Substituted pyrazolo{4,3-D}pyrimidines as kinase inhibitors
Inventors
Thormann, Michael • Treml, Andreas • Almstetter, Michael • Traube, Nadine
Assignees
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Publication Number
US-9802937-B2
Publication Date
2017-10-31
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 substituted pyrazolo[4,3-d]pyrimidine kinase-inhibitor compounds having a compound of formula (I). The compounds include a pyrimidine ring with variable substituents A and R1-R6, and also include pharmaceutically acceptable salts, esters, solvates or hydrates. A is selected from NH, O, S, C=O, NR4, or CR5R6, and R2 is bound to the pyrimidine ring via a carbon-carbon bond.
R1 and R4-R6 are defined as optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl groups. R3 is hydrogen or specified substituents including F, Cl, CH3, CF3, NO2, cyclopropyl, CN, N3, OH, SH, OMe, SMe, NHMe, NMe2 or NH2. The disclosure presents representative chemical structures for variants including formula (I), (Ia), (Ib) and (Ic), with preferred embodiment selections such as A=NH and R3=H.
The disclosed compound family is presented for kinase inhibition, with background rationale targeting kinases including SYK, LRRK2, and MYLK/MLCK. The document links these kinases to immune/inflammatory signaling and related adaptive immune response processes, and associates them with immune/inflammatory diseases, autoimmune and neurodegenerative diseases, cancers, and ocular/skin/infectious indications.
Claims Coverage
The disclosure includes at least one independent claim directed to a compound of formula (I), with dependent claims refining structural substituent definitions and including pharmaceutical use and administration route limitations. The inventive features focus on the pyrazolo[4,3-d]pyrimidine scaffold with defined substituent constraints and the R2 carbon-carbon linkage to the pyrimidine ring.
Substituted pyrazolo[4,3-d]pyrimidine kinase-inhibitor compounds of formula (I)
A compound of formula (I) wherein A is NH, O, S, C=O, NR4 or CR5R6; R1 is an optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group; R2 is an optionally substituted alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group wherein R2 is bound to the pyrimidine ring of formula (I) via a carbon-carbon bond; R3 is a hydrogen atom or one of the specified substituents; R4 is defined as an optionally substituted alkyl/aryl/heteroaryl/cycloalkyl/aralkyl/heteroaralkyl group; R5 and R6 are defined as hydrogen or one of the specified substituents or optionally substituted group selections; and/or a pharmaceutically acceptable salt, ester, solvate or hydrate thereof.
Constrained R2 ring-count selections for substituted aryl/heteroaryl R2
The compound according to a dependent claim wherein R2 is an optionally substituted phenyl/naphthyl, an optionally substituted heteroaryl with specified ring-count and ring-atom constraints, or an optionally substituted arylheterocycloalkyl/heteroarylheterocycloalkyl with specified ring-count and ring-atom constraints.
Formula-based R2 architecture with constrained linking groups X2-L3-Y2 and X2-L3-Y2-L4-Z2
The compound according to a dependent claim wherein R2 is selected as X2-L3-Y2 or X2-L3-Y2-L4-Z2 with X2, Y2, Z2 and linkage groups L3 and L4 constrained to specified optionally substituted aromatic/heteroaryl/cycloalkyl fragments and specified functional group linkers including O, S, N and variants of oxygen/sulfur/nitrogen-containing linker groups.
R3 is hydrogen
The compound according to a dependent claim wherein R3 is a hydrogen atom.
Treatment of a kinase-activity-mediated disease by administering a compound of formula (I)
A method of treating a kinase-activity-mediated disease by administering a therapeutically effective amount of a compound according to claim 1, wherein the disease is selected from pruritus, eczema, asthma, rhinitis, dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis, uveitis, chronic lymphocytic leukemia, B-cell lymphoma, rheumatoid arthritis, thrombosis, graft versus host, inflammatory arthritis, other immune-mediated inflammatory diseases, systemic lupus erythematosus, immune thrombocytopenic purpura, and auto-immune hemolytic anemia.
Topical administration to the skin for the treated method
The method according to a dependent claim wherein the topical administration is to the skin.
Overall, claim coverage is centered on a formula (I) pyrazolo[4,3-d]pyrimidine scaffold with defined substituent ranges for A and R1-R6, including the specific requirement that R2 is carbon-carbon bonded to the pyrimidine ring, and is further refined by dependent claims specifying R2 structural architecture, constraining R3 to hydrogen, and by dependent use claims defining treatment of kinase-activity-mediated diseases with a therapeutically effective amount and specifying topical skin administration in narrower routes.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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