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CN-122029174-A - Novel GalNAc targeted delivery fragment, preparation and application thereof

CN122029174ACN 122029174 ACN122029174 ACN 122029174ACN-122029174-A

Abstract

The invention discloses a GalNAc delivery molecule shown in the following formula (I), or a stereoisomer, an enantiomer or a pharmaceutically acceptable salt thereof, wherein the definition of each group is as described in the specification.

Inventors

  • LU CENBIN
  • TANG GUOZHI
  • ZHOU YUNLONG
  • LIU YONGFU
  • QUE RIMING
  • MA DAWEI

Assignees

  • 维申医药(南通)有限公司

Dates

Publication Date
20260512
Application Date
20240718
Priority Date
20230719

Claims (14)

  1. A GalNAc delivery molecule represented by the following formula (I), or a stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof: Wherein, the Is that R 1 is selected from H, DMTr, phosphate, thiophosphate-siRNA conjugate, or phosphate-siRNA conjugate; Linker has a structure selected from the group consisting of C4-C20 alkylene, Wherein n, n 3 and m are each independently selected from the group consisting of 0, 1,2, 3,4, 5, 6, 7, 8, 9, 10, 11 or 12; n 1 and n 2 are each independently selected from the group consisting of 0 or 1; Z is selected from the group consisting of single bond, substituted or unsubstituted C 1-8 alkylene; Q is selected from the group consisting of a bond, -NH-C (O) -, -C (O) -; r is 0, 1,2, 3, 4, 5 or 6; R 2 is GalNAc targeting moiety and has a structure selected from the group consisting of: wherein each L 1 、L 2 is independently a structure selected from the group consisting of: L 3 is a structure selected from the group consisting of: wherein R 11 is selected from the group consisting of H or C 1-4 alkyl; Each u, v and w is independently selected from 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10 or 11, glu is an unmodified or modified 5-6 membered glycosyl; X 1 is selected from the group consisting of a substituted or unsubstituted C 4-10 saturated or partially unsaturated carbocyclyl, a substituted or unsubstituted 4-10 membered saturated or partially unsaturated heterocyclyl (preferably a nitrogen containing heterocyclyl), a substituted or unsubstituted C 6-10 phenyl, or a substituted or unsubstituted 5-10 membered heteroaryl; X 2 is selected from the group consisting of: -NH- (C 1 -C 6 alkyl) -NH-, -NH- (C 3 -C 8 cycloalkyl) -NH-, -NH- (4-10 membered heterocyclyl) -NH-, a substituted or unsubstituted C 4-10 saturated or partially unsaturated carbocyclyl, a substituted or unsubstituted 4-10 membered saturated or partially unsaturated heterocyclyl (preferably a nitrogen-containing heterocyclyl), a substituted or unsubstituted C 6-10 phenyl, or a substituted or unsubstituted 5-10 membered heteroaryl; Wherein the carbocyclyl and heterocyclyl can be a single ring, a condensed ring, a bridged ring or a spiro ring, R 3 、R 4 and R 5 are each independently a substituted or unsubstituted glycosyl group, preferably a group formed by a substituted or unsubstituted N-acetylgalactosamine molecule; the substituent means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-to 12-membered heterocyclyl, C 3-8 aryl, 5-to 7-membered heteroaryl, halogen, hydroxy, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino, C 1-8 alkoxy, C 1-10 sulfonyl, or two substituents on adjacent ring atoms may together with the attached ring atom form a group selected from the group consisting of a 5-to 7-membered carbocyclic or heterocyclic ring, a benzene ring, or a 5-to 7-membered heteroaryl ring.
  2. The GalNAc delivery molecule of claim 1, or a stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof, wherein the Linker has a structure selected from the group consisting of C4-C20 alkylene.
  3. The GalNAc delivery molecule of claim 1, or a stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof, wherein the siRNA is selected from the group consisting of an siRNA that inhibits expression of Hepatitis B Virus (HBV) gene, an siRNA that inhibits expression of apolipoprotein C3 (APOC 3) gene, an siRNA that inhibits expression of PCSK9 gene, an siRNA that inhibits expression of CCR4 gene, and an siRNA that inhibits expression of Thyroxine Transporter (TTR) gene.
  4. The GalNAc delivery molecule of claim 1, or a stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof, wherein each of L 1 and L 2 is independently of the other a structure of the formula: L 3 is a structure shown as the following formula: Wherein the definition of each group is as defined in claim 1.
  5. The GalNAc delivery molecule of claim 4, or a stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof, wherein R 2 has a structure represented by the formula:
  6. The GalNAc delivery molecule of claim 4, or a stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof, wherein X 1 is a substituted or unsubstituted structure selected from the group consisting of: wherein s1 and s2 are each independently selected from the group consisting of 0,1, or 2; Each M 1 and M 3 is independently selected from the group consisting of CHR, C (R) R, C (O), O, S, NR; R is selected from the group consisting of H, halogen, methyl, or two R's located on adjacent further atoms together with the carbon atom to which they are attached form a substituted or unsubstituted 4-8 membered carbocyclic or heterocyclic ring (including saturated, unsaturated or aromatic rings).
  7. The GalNAc delivery molecule of claim 4, or a stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof, wherein X 2 is a substituted or unsubstituted structure selected from the group consisting of:
  8. The GalNAc delivery molecule of claim 1, or a stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof, wherein the glycosyl has a structure represented by formula III: Wherein R 15 is selected from the group consisting of-NH (C 2 -C 6 acyl), -NH (halogenated C 2 -C 6 acyl), -NH (C 2 -C 6 sulfonyl), -NH (halogenated C 2 -C 6 sulfonyl); R 12 、R 13 and R 14 are each independently selected from the group consisting of H or C 1 -C 6 acyl; Preferably, R 15 is selected from the group consisting of-NH (C 2 -C 4 acyl), R 12 、R 13 and R 14 are each independently selected from the group consisting of H or C 1 -C 4 acyl, more preferably R 15 is-NHAc, and R 12 、R 13 and R 14 are each independently selected from the group consisting of H or Ac.
  9. The GalNAc delivery molecule of any one of claims 1-8, or a stereoisomer, enantiomer, or a pharmaceutically acceptable salt thereof, wherein the GalNAc delivery molecule has a structure selected from the group consisting of:
  10. The GalNAc delivery molecule of any one of claims 1-8, or a stereoisomer, enantiomer, or a pharmaceutically acceptable salt thereof, wherein the GalNAc delivery molecule has a structure selected from the group consisting of:
  11. A pharmaceutical composition comprising one or more of the compounds of formula I, pharmaceutically acceptable salts, racemates, R-isomers, S-isomers or mixtures thereof according to any one of claims 1 to 10, together with one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents.
  12. The use of a compound of formula I according to any one of claims 1 to 10, in the form of a pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or a mixture thereof, for the preparation of a pharmaceutical composition for the treatment or prophylaxis of tumors or infections caused by viruses.
  13. The use of a compound of formula (I) as claimed in any one of claims 1 to 10 for the preparation of a medicament for the treatment and/or prophylaxis of a disease or condition selected from the group consisting of diseases or conditions caused by hepatitis b virus, diseases or conditions caused by abnormal expression of the ANGPTL3 gene, diseases or conditions caused by abnormal expression of the TTR gene, diseases or conditions caused by abnormal expression of the hepatocyte gene, or other liver diseases or conditions.
  14. A GalNAc delivery molecule linker represented by formula (Ia), or a stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof: The moiety of formula (Ia) has a structure selected from the group consisting of Wherein, the Is the site to which R1 is attached.

Description

Novel GalNAc targeted delivery fragment, preparation and application thereof Technical Field The invention relates to the field of medicines, and in particular provides a novel GalNAc targeted delivery fragment, and preparation and application thereof. Background Hepatitis B Virus (HBV) belongs to the family of small, enveloped, mainly hepadnaviridae, and has a partially double-stranded DNA genome of about 3.2kb in size. HBV infection has been a major public health problem. Although safe and effective prophylactic HBV vaccines are available, it is estimated that about 2.5 hundred million people worldwide are chronically infected with hepatitis b virus. Chronic HBV infection places patients at high risk of cirrhosis and liver cancer, and it is estimated that more than 686,000 people die each year from hepatitis b complications. (WHO. Global HEPATITIS REPORT 2017) Current therapies are limited to two classes of drugs, which are nucleoside (nucleotide) analogs (lamivudine, adefovir, tenofovir, telbivudine and entecavir) and interferon alpha (INF-alpha, including non-pegylated and pegylated). Although both therapies can reduce HBV DNA and normalize liver enzymes, neither therapy provides a high level of clinical cure rate, defined by HBV surface antigen (HBsAg) loss (with or without seroconversion). Interferon-based therapies are poorly tolerated and are effective only for certain viral genotypes. Although nucleoside (nucleotide) analogs often require prolonged or possibly lifetime treatment, and some have resistance, low efficacy and tolerability issues. Thus, there remains a great medical need to discover and develop effective and safe anti-HBV drugs with novel mechanisms of action to increase disease cure rate .(Marcellin,Patrick,et al.The Lancet 381.9865(2013):468-475;Tang,Lydia SY,et al.Jama319.17(2018):1802-1813.) Acetylgalactose-mediated liver-targeted delivery of small interfering ribonucleic acid (GalNAc-siRNA) has been recently used in the treatment of various liver-related diseases, in which the basal segment of mRNA translation into protein plays a role in inhibiting target gene expression. GalNAc-siRNA molecule has the characteristics of strong drug effect, high liver targeting specificity, good safety and the like, thus occupying unique advantages in the anti-hepatitis B field, but the current test drug can not effectively reduce the HBsAg content and can not reach high-level clinical cure rate. Therefore, there is a need to optimize such molecules, focusing on structural engineering of GalNAc-containing targeted delivery fragments, improving delivery efficiency and drug properties. Disclosure of Invention The object of the present invention is to provide a GalNAc-siRNA molecule, and a nucleic acid delivery pharmaceutical composition prepared by using the same. In a first aspect of the present invention, there is provided a GalNAc delivery molecule represented by the following formula (I), or a stereoisomer, enantiomer, or pharmaceutically acceptable salt thereof: Wherein, the Ax is a substituted or unsubstituted 4-12 membered saturated or partially unsaturated nitrogen containing heterocyclyl, a substituted or unsubstituted 4-12 membered nitrogen containing heteroaryl; R 1 is selected from H, DMTr, phosphate, thiophosphate-siRNA conjugate, or phosphate-siRNA conjugate; Linker is a divalent linking group; Q is selected from the group consisting of a bond, -NH-C (O) -, -C (O) -; r is 0, 1,2, 3, 4, 5 or 6; R 2 is GalNAc targeting moiety and has a structure selected from the group consisting of: Wherein L 1、L2 is independently a trivalent linking group, L 3 is a divalent linking group, and R 3、R4 and R 5 are independently a substituted or unsubstituted glycosyl group, preferably a group formed by a substituted or unsubstituted N-acetylgalactosamine molecule; the substituent means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-to 12-membered heterocyclyl, C 3-8 aryl, 5-to 7-membered heteroaryl, halogen, hydroxy, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino, C 1-8 alkoxy, C 1-10 sulfonyl, or two substituents on adjacent ring atoms may together with the attached ring atom form a group selected from the group consisting of a 5-to 7-membered carbocyclic or heterocyclic ring, a benzene ring, or a 5-to 7-membered heteroaryl ring. In a further preferred embodiment of the present invention,Has a structure selected from the group consisting of: Wherein R' is selected from the group consisting of H or C 1-8 alkyl; p is 1,2, 3, 4, 5 or 6. In another preferred embodiment, the siRNA is selected from the group consisting of an siRNA that inhibits Hepatitis B Virus (HBV) gene expression, an siRNA that inhibits apolipoprotein C3 (APOC 3) gene expression, an siRNA that inhibits PCSK9 gene expression, an siRNA that inhibits CCR4 gene expression, and an siRNA that in