Substituted imidazoles having cytokine inhibitory activity

A compound represented by formula I:

• ##STR67## or a pharmaceutically acceptable salt thereof, wherein:
• X and X' each independently represent --(CH.sub.2).sub.m --Y--(CH.sub.2).sub.n --, wherein m and n represent integers within the range of from 0-4, such that the sum of m and n is from 0-6;
• Y represents a member selected from the group consisting of:
• a direct bond;
• O;
• S(O).sub.y, with y equal to 0, 1 or 2;
• NR.sup.q', with R.sup.q' as defined below;
• C(O);
• OC(O);
• C(O)O;
• SO.sub.x NR.sup.q' with x equal to 1 or 2 and R.sup.q' as defined below;
• NR.sup.q' SO.sub.x ;
• C(O)NR.sup.q' and NR.sup.q' C(O);
• ##STR68## represents a 4 to 10 membered non-aromatic heterocycle containing at least one N atom, and optionally containing 1-2 additional N atoms and 0-1 O or S atom;
• R.sup.x represents H, C.sub.1-6 alkyl(R.sup.q).sub.3, C.sub.3-8 cycloalkyl, OC.sub.1-6 alkyl(R.sup.q).sub.3 or C(O)C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• each R independently represents a member selected from the group consisting of:
• halo;
• hydroxy;
• C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• OC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• C.sub.3-8 cycloalkyl(R.sup.q).sub.3 ;
• CN;
• CONH.sub.2 ;
• CONHC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• CON(C.sub.1-6 alkyl(R.sup.q).sub.3).sub.2 ;
• NH.sub.2 ;
• NHC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• NHC.sub.3-8 cycloalkyl;
• N(C.sub.1-6 alkyl(R.sup.q).sub.3).sub.2 ;
• CON(C.sub.3-8 cycloalkyl)(C.sub.1-6 alkyl(R.sup.q).sub.3));
• CO.sub.2 H;
• CO.sub.2 C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• C(O)C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• aryl(R.sup.q).sub.3 ;
• heterocyclyl(R.sup.q).sub.3 ;
• heteroaryl(R.sup.q).sub.3 ;
• CF.sub.3 ;
• SH;
• NO.sub.2 ;
• NHSO.sub.2 C.sub.1-6 alkyl(R.sup.q).sub.3, NHSO.sub.2 aryl(R.sup.q).sub.3, NHSO.sub.2 heteroaryl(R.sup.q).sub.3 ;
• N(R.sup.q')C(O)C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• NR.sup.q' C(O)NH(C.sub.1-6 alkyl(R.sup.q).sub.3);
• C.sub.2-4 alkenyl(R.sup.q).sub.2-3 and C.sub.2-4 alkynyl(R.sup.q).sub.1-3 ;
• each R" independently represents a member selected from the group consisting of:
• halo;
• hydroxy;
• C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• OC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• C.sub.3-8 cycloalkyl(R.sup.q).sub.3 ;
• CN;
• CONH.sub.2 ;
• CONHC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• CON(C.sub.1-6 alkyl(R.sup.q).sub.3).sub.2 ;
• NH.sub.2 ;
• NHC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• NHC.sub.3-8 cycloalkyl;
• N(C.sub.1-6 alkyl(R.sup.q).sub.3).sub.2 ;
• CON(C.sub.3-8 cycloalkyl)(C.sub.1-6 alkyl(R.sup.q).sub.3));
• CO.sub.2 H;
• CO.sub.2 C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• C(O)C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• aryl(R.sup.q).sub.3 ;
• heterocyclyl(R.sup.q).sub.3 ;
• heteroaryl(R.sup.q).sub.3 ;
• CF.sub.3 ;
• SH;
• NO.sub.2 ;
• SO.sub.y C.sub.1-6 alkyl(R.sup.q).sub.3, with y as defined above;
• SO.sub.2 NH.sub.2 ;
• SO.sub.2 NHC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• SO.sub.2 N(C.sub.1-6 alkyl(R.sup.q).sub.3).sub.2 ;
• NHSO.sub.2 C.sub.1-6 alkyl(R.sup.q).sub.3, NHSO.sub.2 aryl(R.sup.q).sub.3, NHSO.sub.2 heteroaryl(R.sup.q).sub.3 ;
• N(R.sup.q')C(O)C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• NR.sup.q' C(O)NH(C.sub.1-6 alkyl(R.sup.q).sub.3);
• C.sub.2-4 alkenyl(R.sup.q).sub.2-3 and C.sub.2-4 alkynyl(R.sup.q).sub.1-3 ;
• each R' independently represents a member selected from the group consisting of:
• CONH.sub.2 ;
• CONHC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• CON(C.sub.1-6 alkyl(R.sup.q).sub.3).sub.2 ;
• CONHC.sub.3-8 cycloalkyl(R.sup.q).sub.3 ;
• CON(C.sub.3-8 cycloalkyl(R.sup.q).sub.3).sub.2 ;
• CON(C.sub.3-8 cycloalkyl)(C.sub.1-6 alkyl(R.sup.q).sub.3));
• CO.sub.2 H;
• CO.sub.2 C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• C(O)C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• CO.sub.2 C.sub.3-8 cycloalkyl(R.sup.q).sub.3 ;
• C(O)C.sub.3-8 cycloalkyl(R.sup.q).sub.3 ;
• --›C(O)(CH.sub.2).sub.j --CR.sup.5 R.sup.6 --(CH.sub.2).sub.k --NR.sup.7 !.sub.p --R.sup.8 ;
• --C(O)C.sub.3-8 cycloalkyl(R.sup.q).sub.3 ;
• --C(O)heterocyclyl(R.sup.q).sub.3, --CON›C.sub.1-6 alkyl(R.sup.q).sub.3 !›C.sub.3-8 cycloalkyl(R.sup.q).sub.3 !;
• --C(O)aryl(R.sup.q).sub.3 ;
• --C(O)heteroaryl(R.sup.q).sub.3 ;
• hydroxy;
• C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• C.sub.3-8 cycloalkyl(R.sup.q).sub.3 ;
• OC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• OC.sub.3-8 cycloalkyl(R.sup.q).sub.3 ;
• heterocyclyl(R.sup.q).sub.3 ;
• CN;
• NH(R.sup.q");
• NHC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• N(C.sub.1-6 alkyl(R.sup.q).sub.3).sub.2 ;
• NHC.sub.3-8 cycloalkyl(R.sup.q).sub.3 ;
• N(C.sub.3-8 cycloalkyl(R.sup.q).sub.3).sub.2 ;
• CF.sub.3 ;
• SH;
• NO.sub.2 ;
• C.sub.2-4 alkenyl(R.sup.q).sub.2-3, aryl(R.sup.q).sub.3 ;
• heteroaryl(R.sup.q).sub.3 ;
• C.sub.2-4 alkynyl(R.sup.q).sub.1-3 ;
• --OC(O) C.sub.3-8 cycloalkyl(R.sup.q).sub.3 ;
• SO.sub.2 NH.sub.2 ;
• SO.sub.2 NHC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• SO.sub.2 N(C.sub.1-6 alkyl(R.sup.q).sub.3).sub.2 ;
• NHSO.sub.2 C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• NHSO.sub.2 aryl(R.sup.q).sub.3 ;
• NHSO.sub.2 heteroary(R.sup.q).sub.3 ;
• --OC(O)heterocyclyl(R.sup.q).sub.3 ;
• N(R.sup.q')C(O)C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• NR.sup.q' C(O)NH(C.sub.1-6 alkyl(R.sup.q).sub.3);
• --OC(O)C.sub.1-6 alkyl(R.sup.q).sub.3 ;
• --OC(O)aryl(R.sup.q).sub.3 ;
• --OC(O)heteroaryl(R.sup.q).sub.3 ;
• --C(.dbd.NR.sup.q')NH.sub.2 ;
• --C(.dbd.N.sup.q')NHC.sub.1-6 alkyl(R.sup.q).sub.3 ;
• --C(.dbd.N.sup.q')N(C.sub.1-6 alkyl(R.sup.q).sub.3).sub.2 ;
• ##STR69## wherein j and k independently represent integers of from 0-3;
• R.sup.5 and R.sup.6 are independently H, aryl, C.sub.1-6 alkyl(R.sup.q).sub.3, or CR.sup.5 R.sup.6 in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group;
• p represents 1, 2 or 3, with the proviso that when p represents 1, CR.sup.5 R.sup.6 represents a 3, 4, 5 or 6 membered cycloalkyl group or a heterocyclyl group, an aryl group or a heteroaryl group, and at least one of j and k is 1, 2 or 3;
• R.sup.7 and R.sup.8 are independently H, C.sub.1-6 alkyl or aryl;
• R.sup.9 represents H, a negative charge balanced by a positively charged group or a protecting group;
• R.sup.q represents a member selected from the group consisting of:
• R.sup.q' ;
• halo;
• CN;
• CO.sub.2 H;
• CO.sub.2 C.sub.1-4 alkyl;
• C(O)C.sub.1-4 alkyl;
• NH(R.sup.q");
• aryl(R.sup.a).sub.3 ;
• heteroaryl(R.sup.a).sub.3 ;
• NHC.sub.1-4 alkyl;
• N(C.sub.1-4 alkyl).sub.2 ;
• CONH.sub.2 ;
• SH;
• S(O).sub.y C.sub.1-6 alkyl(R.sup.a).sub.3 ;
• C(O)NHC.sub.1-6 alkyl(R.sup.a).sub.3 ;
• C(O)N(C.sub.1-6 alkyl(R.sup.a).sub.3).sub.2 ;
• C.sub.3-8 cycloalkyl;
• NHC(NH)NH.sub.2 ;
• -heteroalkyl(R.sup.a).sub.3 ;
• --NHC(O)NH.sub.2 ;
• ##STR70## wherein ##STR71## independently represent mono or bicyclic ring systems, non-aromatic or partially aromatic, containing from 5-10 ring atoms, 1-4 of which are N and 0-1 of which are O or S(O).sub.y, with y equal to 0, 1 or 2, optionally containing 1-2 carbonyl groups;
• each R.sup.a independently represents a member selected from the group consisting of:
• H, C.sub.1-6 alkyl, OC.sub.1-6 alkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, aralkoxy, substituted aralkoxy, halo, hydroxy, CN, CONH.sub.2, CONHC.sub.1-6 alkyl, CON(C.sub.1-6 alkyl).sub.2, CO.sub.2 H, CO.sub.2 C.sub.1-6 alkyl, C(O)C.sub.1-6 alkyl, phenyl, CF.sub.3, SH, NO.sub.2, SO.sub.y C.sub.1-6 alkyl, with y as defined above;
• SO.sub.2 NH.sub.2, SO.sub.2 NHC.sub.1-6 alkyl, NHSO.sub.2 (substituted aryl), NHSO.sub.2 (substituted heteroaryl), NHSO.sub.2 C.sub.1-6 alkyl, NHSO.sub.2 aryl, NHSO.sub.2 heteroaryl, NH.sub.2, NHC.sub.1-6 alkyl, N(C.sub.1-6 alkyl).sub.2, NHC(O)C.sub.1-6 alkyl, NHC(O)NH(C.sub.1-6 alkyl), C.sub.2-4 alkenyl and C.sub.2-4 alkynyl;
• R.sup.q' represents H, OH, C.sub.1-4 alkyl, --OC.sub.1-4 alkyl, aryl or C(O)C.sub.1-4 alkyl, and
• R.sup.q" represents H, OH or OC.sub.1-4 alkyl.