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-10183950-B2
Publication Date
2019-01-22
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 thieno[2,3-d]pyrimidine or thieno[3,2-d]pyrimidine small-molecule compounds and pharmaceutically acceptable salts thereof, defined by formula I with specified substituent selections. The disclosed embodiments include H, C1-6 alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, C2-6 alkynyl, and heteroatom-containing linkages such as —NR22R23, —NR24C(=O)R20, —OR20, and —S(=O)2NR22R23, together with stereochemically defined (S)- and (R)-variants.
The disclosure also provides selected enumerated thieno[3,2-d]pyrimidine-containing compounds with explicit names and structures. These examples include pyridinyl-substituted compounds, fluoro, methyl, tert-butyl, methoxy, alkynyl, alcohol, amino, and heteroaryl substituent patterns, as well as terminal alkynyl and alcohol motifs, cyclopropanol and cyclobutanol variants, and additional aryl and heteroaryl substitutions.
Further content describes thieno[2,3-d]pyrimidine and thieno[3,2-d]pyrimidine intermediates and derivatives, including substituted amine, diamine, Boc-protected products, and amino alcohol intermediates. The document also includes characterization data for specific examples, including LCMS, RT, [M+1], and 1H NMR, supporting the identified compounds and intermediates.
Claims Coverage
The consolidated claim coverage includes a broad Formula I compound claim, an independent claim enumerating specific thieno[3,2-d]pyrimidine-containing compounds, and a pharmaceutical composition claim comprising a Formula I compound and a pharmaceutically acceptable excipient. The inventive features are the Formula I scaffold with constrained substituent selections, the separately enumerated set of specific stereodefined compounds, and the composition claim using a Formula I compound with an excipient.
Formula I compound with constrained substituent selection
A compound, or a pharmaceutically acceptable salt thereof, of formula I with R1, R2, and R11 independently chosen from H and C1-6 alkyl optionally substituted by R19; R3 chosen from H, C1-6 alkyl optionally substituted by R19, C7-11 arylalkyl optionally substituted by R19, C6-7 cycloalkylalkyl optionally substituted by R19, and 6-11 membered heteroarylalkyl optionally substituted by R19; R4, R5, and R6 are H; R7 selected from H and C1-6 alkyl optionally substituted by R19; R8 selected from C2-6 alkynyl optionally substituted by R19; R12, R13, R14, and R15 independently chosen from H, C1-6 alkyl optionally substituted by R19, halogen, —NR22R23, —NR24C(=O)R20, —NR24C(=O)NR22R23, —OR20, and —S(=O)2NR22R23; R19 independently chosen from C1-6 alkyl, phenyl, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, —C(=O)OR30, and —OR30; and R20, R22, R23, R24, and R30 independently chosen from H and C1-6 alkyl.
Enumerated thieno[3,2-d]pyrimidine compounds with stereochemistry and named substituent patterns
A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of specific listed thieno[3,2-d]pyrimidine-containing structures, including (S)- and (R)-configured examples and named variants with pyridinyl, fluoro, methyl, tert-butyl, methoxy, piperazinyl, diazepanyl, pyrazolyl, isoxazolyl, thiazolyl, and alkynyl/alcohol or cycloalkanol motifs.
Pharmaceutical composition with Formula I compound and excipient
A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, with Formula I defined by the same multi-parameter substituent-selection framework.
The claims are centered on a Formula I thieno[2,3-d]pyrimidine/thieno[3,2-d]pyrimidine scaffold with extensive substituent constraints, an enumerated set of specific stereodefined thieno[3,2-d]pyrimidine compounds, and a pharmaceutical composition claim that includes a pharmaceutically acceptable excipient.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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