Benzazepine compounds, conjugates, and uses thereof
Inventors
COBURN, Craig Alan • Baum, Peter Robert • Smith, Sean Wesley
Assignees
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Publication Number
US-10442790-B2
Publication Date
2019-10-15
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 describes benzazepine-related compounds represented by Formula (IIB), or pharmaceutically acceptable salts thereof, with defined substituent positions L10, L2, R1, R2, R4, R5, R10, and additional substituents R20-R25 under enumerated constraints. The structure further includes the relationship that R24 and R25 can together form an optionally substituted saturated C3-7 carbocycle.
Within Formula (IIB), L10 is selected from —C(O)— and —C(O)N(R10)—*, where * represents where L10 is bound to R5—, and L2 is selected from —C(O)— and —C(O)N(R10)—. R1 and R2 are independently selected from hydrogen and C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each optionally substituted with one or more substituents independently selected from the listed functional groups.
R4 is selected from —OR10, —N(R10)2, —C(O)N(R10)2, —C(O)R10, —C(O)OR10, —S(O)R10, and —S(O)2R10. R5 is selected from unsaturated C4-8 carbocycle, bicyclic carbocycle, and fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle, with optional substitution, and R10 and R20-R25 are defined by further enumerated options.
The disclosure also includes linker architectures for covalent attachment to antibody constructs and other targeting moieties, including reactive moieties RX or RX* and linker L3 described as cleavable or noncleavable, including lysosomal-enzyme cleavable variants, peptide-containing linkers, self-immolative and enzymatically cleavable linker architectures, and additional linker variants such as disulfide, hydrazone, dipeptide, PEG/backbone cleavables, hydrolyzable ester, carbonate, imine, phosphate, and acetal linkages.
Claims Coverage
The consolidated claim coverage centers on a Formula (IIB) compound or pharmaceutically acceptable salt with defined selections for L10, L2, R1, R2, R4, R5, R10, and R20-R25, including the relationship that R24 and R25 can together form an optionally substituted saturated C3-7 carbocycle. Additional dependent refinements include lysosomal-enzyme cleavable L3, peptide linker and antibody-reactive moiety concepts, and cancer-treatment administration language.
Formula (IIB) compound scaffold
A compound represented by Formula (IIB), or a pharmaceutically acceptable salt thereof, with defined substituent selections for L10, L2, R1, R2, R4, R5, R10, and additional substituent options for R20-R25, including the relationship that R24 and R25 can together form an optionally substituted saturated C3-7 carbocycle.
L10 and L2 carbonyl and amide linkage
L10 is selected from —C(O)— and —C(O)N(R10)—*, where * represents where L10 is bound to R5—; and L2 is selected from —C(O)— and —C(O)N(R10)—.
R1 and R2 substituent options
R1 and R2 are independently selected from hydrogen and C1-10 alkyl, C2-10 alkenyl, and C2-10 alkynyl, each optionally substituted with one or more substituents independently selected from the listed group options.
R4 functional-group selection
R4 is selected from —OR10, —N(R10)2, —C(O)N(R10)2, —C(O)R10, —C(O)OR10, —S(O)R10, and —S(O)2R10.
R5 ring-system selection
R5 is selected from unsaturated C4-8 carbocycle, bicyclic carbocycle, and fused 5-5, fused 5-6, and fused 6-6 bicyclic heterocycle, with optional substitution.
R10 and R20-R25 substituent definitions
R10 is independently selected at each occurrence from hydrogen, —NH2, and —C(O)OCH2C6H5, and R20, R21, R22, and R23 are independently selected from hydrogen, halogen, OR10, —SR10, —N(R10)2, —S(O)R10, —S(O)2R10, —C(O)R10, —C(O)OR10, —OC(O)R10, —NO2, —O—, —S—, —N(R10)—, and —CN; R24 and R25 are independently selected from the same set or taken together form an optionally substituted saturated C3-7 carbocycle.
L3 cleavable by a lysosomal enzyme
A dependent refinement states that linker L3 is cleavable by a lysosomal enzyme.
Peptide linker and antibody-reactive moiety
The disclosure includes a peptide-containing linker in which L4 is the C-terminal of the peptide and L5 is a spacer to an antibody reactive moiety, with RX* or succinimide/hydrolyzed succinimide attachment-related moieties.
Cancer-treatment administration
A dependent method claim states treating cancer by administering an effective amount of the pharmaceutical composition to a subject in need.
The consolidated claim coverage is primarily structural: a Formula (IIB) compound or salt with defined linker-related groups L10 and L2, constrained substituent selections for R1, R2, R4, R5, and R10, and defined options for R20-R25 including the R24/R25 combined saturated C3-7 carbocycle relationship. Dependent claim content further includes lysosomal-enzyme cleavable L3, peptide and antibody-reactive linker concepts, and a cancer-treatment administration method.
Stated Advantages
Reduced extracellular activity.
Mitigation of aggregation for hydrophobic benzazepines.
Reduced bystander effects.
Improved circulation stability.
Improved plasma stability by using self-stabilizing linkers that promote succinimide hydrolysis.
Increased stability from bridged disulfides for homogeneous DAR4 conjugates.
Documented Applications
Release of a benzazepine payload from an antibody construct using protease-driven self-immolative 1,6-elimination and lysosomal enzyme cleavage architectures.
Conjugation to antibody constructs and targeting moieties binding tumor antigens, including HER2 antigen binding domain and TROP2 antigen binding domain.
Treating cancer by administering an effective amount of a pharmaceutical composition to a subject in need.
Cancer therapeutics.
TLR8 modulation.
Tumor cell killing in vivo and TNFα induction as disclosed figure-based activity for TLR8 agonist conjugates.
Preparation and characterization of linker-modified small-molecule payload conjugates in a Compound-Linker series.
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