Azaquinazoline inhibitors of Atypical protein Kinase C
Inventors
Breslin, Henry J. • 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. • Soudy, Christelle N. • Tao, Ming • Zificsak, Craig A. • Zulli, Allison L.
Assignees
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Publication Number
US-9914730-B2
Publication Date
2018-03-13
Expiration Date
Abstract
The present application provides azaquinazoline compounds as defined herein. This application further describes compositions comprising the same. These azaquinazoline compounds and their salts have atypical protein kinase C (“aPKC”) inhibitory activity, and may be used to treat proliferative disorders.
Core Innovation
The invention relates to compounds of formula I, including pharmaceutically acceptable salts thereof, defined by substituent variables R7, R8, R9, X, G, R14, R15, and R12/R13. R7 is an optionally substituted C3-C6 cycloalkyl, R8 and R9 are hydrogen, and X is a 5-10 membered heterocycloalkyl containing 1 or 2 nitrogen atoms, optionally substituted with 1-4 hydroxyl or C1-C3 alkyl. The definitions also specify that R12 and R13 are independently hydrogen or an optionally substituted amino group, or together form an optionally substituted 5 to 15 membered heteroaryl or an optionally substituted 3 to 15 membered heterocycloalkyl.
The disclosure further describes substituted pyrido[3,4-d]pyrimidine scaffold compounds and related heteroaromatic amine analogs, including cyclopropyl and cyclobutyl variants, piperazinyl and piperidinyl variants, and compounds bearing diverse aryl or heteroaryl substituents. Examples explicitly include pyrido[3,4-d]pyrimidine/pyridine/piperazine compounds, substituted pyridinyl amines, and selected group compounds with fluoro, difluoro, chloro, trifluoromethyl, methoxy, ethoxy, and related substituent patterns. The document provides structural depictions and analytical characterization data such as LCMS, retention time, mass, and 1H NMR for multiple exemplified members.
The partial content also identifies azaquinazoline compounds of formula (I) as atypical protein kinase C (aPKC) inhibitors, specifically including aPKC/PKCι and PKCζ, and states that these compounds are used for treating aPKC-dependent disorders and proliferative disorders. A pharmaceutical composition including one or more of the formula (I) compounds, or pharmaceutically acceptable salts, together with a pharmaceutically acceptable carrier, diluent, or excipient is also described.
Claims Coverage
The consolidated claim coverage centers on formula I compounds with constrained substituent definitions, with one independent claim family directed to compounds of formula I and another directed to a selected group of compounds. The independent coverage includes the scaffold definitions for R7, X, and the relationship of R12/R13, and the provided claim set also includes a pharmaceutical composition embodiment.
Formula I compound with constrained substituent definitions
A compound of formula I wherein R7 is an optionally substituted C3-C6 cycloalkyl; R8 is hydrogen; R9 is hydrogen; X is a 5-10 membered heterocycloalkyl containing 1 or 2 nitrogen atoms and optionally substituted with 1-4 hydroxyl or C1-C3 alkyl; G is defined with R14 and R15 as hydrogen; and R12 and R13 are independently hydrogen or an optionally substituted amino group, or together with the atoms to which they are attached form an optionally substituted 5 to 15 membered heteroaryl or an optionally substituted 3 to 15 membered heterocycloalkyl; or a pharmaceutically acceptable salt thereof.
Cyclopropyl or cyclobutyl at R7
The compound of formula I wherein R7 is cyclopropyl or cyclobutyl, including pharmaceutically acceptable salts thereof.
Optionally substituted piperazinyl as X
The compound of formula I wherein X is an optionally substituted piperazinyl group, or a pharmaceutically acceptable salt thereof.
Optionally substituted piperidinyl as X
The compound of formula I wherein X is an optionally substituted piperidinyl group, or a pharmaceutically acceptable salt thereof.
R12 and R13 form an optionally substituted heterocycloalkyl
The compound of formula I wherein R12 and R13, together with the atoms to which they are attached, form an optionally substituted 3 to 10 membered heterocycloalkyl group, or a pharmaceutically acceptable salt thereof.
Selected compound from a defined group
A compound selected from the group consisting of the defined compounds, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition including one or more compounds as defined in formula I or selected from the defined group, together with a pharmaceutically acceptable carrier.
Overall, the claims cover a formula I compound scaffold defined by specific cycloalkyl, heterocycloalkyl, and ring-forming substituent constraints, together with dependent narrowing to cyclopropyl or cyclobutyl at R7, piperazinyl or piperidinyl at X, and a 3 to 10 membered heterocycloalkyl formed by R12 and R13. The claim set also includes a selected-compound claim and a pharmaceutical composition claim with a pharmaceutically acceptable carrier.
Stated Advantages
Treating aPKC-dependent disorders.
Treating proliferative disorders.
Documented Applications
Therapeutic treatment of aPKC-dependent disorders using the described aPKC inhibitors.
Therapeutic treatment of proliferative disorders using the described aPKC inhibitors.
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