Inhibitors of Rho associated coiled-coil containing protein kinase
Inventors
Skucas, Eduardas • Liu, Kevin G. • Kim, Ji-In • Poyurovsky, Masha V. • Mo, Rigen • ZHANG, Jingya
Assignees
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Publication Number
US-11926596-B2
Publication Date
2024-03-12
Expiration Date
Abstract
The invention relates to inhibitors of ROCK1 and/or ROCK2 having the formula I:Also provided are methods of inhibiting ROCK1 and/or ROCK2 useful for the treatment of disease.
Core Innovation
The invention provides ROCK1/ROCK2 inhibitor compounds having a common core represented by Formulas I–IX, with extensive structural definitions and substituent parameters. The disclosure includes pharmaceutically acceptable salts, hydrates, and stereoisomers of the compounds.
The invention also provides pharmaceutical compositions and uses of the ROCK1/ROCK2 inhibitor compounds by formulating the compounds with pharmaceutically acceptable carriers. The disclosure describes use of the compounds to inhibit ROCK1 and/or ROCK2, thereby supporting the overall therapeutic intent of targeting Rho-associated coiled-coil containing protein kinase.
Therapeutic methods and indications are broadly listed, including central nervous system disorders such as Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, and spinal cord injury. The disclosure further lists cardiovascular and ocular diseases, including hypertension and glaucoma/intraocular pressure regulation, and also lists inflammation/autoimmune diseases, thrombotic disorders, neoplasias, fibrotic disorders, metabolic syndrome/insulin resistance, osteoporosis/bone formation, and ocular angiogenic conditions.
Claims Coverage
The provided independent claims cover ROCK1/ROCK2 inhibitor compounds defined by Formula III, Formula VI, Formula IX, and a specific enumerated list of N-(1H-indazol-5-yl)-2-(amino)acetamide analogs. The main inventive features are the constrained scaffold/substituent selections for each formula and, for certain formulation embodiments, pharmaceutically acceptable salts and pharmaceutical compositions with pharmaceutically acceptable carriers and/or solid oral dosage forms.
Formula III defined ROCK1/ROCK2 inhibitor compound
A compound having the formula III with R1 selected from lower alkyl, C3–C6 cycloalkyl, and R10O(CH2)2 where R10 is methyl; R2 as phenyl or pyridyl optionally substituted with 1 to 3 substituents; R3 selected from H, lower alkyl, substituted lower alkyl, and RR′N—(C2-4 alkyl)—; and each R and R′ independently selected from H, lower alkyl, and C3–C6 cycloalkyl or alternatively taken together form a 5 to 6 membered heterocyclic ring, with the compound or a pharmaceutically acceptable salt thereof.
Formula VI defined ROCK1/ROCK2 inhibitor compound
A compound having the formula VI where R1 is selected from lower alkyl, C3–C6 cycloalkyl, substituted C3–C6 cycloalkyl, R10O(CR12R13)c—, W(CR12R13)d—, and R10R11N—C(=O)—(CR12R13)c—; each R10 and R11 is independently selected from lower alkyl and C3–C6 cycloalkyl; each R12 and R13 is independently selected from H and lower alkyl with additional or alternative formation of a C3–C6 cycloalkyl group; W is a 3- to 7-membered heterocyclic ring having 1 to 3 ring heteroatoms; c is 2 to 4 and d is 1 to 4; and the compound or a pharmaceutically acceptable salt thereof.
Formula IX defined ROCK1/ROCK2 inhibitor compound
A compound having the formula IX where R1 is selected from lower alkyl, C3–C6 cycloalkyl, and lower alkyl substituted with —OR where R is a lower alkyl; each R22 is independently selected from H, halo, hydroxy, lower alkyl, lower alkoxy, amino, C1–C3 perfluoro alkyl, and C1–C3 perfluoro alkoxy; and n is 0 to 3; or a pharmaceutically acceptable salt thereof.
Selected N-(1H-indazol-5-yl)-2-(amino)acetamide analogs as ROCK1/ROCK2 inhibitors
A compound selected from a specified enumerated set of substituted N-(1H-indazol-5-yl)-2-(methylamino)-2-phenylacetamide and closely related variants differing in the N-(substituted amino/alkylamino) group and aryl substituents, including optional stereoisomers (R) and (S) for at least one listed member, and including pharmaceutically acceptable salts of the selected compounds.
Pharmaceutical composition with pharmaceutically acceptable carriers
A pharmaceutical composition comprising the compound of the corresponding preceding formula claim, or a pharmaceutically acceptable salt thereof, formulated with one or more pharmaceutically acceptable carriers.
Solid oral dosage form for the pharmaceutical composition
A pharmaceutical composition formulated as a solid oral dosage form for oral administration, as a narrower embodiment of the corresponding pharmaceutical composition including the compound or its pharmaceutically acceptable salt.
The independent claims cover ROCK1/ROCK2 inhibitor compounds defined by Formula III, Formula VI, Formula IX, and a specific enumerated list of N-(1H-indazol-5-yl)-2-(amino)acetamide analogs. The main inventive features are the constrained scaffold/substituent selections for each formula and, for certain formulation embodiments, pharmaceutically acceptable salts and pharmaceutical compositions with pharmaceutically acceptable carriers and/or solid oral dosage forms.
Stated Advantages
ROCK inhibition resulting in oligodendrocyte differentiation/neurite outgrowth.
Blood-brain barrier penetration.
Documented Applications
Functional characterization of ROCK inhibition associated with oligodendrocyte differentiation and neurite outgrowth, including in vitro/in vivo functional characterization in Example 59-61.
Blood-brain barrier (BBB) penetration characterization described in connection with Example 59-61.
Analytical/identity characterization and enantiomeric separation for specific indazole acetamide examples.
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