WO2023208106A1 - Composé ayant un effet d'administration ciblant le foie et conjugué oligonucléotidique de celui-ci - Google Patents

Composé ayant un effet d'administration ciblant le foie et conjugué oligonucléotidique de celui-ci Download PDF

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WO2023208106A1
WO2023208106A1 PCT/CN2023/091131 CN2023091131W WO2023208106A1 WO 2023208106 A1 WO2023208106 A1 WO 2023208106A1 CN 2023091131 W CN2023091131 W CN 2023091131W WO 2023208106 A1 WO2023208106 A1 WO 2023208106A1
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independently selected
alkyl
occurrence
prodrug
solvate
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PCT/CN2023/091131
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English (en)
Chinese (zh)
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赵成龙
王凌宇
马呈鑫
董云霞
陈慧瑜
邵昱
任家凤
孙艺梦
李春雷
苏晓晔
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石药集团中奇制药技术（石家庄）有限公司
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Priority to CN202380008843.3A priority Critical patent/CN117580846A/zh
Publication of WO2023208106A1 publication Critical patent/WO2023208106A1/fr

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • 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
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical

Definitions

  • the present invention relates to the field of medical technology. Specifically, it relates to compounds with liver-targeted delivery effects and oligonucleotide conjugates thereof, their preparation methods and uses. This compound with liver-targeted delivery effects is a new type of compound. GalNAc derivatives.
  • Asialoglycoprotein receptor is an endocytic receptor specifically expressed in liver cells. It mainly exists on the cell membrane surface of liver parenchymal cells facing the sinusoidal space and is specific for sugar. .
  • GalNAc N-acetylgalactosamine
  • this receptor has It has been discovered for many years, but liver-targeted drug delivery based on this receptor and its ligands is radiating continuous energy. Therefore, an in-depth understanding of the characteristics, properties, and mechanisms of ASGPR and its ligands requires innovative basic research, The design and development of new drugs are very important.
  • ASGPR The main function of ASGPR is to remove asialoglycoprotein, apoptotic cells, and lipoproteins from the blood circulation system.
  • ASGPR can also bind to a variety of other asialoglycoproteins, such as erythropoietin, interferon, thyroglobulin, transferrin, hepatoglobulin, fetuin, and prothrombin etc., and these bindings have high specificity.
  • erythropoietin interferon
  • thyroglobulin transferrin
  • hepatoglobulin fetuin
  • prothrombin prothrombin
  • HepG2 cells or primary human urethral epithelial cells by Neisseria gonorrhoeae. , PHUECs), and may also be a major contributor to hemolysis in patients with alcoholic cirrhosis.
  • ASGPR protein The amino acid sequence of ASGPR protein is highly conserved among various species. Human ASGPR is mainly expressed in liver parenchymal cells. After the GalNAc conjugate of the nucleic acid recognizes and binds to the ASGPR receptor, it will be rapidly endocytosed by the liver cells and form endosomes. Afterwards, the pH in the endosome drops, the GalNAc conjugate of the nucleic acid will dissociate from the ASGPR receptor, and the nucleic acid molecule will escape from the endosome. During the escape process, nucleic acid molecules will rapidly dissociate from GalNAc at the same time. About less than 1% of the nucleic acid molecules will escape from the double-layer lipid membrane structure of the endosome into the cytoplasm, and then go through a series of complex processes. Ultimately inducing a robust and sustained RNAi response.
  • the invention provides a class of compounds with liver-targeted delivery effects and oligonucleotide conjugates thereof or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or their pharmaceutical Acceptable salts, this compound with liver-targeted delivery effect is a new type of GalNAc derivative, and also provides such compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or The pharmaceutically acceptable salts thereof are used in the preparation of medicaments, preferably in the preparation of medicaments for the treatment and prevention of physiological conditions or diseases caused by the expression of specific genes in liver cells.
  • the present invention provides a compound represented by formula (I), or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof, which Has the following structure:
  • each R is independently selected from:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 are each independently selected from -O-, -S-, -N(G 1 )-, -C(G 1 ) 2 -;
  • G 1 is each The second occurrence is independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl, or C 1-10 alkyl optionally substituted by one or more of halogen, hydroxyl, amino, carboxyl, C 1-6 alkyl Base, C 1-10 alkoxy group, -N(C 1-10 alkyl) 2 ;
  • Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from C, N + and Si;
  • Each occurrence of A 1 and A 2 is independently selected from hydrogen, or acetyl, propionyl, benzoyl, benzyl, which may be optionally substituted by one or more of halogen, hydroxyl, amino, and carboxyl. benzyloxycarbonyl;
  • Each occurrence of G 3 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, oxo, C 1-6 alkyl, C 1-6 alkoxy, or by deuterium, halogen, hydroxyl, amino One or more optionally substituted C 1-6 alkyl, C 1-6 alkoxy;
  • X 4 is independently selected from bonds, -(C(G 4 ) 2 ) a -, -(C(G 4 ) 2 C(G 3 ) 2 O) b -, -(C(G 4 ) 2 C(G 3 ) 2 S) b -, or C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl optionally substituted by one or more G 4 , 3-10 membered heterocyclyl, C 6-14 aryl, 5-12 membered heteroaryl;
  • Each occurrence of G 4 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, oxo, C 1-6 alkyl, C 1-6 alkoxy, or by deuterium, halogen, hydroxyl, amino One or more optionally substituted C 1-6 alkyl, C 1-6 alkoxy;
  • n and a are independently selected from the integers from 0 to 24 each time they appear, and m and b are independently selected from the integers from 0 to 12 each time they appear;
  • J 1 , J 2 , J 3 , and J 4 are each independently selected from the group consisting of bonds, -O-, -S-, -NH-, -C(O)-, -C(S)-, -S(O)- , -S(O) 2 -, -NHC(O)-, -C(O)NH-, -C(O)O-, -OC(O)-, -SS-, -N(G 5 )C (O)-, -C(O)N(G 5 )-, -N(G 5 )-, -C(G 5 ) 2 -, -Si(G 5 ) 2 -, -P(O)(OH )-, -P(O)O-,
  • Each occurrence of G 5 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, -BH 2 , -B(OH) 2 , -N(C 1-6 alkyl) 2 , C 1-12 alkyl group, C 1-12 alkoxy group, or C 1-12 alkyl group, C 1-12 alkoxy group, C 3-10 ring optionally substituted by one or more of deuterium, halogen, hydroxyl, and amino group Alkyl, C 3-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-14 aryl, 5-12 membered heteroaryl;
  • Each occurrence of J 5 and J 6 is independently selected from the group consisting of bonds, -O-, -S-, -NH-, -C(O)-, -C(S)-, -S(O)-, - S(O) 2 -, -NHC(O)-, -C(O)NH-, -C(O)O-, -OC(O)-, -SS-, -N(G 6 )C(O )-, -C(O)N(G 6 )-, -N(G 6 )-, -C(G 6 ) 2 -, -Si(G 6 ) 2 -, -P(O)(OH)- ,-P(O)O-,
  • Each occurrence of G 6 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, -BH 2 , -B(OH) 2 , -N(C 1-6 alkyl) 2 , C 1-12 alkyl group, C 1-12 alkoxy group, or C 1-12 alkyl group, C 1-12 alkoxy group, C 3-10 ring optionally substituted by one or more of deuterium, halogen, hydroxyl, and amino group Alkyl, C 3-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-14 aryl, 5-12 membered heteroaryl;
  • G 7 is independently selected from halogen, hydroxyl, amino, cyano, oxo, -C 1-12 alkyl -OG 8 , -OG 9 ,
  • Cat is a cation, independently selected from sodium ion, potassium ion, triethylammonium ion, tripropylammonium ion, tributylammonium ion and tetrabutylammonium ion;
  • r is an integer from 0 to 5;
  • Solid support is a solid phase carrier;
  • G 8 is independently selected from the following structures: H,
  • G 9 is independently selected from
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 are each independently selected from -O-, -N(G 1 )-, -C(G 1 ) 2 -.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 are each independently selected from -O-, -NH-, -CH(G 1 )-.
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 are each independently selected from -CH 2 -.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, G 1
  • Each occurrence is independently selected from hydrogen, halogen, hydroxy, amino, carboxyl, or C 1-10 optionally substituted by one or more of halogen, hydroxy, amino, carboxyl, C 1-6 alkyl Alkyl, -N(C 1-10 alkyl) 2 .
  • each occurrence of G1 is independently selected from hydrogen, halogen, hydroxy, amino, carboxyl, or may be optionally substituted by one or more of halogen, hydroxy, amino, carboxyl C 1-6 alkyl, -N(C 1-6 alkyl) 2 .
  • each occurrence of G 1 is independently selected from hydrogen, amino, carboxyl, C 1-4 alkyl, C 1-4 alkyl optionally substituted with one or more fluorine, -N(C 1-4 alkyl) 2 .
  • each occurrence of G 1 is independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkyl optionally substituted with one or more fluorine.
  • each occurrence of G1 is independently selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl.
  • each occurrence of G1 is independently selected from hydrogen, amino, carboxyl, methyl, ethyl, isopropyl, trifluoromethyl, N,N-diisopropylamino.
  • each occurrence of G1 is independently selected from hydrogen.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, Y 1
  • the branch unit composed of , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Z 1 , Z 2 , Z 3 , Z 4 is selected from the following structures:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 together with Z 1 , Z 2 , Z 3 , Z 4 constitute The branch units are selected from
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from C.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, A 1 , each occurrence of A 2 is independently selected from hydrogen, or acetyl, propionyl, benzoyl, benzyl, benzyloxycarbonyl, which may be optionally substituted by one or more halogens.
  • each occurrence of A 1 and A 2 is independently selected from hydrogen, acetyl, trifluoroacetyl, difluoroacetyl, monofluoroacetyl, propionyl, benzoyl, Benzyl, benzyloxycarbonyl.
  • each occurrence of A 1 and A 2 is independently selected from hydrogen, acetyl, and benzoyl.
  • each occurrence of A 1 and A 2 is independently selected from hydrogen and acetyl.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, X 1 , X 2 , _ _ _ _ _ _ _ _ ) 2 C(G 3 ) 2 S) m -, or C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- optionally substituted by one or more G 3 6-membered heterocycloalkyl, C 3-6 cycloalkenyl, C 6-10 aryl, 5-6-membered heteroaryl, the heteroatoms in the heterocycloalkyl and heteroaryl are independently selected from O, N or S, the number of heteroatoms is 1, 2 or 3.
  • X 1 , X 2 , X 3 are each independently selected from the group consisting of bonds, -(CH 2 ) n -, -(CH 2 CH 2 O) m -.
  • X1 , X2 , X3 are each independently selected from the group consisting of bonds, -CH2- , -( CH2 ) 2- , -( CH2 ) 3- , -( CH2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -CH 2 CH 2 O-, -(CH 2 CH 2 O) 2 -, -(CH 2 CH 2 O) 3 -.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, X 1 , X 2 , and X 3 are each independently selected from the bond, -(CH 2 ) n -.
  • X 1 , X 2 , X 3 are each independently selected from the group consisting of bonds, -(CH 2 ) 2 -, -(CH 2 ) 4 -, -(CH 2 ) 6 -.
  • X 1 is independently selected from bond
  • X 2 is independently selected from bond
  • X 3 is independently selected from -(CH 2 ) 2 -, -(CH 2 ) 4 -, -(CH 2 ) 6 -.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, G 3
  • Each occurrence is independently selected from hydrogen, halogen, hydroxyl, amino, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy.
  • each occurrence of G 3 is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH 2 , oxo, -CH 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OC(CH 3 ) 3 , -O( CH 2 F), -O(CHF 2 ), -O(CF 3 ), -CH 2 F, -CHF 2 , -CF 3 , -CHFCH 3 , -CH 2 CHF 2 .
  • each occurrence of G 3 is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH 2 , oxo, -CH 3 , - CH 2 CH 3 .
  • each occurrence of G3 is independently selected from hydrogen.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, X 4 Independently selected from the group consisting of bonds, -(C(G 4 ) 2 ) a -, -(C(G 4 ) 2 C(G 4 ) 2 O) b -, -(C(G 4 ) 2 C(G 4 ) 2 S) b -, or C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl , 3 optionally substituted by one or more G 4 -6-membered heterocycloalkyl, C 6-10 aryl, 5-6-membered heteroaryl, the heteroatoms in the heterocycloalkyl or heteroaryl are independently selected from O, N or S, the number of heteroatoms 1, 2 or 3.
  • X 4 Independently selected from the group consisting of bonds,
  • X 4 is independently selected from the group consisting of bonds, -(CH 2 ) a -, -(CD 2 ) a -, -(CHD) a -, -(CH 2 CH 2 O) b - , -(CH 2 CH 2 S) b -, or C 2-4 alkenyl, C 2-4 alkynyl, C 5-6 cycloalkyl, C 5- optionally substituted by one or more G 4 6- cycloalkenyl, 5-6-membered heterocycloalkyl, C 6-10 aryl, 5-6-membered heteroaryl, the heteroatoms in the heterocycloalkyl and heteroaryl are independently selected from O or N , the number of heteroatoms is 1 or 2.
  • X 4 is independently selected from the group consisting of bonds, -(CH 2 ) a -, -(CD 2 ) a -, -(CHD) a -, -(CH 2 CH 2 O) b - , -(CH 2 CH 2 S) b -, or optionally substituted by G 4
  • X 4 is independently selected from the group consisting of bonds, -(CH 2 ) a -, -(CD 2 ) a -, -(CHD) a -, -(CH 2 CH 2 O) b - ,-(CH 2 CH 2 S) b -,
  • X 4 is independently selected from the group consisting of bonds, -(CH 2 ) a -, -(CD 2 ) a -, -(CHD) a -, -(CH 2 CH 2 O) b - , -(CH 2 CH 2 S) b -.
  • X 4 is independently selected from the group consisting of bonds, -(CH 2 ) a -, -(CH 2 CH 2 O) b -.
  • X 4 is independently selected from bond, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, -(CH 2 ) 8 -, - (CH 2 ) 9 -, -(CH 2 ) 10 -, -(CH 2 ) 11 -, -(CH 2 ) 12 -, -(CH 2 ) 13 -, -(CH 2 ) 14 -, -CH 2 CH 2 O-, -(CH 2 CH 2 O) 2 -, -(CH 2 CH 2 O) 3 -.
  • X4 is independently selected from the group consisting of bonds, -( CH2 ) 8- , -( CH2 ) 9- , -( CH2 ) 10- , -( CH2 ) 11- , - (CH 2 ) 12 -, -(CH 2 ) 13 -, -(CH 2 ) 14 -, -CH 2 CH 2 O-, -(CH 2 CH 2 O) 2 -.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, X 4 Independently selected from -(CH 2 ) a -.
  • X 4 is independently selected from -(CH 2 ) 10 -, -(CH 2 ) 11 -, -(CH 2 ) 12 -.
  • the compound provided by the invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, G 4
  • Each occurrence is independently selected from hydrogen, halogen, hydroxyl, amino, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy.
  • each occurrence of G 4 is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH 2 , oxo, -CH 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OC(CH 3 ) 3 , -O( CH 2 F), -O(CHF 2 ), -O(CF 3 ), -CH 2 F, -CHF 2 , -CF 3 , -CHFCH 3 , -CH 2 CHF 2 .
  • each occurrence of G 4 is independently selected from -H, -F, -Cl, -Br, -I, -OH, -NH 2 , oxo, -CH 3 , - CH 2 CH 3 .
  • each occurrence of G 4 is independently selected from hydrogen.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein n is independent Ground is selected from an integer of 0-15, specifically 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15.
  • n is independently selected from an integer from 0 to 6, specifically 0, 1, 2, 3, 4, 5, 6.
  • n is independently selected from 2, 4, and 6.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, m is independently
  • the ground is selected from an integer from 0 to 6, Specifically, they are 0, 1, 2, 3, 4, 5, and 6.
  • n is independently selected from an integer from 0 to 3, specifically 0, 1, 2, 3.
  • n is independently selected from 0, 1, 2.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof, wherein a is independently Ground is selected from an integer of 0-15, specifically 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15.
  • a is independently selected from an integer from 6 to 12, specifically 6, 7, 8, 9, 10, 11, 12.
  • a is independently selected from 10, 11, 12.
  • b is independently selected from an integer from 0 to 3, specifically 0, 1, 2, 3.
  • b is independently selected from 0, 1, 2.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, J 1 , J 2 , J 3 , J 4 are each independently selected from the group consisting of bonds, -O-, -S-, -NH-, -C(O)-, -NHC(O)-, -C(O)NH-, -C(O)O-, -OC(O)-, -N(G 5 )C(O)-, -C(O)N(G 5 )-, -N(G 5 )-, -C( G 5 ) 2 -.
  • J 1 , J 2 , J 3 , J 4 are each independently selected from the group consisting of bonds, -O-, -NHC(O)-, -C(O)NH-.
  • J 1 is independently selected from bond
  • J 2 is independently selected from bond
  • J 3 is independently selected from -O-, -NHC(O)-, -C(O )NH-
  • J 4 is independently selected from -NHC(O)-, -C(O)NH-.
  • J 1 is independently selected from bond
  • J 2 is independently selected from bond
  • -O- is independently selected from bond
  • J 3 is independently selected from -O-
  • -NHC(O)- is independently selected from bond, -O- Selected from -C(O)NH-.
  • the compound provided by the invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, G 5
  • Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, -BH 2 , -B(OH) 2 , -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl optionally substituted by one or more of deuterium, halogen, hydroxyl, and amino , C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl.
  • each occurrence of G 5 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, -N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3- optionally substituted by one or more of deuterium and halogen 6- cycloalkenyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, the heteroatoms in the heterocycloalkyl and heteroaryl are independently selected from O or N , the number of heteroatoms is 1 or 2.
  • each occurrence of G5 is independently selected from -H, -F, -Cl, -Br, -I, -NH2 , -CD3 , -CH2F , -CHF2 , -CF 3 , -CH 2 Cl , -CH 2 I , -N(CH 3 )(CH 3 ) , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -C(CH 3 ) 3 .
  • each occurrence of G 5 is independently selected from -H, -F, -NH 2 , -CD 3 , -CF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -C(CH 3 ) 3 .
  • each occurrence of G 5 is independently selected from -H.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, J 5 , J 6 are each independently selected from the keys , -O-, -S-, -NH-, -C(O)-, -NHC(O)-, -C(O)NH-, -C(O)O-, -OC(O)-, -N(G 6 )C(O)-, -C(O)N(G 6 )-, -N(G 6 )-, -C(G 6 ) 2 -.
  • J 5 , J 6 are each independently selected from the group consisting of bonds, -C(O)-, -NHC(O)-, -C(O)NH-, -N(G 6 )C (O)-, -C(O)N(G 6 )-.
  • J 5 , J 6 are each independently selected from the group consisting of bonds, -O-, -C(O)-, -NHC(O)-, -C(O)NH-, -OC( O)-.
  • J5 is independently selected from -NHC(O)-, -C(O)NH-.
  • J6 is independently selected from bond, -C(O)-.
  • the compound provided by the invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, G 6
  • Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, -BH 2 , -B(OH)(OH), -N(C 1-6 alkyl)(C 1-6 alkyl ), C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl, C 1-6 alkoxy optionally substituted by one or more of deuterium, halogen, hydroxyl, and amino base, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl.
  • each occurrence of G 6 is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, carboxyl, -N(C 1-6 alkyl)(C 1-6 alkyl), C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkyl, C 1-6 alkoxy, C 3-6 optionally substituted by one or more of deuterium and halogen Cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, heteroatoms in the heterocycloalkyl and heteroaryl Independently selected from O or N, the number of heteroatoms is 1 or 2.
  • each occurrence of G 6 is independently selected from -H, -F, -Cl, -Br, -I, -NH 2 , -CD 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 Cl , -CH 2 I , -N(CH 3 )(CH 3 ) , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -C(CH 3 ) 3 .
  • each occurrence of G 6 is independently selected from -H, -F, -NH 2 , -CD 3 , -CF 3 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -C(CH 3 ) 3 .
  • each occurrence of G 6 is independently selected from -H.
  • the compound provided by the invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, X 5
  • Each occurrence is independently selected from bond, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5 -6-membered heteroaryl; the C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5- 6-membered heteroaryl groups are unsubstituted or optionally substituted with one or more G7 .
  • each occurrence of Heterocycloalkyl is unsubstituted or optionally substituted with one or more G7 .
  • each occurrence of X is independently selected from bond, or methyl, ethyl, n-propyl, isopropyl, optionally substituted by one or more G
  • each occurrence of X5 is independently selected from methyl substituted by one or two G7 ,
  • each occurrence of X 5 is independently selected from the group consisting of substituted with one or two G 7
  • the compound provided by the invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, G 7 Independently selected from hydroxyl, -C 1-6 alkyl-OG 8 , -OG 9 ,
  • G 7 is independently selected from hydroxyl, -C 1-4 alkyl-OG 8 , -OG 9 ,
  • G 7 is independently selected from hydroxyl, -C 1-3 alkyl-OG 8 , -OG 9 ,
  • G 7 is independently selected from hydroxyl, -CH 2 -OG 8 , -OG 9 ,
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, G 8 Independently selected from: H,
  • G 8 is independently selected from H
  • G 8 is independently selected from H
  • G 8 is independently selected from H
  • G 8 is selected from H or
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein Cat is independent Ground is selected from sodium ions, triethylammonium ions, and tetrabutylammonium ions; r is an integer from 1 to 2, specifically 1, 2; Solid support is a resin solid phase carrier.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein Cat is preferably Triethylammonium ion, sodium ion.
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, independently selected from
  • the compound provided by the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, Independently selected from:
  • the present invention provides a compound represented by formula (II), or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof, It is a conjugate of a compound with liver-targeted delivery effect and an oligonucleotide, especially a novel GalNAc derivative-oligonucleotide conjugate. Conjugation of GalNAc derivatives can improve or enhance the pharmacokinetic and pharmacodynamic properties of the linked nucleic acid. Specifically, it has the following structure:
  • each R is independently selected from:
  • the definitions of J 3 , J 4 , J 5 , J 6 , A 1 and A 2 are the same as those of the compound of formula (I) above, and the definition of X 5 ' is only the same as the definition of X 5 in the compound of formula (I) above. Lack of an H, hydroxyl group, OG 8 or OG 9 to connect to E 4 ;
  • E 4 is independently selected from -O-, -S-;
  • E 3 is a functional oligonucleotide molecule, including but not limited to: small interfering RNA, microRNA, immune stimulators, alternative splice bodies, single-stranded RNA, double-stranded RNA, antisense nucleic acids, nucleic acid aptamers, One of stem-loop RNA, mRNA fragment, activating RNA or DNA.
  • the compound provided by the invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof wherein, E 4 Selected from -O-.
  • E3 is small interfering RNA, double-stranded RNA, single-stranded RNA or antisense nucleic acid.
  • relevant modifications can also be made to functional oligonucleotides, including but not limited to the following modifications: locked nucleic acid modification, ring-opening or non-locked nucleic acid modification, 2'-methoxyethyl modification, 2′-O-methyl modification, 2′-O-allyl modification, 2′-C-allyl modification, 2′-fluoro modification, 2′-deoxy modification, 2′-hydroxyl modification, thio Phosphate backbone modification, DNA modification, fluorescent probe modification, ligand modification.
  • its E3 is a functional oligonucleotide, including but not limited to: small interfering RNA (siRNA), microRNA (microRNA), immune stimulatory (immune stimulatory), alternative splicing Splice variant, single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), transfer RNA (tRNA), antisense nucleic acid (antisense), nucleic acid aptamer (Nucleic Acid Aptamer), stem-loop RNA (stem- One of loop RNA), mRNA fragment, small activating RNA (small activating RNA, saRNA) or DNA.
  • small interfering RNA siRNA
  • microRNA microRNA
  • immune stimulatory immuno stimulatory
  • alternative splicing Splice variant single-stranded RNA
  • dsRNA double-stranded RNA
  • tRNA transfer RNA
  • antisense nucleic acid antisense
  • nucleic acid aptamer Nucleic Acid Aptamer
  • the functional oligonucleotide is preferably small interfering RNA, single-stranded RNA, double-stranded RNA, or antisense nucleic acid.
  • the 5' or 3' end of the functional oligonucleotide is connected to the GalNAc derivative of the present invention
  • each of the oligonucleotides binds 1-5 (specifically: 1, 2, 3, 4, 5) GalNAc derivatives of the present invention in one of the present invention.
  • functional oligonucleotides for example: siRNA
  • relevant modifications on functional oligonucleotides including but not limited to: locked nucleic acid modification, ring-opening or non-locked nucleic acid modification, 2'-methoxyethyl modification, 2′-O-methyl modification, 2′-O-allyl modification, 2′-O-methoxyethyl, 2′-C-allyl modification, 2′-fluoro modification, 2′-deoxy Modification, 2′-hydroxyl modification, phosphorothioate backbone modification, DNA modification, fluorescent probe modification, ligand modification;
  • the present invention also relates to an siRNA molecule that inhibits target gene expression, including a sense strand and an antisense strand that complement each other to form a double-stranded region, and the sense strand and/or the antisense strand Comprising or consisting of 15-25 nucleotides, the antisense strand is connected to at least 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 consecutive nucleotides are completely or partially complementary, the length of the double-stranded region is 15-25bp, and at least one nucleotide in the siRNA molecule is modified;
  • any strand of the siRNA molecule contains an overhang of 0-5 bases;
  • the target genes include but are not limited to: ApoB, ApoC, ANGPTL3, PCSK9, FVII, p53, HAV, HBV, HCV, HDV, HEV, AGT, Lp(a), XDH, HSD17B13, SCD1, PNPLA3, HMGCR, etc.
  • the oligonucleotide in formula (II) that can be conjugated with the novel GalNAc derivative at the 5' or 3' end can be selected from the following sequences:
  • the present invention provides a compound of formula (I) or formula (II) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof, wherein,
  • the compound has the following structure:
  • the object of the present invention also includes providing the preparation of compounds represented by general formula (I), general formula (II) or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable compounds thereof. Salt method.
  • Another aspect of the present invention also provides a pharmaceutical composition, which contains the compound of the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable of salt.
  • composition of the present invention also contains pharmaceutically acceptable excipients.
  • the compound of the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or its pharmaceutical Administration of the above acceptable salts may be carried out in pure form or in the form of a suitable pharmaceutical composition by any acceptable mode of administration for drugs providing similar uses.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof with a suitable pharmaceutically acceptable salt. Prepared by combining auxiliary materials.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations. Generally, the above-mentioned pharmaceutical compositions can be prepared by conventional preparation methods using conventional excipients in the field of preparation.
  • the present invention also provides the compound of the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention. Use in the preparation of medicines.
  • the present invention also provides the compound of the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention.
  • the specific genes include but are not limited to: ApoB, ApoC, ANGPTL3, PCSK9, FVII, p53, HAV, HBV, HCV, HDV, HEV, AGT, Lp(a), XDH, HSD17B13, SCD1, PNPLA3, HMGCR wait.
  • the invention provides uses, wherein the diseases are chronic liver diseases, hepatitis, liver fibrosis diseases, liver proliferative diseases and dyslipidemia.
  • the dyslipidemia is hypercholesterolemia, hypertriglyceridemia, or atherosclerosis.
  • the disease also includes other liver diseases, including malignant diseases characterized by cell proliferation, hematological diseases, diseases characterized by inflammation, or metabolic diseases.
  • malignant diseases characterized by liver cell proliferation can be benign or malignant tumors, such as cancer, liver metastasis or hepatoblastoma.
  • Hematologic disorders or disorders characterized by inflammation may be disorders involving coagulation factors, complement-mediated inflammation, or fibrosis.
  • Metabolic diseases include dyslipidemia and disorders of glucose regulation.
  • liver disease can also be treated by administering one or more oligonucleotides that have high sequence homology to genes involved in liver disease.
  • the invention provides a method for preventing and/or treating physiological conditions or diseases caused by the expression of specific genes in hepatocytes, comprising administering to an individual in need thereof a compound of the invention or a prodrug thereof.
  • a compound of the invention or a prodrug thereof comprising administering to an individual in need thereof a compound of the invention or a prodrug thereof.
  • the diseases are chronic liver disease, hepatitis, liver fibrosis disease, and liver hyperplasia diseases and dyslipidemia.
  • the dyslipidemia is hypercholesterolemia, hypertriglyceridemia, or atherosclerosis.
  • the disease also includes other liver diseases, including malignant diseases characterized by cell proliferation, hematological diseases, diseases characterized by inflammation, or metabolic diseases.
  • malignant diseases characterized by liver cell proliferation can be benign or malignant tumors, such as cancer, liver metastasis or hepatoblastoma.
  • Hematologic disorders or disorders characterized by inflammation may be disorders involving coagulation factors, complement-mediated inflammation, or fibrosis.
  • Metabolic diseases include dyslipidemia and disorders of glucose regulation.
  • the invention provides compounds of the invention or prodrugs, tautomers, stereoisomers thereof for preventing and/or treating physiological conditions or diseases caused by the expression of specific genes in hepatocytes. isotopes, solvates, isotope derivatives or pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present invention;
  • the diseases described are chronic liver diseases, hepatitis, liver fibrosis diseases, liver proliferative diseases and dyslipidemia.
  • the dyslipidemia is hypercholesterolemia, hypertriglyceridemia, or atherosclerosis.
  • the disease also includes other liver diseases, including malignant diseases characterized by cell proliferation, hematological diseases, diseases characterized by inflammation, or metabolic diseases.
  • malignant diseases characterized by liver cell proliferation can be benign or malignant tumors, such as cancer, liver metastasis or hepatoblastoma.
  • Hematologic disorders or disorders characterized by inflammation may be disorders involving coagulation factors, complement-mediated inflammation, or fibrosis.
  • Metabolic diseases include dyslipidemia and disorders of glucose regulation.
  • oxo means that two hydrogen atoms in the same substitution position are replaced by the same oxygen atom to form a double bond.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms (i.e., C 1 to 10 Alkyl), further preferably contains 1-8 carbon atoms (C 1-8 alkyl), more preferably contains 1-6 carbon atoms (i.e. C 1-6 alkyl), such as "C 1-6 alkyl” It means that the group is an alkyl group, and the number of carbon atoms on the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6).
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl , n-octyl, etc.
  • alkenyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond.
  • the alkenyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C 2-10 alkenyl), further preferably 2-8 carbon atoms (C 2-8 alkenyl), and more preferably 2-8 carbon atoms (C 2-8 alkenyl).
  • 2-6 carbon atoms i.e. C 2-6 alkenyl
  • 2-5 carbon atoms i.e. C 2-5 alkenyl
  • 2-4 carbon atoms i.e.
  • C 2-4 alkenyl 2- 3 carbon atoms (i.e. C 2-3 alkenyl), 2 carbon atoms (i.e. C 2 alkenyl), for example "C 2-6 alkenyl” means that the group is alkenyl, and the carbon chain The number of carbon atoms is between 2 and 6 (specifically 2, 3, 4, 5 or 6).
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond.
  • the alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C 2-10 alkynyl group), further preferably 2-8 carbon atoms (C 2-8 alkynyl group), and more preferably 2-8 carbon atoms (C 2-8 alkynyl group).
  • 2-6 carbon atoms i.e. C 2-6 alkynyl
  • 2-5 carbon atoms i.e. C 2-5 alkynyl
  • 2-4 carbon atoms i.e.
  • C 2-4 alkynyl 2- 3 carbon atoms (i.e. C 2-3 alkynyl), 2 carbon atoms (i.e. C 2 alkynyl), for example "C 2-6 alkynyl” means that the group is an alkynyl group, and the carbon chain The number of carbon atoms is between 2 and 6 (specifically 2, 3, 4, 5 or 6).
  • alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
  • alkoxy refers to -O-alkyl, which is as defined above, that is, containing 1-20 carbon atoms, preferably 1-10 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6).
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy Oxygen, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2 , 2-dimethylpropoxy, 1-ethylpropoxy, etc.
  • halogen refers to F, Cl, Br, I.
  • haloalkyl means an alkyl group as defined above in which one, two or more hydrogen atoms or all of the hydrogen atoms are replaced by halogen.
  • Representative examples of haloalkyl groups include CCl 3 , CF 3 , CHCl 2 , CH 2 Cl, CH 2 Br, CH 2 I, CH 2 F, CH 2 CF 3 , CF 2 CF 3 , and the like.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group with a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl), more preferably 3-7 carbon atoms (C 3-7 cycloalkyl), 4-6 carbon atoms (C 4-6 cycloalkyl), 5-6 carbon atoms (C 5-6 cycloalkyl).
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
  • cycloalkenyl means composed of the subgroups monocyclic hydrocarbon ring, bicyclic hydrocarbon ring and spiro-hydrocarbon ring, however, the system is unsaturated, that is, there is at least one CC double bond but no aromatic system.
  • it contains 3-12 carbon atoms (i.e. C 3-12 cycloalkenyl), more preferably 3-10 carbon atoms (C 3-10 cycloalkenyl), further preferably 3-6 carbon atoms (C 3 -6 cycloalkenyl), 4-6 carbon atoms (C 4-6 cycloalkenyl), 5-6 carbon atoms (C 5-6 cycloalkenyl).
  • heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic non-aromatic substituent having ring carbon atoms and 1 to 4 ring heteroatoms, including 3-20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C.
  • the number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (ie, 1, 2 or 3).
  • Examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like.
  • Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
  • Heterocyclyl may be a monocyclic (“monocyclic heterocyclyl”) or a fused (“fused heterocyclyl” or “heterofused cyclyl”), bridged (“heterobridged cyclyl” or “bridged heterocyclyl”) or spiro-fused (“heterospiryl” or “spiroheterocyclyl”) ring system, such as a bicyclic system (“bicyclic heterocyclyl”), and can Is saturated or may be partially unsaturated.
  • Heterocyclyl bicyclic systems may include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems in which the heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or "Heterocyclyl” also includes ring systems in which the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, or a cycloalkyl ring, as defined above, is fused with one or more aryl or heteroaryl groups.
  • a fused ring system of a heteroaryl group wherein the point of attachment is on the heterocyclyl ring or cycloalkyl ring, and in such cases the membership of the heterocyclyl ring system is the post-fused ring system Number of atoms.
  • each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl").
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuryl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolyl, and pyrrole.
  • Base-2,5-dione is
  • Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolyl, and oxazolidin-2-one .
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazinyl, thiadiazinyl, oxothiazinyl, and dioxo Dioxazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxpanyl, and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azacyclooctyl, oxacyclooctanyl, and thiocyclyl.
  • Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring include, but are not limited to, indolyl, isodihydro Indolyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinoline Key et al.
  • heterocycloalkyl refers to a monocyclic, saturated “heterocyclyl” or “heterocycle” as defined above.
  • the ring atoms are as defined above, that is, containing 3 to 20 ring atoms ("3 -20-membered heterocycloalkyl”), the number of heteroatoms is 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein heteroatoms
  • the atoms are each independently selected from N, O, or S.
  • ring atoms 3-12 membered heterocycloalkyl
  • 3-12 membered heterocycloalkyl 3-12 membered heterocycloalkyl
  • 3-10 membered heterocycloalkyl 3-10 membered heterocycloalkyl
  • 3-10 membered heterocycloalkyl 3-10 membered heterocycloalkyl
  • ring atoms 3-8-membered heterocycloalkyl
  • 4-7 ring atoms 4--7 ring atoms
  • 5-10 ring atoms 5-10 membered heterocycloalkyl
  • each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an “unsubstituted heterocycloalkyl”) or substituted with one or more substituents Substituted (a "substituted heterocycloalkyl").
  • heterocyclyl or “heterocycle” section has given some exemplary “heterocycloalkyl”, which also includes, but is not limited to, aziridinyl, oxirinyl, thiirane base, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , oxathiacyclohexyl, oxazolidinyl, dioxanyl, dithiocyclohexyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, etc.
  • aryl or “aryl” means an aryl group containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms. carbon atoms, or monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems of 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl, and the like.
  • heteroaryl or “heteroaryl ring” means a 5-14-membered structure, or preferably a 5-10-membered structure, or preferably a 5-8-membered structure, more preferably a 5-6-membered structure.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl , tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazine, phthalazinyl, quinolyl, isoquinolinyl, pyridinyl, purinyl, indyl Indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrole Para[2,3-b]pyridyl,
  • Solid support or “solid support” refers to inorganic particles, polymers or other solid materials as a matrix, with active groups that can be linked to target compounds through surface modification, thereby being used for the synthesis of oligonucleotides.
  • the term "pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” means salts that are suitable within the scope of reasonable medical judgment for contact with mammalian, especially human, tissue without undue toxicity, irritation, or allergic reaction. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art and are commensurate with a reasonable benefit/risk ratio. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent.
  • isotopic derivative means that the compounds of the invention may exist in isotopically traced or enriched form, containing one or more atoms having an atomic weight or mass number different from that found in nature The atomic weight or mass number of the largest number of atoms.
  • Isotopes may be radioactive or non-radioactive isotopes.
  • the isotopes commonly used as isotope labels are: hydrogen isotopes, 2 H and 3 H; carbon isotopes: 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I ; Nitrogen isotopes: 13 N and 15 N; Oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotope 35 S.
  • These isotopically labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 2 H and 13 C are more widely used because they are easy to label and detect.
  • Isotopically labeled compounds generally start from labeled starting materials and are synthesized using known synthetic techniques as for non-isotopically labeled compounds.
  • solvate and “solvate” mean the physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain circumstances, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be separated.
  • the solvent molecules in a solvate may exist in regular and/or disordered arrangements.
  • Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules.
  • “Solvate” encompasses both solution phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methoxides, and isopropoxides. Solvation methods are well known in the art.
  • stereoisomer refers to compounds that have the same chemical structure but different arrangements of atoms or groups in space.
  • Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography. method and/or fractional crystallization method.
  • tautomers refers to structural isomers with different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also known as proton transfer tautomers
  • proton migration tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization.
  • Valence tautomers involve interconversions through the reorganization of some of the bonding electrons.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Therefore, individual stereochemical isomers or mixtures of enantiomers, diastereomers, or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.
  • prodrug refers to a drug that is converted in the body to the parent drug.
  • Prodrugs are often useful in that they improve some defined, undesirable physical or biological property. Physical properties are often related to solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too rapid metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they are bioavailable via oral administration, whereas the parent body is not. Prodrugs also have increased solubility in pharmaceutical compositions compared to the parent drug.
  • prodrug may be any compound of the invention administered as an ester ("prodrug") to facilitate delivery across cell membranes, where water solubility is detrimental to mobility, but once inside Intracellular water solubility is beneficial and is subsequently metabolically hydrolyzed to carboxylic acids, the active entities.
  • prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active moiety.
  • Functional oligonucleotides described in the present invention refer to oligonucleotides that can utilize RNA activation (RNA activation) by generating stable and specific hybridization with target sequences.
  • RNA activation RNA activation
  • Principles such as RNAa), RNA interference (RNAi), antisense nucleic acid technology, and exon skipping technology can up-regulate or down-regulate the expression of target genes, or lead to alternative splicing of mRNA.
  • functional oligonucleotides can also be nucleic acid structures that produce stable and specific binding to target proteins.
  • polynucleotides are also suitable for conjugation with the conjugation molecules provided by the present disclosure to form conjugates to achieve targeted delivery, such as liver targeting. delivery, thereby regulating the expression of proteins transcribed from the mRNA.
  • Target sequence refers to the target mRNA.
  • target mRNA refers to the mRNA corresponding to a gene that is abnormally expressed in liver cells. It can be either the mRNA corresponding to an overexpressed gene or the mRNA corresponding to an underexpressed gene.
  • the target mRNA can be ApoB, ApoC, ANGPTL3, PCSK9, FVII, p53, HAV, HBV, HCV, HDV, HEV, AGT, Lp(a ), XDH, HSD17B13, SCD1, PNPLA3, HMGCR and other genes corresponding mRNA.
  • the target mRNA can be the mRNA transcribed from the corresponding PCSK9 gene, or the mRNA corresponding to the ANGPTL3 gene, or the mRNA corresponding to the XDH gene, or the mRNA corresponding to the APOC3 gene.
  • the complete complementarity in the present invention means that the bases of nucleotides follow the classic Watson-Crick base pairing principle (for example: A-U, G-C, A-T); the partial complementarity means that some bases are not Satisfy the Watson-Crick base pairing principle, for example: there is non-Watson-Crick base pairing mode (for example: G-U, A-A).
  • conjugate or “conjugated molecule” used in the present invention refers to a compound formed by covalent linkage between various chemical moieties.
  • CPG glass-based solid carrier CPG- NH2 glass solid phase carrier with amino-modified surface
  • CBz benzyloxycarbonyl DMTr dimethoxytrityl DIPEA N,N'-Diisopropylethylamine DCM dichloromethane DMF N,N-dimethylformamide
  • EDCI.HCl 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • the present invention designs a class of compounds with liver-targeted delivery effects and oligonucleotide conjugates thereof.
  • This compound with liver-targeted delivery effects is a new type of GalNAc derivative, which is used for the treatment of diseases occurring in the liver or related to the liver. Liver-related diseases provide a new direction.
  • Tests have shown that compared with the existing technology (ligand L96), the oligonucleotide conjugate of the novel GalNAc derivative molecule of the present invention has stronger binding ability to ASGPR, is more easily absorbed by liver cells, and inhibits target mRNA higher activity.
  • the present invention studies a specific synthesis method, which has simple process, convenient operation, and is conducive to large-scale industrial production and application.
  • Figure 1 In vivo imaging of mice administered subcutaneous injection of PC01 and PC02 at 2h and 4h (Figure 1-1 is PC012h; Figure 1-2 is PC022h; Figure 1-3 is PC014h; Figure 1-4 is PC024h);
  • Figure 2 Average fluorescence density of PC01 and PC02 in Huh7 cells
  • Figure 3 Average fluorescence density of PC01 and PC02 in mouse liver primary cells
  • Figure 4 The number of positive cells of PC01 and PC02 in mouse liver primary cells; where AF647 refers to the name of the detection channel of the flow cytometer;
  • Figure 5 Effect diagram of in vitro uptake efficiency of GalNAc ligand-coupled siRNA
  • Figure 6 The results of using human primary hepatocytes to evaluate the in vitro inhibition of PCSK9 mRNA activity by siRNA of the test compound
  • the product 6-c (8.79g, 137mmol, 1eq.) obtained in the above step was dissolved in anhydrous DMF (500mL), and piperidine (548mmol 4eq.) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with chloroform (500 mL) and the organic phase was washed with saturated aqueous NaHCO (2 x 500 mL) and brine (500 mL). The organic layer was separated, dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure to obtain an oil, which was purified by column chromatography (methanol: dichloromethane 5% elution column must be alkalized first), and the yield was 71%. .
  • Conjugate 9 was prepared from compound 9 with reference to the method of Example 7 below.
  • Example 2-6 (compounds 16-18, 24-26, 33, 34-36, 37-39 and conjugates 18, 26, 33, 36, 39).
  • Oligonucleotide conjugates of related GalNAc derivative molecules prepared according to the above method and their related oligonucleotide sequences:
  • the relevant sequence numbered XD targets the XDH gene; the relevant sequence numbered PC targets the PCSK9 gene; and the relevant sequence numbered AN targets the ANGPTL3 gene.
  • Test Example 1 Evaluation experiment of liver targeting effect of GalNAc ligand-conjugated siRNA with different structures in C57BL/6 mice
  • mice A total of 12 C57BL/6 female mice were used in the experiment. They were divided into 2 groups. The group information is as follows: Group 1 PC01 and Group 2 PC02. There were 6 mice in each group. They were all administered by subcutaneous injection. The drugs PC01 and PC02 were subcutaneously injected respectively. PC02 (recorded as 0h at the time of administration), the dosage was 5 mg/kg. In vivo imaging was performed on all mice in Group 1 PC01 and Group 2 PC02 at 2h, 4h, 24h and 48h; at 48h, mice in Group 1 PC01 and Group 2 PC02 were euthanized.
  • the 2h and 4h experimental results showed that after subcutaneous injection of the test drug in Group 1 PC01 and Group 2 PC02, the fluorescence signal was mainly detected in the liver, and gradually weakened as time went by. After 24 hours, the in vivo fluorescence signal decreased to an unobservable level. After 48 hours, the hearts, livers, spleens, lungs and kidneys of the euthanized mice were separated and in vitro images were taken. Signals of similar levels were detected in the isolated livers of PC01 in group 1 and PC02 in group 2.
  • Test Example 2 Comparison of the in vitro uptake efficiency of GalNAc ligand-coupled siRNA with different structures
  • Huh7 cells were cultured in a 37°C, 5% CO2 saturated humidity incubator containing 10% FBS/DMEM medium (100 ⁇ g/mL streptomycin, 100 U/mL penicillin). Huh7 cells cultured to 75% confluence were digested using trypsin (Gibico) and resuspended in 2% BSA/PBS buffer to prepare a cell suspension (1 ⁇ 10 6 cells/mL). Take 100 ⁇ L of each cell suspension and add it to two different centrifuge tubes, and then add PC01 and PC02 coupled with fluorescent groups to the two centrifuge tubes (so that the final concentrations are both 20 nM). Incubate at room temperature in the dark for 1 hour, wash the cells twice with 2% BSA/PBS buffer, and use a flow cytometer to detect the average fluorescence density of the cells at an excitation wavelength of 647 nm.
  • FBS/DMEM medium 100 ⁇ g/mL streptomycin, 100 U/mL penicillin.
  • PC01 and PC02 were tested in primary mouse liver cells. Resuspend fresh mouse liver primary cells in 2% BSA/PBS to make a cell suspension (1 ⁇ 10 6 cells/mL). Take 100 ⁇ L of cell suspension into two different centrifuge tubes and add PC01 and PC02 coupled with fluorescent groups (final concentration 20nM). After incubation at room temperature in the dark for 1 hour, the cells were washed twice with PBS buffer, and then a flow cytometer was used to detect the average fluorescence density of the cells and the number of positive cells at an excitation wavelength of 647 nm.
  • the molecules designed in the present invention are more easily taken up by liver cells
  • the molecules designed in the present invention are coupled to different sequences targeting the same target or sequences targeting different targets, the following process is followed to evaluate the response of Huh7 cells to these molecules. uptake efficiency.
  • Huh7 cells in advance.
  • the Huh7 cells cultured in a 10cm culture dish were digested and counted, and plated according to the number of 250,000 cells per well.
  • follow-up treatment will be carried out after 24 hours of adhesion to the wall. Wash Huh7 cells twice with PBS, then use DMEM containing 2% FBS to dilute different GalNac-coupled siRNA, adjust the concentration of siRNA to 200 nM, add it to the culture dish, and culture for 24 hours.
  • compound ligands are used for different targets and siRNA sequences (the related sequence numbered XD targets the XDH gene; the related sequence numbered PC targets the PCSK9 gene; and the related sequence numbered AN targets the ANGPTL3 gene).
  • the 26 oligonucleotide conjugates (XD05 and XD11, PC07 and PC13, and AN05 and AN11) all had the highest uptake efficiency.
  • the above experimental results show that the present invention obtains the targeting effect of the compound with liver-targeted delivery function. Does not depend on the target and siRNA sequence delivered.
  • Test Example 3 Using primary human hepatocytes (PHH) to evaluate the in vitro inhibition of PCSK9 mRNA activity by siRNA of the test compound
  • the expression level of target gene mRNA in each sample was calculated by the ⁇ Ct relative quantification method.
  • PC02 containing ligand 9 inhibits PCSK9 mRNA activity in primary human hepatocytes (PHH) with an IC 50 of 5.65 nM, which is better than the IC 50 value of PC01 containing ligand L96 in the control group of 16.57 nM.
  • PC02 is more active than PC01.
  • PCSK9 male and female mice were used in the experiment. They were randomly divided into groups according to body weight, with 8 mice in each group, 4 males and 4 males, and a single dose of 3 mg/kg. Subcutaneous injection was administered in 4 groups. The blank is the negative control group injected with normal saline, PC15 is the positive control group, and the two groups PC17 and PC18 are the experimental groups. Blood was collected on days -3 (the third day before administration), 7, 14, 21, 28, and 35 (fasting for 4 hours before blood collection, the first dose was on day 0), and 0.1 ml of blood was collected by bleeding from the back of the eyeball. Human PCSK9 ELISA Kit (proteintech) was used to detect the expression level of PCSK9 protein in the serum of the blood separated serum, and comparisons were made between groups.
  • the mouse drug efficacy results show (Figure 7) that PCSK9 protein levels of PC15 (L96), PC17 (ligand 18) and PC18 (ligand 26) all dropped to the lowest on the 4th day, and then began to rebound. On the 28th day, PC15 (L96) basically returned to the pre-drug level, while the PCSK9 protein levels in the PC17 (ligand 18) and PC18 (ligand 26) groups were still lower than the pre-drug level.
  • the blank is the negative control group injected with normal saline.
  • PC15 is the positive control group
  • PC19 is the experimental group.
  • Blood was collected on days -3 (the 3rd day before administration), 7, 14, 21, and 28 (fasting for 4 hours before blood collection, the first dose was on day 0), and 0.1ml of blood was collected by bleeding from the back of the eye. Separation of serum using Human PCSK9 ELISA Kit (proteintech) was used to detect the expression level of PCSK9 protein in serum and make comparisons between groups.
  • mice showed (Figure 8) that the PCSK9 protein levels of both PC15 (L96) and PC19 (ligand 39) dropped to the lowest on the 7th day, then began to increase, and returned to the pre-administration level on the 28th day.

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Abstract

La présente invention concerne un composé représenté par la formule (I), ou un promédicament, un tautomère, un stéréoisomère, un solvate, un dérivé isotopique, ou un sel pharmaceutiquement acceptable de celui-ci. Le composé de la présente invention est un nouveau dérivé GalNAc, qui peut former un conjugué chimique représenté par la formule (II) avec un oligonucléotide, le conjugué chimique ayant un effet d'administration ciblant le foie.
PCT/CN2023/091131 2022-04-29 2023-04-27 Composé ayant un effet d'administration ciblant le foie et conjugué oligonucléotidique de celui-ci WO2023208106A1 (fr)

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CN109563168A (zh) * 2016-06-08 2019-04-02 艾伯维公司 抗egfr抗体药物偶联物
CN109562188A (zh) * 2016-04-05 2019-04-02 赛伦斯治疗有限公司 与三价糖缀合物连接的核酸

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Publication number Priority date Publication date Assignee Title
CN109562188A (zh) * 2016-04-05 2019-04-02 赛伦斯治疗有限公司 与三价糖缀合物连接的核酸
CN109563168A (zh) * 2016-06-08 2019-04-02 艾伯维公司 抗egfr抗体药物偶联物

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