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-11897874-B2
Publication Date
2024-02-13
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 of Formula (IIA) in which R1, R3, and R5 are selected from broad substituent sets, and in which L3, L4, E, and R6 define the structural framework. The variables include halogen options for X, X1, and X3, integer ranges for n1 and n3, and values of 1 or 2 for m1, m3, v1, and v3. The scope includes carbonyl-containing motifs and sulfonamide- or amide-type substituent patterns, together with substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups.
Within Formula (IIA), L3 is selected from —C(O)—, a bond, —N(R6)—, or —C(O)N(R6)—, with R6 being hydrogen or methyl. L4 is substituted or unsubstituted 5 to 8 membered monocyclic heterocycloalkylene, and E is —C(O)CH=CH2. The additional substituent positions R1A, R1B, R1C, R1D, R3A, R3B, R3C, and R3D are independently hydrogen or selected from explicitly listed groups, including —CX3, —CN, —COOH, —CONH2, —CHX2, —CH2X, and unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
The disclosed embodiments include extensive structural variation around the common Formula (IIA) scaffold, with example compounds and partial-content descriptions identifying different heteroaromatic, piperidine, sulfanthiazole, and amide-containing frameworks. The compound family is presented as a broad chemical space with many substitution patterns, while the claim coverage narrows that space through the defined L3, L4, E, halogen, and index constraints.
Claims Coverage
The independent claim coverage centers on one Formula (IIA) compound claim, with dependent refinements and at least one treatment claim. The main inventive features are the Formula (IIA) scaffold itself, the defined linkage and ring elements, the enumerated substituent options at R1, R3, and R5, and the application of the compound to T-cell lymphoma treatment.
Formula (IIA) compound scaffold
A compound of Formula (IIA) with variable R1, R3, and R5 substituents, together with L3, L4, E, R6, X, X1, X3, n1, n3, m1, m3, v1, and v3 defining the structural scope.
L3, L4, and E structural constraints
L3 is —C(O)—, a bond, —N(R6)—, or —C(O)N(R6)—; L4 is substituted or unsubstituted 5 to 8 membered monocyclic heterocycloalkylene; E is —C(O)CH=CH2; and R6 is hydrogen or methyl.
Enumerated substituent options for R1 and R3
R1 and R3 are selected from hydrogen, halogen, CX- and CHX- type groups, OCX- and OCHX- type groups, CN, carbonyl-related groups, sulfonamide- and amide-type groups, and substituted or unsubstituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
R5 ring and chain options
R5 is selected from substituted or unsubstituted cycloalkyl, alkyl, heteroalkyl, heterocycloalkyl, aryl, or heteroaryl, with dependent refinements selecting named heteroaryl groups in some claim sets.
Halogen and index constraints
X, X1, and X3 are each independently F, Cl, Br, or I; n1 and n3 are independently an integer from 0 to 4; and m1, m3, v1, and v3 are independently 1 or 2.
Treatment of T-cell lymphoma
A method for treating T-cell lymphoma in a patient by administering an effective amount of the compound, including claim-set references to cutaneous T-cell lymphoma and peripheral T-cell lymphoma.
Pharmaceutical composition
A pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient.
Overall, the claim coverage defines a Formula (IIA) compound family with broad substituent variability but explicit structural limits at L3, L4, E, R6, halogens, and indices, and it also includes treatment and composition claims for T-cell lymphoma.
Stated Advantages
Inhibits ITK and IL-2-inducible T-cell kinase activities.
Inhibits ITK more potently/selectively versus other TEC kinases including BTK, BMX, TXK, and TXK/RLK.
Covalently bonds ITK to a compound portion, including covalent bonding to a cysteine residue and irreversible covalent bonding.
Capable of CNS entry after systemic administration.
Kinase inhibition by contacting ITK.
Irreversible covalent conjugation of Interleukin-2-inducible T-cell kinase (ITK) via cysteine residue covalent bonding.
Documented Applications
Treating cancer.
Treating inflammatory diseases.
Treating autoimmune diseases.
Treating infectious diseases.
Treating ITK-associated diseases.
Treating T-cell lymphoma in a patient by administering an effective amount of the compound or pharmaceutical composition.
Treating cutaneous T-cell lymphoma.
Treating peripheral T-cell lymphoma.
Inhibiting TEC kinase and ITK by contacting the kinase with a compound.
Pharmaceutical compositions including the disclosed compounds.
Treatment of T-cell lymphoma in a patient by administering an effective amount of the compound.
Treatment of T-cell lymphoma using a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.
Kinase binding characterization against ITK and TXK, including TXK/ITK ratios, and against JAK3 and BTK.
Pharmacokinetic results in rat and mouse models using Jurkat IL2 PO and IP dosing.
1H NMR characterization for several compounds.
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