Patent ID: 6110932
Filing Date: 2000-08-29
Classification: A61K,A61P,C07D,C07K

Abstract:
A compound of the formula ##STR51## the racemic-diastereomeric mixtures and optical isomer of said compounds and the pharmaceutically-acceptable salts and prodrugs thereof,whereine is 0;n is 0 and w is 2, or n is 1 and w is 1, or n is 2 and w is 0;Y is oxygen or sulfur;R.sup.1 is hydrogen, --CH, --(CH.sub.2).sub.q N(X.sup.6)C(O)X.sup.6, --(CH.sub.2).sub.q N(X.sup.6)C(O)(CH.sub.2).sub.t --A.sup.1, --(CH.sub.2).sub.q N(X.sup.6)SO.sub.2 (CH.sub.2).sub.t --A.sup.1, --(CH.sub.2).sub.q N(X.sup.6)SO.sub.2 X.sup.6, --(CH.sub.2).sub.q N(X.sup.6)C(O)N(X.sup.6)(CH.sub.2).sub.t --A.sup.1, --(CH.sub.2).sub.q N(X.sup.6)C(O)N(X.sup.6)(X.sup.6), --(CH.sub.2).sub.q C(O)N(X.sup.6)(X.sup.6), --(CH.sub.2).sub.q C(O)N(X.sup.6)(CH.sub.2).sub.t --A.sup.1, --(CH.sub.2).sub.q C(O)OX.sup.6, --(CH.sub.2).sub.q C(O)O(CH.sub.2).sub.t --A.sup.1, --(CH.sub.2).sub.q OX.sup.6, --(CH.sub.2).sub.q OC(O)X.sup.6, --(CH.sub.2).sub.q OC(O)(CH.sub.2).sub.t --A.sup.1, --(CH.sub.2).sub.q OC(O)N(X.sup.6)(CH.sub.2).sub.t --A.sup.t, --(CH.sub.2).sub.q OC(O)N(X.sup.6)(X.sup.6), --(CH.sub.2).sub.q C(O)X.sup.6, --(CH.sub.2).sub.q C(O)(CH.sub.2).sub.t --A.sup.1, --(CH.sub.2).sub.q N(X.sup.6)C(O)OX.sup.6, --(CH.sub.2).sub.q N(X.sup.6)SO.sub.2 N(X.sup.6)(X.sup.6), --(CH.sub.2).sub.q S(O).sub.m X.sup.6, --(CH.sub.2).sub.q S(O).sub.m (CH.sub.2).sub.t --A.sup.1, --(C.sub.1 -C.sub.10)alkyl, --(CH.sub.2).sub.t --A.sup.1, --(CH.sub.2).sub.q --(C.sub.3 -C.sub.7)cycloalkyl, --(CH.sub.2).sub.q --Y.sup.1 --(C.sub.1 -C.sub.6)alkyl, --(CH.sub.2).sub.q --Y.sup.1 --(CH.sub.2).sub.t --A.sup.1 or --(CH.sub.2).sub.q --Y.sup.1 --(CH.sub.2).sub.t --(C.sub.3 -C.sub.7)cycloalkyl;where the alkyl and cycloalkyl groups in the definition of R.sup.1 are optionally substituted with (C.sub.1 -C.sub.4)alkyl, hydroxyl, (C.sub.1 -C.sub.4)alkoxy, carboxy, --CONH.sub.2, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --CO.sub.2 (C.sub.1 -C.sub.4)alkyl, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y.sup.1 is O, S(O).sub.m, --C(O)NX.sup.6 --, --CH.dbd.CH--, --C.tbd.C--, --N(X.sup.6)C(O)--, --C(O)NX.sup.6 --, --C(O)O--, --OC(O)N(X.sup.6)-- or --OC(O)--;q is 0, 1, 2, 3 or 4;t is 0, 1, 2, or 3;said (CH.sub.2).sub.q group and (CH.sub.2).sub.t group may each be optionally substituted with hydroxyl, (C.sub.1 -C.sub.4)alkoxy, carboxyl, --CONH.sub.2, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --CO.sub.2 (C.sub.1 -C.sub.4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C.sub.1 -C.sub.4)alkyl;R.sup.2 is hydrogen, (C.sub.1 -C.sub.8)alkyl, --(C.sub.0 -C.sub.3)alkyl-C.sub.3 -C.sub.8)cycloalkyl, --(C.sub.1 -C.sub.4)alkyl-A.sup.1 or A.sup.1 ;where the alkyl groups and the cycloalkyl groups in the definition of R.sup.2 are optionally substituted by hydroxyl, --C(O)OX.sup.6, --C(O)N(X.sup.6)(X.sup.6), --N(X.sup.6)(X.sup.6), --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --C(O)A.sup.1, --C(O)(X.sup.6), CF.sub.3, CN or 1, 2 or 3 halogen;R.sup.3 is A.sup.1, (C.sub.1 -C.sub.10)alkyl, --(C.sub.1 -C.sub.6)alkyl-A.sup.1, --(C.sub.1 -C.sub.6)alkyl-(C.sub.3 -C.sub.7)cycloalkyl, --(C.sub.1 -C.sub.5)alkyl-X.sup.1 --(C.sub.1 -C.sub.5)alkyl, --(C.sub.1 -C.sub.5)alkyl-X.sup.1 -(C.sub.0 -C.sub.5)alkyl-A.sup.1 or --(C.sub.1 -C.sub.5)alkyl-X.sup.1 --(C.sub.1 -C.sub.5)alkyl-(C.sub.3 -C.sub.7)cycloalkyl;where the alkyl groups in the definition of R.sup.3 are optionally substituted with, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --C(O)OX.sup.3, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3 OX.sup.3 ; X.sup.1 is O, S(O).sub.m, --N(X.sup.2)C(O)--, --C(O)N(X.sup.2)--, --OC(O), --C(O)O--, --CX.sup.2 .dbd.CX.sup.2 --, --N(X.sup.2)C(O)O--, --OC(O)N(X.sup.2)-- or --C.tbd.C--;R.sup.4 is hydrogen, (C.sub.1 -C.sub.6)alkyl or (C.sub.3 -C.sub.7)cycloalkyl;X.sup.4 is hydrogen or (C.sub.1 -C.sub.6)alkyl or X.sup.4 is taken together with R.sup.4 and the nitrogen atom to which X.sup.4 is attached and the carbon atom to which R.sup.4 is attached and form a five to seven membered ring; ##STR52## where a and b are independently 0, 1, 2 or 3; X.sup.5 and X.sup.5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A.sup.1 and optionally substituted (C.sub.1 -C.sub.6)alkyl;the optionally substituted (C.sub.1 -C.sub.6)alkyl in the definition of X.sup.5 and X.sup.5a is optionally substituted with a substituent selected from the group consisting of A.sup.1, OX.sup.2, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --C(O)OX.sup.2, (C.sub.3 -C.sub.7)cycloalkyl, --N(X.sup.2)(X.sup.2) and --C(O)N(X.sup.2)(X.sup.2);Z.sup.1 is a bond, O or N--X.sup.2, provided that when a and b are both 0 then Z.sup.1 is not N--X.sup.2 or O;R.sup.7 and R.sup.8 are independently hydrogen or optionally substituted (C.sub.1 -C.sub.6)alkyl;where the optionally substituted (C.sub.1 -C.sub.6)alkyl in the definition of R.sup.7 and R.sup.8 is optionally independently substituted with A.sup.1, --C(O)O--(C.sub.1 -C.sub.6)alkyl, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 --O--C(O)(C.sub.1 -C.sub.10)alkyl or 1 to 3 (C.sub.1 -C.sub.6)alkoxy; orR.sup.7 and R.sup.8 can be taken together to form --(CH.sub.2).sub.r --L--(CH.sub.2).sub.r --;where L is C(X.sup.2)(X.sup.2), S(O).sub.m or N(X.sup.2);A.sup.1 in the definition of R.sup.1 is a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- to 6-membered ring, having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- to 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;A.sup.1 in the definition of R.sup.2, R.sup.3, R.sup.6, R.sup.7 and R.sup.8 is independently (C.sub.5 -C.sub.7)cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- to 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- to 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;A.sup.1 for each occurrence is independently optionally substituted, in one or optionally both rings if A.sup.1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF.sub.3, OCF.sub.2 H, CF.sub.3, CH.sub.3, OCH.sub.3, --OX.sup.6, --C(O)N(X.sup.6)(X.sup.6), --C(O)OX.sup.6, oxo, (C.sub.1 -C.sub.6)alkyl, nitro, cyano, benzyl, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, --N(X.sup.6)(X.sup.6), --N(X.sup.6)C(O)(X.sup.6), --SO.sub.2 N(X.sup.6)(X.sup.6), --N(X.sup.6)SO.sub.2 -phenyl, --N(X.sup.6)SO.sub.2 X.sup.6, --CONX.sup.11 X.sup.12, --SO.sub.2 NX.sup.11 X.sup.12, --NX.sup.6 SO.sub.2 X.sup.12, --NX.sup.6 CONX.sup.11 X.sup.12, --NX.sup.6 SO.sub.2 NX.sup.11 X.sup.12, --NX.sup.6 C(O)X.sup.12, imidazolyl, thiazolyl and tetrazolyl, provided that if A.sup.1 is optionally substituted with methylenedioxy then it can only be substituted by one methylenedioxy;where X.sup.11 is hydrogen or optionally substituted (C.sub.1 -C.sub.6)alkyl;the optionally substituted (C.sub.1 -C.sub.6)alkyl defined for X.sup.11 is optionally independently substituted with phenyl, phenoxy, (C.sub.1 -C.sub.6)alkoxycarbonyl, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 (C.sub.1 -C.sub.10)alkanoyloxy or 1 to 3 (C.sub.1 -C.sub.6)alkoxy;X.sup.12 is hydrogen, (C.sub.1 -C.sub.6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X.sup.12 is not hydrogen, X.sup.12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH.sub.3, OCH.sub.3, OCF.sub.3 and CF.sub.3 ;or X.sup.11 and X.sup.12 are taken together to form --(CH.sub.2).sub.r --L.sup.1 --(CH.sub.2).sub.r --;where L.sup.1 is C(X.sup.2)(X.sup.2), O, S(O).sub.m or N(X.sup.2);r for each occurrence is independently 1, 2 or 3;X.sup.2 for each occurrence is independently hydrogen, optionally substituted (C.sub.1 -C.sub.6)alkyl, or optionally substituted (C.sub.3 -C.sub.7)cycloalkyl, where the optionally substituted (C.sub.1 -C.sub.6)alkyl and optionally substituted (C.sub.3 -C.sub.7)cycloalkyl in the definition of X.sup.2 are optionally independently substituted with --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --C(O)OX.sup.3, 1 to 5 halogens or 1-3 OX.sup.3 ;X.sup.3 for each occurrence is independently hydrogen or (C.sub.1 -C.sub.6)alkyl;X.sup.6 is independently hydrogen, optionally substituted (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6 halogenated alkyl, optionally substituted (C.sub.3 -C.sub.7)cycloalkyl, (C.sub.3 -C.sub.7)-halogenatedcycloalkyl, where optionally substituted (C.sub.1 -C.sub.6)alkyl and optionally substituted (C.sub.3 -C.sub.7)cycloalkyl in the definition of X.sup.6 is optionally independently substituted by 1 or 2 (C.sub.1 -C.sub.4)alkyl, hydroxyl, (C.sub.1 -C.sub.4)alkoxy, carboxyl, CONH.sub.2, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, carboxylate (C.sub.1 -C.sub.4)alkyl ester, or 1H-tetrazol-5-yl; or when there are two X.sup.6 groups on one atom and both X.sup.6 are independently (C.sub.1 -C.sub.6)alkyl, the two C.sub.1 -C.sub.6)alkyl groups may be optionally joined and, together with the atom to which the two X.sup.6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX.sup.8 ;X.sup.7 is hydrogen or (C.sub.1 -C.sub.6)alkyl optionally substituted with hydroxyl; andm for each occurrence is independently 0, 1 or 2;with the proviso that:X.sup.6 and X.sup.12 cannot be hydrogen when it is attached to C(O) or SO.sub.2 in the form C(O)X.sup.6, C(O)X.sup.12, SO.sub.2 X.sup.6 or SO.sub.2 X.sup.12, andwhen R.sup.6 is a bond then L is N(X.sup.2) and each r in the definition --(CH.sub.2).sub.r --L--(CH.sub.2).sub.r -- is independently 2 or 3.