Nuclear transport modulators and uses thereof
Inventors
Baloglu, Erkan • Shacham, Sharon • McCauley, Dilara • Kashyap, Trinayan • Senapedis, William • Landesman, Yosef • Golan, Gali • Kalid, Ori • Shechter, Sharon
Assignees
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Publication Number
US-11945794-B2
Publication Date
2024-04-02
Expiration Date
Abstract
The present invention relates to compounds of formula I: and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds of formula I or their pharmaceutically acceptable salts, and methods of using said compounds, salts and compositions in the treatment of various disorders associated with CRM1 activity.
Core Innovation
The invention relates to compounds represented by structural formulas IV and III, and pharmaceutically acceptable salts thereof. The compounds include an optionally substituted heteroaryl or optionally substituted aryl substituent R2 in structural formula IV, and an optionally substituted C5-C15 heteroaryl substituent R2 in structural formula III, with additional structural definitions for Rb, R4, R5, R6, and R7.
For structural formula III, Rb is selected from C(O)OH, C(O)NH2, C(O)-N(R7)-N(R5)(R6), C(O)-N(R7)-N(R7)-C(O)-R4, and C(O)-N(R7)-N(R7)-S(O)1-2-R4, with R4, R5, R6, and R7 defined by specific structural options and optional substitution rules. For structural formula IV, R2 is selected from optionally substituted heteroaryl and optionally substituted aryl, with dependent refinements narrowing R2 by ring size, heteroatom type, and number of substituents.
The disclosed embodiments include compounds such as (E)- and (Z)-configured 3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-2-substituted acrylamide/acrylate/acrylic acid derivatives, as well as fluorinated heteroaromatic compounds and compounds with pyridine-like and related heteroaryl substituents. The examples and descriptions report synthesis and characterization, and identify biological evaluation in CRM1 (Rev-GFP) inhibition and MTT cytotoxicity assays, together with reported in vivo activity in anti-arthritis and xenograft tumor models and wound healing context.
Claims Coverage
The consolidated claim coverage includes independent claims directed to structural formula IV compounds, structural formula III compounds, and alternative structural formulas, with one independent method claim also present in the input set. Across these claims, the inventive features are the defined compound frameworks and the selected substituent groups, especially R2 and the carbonyl-related substituent pattern Rb.
Optionally substituted heteroaryl or aryl R2 in structural formula IV
A compound represented by structural formula IV, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from optionally substituted heteroaryl and optionally substituted aryl.
Selected carbonyl-containing substituent pattern Rb and defined R4, R5, R6, R7, and R2 in structural formula III
A compound of structural formula III, or a pharmaceutically acceptable salt thereof, wherein Rb is selected from C(O)OH, C(O)NH2, C(O)-N(R7)-N(R5)(R6), C(O)-N(R7)-N(R7)-C(O)-R4, and C(O)-N(R7)-N(R7)-S(O)1-2-R4; R4 is selected from N(H)(C3-C6 cycloalkyl), N(C1-C4 alkyl)(C3-C6 cycloalkyl), C1-C6 alkyl, (C0-C4 alkylene)-carbocyclyl, (C0-C4 alkylene)-heterocyclyl, (C0-C4 alkylene)-aryl, and (C0-C4 alkylene)-heteroaryl; R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, carbocyclyl, aryl, heterocyclyl and heteroaryl, or taken together with the nitrogen atom to form a heterocyclyl or heteroaryl; each R7 is independently hydrogen or C1-C4 alkyl; and R2 is an optionally substituted C5-C15 heteroaryl.
Multiple alternative structural formulas for compounds and salts
A compound represented by any one of the following structural formulas, or a pharmaceutically acceptable salt of any of the foregoing.
Promoting wound healing by administering the compound
A method of promoting wound healing by administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1.
The claim coverage is centered on structurally defined compounds and salts, with the main inventive constraints being the selection of R2 as optionally substituted heteroaryl or aryl in structural formula IV, and as optionally substituted C5-C15 heteroaryl in structural formula III, together with the specified Rb, R4, R5, R6, and R7 selections. The input set also includes a method claim for promoting wound healing.
Stated Advantages
Promoting wound healing.
Reduces clinical arthritis score in an anti-arthritis CAIA mouse model.
Reduces tumor volume in multiple xenograft tumor models.
Inhibits CRM1/XPO1-related functions, including covalent binding, effects on XPO1 cargo nuclear localization, and XPO1 degradation.
Shows cytotoxicity in MTT assays across many hematological and solid cancer cell lines compared with normal lines.
Documented Applications
Promoting wound healing by administering to a subject in need thereof a therapeutically effective amount of the compound.
Anti-arthritis treatment in a CAIA mouse model, assessed by clinical arthritis score reduction.
Cancer treatment evaluation in multiple xenograft tumor models, assessed by reduced tumor volume.
Combination cancer treatment regimens using the invention’s compound with additional agents, including chemotherapy, targeted therapy, immunotherapy, and hormonal therapy.
Angiogenesis and VEGF-related anti-angiogenic approaches using the invention’s compound.
Epigenetics therapies, including DNA methylation and histone deacetylase inhibitors, in combination with or involving the invention’s compound.
Inflammation and autoimmune disease uses involving the invention’s compound.
Viral infection indications involving the invention’s compound.
Ophthalmology indications involving the invention’s compound.
Neurodegenerative disease indications involving the invention’s compound.
Wound healing, including diabetic wounds, involving topical and/or systemic delivery and scar formation reduction using the invention’s compound.
Combination radiation therapy, where the invention’s compound is used as a radiosensitizer, with external beam radiation therapy, brachytherapy, and radiopharmaceutical agent considerations.
CRM1 (Rev-GFP) nuclear export inhibition assay for compounds described by the patent document.
MTT cytotoxicity assay with results summarized across cell lines.
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