Fluoroalkyl-oxadiazoles and uses thereof
Inventors
Patel, Snahel • Mandegar, Mohammad A. • Sperandio, David • Medina, Julio • Bhatt, Ulhas • NERURKAR, Alok • WIDJAJA, Tien
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11926622-B2
Publication Date
2024-03-12
Expiration Date
Abstract
Provided herein are compounds identified as inhibitors of HDAC6 activity having the formula: or a pharmaceutically acceptable salt thereof, that can be used to treat various diseases and disorders.
Core Innovation
The disclosed subject matter provides compounds having specified chemical structures, or pharmaceutically acceptable salts thereof, defined by formulae in which X1 is S and variable substituents are constrained to specified groups. The scaffold includes substituent options for Ra, R1, R4, and R5, with R4 selected from alkyl and multiple sulfonyl-substituted forms, and with R5 as aryl or, together with R4 and the attached atom, forming a heterocyclyl optionally substituted with halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy.
The disclosure further describes Formula (Ih), Formula (Ii), and Formula (Ij) embodiments with defined substituent meanings for U, X1-X4, Rb, Rc, Rd, p, q, and m, including discrete assignments such as U equals CH2 and p equals 0. Additional refinements include enumerated substituted phenyl options for R5 and ring-forming relationships in which two Rc groups together with the attached carbon atom form a cyclopropyl ring optionally substituted with F or CH3.
The partial content also identifies related heteroaromatic and heterocyclic compounds featuring sulfur-containing and nitrogen-containing rings, fluorinated substituents, difluoromethyl motifs, oxadiazole-, thiazole-, pyrazolo[1,5-a]pyrimidine-, and pyrazolo[3,2-c][1,4]oxazine-related scaffolds, and sulfonamide or sulfonyl functionality. Representative structures are presented as specific embodiments within these broader formula-defined compound families.
Claims Coverage
The provided claim coverage is centered on compound claims and structure-defined claims. Across the independent claims, the inventive features define sulfur-containing or structure-defined scaffolds with constrained substituent selections, including optional pharmaceutically acceptable salts, and dependent refinements that narrow aryl, heteroaryl, ring-forming, and discrete parameter choices.
Sulfur-containing formula-defined compound with constrained substituents
A compound, or a pharmaceutically acceptable salt thereof, wherein X1 is S; Ra is selected from H, halogen, and C1-3 alkyl; R1 is H or alkyl; R4 is selected from alkyl and multiple “—(SO2)” substituted options including “—(SO2)alkyl,” “—(SO2)alkyleneheterocyclyl,” “—(SO2)haloalkyl,” “—(SO2)haloalkoxy,” “—(SO2)cycloalkyl,” and “—(SO2)N(alkyl)(R3);” and R5 is aryl, with R4 and R5 together with the atom to which they are attached optionally forming a heterocyclyl.
Aryl and heteroaryl constraints for R5
R5 is phenyl optionally substituted with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, C3-6 cycloalkyl, or a 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S.
Enumerated substituted phenyl options for R5
R5 is selected from phenyl, 3-chlorophenyl, 3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3,4-difluorophenyl, or 2,6-difluorophenyl.
Cyclopropyl ring formation from Rc groups
Two Rc groups, together with the carbon atom to which they are attached, form a cyclopropyl ring optionally substituted with F or CH3.
Discrete parameter assignment for U and p
U equals CH2 and p equals 0.
Structure-defined compound recitations
Independent claims also recite compounds having the structure as shown, or pharmaceutically acceptable salts thereof.
Overall, the claims define sulfur-containing formula-based compounds and structure-defined compounds, with the principal inventive limitations being the X1 = S core, constrained R-group definitions, optional heterocyclyl formation from R4 and R5, and narrower dependent claim selections for R5, Rc, U, and p.
Stated Advantages
Selective HDAC6 biochemical activity supported by reported HDAC6 biochemical IC50 values and HDAC6 over HDAC1 selectivity ratios.
Avoidance of pan-HDAC toxicity while emphasizing HDAC6-selective inhibition.
Documented Applications
HDAC6-selective inhibitors.
HDAC6 activity is documented for example compounds using IC50 values shown under an HDAC6 activity table header.
Treating diseases or disorders.
Treating aberrant cell proliferative disorders [procedural detail omitted for safety].
Treating neurodegenerative diseases and diseases associated with β-amyloid protein aggregation and polyglutamine protein aggregation [procedural detail omitted for safety].
Treating inflammatory diseases, including IBD, IBS, Crohn’s disease, and ulcerative colitis [procedural detail omitted for safety].
Treating psychiatric disorders, including depression [procedural detail omitted for safety].
Treating cardiovascular and cardiac diseases, including stroke, glaucoma, psoriasis, rheumatoid arthritis, spondyloarthritis, osteoarthritis, sepsis, acute kidney injury, lung injury, ischemia reperfusion injury, HFpEF, and cardiac diseases [procedural detail omitted for safety].
Treating conditions described in the summary content including inflammasome formation, chemotherapy-induced neuropathy, Charcot-Marie-Tooth disease, idiopathic pulmonary fibrosis, erectile dysfunction, hypertension, and muscular dystrophy [procedural detail omitted for safety].
HDAC6 biochemical assay context, including HDAC6 over HDAC1 selectivity, with reported IC50 values and compound characterization.
Interested in licensing this patent?