Benzazepine compounds, conjugates, and uses thereof
Inventors
COBURN, Craig Alan • Baum, Peter Robert • Smith, Sean Wesley
Assignees
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Publication Number
US-10239862-B2
Publication Date
2019-03-26
Expiration Date
Abstract
Benzazepine compounds, conjugates, and pharmaceutical compositions for use in the treatment of disease, such as cancer, are disclosed herein. The disclosed benzazepine compounds are useful, among other things, in the treating of cancer and modulating TLR8. Additionally, benzazepine compounds incorporated into a conjugate with an antibody construct are described herein.
Core Innovation
The disclosure concerns benzazepine compounds and pharmaceutically acceptable salts represented by Formula (IIA), including an optional double bond and defined selections for L10, L2, R1, R2, R4, R5, and R10. L10 is selected from —C(O)— and —C(O)N(R10)—, and L2 is selected from a bond and —C(O)—, with detailed substituent-selection rules for the variable groups.
The compounds are also described in the context of linker L3 attachment to benzazepine compound or salt scaffolds within antibody-drug conjugates and related antibody conjugates. Linker L3 can be cleaved by a lysosomal enzyme, RX includes either a leaving group or a maleimide, and conjugation is described through antibody constructs and reactive attachment to nucleophilic residues or antibody conjugation sites.
The disclosure further describes embodiments in which the benzazepine payload is linked through self-immolative or enzymatically cleavable linker architectures, including β-glucuronic acid/β-glucuronidase and β-galactoside systems, peptide-containing lysosome-cleavable motifs, and other cleavable or non-cleavable linker types. It states that the conjugation design is intended to modulate bystander killing via intracellular metabolism while reducing aggregation and preserving Fc receptor binding and antigen binding.
Claims Coverage
The consolidated claim coverage centers on a Formula (IIA) benzazepine scaffold, with additional refinements to linker behavior, conjugation structure, and therapeutic use. The inventive coverage includes 8 merged inventive features.
Formula (IIA) benzazepine scaffold with optional double bond
A compound represented by Formula (IIA) or a pharmaceutically acceptable salt thereof, including an optional double bond and defined variable positions for L10, L2, R1, R2, R4, R5, and R10.
L10 and L2 structural link selection
L10 is selected from —C(O)— and —C(O)N(R10)—, and L2 is selected from a bond and —C(O)—.
Substituent selection for R1 and R2
R1 and R2 are independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl.
Functional group selection for R4
R4 is selected from —OR10, —N(R10)2, —C(O)N(R10)2, —C(O)R10, —C(O)OR10, —S(O)R10, —S(O)2R10, C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl.
Bicyclic or heterocyclic selection for R5
R5 is selected from unsaturated C4-s carbocycle, bicyclic carbocycle, and fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle, with optional substitution by the listed groups including halogen, —OR10, —SR10, —C(O)N(R10)2, —N(R10)C(O)R10, —N(R10)2, —C(O)R10, —C(O)OR10, —NO2, and —CN.
R10 definition and allowed substitution patterns
R10 is independently selected at each occurrence from hydrogen, —NH2, and —C(O)OCH2C6H5, and may also define optionally substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle groups.
Linker L3 cleavable by a lysosomal enzyme
The compound or pharmaceutically acceptable salt is defined such that L3 can be cleaved by a lysosomal enzyme.
Antibody conjugate formed by covalent attachment via linker L3
A compound or salt is covalently attached via linker L3 to an antibody construct to form an antibody conjugate.
The claim coverage is centered on the Formula (IIA) benzazepine scaffold and its variable-group definitions, and is further narrowed by linker cleavability and covalent antibody-conjugate attachment via L3.
Stated Advantages
Reduced bystander effects and nonspecific toxicity.
Improved circulation stability.
Improved hydrophilicity.
More stable, more homogeneous DAR4 conjugates.
Modulates bystander killing via intracellular metabolism using neutral cytotoxic metabolites.
Reduces aggregation, including aggregation characterized by SEC aggregation thresholds.
Maintains Fc receptor binding and antigen binding when conjugated.
Documented Applications
Breast cancer treatment by administering a pharmaceutical composition comprising an antibody construct that specifically binds to human HER2, TROP2, or Liv-1.
Cancer treatment, including tumor cell killing in vivo, using benzazepine delivery via antibody conjugates.
Use in antibody-drug conjugates formed with benzazepine compound or salt scaffolds attached via linker L3.
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