Thienopyrimidine inhibitors of atypical protein kinase C
Inventors
Dorsey, Bruce D • Learn, Keith S. • Morris, Emma L. • Ott, Gregory R • Roffey, Jonathan R. A. • Soudy, Christelle N. • Wagner, Jason C.
Assignees
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Publication Number
US-9604994-B2
Publication Date
2017-03-28
Expiration Date
Abstract
The present application provides a compound of formula (I)or a salt thereof, wherein R1, R2, R3, R4, R5, R6, A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have aPKC inhibitory activity, and may be used to treat proliferative disorders.
Core Innovation
The invention relates to compounds of formula (I), or salt forms thereof, in which A is NR11, O or S, and the compound is defined by M-Q-X and G together with multiple independently selected substituent groups. The scaffold allows extensive structural variation across the core while maintaining the formula (I) framework, including broad classes such as alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and related optionally substituted fragments.
The structure definition permits selected pairs of substituent variables, together with the atoms linking them, to form 3-15 membered heterocycloalkyl, 5-15 membered heteroaryl, C6-11 aryl, or C3-11 cycloalkyl. It also allows selected pairs to form a double bond or heteroatom linkages such as O, NR20, NOR20, or S, together with functional-group options including halogen, CN, carbonyl-derived groups, nitro, amino- and urea-like motifs, sulfonyl/sulfoxide/ether patterns, phosphorus-containing groups, and silicon-based groups.
The disclosed examples and analytical entries describe substituted thieno[3,2-d]pyrimidine and benzo[4,5]thieno[2,3-d]pyrimidine scaffolds, including pyridinyl-substituted cores and varied fused ring systems. The examples include stereodefined variants, side-chain amines or aminoalkyl groups, and motifs such as pyrazolyl, piperazine, diazepane, pyrrolidine, azetidinyl, triazolyl, isoxazolyl, and thiazolyl, with characterization by LCMS and 1H NMR.
Claims Coverage
The consolidated claim coverage centers on one independent claim family for compounds of formula (I) or salt forms thereof, with a highly substituted scaffold and broad variable-position definitions. The inventive features are defined by the scaffold regions A, M-Q-X, and G; multiple independently selected R groups; optional ring formation; optional double-bond formation; and, in one item, pharmaceutical composition coverage.
Compound of formula (I) or salt forms thereof
A compound of formula (I) or a salt form thereof, wherein A is NR11, O or S; M-Q-X is a group of formula; and G is a group of formula, with broad independently selected substituent groups across the scaffold.
Broad substituent selection across the scaffold
R positions are independently chosen from broad sets including hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-11 aryl, C7-16 arylalkyl, C3-11 cycloalkyl, C4-17 cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, and 6-21 membered heteroarylalkyl, with additional halogen, CN, carbonyl-containing, amino-like, sulfonyl/sulfoxide/ether, phosphorus-containing, and silicon-containing options.
Optional ring formation and double bond formation
Selected pairs of R groups can, together with the atoms linking them, form heterocycloalkyl, heteroaryl, aryl, or cycloalkyl ring systems, and R3 and R5 or R4 and R6 can together form a double bond; other paired R groups can together form O, NR20, NOR20, or S.
Pharmaceutical composition scope
A pharmaceutical composition including a compound of formula (I) or one of its salts together with a pharmaceutically acceptable excipient.
The claim coverage is focused on a highly variable formula (I) scaffold with broad substituent definitions, explicit ring-forming and heteroatom-linkage rules, optional unsaturation, and dependent pharmaceutical composition coverage.
Stated Advantages
Treatment of aPKC-dependent and proliferative diseases.
Provides compounds with aPKC inhibitory activity (atypical protein kinase C; PKCι/PKCζ).
Documented Applications
Treating aPKC-dependent and proliferative diseases using compounds of formula (I) or salts with aPKC inhibitory activity.
Pharmaceutical compositions comprising a compound of formula (I) or a salt and a pharmaceutically acceptable excipient.
In vitro PKCι inhibition screening using an IMAP™ fluorescence-polarization assay with a FAM-PKCε pseudopeptide substrate and ATP, including classification into IMAP activity bins for example compounds.
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