Inhibitors of RHO associated coiled-coil containing protein kinase
Inventors
Skucas, Eduardas • Liu, Kevin G. • Kim, Ji-In • Poyurovsky, Masha V. • Mo, Rigen
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11613531-B2
Publication Date
2023-03-28
Expiration Date
Abstract
The invention relates to inhibitors of ROCK1 and/or ROCK2. Also provided are methods of inhibiting ROCK1 and/or ROCK2 that are useful for the treatment of disease.
Core Innovation
The disclosure relates to compounds defined by Formula IIj and related structural variants, including pharmaceutically acceptable salts. The compound definitions use variable substituents such as L1, L2, R2, R3, R5, R61, a, f, g, and x, with the option that R2 and R3 are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms and defined substitution options.
The disclosed examples support substituted pyrimidin-4-yl 1H-indazol-5-amine compounds and related indazole–pyrimidine frameworks bearing nitrogen-containing ring substituents. The partial content also describes compounds with a pyrimidin-4-amine core linked to an indazol-5-amine or other heteroaryl/heterocycle region, together with attached cyclic amines such as diazaspiro, diazabicyclo, piperazine, piperidine, diazepane, and pyrrolidine motifs.
The patent frames the compounds as ROCK inhibitor compounds and connects them to therapeutic treatment by inhibition of Rho Associated Coiled-Coil Containing Protein Kinases. The stated treatment scope includes fibrotic disorders and glaucoma, with fibrotic disorders including pulmonary fibrosis, renal fibrosis, lung fibrosis, and idiopathic pulmonary fibrosis.
Claims Coverage
The consolidated claim coverage includes two independent compound claim groups centered on Formula IIj and a separate formula-defined compound, each including pharmaceutically acceptable salts. The inventive features combine detailed substituent and ring-variable constraints, a related structural variant (Formula IIk), pharmaceutical compositions, and therapeutic method claims tied to inhibition of Rho Associated Coiled-Coil Containing Protein Kinases and treatment of fibrotic disorders and glaucoma.
Formula IIj compound definition with variable substituent constraints
A compound having the formula IIj, wherein each of L1 and L2 is independently selected from N and CH; R2 and R3 are selected from specified groups and alternatively are taken together to form a 4- to 7-membered fused ring having from 0 to 3 ring heteroatoms with specified substitution options; R5 is selected from specified groups; each R61 is independently selected from specified groups; each R is independently selected from H and lower alkyl; each R' is independently selected from H, lower alkyl, aryl, substituted aryl, aralkyl, and substituted aralkyl; a is selected from 0 to 3; each f is independently 1 to 3; each g is independently 2 or 3; and x is selected from 1 to 3; or a pharmaceutically-acceptable salt thereof.
Formula IIk structural variant
A compound according to formula IIk, where the compound is defined by the structural formula shown and includes substituents labeled R2, R3, R5, R61, and the variables x and a', together with a pharmaceutically acceptable salt.
Compound defined by structural formula
A compound having the formula shown in the claim or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with excipients
A pharmaceutical composition containing a therapeutically effective amount of the compound of the formula-defined claim, or a pharmaceutically acceptable salt thereof, formulated with one or more pharmaceutically acceptable excipients.
Solid oral dosage form
The pharmaceutical composition is formulated into a solid oral dosage form.
Treatment of fibrotic disorders
A method for treating a fibrotic disorder in a subject by administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, where the fibrotic disorder is selected from pulmonary fibrosis, renal fibrosis, and lung fibrosis.
Idiopathic pulmonary fibrosis treatment
A method for treating pulmonary fibrosis that is idiopathic pulmonary fibrosis by administering a therapeutically effective amount of a compound from the preceding claim, or a pharmaceutically acceptable salt.
Inhibition of Rho Associated Coiled-Coil Containing Protein Kinases
A method for treating a disorder by administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, to inhibit Rho Associated Coiled-Coil Containing Protein Kinases in a subject.
Glaucoma treatment
A method for treating glaucoma in a subject by administering a therapeutically effective amount of a compound described in claim 1, or a pharmaceutically acceptable salt of that compound.
Overall, the claim coverage defines a broad compound class through Formula IIj with detailed substituent and fused-ring constraints, includes a related Formula IIk variant and another formula-defined compound, and extends to pharmaceutically acceptable salts and pharmaceutical compositions. The method claims tie these compounds to treatment of fibrotic disorders, including pulmonary fibrosis, renal fibrosis, lung fibrosis, and idiopathic pulmonary fibrosis, as well as glaucoma, and to treatment by inhibition of Rho Associated Coiled-Coil Containing Protein Kinases.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating fibrotic disorders in a subject, including pulmonary fibrosis, renal fibrosis, and lung fibrosis.
Treating pulmonary fibrosis that is idiopathic pulmonary fibrosis.
Treating a disorder by inhibiting Rho Associated Coiled-Coil Containing Protein Kinases in a subject.
Treating glaucoma in a subject.
Interested in licensing this patent?