JPWO2020247782A5

JPWO2020247782A5 -

Info

Publication number: JPWO2020247782A5
Application number: JP2021572518A
Authority: JP
Publication date: 2023-04-25

Claims

A compound suitable for the synthesis of oligonucleotides, said compound comprising formula (II),

During the ceremony,
each R ¹ is independently unsubstituted or substituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ fluoroalkyl, or substituted or unsubstituted C ₁ -C ₆ heteroalkyl;
each R ² is independently substituted or unsubstituted C ₁ -C ₆ alkyl, hydrogen, deuterium, or substituted or unsubstituted C ₁ -C ₆ heteroalkyl ; or
two R ² together with the nitrogen atom to which they are attached form a substituted or unsubstituted C ₂ -C ₁₀ heterocycloalkyl;
L ¹ is unsubstituted or substituted C ₁ -C ₅ alkylene, a bond, substituted or unsubstituted C ₂ -C ₅ alkenylene, or substituted or unsubstituted C ₂ -C ₅ alkynylene;
L ² is methylene, a bond, O, S, NR ³ , substituted or unsubstituted C ₄ -C ₇ cycloalkylene , substituted or unsubstituted C ₅ -C ₈ arylene, or substituted or unsubstituted C ₄ — _C8 heteroarylene,
R ³ , if present, is hydrogen, unsubstituted or substituted C ₁ -C ₆ alkyl, unsubstituted or substituted C ₁ -C ₆ fluoroalkyl, unsubstituted or substituted C ₁ -C ₆ heteroalkyl, unsubstituted or substituted monocyclic carbocycles and unsubstituted or substituted monocyclic heterocycles;
L ³ is unsubstituted or substituted C ₁ -C ₅ alkylene, a bond, substituted or unsubstituted C ₂ -C ₅ alkenylene, or substituted or unsubstituted C ₂ -C ₅ alkynylene, and
at least two of L ¹ , L ² , and L ³ are not a bond;
Compound.

L. ^１1 is C _１1 -C _５5 Alkylene, C _２2 -C _３3 alkenylene, or C _２2 -C _５5 is alkynylene, and
L. ^３3 is C _１1 -C _５5 Alkylene, C _２2 -C _３3 alkenylene, or C _２2 -C _５5 2. The compound of claim 1, which is alkynylene.

L. ^１1 is C _１1 -C _５5 is alkylene, and
L. ^３3 is C _１1 -C _５5 3. The compound of claim 1 or 2, which is alkylene.

R. ^１1 are each independently -CH _３3 , -CH _２2 CH _３3 , -CH _２2 CH _２2 CH _３3 , or -CH _２2 (CH _３3 ) _２2 A compound according to any one of claims 1-3, which is

R. ^２2 are each independently -CH _２2 (CH _３3 ) _２2 , -CH _３3 , -CH _２2 CH _３3 , or -CH _２2 CH _２2 CH _３3 A compound according to any one of claims 1-4, which is

is selected from the group consisting of
In the formula, R ^ｘx is H, halogen, unsubstituted or substituted C _１1 -C _６6 alkyl, unsubstituted or substituted C _１1 -C _６6 fluoroalkyl, unsubstituted or substituted C _１1 -C _６6 heteroalkyl, unsubstituted or substituted monocyclic carbocycle, unsubstituted or substituted monocyclic heterocycle, —CN, —OH, —O-alkyl, —CO _２2 H, -CO _２2 -alkyl, -CH _２2 CO _２2 H, -CH _２2 CO _２2 -alkyl, -C(=O)NH _２2 , —C(=O)NH-alkyl, —CH _２2 C(=O)NH _２2 , -CH _２2 C(=O)NH-alkyl, -NH _２2 , —NH-alkyl, —CH _２2 NH _２2 , -CH _２2 NH-alkyl, -NHC(=O)alkyl, -CH _２2 NHC(=O)alkyl, -SH, -S-alkyl, -S(=O)H, -S(=O)alkyl, -SO _２2 H, -SO _２2 -alkyl, -SO _２2 NH _２2 , or -SO _２2 A compound according to any one of claims 1-5, which is NH-alkyl.

An oligonucleotide comprising a compound of formula (IIa) at one of its ends,

During the ceremony,
R. ^１1 each independently a substituted or unsubstituted C _１1 -C _６6 alkyl, substituted or unsubstituted C _１1 -C _６6 fluoroalkyl or substituted or unsubstituted C _１1 -C _６6 heteroalkyl,
L. ^１1 is a bonded, substituted or unsubstituted C _１1 -C _５5 alkylene, substituted or unsubstituted C _２2 -C _５5 alkenylene or substituted or unsubstituted C _２2 -C _５5 is an alkynylene,
L. ^２2 is a bond, O, S, NR ^３3 , substituted or unsubstituted C _４4 -C _７7 cycloalkylene, substituted or unsubstituted C _４4 -C _７7 heterocycloalkylene, substituted or unsubstituted C _５5 -C _８8 Arylene or substituted or unsubstituted C _４4 -C _８8 is heteroarylene,
R. ^３3 is, if present, hydrogen, unsubstituted or substituted C _１1 -C _６6 alkyl, unsubstituted or substituted C _１1 -C _６6 fluoroalkyl, unsubstituted or substituted C _１1 -C _６6 selected from heteroalkyl, unsubstituted or substituted monocyclic carbocycle, and unsubstituted or substituted monocyclic heterocycle;
L. ^３3 is a bonded, substituted or unsubstituted C _１1 -C _５5 alkylene, substituted or unsubstituted C _２2 -C _５5 alkenylene or substituted or unsubstituted C _２2 -C _５5 is an alkynylene,
J is an internucleotide linking group that binds adjacent nucleotides of a polynucleotide, and
L. ^１1 , L ^２2 , and L ^３3 is not a bond,
oligonucleotide.

8. The oligonucleotide of Claim 7, wherein said oligonucleotide is an RNA oligonucleotide.

2'-O-methyl, 2'-O-methoxyethyl (2'-O-MOE), 2'-deoxy, 2-deoxy-2'-fluoro, 2'-O-aminopropyl (2'-O- AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′ -O-DMAEOE), 2'-ON-methylacetamide (2'-O-NMA) modified nucleotides, locked nucleic acids (LNA), or ethylene nucleic acids (ENA). 9. The oligonucleotide according to claim 7 or 8, further comprising a sequenced nucleotide.

10. Any one of claims 7-9, further comprising at least one modified internucleotide linkage selected from phosphorothioate, phosphorodithioate, methylphosphonate, phosphotriester, or amide linkages. of oligonucleotides.

The oligonucleotide of any one of claims 7-10, wherein said oligonucleotide is conjugated to a binding moiety.

Said binding moiety may be a humanized antibody or binding fragment thereof, chimeric antibody or binding fragment thereof, monoclonal antibody or binding fragment thereof, monovalent Fab', bivalent Fab2, single chain variable fragment (scFv), diabodies, minibodies , a nanobody, a single domain antibody (sdAb), or a camelid antibody, or a binding fragment, peptide, aptamer or small molecule thereof.

The oligonucleotide of any one of claims 7-12, comprising about 15 to about 25 nucleotides.

14. An oligonucleotide according to any one of claims 7-13 for use in the treatment of a disease characterized by defective expression of a protein of interest, wherein said treatment comprises the gene encoding said protein administering said oligonucleotide to said subject to modulate the expression of .

14. An oligonucleotide according to any one of claims 7-13 for use in the treatment of a disease characterized by overexpression of a protein of interest, said treatment comprising the gene encoding said protein. administering said oligonucleotide to said subject to modulate the expression of .