Heteroaryl compounds and their use as Mer inhibitors
Inventors
Kim, Jin Kwan • Kim, Hadong • RYU, Ki Moon • Park, Seong Jin • Yoon, Taeyoung • JANG, Mi Yeon
Assignees
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Publication Number
US-10913730-B2
Publication Date
2021-02-09
Expiration Date
Abstract
Compounds of formula (I) and a pharmaceutically acceptable salt thereof, wherein A, R1, R2, R3, R4, R5, R6, R7, R24, X, L, n and p are as defined in the specification, are useful for treating or preventing Mer tyrosine kinase receptor modulated disease or conditions. Also described are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
Core Innovation
The invention relates to Mer (TAM family) tyrosine kinase inhibitors and selective inhibition of Mer kinase. The disclosed compounds are compounds of formula (II), or pharmaceutically acceptable salts thereof, defined by Ring A, X, L, and substituent groups R1 through R20, with selected embodiments also described as nicotinamide-pyrazole scaffold compounds. The structural scope includes aryl and heteroaryl substituents, biphenyl variants, stereochemically defined compounds, and isotopically labeled compounds.
In the compounds of formula (II), X is —C(=O)N(R8)—, —N(R8)—, or —O—, L is C1-3 alkyl, —C(=O)—, —C(=O)O—, or —C(=O)N(R8)—, and R1 is NH2. R2 is —Br, heteroaryl, or phenyl optionally substituted with one or more R18, and R3 is phenyl or biphenyl optionally substituted with one or more R9. R4, R5, R6, and R7 are each independently H, while R8, R9, R10, R11, R16, R17, R18, R19, and R20 are defined within constrained substitution sets and nested J-linked group options.
The disclosure includes pharmaceutical compositions and methods of modulating Mer tyrosine kinase receptor activity. The technical field emphasizes therapeutic use for preventing or treating cancer and immune-related diseases, including infection and sepsis, and provides biological testing for TAM-family kinases including MER, AXL, and TYRO3.
Claims Coverage
The consolidated claim coverage includes two independent claims: one compound claim for formula (II) and one method claim for Mer kinase inhibition. The compound claim centers on a structured substituent framework across Ring A, X, L, and R1 through R20, with nested J-group definitions and substitution limits.
Compound of formula (II) with defined Ring A, X, L, and R1
A compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein Ring A is defined with X as —C(=O)N(R8)—, —N(R8)—, or —O—; L as C1-3 alkyl, —C(=O)—, —C(=O)O—, or —C(=O)N(R8)—; and R1 as NH2.
Phenyl, heteroaryl, and biphenyl substitution pattern
R2 is —Br, heteroaryl, or phenyl optionally substituted with one or more R18; R3 is phenyl or biphenyl optionally substituted with one or more R9; and R4, R5, R6, and R7 are each independently H.
Extended substituent framework with R8 through R20 and J groups
R8, R9, R10, R11, R16, R17, R18, R19, and R20 are defined within allowed halogen, hydroxyl, carbonyl, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, heterocycle, and heteroaryl options, including nested J9, J16, J18, and J19 group definitions and substitution limits.
Mer kinase inhibition method
A method for inhibiting Mer kinase comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a subject with cancer or an immune-related disease.
The claims cover a formula (II) compound defined by fixed core features and extensive variable substituent definitions, together with a Mer kinase inhibition method that uses the claimed compound in subjects with cancer or immune-related disease.
Stated Advantages
Selective inhibition of Mer kinase.
Therapeutic use for preventing or treating cancer and immune-related diseases, including infection and sepsis.
Documented Applications
Preventing or treating cancer.
Preventing or treating immune-related diseases, including infection and sepsis.
Biological testing and biochemical and in-cell kinase activity assays for TAM-family kinases, including MER, AXL, and TYRO3.
Characterization of selected example compounds using 1H NMR and ESI-MS.
Inhibiting Mer kinase in a subject with cancer or an immune-related disease [procedural detail omitted for safety].
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