Substituted indazoles as phosphatidylinositol kinase inhibitors
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Publication Number
US-11001587-B2
Publication Date
2021-05-11
Expiration Date
Abstract
A compound of formula (I) or a pharmaceutically acceptable salt thereof, useful in therapy, in particular in the treatment of a viral infection or a disease linked to impaired or abnormal autophagy.
Core Innovation
The invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, with structural variables including m, ring A, X/Y/Z selections, and multiple substituent groups with defined allowable atom and functional group options. Ring A is phenyl or 5- or 6-membered heteroaryl containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.
The document discloses compounds within a pyrazolo[1,5-a][1,3,5]triazin-4-amine scaffold, including named structural embodiments Ia–Im and moieties II/IIa that support the structural scope of formula (I). The disclosed examples include indazol-5-yl substitution patterns such as aminomethyl-benzene sulfonamide and methanesulfonamide substituents, as well as benzyl and heteroaryl/alkylamine substituents.
The invention is directed to using the compounds of formula (I) as inhibitors of phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ) and as inhibitors of picornavirus replication and picornaviral cytopathogenic effects. A further use described in the document is modulation of impaired or abnormal autophagy for treating viral infections, including non-enveloped single-stranded (+) RNA viruses, especially picornaviruses.
Claims Coverage
The provided claim content includes one independent claim defining a compound of formula (I) or a pharmaceutically acceptable salt thereof, with extensive structural definitions and related method-of-use and composition coverage. The inventive features center on the formula (I) scaffold, defined ring A and X/Y/Z selections, broad R-group patterning, and pharmaceutical composition and treatment claims. Six inventive features are identified.
Formula (I) compound with defined m and ring A
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2, and ring A is phenyl, 5-membered heteroaryl, or 6-membered heteroaryl having one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.
X, Y, Z structural selections
The compound is defined with X being CH or N; Y is N and Z is C, or Y is C and Z is N.
Multisubstituent R1–R16 patterning
The compound includes substituents R1 through R16 with specified options, including halogen, C1-C6 alkyl optionally substituted by halogen, carbonyl-containing groups, amide/amine-related groups, ether OR2, sulfone S(O)2R3, and hydrogen or C1-C6 alkyl for several positions.
Pharmaceutical composition with excipient
A pharmaceutical composition includes a pharmaceutically acceptable excipient and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
Treating viral infection in a mammal
A method for treating a viral infection in a mammal includes administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
Inhibiting phosphatidylinositol kinase activity
A method of inhibiting phosphatidylinositol kinase activity in a mammal includes administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage focuses on a structurally defined formula (I) scaffold with constrained ring A selection, defined X/Y/Z selections, extensive R1–R16 substitution options, and coverage extending to pharmaceutical compositions and methods for treating viral infection in a mammal and inhibiting phosphatidylinositol kinase activity.
Stated Advantages
Inhibits picornavirus replication and picornaviral cytopathogenic effects.
Inhibits virus-induced cytopathicity.
Acts as an inhibitor of phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ).
Modulates impaired or abnormal autophagy for treating viral infections, including non-enveloped single-stranded (+) RNA viruses, especially picornaviruses.
Documented Applications
Use of the compounds as inhibitors of phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ).
Inhibition of picornavirus replication and picornaviral cytopathogenic effects.
Treatment of viral infection in a mammal by administering the compound or a pharmaceutically acceptable salt, including viral infections caused by non-enveloped single-stranded (+) RNA viruses, especially picornaviruses.
Modulation of impaired or abnormal autophagy as a treatment approach for viral infections, including non-enveloped single-stranded (+) RNA viruses, especially picornaviruses.
In vivo readouts related to pancreatitis, virus titers, and viral load.
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