# US 11,993,626 B2 · Functionalized N-acetylgalactosamine analogs

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,993,626 B2
- Document ID: US11993626B2
- Status: Granted
- Kind: B2
- Application number: 18/065,503
- Filed: 2022-12-13
- Published: 2023-09-07
- Granted: 2024-05-28
- Earliest claimed: 2021-12-15
- Assignees: Hongene Biotech Corporation
- Applicants: Hongene Biotech Corporation
- Inventors: Wing C. Poon; Xiaoyang Guan; David Yu; Ruiming Zou; Xiaojun Li; Michael Su; Gang Zhao; Gengyu Du; Yun-Chiao Yao; Aldrich N. K. Lau
- Web page: https://patentgrep.com/patent/US11993626B2

## CPC

- C07H 15/26: Acyclic or carbocyclic radicals, substituted by hetero rings
- C07H 1/00: Processes for the preparation of sugar derivatives
- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H 21/02: with ribosyl as saccharide radical
- C07H 21/04: with deoxyribosyl as saccharide radical
- 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)

## Abstract

Embodiments of the present application relate to functionalized N-acetylgalactosamine-analogs, methods of making, and uses of the same. In particular, mono or trivalent N-acetylgalactosamine analogs may be prepared by utilizing a wide variety of linkers containing functional groups. These functionalized N-acetylgalactosamine-analogs may be used in the preparation of targeted delivery of oligonucleotide-based therapeutics.

## Claims

### Claim 1

A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein
each of R1a, R1b, R1c, R2a, R2b, R2c, R3a, R3b, and R3c is independently hydrogen, benzyl, or —C(═O)R8;
each of R4a, R4b and R4c is independently —C(═O)C1-6 alkyl or —C(═O)C1-6 haloalkyl;
R5 is a hydroxy protecting group;
R6 is hydrogen, a phosphoramidite moiety, —C(═O)CH2CH2C(═O)R6A, or —P(OR6B)NR6CR6D;
Y2 is a bond, NR7, NR7C(═O), C(═O)O, or O;
each of X1, X2 and X3 is independently —O(CH2)1-3—, —NH(CH2)1-3—, —C(═O)(CH2)1-3— or —NHC(═O)(CH2)1-3-;
each of L1a, L1b, L1c, L2a, L2b, L2c, L3a, L3b, and L3c is independently a bond, —C(═O)—, —C(═S)—, —S(═O)2—, —C(═O)NR9—, —C(═S)NR9—, —C(═O)O—, —C(═S)O—, —NR9C(═O)NR9—, —NR9C(═S)NR9—, —OP(═O)(OH)O—, —OP(═S)(OH)O—, —O—, —S—, —NR9—, optionally substituted C1-10 alkylene, optionally substituted C6-10 arylene, optionally substituted C3-10 cycloalkylene, optionally substituted 5-10 membered hetetroarylene, optionally substituted 5 to 10 membered heterocyclylene, or optionally substituted 2 to 15 membered heteroalkylene wherein one or more carbon atoms are replaced with C(═O), O, S or N, provided that at least one of L1a, L1b and L1c is not a bond, at least one of L2a, L2b and L2c is not a bond, and at least one of L3a, L3b and L3c is not a bond;
L4 is a bond, optionally substituted C1-8 alkylene or —(CH2)1-3(OCH2CH2)1-5OCH2-;
L5 is a bond, optionally substituted C1-10 alkylene, or optionally substituted 2 to 15 membered heteroalkylene wherein one or more carbon atoms are replaced with C(═O), O, S or N;
each of R7 and R9 is independently hydrogen, unsubstituted C1-6 alkyl, or substituted C1-6 alkyl;
each R8 is independently C1-6 alkyl, C1-6 haloalkyl, or optionally substituted phenyl;
R6A is —OH, —OR10 or —NR11R12;
each of R6B, R6C and R6D is independently H, C1-6 haloalkyl, or unsubstituted or substituted C1-6 alkyl;
R10 is unsubstituted or substituted C1-6 alkyl, or a hydroxy protecting group;
each of R11 and R12 is independently H, unsubstituted or substituted C1-6 alkyl, or an amino protecting group;
each of m and n is independently 1, 2, 3, 4, 5 or 6;
k is 0 or 1;
x is 0, 1, 2, 3, 4, 5 or 6; and
each RN is independently halo, cyano, hydroxy, amino, unsubstituted C1-6 alkyl, substituted C1-C6 alkyl, C1-C6 haloalkyl, hydroxy(C1-C6 alkyl), amino(C1-C6 alkyl), (C1-C6 alkyl)amino, C1-C6 alkoxy, C1-C6 haloalkoxy, (C1-C6 alkoxy)C1-C6 alkyl, or —O(C1-C6 alkoxy)C1-C6 alkyl, or two adjacent RN attached to the same carbon atom form oxo (═O).

### Claim 2 (depends on 1)

The compound of claim 1, wherein k is 0, R7 is H, and the compound is also represented by Formula (IIa):
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein x is 0.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound is also represented by Formula (IIb):
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein L4 is a C1-6 alkylene.

### Claim 6 (depends on 1)

The compound of claim 1, wherein Y2 is C(O)O and the compound is also represented by Formula (IIc):
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1, wherein Y2 is NHC(O) and the compound is also represented by Formula (IId):
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1, wherein L4 is a bond.

### Claim 9 (depends on 1)

The compound of claim 1, wherein Y2 is a bond.

### Claim 10 (depends on 1)

The compound of claim 1, wherein L5 is 2 to 15 membered heteroalkylene where one or more carbon atoms are replaced with C(═O), O or N.

### Claim 11 (depends on 10)

The compound of claim 10, wherein L5 is —C(═O)—(CH2)1-5.

### Claim 12 (depends on 1)

The compound of claim 1, wherein L5 is a bond.

### Claim 13 (depends on 1)

The compound of claim 1, wherein each of X1 and X3 is —C(═O)CH2CH2—, and X2 is —C(═O)CH2-.

### Claim 14 (depends on 1)

The compound of claim 1, wherein each of X1 and X3 is —NHC(═O)CH2CH2—, and X2 is-NHC(═O)CH2-.

### Claim 15 (depends on 1)

The compound of claim 1, wherein each of X1, X2 and X3 is —OCH2—, —NHCH2—, —C(═O)CH2CH2—, —C(═O)CH2—, —NHC(═O)CH2CH2— or —NHC(═O)CH2-.

### Claim 16 (depends on 1)

The compound of claim 1, wherein each of L1a, L1b, L1c, L2a L2b, L2c, L3a, L3b, and L3c is independently a bond, C1-10 alkylene, or 3 to 15 membered heteroalkylene where one or more carbon atoms are replaced with C(═O), O or N.

### Claim 17 (depends on 16)

The compound of claim 16, wherein the 3 to 15 membered heteroalkylene is a PEG linker comprising one to five —OCH2CH2— repeating unit.

### Claim 18 (depends on 1)

The compound of claim 1, wherein each of R1a, R1b, R1c, R2a, R2b, R2c, R3a, R3b, and R3c is independently H, —C(═O)CH3 or —C(═O)Ph.

### Claim 19 (depends on 18)

The compound of claim 18, wherein each of R1a, R1b, R1c, R2a, R2b, R2c, R3a, R3b, and R3c is —C(═O)CH3.

### Claim 20 (depends on 1)

The compound of claim 1, wherein each of R4a, R4b and R4c is —C(═O)CH3 or —C(═O)CF3.

### Claim 21 (depends on 1)

The compound of claim 1, wherein both m and n are 1, 2 or 3.

### Claim 22 (depends on 1)

The compound of claim 1, wherein R5 is a trityl type of hydroxy protecting group selected from (4-methoxyphenyl)diphenylmethyl, bis(4-methoxyphenyl)phenylmethyl (DMTr), tris(4-methoxyphenyl)methyl, 9-phenylxanthen-9-yl, or 9-(4-methoxyphenyl)xanthen-9-yl.

### Claim 23 (depends on 1)

The compound of claim 1, wherein R6 is —C(═O)CH2CH2C(═O)OH or

### Claim 24 (depends on 1)

The compound of claim 1, selected from the group consisting of:
and pharmaceutically acceptable salts thereof, wherein
each of X1, X2 and X3 is —OCH2—, —NHCH2—, —C(═O)CH2CH2—, —C(═O)CH2—, —NHC(═O)CH2CH2— or —NHC(═O)CH2—, or each of X1 and X3 is —C(═O)CH2CH2—, and X2 is —C(═O)CH2—, or each of X1 and X3 is —NHC(═O)CH2CH2—, and X2 is —NHC(═O)CH2-;
Ac is —C(O)CH3;
each of m and n is independently 1, 2, or 3;
R5 is DMTr; and
R6 is —C(═O)CH2CH2C(═O)OH or

### Claim 25 (depends on 24)

The compound of claim 24, having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 1)

A method of preparing a synthetic oligonucleotide, comprising reacting a compound of claim 1, with an oligonucleotide.

### Claim 27 (depends on 26)

An oligonucleotide prepared by the method of claim 26.

### Claim 28 (depends on 1)

A solid support comprising the compound of claim 1 covalently attached thereto via R6 of the compound of Formula (II).

### Claim 29 (depends on 28)

The solid support of claim 28, wherein the compound is covalently attached to the solid support via a moiety:
wherein W is O or NH; the dashed line refers to the connection with the solid support, optionally through an additional linker, and wherein the squiggly line refers to the point of the attachment of the oxygen atom that covalently attached to R6 of the compound, to the remaining portion of the compound.

### Claim 30 (depends on 24)

The compound of claim 24, wherein each of L1a, Lib, L1c, L2a, L26, L2c, L3a, L3b, and L3c is independently a bond, C1-10 alkylene, 3 to 15 membered heteroalkylene where one or more carbon atoms are replaced with C(═O), O or N, or a PEG linker comprising one to five —OCH2CH2— repeating unit.

### Claim 31 (depends on 30)

The compound of claim 30, wherein L5 is a bond or C(═O)—(CH2)1-5.