Pyrazolo[4,3-D]pyrimidines as kinase inhibitors
Inventors
Almstetter, Michael • Thormann, Michael • Treml, Andreas • Traube, Nadine
Assignees
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Publication Number
US-9637491-B2
Publication Date
2017-05-02
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 disclosure relates to compounds of formula (I), including 1H-pyrazolo[4,3-d]pyrimidin-7-amine derivatives and pyrazolo[4,3-d]pyrimidine kinase inhibitors, having substituent groups designated R1 and R2. R1 and R2 are described by broad optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl, and heteroaralkyl group classes, and R2 is bound to the pyrimidine ring of formula (I) via a carbon-carbon bond.
Preferred embodiments specify pyrazolo[4,3-d]pyrimidine derivatives, with R2 further described by structured patterns including X2-L3-Y2 and optional X2-L3-Y2-L4 variants, as well as ring-structured optionally substituted aryl, heteroaryl, or heterocycloalkyl group types defined by ring size and heteroatom count. Additional substituent scope is described for R1, R3, and related substituents R3a-R3c, including selected ureas, amides, amines, and optional halogen, OH, O=C, and CN substituents.
The disclosed chemistry includes protecting-group strategy using para-methoxybenzyl and Cbz, preferred pyrazolo[4,3-d]pyrimidine intermediates of formula II, IIIa and IIIb bearing a 4-methoxybenzyl protection, and 5-substituted 1,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one regioisomers. The compounds are presented as inhibitors of kinases including SYK, LRRK2, and MYLK or mutants, and the document includes pharmaceutically acceptable salts, solvates, hydrates, pharmaceutically acceptable formulations, biological testing in kinase assays, and analytical HPLC-MS characterization.
Claims Coverage
The independent claims cover one main structural family of compounds of formula (I) and one therapeutic method family for kinase-activity-mediated disease. The structural claims define the R1 and R2 substituent scope, require that R2 is bound to the pyrimidine ring via a carbon-carbon bond, and extend to pharmaceutically acceptable salts, solvates, hydrates, and formulations.
Compounds of formula (I) with pyrimidine-bound R2 via carbon-carbon bond
A compound of formula (I) wherein R1 and R2 are optionally substituted groups selected from the defined classes, and wherein R2 is bound to the pyrimidine ring of formula (I) via a carbon-carbon bond, including pharmaceutically acceptable salt, solvate, hydrate, or formulation forms.
Structured R2 linking pattern X2-L3-Y2 and optional X2-L3-Y2-L4
A compound in which R2 has X2-L3-Y2 or X2-L3-Y2-L4 groups, with X2, Y2, and Z2 being optionally substituted phenyl/heteroaryl or optionally substituted cycloalkyl/heterocycloalkyl groups and L3 and L4 being selected from specified bond or linker moieties.
R2 selected from ring-structured optionally substituted aryl, heteroaryl, or heterocycloalkyl group types
A compound in which R2 is selected from optionally substituted aryl, heteroaryl, or heterocycloalkyl group types defined by ring structure and specified ring-atom and heteroatom constraints.
Treating kinase-activity-mediated disease via SYK, LRRK2, and/or MYLK/MLCK administration
A method for treating a kinase-activity-mediated disease in a patient by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition, where the kinase is SYK, LRRK2, and/or Myosin light chain kinase (MYLK/MLCK) or mutants, and the disease is selected from the listed disease indications.
Overall, the claims center on formula (I) compounds with a pyrimidine ring in which R2 is attached via a carbon-carbon bond, with additional refinement of R1 and R2 substituent classes and linking patterns, together with salt, solvate, hydrate, and formulation coverage. The claim set also includes therapeutic treatment coverage for kinase-activity-mediated diseases using the claimed compounds or pharmaceutical compositions targeting SYK, LRRK2, and/or MYLK/MLCK or mutants.
Stated Advantages
Inhibits kinases including SYK, LRRK2, and MYLK or mutants.
Documented Applications
Biological testing in kinase assays involving SYK and LRRK2, including LRRK2 G2019S, supported by assay frameworks and analytical HPLC-MS characterization.
Therapeutic treatment of kinase-activity-mediated diseases in a patient by administering compounds of formula (I) or pharmaceutical compositions, where the kinases are SYK, LRRK2, and/or MYLK/MLCK or mutants, for diseases including pruritus, eczema, asthma, rhinitis, dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis, and uveitis.
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