Kinase inhibitors
Inventors
Almstetter, Michael • Thormann, Michael • Treml, Andreas • Koestler, Roland • Yehia, Nasser
Assignees
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Publication Number
US-10000482-B2
Publication Date
2018-06-19
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 is directed to a compound of formula (I) with a pyrazolo[3,4-c]quinolin-4-amine scaffold in which n is 1, 2, 3 or 4. The scope includes substituent-defined options for R1 and R2, including optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, phenyl, naphthyl, heteroaryl, arylheterocycloalkyl, heteroarylcycloalkyl, and heteroarylheterocycloalkyl groups, together with groups of formula X1-L1-Y1 or X1-L1-Y1-L2-Z1.
R2 is independently selected from halogen, OH, C1-6 alkyl, C1-6 heteroalkyl, or C3-6 cycloalkyl. The compounds are also covered as pharmaceutically acceptable salts, solvates, hydrates, and pharmaceutically acceptable formulations. The description further includes specific pyrazolo[3,4-c]quinolin-4-amine derivatives and related substituted variants.
The document additionally frames therapeutic use through kinase activity mediated disease treatment. It specifically targets inhibition of kinase activity involving Spleen Tyrosine Kinase and Leucine-rich repeat kinase 2, and includes Myosin light chain kinase in the therapeutic framing.
Claims Coverage
The consolidated claims coverage centers on formula (I) pyrazolo[3,4-c]quinolin-4-amine derivatives with defined n, R1, and R2 substituents, including X1-L1-Y1 and X1-L1-Y1-L2-Z1 frameworks and coverage for pharmaceutically acceptable salts, solvates, hydrates, and formulations. The claim set also includes explicitly listed compound selections and a method claim for kinase inhibition in a patient, for a total of three inventive features.
Compound of formula (I) with defined substituent scope
A compound of formula (I) wherein n is 1, 2, 3 or 4; R1 is defined by the specified optionally substituted group classes and linkage constructions, including the X1-L1-Y1 and X1-L1-Y1-L2-Z1 frameworks; R2 is independently selected from halogen, OH, C1-6 alkyl, C1-6 heteroalkyl, or C3-6 cycloalkyl; and the compound includes a pharmaceutically acceptable salt, solvate or hydrate or a pharmaceutically acceptable formulation thereof.
Explicitly listed pyrazolo[3,4-c]quinolin-4-amine compounds
A compound selected from the group consisting of the explicitly listed pyrazolo[3,4-c]quinolin-4-amine derivatives and related named variants, with coverage for a pharmaceutically acceptable salt, solvate or hydrate or a pharmaceutically acceptable formulation thereof where stated.
Kinase inhibition using the defined compounds
Inhibiting a kinase in a patient by administering a therapeutically effective amount of a compound of claim 1, 15, or 16 or a pharmaceutical composition of claim 17, wherein the kinase is either Spleen Tyrosine Kinase or Leucine-rich repeat kinase 2.
Across the independent claim scope, the inventive features center on a formula (I) compound with constrained substitution patterns and linkage options, closed sets of explicitly enumerated compound identities, and a method of kinase inhibition for Spleen Tyrosine Kinase or Leucine-rich repeat kinase 2.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Inhibiting a kinase in a patient by administering a therapeutically effective amount of the claimed compound(s) or a pharmaceutical composition, where the kinase is either Spleen Tyrosine Kinase or Leucine-rich repeat kinase 2.
Kinase assay evaluation and activity measurement for SYK and LRRK2, including the LRRK2 G2019S mutant, with IC50 determination and binding/displacement readouts.
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