# US 12,178,876 B2 · Conjugates comprising cleavable linkers

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- Number: US 12,178,876 B2
- Document ID: US12178876B2
- Status: Granted
- Kind: B2
- Application number: 18/630,197
- Filed: 2024-04-09
- Published: 2024-11-07
- Granted: 2024-12-31
- Earliest claimed: 2023-04-18
- Assignees: AstraZeneca AB
- Applicants: AstraZeneca AB
- Inventors: Akbar Husain Khan; Andreas Lothar Severino Maderna; Maximillian Taro William Lee; Nicole Danielle Bartolo; William Robert Fraser Goundry
- Web page: https://patentgrep.com/patent/US12178876B2

## CPC

- A61K 47/68037: {the drug being a camptothecin [CPT] or derivatives}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6883: {Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy}
- A61P 35/00: Antineoplastic agents
- C07H 15/203: Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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

The specification relates to conjugates comprising a linker of Formula (ICA): and pharmaceutically acceptable salts thereof. The specification also relates the use of the conjugates for the treatment of diseases such as cancer, and intermediates useful for the synthesis of the conjugates.

## Claims

### Claim 1

A conjugate of Formula (IC)
Ab-(GA-JA-DC)k (IC)
or a pharmaceutically acceptable salt thereof,
wherein
Ab is an antibody or antigen-binding fragment thereof,
k is an integer from 1 to 10,
each GA is independently a conjugation group conjugated to the antibody or antigen-binding fragment thereof,
each DC is
each JA is independently a group of Formula (ICA)
E is (CH2)n1, wherein n1 is 0, 1, 2 or 3,
Q is
R1 is C1-4 alkyl,
X is (CH2)n2, wherein n2 is 0, 1, 2 or 3,
Y is (CH2)n3, wherein n3 is 0, 1, 2, 3 or 4,
Z is (CH2)n4, wherein n4 is 1, 2, 3, 4 or 5,
m is an integer from 5 to 17,
p is 1 or 0,
(GA) indicates the point of attachment to GA, and
(DC) indicates the point of attachment to DC.

### Claim 2 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein Q is

### Claim 3 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein m is 9, 10, 11, 12 or 13.

### Claim 4 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R1 is CH3.

### Claim 5 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein E is CH2.

### Claim 6 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein X is CH2.

### Claim 7 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein Y is (CH2)2.

### Claim 8 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein Z is (CH2)2.

### Claim 9 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein p is 1.

### Claim 10 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein each JA is a group of Formula (ICB)

### Claim 11 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein GA is selected from
wherein RK is H or CH3, RL is C1-6 alkyl, and indicates the point of attachment to the antibody or antigen-binding fragment thereof.

### Claim 12 (depends on 11)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 11, wherein GA is

### Claim 13 (depends on 11)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 11, wherein GA is

### Claim 14 (depends on 10)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 10, wherein GA is
wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.

### Claim 15 (depends on 10)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 10, wherein GA is
wherein indicates the point of attachment to the antibody or antigen-binding fragment thereof.

### Claim 16 (depends on 1)

The conjugate of Formula (IC) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein k is an integer from 2 to 8.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising the conjugate of Formula (IC), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, and a pharmaceutically acceptable excipient.

### Claim 18 (depends on 1)

A compound of Formula (IIC)
GB-JB-DC (IIC)
or a salt thereof, wherein GB is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof,
JB is a group of Formula (IICA)
wherein DC, E, Q, R1, X, Y, Z, m and p are as defined for a conjugate of Formula (IC) in claim 1, (GB) indicates the point of attachment to GB, and (DC) indicates the point of attachment to DC.

### Claim 19 (depends on 18)

The compound of Formula (IIC) or a salt thereof, as claimed in claim 18, wherein
GB is selected from
wherein X1 is CH or N,
h is 0 or 1,
Hal is Cl, Br or I,
RK is H or CH3, and
RL is C1-6 alkyl.

### Claim 20 (depends on 19)

The compound of Formula (IIC) or a salt thereof, as claimed in claim 19, wherein
GB is

### Claim 21 (depends on 19)

The compound of Formula (IIC) or a salt thereof, as claimed in claim 19, wherein
GB is

### Claim 22 (depends on 18)

The compound of Formula (IIC) or a salt thereof, as claimed in claim 18, that is
(2S,3S,4S,5R,6S)-6-(2-((3-((S)-6-(((3 S,3aR,6S,6aR)-6-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amido)hexahydrofuro[3,2-b]furan-3-yl)amino)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-6-oxohexanamido)propanamido)methyl)-4-(((((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-1-yl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, or a salt thereof.

### Claim 23 (depends on 18)

The compound of Formula (IIC) or a salt thereof, as claimed in claim 18, that is
(2S,3S,4S,5R,6S)-6-(2-((S)-8-(4-(((3S,3aR,6S,6aR)-6-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amido)hexahydrofuro[3,2-b]furan-3-yl)amino)-4-oxobutyl)-15-bromo-3,7,10,14-tetraoxo-2,6,9,13-tetraazapentadecyl)-4-(((((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3′,4′:6,7]indolizino-[1,2-b]quinolin-1-yl)carbamoyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid, or a salt thereof.

### Claim 24 (depends on 1)

A compound of Formula (IXC)
or a salt thereof, wherein GB is a conjugation group for conjugation to an antibody or antigen-binding fragment thereof, and E, Y, Z and p are as defined for a conjugate of Formula (IC) in claim 1, RQ1 is H or RP1, each RQ2 is independently H or RP2 and RQ3 is H or RP3, wherein RP1 is a carboxylic acid protecting group, each RP2 is independently an alcohol protecting group and RP3 is an amine protecting group.