Kinase inhibitors
Inventors
Thormann, Michael • Treml, Andreas • Almstetter, Michael • Koestler, Roland • Yehia, Nasser
Assignees
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Publication Number
US-9499535-B2
Publication Date
2016-11-22
Expiration Date
Abstract
The present invention relates to novel compounds of formula (I) that are capable of inhibiting one or more kinases, especially SYK (Spleen Tyrosine Kinase), LRRK2 (Leucine-rich repeat kinase 2) and/or MYLK (Myosin light chain kinase) or mutants thereof. The compounds find applications in the treatment of a variety of diseases.
Core Innovation
The invention relates to compounds of formula (I) comprising a substituted pyrazolo[3,4-c]quinoline framework in which substituent variables A, Cy, and R1 to R5 are defined. The disclosure includes pharmaceutically acceptable salts, esters, solvates, hydrates, formulations, pharmaceutically acceptable carriers, stereochemical forms, and deuterated variants.
A is selected from NH, O, S, C(O), NR3, C(=O)R3, or CR4R5, and Cy is an optionally substituted phenylene group or an optionally substituted heteroarylene group having 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N, or an optionally substituted heterocycle or heteroaromatic system, including oxazole, thiazole, isoxazole, 1,2,5-thiadiazole, furan, thiophene, 1H-imidazole, 1H-pyrazole, and related regioisomers. R1, R3, R4, and R5 are defined as hydrogen or optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl, or heteroaralkyl groups, while R2 is hydrogen or methyl.
The invention further provides exemplary substituted pyrazolo[3,4-c]quinoline derivatives obtained through coupling of a chloro-methoxy pyrazoloquinoline intermediate with various amines, together with analytical characterization. It also describes deprotection of a para-methoxybenzyl-protected 4-chloro-2-(4-methoxy-benzyl)-2H-pyrazolo[3,4-c]quinoline to yield the deprotected compound for biological characterization, and states that formula (I) compounds inhibit one or more kinases and are therapeutic agents targeting kinase activity in a broad range of diseases associated with immune and inflammatory signaling.
Claims Coverage
The consolidated claim coverage centers on a formula (I) compound with defined A, Cy, and R1–R5 variables, together with pharmaceutically acceptable salts, esters, solvates, hydrates, and formulations. It also includes a protecting-group option for related formulas, enumerated example compounds, and a treatment method directed to kinase-activity-mediated disease. Overall, the claim set presents six inventive features.
Formula (I) compound with defined A and Cy
A compound of formula (I) wherein A is NH, O, S, C(O), NR3, or CR4R5; and Cy is an optionally substituted phenylene group or an optionally substituted heteroarylene group having 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, S and N, or an optionally substituted oxazole, thiazole, isoxazole, 1,2,5-thiadiazole, furan, thiophene, 1,2,3-thiadiazole, 1,2,5-oxadiazole, 1,2,3-oxadiazole, 1H-imidazole, 1H-1,2,4-triazole, 1H-1,2,3-triazole, 1H-tetrazole, 4H-1,2,4-triazole, 1H-pyrazole, 1,2,5-selenadiazole, 1,3-selenazole, selenophene, 2H-1,2,3-triazole, 1,3-dithiol-1-ium, 1,4-dithiine, or a regioisomer thereof.
Substituent definition for R1 to R5
R1, R3, R4, and R5 are hydrogen or optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl, or heteroaralkyl groups; R2 is hydrogen or methyl.
Pharmaceutically acceptable forms of the formula (I) compound
The formula (I) compound is optionally provided as a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof.
Protecting group selection for defined formulas
A compound of formula (II), (IIIa) or (IIIb) in which R2 and Cy are defined as in claim 1 and PG is a protecting group selected from a 4-methoxybenzyl group or a carboxybenzyl group.
Enumerated example pyrazolo[3,4-c]quinoline derivatives
A claim providing exemplified compounds by listing numerous specific substituted pyrazolo[3,4-c]quinolines and related heterocycle-containing derivatives with named substituents.
Kinase-activity-mediated disease treatment using a formula (I) compound
A treatment method for a kinase-activity-mediated disease by administering to a patient a therapeutically effective amount of a compound of claim 1, where the targeted kinase is SYK, LRRK2, and/or Myosin light chain kinase (MYLK/MLCK) or mutants and the disease is selected from the listed group.
The claims are directed to Formula (I) compounds defined by broad but structured substitution variables, extend to pharmaceutically acceptable salt, ester, solvate, hydrate, and formulation forms, and further include protecting-group and exemplar compound claims. The claim set also contains a treatment embodiment for kinase-activity-mediated disease involving SYK, LRRK2, and/or MYLK/MLCK or mutants.
Stated Advantages
Therapeutic potential across a broad range of diseases.
Documented Applications
Treatment of kinase-activity-mediated disease by administering a therapeutically effective amount of a compound of formula (I). Diseases explicitly listed include pruritus, eczema, asthma, rhinitis, dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis, and uveitis.
Kinase assays for SYK, LRRK2 (including LRRK2 G2019S), and MYLK using Invitrogen OMNIA KINASE ASSAY and related assay formats, with europium-labeled and Alexa Fluor 647 labeled components and FRET readout.
Cellular assay using LAD2 mast cells for IgE-mediated histamine release.
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