Substituted oximes, hydrazones and olefins useful as neurokinin antagonists

A compound represented by the structural formula ##STR128## or a pharmaceutically acceptable salt thereof, wherein:

• a is 0, 1, 2 or 3;
• b and d are independently 0, 1 or 2;
• R is H, C.sub.1-6 alkyl, --OR.sup.6 or C.sub.2 -C.sub.6 hydroxyalkyl;
• A is .dbd.N--OR.sup.1, .dbd.N--N(R.sup.2)(R.sup.3), .dbd.C(R.sup.11)(R.sup.12) or .dbd.NR.sup.25 ;
• X is a bond, --C(O)--, --O--, --NR.sup.6 --, --S(O).sub.e --, --N(R.sup.6)C(O)--, --C(O)N(R.sup.6)-- --OC(O)NR.sup.6 --, --OC(.dbd.S)NR.sup.6 --, --N(R.sup.6)C(.dbd.S)O--, --C(.dbd.NOR.sup.1)--, --S(O).sub.2 N(R.sup.6)--, --N(R.sup.6)S(O).sub.2 --, --N(R.sup.6)C(O)O-- or --OC(O)--, provided that when d is 0, X is a bond, --C(O)--, --NR.sup.6 --, --C(O)N(R.sup.6)--, --N(R.sup.6)C(O)--, --OC(O)NR.sup.6 --, --C(.dbd.NOR.sup.1)--, --N(R.sup.6)C(.dbd.S)O--, --OC(.dbd.S)NR.sup.6 --, --N(R.sup.6)S(O).sub.2 -- or --N(R.sup.6)C(O)O--;
• provided that when A is .dbd.C(R.sup.11)(R.sup.12) and d is 0, X is not --NR.sup.6 -- or --N(R.sup.6)C(O)--;
• and provided that when A is .dbd.NR.sup.25, d is 0 and X is --NR.sup.6 -- or --N(R.sup.6)C(O)--;
• T is H, R.sup.4 -aryl, R.sup.4 -heterocycloalkyl, R.sup.4 -heteroaryl, phthalimidyl, R.sup.4 -cycloalkyl or R.sup.10 -bridged cycloalkyl;
• Q is R.sup.5 -heteroaryl;
• R.sup.1 is H, C.sub.1-6 alkyl, --(C(R.sup.6)(R.sup.7)).sub.n --G, --G.sup.2, --(C(R.sup.6)(R.sup.7)).sub.p --M-- (C(R.sup.13)(R.sup.14)).sub.n --(C(R.sup.8)(R.sup.9)).sub.u --G, --C(O)N(R.sup.6)--(C(R.sup.13)(R.sup.14)).sub.n --(C(R.sup.8)(R.sup.9)).sub.u --G or --(C(R.sup.6)(R.sup.7)).sub.p --M--(R.sup.4 -heteroaryl);
• R.sup.2 and R.sup.3 are independently selected from the group consisting of H, C.sub.1-6 alkyl, --CN, --(C(R.sup.6)(R.sup.7)).sub.n --G, --G.sup.2, --C(O)--(C(R.sup.8)(R.sup.9)).sub.n --G and --S(O).sub.e R.sup.13 ;
• or R.sup.2 and R.sup.3, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of --O--, --S-- and --N(R.sup.19)--;
• R.sup.4 and R.sup.5 are independently 1-3 substituents independently selected from the group consisting of H, halogeno, --OR.sup.6, --OC(O)R.sup.6, --OC(O)N(R.sup.6)(R.sup.7), --N(R.sup.6)(R.sup.7), C.sub.1-6 alkyl, --CF.sub.3, --C.sub.2 F.sub.5, --COR.sup.6, --CO.sub.2 R.sup.6, --CON(R.sup.6)(R.sup.7), --S(O).sub.e R.sup.13, --CN, --OCF.sub.3, --NR.sup.6 CO.sub.2 R.sup.16, --NR.sup.6 COR.sup.7, --NR.sup.8 CON(R.sup.6)(R.sup.7), R.sup.15 -phenyl, R.sup.15 -benzyl, NO.sub.2, --N(R.sup.6)S(O).sub.2 R.sup.13 or --S(O).sub.2 N(R.sup.6)(R.sup.7);
• or adjacent R.sup.4 substituents or adjacent R.sup.5 substituents can form a --O--CH.sub.2 --O-- group;
• and R.sup.4 can also be R.sup.15 -heteroaryl;
• R.sup.6, R.sup.7, R.sup.8, R.sup.6a, R.sup.7a, R.sup.8a, R.sup.13 and R.sup.14 are independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.2 -C.sub.6 hydroxyalkyl, C.sub.1 -C.sub.6 alkoxy-C.sub.1 -C.sub.6 alkyl, R.sup.15 -phenyl, and R.sup.15 -benzyl;
• or R.sup.6 and R.sup.7, together with the nitrogen to which they are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ring members are selected from the group consisting of --O--, --S-- and --N(R.sup.19)--;
• R.sup.9 and R.sup.9a are independently selected from the group consisting of R.sup.6 and --OR.sup.6
• R.sup.10 and R.sup.10a are independently selected from the group consisting of H and C.sub.1-6 alkyl;
• R.sup.11 and R.sup.12 are independently selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, --CO.sub.2 R.sup.6, --OR.sup.6, --C(O)N(R.sup.6)(R.sup.7), C.sub.1 -C.sub.6 hydroxyalkyl, --(CH.sub.2).sub.r --OC(O)R.sup.6, --(CH.sub.2).sub.r --OC(O)CH.dbd.CH.sub.2, --(CH.sub.2).sub.r --O(CH.sub.2).sub.s --CO.sub.2 R.sup.6, --(CH.sub.2).sub.r --O--(CH.sub.2).sub.s --C(O)N(R.sup.6)(R.sup.7) and --(CH.sub.2).sub.r --N(R.sup.6)(R.sup.7);
• R.sup.15 is 1 to 3 substituents independently selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkylthio, halogeno, --CF.sub.3, --C.sub.2 F.sub.5, --COR.sup.10, --CO.sub.2 R.sup.10, --C(O)N(R.sup.10).sub.2, --S(O).sub.e R.sup.10a, --CN, --N(R.sup.10)COR.sup.10, --N(R.sup.10)CON(R.sup.10).sub.2 and --NO.sub.2 ;
• R.sup.16 is C.sub.1-6 alkyl, R.sup.15 -phenyl or R.sup.15 -benzyl;
• R.sup.19 is H, C.sub.1 -C.sub.6 alkyl, --C(O)N(R.sup.10).sub.2, --CO.sub.2 R.sup.10, --(C(R.sup.8)(R.sup.9)).sub.f --CO.sub.2 R.sup.10 or --(C(R.sup.8)(R.sup.9)).sub.u --C(O)N(R.sup.10).sub.2 ;
• f, n, p, r and s are independently 1-6;
• u is 0-6;
• G is selected from the group consisting of H, R.sup.4 -aryl, R.sup.4 -heterocycloalkyl, R.sup.4 -heteroaryl, R.sup.4 -cycloalkyl, --OR.sup.6, --N(R.sup.6)(R.sup.7), --COR.sup.6, --CO.sub.2 R.sup.6, --CON(R.sup.7)(R.sup.9), --S(O).sub.e R.sup.13, --NR.sup.6 CO.sub.2 R.sup.16, --NR.sup.6 COR.sup.7, --NR.sup.8 CON(R.sup.6)(R.sup.7), --N(R.sup.6)S(O).sub.2 R.sup.13, --S(O).sub.2 N(R.sup.6)(R.sup.7), --OC(O)R.sup.6, --OC(O)N(R.sup.6)(R.sup.7), --C(.dbd.NOR.sup.8)N(R.sup.6)(R.sup.7), --C(.dbd.NR.sup.25)N(R.sup.6)(R.sup.7), --N(R.sup.8)C(.dbd.NR.sup.25)N(R.sup.6)(R.sup.7), --CN, --C(O)N(R.sup.6)OR.sup.7, and --C(O)N(R.sup.9)--(R.sup.4 -heteroaryl), provided that when n is 1 and u is 0, or when R.sup.9 is --OR.sup.6, G is not --OH or --N(R.sup.6)(R.sup.7);
• M is selected from the group consisting of a double bond, --O--, --N(R.sup.6)--, --C(O)--, --C(R.sup.6)(OR.sup.7)--, --C(R.sup.8)(N(R.sup.6)(R.sup.7))--, --C(.dbd.NOR.sup.6)N(R.sup.7)--, --C(N(R.sup.6)(R.sup.7)).dbd.NO--, --C(.dbd.NR.sup.25)N(R.sup.6)--, --C(O)N(R.sup.9)--, --N(R.sup.9)C(O)--, --C(.dbd.S)N(R.sup.9)--, --N(R.sup.9)C(.dbd.S)-- and --N(R.sup.6)C(O)N(R.sup.7)--, provided that when n is 1, G is not OH or --NH(R.sup.6);
• and when p is 2-6, M can also be --N(R.sup.6)C(.dbd.NR.sup.25)N(R.sup.7)-- or --OC(O)N(R.sup.6)--;
• G.sup.2 is R.sup.4 -aryl, R.sup.4 -heterocycloalkyl, R.sup.4 -heteroaryl, R.sup.4 -cycloalkyl, --COR.sup.6, --CO.sub.2 R.sup.16, --S(O).sub.2 N(R.sup.6)(R.sup.7) or --CON(R.sup.6)(R.sup.7);
• e is 0, 1 or 2, provided that when e is 1 or 2, R.sup.13 and R.sup.10a are not H;
• R.sup.25 is H, C.sub.1 -C.sub.6 alkyl, --CN, R.sup.15 -phenyl or R.sup.15 -benzyl;
• Z is ##STR129## or morpholinyl;
• g and j are independently 0-3;
• h and k are independently 1-4, provided the sum of h and g is 1-7;
• J is two hydrogen atoms, .dbd.O, .dbd.S, .dbd.NR.sup.9 or .dbd.NOR.sup.1 ;
• L and L.sup.1 are independently selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, --CH.sub.2 -cycloalkyl, R.sup.15 -benzyl, R.sup.15 -heteroaryl, --C(O)R.sup.6, --(CH.sub.2).sub.m --OR.sup.6, --(CH.sub.2).sub.m --N(R.sup.6)(R.sup.7), --(CH.sub.2).sub.m --C(O)--OR.sup.6 and --(CH.sub.2).sub.m --C(O)N(R.sup.6)(R.sup.7);
• m is 0 to 4, provided that when j is 0, m is 1-4;
• R.sup.26 and R.sup.27 are independently selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, R.sup.4 -aryl and R.sup.4 -heteroaryl;
• or R.sup.26 is H, C.sub.1 -C.sub.6 alkyl, R.sup.4 -aryl or R.sup.4 -heteroaryl, and R.sup.27 is --C(O)R.sup.6, --C(O)--N(R.sup.6)(R.sup.7), --C(O)(R.sup.4 -aryl), --C(O)(R.sup.4 -heteroaryl), --SO.sub.2 R.sup.13 or --SO.sub.2 --(R.sup.4 -aryl);
• R.sup.28 is H, --(C(R.sup.6)(R.sup.19)).sub.t --G, --(C(R.sup.6)(R.sup.7)).sub.v --G.sup.2 or --NO.sub.2 ;
• t and v are 0, 1, 2 or 3, provided that when j is 0, t is 1, 2 or 3;
• R.sup.29 is H, C.sub.1 -C.sub.6 alkyl, --C(R.sup.10).sub.2 S(O).sub.e R.sup.6, R.sup.4 -phenyl or R.sup.4 -heteroaryl;
• R.sup.30 is H, C.sub.1 -C.sub.6 alkyl, R.sup.4 -cycloalkyl, --(C(R.sup.10).sub.2).sub.w --(R.sup.4 -phenyl), --(C(R.sup.10).sub.2).sub.w --(R.sup.4 -heteroaryl), --C(O)R.sup.6, --C(O)OR.sup.6, --C(O)N(R.sup.6)(R.sup.7), ##STR130## w is 0, 1, 2, or 3;
• V is .dbd.O, .dbd.S or .dbd.NR.sup.6 ;
• and
• q is 0-4.