MAP4K1 inhibitors
Inventors
Brubaker, Jason D. • Close, Joshua T. • Dineen, Thomas A. • Miduturu, Chandrasekhar V. • Perola, Emanuele
Assignees
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Publication Number
US-12202844-B2
Publication Date
2025-01-21
Expiration Date
Abstract
One embodiment of the disclosure is a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The variables in Formula I are defined herein. Compounds of Formula I are MAP4K1 inhibitors, which can be used to treat a diseases or disorders in a subject that benefits from control of MAP4K1 activity.
Core Innovation
The disclosure describes compounds of Formula I, or pharmaceutically acceptable salts thereof, defined by a substituted scaffold with variable ring systems, linker/side-chain substituents, and multiple selection constraints. T is selected from specified heterocycle options and may be optionally substituted with 1-2 R6; Ring A is selected from C4-6 cycloalkyl or a 4-6 membered heterocycle containing nitrogen and may also be optionally substituted with 1-2 R6. Z is absent, O, or NH; L1 is selected from bond or C1-C3 alkylene optionally substituted with 1-2 R11; L2 is selected from bond or C1-C3 alkylene; B is O or NH; Q is N or CH; x is 0, 1, or 2; and n is 0, 1, 2, 3, or 4.
The substituent sets R1-R12 are defined by allowed atom types and optional substitution patterns. R1 and R2 are independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or 4 to 6-membered heterocycle, with optional substitution by 1-2 R3; each R3 is halogen, hydroxyl, or OR4; and each R4 is C1-3 alkyl, CF3, CH2F, or CHF2. R5, R6, R7, R8, R9, R10, R11, and R12 are further constrained, including cycloalkyl and cyclopropyl formation rules when two R5 or R11 groups are attached in the stated positions.
The provided material also includes azide-containing and chloro-substituted naphthyridine-based intermediates, thietane O-linker motifs, and sulfonyl-containing heterocycle/ether linker systems. Additional examples reference 6-chloro-2,7-naphthyridine derivatives, azidopropyl substituents, thietane 1,1-dioxide or related oxidized thioether forms, and stereochemically defined intermediates and isomers. The text repeatedly presents these structures as example intermediates and claim-linked embodiments within the broader Formula I framework.
Claims Coverage
The provided independent claims center on a Formula I compound, or pharmaceutically acceptable salt thereof, with multiple structural variables and extensive substituent constraints. Across the input items, three independent inventive feature groupings are consistently represented: the Formula I scaffold, inhibition of MAP4K1, and activation of T-cells with increased IL-2 levels and increased T-cell proliferation.
Formula I compound scaffold with constrained ring systems and substituent groups
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein T is selected from specified heterocycles optionally substituted with 1-2 R6; Z is absent, O or NH; Ring A is C4-6 cycloalkyl or a 4-6 membered heterocycle containing nitrogen optionally substituted with 1-2 R6; L1 is selected from bond and C1-C3 alkylene optionally substituted with 1-2 R11; L2 is selected from bond and C1-C3 alkylene; B is O or NH; Q is N or CH; x is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and R1-R12 are restricted to the enumerated allowed groups and substitution patterns.
Inhibiting MAP4K1 by contacting with an effective amount
A method to inhibit MAP4K1 in a subject by contacting MAP4K1 with an effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
Activating T-cells via administering an effective amount with IL-2 increase and proliferation
A method for activating T-cells in a subject by administering an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt, resulting in increased IL-2 levels and increased T-cell proliferation.
Claim coverage is anchored on the Formula I chemical scaffold with defined ring, linker, and substituent constraints, and further extends to biological-use claims directed to MAP4K1 inhibition and T-cell activation characterized by increased IL-2 and increased T-cell proliferation.
Stated Advantages
Inhibition of MAP4K1 in a subject.
Activation of T-cells in a subject.
Increased IL-2 levels.
Increased T-cell proliferation.
Documented Applications
Inhibiting MAP4K1 in a subject by contacting MAP4K1 with an effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
Activating T-cells in a subject by administering an effective amount of the compound of Formula I or a pharmaceutically acceptable salt, resulting in increased IL-2 levels and increased T-cell proliferation.
Treating MAP4K1-dependent disorders, including cancer and viral infection.
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