Phosphoinositide 3-kinase inhibitors with a zinc binding moiety
Inventors
Cai, Xiong • Zhai, Haixiao • Lai, Chengjung • Qian, Changgeng
Assignees
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Publication Number
US-11261195-B2
Publication Date
2022-03-01
Expiration Date
Abstract
The instant application relates to deazapurines, thienopyrimidines and furopyrimidines with zinc-binding moiety based derivatives and their use in the treatment of phosphoinositide 3-kinase related diseases and disorders such as cancer. The instant application further relates to the treatment of histone deacetylase related disorders and diseases related to both histone deacetylase and phosphoinositide 3-kinase.
Core Innovation
The invention provides a compound represented by Formula (X) or Formula (XI), or a pharmaceutically acceptable salt thereof. The compounds are defined by a heteroaromatic and heterocyclic framework in which substituent groups are systematically constrained, including selections for G1, G2, and G4, and variable substituents R1, R2, R10, Ra, Rb, and R8. The definitions specify allowed heteroatom patterns such as CR1, S, O, NR10, and NS(O)2R10 together with allowed aromatic or heteroaromatic substituents for G2.
The structural definitions further specify that Ra and Rb are selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl, and Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group. R8 is hydrogen, acyl, aliphatic, or substituted aliphatic, and B is a direct bond or a linker. The formula is also constrained by an additional C-portion defined with R33 as hydrogen and restricted values for n and p.
The partial content describes multiple specific compound embodiments that share a common scaffold with a sulfur-linked core, fused or linked multi-heteroaromatic systems, and variable terminal aryl or heteroaryl substituents. The examples include morpholine-like or piperazine-like rings, amide or hydroxamic acid-related terminal functionality, and related substituted heteroaryl motifs, and are presented as members or selected examples within the Formula (X)/(XI) chemical space.
Claims Coverage
Independent claim coverage centers on a compound represented by Formula (X) or Formula (XI), or a pharmaceutically acceptable salt thereof, with structural definitions for G1, G2, G4, R1, R2, R10, Ra/Rb, R8, B, and a C-portion defined by R33, n, and p. The dependent claims further refine linker B, specify permitted G2 ring types, and include selection of specific example compounds; one item also recites a method for treating a PI3K-related disease or disorder.
Formula (X) or Formula (XI) compound scaffold
A compound represented by Formula (X) or Formula (XI), or a pharmaceutically acceptable salt thereof, wherein G1 is CR1, S, O, NR10 or NS(O)2R10; G2 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic; G4 is NR8, S or O; and B is a direct bond or a linker.
Defined substituent sets for variable groups
Each R1 and R2 is independently selected from absent, hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF3, CN, NO2, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and R10 is selected from hydrogen, hydroxy, amino, alkoxy, alkylamino, dialkylamino, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
Ra and Rb form an optionally substituted heterocyclic group
Ra is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; Rb is hydrogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; and Ra and Rb together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group.
C-portion defined by R33, n, and p
C is defined where R33 is hydrogen; n is 0, 1, 2, 3, or 4; and p is 0 or 1.
Enumerated linker options for B
B is defined as a direct bond or a specified linker selected from enumerated C1–C10 linker categories, including C1–C10 alkyl, C1–C10 alkenyl, C1–C10 alkynyl, C1–C10 alkoxy, alkoxyC1–C10 alkoxy, alkylamino and carbonyl-linked variants, aryloxy-linked variants, and heteroaryl-linked variants.
Restricted G2 ring set
G2 is optionally substituted with one of phenyl, pyridyl, pyrimidyl, indazolyl, pyrrolyl, or benzimidazolyl groups.
Selection from specific example compounds
A compound of claim 1 is selected from the specific compounds shown in the document, or from a pharmaceutically acceptable salt thereof.
PI3K-related disease treatment
A method for treating a PI3K-related disease or disorder by administering a therapeutically effective amount of the pharmaceutical composition of claim 6 to a subject in need.
The claim coverage focuses on a Formula (X)/(XI) compound class with defined heteroatom-containing group options, broad but enumerated substituent sets, optional ring formation from Ra and Rb, a direct-bond-or-linker B, and a constrained C-portion. Dependent claims narrow B and G2, select specific example compounds, and include a PI3K-related treatment method.
Stated Advantages
Treating or preventing cancers and other proliferative disorders.
Reducing circulating lymphocyte counts (lymphopenia).
Applicable to combination therapies with kinase modulators, HDAC agents, chemotherapeutic agents, radiation therapy, and immunotherapeutic agents.
Significant inhibitory activity toward PI3 kinase.
Significant inhibitory activity toward HDAC.
Possible mTOR activity for certain preferred embodiments.
Potential for synergistic anti-cancer activity through multi-target inhibition including zinc binding and HDAC, and optionally mTOR/MMP.
Potential to overcome drug resistance associated with single-agent PI3K inhibitors.
Documented Applications
Treatment or prevention of cancers and other proliferative disorders, including PI3K- and HDAC/mTOR-related indications.
Use in combination therapies for cancer/proliferative disorders with kinase modulators, HDAC agents, chemotherapeutic agents, radiation therapy, and immunotherapeutic agents.
Method for treating a PI3K-related disease or disorder by administering a therapeutically effective amount of a pharmaceutical composition to a subject in need.
Inhibition of PI3K activity by contacting PI3 kinase with Formula I compounds.
Biological assay information is provided for biochemical PI3K isoform inhibition and HDAC inhibition.
Cell proliferation antiproliferative evaluation is provided across numerous cancer cell lines.
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