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US 2026/0256929 A1Published application
Protease/enzyme cleavable linker-payloads and protein conjugates
OwnerKrishna BAJJURI, Andreas MADERNA +1inventors
InventorsKrishna BAJJURI, Andreas MADERNA, Valery Rostislavovich Polyakov
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Abstract
Provided herein are compounds, conjugate products thereof, methods, and pharmaceutical compositions for use in treatment and diagnosis.
Claims152
A compound of Formula (I):
- or a pharmaceutically acceptable salt and/or regioisomer thereof;
- wherein
- L1 is selected from
- Ring A is an optionally substituted bridged, fused, or spirocyclic bicyclic carbocycle, or an optionally substituted bridged, fused, or spirocyclic bicyclic heterocycle, wherein the carbocycle or the heterocycle of Ring A are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, —CN, —NO2, —OH, —N(R2R3)2, —C(O)—, —C(O)N(R2R3)2, —C(O)OR2, aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
- Ring B is an optionally substituted N-linked bridged, fused, or spirocyclic bicyclic heterocycle, wherein Ring B is optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, —CN, —NO2, —OH, —N(R2R3)2, —C(O)—, —C(O)N(R2R3)2, —C(O)OR2, aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
- Ra and Rb are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, —CN, —NO2, —OH, —N(R2R3)2, —C(O)N(R2R3)2, —C(O)OR2, aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
- a is an integer independently selected from 0, 1, 2, 3, 4, 5, and 6;
- b in an integer selected from 0 and 1;
- R1 is hydrogen or alkyl optionally substituted with one or more substituents selected from cycloalkyl, halogen, alkoxy, —CN, —NO2, —OH, —N(R2R3)2, —C(O)N(R2R3)2, —C(O)OR2, aryl, and heteroaryl;
- R2 and R3 are independently selected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
- Y is *—C(O)—(CRaRb)c—NH— or *—C(O)—(CRaRb)c—, wherein * represents where Y is bound to RG;
- c is an integer selected from 1, 2, 3, 4, 5, and 6;
- RG is a reactive group;
- L2 is absent or a linker comprising a hydrophilic polymer residue;
- L3 is absent, —C(O)-AA-, —C(O)-AA-Z—(CRaRb)a—Z—(CRaRb)a—C(O)—, —C(O)—Z—(CRaRb)a—C(O)—Z-L4-OC(O)—, —Z-AA-, -AA-, —C(O)—, —C(O)-AA-Z—(CRaRb)a—, -AA-C(O)—, —C(O)—(CRaRb)a—Z—(CRaRb)a—Z-AA-C(O)—, —C(O)O-L4-Z—C(O)—(CRaRb)a—Z—C(O)—, -AA-Z—, or —(CRaRb)a—Z-AA-C(O)—;
- Z is selected from —NR2— and —O—;
- AA is an amino acid residue or a peptide residue;
- L4 is
- wherein Su is a hexose form of a monosaccharide;
- d is an integer independently selected from 1, 2, and 3;
- D is a cytotoxic payload;
- and
- represents attachment to the remainder of the compound.
20 more elements
A compound of Formula (III):
- or a pharmaceutically acceptable salt and/or regioisomer thereof;
- wherein
- L5 is a linker comprising an unnatural amino acid;
- Y is *—C(O)—(CRaRb)—NH— or *—C(O)—(CRaRb)c—, wherein * represents where Y is bound to RG;
- c is an integer selected from 1, 2, 3, 4, 5, and 6;
- RG is a reactive group;
- L2 is absent or a linker comprising a hydrophilic polymer residue;
- L3 is absent, —C(O)-AA-, —C(O)-AA-Z—(CRaRb)a—Z—(CRaRb)a—C(O)—, —C(O)—Z—(CRaRb)a—C(O)—Z-L4-OC(O)—, —Z-AA-, -AA-, —C(O)—, —C(O)-AA-Z—(CRaRb)a—, -AA-C(O)—, —C(O)—(CRaRb)a—Z—(CRaRb)a—Z-AA-C(O)—, —C(O)O-L4-Z—C(O)—(CRaRb)a—Z—C(O)—, -AA-Z—, or —(CRaRb)a—Z-AA-C(O)—;
- Ra and Rb are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, alkoxy, —CN, —NO2, —OH, —N(R2R3)2, —C(O)N(R2R3)2, —C(O)OR2, aminoalkyl, hydroxyalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
- a is an integer independently selected from 0, 1, 2, 3, 4, 5, and 6;
- Z is selected from —NR2— and —O—;
- AA is an amino acid residue or a peptide residue;
- L4 is
- wherein Su is a hexose form of a monosaccharide;
- d is an integer independently selected from 1, 2, and 3;
- D is a cytotoxic payload;
- and represents attachment to the remainder of the compound.
14 more elements
The conjugate of claim 79 or 90, wherein COMP is a residue of a polypeptide.
The conjugate of any one of claims 79 and 8-183, wherein L1 is
Dependencies are inferred from the claim text.