Vinylheterocycles as Rho-associated coiled-coil kinase (ROCK) inhibitors
Inventors
Li, An-Hu • Dana, Dibyendu • Lim, Dong Sung • Gadhiya, Satishkumar • Jung, Dawoon • Narayan, Prakash • Ali, Quaisar • Paka, Swarnalatha • Goldberg, Itzhak D.
Assignees
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Publication Number
US-11542256-B2
Publication Date
2023-01-03
Expiration Date
Abstract
The present invention provides compounds having formula (I): and pharmaceutically acceptable salts thereof, wherein Cy1, Cy2, Cy3, R, R1, R2, R3, A1 and A2 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases in which inhibiting ROCK1, ROCK2, or ROCK1/2 has a therapeutically useful role.
Core Innovation
The invention relates to compounds of formula Ic, or pharmaceutically acceptable salts thereof, in which Y1 and Y2 are each independently N or C-R3, and two R3 groups together with the carbons they are attached to optionally form a 3-7 membered aromatic, heteroaromatic, or heterocyclic ring. The compounds further include variable substituents defined for R1, R2, R3, and R4, with substituent options including hydrogen, deuterium, halo, and a range of aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic, and heteroaromatic rings.
The document describes ROCK1/ROCK2 inhibitory small-molecule compounds, specifying inhibitory activity against ROCK1, ROCK2, or ROCK1/2. It includes selected (E)-vinyl substituted examples with pyridinyl, bipyrimidinyl, and isoindolinyl structural motifs and optional substitutions such as methoxy, fluoro, chloro, bromo, iodo, carbonitrile, carboxamide, morpholine, and piperazinyl.
The document further discloses pharmaceutical compositions comprising one or more of the described compounds together with a pharmaceutically acceptable carrier, excipient, or diluent. It states methods for treating or lessening severity of diseases associated with ROCK activity, with emphasis on antifibrotic activity and antipoptotic treatment in fibrotic liver disease.
Claims Coverage
The provided claim set centers on one broad structural class and related functional and composition features. It defines formula Ic compounds, characterizes them by ROCK1, ROCK2, or ROCK1/2 inhibitory activity, and includes pharmaceutical compositions with carriers, excipients, or diluents; an additional functional limitation specifies antifibrotic activity in the composition chain.
Compound of formula Ic with variable substituents
A compound of formula Ic or a pharmaceutically acceptable salt thereof, wherein Y1 and Y2 are each independently N or C-R3; two R3 groups together with the carbons they are attached to may optionally form a 3-7 membered aromatic, heteroaromatic, or heterocyclic ring; and R1, R2, R3, and R4 are defined by broad substituent options.
ROCK1/ROCK2 inhibitory activity
The claimed compound is characterized by inhibitory activity against ROCK1, ROCK2, or ROCK1/2.
Pharmaceutical composition with carrier, excipient, or diluent
A pharmaceutical composition includes one or more compounds together with a pharmaceutically acceptable carrier, excipient, or diluent.
Antifibrotic activity for the composition
The composition is defined as a compound having antifibrotic activity.
Overall, the claims focus on a broad formula Ic structural class, ROCK1/ROCK2/ROCK1/2 inhibitory activity, and pharmaceutical compositions comprising the compounds with pharmaceutically acceptable carriers, excipients, or diluents, with antifibrotic activity specified for the composition chain.
Stated Advantages
ROCK1/ROCK2 inhibitory activity.
Antifibrotic activity in the claimed composition context.
Antipoptotic treatment in fibrotic liver disease.
Treatment or lessening severity of diseases associated with ROCK activity.
Documented Applications
Treating or lessening severity of fibrotic liver disease.
Treating or lessening severity of hepatic ischemia-reperfusion injury.
Treating or lessening severity of cerebral infarction/stroke.
Treating or lessening severity of ischemic heart disease.
Treating or lessening severity of renal disease/renal fibrosis.
Treating or lessening severity of lung/pulmonary fibrosis including idiopathic pulmonary fibrosis.
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