Anti-liferative agents comprising substituted benzo[e]pyrido[1,2-a][1,4]diazepines
Inventors
JACKSON, Paul joseph Mark • Thurston, David Edwin • Rahman, Khondaker Mirazur
Assignees
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Publication Number
US-10975074-B2
Publication Date
2021-04-13
Expiration Date
Abstract
The invention relates to compounds comprising a substituted pyrrolo-, indolino- or tetrahydroisoquinoline-benzodiazepines alkylating moiety linked via the A-ring to aromatic groups of formula (Ia), and to pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents.
Core Innovation
The invention relates to compounds of formula (Ia), or pharmaceutically acceptable salts thereof, defined by a variable ring designation p and a heteroaryl group H1. When p is 0, H1 is C9 heteroaryl, and when p is 1, H1 is C5 heteroaryl, each optionally substituted with defined groups including C1-6 alkyl, (CH2)j-CO2R11, (CH2)j-NR11R12, C(=O)NH-R24, C(=O)NH-(CH2)k-NR11R12, C(=O)NH-(CH2)k-C(=NH)NR11R12, OH, OC1-6 alkyl, and O-(CH2)k-NR11R12. The structure also includes phenyl R24 groups, R25 and R26 substituents, and the variable R11 and R12, each independently H or C1-6 alkyl.
The formula (Ia) further defines R19 as H or (CH2)t-NR20R21, with R20 and R21 independently H or C1-6 alkyl, and uses integer ranges for j, k, and t. Linker L is selected from an amino acid, a peptide chain having 2, 3, 4, 5, or 6 amino acids optionally interrupted by NH, O, S, phenylene, and C5-9 heteroarylene, a C1-12 alkylene optionally interrupted by the same groups, or OCH2- and OCH2CH2-containing segments optionally interrupted by the same groups. The structure further includes X1, X2, Y1, Y2, Y3, Y4, Y5, and AM defined by formula (XXVII).
AM is defined by formula (XXVII) with v being 0 or 1 and with dotted-line connectivity representing either single bonds or one single bond and one double bond. The claim framework sets alternative structural cases for R1, R2, R3, R5, R6, and RD1 through RD7, including aromatic 6-membered ring formation in specified cases. The provision that at least one of Y1 and Y2 is CH is retained within the overall structural definition.
Claims Coverage
The consolidated claim coverage identifies one independent claim directed to a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, with extensive structural variability. The claim covers p-dependent heteroaryl selection, defined substituent families on the heteroaryl and phenyl elements, linker L selection, connection fragments X1 and X2, ring-position variables Y1-Y5, and an alkylating moiety AM defined by formula (XXVII).
Formula (Ia) compound with p-dependent heteroaryl core
A compound of formula (Ia), or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1, and H1 is C9 heteroaryl when p is 0 or C5 heteroaryl when p is 1, each optionally substituted with 1 or 2 substituents selected from the recited functional groups.
Phenyl-substituted R24 and defined R25/R26 substitution patterns
Each R24 is phenyl optionally substituted with 1, 2, or 3 substituents, and R25 and R26 are independently selected from H, C1-6 alkyl, (CH2)j-CO2R11, (CH2)j-NR11R12, and the corresponding carbonyl- or O-(CH2)k-NR11R12 substituent forms as recited.
Linker L selected from amino acid, peptide chain, and alkylene or alkyleneoxy fragments
L is selected from an amino acid; a peptide chain having 2, 3, 4, 5, or 6 amino acids optionally interrupted by NH, O, S, phenylene, and C5-9 heteroarylene; a C1-12 alkylene optionally interrupted by the same groups; or OCH2- and OCH2CH2-containing fragments optionally interrupted by the same groups.
Connectivity variables X1 and X2 and ring-position variables Y1-Y5 with Y1/Y2 proviso
X1 is selected from recited carbonyl- and heteroatom-containing fragments, X2 is selected from the corresponding set or is absent, Y1 and Y2 are N or CH, Y3 and Y4 follow the recited NR17/O/S and CH combinations, Y5 is CH, COH, N, or S, and at least one of Y1 and Y2 is CH.
AM moiety defined by formula (XXVII) with dotted-line connectivity and enumerated substituent cases
AM is formula (XXVII) with v being 0 or 1 and the dotted line representing either single bonds or one single bond and one double bond, with allowed cases for R1, R2, R3, R5, R6, and RD1 through RD7 as recited.
The consolidated claim coverage centers on the formula (Ia) compound family with p-dependent heteroaryl selection, enumerated substituent patterns for R24, R25, and R26, a defined linker L, structural fragments X1 and X2, ring variables Y1-Y5 with the proviso that at least one of Y1 and Y2 is CH, and an AM moiety defined by formula (XXVII).
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating proliferative diseases, including specified cancer types, via administration of compounds of formula (I)/(XXIV)/(XXV)/(XXVI).
Using the compounds as payloads in targeted conjugates, especially antibody-drug conjugates, with targeting agents and optional linkers.
Using these compounds in DNA sequence targeting contexts, including discussion of an NFκB transcription factor binding sequence.
Inhibiting cancer cell proliferation in a patient by administering a therapeutically effective amount of a compound or pharmaceutical composition.
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