Granted Patent B2

US 12,478,682 · App. 17/552,750 · Granted Nov 25, 2025

Inventors: Balkrishen Bhat (Carlsbad, CA); Saswata Karmakar (Acton, MA); Debatosh Majumdar (Lexington, MA); Jia Tay (Acton, MA); Nelson Chau (Needham, MA)

Assignee: Translate Bio MA, Inc.

A61K47/549A61K31/7088A61K47/60C12N15/113C12N15/87C12N2310/315C12N2310/351

Abstract

Claims (59)

1 . A conjugate of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is a nucleic acid;

X is O or S;

each Z independently is a sugar, a folate, or a cell-penetrating peptide;

each of L 2 and L 3 is independently a bond, optionally substituted alkylene, or optionally substituted heteroalkylene;

wherein each L 1 comprises a triazole;

m is an integer from 3 to 10, inclusive; and

n is an integer from 4 to 10, inclusive.

2 . The conjugate of claim 1 having the structure of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

each of L′ and L″ is independently a bond, optionally substituted alkylene, or optionally substituted heteroalkylene.

3 . The conjugate of claim 1 , wherein m is 3, each Z independently is a sugar, and the conjugate is of Formula (III):

or a pharmaceutically acceptable salt thereof.

4 . The conjugate of claim 2 , wherein m is 3, each Z independently is a sugar, and the conjugate is of Formula (IV):

or a pharmaceutically acceptable salt thereof.

5 . The conjugate of claim 1 , wherein each Z is GalNAc or a derivative thereof or a mannose or a derivative thereof.

6 . The conjugate of claim 4 , wherein

(i) the conjugate is of Formula (IV-a):

wherein each instance of R O is independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group (IV-b).

7 . The conjugate of claim 1 , wherein each instance of L 1 is independently optionally substituted heteroalkylene.

8 . The conjugate of claim 1 , wherein L 2 is optionally substituted heteroalkylene.

9 . The conjugate of claim 1 , wherein L 3 is optionally substituted alkylene.

10 . The conjugate of claim 6 , wherein each instance of R O is hydrogen or an oxygen protecting group.

11 . The conjugate of claim 1 , wherein group A is:

(ii) a single-stranded oligonucleotide;

(iii) a double-stranded oligonucleotide;

(iv) an antisense oligonucleotide; or

(v) an mRNA.

12 . A pharmaceutical composition comprising a conjugate of claim 1 , and a pharmaceutically acceptable carrier or excipient.

13 . A method for preparing a conjugate of Formula (I-a):

or a pharmaceutically acceptable salt thereof, wherein:

A is a group comprising a nucleic acid;

X is O or S;

Z is a sugar, a folate, or a cell-penetrating peptide;

each of L 2 , and L 3 is independently a bond, optionally substituted alkylene, or optionally substituted heteroalkylene;

wherein each L 1 comprises a triazole;

m is an integer from 3 to 10, inclusive; and

n is an integer from 1 to 10, inclusive;

comprising contacting a compound of Formula (I-a-Az):

or a salt thereof, with a compound of Formula (I-a-Alk):

under conditions suitable to yield the conjugate of Formula (I-a).

14 . A method for preparing a conjugate of Formula (I-h):

or a pharmaceutically acceptable salt thereof, wherein:

A is a group comprising a nucleic acid;

X is O or S;

Z is a sugar, a folate, or a cell-penetrating peptide;

each of L 2 , and L 3 is independently a bond, optionally substituted alkylene, or optionally substituted heteroalkylene;

wherein each L 1 comprises a triazole;

m is an integer from 3 to 10, inclusive; and

n is an integer from 1 to 10, inclusive;

comprising contacting a compound of Formula (I-h-Alk):

or a salt thereof,

with a compound of Formula (I-h-Az):

under conditions suitable to yield the conjugate of Formula (I-h).

15 . The conjugate of claim 4 , wherein the conjugate is of Formula (IV-b):

16 . The conjugate of claim 4 , wherein the conjugate is of Formula (IV-c):

17 . The conjugate of claim 4 , wherein the conjugate is of Formula (IV-d):

18 . The conjugate of claim 4 , wherein the conjugate is of Formula (IV-e):

Assignments (1)

Continuity (4)

References Cited (240)