# US 2014/0193437 A1 · Hydrophilic self-immolative linkers and conjugates thereof

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- Number: US 2014/0193437 A1
- Document ID: US20140193437A1
- Status: Published application
- Kind: A1
- Application number: 14/137,799
- Filed: 2013-12-20
- Published: 2014-07-10
- Earliest claimed: 2012-12-21
- Assignees: BioAlliance C.V.; AbGenomics International Inc.
- Applicants: BioAlliance C.V.; AbGenomics International Inc.
- Inventors: Rong-Hwa LIN; Shih-Yao LIN; Yu-Chi HSIEH; Chiu-Chen HUANG
- Web page: https://patentgrep.com/patent/US20140193437A1

## CPC

- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 38/06: Tripeptides
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61K 47/68031: {the drug being an auristatin}
- A61K 47/6817: {Toxins}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6863: {the tumour determinant being from stomach or intestines cancer cell}
- 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}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 35/00: Antineoplastic agents
- C07D 241/36: condensed with carbocyclic rings or ring systems
- C07D 295/192: from aromatic carboxylic acids
- C07K 7/02: Linear peptides containing at least one abnormal peptide link
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present disclosure provides compounds with a hydrophilic self-immolative linker, which is cleavable under appropriate conditions and incorporates a hydrophilic group to provide better solubility of the compound. The compounds of the present disclosure comprise a drug moiety, a targeting moiety capable of targeting a selected cell population, and a linker which contains an acyl unit, an optional spacer unit for providing distance between the drug moiety and the targeting moiety, a peptide linker which can be cleavable under appropriate conditions, a hydrophilic self-immolative linker, and an optional second self-immolative spacer or cyclization self-elimination linker.

## Claims

### Claim 1

A compound of the formula (I):
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
T is a targeting moiety;
X is a hydrophilic self-immolative linker;
L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker;
L4 is bond or a spacer; and
A is an acyl unit.

### Claim 2

A compound of the formula (II):
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
T is a targeting moiety;
R1 is hydrogen, unsubstituted or substituted C1-3 alkyl, or unsubstituted or substituted heterocyclyl;
L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker;
L4 is bond or a spacer; and
A is an acyl unit.

### Claim 3 (depends on 1)

The compound of claim 1, wherein L1 is a bond.

### Claim 4 (depends on 1)

The compound of claim 1, wherein L1 is a second self-immolative linker or a cyclization self-elimination linker.

### Claim 5 (depends on 4)

The compound of claim 4, wherein L1 is an aminobenzyloxycarbonyl linker.

### Claim 6 (depends on 4)

The compound of claim 4, wherein L1 is selected from the group consisting of
wherein n is 1 or 2.

### Claim 7 (depends on 4)

The compound of claim 4, wherein L1 is selected from the group consisting of

### Claim 8 (depends on 1)

The compound of claim 1, wherein L2 is a bond.

### Claim 9 (depends on 3)

The compound of claim 3, wherein L2 is a second self-immolative linker.

### Claim 10 (depends on 9)

The compound of claim 9, wherein L2 is an aminobenzyloxycarbonyl linker.

### Claim 11 (depends on 9)

The compound of claim 9, wherein L2 is selected from
wherein n is 1 or 2.

### Claim 12 (depends on 1)

The compound of claim 1, wherein L3 is a peptide linker of 1 to 10 amino acid residues.

### Claim 13 (depends on 12)

The compound of claim 12, wherein L3 is a peptide linker of 2 to 4 amino acid residues.

### Claim 14 (depends on 1)

The compound of claim 1, wherein L3 is a peptide linker comprising at least one lysine or arginine residue.

### Claim 15 (depends on 1)

The compound of claim 1, wherein L3 is a peptide linker comprising an amino acid residue selected from lysine, D-lysine, citrulline, arginine, proline, histidine, ornithine and glutamine.

### Claim 16 (depends on 1)

The compound of claim 1, wherein L3 is a peptide linker comprising an amino acid residue selected from valine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine.

### Claim 17 (depends on 12)

The compound of claim 12, wherein L3 is a dipeptide unit selected from valine-citrulline, proline-lysine, methionine-D-lysine, asparagine-D-lysine, isoleucine-proline, phenylalanine-lysine, and valine-lysine.

### Claim 18 (depends on 17)

The compound of claim 17, wherein L3 is valine-citrulline.

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 1)

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

### Claim 21 (depends on 20)

The compound of claim 20, wherein the spacer is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.

### Claim 22 (depends on 20)

The compound of claim 20, wherein L4 is L4a-C(O), L4a-C(O)—NH, L4a-S(O)2, or L4a-S(O)2—NH, wherein each L4a is independently polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.

### Claim 23 (depends on 20)

The compound of claim 20, wherein L4 is L4a-C(O), wherein L4a is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.

### Claim 24 (depends on 20)

The compound of claim 20, wherein L4 is L4a-C(O), wherein L4a is a polyalkylene glycol.

### Claim 25 (depends on 20)

The compound of claim 20, wherein L4 is L4a-C(O), wherein L4a is a polyethylene glycol.

### Claim 26 (depends on 20)

The compound of claim 20, wherein the spacer is of the formula —CH2—(CH2-β-CH2)m—CH2—C(O)—, wherein m is an integer from 0 to 30.

### Claim 27 (depends on 20)

The compound of claim 20, wherein L4 is L4a-C(O), wherein L4a is alkylene.

### Claim 28 (depends on 1)

The compound of claim 1, wherein A is selected from the group consisting of
wherein each Q2 is NH or O, and each q is independently an integer from 1 to 10.

### Claim 29 (depends on 28)

The compound of claim 28, wherein A is selected from the group consisting of
wherein each Q2 is independently NH or O and each q is independently an integer from 1 to 10.

### Claim 30 (depends on 29)

The compound of claim 29, wherein q is 2, 3, 4, or 5.

### Claim 31 (depends on 1)

The compound of claim 1, wherein A is selected from the group consisting of
wherein each Q2 is independently NH or O.

### Claim 32 (depends on 1)

The compound of claim 1, wherein T is an antibody targeting molecule.

### Claim 33 (depends on 32)

The compound of claim 32, wherein T is h5F1Ca.1 or c5D7.

### Claim 34 (depends on 1)

The compound of claim 1, wherein D is an amino-containing drug moiety, wherein the drug is connected to L1 or X through the amino group.

### Claim 35 (depends on 34)

The compound of claim 34, wherein D is duocarmycin, dolastatin, tubulysin, doxorubicin (DOX), paclitaxel, or mitomycin C (MMC), or an amino derivative thereof.

### Claim 36 (depends on 34)

The compound of claim 34, wherein D is an amino derivative of duocarmycin selected from the group consisting of

### Claim 37 (depends on 34)

The compound of claim 34, wherein D is dolastatin:

### Claim 38 (depends on 1)

The compound of claim 1, wherein -A-L4-L3-L2- is

### Claim 39 (depends on 1)

The compound of claim 1, wherein -A-L4-L3-L2-X-L1-D is:

### Claim 40 (depends on 1)

The compound of claim 1, wherein -A-L4-L3-L2-X-L1-D is:

### Claim 41 (depends on 1)

The compound of claim 1, wherein -A-L4-L3-L2-X-L1-D is:

### Claim 42 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a salt or solvate or stereoisomer thereof; and a pharmaceutically acceptable carrier.

### Claim 43 (depends on 1)

A method of killing a cell, comprising administering to the cell an amount of the compound of claim 1, or a salt or solvate or stereoisomer thereof, sufficient to kill the cell.

### Claim 44 (depends on 43)

The method of claim 43, wherein the cell is a cancer cell.

### Claim 45 (depends on 44)

The method of claim 44, wherein the cancer cell is a gastric cancer cell, pancreatic cancer cell, colorectal cancer cell, lung cancer cell or ovarian cancer cell.

### Claim 46 (depends on 1)

A method of treating cancer in an individual in need thereof comprising administering to the individual an effective amount of a compound of claim 1, or a salt or solvate or stereoisomer thereof.

### Claim 47 (depends on 46)

The method of claim 46, wherein the cancer is gastric cancer, pancreatic cancer, colorectal cancer, lung cancer or ovarian cancer.

### Claim 48 (depends on 1)

A kit comprising a compound of claim 1, or a salt or solvate or stereoisomer thereof.

### Claim 49 (depends on 48)

The kit of claim 48, further comprising instructions for use in the treatment of cancer.

### Claim 50

A compound of Formula (XII)
or a salt or solvate or stereoisomer thereof; wherein R is NO2 or NH2.

### Claim 51

A method of preparing Compound X:
or a salt or solvate or stereoisomer thereof;
wherein:
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker;
L4 is bond or a spacer; and
A is an acyl unit; and
R1 is NO2 or NH2;
comprising reacting Compound W: A-L4-L3-L2; and Compound I:

### Claim 52

A method of preparing Compound Z:
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker;
L4 is bond or a spacer; and
A is an acyl unit
R1 is NO2 or NH2;
comprising: reacting Compound X:
and p-nitrophenylchloroformate to form Compound Y:
reacting Compound Y with a compound comprising L1-D.

### Claim 53

A method of preparing Compound X1:
or a salt or solvate or stereoisomer thereof;
wherein:
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker; and
R1 is NO2 or NH2;
comprising: reacting Compound W1: L3-L2; and Compound I:

### Claim 54

A method of preparing Compound Y1:
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker; and
R1 is NO2 or NH2;
comprising: reacting Compound X1:
and a compound comprising L1-D.

### Claim 55

A method of preparing Compound Z:
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker;
L4 is bond or a spacer;
A is an acyl unit; and
R1 is NO2 or NH2;
comprising: reacting Compound Y1:
and a compound comprising A-L4.

### Claim 56

A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker;
L4 is bond or a spacer; and
A is an acyl unit; and
R1 is NO2 or NH2.

### Claim 57

A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker;
L4 is bond or a spacer; and
A is an acyl unit; and
R1 is NO2 or NH2.

### Claim 58

A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker; and
R1 is NO2 or NH2.

### Claim 59

A compound of formula:
or a salt or solvate or stereoisomer thereof;
wherein:
D is drug moiety;
L1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L2 is a bond or a second self-immolative linker;
wherein if L1 is a second self-immolative linker or a cyclization self-elimination linker, then L2 is a bond;
wherein if L2 is a second self-immolative linker, then L1 is a bond;
L3 is a peptide linker; and
R1 is NO2 or NH2.