Compounds and methods for modulating interleukin-2-inducible t-cell kinase
Inventors
Hudson, Ryan • Beausoleil, Anne-Marie
Assignees
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Publication Number
US-11008314-B2
Publication Date
2021-05-18
Expiration Date
Abstract
Provided herein, inter alia, are methods and compounds for modulating Interleukin-2-inducible T-cell kinase.
Core Innovation
The invention provides compounds having a formula in which Ring A, R1 to R6, L1 to L4, and group E are defined by enumerated structural options. Ring A and the substituents are independently selected from hydrogen, halogen, cyano, carbonyl- and heteroatom-containing groups, and substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. The disclosed scaffold is further varied through linkers L1 to L4 and an additional group E.
L1 is selected from O, S, substituted or unsubstituted C1-C2 alkylene, or substituted or unsubstituted 2 membered heteroalkylene; L2 is a bond, NH, or NHC(O); and L3 is a bond or one of several specified heteroatom- and carbonyl-containing linkages, together with substituted or unsubstituted alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene. L4 is substituted or unsubstituted heterocycloalkylene. The compound definition also includes R6 and E, with E expressed through independently selected R1A to R4D and R6A to R6C substituents.
The disclosed material further states that the compound family includes additional embodiment structures and stereochemical variants, including bicyclic, bridged, and spirocyclic heterocycloalkylene linkers and a covalent cysteine modifier moiety for E in some embodiments. Example compounds are described with varying substituent patterns and, in some portions of the input, with reported characterization data such as MS (M+H), 1H NMR, and bioactivity or inhibition data for selected compounds.
Claims Coverage
The consolidated input centers on one independent claim that broadly covers a compound defined by an enumerated chemical formula. The inventive scope is carried by the variable Ring A substituents, the linker set L1 to L4, the substituent set R1 to R6, and the group E definition, with some items adding dependent claim content.
Core compound formula with variable Ring A substituents
A compound having the formula wherein Ring A and substituents R1, R2, R3, R4, and R5 are independently selected from enumerated chemical groups including hydrogen, halogen, cyano, carbonyl-related groups, sulfur- and nitrogen-containing groups, and substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
Defined linker framework L1 to L4
L1 is O, S, substituted or unsubstituted C1-C2 alkylene, or substituted or unsubstituted 2 membered heteroalkylene; L2 is a bond, NH, or NHC(O); L3 is a bond or multiple specified heteroatom- and carbonyl-containing linkages and substituted or unsubstituted alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; and L4 is substituted or unsubstituted heterocycloalkylene.
Group E with enumerated substituent sets
Group E is defined through independently selected R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R6A, R6B, and R6C substituents, each selected from hydrogen, halogen, CX3, CN, COOH, CONH2, CHX2, CH2X, or substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, with optional joining of paired substituents on the same nitrogen atom.
Additional constrained substituent variables and embodiment refinements
The claim set also includes constrained halogen identities, integer ranges, and additional variables such as R15 to R18 in some items, together with embodiment language describing covalent cysteine modifier moieties and stereochemical variants.
The consolidated claim coverage is a broad formula-defined compound claim built from variable Ring A substituents, the linker framework L1 to L4, and the group E substituent scheme, with some input items adding narrower embodiment constraints and dependent elements.
Stated Advantages
Documented Applications
Treatment of T-cell lymphoma in a subject by administering an effective amount of the compound of claim 1.
Treatment of cutaneous T-cell lymphoma or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).
A pharmaceutical composition including the compound of claim 1 and a pharmaceutically acceptable excipient.
ITK, TXK, JAK3, and BTK inhibition is documented for representative compounds in the input.
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