# US 11,078,227 B2 · 5′-cyclo-phosphonate modified nucleotides

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- Number: US 11,078,227 B2
- Document ID: US11078227B2
- Status: Granted
- Kind: B2
- Application number: 16/207,870
- Filed: 2018-12-03
- Published: 2019-03-21
- Granted: 2021-08-03
- Earliest claimed: 2016-06-06
- Assignees: Arrowhead Pharmaceuticals, Inc.
- Applicants: Arrowhead Pharmaceuticals, Inc.
- Inventors: Zhen Li; Tao Pei; Michael Lawler
- Web page: https://patentgrep.com/patent/US11078227B2

## CPC

- C07H 19/10: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 31/20: for DNA viruses
- C07H 19/06: Pyrimidine radicals
- C07H 19/16: Purine radicals
- C07H 19/207: the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
- C07H 21/02: with ribosyl as saccharide radical
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/31: of the backbone
- C12N 2310/312: Phosphonates
- C12N 2310/323: modified ring structure
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/3233: Morpholino-type ring
- C12N 2310/3519: Fusion with another nucleic acid
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Described are 5′-cyclo-phosphonate modified nucleotides, and oligonucleotides, such as interference (RNAi) agents, containing 5′-cyclo-phosphonate modified nucleotides. The RNAi agents having either double-stranded or single-stranded oligonucleotides described herein comprising 5′cyclo-phosphonate modified nucleotides are useful in modulating gene expression as well as therapeutic, diagnostic, target validation, and genomic discovery applications. The RNAi agents and single-stranded antisense oligonucleotides comprising 5′-cyclo-phosphonate modified nucleotides are useful in the treatment of diseases or conditions that respond to inhibition of gene expression or activity in a cell, tissue, or organism.

## Claims

### Claim 1

A compound having Formula A:
wherein:
Cyclo is
X′ is
X″ comprises a substituent derived from a phosphate or phosphorothioate moiety of an RNAi agent;
D is O or S;
X is a 9-purinyl or 1-pyrimidinyl base;
Z is H, —OH, F, OCH3, —O—(CH2)2—OCH3 or halogen;
Y1, Y2, Y3, and Y4 are each, independently, H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl,
J is O r S; and
K and L are each independently selected from OH, OR16, SR16, or NR16, wherein R16 is selected from H, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or
wherein R14 is selected from H or C1-C4 alkyl optionally substituted with one to three substituents independently selected from SH, S—(C1-C4 alkyl), amino, hydroxyl, oxo or —NH—C═(NH)NH2, and R15 is selected from H, or C1-C18 alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, having Formula I or Formula II:
wherein,
Q is a divalent moiety selected from O, S, N(R30), or C(R31)(R32), wherein R30 is H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, and R31 and R32 are each, independently, H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; and
A a substituent derived from a phosphate or phosphorothioate moiety of an RNAi agent.

### Claim 3 (depends on 2)

The compound of claim 2 wherein Q is O.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Cyclo is:

### Claim 5 (depends on 1)

The compound of claim 1, wherein the RNAi agent is double-stranded.

### Claim 6 (depends on 1)

The compound of claim 1, wherein X is 1-uracilyl, 1-thyminyl, 1-cytosinyl, 5-methyl-1-cytosinyl, 9-adeninyl, 9-guaninyl, or 9-inosinyl.

### Claim 7 (depends on 1)

A composition comprising the compound of claim 1.

### Claim 8 (depends on 1)

A composition comprising an RNAi agent, wherein the RNAi agent comprises the compound of claim 1.

### Claim 9 (depends on 8)

The composition of claim 8, wherein the RNAi agent is double stranded.

### Claim 10

A compound having the structure of Formula I-b or Formula II-b:
wherein,
D is O or S;
X is a 9-purinyl or 1-pyrimidinyl base:
Z is H, —OH, F, OCH3, —O—(CH2)2—OCH3 or halogen;
Y1, Y2, Y3, and Y4 are each, independently, H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl,
J is O or S;
K and L are each independently selected from OH, OR16, SR16, or NR16, wherein R16 is selected from H, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or
wherein R14 is selected from H or C1-C4 alkyl optionally substituted with one to three substituents independently selected from SH, S—(C1-C4 alkyl), amino, hydroxyl, oxo or —NH—C═(NH)NH2, and R15 is selected from H, or C1-C18 alkyl;
Q is a divalent moiety selected from O, S, N(R30), or C(R31)(R32), wherein R30 is H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl, and R31 and R32 are each, independently, H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; and
A comprises a substituent derived from a phosphate or phosphorothioate moiety of an RNAi agent; and
G1, G2, G3 and G4 are each H.

### Claim 11 (depends on 10)

The compound of claim 10, wherein Q is O.

### Claim 12

A compound having Formula I-b-5 or Formula II-b-5:
wherein,
D is O or S,
X is a 9-purinyl or 1-pyrimidinyl base;
Z is H, —OH, F, OCH3, —O—(CH2)2—OCH3 or halogen;
Y1, Y2, Y3, and Y4 are each, independently, H, halogen, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkenyl, C2-C6 alkynyl, or C2-C6 alkynyl;
J is O or S;
K and L are each independently selected from OH, OR16, SR16, or NR16, wherein R16 is selected from H, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, or
wherein R14 is selected from H or C1-C4 alkyl optionally substituted with one to three substituents independently selected from SH, S—(C1-C4 alkyl), amino, hydroxyl, oxo or —NH—C═(NH)NH2, and R15 is selected from H, or C1-C18 alkyl; and
G1, G2, G3 and G4 are each independently selected from the group consisting of H, F, halogen, C1-C6 alkyl, CN, CH2(R33), CH2—O—(R33), C(═O)(R33), C(═S)(R33), or (R34)(R33), wherein R33 is O(R35), S(R35), or N(R35)(R36), wherein R34, R35, and R36 are each independently selected from H, halogen, or C1-C6 alkyl.

### Claim 13 (depends on 12)

The compound of claim 12, wherein the compound has the following structure:

### Claim 14

A compound having Formula III-b or Formula IV-b:
wherein:
X is a 9-purinyl or 1-pyrimidinyl base;
Z is H, —OH, F, OCH3, —O—(CH2)2—OCH3 or halogen;
J and J′ are each independently O or S; and
comprises a substituent derived from an RNAi agent.

### Claim 15 (depends on 1)

The compound of claim 1, wherein the compound has the formula selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

A composition comprising the RNAi agent of claim 1 and a pharmaceutically acceptable excipient.

### Claim 17 (depends on 1)

A method of inhibiting expression of a target nucleic acid in a subject in need thereof, the method comprising administering to the subject a therapeutic amount of an RNAi agent of claim 1.

### Claim 18 (depends on 8)

A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutic amount of the composition of claim 8 to a subject in need of treatment thereof.

### Claim 19 (depends on 8)

A method of inhibiting expression of a target nucleic acid in a subject in need thereof, the method comprising administering to the subject a therapeutic amount of a composition of claim 8.