Patent EA-004885-B1 (EA)
Title: Nicotinamide benzofused heterocyclyl derivatives useful as selective inhibitors of pde4-isozymes
Inventor: MARFAT ANTHONY
IPC: C07D417/12
Filed: 2001-01-30
Abstract: 1. A compound of Formula (1.0.0): wherein m is 1; n is 1; R<A> and R<B> are -H, -CF3 or -(C1-C6) alkyl, substituted -F, -Cl, -CF3, -CN, -NH2 or -C((O)NH2 by 0 or 1, or both taken together are spiro -(C3-C6) cycloalkyl- substituted by 0 or 1 of -F, -Cl, -CF3, or -CN; one of R<C> and R<D> is -H, and the other is -H, -(C1-C4) alkyl, or phenyl, each substituted by 0 or 1 of -F, -Cl, or -CN; W is -O- or -S-; Y is = C(R<E>)-, where R<E> is -H, -F, Cl, -CN, -CH3, or -OCH3; R<1> and R<2> are -H, -F, -Cl, -CN, -NO2, -OH, -CH3, -OCH3, -OCHF2, or OCF3; R<3> is -H or -CH3; R<4> is -H, -F, -CN, -NO2, -OH, -CH3, or -OCH3; R<5> and R<6> are taken together to form a moiety of partial Formula (1.1.1), partial Formula (1.1.4), or partial Formula (1.1.5): where R<7> and R<8> are absent in each said partial Formula, or independently of each other are -H or -CH3; Q is phenyl, norbornanyl, furanyl, thienyl, pyrimidinyl, cyclohexenyl, or cyclohexyl, cyclopentyl, cycloheptenyl, cyclodecanyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, imidazolyl, norbornenyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.2]octanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]oct-5-enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo[3.3.1]nonanyl or adamantyl; and Z is -OR<12>, C(=O)R<12> or -CN, where R<12> is -H, -CH3, -CH2CH3, or -C(CH3)3; and a pharmaceutically acceptable salt thereof. 2. A compound according to Claim 2 wherein R<A> and R<B> are both -CH3, or one is -CH3 and the other is -CH(CH3)2 or -C(CH3)3, or one is -H and the other is CH3 or -CF3, or both taken together are spiro cyclopropyl or spiro cyclobutyl; one of R<C> and R<D> is -H and the other is -H or -CH3; Y is = C(R<E>)- where R<E> is -H, -F, or -Cl; R<1> and R<2> are -H, -F, or Cl; R<3> is -H; R<4> is -H; R<5> and R<6> are taken together to form a moiety of partial Formula (1.1.1) or partial Formula (1.1.4) where R<7> and R<8> are both absent; Q is phenyl, thienyl, cyclohexenyl, or cyclohexyl; and Z is -OR<12> where R<12> is -H, or Z is -C(=O)R<12> where R<12> is H or -CH3, or Z is -CN. 3. A compound according to Claim 2 wherein R<A> and R<B> are both -CH3, or both taken together are spiro cyclopropyl; R<5> and R<6> are taken together to form a moiety of partial Formula (1.1.1) where R<7> and R<8> are both absent; and Z is -OR<12> where R<12> is -H. 4. A compound according to Claim 3 wherein R<A> and R<B> are both -CH3; R<C> and R<D> are both -H; Y is = C(R<E>) where R<E> is -H; and one of R<1> and R<2> is -H and the other is -F. 5. A compound according to Claim 1 wherein Y is = C(R<E>)- where R<E> is -F; and R<1> and R<2> are both -H. 6. A compound according to Claim 5 wherein R<5> and R<6> are taken together to form a moiety of partial Formula (1.1.4), and further wherein R<A> and R<B> are both -CH3, or one is -H and the other is -CH3, or both together are spiro cyclopropyl; one of R<C> and R<D> is -H and the other is -H or -CH3; Y is = C(R<E>)- where R<E> is -H or -F; R<1> and R<2> are -H, -F, or Cl;R<3> is -H; R<4> is -H; R<7> and R<8> are both absent; Q is phenyl, norbornanyl, furanyl, thienyl, pyrimidinyl, or cyclohexyl; and Z is -OR<12> where R<12> is -H. 7. A compound according to Claim 1 wherein W is -O-; R<3> is -H; R<5> and R<6> are taken together to form a moiety of partial Formula (1.1.5) where R<7> is -H or -CH3; Q is phenyl, norbornanyl, furanyl, thienyl, pyrimidinyl, cyclohexenyl, or cyclohexyl; and Z is -OR<12>, where R<12> is -H, -CH3, -CH2CH3, or -C(CH3)3; or Z is -CN. 8. A compound according to Claim 1 wherein R<A> and R<B> are both -CH3, or one is -CH3 and the other is -CH(CH3)2 or -C(CH3)3, or one is -H and the other is CH3 or -CF3, or both taken together are spiro cyclopropyl or spiro cyclobutyl; one of R<C> and R<D> is -H and the other is -H or -CH3; Y is = C(R<E>)- where R<E> is -H, -F, or -Cl; R<1> and R<2> are -H, -F, or Cl; R<3> is -H; R<4> is -H; Q is phenyl, thienyl, cyclohexenyl, or cyclohexyl; and Z is -OR<12> where R<12> is -H, or Z is -C(=O)R<12> where R<12> is -H or -CH3, or Z is -CN. 9. A compound according to Claim 1 wherein said compound is a member selected from the group consisting of the following: 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[4-[1-hydroxy-1-methyl-ethyl]-benzyl]-nicotinamide of Formula (5.5.1); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[2-fluoro-4-[1-hydroxy-1-methyl-ethyl]-benzyl]-nicotinamide of Formula (5.5.2); Trans-2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[4-[1-hydroxy-1-methyl-ethyl]-cyclohexyl-methyl]-nicotinamide of Formula (5.5.3); 2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-[4-(1-hydroxy-cyclobutyl)-benzyl]-nicotinamide of Formula (5.5.4); (+-)-2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[4-[2,2,2-trifluoro-1-hydroxy-ethyl]-benzyl]-nicotinamide of Formula (5.5.5); (+-)-2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[5-[1-hydroxy-ethyl]-thiophen-2-yl-methyl]-nicotinamide of Formula (5.5.6); N-[4-Acetyl-benzyl]-2-[benzo[2,1,3]oxadi-azol-5-yl-oxy]-nicotinamide of Formula (5.5.7); (+-)-2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-{1-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl}-nicotinamide of Formula (5.5.8); 2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-[2-chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-nicotinamide of Formula (5.5.9); (+-)-2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-[4-(1-hydroxy-ethyl)-benzyl]-nicotinamide of Formula (5.5.10); (-)-2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-{1-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl}-nicotinamide of Formula (5.5.11); (+)-2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-{1-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl}-nicotinamide of Formula (5.5.12); (+)-2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohex-1-enylmethyl]-nicotinamide of Formula (5.5.13); (-)-2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohex-1-enylmethyl]-nicotinamide of Formula (5.5.14); 2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-[4-(1-hydroxy-cyclopropyl)-benzyl]-nicotinamide of Formula (5.5.15); 2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-[2-fluoro-4-(1-hydroxy-cyclopropyl)-benzyl]-nicotinamide of Formula (5.5.16); (+-)-2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-{1-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl}-nicotinamide of Formula (5.5.17); (+-)-2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-[4-(1-hydroxy-1,2,2-trimethyl-propyl)-benzyl]-nicotinamide of Formula (5.5.18); (+-)-2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-[4-(1-hydroxy-1,2-dimethyl-propyl)-benzyl]-nicotinamide of Formula (5.5.19); 2-(Benzo[2,1,3]oxadiazol-5-yl-oxy)-N-[4-(1-cyano-1-methyl-ethyl)-benzyl]-nicotinamide of Formula (5.5.20); 2-[Benzo[2,1,3]thiadiazol-5-yl-oxy]-N-[4-[1-hydroxy-1-methyl-ethyl]-benzyl]-nicotinamide of Formula (5.5.21); 2-[Benzo[2,1,3]thiadiazol-5-yl-oxy]-N-[2-fluoro-4-[1-hydroxy-1-methyl-ethyl]-benzyl]-nicotinamide of Formula (5.5.22); 2-(Benzo[2,1,3]thiadiazol-5-yl-oxy)-N-[4-(1-hydroxy-cyclobutyl)-benzyl]-nicotinamide of Formula (5.5.23); (+)-2-(Benzo[2,1,3]thiadiazol-5-yl-oxy)-N-{1-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl}-nicotinamide of Formula (5.5.24); (+)-2-(Benzo[2,1,3]thiadiazol-5-yl-oxy)-N-[4-(1-hydroxy-1-methyl-ethyl)-cyclohex-1-enylmethyl]-nicotinamide of Formula (5.5.25); 2-(Benzo[2,1,3]thiadiazol-5-yl-oxy)-N-[2-fluoro-4-(1-hydroxy-cyclopropyl)-benzyl]-nicotinamide of Formula (5.5.26); (+-)-2-(Benzo[2,1,3]thiadiazol-5-yl-oxy)-N-[4-(1-hydroxy-1,2,2-trimethyl-propyl)-benzyl]-nicotinamide of Formula (5.5.27); 2-[2-Methyl-benzo[1,2,3]triazol-5-yl-oxy]-N-[2-fluoro-4-[1-hydroxy-1-methyl-ethyl]-benzyl]-nicotinamide of Formula (5.5.28); (+-)-2-(2-Methyl-benzo[1,2,3]triazol-5-yl-oxy]-N-[4-[2,2,2-trifluoro-1-hydroxy-ethyl]-benzyl]-nicotinamide of Formula (5.5.29); (-)-2-(2-Methyl-benzo[1,2,3]triazol-5-yl-oxy)-N-{1-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl}-nicotinamide of Formula (5.5.30); 2-(2-Methyl-benzo[1,2,3]triazol-5-yl-oxy)-N-[4-(1-cyano-1-methyl-ethyl)-benzyl]-nicotinamide of Formula (5.5.31); 2-(2-Methyl-benzo[1,2,3]triazol-5-yl-oxy)-N-[2-fluoro-4-(1-hydroxy-cyclopropyl)-benzyl]-nicotinamide of Formula (5.5.32); Trans-2-[2-Methyl-benzo[1,2,3)triazol-5-yl-oxy]-N-[4-[1-hydroxy-1-methyl-ethyl]-cyclohexyl-methyl]-nicotinamide of Formula (5.5.33); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[4-[1-hydroxy-1-methyl-ethyl]-cyclopent-1-enyl-methyl]-nicotinamide of Formula (5.5.34); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[3-[1-hydroxy-1-methyl-ethyl]-norbornan-6-yl-methyl]-nicotinamide of Formula (5.5.35); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[3-[1-hydroxy-1-methyl-ethyl]-norbornan-6-yl-methyl]-nicotinamide; 2-(Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[3-[1-hydroxy-1-methyl-ethyl]-7-fluoro-norborn-5-en-6-yl-methyl]-nicotinamide of Formula (5.5.36); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[2-[2,2,2-trifluoro-1-hydroxy-ethyl]-bicyclo[2.2.2.]octan-5-yl-methyl]-nicotinamide of Formula (5.5.37); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[3-acetyl-bicyclo[2.2.2]oct-7-en -5-yl-methyl]-nicotinamide of Formula (5.5.38); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[8-(1-hydroxy-1-methyl-ethyl)-bicyclo[3.2.1 ]octan-3-yl-methyl]-nicotinamide of Formula (5.5.39); (+-)-2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[5-[1-hydroxy-ethyl]-furan-2-yl-methyl]-nicotinamide of Formula (5.5.40); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[5-[1-hydroxy-1-methyl-ethyl]-pyridin-2-yl-methyl]-nicotinamide of Formula (5.5.41); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[5-[1-hydroxy-1-methyl-ethyl]-oxazol-2-yl-methyl]-nicotinamide of Formula (5.5.42); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[5-[1-hydroxy-1-methyl-ethyl]-thiazol-2-yl-methyl]-nicotinamide of Formula (5.5.43); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[6-[1-hydroxy-1-methyl-ethyl]-pyridin-3-yl-methyl]-nicotinamide of Formula (5.5.44); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[5-(1-hydroxy-cyclopropyl)-pyridin-2-yl-methyl]-nicotinamide of Formula (5.5.45); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-(5-(1-hydroxy-1,2-dimethyl-propyl)-oxazol-2-yl-methyl]-nicotinamide of Formula (5.5.46); 2-[Benzo[2,1,3]oxadiazol-5-yl-oxy]-N-[5-(1-cyano-1-methyl-ethyl)-thiazol-2-yl-methyl]-nicotinamide of Formula (5.5.47); 2-[Benzo[2,1,3]oxadiazol-5-yl-thio]-N-[2-fluoro-4-[1-hydroxy-1-methyl-ethyl]-benzyl]-nicotinamide of Formula (5.5.48); 2-[Benz