Kinase inhibitors
Inventors
Almstetter, Michael • Thormann, Michael • Treml, Andreas • Koestler, Roland • Yehia, Nasser
Assignees
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Publication Number
US-10752624-B2
Publication Date
2020-08-25
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. These diseases include autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, alzheimer's disease, parkinson's disease, skin disorders, eye diseases, infectious diseases and hormone-related diseases.
Core Innovation
The invention relates to pyrazolo[3,4-c]quinoline compounds defined by formulas (I), (II), (IIIa) and/or (IIIb), including 2H-pyrazolo[3,4-c]quinoline and 3H-pyrazolo[3,4-c]quinoline derivatives. Substituent options are defined for R1, R2, R3, R3a, R3b and optionally R3c, with broad classes including alkyl, alkenyl, alkynyl, alkoxyalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl, and with optional substitution by halogen, OH, =O, CN and phenyl.
The compounds include n selected as 1, 2, 3 or 4, defined R2 groups such as —OMe, —SMe, —SO2Me, cyclopropyl and methyl, and PG that is a 4-methoxy benzyl group or a carboxybenzyl group. The description further specifies structural substitution patterns through the R1 framework and its subcomponents, including amines, amides, ureas and related moieties such as piperazine, piperidine, morpholine, thiazole-5-amine and pyrimidin-5-amine.
The document also describes kinase inhibitor compounds and pharmaceutical compositions, with particular emphasis on SYK, LRRK2 and MYLK/MLCK, including kinase mutants. It further provides extensive structural exemplars consistent with the disclosed pyrazolo[3,4-c]quinoline scaffold.
Claims Coverage
The claim coverage centers on compounds defined by formulas (I), (II), (IIIa) and/or (IIIb), with independent claims specifying three principal inventive features: a constrained n value, a defined R2 selection set, and a restricted PG group. Dependent claims further narrow these parameters and enumerate specific substituted pyrazolo[3,4-c]quinoline exemplars.
Formula-defined pyrazolo[3,4-c]quinoline compounds
A compound of formula (I), (II), (IIIa) and/or (IIIb), including 2H-pyrazolo[3,4-c]quinoline and 3H-pyrazolo[3,4-c]quinoline derivatives.
Variable n constraint
n is 1, 2, 3 or 4, with dependent forms narrowing n to 1.
Defined R2 substituent set
Groups R2 are independently selected from —OMe, —SMe, —SO2Me, cyclopropyl and methyl.
Restricted PG benzyl group
PG is a 4-methoxy benzyl group or a carboxybenzyl group.
Enumerated substituted exemplars
Specified substituted pyrazolo[3,4-c]quinoline derivatives comprise defined combinations such as chloro with methylthio or methylsulfonyl and, where present, optional 4-methoxybenzyl at the 2-position and methyl at the 8- or 9-positions.
Overall, the claims are directed to compound classes defined by formula and constrained substituent options, especially n, R2 and PG. Dependent claims further narrow the selection and provide specific substituted pyrazolo[3,4-c]quinoline examples.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Biological testing and biological characterisation using Protein Kinase Assays for SYK and LRRK2, including a LanthaScreen Eu Kinase Binding Assay and fluorescence chelation-enhanced fluorophore SOX with an Alexa Fluor 647 kinase tracer.
Kinase activity mediated disease treatment with preferred kinases SYK, LRRK2 and MYLK/MLCK.
Pharmaceutical compositions for the stated therapeutic use.
Topical administration.
Inhalation administration.
Intranasal administration.
Broad therapeutic disease areas including autoimmune/inflammatory, neurodegenerative (Alzheimer’s/Parkinson’s), cancer, metabolic, cardiovascular, allergies/asthma, infections, skin and eye disorders, and hormone-related diseases.
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