH 2 ) 4 -, -(CH 2 ) 3 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 4 -, -(CH 2 ) 3 -Pyraz
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • R 2 represents the structural formula of formula (I-2)
  • LIN represents a substituted or unsubstituted linear or branched alkylene group.
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group; and
  • a 2 is absent.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group
  • a 2 does not exist.
  • LIN represents a substituted or unsubstituted linear or branched C 1-30 alkylene group, and the substituent is selected from C 1 -C 3 Alkyl, hydroxyl, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g. C 1-6 alkoxy), alkylamino ( For example, C 1-6 alkylamino), haloalkyl (e.g.
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • a 2 does not exist or represents a carbonyl group
  • R 2 represents the structural formula of formula (I-1) or formula (I-2):
  • X represents CH 2 or CO
  • R 3 is absent or represents N(R 4 ), S, ethynylene or vinylene
  • R 4 represents H or C 1-3 alkyl
  • LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more selected from oxygen, optionally substituted heterocyclylene, or any combination thereof
  • R 2 represents:
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Is optionally interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene, or any combination thereof; and
  • a 2 is not present.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Is optionally interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene, or any combination thereof
  • a 2 is not present.
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Optionally interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof; and
  • a 2 represents a carbonyl group.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Optionally interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof
  • a 2 represents a carbonyl group.
  • LIN is absent, one of A 1 and A 2 is absent and the other represents a carbonyl group, and R 2 represents formula (I-1 ), wherein the R 3 group represents an ethynylene group or a vinylene group.
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, and preferably represents a substituted or unsubstituted linear or branched alkylene group.
  • C 1-3 haloalkyl e.g. trifluoromethyl
  • cyano e.g. trifluoromethyl
  • the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20).
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g., C 1-3 haloalkyl, such as trifluoromethyl
  • cyano or any combination thereof.
  • the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group
  • the group is optionally interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof, wherein the substituent is selected from C 1 -C 3 alkyl, hydroxyl, amino, Mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g. C 1-6 alkoxy), alkylamino (e.g.
  • C 1-6 alkyl Amino e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20).
  • LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(O (CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -,-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -, or -(CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -, where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7
  • n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1- 6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group
  • the group is optionally interrupted by one or more optionally substituted heterocyclylenes (especially five- or six-membered heterocyclylenes) having heteroatoms selected from O, N and S, wherein the substituents are selected from From C 1 -C 3 alkyl, hydroxyl, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g.
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or Multiple (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents -(CH 2 ) n1 -heterocyclylene -(CH 2 ) n2 -, wherein n1 and n2 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and the heterocyclylene is not Substituted or substituted with a substituent selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano or any combination thereof .
  • the heterocyclylene is azetidinyl, oxetanylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, imidazolylidene, Pyrazolidinyl, pyrazolylidene, pyridinylene, triazolylidene, tetrahydrofuranyl, furanylene, tetrahydropyranyl, tetrahydrothienyl, thienylene, tetrahydrothiopyran Group, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazolyl, piperidinylene, Piperazinylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, morpholinylene,
  • LIN represents -(CH 2 ) n7 -piperidinylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • LIN represents -CH 2 -piperidinylene-CH 2 -, -(CH 2 ) 2 -piperidinylene-CH 2 -, -CH 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-( CH 2 ) 3 -, -(CH 2 ) 3 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 3 -piperidinylene-(CH 2 ) 3 -, -(CH 2 ) 3 -Piperidinylene-(CH 2 ) 4 -or -(CH 2 ) 4 -Piperidinylene-(CH 2 ) 3 -.
  • LIN represents -(CH 2 ) n7 -piperazinylidene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the LIN represents - (CH 2) 2 - piperazinyl alkylene -CH 2 -, - CH 2 - -CH 2 alkylene piperazinyl -, -CH 2 -piperazinyl -(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-( CH 2 ) 3 -, -(CH 2 ) 3 -piperazinylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -piperazinylidene-(CH 2 ) 3 -, -(CH 2 ) 3 -Piperazinyl-(CH 2 ) 4 -, or-(CH 2 ) 4 -Piperazinyl-(CH 2 ) 3 -, or
  • LIN represents -(CH 2 ) n7 -triazolylidene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • a sub-embodiment of embodiment, in the compound of formula (I) in the LIN represents -CH 2 - triazolyl alkylene -CH 2 -, - CH 2 - triazolyl alkylene - (CH 2) 2 -, -CH 2 -triazolylidene -(CH 2 ) 3 -, -CH 2 -triazolylidene -(CH 2 ) 4 -, -(CH 2 ) 2 -triazolylidene -CH 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -triazolylidene- (CH 2 ) 4 -, -(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -triazolylid
  • LIN represents -(CH 2 ) n7 -imidazolylidene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • a sub vii) in the embodiment, in the compound of formula (I) in the LIN represents -CH 2 - imidazolyl alkylene -CH 2 -, - CH 2 - imidazolyl alkylene - (CH 2) 2 -, -CH 2 -imidazolylidene -(CH 2 ) 3 -, -CH 2 -imidazolylidene -(CH 2 ) 4 -, -(CH 2 ) 2 -imidazolylidene -CH 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 4 -,- (CH 2 ) 3 -imidazolylidene-(CH 2 ) 2 -, -(CH 2 ) 3
  • LIN represents -(CH 2 ) n7 -pyrazolylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • a sub-embodiment of embodiment, in the compound of formula (I) in the LIN represents -CH 2 - pyrazolyl alkylene -CH 2 -, - CH 2 - pyrazol-alkylene group - (CH 2) 2 -, -CH 2 -Pyrazolylene -(CH 2 ) 3 -, -CH 2 -Pyrazolylene -(CH 2 ) 4 -, -(CH 2 ) 2 -Pyrazolylene -CH 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 3 -, -(CH 2 ) 2 -Pyrazolylene- (CH 2 ) 4 -, -(CH 2 ) 3 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 4 -,
  • R 1 represents:
  • R 2 means:
  • a 1 , LIN, A 2 , X and R 3 are as defined in vii) above and include all sub-embodiments thereof.
  • R 1 represents:
  • R 2 means:
  • a 1 , LIN, A 2 , X and R 3 are as defined in vii) above and include all sub-embodiments thereof.
  • R 1 represents:
  • R 2 means:
  • a 1 , LIN, A 2 , X and R 3 are as defined in vii) above and include all sub-embodiments thereof.
  • R 1 represents:
  • R 2 means:
  • a 1 , LIN, A 2 , X and R 3 are as defined in vii) above and include all sub-embodiments thereof.
  • R 1 means:
  • a 1 does not exist or represents a carbonyl group
  • a 2 does not exist or represents a carbonyl group
  • R 2 represents the structural formula of formula (I-1) or formula (I-2):
  • X represents CH 2 or CO
  • R 3 is absent or represents N(R 4 ), S, ethynylene or vinylene
  • R 4 represents H or C 1-3 alkyl
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof.
  • the group is interrupted.
  • R 2 represents:
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Is optionally interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene, or any combination thereof; and
  • a 2 is not present.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Is optionally interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene, or any combination thereof
  • a 2 is not present.
  • a 1 is absent;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Optionally interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof; and
  • a 2 represents a carbonyl group.
  • a 1 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Optionally interrupted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof
  • a 2 represents a carbonyl group.
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, preferably a substituted or unsubstituted C 1-30 Alkylene, where the substituent is selected from C 1 -C 3 alkyl, hydroxyl, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy ( For example, C 1-6 alkoxy), alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g. C 1-3 haloalkyl, e.g. trifluoromethyl), cyano or any combination thereof.
  • the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20).
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g., C 1-3 haloalkyl, such as trifluoromethyl
  • cyano or any combination thereof.
  • the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20).
  • LIN represents a substituted or unsubstituted C 2-30 alkylene group, wherein the C 2-30 alkylene group is optionally substituted by One or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof are interrupted, wherein the substituent is selected from C 1 -C 3 alkyl, hydroxyl, amino, mercapto, halogen, aromatic Group (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g. C 1-6 alkoxy), alkylamino (e.g.
  • C 1-6 alkylamino C 1-6 alkylamino
  • haloalkyl E.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof The number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20).
  • LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(O (CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -,-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -, or -(CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -, where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a6 , R a5 , R a6 , R a6 , R a5 ,
  • n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g., C 1-3 haloalkyl, such as trifluoromethyl
  • cyano or any combination thereof.
  • the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20).
  • LIN represents a substituted or unsubstituted C 2-30 alkylene group, wherein the C 2-30 alkylene group is optionally substituted by One or more optionally substituted heterocyclylenes (especially five- or six-membered heterocyclylenes) having heteroatoms selected from O, N and S interrupt, wherein the substituents are selected from C 1 -C 3 alkyl group, a hydroxyl group, an amino group, a mercapto group, a halogen, an aryl group (e.g., C 5-14 aryl, especially C 6-10 aryl group), an alkoxy group (e.g., C 1- 6 alkoxy), alkylamino (E.g.
  • C 1-6 alkylamino e.g. C 1-3 haloalkyl, such as trifluoromethyl
  • cyano e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents -(CH 2 ) n1 -heterocyclylene -(CH 2 ) n2 -, wherein n1 and n2 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and the heterocyclylene is not Substituted or substituted with a substituent selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano or any combination thereof .
  • the heterocyclylene is azetidinyl, oxetanylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, imidazolylidene, Pyrazolidinyl, pyrazolylidene, pyridinylene, triazolylidene, tetrahydrofuranyl, furanylene, tetrahydropyranyl, tetrahydrothienyl, thienylene, tetrahydrothiopyran Group, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazolyl, piperidinylene, Piperazinylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, morpholinylene,
  • LIN represents -(CH 2 ) n7 -piperidinylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • LIN represents -CH 2 -piperidinylene-CH 2 -, -(CH 2 ) 2 -piperidinylene-CH 2 -, -CH 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 2 -piperidinylene-( CH 2 ) 3 -, -(CH 2 ) 3 -piperidinylene-(CH 2 ) 2 -, -(CH 2 ) 3 -piperidinylene-(CH 2 ) 3 -, -(CH 2 ) 3 -Piperidinylene-(CH 2 ) 4 -or -(CH 2 ) 4 -Piperidinylene-(CH 2 ) 3 -.
  • LIN represents -(CH 2 ) n7 -piperazinylidene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the LIN represents - (CH 2) 2 - piperazinyl alkylene -CH 2 -, - CH 2 - -CH 2 alkylene piperazinyl -, -CH 2 -piperazinyl -(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-(CH 2 ) 2 -, -(CH 2 ) 2 -piperazinyl-( CH 2 ) 3 -, -(CH 2 ) 3 -piperazinylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -piperazinylidene-(CH 2 ) 3 -, -(CH 2 ) 3 -Piperazinyl-(CH 2 ) 4 -, or-(CH 2 ) 4 -Piperazinyl-(CH 2 ) 3 -,
  • LIN represents -(CH 2 ) n7 -triazolylidene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • a sub-embodiment of embodiment, in the compound of formula (I) in the LIN represents -CH 2 - triazolyl alkylene -CH 2 -, - CH 2 - triazolyl alkylene - (CH 2) 2 -, -CH 2 -triazolylidene -(CH 2 ) 3 -, -CH 2 -triazolylidene -(CH 2 ) 4 -, -(CH 2 ) 2 -triazolylidene -CH 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -triazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -triazolylidene- (CH 2 ) 4 -, -(CH 2 ) 3 -triazolylidene-(CH 2 ) 2 -, -(CH 2 ) 4 -, -(
  • LIN represents -(CH 2 ) n7 -imidazolylidene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • a sub viii) embodiment in the compound of formula (I) in the LIN represents -CH 2 - imidazolyl alkylene -CH 2 -, - CH 2 - imidazolyl alkylene - (CH 2) 2 -, -CH 2 -imidazolylidene -(CH 2 ) 3 -, -CH 2 -imidazolylidene -(CH 2 ) 4 -, -(CH 2 ) 2 -imidazolylidene -CH 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 2 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 3 -, -(CH 2 ) 2 -imidazolylidene-(CH 2 ) 4 -,- (CH 2 ) 3 -imidazolylidene-(CH 2 ) 2 -, -(CH 2 ) 3 -
  • LIN represents -(CH 2 ) n7 -pyrazolylene-(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • a sub-embodiment of embodiment, in the compound of formula (I) in the LIN represents -CH 2 - pyrazolyl alkylene -CH 2 -, - CH 2 - pyrazol-alkylene group - (CH 2) 2 -, -CH 2 -Pyrazolylene -(CH 2 ) 3 -, -CH 2 -Pyrazolylene -(CH 2 ) 4 -, -(CH 2 ) 2 -Pyrazolylene -CH 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 2 -Pyrazolylene-(CH 2 ) 3 -, -(CH 2 ) 2 -Pyrazolylene- (CH 2 ) 4 -, -(CH 2 ) 3 -Pyrazolylene-(CH 2 ) 2 -, -(CH 2 ) 4 -,
  • Another aspect of the present disclosure provides a compound of formula (II) or a salt, enantiomer, stereoisomer, solvate, or polymorph thereof,
  • R 12 means:
  • R x means
  • connection point with NH and the symbol ** represents the connection point with A 12
  • n represents an integer of 1-3
  • R b1 , R b2 , R b3 and R b4 are the same or different and are independently H Or oxo group
  • R b5 represents H or C 1-3 alkyl
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist or represents a carbonyl group
  • R 22 represents an optionally substituted adamantyl group, formula (II-1) structural formula, or formula (II-2) structural formula:
  • R c does not exist or represents N(R c1 ), O, S, ethynylene, vinylene, or five- or six-membered heterocyclylene, where R c1 and R c2 are independent of each other ⁇ represents H or C 1-3 alkyl, and R d represents H or methyl;
  • LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more selected from oxygen, optionally substituted heterocyclylene, or any combination thereof
  • the group of the composition is interrupted, wherein when LIN is not present, one of A 12 and A 22 is not present and the other represents a carbonyl group or both A 12 and A 22 are not present, and R 22 represents an optional substitution
  • R 22 represents the structural formula of formula (II-1), wherein R c does not exist or represents an ethynylene group, a vinylene group, or a five- or six-membered heterocyclylene;
  • R x means The symbol * indicates the connection point with NH, and the symbol ** indicates the connection point with A 12,
  • R 22 represents an optionally substituted adamantyl group, or the structural formula of formula (II-1), wherein X represents CH 2 or CO, and R c represents a five-membered or six-membered heterocyclylene, and R c2 represents H or C 1-3 alkyl, and LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene, wherein the alkylene is optionally substituted by one or more selected from oxygen, optionally substituted
  • the group consisting of heterocyclylene or any combination thereof is interrupted, wherein in the absence of LIN, one of A 12 and A 22 does not exist and the other represents a carbonyl group or neither A 12 nor A 22 Exists, or
  • R 22 represents the structural formula of formula (II-1) wherein X represents CH 2 or CO.'S, and R c represents O, and R c2 represents H or C 1- 3 alkyl, LIN, and a substituted or unsubstituted straight or Branched alkylene, or
  • R 22 represents the structural formula of formula (II-2), wherein R d represents a methyl group, and A 22 is not present, and LIN represents a substituted or unsubstituted linear or branched alkylene group;
  • R x means
  • R 22 represents an optionally substituted adamantyl group, or the structural formula of formula (II-1), wherein X represents CH 2 or CO, and R c represents a five-membered or six-membered heterocyclylene or O, and R c2 represents H or C 1-3 alkyl, and LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally selected from oxygen, optionally The group consisting of substituted heterocyclylene or any combination thereof is interrupted, wherein in the absence of LIN, one of A 12 and A 22 is absent and the other represents a carbonyl group or both A 12 and A 22 None, and R 22 represents an optionally substituted adamantyl group, or R 22 represents the structural formula of formula (II-1), wherein R c represents a five-membered or six-membered heterocyclylene, or
  • R 22 represents the structural formula of formula (II-1), where X represents CH 2 or CO, and R c represents vinylene or ethynylene, and R c2 represents C 1-3 alkyl, and LIN does not exist or represents substitution Or an unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof Interrupt, or
  • R 22 represents the structural formula of formula (II-2), wherein R d represents a methyl group, and LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more A group selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted.
  • the alkylene group when LIN represents a substituted or unsubstituted linear or branched alkylene group, the alkylene group is optionally substituted by one or more (e.g., 1-20, 1 -15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) selected from oxygen, optional
  • the group consisting of the substituted heterocyclylene or any combination thereof is interrupted.
  • either one of the two ends of the alkylene group may be connected to the group A 12 , and the other end is connected to the group A 22 .
  • R c does not exist or represents N(R c1 ), O, S, ethynylene, vinylene, or five- or six-membered heterocyclylene, where R c1 and R c2 are independent of each other Denotes H or C 1-3 alkyl (for example, methyl, ethyl, n-propyl or isopropyl).
  • a 12 does not exist;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 22 is not present.
  • a 12 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 22 is not present.
  • a 12 does not exist;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof interrupted; and
  • a 22 represents a carbonyl group.
  • a 12 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally One or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof interrupted; and
  • a 22 represents a carbonyl group.
  • LIN is not present, one of A 12 and A 22 is not present and the other represents a carbonyl group or both A 12 and A 22 are not present, and R 22 represents an optionally substituted adamantyl group, or R 22 represents the structural formula of formula (II-1), wherein R c is absent or represents an ethynylene group, a vinylene group, or a five- or six-membered heterocyclylene.
  • the five-membered or six-membered heterocyclylene includes but is not limited to Triazolylidene, azetidinylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, imidazolylidene, pyrazolidinylene, pyrazolylidene, tetrahydrofuranylene, furanylene, sub Tetrahydropyranyl, tetrahydrothienylene, thienylene, tetrahydrothiopyranyl, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine , Thiazolylidene, isothiazolylidene, thiadiazolylidene, piperidinylene, piperaz
  • R 22 represents an adamantyl group, and the adamantyl group is adamantane-1-yl, adamantane-2-yl, or adamantane-3-yl.
  • Adamantane-4-yl, adamantane-5-yl, adamantane-6-yl, adamantane-7-yl, adamantane-8-yl, adamantane-9-yl or adamantane-10-yl which is optionally selected from halogen, hydroxy, mercapto, oxo, cyano, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkane amino group, C 1-3 alkyl -NHC (O) - group, or any combination thereof one or more substituents (e.g., 1,2,3,4,5,6,7,8, or 9) replace.
  • LIN represents a substituted or unsubstituted linear or branched C 1-30 alkylene group
  • the substituent is selected from a C 1 -C 3 alkyl group , Hydroxy, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g. C 1-6 alkoxy), alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g. C 1-3 haloalkyl, e.g. trifluoromethyl), cyano or any combination thereof, wherein the number of substituents can be one or more (e.g., 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or more (e.g., 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group may Selected by one or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted, wherein the substituents of the C 2-30 alkylene and heterocyclylene are independently Is selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl (e.g.
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkane
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be One or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -,-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -, or -(CR a5 R a6 ) n1 -(O (CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -, where Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 , Ra9 , R a10 each independently represent
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino such as C 1-6 alkylamino
  • R a1 , R a2 , R a3 , R a4 , or R a5 , R a6 , R a7 , R a8 , R a9 , and R a10 are not H at the same time;
  • n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1- 6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group may Selected by one or more (e.g.
  • an optionally substituted heterocyclylene especially a five-membered or six-membered heterocyclylene having a heteroatom selected from O, N and S interrupted, wherein C 2-30 alkylene
  • the substituents of the group and the heterocyclylene group are each independently selected from C 1 -C 3 alkyl, hydroxyl, amino, mercapto, halogen, aryl (for example, C 5-14 aryl, especially C 6-10 aryl) , Alkoxy (e.g. C 1-6 alkoxy), alkylamino (e.g.
  • C 1-6 alkylamino e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or Any combination thereof, wherein the number of substituents can be one or more (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents -(CH 2 ) n7 -heterocyclylene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent an integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and the heterocyclylene is unsubstituted or It is substituted with a substituent selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano or any combination thereof.
  • heterocyclylene examples include, but are not limited to, azetidinyl, oxetanylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, Imidazolylidene, pyrazolidine, pyrazolylidene, pyridinylene, triazolylidene, tetrahydrofuranylene, furanylene, tetrahydropyranylene, tetrahydrothienylene, thienylene, Tetrahydrothiopyranyl, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazole, Piperidinylene, piperazinylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene,
  • alkyl Oxy group e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • LIN is not present, one of A 12 and A 22 is not present and the other represents a carbonyl group or both A 12 and A 22 are not present, and R 22 represents an optionally substituted adamantyl group.
  • the adamantyl group is adamantane-1-yl, adamantane-2-yl, adamantane-3-yl, adamantane-4-yl, and adamantane-5-yl.
  • R 12 means:
  • R x means
  • R b1 , R b2 , R b3 and R b4 are the same or different and are independently H Or an oxo group (for example, where one of R b1 , R b2 , R b3 and R b4 is an oxo group, and the rest are H; or R b1 , R b2 , R b3 and R b4 are all H), and R b5 Represents H or C 1-3 alkyl;
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist or represents a carbonyl group
  • R 22 represents an optionally substituted adamantyl group, formula (II-1) structural formula, or formula (II-2) structural formula:
  • R c does not exist or represents N(R c1 ), O, S, ethynylene, vinylene, or five- or six-membered heterocyclylene, where R c1 and R c2 are independent of each other ⁇ represents H or C 1-3 alkyl, and R d represents H or methyl;
  • LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 1-15, 1-10, 1- 9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) selected from oxygen, optionally substituted heterocyclylene or any The interruption of the group consisting of combination, where when LIN is not present, one of A 12 and A 22 is not present and the other represents a carbonyl group or both A 12 and A 22 are not present, and R 22 represents an optionally substituted Adamantyl, or R 22 represents the structural formula of formula (II-1), wherein R c does not exist or represents an ethynylene group, a vinylene group, or a five- or six-membered heterocyclylene.
  • R c does not exist or represents an ethynylene group, a vinylene group, or a five- or six-member
  • a 12 does not exist;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1 -2, or 1) the group selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 22 is not present.
  • a 12 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1 -2, or 1) the group selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 22 is not present.
  • a 12 does not exist;
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1 -2, or 1) to group interrupted selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof; and
  • a 22 represents a carbonyl group.
  • a 12 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group may Selected by one or more (e.g. 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and
  • a 22 represents a carbonyl group.
  • LIN is not present, one of A 12 and A 22 is not present and the other represents a carbonyl group or both A 12 and A 22 are not present Exists, and R 22 represents an optionally substituted adamantyl group, or R 22 represents the structural formula of formula (II-1), wherein R c is absent or represents an ethynylene group, a vinylene group, or a five-membered or six-membered heterozylidene group Ring base.
  • the five-membered or six-membered heterocyclylene includes But not limited to triazolylidene, azetidinylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolylidene, tetrahydrofuranyl, furylene Group, tetrahydropyranylene, tetrahydrothiophenylene, thienylene, tetrahydrothiophenylene, oxazolidinyl, oxazolylidene, isoxazolylidene, oxadiazolylidene, Thiazolidine, thiazolylidene, isothiazolylidene, thiadiazolylidene
  • R 22 represents the structural formula of formula (II-1), and the structural formula of formula (II-1) is also a combination of the following general structural formulas:
  • R c does not exist or represents N(R c1 ), O, S, ethynylene, vinylene, or five- or six-membered heterocyclylene, where R c1 and R c2 are independent of each other ⁇ denotes H or C 1-3 alkyl.
  • R 22 represents the structural formula of formula (II-2)
  • R d represents H or methyl
  • R 22 represents an adamantyl group
  • the adamantyl group is adamantane-1-yl, adamantane-2-yl, or adamantane -3-yl, adamantane-4-yl, adamantane-5-yl, adamantane-6-yl, adamantane-7-yl, adamantane-8-yl, adamantane-9-yl or adamantane- 10-group, which is optionally selected from halogen, hydroxy, mercapto, oxo, cyano, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, C 1 -3 alkylamino, C 1-3 alkyl-NHC(O)- or any combination thereof is one or more substituents (e.g., 1, 2, 3,
  • LIN represents a substituted or unsubstituted linear or branched C 1-30 alkylene group, and the substituent is selected from C 1 -C 3 Alkyl, hydroxyl, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g. C 1-6 alkoxy), alkylamino (E.g. C 1-6 alkylamino), haloalkyl (e.g.
  • C 1-3 haloalkyl such as trifluoromethyl
  • cyano or any combination thereof, wherein the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or more (e.g., 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group The alkyl group is optionally substituted by one or more (e.g.
  • the groups are independently selected from C 1 -C 3 alkyl, hydroxyl, amino, mercapto, halogen, aryl (e.g. C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g. C 1 -6 alkoxy), alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g.
  • LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(O (CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -,-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -, or -(CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -, where R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a6 , R a5 , R a6 , R a6 , R a5 ,
  • n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1- 6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group, wherein the C 2-30 alkylene group The alkyl group is optionally substituted by one or more (e.g.
  • heterocyclylene especially five- or six-membered heterocyclylene having heteroatoms selected from O, N and S interrupt
  • C 2- 30 Alkylene and heterocyclylene substituents are independently selected from C 1 -C 3 alkyl, hydroxyl, amino, mercapto, halogen, aryl (for example, C 5-14 aryl, especially C 6-10 Aryl), alkoxy (e.g. C 1-6 alkoxy), alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g.
  • C 1-3 haloalkyl such as trifluoromethyl
  • Cyano or any combination thereof, wherein the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19 or 20).
  • LIN represents -(CH 2 ) n7 -heterocyclylene -(CH 2 ) n8 -, wherein n7 and n8 each independently represent Integer 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and the heterocyclylene is not Substituted or substituted with a substituent selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano or any combination thereof .
  • heterocyclylene examples include, but are not limited to, azetidinyl, oxetanylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, Imidazolylidene, pyrazolidine, pyrazolylidene, pyridinylene, triazolylidene, tetrahydrofuranylene, furanylene, tetrahydropyranylene, tetrahydrothienylene, thienylene, Tetrahydrothiopyranyl, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazole, Piperidinylene, piperazinylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene,
  • alkyl Oxy group e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • the adamantyl group is adamantane-1-yl, adamantane-2-yl, adamantane-3-yl, adamantane-4-yl, and adamantane-5-yl.
  • R 12 represents:
  • R 22 represents an optionally substituted adamantyl group, formula (II-1) structural formula, or formula (II-2) structural formula:
  • a 12 , LIN, A 22 , X, n, R c , R c2 and Rd are as defined in x) above, and include all sub-embodiments thereof.
  • R 12 represents:
  • R b means Or N(R b5 ), wherein R b1 , R b2 , R b3 and R b4 are the same or different and are each independently H or oxo group, and R b5 represents H or C 1-3 alkyl;
  • R 22 represents an optionally substituted adamantyl group, formula (II-1) structural formula, or formula (II-2) structural formula:
  • a 12 , LIN, A 22 , X, R c , R c2 and Rd are as defined in x) above and include all sub-embodiments thereof.
  • R 12 represents any one of the following structural formulas:
  • R 22 represents an optionally substituted adamantyl group, formula (II-1) structural formula, or formula (II-2) structural formula:
  • a 12 , LIN, A 22 , X, R c , R c2 and Rd are as defined in x) above and include all sub-embodiments thereof.
  • R 12 represents:
  • R 22 represents an optionally substituted adamantyl group, formula (II-1) structural formula, or formula (II-2) structural formula:
  • a 12 , LIN, A 22 , X, R c , R c2 and Rd are as defined in x) above and include all sub-embodiments thereof.
  • R 12 represents:
  • R 22 represents an optionally substituted adamantyl group, formula (II-1) structural formula, or formula (II-2) structural formula:
  • a 12 , LIN, A 22 , X, m, R c , R c2 and Rd are as defined in x) above, and include all sub-embodiments thereof.
  • R 12 means:
  • R x means The symbol * indicates the connection point with NH, and the symbol ** indicates the connection point with A 12,
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist or represents a carbonyl group
  • R 22 represents an optionally substituted adamantyl group, or the structural formula of formula (II-1):
  • X represents CH 2 or CO
  • R c represents a five-membered or six-membered heterocyclylene
  • R c2 represents H or C 1-3 alkyl (such as methyl, ethyl or propyl)
  • LIN is not present
  • R c2 represents H or C 1-3 alkyl (such as methyl, ethyl or propyl)
  • LIN is not present
  • R c2 represents H or C 1-3 alkyl (such as methyl, ethyl or propyl)
  • LIN is not present
  • Interruption of the group where in the
  • R 22 represents the structural formula of formula (II-1) wherein X represents CH 2 or CO.'S, and R c represents O, and R c2 represents H or C 1- 3 alkyl, LIN, and a substituted or unsubstituted straight or Branched alkylene, or
  • R 22 represents the structural formula of formula (II-2):
  • R d represents a methyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, provided that A 22 is not present.
  • R 12 means:
  • R x means The symbol * indicates the connection point with NH, and the symbol ** indicates the connection point with A 12,
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist or represents a carbonyl group
  • R 22 represents an optionally substituted adamantyl group, or the structural formula of formula (II-1):
  • X represents CH 2 or CO
  • R c represents a five-membered or six-membered heterocyclylene
  • R c2 represents H or C 1-3 alkyl (such as methyl, ethyl or propyl)
  • LIN is not present
  • R c2 represents H or C 1-3 alkyl (such as methyl, ethyl or propyl)
  • LIN is not present
  • R c2 represents H or C 1-3 alkyl (such as methyl, ethyl or propyl)
  • LIN is not present
  • LIN represents H or C 1-3 alkyl (such as methyl, ethyl or propyl)
  • LIN is not present
  • LIN represents H or C 1-3 alkyl (such as methyl, ethyl or propyl)
  • LIN is not present
  • alkylene group is optionally substituted by one or more (e.g., 1-20, 1-15, 1-10, 1-9, 1 -8, 1
  • R 12 means:
  • R x means The symbol * indicates the connection point with NH, and the symbol ** indicates the connection point with A 12,
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist or represents a carbonyl group
  • R 22 represents the structural formula of formula (II-1):
  • X represents CH 2 or CO
  • R c represents O
  • R c2 represents H or C 1-3 alkyl
  • LIN represents a substituted or unsubstituted linear or branched alkylene group.
  • R 12 means:
  • R x means The symbol * indicates the connection point with NH, and the symbol ** indicates the connection point with A 12,
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist
  • R 22 represents the structural formula of formula (II-2):
  • R d represents a methyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group
  • a 12 does not exist;
  • LIN represents a substituted or unsubstituted linear or branched alkylene Group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 22 is not present.
  • a 12 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene Group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and A 22 is not present.
  • a 12 does not exist;
  • LIN represents a substituted or unsubstituted linear or branched alkylene Group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and
  • a 22 represents a carbonyl group.
  • a 12 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene Group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted; and
  • a 22 represents a carbonyl group.
  • LIN does not exist, one of A 12 and A 22 does not exist and the other represents a carbonyl group or Neither A 12 nor A 22 exist.
  • a 12 represents a carbonyl group
  • LIN represents a substituted or unsubstituted A substituted linear or branched alkylene group
  • a 22 does not exist.
  • a 12 does not exist;
  • LIN represents a substituted or unsubstituted linear or Branched alkylene; and
  • a 22 represents a carbonyl group.
  • a 12 represents a carbonyl group
  • LIN represents a substituted or unsubstituted linear or Branched alkylene
  • a 22 represents a carbonyl group
  • the five Member or six-membered heterocyclylene is triazolylidene, azetidinyl, pyrrolidinylene, pyrrolylene, imidazolidinylene, imidazolylidene, pyrazolidinylene, pyrazolylidene, Tetrahydrofuranyl, furanylene, tetrahydropyranyl, tetrahydrothiophenylene, thienylene, tetrahydrothiophenylene, oxazolidinylene, oxazolylidene, isoxazolylidene, sub Oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazolyl, piperidinylene
  • R 22 represents the structural formula of formula (II-1), and formula (II)
  • the structural formula of -1) is also a combination of the following general structural formulas:
  • R 22 represents the structural formula of formula (II-2)
  • R d represents H or methyl
  • LIN represents a substituted or unsubstituted linear or branched alkylene group.
  • R 22 represents an adamantyl group
  • the adamantyl group is an adamantyl-1-yl group, Adamantane-2-yl, adamantane-3-yl, adamantane-4-yl, adamantane-5-yl, adamantane-6-yl, adamantane-7-yl, adamantane-8-yl, adamantane-8-yl, adamantane Alk-9-yl or adamantane-10-yl, which is optionally selected from halogen, hydroxyl, mercapto, oxo, cyano, C 1-3 alkyl, halo C 1-3 alkyl, C One or more substituents of the group consisting of 1-3 alkoxy, C 1-3 alkylamino
  • LIN represents a substituted or unsubstituted linear or Branched C 1-30 alkylene
  • the substituent is selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl (such as C 5-14 aryl, especially C 6-10 aryl ), alkoxy (e.g. C 1-6 alkoxy), alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g. C 1-3 haloalkyl, e.g. trifluoromethyl), cyano Or any combination thereof, wherein the number of substituents can be one or more (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19 or 20).
  • LIN represents a substituted or unsubstituted group group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or more (e.g., 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group , wherein the C 2-30 alkylene group is optionally substituted by one or more (e.g., 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof interrupted, wherein C 2-30
  • the substituents of the alkyl group and the heterocyclylene group are independently selected from C 1 -C 3 alkyl, hydroxyl, amino, mercapto, halogen, aryl (for example, C 5-14 aryl, especially C 6-10 aryl).
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -, -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -, -(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -, Or -(CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -, where R a1 , R a2 , R a3 , R a4 , R a5
  • alkylamino e.g. C 1-6 alkylamino
  • R a1 , R a2 , R a3 , and R a4 are not H at the same time, or R a5 , R a6 , R a7 , R a8 , R a9 , and R a10 are not H at the same time;
  • n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1- 6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2-30 alkylene group , wherein the C 2-30 alkylene group is optionally substituted by one or more (e.g., 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1 -5, 1-4, 1-3 or 1-2, or 1) optionally substituted heterocyclylene having heteroatoms selected from O, N and S (especially five-membered or six-membered heterocyclylene cycloalkyl group) interrupted, wherein C 2- 30 alkylene and heterocyclyl substituents each independently selected from C 1 -C 3 alkyl group, a hydroxyl group, an amino group, a mercapto group, a halogen, an aryl group (e.g., C 5-14 Aryl, especially C 6-10 aryl), al
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl
  • cyano e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents -(CH 2 ) n7 -heterocyclylene -(CH 2 ) n8- , Where n7 and n8 respectively independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, And the heterocyclylene is unsubstituted or selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano Group or any combination of substituents.
  • heterocyclylene examples include, but are not limited to, azetidinyl, oxetanylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, Imidazolylidene, pyrazolidine, pyrazolylidene, pyridinylene, triazolylidene, tetrahydrofuranylene, furanylene, tetrahydropyranylene, tetrahydrothienylene, thienylene, Tetrahydrothiopyranyl, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazole, Piperidinylene, piperazinylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene,
  • alkyl Oxy group e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • the compound of formula (II) when LIN is not present, one of A 12 and A 22 is not present and the other represents The carbonyl group or both A 12 and A 22 are not present, and R 22 represents an optionally substituted adamantyl group.
  • the adamantyl group is adamantane-1-yl, adamantane-2-yl, adamantane-3-yl, adamantane-4-yl, and adamantane-5-yl.
  • R 12 means:
  • R x means
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist or represents a carbonyl group
  • R 22 represents an optionally substituted adamantyl group, or the structural formula of formula (II-1):
  • R c represents a five-membered or six-membered heterocyclylene or O
  • R c2 represents H or a C 1-3 alkyl group (such as methyl, ethyl or propyl)
  • LIN is not Exist or represent a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally composed of one or more selected from oxygen, optionally substituted heterocyclylene or any combination thereof
  • the group of groups is interrupted, where in the absence of LIN, one of A 12 and A 22 is absent and the other represents a carbonyl group or both A 12 and A 22 are absent, and R 22 represents an optional substitution
  • R 22 represents the structural formula of formula (II-1), where R c represents a five-membered or six-membered heterocyclylene,
  • R 22 represents the structural formula of formula (II-1), where X represents CH 2 or CO, and R c represents vinylene or ethynylene, and R c2 represents C 1-3 alkyl, and LIN does not exist or represents substitution Or an unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more groups selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof Interrupt,
  • R 22 represents the structural formula of formula (II-2), wherein R d represents a methyl group, and LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more A group selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted.
  • R 12 means:
  • R x means
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist or represents a carbonyl group
  • R 22 represents an optionally substituted adamantyl group, or the structural formula of formula (II-1):
  • R c represents a five-membered or six-membered heterocyclylene or O
  • R c2 represents H or a C 1-3 alkyl group (such as methyl, ethyl or propyl)
  • LIN is not Exist or represent a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally composed of one or more selected from oxygen, optionally substituted heterocyclylene or any combination thereof
  • the group of groups is interrupted, where in the absence of LIN, one of A 12 and A 22 is absent and the other represents a carbonyl group or both A 12 and A 22 are absent, and R 22 represents an optional substitution
  • R 22 represents the structural formula of formula (II-1), wherein R c represents a five-membered or six-membered heterocyclylene.
  • R 12 means:
  • R x means
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist or represents a carbonyl group
  • R 22 represents the structural formula of formula (II-2):
  • R d represents a methyl group
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more heterocyclic ring groups selected from oxygen and optionally substituted
  • the group consisting of the group or any combination thereof is interrupted.
  • R 12 means:
  • R x means
  • a 12 does not exist or represents a carbonyl group
  • a 22 does not exist or represents a carbonyl group
  • R 22 represents the structural formula of formula (II-1), wherein X represents CH 2 or CO, and R c represents vinylene or ethynylene, and R c2 represents C 1-3 alkyl (such as methyl, ethyl or Propyl), and LIN does not exist or represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more heterocyclic ring groups selected from oxygen and optionally substituted The group consisting of the group or any combination thereof is interrupted.
  • a 12 does not exist;
  • LIN represents substituted or unsubstituted A substituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted ;
  • a 22 does not exist.
  • a 12 represents a carbonyl group
  • LIN represents a substituted or unsubstituted A substituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted ;
  • a 22 does not exist.
  • a 12 does not exist;
  • LIN represents substituted or unsubstituted A substituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted ;
  • a 22 represents a carbonyl group.
  • a 12 represents a carbonyl group
  • LIN represents a substituted or unsubstituted A substituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (e.g., 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted
  • a 22 represents a carbonyl group.
  • the five Member or six-membered heterocyclylene is triazolylidene, azetidinyl, pyrrolidinylene, pyrrolylene, imidazolidinylene, imidazolylidene, pyrazolidinylene, pyrazolylidene, Tetrahydrofuranyl, furanylene, tetrahydropyranyl, tetrahydrothiophenylene, thienylene, tetrahydrothiophenylene, oxazolidinylene, oxazolylidene, isoxazolylidene, sub Oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazolyl, piperidin
  • R 22 represents the structural formula of formula (II-1), and formula ( The structural formula of II-1) is also a combination of the following general structural formulas:
  • R 22 represents the structural formula of formula (II-2)
  • R d represents H or methyl
  • LIN represents a substituted or unsubstituted linear or branched alkylene group, wherein the alkylene group is optionally substituted by one or more (e.g. 1-20, 1-15) , 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) selected from oxygen, optionally substituted
  • the group consisting of heterocyclylene or any combination thereof is interrupted.
  • R 22 represents an adamantyl group
  • the adamantyl group is an adamantyl-1-yl group, Adamantane-2-yl, adamantane-3-yl, adamantane-4-yl, adamantane-5-yl, adamantane-6-yl, adamantane-7-yl, adamantane-8-yl, adamantane-8-yl, adamantane Alk-9-yl or adamantane-10-yl, which is optionally selected from halogen, hydroxyl, mercapto, oxo, cyano, C 1-3 alkyl, halo C 1-3 alkyl, C One or more substituents of the group consisting of 1-3 alkoxy, C 1-3 alkyla
  • R 22 represents the structural formula of formula (II-1), wherein X represents CH 2 or CO, and R c represents vinylidene Or ethynylene, and R c2 represents methyl, ethyl or propyl.
  • LIN represents a substituted or unsubstituted linear or branched C 1 -30 alkylene
  • the substituent is selected from C 1 -C 3 alkyl, hydroxyl, amino, mercapto, halogen, aryl (for example, C 5-14 aryl, especially C 6-10 aryl), alkoxy (E.g. C 1-6 alkoxy), alkylamino (e.g. C 1-6 alkylamino), haloalkyl (e.g. C 1-3 haloalkyl, e.g. trifluoromethyl), cyano or any combination thereof
  • the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or more (e.g., 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2 -30 alkylene group, wherein the C 2-30 alkylene group is optionally substituted by one or more (e.g., 1-20, 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 selected from the group consisting of oxygen, optionally substituted heterocyclylene or any combination thereof is interrupted, wherein
  • the substituents of C 2-30 alkylene and heterocyclylene are each independently selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl (for example, C 5 to 14 aryl, especially C 6-10 aryl), alkoxy (e.g.
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, such as trifluoromethyl Group
  • cyano group or any combination thereof wherein the number of substituents can be one or more (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents -(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -,-(CH 2 ) n1 -(O(CH 2 ) n2 ) m1 -(O(CH 2 ) n3 ) m2 -,-(CR a1 R a2 ) n1 -(O(CR a3 R a4 ) n2 ) m1 -, or -(CR a5 R a6 ) n1 -(O(CR a7 R a8 ) n2 ) m1 -(O(CR a9 R a10 ) n3 ) m2 -, where R a1 , R a2 , R a3 , R a4
  • C 5-14 aryl Group especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • R a1 , R a2 , R a3 , and R a4 are not H at the same time, or R a5 , R a6 , R a7 , Ra8 , R a9 , and R a10 are not H at the same time;
  • n1, n2, n3, m1, m2 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • LIN represents the following substituted or unsubstituted group:
  • C 5-14 aryl especially C 6-10 aryl
  • alkoxy e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1- 6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • cyano or any combination thereof the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20).
  • LIN represents a substituted or unsubstituted linear or branched C 2 -30 alkylene group, wherein the C 2-30 alkylene group is optionally substituted by one or more (e.g., 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2, or 1) optionally substituted heterocyclylene (especially five-membered) with heteroatoms selected from O, N and S Or six-membered heterocyclylene) interrupted, wherein the substituents of C 2-30 alkylene and heterocyclylene are independently selected from C 1 -C 3 alkyl, hydroxyl, amino, mercapto, halogen, aryl ( For example, C 5-14 aryl, especially C 6-10 aryl), alkoxy (e.g.
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, such as trifluoromethyl
  • cyano or any combination thereof wherein the number of substituents can be one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8 , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20).
  • LIN represents -(CH 2 ) n7 -heterocyclylene- ( CH 2) n8 -, where n7 and n8 independently represent integers 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19 or 20, and the heterocyclylene is unsubstituted or selected from C 1 -C 3 alkyl, hydroxy, amino, mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino , Haloalkyl, cyano or any combination of substituents.
  • heterocyclylene examples include, but are not limited to, azetidinyl, oxetanylene, pyrrolidinylene, pyrrolylene, imidazolidinyl, Imidazolylidene, pyrazolidine, pyrazolylidene, pyridinylene, triazolylidene, tetrahydrofuranylene, furanylene, tetrahydropyranylene, tetrahydrothienylene, thienylene, Tetrahydrothiopyranyl, oxazolidinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolidine, thiazolyl, isothiazolyl, thiadiazole, Piperidinylene, piperazinylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene,
  • alkyl Oxy group e.g. C 1-6 alkoxy
  • alkylamino e.g. C 1-6 alkylamino
  • haloalkyl e.g. C 1-3 haloalkyl, e.g. trifluoromethyl
  • the compound of formula (II) when LIN is not present, one of A 12 and A 22 is not Exist and the other represents a carbonyl group or both A 12 and A 22 are absent, and R 22 represents an optionally substituted adamantyl group.
  • the adamantyl group is adamantane-1-yl, adamantane-2-yl, adamantane-3-yl, adamantane-4-yl, and adamantane-5-yl.
  • the compound of formula (I) or the compound of formula (II) of the present invention may have a stereo configuration and therefore can exist in more than one stereoisomer form.
  • the present invention also relates to compounds having a stereoconfiguration in substantially pure isomeric form, such as greater than about 90% ee, such as about 95% ee or 97% ee, or greater than 99% ee, and mixtures thereof, including racemic mixtures.
  • the purification and separation of these isomers can be performed by conventional methods well known to those of ordinary skill in the art (for example, column chromatography, preparative TLC, preparative HPLC, asymmetric synthesis (for example, by using chiral intermediates) and/or by chiral Split, etc.)) to achieve.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient the compound of formula (I), or compound of formula (II), or a pharmaceutically acceptable salt thereof, as an active ingredient of the present invention Racemates, enantiomers, diastereomers, solvates or polymorphs, and pharmaceutically acceptable carriers.
  • the pharmaceutical composition of the present invention further includes at least one additional drug or therapeutic agent (for example, a drug or therapeutic agent for treating or preventing diseases related to BCL-2 family proteins or Hedgehog signaling pathway).
  • additional drug or therapeutic agent for example, a drug or therapeutic agent for treating or preventing diseases related to BCL-2 family proteins or Hedgehog signaling pathway.
  • the pharmaceutical composition of the present invention can be prepared according to methods well known to those of ordinary skill in the art, and is conveniently presented in the form of a unit dosage form.
  • the method includes making the compound of formula (I), or compound of formula (II), or a pharmaceutically acceptable salt thereof, optionally combined with other therapeutically valuable substances, together with pharmaceutical excipients (for example, therapeutically Compatible non-toxic inert suitable solid or liquid carrier materials) and (if necessary) common pharmaceutical adjuvants together form the desired formulation.
  • pharmaceutical excipients for example, therapeutically Compatible non-toxic inert suitable solid or liquid carrier materials
  • common pharmaceutical adjuvants together form the desired formulation.
  • the content of the compound of formula (I) or the compound of formula (II) as an active ingredient is sufficient to have a desired effect on the process or condition of the disease.
  • the pharmaceutical composition can be prepared into various dosage forms after sterilization based on methods known in the pharmaceutical field.
  • the pharmaceutical composition according to the present invention containing the compound of formula (I) or the compound of formula (II) according to the present invention as an active ingredient may be in the form of enteral or parenteral administration, for example, according to appropriate administration Routes (including but not limited to nasal cavity administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, peritoneal administration, vaginal administration, intramuscular administration, subcutaneous administration Administration, transdermal administration, epidural administration, intrathecal administration and intravenous administration) are prepared into suitable spray formulations, patches, tablets (such as conventional tablets, dispersible tablets, orally disintegrates) Tablets), capsules (such as soft capsules, hard capsules, enteric-coated capsules), dragees, lozenges, powders, granules, powder injections, or liquid preparations (such as aqueous or oily suspensions, solutions
  • the compound of formula (I), or compound of formula (II), or a pharmaceutically acceptable salt, racemate, enantiomer, or diastereomer of the present invention Isomers, solvates or polymorphs, which are used as medicaments.
  • the compound of formula (I), or compound of formula (II), or a pharmaceutically acceptable salt, racemate, enantiomer, or diastereomer of the present invention Isomers, solvates or polymorphs, which prevent and/or treat diseases related to BCL-2 family proteins or Hedgehog signaling pathway (including tumors, and non-neoplastic diseases such as bone marrow fibrosis, renal fibrosis, liver Fibrosis, liver cirrhosis, etc.).
  • the tumor includes hematological tumors and solid tumors.
  • the tumor is a tumor that depends on BCL-2 family proteins (for example, BCL-2, MCL-1, and/or BCL-XL), or a tumor that depends on the Hedgehog signaling pathway.
  • BCL-2 family proteins for example, BCL-2, MCL-1, and/or BCL-XL
  • Hedgehog signaling pathway for example, BCL-2, MCL-1, and/or BCL-XL
  • the disease associated with the BCL-2 family protein or Hedgehog signaling pathway is selected from the group consisting of: myeloma, including multiple myeloma (MM); leukemia, including chronic lymphocytic leukemia (CLL) ), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML); lymphoma, including non-Hodgkin’s lymphoma, anaplastic large cell lymphoma, diffuse large B-cell lymphoma; myelodysplastic syndrome; Myelofibrosis, renal fibrosis, liver fibrosis; breast cancer; lung cancer, including non-small cell lung cancer and small cell lung cancer; melanoma; mesothelioma; neuroblastoma; osteosarcoma; ovarian cancer; prostate cancer; medulla Cell tumor; Basal cell carcinoma; Goering syndrome; Esophageal cancer; Colorectal cancer; Medulloblastoma; Rhabdomyosar
  • Another aspect of the present invention provides a compound of formula (I), or a compound of formula (II), or a pharmaceutically acceptable salt, racemate, enantiomer, or diastereomer of the present invention
  • constructs, solvates or polymorphs for the prevention and/or treatment of diseases related to BCL-2 family proteins or Hedgehog signaling pathways (including tumors, and non-neoplastic diseases such as myelofibrosis) , Kidney fibrosis, liver fibrosis, liver cirrhosis, etc.).
  • the tumor includes hematological tumors and solid tumors.
  • the tumor is a tumor that depends on BCL-2 family proteins (for example, BCL-2, MCL-1, and/or BCL-XL), or a tumor that depends on the Hedgehog signaling pathway.
  • the disease related to the BCL-2 family protein or the Hedgehog signaling pathway is selected from the group consisting of: myeloma, including multiple myeloma (MM); leukemia, including chronic lymphocytes Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML); Lymphoma, including non-Hodgkin’s lymphoma, Anaplastic large cell lymphoma, Diffuse large B cell lymphoma; Myeloproliferation Abnormal syndrome; myelofibrosis, renal fibrosis, liver fibrosis; breast cancer; lung cancer, including non-small cell lung cancer and small cell lung cancer; melanoma; mesothelioma; neuroblastoma; osteosarcoma; ovarian cancer; prostate Carcinoma; Medulloblastoma; Basal cell carcinoma; Goring syndrome; Esophageal cancer; Colorectal cancer; Medulloblastom
  • Another aspect of the present invention also provides treatment or prevention of diseases related to BCL-2 family proteins or Hedgehog signaling pathway in a subject (including tumors, and non-neoplastic diseases such as myelofibrosis, renal fibrosis, liver fibrosis) , Liver cirrhosis, etc.), which comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or a compound of formula (II) of the present invention, or a pharmaceutically acceptable salt, racemic Isomers, enantiomers, diastereomers, solvates or polymorphs, or the pharmaceutical composition of the present invention.
  • the tumor is a tumor that depends on BCL-2 family proteins (for example, BCL-2 and/or MCL-1 and/or BCL-XL), or a tumor that depends on the Hedgehog signaling pathway.
  • the disease associated with the BCL-2 family protein or Hedgehog signaling pathway is selected from the group consisting of: myeloma, including multiple myeloma (MM); leukemia, including chronic lymphoma Cellular Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML); Lymphoma, including non-Hodgkin’s lymphoma, anaplastic large cell lymphoma, diffuse large B cell lymphoma; bone marrow Dysplasia syndrome; myelofibrosis, renal fibrosis, liver fibrosis; breast cancer; lung cancer, including non-small cell lung cancer and small cell lung cancer; melanoma; mesothelioma; neuroblastoma; osteosarcoma; ovarian cancer; Prostate cancer; Medulloblastoma; Basal cell carcinoma; Goring syndrome; Esophageal cancer; Colorectal cancer; Medulloblastom
  • At least one selected from the group consisting of nasal administration, inhalation administration, topical administration, oral administration, oral mucosal administration, rectal administration, pleural cavity administration, and peritoneal administration Drugs, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration and intravenous administration are administered to the subject.
  • the term “approximately” means approximately, approximately, approximately or approximately. When the term “about” is used in conjunction with a range of values, it modifies the range by extending boundaries above and below the stated value. For example, the term “approximately” as used herein may modify the value to be higher and lower than the stated value by, for example, ⁇ 20% or ⁇ 15%, or ⁇ 10%, ⁇ 5%, or ⁇ 1.
  • absent as used herein in combination with a substituent or group means that the substituent or group does not exist. In other words, when the substituent or group is not present, it becomes a bond or bond linker.
  • the R 1 group when the A 1 group is not present, the R 1 group is directly covalently bonded (or connected) to LIN.
  • the compound of formula (I) and the compound of formula (II) of the present invention are also referred to as protein degrading agents (compounds) or PROTAD drugs, and they can be used interchangeably.
  • LIN and “linker” are used interchangeably, and both represent the linking group in the compound of formula (I) and the compound of formula (II).
  • intermediate LM refers to the intermediate compound used to construct the -A 1 -LIN-A 2 -R 2 part of the compound of formula (I) in the following schemes and examples, as well as to construct formula (II) The intermediate compound of the -A 12 -LIN-A 22 -R 22 part of the compound.
  • intermediate BINDER refers to the intermediate compound used to construct the R 1 group of the compound of formula (I) or the R 12 group of the compound of formula (II) in the following schemes and examples.
  • the intermediate LM and the intermediate BINDER are coupled under appropriate conditions to synthesize the target protein degrading agent of the present invention.
  • halogen atom or halogen used alone or in combination means fluorine, chlorine, bromine or iodine, and is, for example, F, Cl or Br.
  • alkyl used alone or in combination refers to a linear or branched alkyl group.
  • C x -C y alkyl or “C xy alkyl” (x and y are each an integer) refers to a straight or branched chain alkyl group containing x to y carbon atoms.
  • C 1-10 alkyl group used alone or in combination in the present invention refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms.
  • the C 1-10 alkyl group of the present invention is preferably a C 1-9 alkyl group, more preferably a C 1-8 alkyl group, still more preferably a C 2-8 alkyl group, more preferably a C 1-7 alkyl group, and even More preferably, it is a C 1-6 alkyl group, a C 1-5 alkyl group, or a C 1-4 alkyl group.
  • C 1-3 alkyl in the present invention refers to an alkyl group containing 1 to 3 carbon atoms, and representative examples thereof include methyl, ethyl, n-propyl and isopropyl.
  • the "alkyl” is optionally substituted, and the substituent is preferably one or more selected from halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, tri Substituents of fluoromethyl, heterocyclic group or any combination thereof.
  • alkylene or “alkylene chain” (the two are used interchangeably), used alone or in combination, refer to a straight or branched divalent saturated hydrocarbon group composed of carbon and hydrogen atoms.
  • C x -C y alkylene or “C xy alkylene” (x and y are each an integer) refers to a linear or branched alkylene group containing x to y carbon atoms.
  • the C 1 -C 30 alkylene group of the present invention is preferably a C 1 -C 29 alkylene group, a C 1 -C 28 alkylene group, a C 1 -C 27 alkylene group, a C 1 -C 26 alkylene group, and 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 Alkyl, 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, C 1 -C 9 alkylene Group, C 1 -C 8 alkylene
  • Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylidene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene , Neopentylene, terpentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, decylene Tetraalkyl, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecanyl, eicosylene, eicosylene, arachidylene Dialkyl, trichenylene, tetracosene, pentadecylene, hexadecylene, heptadecylene, octadecylene, and twenty-nine de
  • alkylene is optionally substituted, and the substituent may be one or more selected from hydroxyl, amino, mercapto, halogen, cyano, C 1-3 alkyl, C 1 -3 Substituents of alkoxy, trifluoromethyl, heterocyclyl or any combination thereof.
  • the expression "the alkylene group is interrupted by one or more groups” means that one or more (for example, 1-10 1, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) groups as defined herein, namely Any one or more pairs of two adjacent carbon atoms in the carbon chain main chain structure of the linear or branched alkylene are covalently connected through the group.
  • the expression "the alkylene group is interrupted by one or more oxygens” means that one or more (for example, 1-10, 1- 8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) oxygen atoms to form one or more (for example, 1 -10, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, or 1) "-CH 2 -O- The oxaalkylene group of the CH 2 -" fragment.
  • aryl used alone or in combination refers to an aromatic hydrocarbon group containing 5 to 14 carbon atoms (for example, 6-10 carbon atoms) and optionally one or more fused rings, such as Phenyl, naphthyl or fluorenyl.
  • the "aryl group” is an optionally substituted aryl group.
  • a substituted aryl group refers to an aryl group substituted 1-3 times with a substituent (that is, the aryl group is mono-substituted, di-substituted or tri-substituted with a substituent), wherein the substituent may be selected from , for example, a C 1-3 alkyl group, C 1-3 alkoxy, trifluoromethyl, mercapto, cyano, halogen, amino, hydroxyl or any combination thereof.
  • alkoxy used alone or in combination refers to a straight-chain or branched alkoxy group, the structural formula of which is -O-alkyl.
  • the alkyl portion of the alkoxy group may contain 1-10 carbon atoms.
  • Representative examples of "alkoxy” include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, 2 -Pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, etc.
  • 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 groups include, but are not limited to, methoxy, ethoxy, n-propoxy and isopropoxy, methoxy and ethoxy, for example.
  • alkylamino used alone or in combination refers to a linear or branched alkylamino group, and its structural formula is -NH-alkyl.
  • the alkyl portion of the alkylamino group may contain 1-10 carbon atoms.
  • alkylamino include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, pentylamino, 2 -Pentylamino, isopentylamino, neopentylamino, hexylamino, 2-hexylamino, 3-hexylamino, 3-methylpentylamino, etc.
  • C 1 -C 3 alkylamino or "C 1-3 alkylamino” refers to a linear or branched alkylamino group containing 1 to 3 carbon atoms.
  • Representative examples of C 1-3 alkylamino include, but are not limited to, methylamino, ethylamino, n-propylamino, and isopropylamino. Preferably they are methylamino and ethylamino.
  • haloalkyl used alone or in combination refers to a straight or branched chain alkyl group substituted with one or more halogen atoms.
  • C x -C y haloalkyl (x and y are each an integer) refers to a linear or branched haloalkyl group containing x to y carbon atoms.
  • the alkyl portion of the haloalkyl group may contain 1-10 carbon atoms, 1-8 carbon atoms, 1-5 carbon atoms, or 1-3 carbon atoms.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl , 2-fluoroethyl, 2-chloroethyl, tetrafluoroethyl (CF 3 CFH), pentafluoroethyl, 1,1,1-trifluoroprop-2-yl, etc.
  • heterocyclylene or “heterocyclylene” used alone or in combination means containing one or more (for example, containing 1 to 5 or 1 to 4, 1-3, 1-2 One or one) independently selected from 3 to 20 members of heteroatoms of sulfur, oxygen and nitrogen (e.g., 3 to 15, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 6-membered, or 3- to 5-membered) monocyclic, bicyclic or tricyclic saturated or unsaturated (that is, with one or more double bonds, conjugated or incompletely conjugated) divalent cyclic hydrocarbon group, which may include condensed Ring, bridge ring or spiro ring system.
  • heteroatoms of sulfur, oxygen and nitrogen e.g., 3 to 15, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 6-membered, or 3- to 5-membered
  • monocyclic, bicyclic or tricyclic saturated or unsaturated that is, with one or more double bonds, conjugated or incompletely conjugated
  • heterocyclylene may include an aromatic heterocyclic ring or a non-aromatic heterocyclic ring or an aliphatic heterocyclic ring having at least one heteroatom.
  • heterocyclylene may preferably refer to a 3- to 15-membered (for example, 3- to 8-membered or 3- to 6-membered) heteroatom containing one or more heteroatoms independently selected from sulfur, oxygen, and nitrogen
  • Monocyclic, bicyclic or tricyclic saturated or unsaturated that is, with one or more double bonds, conjugated or incompletely conjugated
  • Representative examples include, but are not limited to, azetidinyl, oxetanylene, pyrrolidinylene, imidazolidinyl, pyrazolidinylene, pyridinylene, triazolylidene, tetrahydrofuranyl , Tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyran, oxazolidinyl, thiazolidine, piperidinylene, piperazinylene, morpholinylene, thiosulfide Morpholinyl, dioxanyl, diazacycloheptane subunits (e.g.
  • the heterocyclylene may be unsubstituted or substituted as clearly defined, for example, having 1 to 3 identical or different substituents, and the substituents may for example be selected from C 1 -C 3 alkyl, hydroxyl, amino, Mercapto, halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano or any combination thereof.
  • heterocyclic group used alone or in combination means containing one or more (for example, containing 1 to 5 or 1 to 4, 1-3, 1-2 or 1) independently selected From 3 to 20 members of heteroatoms of sulfur, oxygen, and nitrogen (e.g., 3 to 15, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 6, or 3 to 5 ) Monocyclic, bicyclic or tricyclic saturated or unsaturated (that is, having one or more double bonds, conjugated or incompletely conjugated) divalent cyclic hydrocarbon group, which may include fused ring, bridged ring or spiro ring system .
  • heterocyclic group may include an aromatic heterocyclic group or a non-aromatic heterocyclic group or an aliphatic heterocyclic group having at least one heteroatom.
  • heterocyclyl may preferably refer to a 3 to 15 membered (e.g., 3 to 8 membered or 3 to 6 membered) monomer containing one or more heteroatoms independently selected from sulfur, oxygen, and nitrogen. Cyclic, bicyclic or tricyclic saturated or unsaturated (ie, with one or more double bonds, conjugated or incompletely conjugated) divalent cyclic hydrocarbon group.
  • Representative examples include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyridinyl, triazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranyl Hydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, diazacycloheptanyl (E.g.
  • the heterocyclic group may be unsubstituted or substituted as clearly defined, for example, having 1-3 identical or different substituents, and the substituents may be selected from, for example, C 1 -C 3 alkyl, hydroxyl, amino, and mercapto groups. , Halogen, aryl, C 1-3 alkoxy, alkylamino, haloalkyl, cyano or any combination thereof.
  • 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 as follows:
  • adamantyl refers to a monovalent group of adamantane, that is, the group remaining after any hydrogen in the adamantane is removed. Representative examples 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.
  • salts or pharmaceutically acceptable salts, enantiomers, stereoisomers, solvates, and polymorphs of the compounds of formula I and the compounds of formula II described in the present disclosure are also encompassed within the scope of the present disclosure.
  • the salt or pharmaceutically acceptable salt of the compound of formula I and the compound of formula II refers to non-toxic inorganic or organic acid and/or base addition salts.
  • examples include: sulfate, hydrochloride, citrate, maleate, sulfonate, citrate, lactate, tartrate, fumarate, phosphate, dihydrophosphate, pyrophosphate Salt, metaphosphate, oxalate, malonate, benzoate, mandelate, succinate, glycolate or p-toluenesulfonate, etc.
  • “Pharmaceutically acceptable carrier” refers to pharmaceutically acceptable materials, such as fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, solvents, or encapsulating materials.
  • the compounds useful in the invention are carried or transported into the patient's body or administered to the patient so that it can perform its intended function. Generally, such constructs are carried or transported from one organ or part of the body to another organ or part of the body.
  • the carrier is compatible with the other ingredients of the formulation (including the compounds useful in this disclosure) and is not harmful to the patient, the carrier must be "acceptable.”
  • materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl acetate Base cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; 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,
  • treatment refers to the administration of a compound of formula (I) or a compound of formula II, or a pharmaceutically acceptable salt thereof, according to the present disclosure, or a compound of formula I or formula II as an active ingredient.
  • the beneficial or desired clinical results of the present disclosure include, but are not limited to: alleviating symptoms, reducing the severity of the disease, stabilizing the state of the disease, delaying or delaying the progression of the disease, improving or alleviating the disease, and alleviating the disease.
  • the "therapeutically effective amount" of the 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 patient's age, sex and weight, the patient's general medical condition, and administration Method and time, excretion rate, combination medication, and disease or disease progression of the patient being treated. Those skilled in the art can determine the appropriate dosage based on these and other factors.
  • the dosing and dosing regimen should be within the capabilities of those skilled in the art, and the appropriate dosage depends on many factors including the level of knowledge and ability of general technical doctors, veterinarians or researchers (see, for example, Wells et al.eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000)).
  • the patients or subjects treated above 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, and mice Wait.
  • mammals including but not limited to primates (such as humans), cattle, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, and mice Wait.
  • room temperature in the present disclosure refers to the ambient temperature, for example, a temperature of 20-30°C.
  • the solvents used in the reaction such as DCM, DMF, NMP, anhydrous EtOH, anhydrous MeOH, etc. are all purchased from Sinopharm;
  • HPLC preparation uses preparative CH 3 CN and deionized water
  • intermediate Binder such as 4-fluoro-3-nitrobenzenesulfonamide
  • intermediate LM such as pomalidomide
  • the compounds described herein and/or pharmaceutically acceptable salts thereof can be synthesized by methods known in the art using commercially available raw materials.
  • the synthesis scheme described below exemplifies the preparation of most compounds.
  • the compound of formula (I) and the compound of formula (II) of the present invention can be prepared by coupling (constructing R 1 group or R 12 ) intermediate BINDER and intermediate LM under appropriate conditions, including the following methods and implementations Examples of suitable variants or alternative forms.
  • Those skilled in the art can prepare the salt, racemate, enantiomer, carbamate, phosphate, sulfate, salt of the compound of formula (I) or compound of formula (II) of the present invention according to conventional techniques in the art Salt and prodrug forms.
  • n is an integer from 0-20.
  • n is an integer of 1-20.
  • n is an integer from 0-20.
  • n is an integer from 0-20.

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Abstract

L'invention concerne des composés de formules (I) et (II), ou un sel, un énantiomère, un stéréoisomère, un solvate ou un polymorphe de ceux-ci, et leur utilisation pour le traitement de maladies. R1-A 1-LIN-A 2-R2 (I) R 12-A 12-LIN-A 22-R 22 (II)
PCT/CN2020/123731 2019-10-24 2020-10-26 Agent de dégradation de protéine et son utilisation dans le traitement de maladies WO2021078301A1 (fr)

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WO2023215482A1 (fr) 2022-05-06 2023-11-09 Treeline Biosciences, Inc. Agents de dégradation bcl-xl hétérobifonctionnels de tétrahydroisoquinoléine
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