MAP4K1 inhibitors
Inventors
Brubaker, Jason D. • Burke, Michael J. • Close, Joshua T. • Dineen, Thomas A. • Kim, Joseph L. • Miduturu, Chandrasekhar V. • Perola, Emanuele
Assignees
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Publication Number
US-12042495-B2
Publication Date
2024-07-23
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 selective 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 invention relates to a method for treating a MAP4K1-dependent disorder or disease that is a cancer or a viral infection by administering to a subject in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The compounds of Formula I are defined by constrained choices for A1, A2, A3, X, B, Y, and multiple substituent groups, with allowed ring-formation and substitution patterns.
The structural definition includes cases where the bond between Y and B is a double bond or a single bond, and cases where Y and B taken together form a 5 to 7-membered heterocycle or a C5-6 cycloalkyl, optionally substituted by 1-6 R8. R1 and R2 are each independently selected from hydrogen, C1-4 alkyl, C3-5 cycloalkyl, and 3 to 5-membered heterocycle, with optional OH, C1-6 alkoxy, or halogen substitution, or they together form a 4 to 6-membered heterocycle or C3-6 cycloalkyl.
The document further describes stereochemically defined intermediates and related scaffold examples, including chiral separation by SFC and characterization by MS and 1H NMR. The described intermediates include azide-containing naphthyridines, pyrano[4,3-b]pyridin-5-one and spiro[cyclopropane-1,8′-pyrano] scaffolds, as well as pyrazine and related heteroaromatic intermediates that support the MAP4K1-targeting compound series.
Claims Coverage
The claim coverage centers on one independent method claim for treating MAP4K1-dependent disorders or diseases that are cancers or viral infections by administering an effective amount of a Formula I compound or pharmaceutically acceptable salt. The independent claim is defined by extensive structural constraints across the Formula I scaffold, including the heteroatom and ring/bond selections and multiple substituent variables.
Treating MAP4K1-dependent disorder or disease with formula I compound administration
A method for treating a MAP4K1-dependent disorder or disease that is a cancer or a viral infection by administering to a subject in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
Formula I substituent and ring-structure constraints
Formula I wherein A1 and A2 are selected from N and CH; A3 is selected from CH and N; X is selected from C1-3 alkyl, OR6, NHR7 and halogen; and B and Y are defined by the specified double bond, single bond, heterocycle, or C5-6 cycloalkyl alternatives with optional substitution by R8.
Selected substitution ranges for multiple R groups
R1 and R2 are each independently selected from hydrogen, C1-4 alkyl, C3-5 cycloalkyl, and 3 to 5-membered heterocycle with optional OH, C1-6 alkoxy, or halogen substitution; R3 and R4, R6, R7, R9, R11, R12, R13, R14, R15, and R16 are further restricted by the definitions given in the claim.
Cancer indication includes enumerated cancer types
The cancer comprises at least one cancer selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, bladder cancer, stomach cancer, liver cancer, cancer of the head and neck, lymphoma, leukemia, melanoma, urothelial carcinoma, merkel cell carcinoma, gastroesophageal junction carcinoma, esophageal squamous cell carcinoma, skin squamous cell carcinoma, endometrial cancer, thyroid cancer, brain cancer, multiple myeloma, myeloproliferative diseases, and sarcoma.
Overall, the claim coverage is directed to administering a Formula I compound or salt for MAP4K1-dependent cancer or viral infection, with the principal inventive scope defined by the constrained Formula I architecture, the B/Y bonding and ring-forming relationships, and the explicitly enumerated cancer types.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a MAP4K1-dependent disorder or disease that is a cancer or a viral infection by administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt.
Treating cancer comprising at least one cancer selected from an enumerated group of cancer types including colon, pancreatic, breast, prostate, lung, ovarian, cervical, renal, bladder, stomach, liver, head and neck, lymphoma, leukemia, melanoma, urothelial carcinoma, merkel cell carcinoma, gastroesophageal junction carcinoma, esophageal squamous cell carcinoma, skin squamous cell carcinoma, endometrial cancer, thyroid cancer, brain cancer, multiple myeloma, myeloproliferative diseases, and sarcoma.
Treating viral infection as a MAP4K1-dependent disorder or disease indication.
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