Heterocycle compounds as Tyro3, Axl and MerTK (TAM) family of receptor tyrosine kinase inhibitors
Inventors
Yen, Shih-Chieh • Liao, Chu-Bin • Wang, Hui-Chen • Chen, Po-Ting • PAN, Yu-Chih • Li, Tsung-Hui • Chen, Bo-Rong • Chiou, Shian-Yi
Assignees
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Publication Number
US-11407757-B2
Publication Date
2022-08-09
Expiration Date
Abstract
Disclosed are compounds of formula (I) below and tautomers, stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof: in which each of variables R1, ring A, L, W, V, and G is defined herein. Also disclosed are a method for treating disease or disorder mediated by Tyro3, Axl, and/or Mer kinase with a compound of formula (I) or a tautomer, stereoisomer, isotopologue, or salt thereof and a pharmaceutical composition containing same.
Core Innovation
The disclosure relates to compounds of formula (I), including a tautomer, stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof, featuring a substituted pyrrolo[2,3-d]pyrimidin-2-amine core. The compounds are defined by structural variables including R1, L, Ring A, Q, Ar, and further variables such as W, V, G, R2, R3, and R4, with limited optional substitution patterns on the ring systems.
The chemical framework includes defined selections for L, Ring A, Q, and Ar, with Ar selected from benzodioxanyl, indazolyl, isoquinolinyl, isoxazolyl, naphthyl, oxadiazolyl, phenyl, pyridinyl, pyrimidinyl, pyridinonyl, and quinolinyl groups, and with optional substitution by groups such as halo, OR5, CN, NO2, and multiple amide-, sulfonamide-, carbonyl-, and alkyl-related moieties. The disclosed examples are supported by analytical data including 1H NMR and ESI-MS, and include representative compound structures.
The compounds are presented as TAM-family receptor tyrosine kinase inhibitor compounds and are associated with Tyro3/Axl/Mer-mediated disease, including cancer and inflammation. The disclosure reports preferential in vitro inhibition of Axl/Mer and cellular Gas6/TAM pathway inhibition via AKT phosphorylation, and also describes pharmaceutical compositions comprising an effective amount of the compounds.
Claims Coverage
The independent claim coverage centers on a compound of formula (I) with extensive structural definitions, together with therapeutic method coverage for diseases or disorders mediated by Tyro3, Axl, and/or Mer kinase. Across the provided claims, there are 2 principal inventive features: the compound definition and the treatment method, with further dependent narrowing to specific cancer indications and selected substituent constraints.
Formula (I) substituted pyrrolo[2,3-d]pyrimidin-2-amine compounds
A compound of formula (I), or a tautomer, stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof, wherein R1, L, Ring A, Q, Ar, and additional variables including W, V, G, R2, R3, and R4 are limited to specified chemical groups and optionally substituted ring patterns.
Treating Tyro3/Axl/Mer-mediated disease by administering a compound of formula (I)
A method for treating a disease or disorder mediated by Tyro3, Axl, and/or Mer kinase by administering an effective amount of the compound of formula (I), or a tautomer, stereoisomer, isotopologue, or pharmaceutically acceptable salt thereof, to a subject in need.
Cancer selection within Tyro3/Axl/Mer-mediated treatment
A method wherein the disease treated is cancer selected from an enumerated group including lung cancer, colon cancer, colorectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, bladder cancer, gastric cancer, renal cancer, salivary gland cancer, ovarian cancer, uterine body cancer, cervical cancer, oral cancer, skin cancer, brain cancer, lymphoma, and leukemia.
The claim set combines a broadly defined formula (I) chemical space for substituted pyrrolo[2,3-d]pyrimidin-2-amine compounds with therapeutic use coverage for Tyro3/Axl/Mer-mediated diseases. The therapeutic scope is further narrowed in dependent claims to specified cancer indications and selected structural restrictions.
Stated Advantages
Preferential in vitro inhibition of Axl/Mer reported for 112 compounds.
Cellular Gas6/TAM pathway inhibition via AKT phosphorylation reported for listed compounds.
The compounds show higher efficacies against Axl and Mer versus known agents.
Documented Applications
In vitro AlphaScreen assessment of Axl/Mer inhibition using 112 compounds.
Cellular inhibition of Gas6/TAM pathway via AKT phosphorylation in H1299 NSCLC cells, assessed by western blot.
Treatment of cancer associated with Tyro3/Axl/Mer-mediated disease, including lung cancer, colon cancer, colorectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, bladder cancer, gastric cancer, renal cancer, salivary gland cancer, ovarian cancer, uterine body cancer, cervical cancer, oral cancer, skin cancer, brain cancer, lymphoma, and leukemia.
Treatment of inflammation associated with targeting Tyro3/Axl/Mer using TAM-family receptor tyrosine kinase inhibitor compounds of formula (I).
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