Tripeptide linkers and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2025262315-A1
Application number	US-202218722251-A
Country	US
Kind code	A1
Filing date	Dec 20, 2022
Priority date	Dec 20, 2021
Publication date	Aug 21, 2025
Grant date	—

Abstract

Provided herein are peptide linkers which may be used to prepare drug conjugates, drug conjugates prepared using these linkers, and compositions and methods of treatment thereof.

First claim

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is a covalent bond, alkanediyl (C≤12) , or substituted alkanediyl (C≤12) ;
R 1 is hydrogen, —ZR 6 , —(OCH 2 CH 2 ) 0-50 ZR 6 , or substituted —(OCH 2 CH 2 ) 0-50 ZR 6 , wherein:
R 6 is hydrogen, hydroxy, aminohydroxy, amino, mercapto, hydroxylamino, hydrazino, or azide;
alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , alkylhydrazine (C≤12) , or a substituted version thereof;
a polyglycine comprising from 1 to 6 glycine units; or
a substructure of the formula:

wherein:
 A 1 and A 2 are each independently absent or arenediyl (C≤12) , substituted arenediyl (C≤12) , heteroarenediyl (C≤12) , or substituted heteroarenediyl (C≤12) , and form a fused arene (C≤12) , substituted arene (C≤12) , heteroarene (C≤12) , or substituted heteroarene (C≤12) ;
 A 3 is a covalent bond, O, alkanediyl (C≤8) , substituted alkanediyl (C≤8) , alkoxydiyl (C≤8) , or substituted alkoxydiyl (C≤8) ;
 A 4 and A 5 are each independently selected from a covalent bond, alkanediyl (C≤8) , substituted alkanediyl (C≤8) , arenediyl (C≤8) , and substituted arenediyl (C≤8) ;
 R d , R e , R e ′, and R h are each independently selected from hydrogen, halo, thioether, selenoether, sulfate, tosylate, mesylate, aryl (C≤8) , and substituted aryl (C≤8) ;
 R f is halo;
 R g is amine, hydrazine, alkylamino(ccs), substituted alkylamino(ccs), dialkylamino(ccs), substituted dialkylamino(ccs), alkylhydrazine (C≤8) , or substituted alkylhydrazine (C≤8) ;
 X 4 and X 5 are each independently O, N, C(O), or CH 2 , or X 4 and X 5 are alkanediyl (C≤8) or substituted alkanediyl (C≤8) and are taken together to form a fused cycloalkane group consisting of 3 to 8 ring atoms;
 R 7 is hydrogen, hydroxy, amino, or oxo;
 R 8 is carboxy; or
 alkyl (C≤12) , amido (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , —C(O)OR 11 , —C(O)NR 11 R 11 ′, or a substituted version thereof, wherein:
 R 11 and R 11 ′ are each independently hydrogen; or
 alkyl (C≤12) , aryl (C≤12) , or a substituted version thereof;
 R 9 and R 10 are each independently hydroxy, amino, or halo; or
 alkyl (C≤12) , aryl (C≤12) , or a substituted version thereof;
 x is 0-4, as valency permits;
 y is 0-4, as valency permits;
 z is 0-4;

Z is a covalent bond, alkanediyl (C≤12) , —C(O)-alkanediyl (C≤12) , —C(O)-alkanediyl (C≤12) —C(O)NH—, or a substituted version thereof;

R 2 is hydrogen, alkyl (C≤12) , substituted alkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , aralkyl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , or a monovalent amino protecting group;
W is a covalent bond or a polyvalent polymer having 2-21 connection points;
n is 1 to 20 provided that: when W is a covalent bond, then n is 1; and when W is a polyvalent polymer, then n is less than or equal to one less than the number of connection points;
each X is independently a covalent bond, alkanediyl (C≤12) , substituted alkanediyl (C≤12) , one or more amino acid residues, or an oligomeric peptide;
each X 2 is independently alkanediyl (C≤12) or substituted alkanediyl (C≤12) ;
each R 3 is independently hydroxy or amino;
alkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , amido (C≤12) , heteroaryl (C≤12) , or a substituted version thereof; or
—X 6 —C(O)R 12 , wherein:
X 6 is O, —NR b —, or a covalent bond;
 R b is hydrogen, alkyl (C≤6) , substituted alkyl (C≤6) , or a monovalent amino protecting group;
R 12 is hydroxy or amino; or
 alkoxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , or a substituted version thereof; or

—OSO 2 NR 13 R 13 ′, —OP(O)(OH)OR 14 , —OSO 2 OR 14 ′, —NR c —SO 2 NR 13 R 13 ′, —NR c —P(O)(OH)OR 14 , —NR c —SO 2 OR 14 ′, —SO 2 NR 13 R 13 ′, —P(O)(OH)OR 14 , or —SO 2 OR 14 ′, wherein:
R c is hydrogen, alkyl (C≤6) , substituted alkyl (C≤6) , aryl (C≤12) heteroaryl (C≤12) , aralkyl (C≤12) , heteroaralkyl (C≤12) , or a monovalent amino protecting group;

R 13 , R 13 ′, R 14 , and R 14 ′ are each independently hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , aralkyl (C≤12) , heteroaralkyl (C≤12) , or a substituted version thereof;

each m is independently 0 or 1;
each R 4 is independently the side chain moiety of glycine or valine; and
each R 4 ′ is hydrogen, alkyl (C≤12) , substituted alkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , aralkyl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , or a monovalent amino protecting group;
each R 5 is independently the side chain moiety of glycine, alanine, ornithine, lysine, arginine, citrulline, asparagine, or glutamine, or an amino-protected version thereof;
each R 5 ′ is hydrogen, alkyl (C≤12) , substituted alkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , aralkyl (C≤12) , heteroaralkyl (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , or a monovalent amino protecting group;
Q is a group of the formula:

wherein:
R 15 is hydrogen, —R 16 , or —C(O)—R 16 , wherein:
R 16 is a therapeutic agent or an imaging agent;

X 7 is a covalent bond, O, S, —NH—, alkanediyl (C≤12) , substituted alkanediyl (C≤12) , —(OCH 2 CH 2 ) p —, or substituted —(OCH 2 CH 2 ) p —, wherein:
p is 0-50; or
a group of the formula:

wherein:
 R a and R a ′ are each independently hydrogen, alkyl (C≤12) , substituted alkyl (C≤12) , aryl (C≤12) , or heteroaryl (C≤12) ;
 X 8 is O or —NR 17 R 17 ′—, wherein:
 R 17 and R 17 ′ are each independently alkyl (C≤12) or substituted alkyl (C≤12) ;
 R 19 is hydrogen, sugar, or a sugar derivative; and
 X 9 is a covalent bond, O, S, —NH—, —(OCH 2 CH 2 ) q , or substituted —(OCH 2 CH 2 ) q , wherein:
 q is 0-50; or
 a group of the formula:
 Y 1

 wherein:
 Y 1 is O or S;
 Y 2 is a covalent bond, O, S, —NH—, or —NR 18 —, wherein:
 R 18 is alkyl (C≤12) or substituted alkyl (C≤12) ; and
 X 10 is a covalent bond, alkyl (C≤12) , substituted alkyl (C≤12) , O, S, —NH—, —(CH 2 CH 2 O) r —, substituted —(CH 2 CH 2 O) r —, —(CH 2 CH 2 NR 20 ) r —, or substituted —(CH 2 CH 2 NR 20 ) r —;
 r is 0-50;
 R 20 is hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;

provided that when R 4 is valine, then R 4 ′ is not hydrogen; or
a compound selected from:

 and

and pharmaceutically acceptable salts thereof.

2 .- 10 . (canceled)

Assignees

• Univ Texas

Inventors

• Tsuchikama Kyoji
• Anami Yasuaki
• Ha Yin Yuen
• Tsuchikama Chisato
• An Zhiqiang
• Zhang Ningyan

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title

• A61K47/6889

  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 · CPC title

• A61K47/68031 Primary

  the drug being an auristatin · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title