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CN-122028913-A - Oligonucleotides containing ligands in nucleobases, 2 'or 3' positions

CN122028913ACN 122028913 ACN122028913 ACN 122028913ACN-122028913-A

Abstract

The present disclosure provides oligonucleotides comprising at least one group of a central nervous system receptor ligand at the nucleobase, the 2 'position of a nucleoside or the 3' position of a nucleoside. The disclosure also provides pharmaceutical compositions and kits comprising the oligonucleotides, methods of delivering the oligonucleotides, methods of modulating protein activity using the oligonucleotides, and methods of treating, preventing, or diagnosing a disease (e.g., central nervous system disease, neurodegenerative disease, and neurocognitive disease) in a subject in need thereof using the oligonucleotides or pharmaceutical compositions thereof. The present disclosure also provides oligonucleotides useful for preparing the oligonucleotides.

Inventors

  • LI ZHEN
  • ZHU RUI
  • Chandra Munli Cheruta
  • Jin .fang

Assignees

  • 阿达尔克斯制药有限公司

Dates

Publication Date
20260512
Application Date
20240816
Priority Date
20230817

Claims (20)

  1. 1. An oligonucleotide comprising a modified oligonucleotide strand, the modified oligonucleotide strand comprising: S1 examples of modified nucleosides independently comprising a moiety of formula I: (I) And (C) sum V1 instances of the internucleoside linker of the modified oligonucleotide chain are independently Replacement; Wherein: s1 is 1, 2, 3, 4, 5 or 6; Each instance of N 1 is independently a group or bond of a nucleobase; Each instance of t1 is independently 1,2, or 3; Each instance of y1, y2, and y3 is independently 0,1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; each instance of a 1 、A 2 and a 3 , if present, is independently a group of ligands or lipids, provided that at least one instance of a 1 、A 2 and a 3 is a group of central nervous system receptor ligands; When (when) When y1 of examples of (1) is 0, L 1 is hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted heteroalkenyl, substituted OR unsubstituted heteroalkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl 、–CN、–OR b 、–SCN、–SR b 、–SSR b 、–N 3 、–NO、–N(R b ) 2 、–NO 2 、–C(=O)R b 、–C(=O)OR b 、–C(=O)SR b 、–C(=O)N(R b ) 2 、–S(=O)R b 、–S(=O)OR b 、–S(=O)SR b 、–S(=O)N(R b ) 2 、–S(=O) 2 R b 、–S(=O) 2 OR b 、–S(=O) 2 SR b 、–S(=O) 2 N(R b ) 2 、–OC(=O)R b 、–OC(=O)OR b 、–OC(=O)SR b 、–OC(=O)N(R b ) 2 、–OS(=O)R b 、–OS(=O)OR b 、–OS(=O)SR b 、–OS(=O)N(R b ) 2 、–OS(=O) 2 R b 、–OS(=O) 2 OR b 、–OS(=O) 2 SR b 、–OS(=O) 2 N(R b ) 2 、–ON(R b ) 2 、–SC(=O)R b 、–SC(=O)OR b 、–SC(=O)SR b 、–SC(=O)N(R b ) 2 、–NR b C(=O)R b 、–NR b C(=O)OR b 、–NR b C(=O)SR b 、–NR b C(=O)N(R b ) 2 、–NR b S(=O)R b 、–NR b S(=O)OR b 、–NR b S(=O)SR b 、–NR b S(=O)N(R b ) 2 、–NR b S(=O) 2 R b 、–NR b S(=O) 2 OR b 、–NR b S(=O) 2 SR b 、–NR b S(=O) 2 N(R b ) 2 、–Si(R b ) 3 、–Si(R b ) 2 OR b 、–Si(R b )(OR b ) 2 、–Si(OR b ) 3 、–OSi(R b ) 3 、–OSi(R b ) 2 OR b 、–OSi(R b )(OR b ) 2 OR-OSi (OR b ) 3 ; OR when When y1 of an example of (1), 2, 3, 4, 5 or 6, L 1 is a linker; Each instance of R b is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R b instances attached to the same intervening atom are joined together by an intervening atom to form a substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl ring; When (when) When y2 of an example of (C) is 0, L 2 is-OH, -OR h , halogen, -CN OR-N 3 , OR when When y2 of an example of (1), 2, 3, 4, 5 or 6, L 2 is a linker; Each instance of R h is independently a substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group; When the moiety of formula I is part of an example of the modified nucleoside at the 5' -end or at an internal position of the modified oligonucleotide chain, y3 is 0 and L 3 is an internucleoside linker, or When the moiety of formula I is part of an example of the modified nucleoside at the 3' end of the modified oligonucleotide chain: When y3 is 0, L 3 is-OH, -OR d , halogen, -CN OR-N 3 , and each instance of R d is independently a substituted OR unsubstituted C 1-6 alkyl OR an oxygen protecting group, OR When y3 is 1, 2,3, 4, 5 or 6, L3 is a linker; v1 is 0, 1,2, 3, 4, 5 or 6; When present, each instance of L A and L 4 is independently a linker; when present, each instance of y4 is independently 1, 2, 3,4, 5 or 6, and When present, each instance of a 4 is independently a group of a ligand or lipid.
  2. 2. A nucleoside comprising a moiety of the formula: , Wherein: n 1 is a group or bond of a nucleobase; t1 is 1, 2 or 3; Each instance of y1, y2, and y3 is independently 0,1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; each instance of a 1 、A 2 and a 3 , if present, is independently a group of ligands or lipids, provided that at least one instance of a 1 、A 2 and a 3 is a group of central nervous system receptor ligands; When (when) When y1 of examples of (1) is 0, L 1 is hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted heteroalkenyl, substituted OR unsubstituted heteroalkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl 、–CN、–OR b 、–SCN、–SR b 、–SSR b 、–N 3 、–NO、–N(R b ) 2 、–NO 2 、–C(=O)R b 、–C(=O)OR b 、–C(=O)SR b 、–C(=O)N(R b ) 2 、–S(=O)R b 、–S(=O)OR b 、–S(=O)SR b 、–S(=O)N(R b ) 2 、–S(=O) 2 R b 、–S(=O) 2 OR b 、–S(=O) 2 SR b 、–S(=O) 2 N(R b ) 2 、–OC(=O)R b 、–OC(=O)OR b 、–OC(=O)SR b 、–OC(=O)N(R b ) 2 、–OS(=O)R b 、–OS(=O)OR b 、–OS(=O)SR b 、–OS(=O)N(R b ) 2 、–OS(=O) 2 R b 、–OS(=O) 2 OR b 、–OS(=O) 2 SR b 、–OS(=O) 2 N(R b ) 2 、–ON(R b ) 2 、–SC(=O)R b 、–SC(=O)OR b 、–SC(=O)SR b 、–SC(=O)N(R b ) 2 、–NR b C(=O)R b 、–NR b C(=O)OR b 、–NR b C(=O)SR b 、–NR b C(=O)N(R b ) 2 、–NR b S(=O)R b 、–NR b S(=O)OR b 、–NR b S(=O)SR b 、–NR b S(=O)N(R b ) 2 、–NR b S(=O) 2 R b 、–NR b S(=O) 2 OR b 、–NR b S(=O) 2 SR b 、–NR b S(=O) 2 N(R b ) 2 、–Si(R b ) 3 、–Si(R b ) 2 OR b 、–Si(R b )(OR b ) 2 、–Si(OR b ) 3 、–OSi(R b ) 3 、–OSi(R b ) 2 OR b 、–OSi(R b )(OR b ) 2 OR-OSi (OR b ) 3 ; OR when When y1 of an example of (1), 2, 3, 4, 5 or 6, L 1 is a linker; Each instance of R b is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R b instances attached to the same intervening atom are joined together by an intervening atom to form a substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl ring; L 2 is-OH, -OR h , halogen, -CN OR-N 3 when y2 is 0, OR L 2 is a linker when y2 is 1, 2, 3, 4, 5 OR 6; R h is a substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group; L 3 is-OH, -OR d , halogen, -CN OR-N 3 when y3 is 0, OR L 3 is a linker when y3 is 1,2, 3, 4, 5 OR 6, and R d is a substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group.
  3. 3. The oligonucleotide of claim 1 or nucleoside of claim 2, wherein each instance of a 1 、A 2 and a 3 , if present, is independently a group of a central nervous system receptor ligand or lipid, provided that at least one instance of a 1 、A 2 and a 3 is a group of a central nervous system receptor ligand.
  4. 4. The nucleoside of claim 2, wherein the nucleoside has the formula: , Or a pharmaceutically acceptable salt or prodrug thereof, wherein E 1 is –OP(=O)(OR b ) 2 、–SP(=O)(OR b ) 2 、–OP(=O)(OR b )(SR b )、–OR b 、–SR b 、–SSR b 、–N(R b ) 2 、–OC(=O)R b 、–OC(=O)OR b 、–OC(=O)SR b 、–OC(=O)N(R b ) 2 、–OS(=O)R b 、–OS(=O)OR b 、–OS(=O)SR b 、–OS(=O)N(R b ) 2 、–OS(=O) 2 R b 、–OS(=O) 2 OR b 、–OS(=O) 2 SR b 、–OS(=O) 2 N(R b ) 2 、–ON(R b ) 2 、–SC(=O)R b 、–SC(=O)OR b 、–SC(=O)SR b 、–SC(=O)N(R b ) 2 、–NR b C(=O)R b 、–NR b C(=O)OR b 、–NR b C(=O)SR b 、–NR b C(=O)N(R b ) 2 、–NR b S(=O)R b 、–NR b S(=O)OR b 、–NR b S(=O)SR b 、–NR b S(=O)N(R b ) 2 、–NR b S(=O) 2 R b 、–NR b S(=O) 2 OR b 、–NR b S(=O) 2 SR b or-NR b S(=O) 2 N(R b ) 2 .
  5. 5. The oligonucleotide of claim 1, wherein the oligonucleotide is a single stranded oligonucleotide.
  6. 6. The oligonucleotide of claim 1, wherein the oligonucleotide is a double-stranded oligonucleotide comprising a sense oligonucleotide strand and an antisense oligonucleotide strand.
  7. 7. The oligonucleotide of any one of claims 1-6, wherein the modified oligonucleotide strand is the sense oligonucleotide strand.
  8. 8. The oligonucleotide of any one of claims 1-7, wherein the modified oligonucleotide strand is the antisense oligonucleotide strand.
  9. 9. The oligonucleotide of any one of claims 1-8, wherein the nucleobases of the antisense oligonucleotide strand are complementary to the nucleobases of the sense oligonucleotide strand.
  10. 10. The oligonucleotide of any one of claims 1-9, wherein the oligonucleotide comprises RNA.
  11. 11. The oligonucleotide of any one of claims 1-10, wherein the oligonucleotide is RNA.
  12. 12. The oligonucleotide of any one of claims 1-11, wherein the oligonucleotide is an siRNA.
  13. 13. The oligonucleotide of any one of claims 1-12, wherein the modified oligonucleotide strand comprises between 6 and 100 nucleosides (inclusive).
  14. 14. The oligonucleotide of any one of claims 1-13, wherein the modified oligonucleotide strand comprises between 10 and 30 (inclusive) nucleosides.
  15. 15. The oligonucleotide of any one of claims 1-14, wherein the modified oligonucleotide strand comprises between 14 and 23 (inclusive) nucleosides.
  16. 16. The oligonucleotide of any one of claims 1-15, wherein s1 is 1 and the modified nucleoside is located at the 5' end of the modified oligonucleotide strand.
  17. 17. The oligonucleotide of any one of claims 1-16, wherein s1 is 1 and the modified nucleoside is located at an internal position of the modified oligonucleotide strand.
  18. 18. The oligonucleotide of any one of claims 1-17, wherein s1 is 1 and the modified nucleoside is located at the 3' end of the modified oligonucleotide strand.
  19. 19. The oligonucleotide of any one of claims 1-18, wherein: s1 is 2; One example of the modified nucleoside is located at the 5' -end of the modified oligonucleotide chain, and Another example of the modified nucleoside is located at an internal position of the modified oligonucleotide strand.
  20. 20. The oligonucleotide of any one of claims 1-19, wherein: s1 is 2; One example of the modified nucleoside is located at the 3' -end of the modified oligonucleotide chain, and Another example of the modified nucleoside is located at an internal position of the modified oligonucleotide strand.

Description

Oligonucleotides containing ligands in nucleobases, 2 'or 3' positions RELATED APPLICATIONS The application is based on 35 U.S. C.119 (E) priority of U.S. S. N. 63/520,093, U.S. provisional application filed on 8/17 of 2023, the contents of which are incorporated herein by reference. Background In therapeutic, prophylactic or diagnostic applications using compounds (e.g., oligonucleotides), it is often desirable to deliver the compound to a particular location (e.g., to a desired cell, to a desired organ or tissue, or to a particular location in a subject) to enhance therapeutic or prophylactic effects or to facilitate diagnostic purposes. This is often the case when attempting to deliver therapeutic compounds in vivo. Furthermore, being able to effectively deliver a compound to a particular location may limit or potentially eliminate unexpected consequences (such as off-target effects) that may result from administration of the compound. One strategy that facilitates the in vivo delivery of a compound (such as a therapeutic, prophylactic or diagnostic compound) to a desired location is to link or attach the compound to a targeting ligand. One class of compounds that can be targeted using targeting ligands are oligomeric compounds, such as, for example, proteins, peptides, antibodies, and oligonucleotides. Oligomeric compounds (e.g., oligonucleotides) comprising nucleotide sequences at least partially complementary to a target nucleic acid have been demonstrated to alter the function and activity of the target in vitro and in vivo. Oligonucleotides have been demonstrated to modulate expression or activity of a target nucleic acid when delivered to cells containing the target nucleic acid, such as mRNA or pre-mRNA. In some cases, the oligonucleotides can reduce expression of a gene by inhibiting translation of a nucleic acid target and/or triggering degradation of the target nucleic acid. If the target nucleic acid is mRNA, one mechanism by which the oligonucleotide can modulate mRNA target expression is by RNA interference. RNA interference is a biological process by which RNA or RNA-like compounds, such as chemically modified RNA compounds, can be used to silence gene expression at least in part through the RNA-induced silencing complex (RISC) pathway. In addition, oligonucleotides can modulate expression of a target nucleic acid (such as a target mRNA) by an rnase recruitment mechanism, a microrna mechanism, an occupancy-based mechanism, and an editing mechanism. The oligonucleotides may be single-stranded or double-stranded. Oligonucleotides may include DNA, RNA, and RNA-like compounds, which may also comprise modified nucleosides that include one or more modified sugars, modified nucleobases, and modified internucleoside linkages. There is a need for new compounds for delivering agents (e.g., therapeutic, prophylactic, and diagnostic agents) to a subject. Disclosure of Invention In one aspect, the present disclosure provides oligonucleotides comprising at least one group of a central nervous system receptor ligand at the nucleobase, at the 2 'position of a nucleoside or at the 3' position of a nucleoside. In another aspect, the disclosure relates to an oligonucleotide comprising a modified oligonucleotide strand comprising s1 examples of modified nucleosides independently comprising a moiety of formula I: (I) And (C) sum V1 instances of the internucleoside linker of the modified oligonucleotide chain are independentlyReplacement; Wherein: s1 is 1, 2, 3, 4, 5 or 6; Each instance of N 1 is independently a group or bond of a nucleobase; Each instance of t1 is independently 1,2, or 3; Each instance of y1, y2, and y3 is independently 0,1, 2, 3, 4, 5, or 6, provided that at least one instance of y1, y2, and y3 is 1, 2, 3, 4, 5, or 6; each instance of a 1、A2 and a 3, if present, is independently a group of ligands or lipids, provided that at least one instance of a 1、A2 and a 3 is a group of central nervous system receptor ligands; When (when) When y1 of examples of (1) is 0, L 1 is hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted heteroalkenyl, substituted OR unsubstituted heteroalkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl 、–CN、–ORb、–SCN、–SRb、–SSRb、–N3、–NO、–N(Rb)2、–NO2、–C(=O)Rb、–C(=O)ORb、–C(=O)SRb、–C(=O)N(Rb)2、–S(=O)Rb、–S(=O)ORb、–S(=O)SRb、–S(=O)N(Rb)2、–S(=O)2Rb、–S(=O)2ORb、–S(=O)2SRb、–S(=O)2N(Rb)2、–OC(=O)Rb、–OC(=O)ORb、–OC(=O)SRb、–OC(=O)N(Rb)2、–OS(=O)Rb、–OS(=O)ORb、–OS(=O)SRb、–OS(=O)N(Rb)2、–OS(=O)2Rb、–OS(=O)2ORb、–OS(=O)2SRb、–OS(=O)2N(Rb)2、–ON(Rb)2、–SC(=O)Rb、–SC(=O)ORb、–SC(=O)SRb、–SC(=O)N(Rb)2、–NRbC(=O)Rb、–NRbC(=O)ORb、–NRbC(=O)SRb、–NRbC(=O)N(Rb)2、–NRbS(=O)Rb、–NRbS(=O)ORb、–NRbS(=O)SRb、–NRbS(=O)N(Rb)2、–NRbS(=O)2Rb、–NRbS(=O)2ORb、–NRbS(=O)2SRb、–