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The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine to explore the SAR of of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b...

For every uncountable regular cardinalκ and any cardinalλ≧κ,P κ λ denotes the set $$\left\{ {x \subseteqq \lambda :\left| x \right|< \kappa } \right\}$$ . Furthermore, < denotes the binary operation defined inP κ λ byx

Let κ \kappa be an uncountable regular cardinal, let C F κ C{F_\kappa } be the cub filter on κ \kappa and let F S F κ FS{F_\kappa } be the filter generated by { { β > κ : β > α } : α > κ } \{ \{ \beta > \kappa :\beta > \alpha \} :\alpha > \kappa \} . It is well known that C F k C{F_k} is normal, that C F κ = Δ F S F κ C{F_\kappa } = \Delta FS{F_\kappa } and hence that every normal filter on κ \kappa extends C F κ C{F_\kappa } . Jech extended some of these results to the context of P κ λ {P_\kappa }\lambda . Let λ \lambda be a cardinal ⩾ κ \geqslant \kappa and let C F κ λ C{F_{\kappa \lambda }} denote the cub filter on P κ λ {P_{\kappa \lambda }} as defined by Jech; he showed that C F κ λ C{F_{\kappa \lambda }} is normal and that every normal ultrafilter on P κ λ {P_{\kappa \lambda }} extends C F κ λ C{F_{\kappa \lambda }} . In this paper we extend these results further. In particular, we show that F κ λ = Δ Δ F S F κ λ {F_{\kappa \lambda }} = \Delta \Delta FS{F_{\kappa \lambda }} where F S F κ λ FS{F_{\kappa \lambda }} is the filter generated by { { y ∈ P κ λ : x ⊂ y } : x ∈ P κ λ } \{ \{ y \in {P_\kappa }\lambda :x \subset y\} :x \in {P_\kappa }\lambda \} , and that every normal filter on P κ λ {P_\kappa }\lambda extends C F P κ λ CF{P_{\kappa \lambda }} . Finally, we show that for any λ ⩾ κ \lambda \geqslant \kappa and any ideal I I on P κ λ , ∇ ∇ ∇ I = ∇ ∇ I {P_\kappa }\lambda ,\nabla \nabla \nabla I = \nabla \nabla I