Pyridine and piperidine derivatives as novel sodium channel blockers

摘要

The invention provides compounds that are useful as sodium channel blockers. In one aspect, the invention provides compounds of Formula I:;
or pharmaceutically acceptable salts, solvates, hydrates, or diastereomers thereof, wherein R1, R4, X, G, n, p, W1, W2, W3, W4, and the E ring are defined in the disclosure. In certain embodiments, the invention provides compounds of Formulae II-XIII as set forth supra. The invention also provides the use of compounds of any of the above discussed formulae to treat a disorder responsive to blockade of sodium channels. In one embodiment, Compounds of the Invention are useful for treating pain.

主权项

1. A compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or diastereomer thereof:Wherein
stands for a double bond or a single bond, wherein s are either all double bonds or all single bonds within said compound of Formula I, and
i) when s are all double bonds, then
W1 is N or N-oxide; andeach of W2, W3, and W4, independently is C(R3), N, or N-oxide, provided that at least one of W2, W3, and W4 is C(R3); andii) when s are all single bonds, then
W1 is NR5; andeach of W2, W3, and W4, independently is C(R3a)2 or NR5, provided that at least one of W2, W3, and W4 is C(R3a)2; n is 0, 1, 2, 3, or 4; m, each independently, is 0, 1, or 2; p is 0, 1, 2, 3, or 4; X is —CH2— or —CH2CH2—; R1, on each occurrence, independently is H, alkyl, haloalkyl, —S(O)m-alkyl, alkoxy, haloalkoxy, carboxamido, amino, (alkyl)amino, (dialkyl)amino, ureido, hydroxyl, halogen, sulfonamido, R2OC(O)—, R2C(O)O—, (R2)2NC(O)O—, cyano, cycloalkyl, heterocyclyl, or nitro; R3, on each occurrence, independently is H, alkyl, haloalkyl, —S(O)m-alkyl, alkoxy, haloalkoxy, amino, (alkyl)amino, (dialkyl)amino, carboxamido, cyano, hydroxyl, halogen, R2OC(O)—, R2C(O)O—, (R2)2NC(O)O—, nitro, or sulfonamido; R3a, on each occurrence, independently is H, alkyl, haloalkyl, —S(O)m-alkyl, amino, (alkyl)amino, (dialkyl)amino, carboxamido, aryl, cyano, heterocyclyl, R2OC(O)—, nitro, ureido, or sulfonamido; R2, on each occurrence, independently is H, alkyl, aryl, cycloalkyl, heteroaryl, or heterocyclyl, wherein each of said alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl is optionally substituted; G is selected from the group consisting of
i) Hydroxyl;ii) Optionally-substituted (C4-9)cycloalkyl;iii) Optionally-substituted aryl;iv) Optionally-substituted heteroaryl; andv) Optionally-substituted heterocyclyl; E ring is phenyl or a 5- or 6- membered heteroaryl group; R4, on each occurrence, independently is selected from the group consisting of alkyl, amino, alkoxy, (alkyl)amino, halogen, hydroxyl, nitro, cyano, (alkyl)carbonyl, alkylsulfonyl, arylsulfonyl, —S-alkyl, carboxamido, (alkoxy)carbonyl, ureido, guanidino, carboxy, cycloalkyl, heterocyclyl, (cycloalkyl)carbonyl, sulfonamido, and (heterocyclyl)carbonyl, wherein each of said alkyl, amino, alkoxy, (alkyl)amino, (alkyl)carbonyl, alkylsulfonyl, arylsulfonyl, —S-alkyl, carboxamido, (alkoxy)carbonyl, cycloalkyl, heterocyclyl, (cycloalkyl)carbonyl, sulfonamido, and (heterocyclyl)carbonyl groups is further optionally substituted; R5, on each occurrence, independently is H, carboxamido, optionally-substituted alkyl, optionally-substituted (alkyl)carbonyl, or optionally substituted cycloalkyl; Provided that
1) when s are all double bonds and G is OH, then
R1 is H;andR3, on each occurrence, is H;2) when s are all double bonds and G is unsubstituted phenyl, then
the E ring is optionally-substituted 5 to 6-membered heteroaryl or optionally-substituted phenyl;and3) when s are all double bonds and G is methoxy-substituted pyridyl or pyrrolidinyl, then
R3, on each occurrence, is H.