Azaquinazoline inhibitors of atypical protein kinase C
Inventors
Dorsey, Bruce D. • Dugan, Benjamin J. • Fowler, Katherine M. • Hudkins, Robert L. • Mesaros, Eugen F. • Monck, Nathaniel J T • Morris, Emma L. • Olowoye, Ikeoluwa • Ott, Gregory R. • Pave, Gregoire A. • Roffey, Jonathan R. A. • Soudy, Christelle N. • Zificsak, Craig A. • Zulli, Allison L.
Assignees
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Publication Number
US-10414763-B2
Publication Date
2019-09-17
Expiration Date
Abstract
The present application provides a compound of formula (I) and/or a salt thereof, wherein R1, G, and X are as defined herein. A compound of formula (I) and/or its salts have aPKC inhibitory activity, and may be used to treat proliferative disorders. Compositions comprising a compound of Formula (I) and/or a salt thereof are also provided.
Core Innovation
The invention relates to compounds of formula (I), or salts thereof, defined by structural variables including G, X, R1, R2, R3, R4, R5, R19, R20-R41, and n. G and X are restricted to enumerated structural and functional group classes, and the remaining variables are selected from broad classes of alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups, with optional substitution limits and ring-forming constraints.
The disclosed embodiments include substituted pyrido[3,4-d]pyrimidine and related fused heterocyclic scaffolds, including pyrrolo[2,3-b]pyridine, pyrido[2,3-b]indole, and azaquinazoline derivatives. The examples describe cyclopropyl and cyclobutyl motifs, fluorinated pyridyl and pyrrolo-pyridinyl substituents, and amine side chains such as piperazine, piperidine, azepane, and related ring systems, together with stereochemical variants and salts in some cases.
The provided content also includes explicit characterization for named compounds using MS (M+H)+ and 1H NMR data. A further portion states that the compounds inhibit aPKC and may be formulated as pharmaceutical compositions for treating an aPKC-dependent disorder or a proliferative disorder.
Claims Coverage
The consolidated claims coverage centers on a single independent claim of formula (I) or a salt thereof, defined by G, X, R1, R2, R3, R4, R5, R19, R20-R41, and n. The claim defines a broad genus through enumerated structural and substituent classes, including optional ring formation by certain paired substituents, and the provided material also identifies aPKC-related claim context.
Compound of formula (I) or a salt thereof
A compound of formula (I) or a salt thereof, defined by structural variables G and X together with R1, R2, R3, R4, and R5, and additional variables R19, R20-R41, and n.
Defined group G and enumerated X
G is a group of formula as defined in the claim, and X is chosen from enumerated halogen, carbonyl, heteroatom-containing, sulfur-containing, phosphorus-containing, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl classes, optionally substituted by R19.
R1 selection
R1 is chosen from C3-11 cycloalkyl optionally substituted by R19, or C1-6 haloalkyl.
R2 to R5 substituent framework
R2, R3, R4, and R5 are each independently selected from enumerated H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl classes, optionally substituted by R19, and paired substituents may form ring systems with the attached nitrogen atom.
R19 and additional variables
R19, R20-R41, and n are independently selected from enumerated substituent classes and limits, with n selected from 0, 1, and 2.
The claim coverage is a broad genus claim built around formula (I), with enumerated constraints on G, X, R1, R2-R5, R19, R20-R41, and n, including optional ring formation and optional substitution limits.
Stated Advantages
The compounds inhibit aPKC.
The compounds may be formulated as pharmaceutical compositions.
The compounds may be used for treating an aPKC-dependent disorder or a proliferative disorder.
The patent reports PKC9 inhibition evaluation and IC50 potency values for example compounds.
Documented Applications
Treating a subject with an aPKC-dependent disorder or condition by administering a compound of formula (I) or a salt thereof.
Treating a subject with a proliferative disorder by administering a compound of formula (I) or a salt thereof.
PKC9 inhibition evaluation using IMAP fluorescence polarization with an FAM-PKC9 pseudosubstrate and recombinant human PKC9.
Characterization of named compounds by MS (M+H)+ and 1H NMR data.
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