Isochromene derivatives as phosphoinositide 3-kinases inhibitors
Inventors
Biagetti, Matteo • RONCHI, Paolo • FIORELLI, Claudio • BRUNO, PAOLO
Assignees
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Publication Number
US-12527797-B2
Publication Date
2026-01-20
Expiration Date
Abstract
The invention relates to compounds of formula (I) inhibiting phosphoinositide 3-kinases (PI3K), to pharmaceutical compositions comprising them and therapeutic use thereof in the treatment of disorders associated with PI3K enzymes.
Core Innovation
The invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, with specific substituent selections and a fixed structural relationship where R1 and R2 taken together with the nitrogen atom they are linked to form a 4-methylpiperazine-1-yl group, while R3 and R4 are H. The parameter p is zero or an integer ranging from 1 to 4, and the remaining substituents are selected from groups including OR7, halogen, and (C1-C6) alkyl, with R5, R6, and R7 defined by the stated options.
The disclosed material further includes specific isochromen-1-one derivatives bearing a pyrazolo[3,4-d]pyrimidin-1-yl core, an ethyl linker to an aniline/phenyl substituent, and phenyl substitution patterns that include a (4-methylpiperazin-1-yl)methyl group or dimethylamino-containing alternatives. Chiral embodiments are also covered, including (R) and/or (S) forms and explicit pharmaceutically acceptable salt forms for selected chiral isochromen-1-one compounds.
The invention relates to iso-chromen-1-one pyrazolopyrimidine derivatives provided as multiple stereoisomeric forms, including (R) and (S) enantiomers, diastereomers, and salt forms. The document describes preparation and characterization of specific derivatives within an iodinated pyrazolopyrimidine/isochromen-1-one scaffold, and provides confirmation of stereochemical assignments for selected derivatives through chiral preparative chromatography, chiral HPLC, and single-crystal X-ray diffraction with a Flack parameter.
Claims Coverage
The consolidated claim coverage includes three independent claim themes: a broad compound formula (I) with defined substituent selections and a parameter p, a group of specific substituted 1H-isochromen-1-one pyrazolo[3,4-d]pyrimidine compounds including chiral (R)/(S) members and listed pharmaceutically acceptable salt forms, and specific stereoisomeric derivatives within an iodinated pyrazolopyrimidine/isochromen-1-one scaffold. Across these claims, the coverage centers on a pyrazolo[3,4-d]pyrimidin-1-yl substituted isochromen-1-one or iso chromene scaffold with constrained side chains, stereochemistry, and salt forms.
Compound of formula (I) with defined substituent selections and p
A compound of formula (I) or a pharmaceutically acceptable salt, in which each R is independently selected from OR7, halogen, and (C1-C6) alkyl; R1 and R2 taken together with the nitrogen atom form a 4-methylpiperazine-1-yl group; R3 and R4 are H; R5 is OR7; R6 is selected from H, OR7, (C1-C6) alkyl, (C1-C6) haloalkyl, and (C1-C6) hydroxyalkyl; R7 is selected from H and (C1-C6) alkyl; and p is zero or an integer ranging from 1 to 4.
Selected substituted 1H-isochromen-1-one compounds as a group
A compound selected from the group consisting of the listed substituted 3-(1-[4-Amino-3-(5-hydroxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl)-4-aryl-1H-isochromen-1-one structures, including variants with methylpiperazinylmethyl, dimethylaminomethyl, halo substituents, and a (2R)-1-methylpyrrolidin-2-yl phenyl substituent, or a pharmaceutically acceptable salt of said compound.
Chiral (R)/(S) scaffold with enumerated pharmaceutically acceptable salt forms
A compound selected from the group consisting of (R) and/or (S)-3-(1-(4-amino-3-(5-hydroxypyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-isochromen-1-one provided as the enumerated salt forms, including hydrobromide, hydrochloride, hemi/hemisulfate, tosylate, mesylate, 2-naphthalene sulfonate, isethionate, maleate, esylate, hemipamoate, xinafoate, salicylate, benzoate, or a pharmaceutically acceptable salt of said compound.
Stereoisomeric iodinated pyrazolopyrimidine/isochromen-1-one derivatives
Iso-chromen-1-one pyrazolopyrimidine derivatives in multiple stereoisomeric forms, including (R) and (S) enantiomers, diastereomers, and salt forms, with characterization of specific derivatives within an iodinated pyrazolopyrimidine/isochromen-1-one scaffold.
Overall, the claim coverage focuses on defined PI3K inhibitor compounds by structural constraints of formula (I), including fixed substituent selections, a 4-methylpiperazine-1-yl linkage formed by R1 and R2, and p restricted to 0 or 1-4. The independent claims also cover specific substituted 1H-isochromen-1-one pyrazolo[3,4-d]pyrimidine compounds, chiral (R)/(S) members of the scaffold with explicitly listed pharmaceutically acceptable salt forms, and stereoisomeric iodinated pyrazolopyrimidine/isochromen-1-one derivatives.
Stated Advantages
Durable efficacy at 12 h with ≥45% superiority for the intratracheal suspension protocol and ≥50% (preferably ≥70%) inhibition in the dry-powder protocol at 12 h.
The compounds are described as PI3K inhibitors, with emphasis on PI3Kδ potency.
In vitro and cellular assay results are reported, including IC50 categories, THP-1 Delta IC50 values, kinase assays, and pAKT HTRF assay readouts.
In vivo efficacy is documented using rat OVA-induced lung eosinophilia, with emphasis on durable versus non-durable efficacy.
The document highlights differences tied to administration timing and reports ED80 and durability outcomes.
Documented Applications
Treating respiratory disorders associated with PI3K enzyme mechanisms by administering the compound or a salt of the compound to a subject in need thereof, including idiopathic chronic cough, cough-variant asthma, viral or post-viral cough, upper airways cough syndrome (UACS), post nasal drip cough, cough associated gastro-oesophageal reflux disease, cough associated with thoracic tumour or lung cancer, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), and interstitial lung disease.
Evaluating anti-inflammatory activity in a rat model of ovalbumin (OVA) induced lung eosinophilia, with outcomes measured via bronchoalveolar lavage fluid (BALF) cell counts and inhibition of eosinophil recruitment.
Treatment of one or more respiratory disorders linked to PI3K enzyme mechanisms by administering the compound or a salt thereof to a subject in need thereof, including idiopathic chronic cough, cough-variant asthma, upper airways cough syndrome (UACS), post nasal drip cough, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), interstitial lung disease, idiopathic pulmonary fibrosis (IPF), and other listed PI3K-mechanism-associated cough conditions.
Inhalation use through a dry powder formulation, including a dry powder inhaler device filled with the pharmaceutical composition and delivery context described alongside nebulizer options.
Medicament comprising the compounds or salts, with inhalation device contexts such as DPI and nebulizer formats.
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