Patent ID: 6011158
Filing Date: 2000-01-04
Classification: A61K,C07D,C07K

Abstract:
A compound of formula: ##STR228## wherein (a) X is selected from the group consisting of --S(O).sub.2 --, --N(R')--S(O).sub.2 --, --(C.dbd.O)--, --OC(.dbd.O)--, --NH--C(.dbd.O)--, --P(O) (R"")-- and a direct link, wherein R' is hydrogen, alkyl of 1 to about 4 carbon atoms, aryl of about 6 to about 14 carbon atoms or aralkyl of about 6 to about 16 carbon atoms, and R"" is NR', OR', R', or SR', with the proviso that R"" is not NH, OH, H, or SH, and;(b) R.sub.1 is selected from the group consisting of:(1) alkyl of 1 to about 12 carbon atoms,(2) alkyl of 1 to about 3 carbon atoms substituted with cyclic alkyl of about 3 to about 8 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbons,(3) cyclic alkyl of 3 to about 15 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbons,(4) heterocycloalkyl of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, and which is optionally substituted on the ring carbons with hydroxyl, alkoxyl or alkyl of 1 to about 3 carbons, amino, guanidino, or amidino,(5) heterocyclo of 4 to about 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O)i, wherein i is 0, 1 or 2, and including ##STR229## wherein ##STR230## is a 5 to 7 member heterocycle of 3 to 6 ring carbon atoms, where V is --CH.sub.2 --, --O--, --S(.dbd.O)--, --S(O).sub.2 -- or --S--,optionally substituted on the ring carbons with hydroxyl, alkoxyl or alkyl each of 1 to about 3 carbons, amino, guanidino, or amidino,(6) alkenyl of 2 to about 6 carbon atoms which is optionally substituted with cyclic alkyl of about 3 to about 8 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, or alkoxyl or alkyl each of 1 to about 3 carbons,(7) aryl of about 6 to about 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3,(8) heteroaryl of 5 to 14 atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, and which is optionally mono-, di- or tri-substituted with Y.sub.1, Y.sub.2, and/or Y.sub.3,(9) aralkyl of about 7 to about 15 carbon atoms which is optionally substituted on the alkyl chain with hydroxy or halogen and optionally mono-, di-, or tri-substituted on the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3,(10) heteroaralkyl of 6 to 11 atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, and which is optionally substituted on the alkyl chain with hydroxy or halogen and optionally mono-, di- or tri-substituted on the ring with Y.sub.1, Y.sub.2, and/or Y.sub.3,(11) aralkenyl of about 8 to about 16 carbon atoms which is optionally mono-, di-, or tri-substituted on the aryl ring with Y.sub.1, Y.sub.2, and/or Y.sub.3,(12) heteroaralkenyl of 7 to 12 atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and S(O).sub.i, wherein i is 0, 1 or 2, and which is optionally mono-, di- or tri-substituted on the ring with Y.sub.1, Y.sub.2, and/or Y.sub.3, ##STR231## (17) difluoromethyl and perfluoroalkyl of 1 to about 12 carbon atoms, (18) perfluoroaryl of about 6 to about 14 carbon atoms,(19) perfluoroaralkyl of about 7 to about 15 carbon atoms, and(20) hydrogen,wherein Y.sub.1, Y.sub.2, and Y.sub.3 are(i) independently selected from the group consisting of hydrogen, halogen, cyano, tetrazolyl, amino, guanidino, amidino, methylamino, and methylguanidino, --CF.sub.3, --CF.sub.2 H, --CF.sub.2 CF.sub.3, --CH(CF.sub.3).sub.2, --C(OH)(CF.sub.3).sub.2, --OCF.sub.3, OCF.sub.2 CF.sub.3, --OC(O)NH.sub.2, --OC(O)NHZ.sub.1, --OC(O)NZ.sub.1 Z.sub.2, --NHC(O)Z.sub.1, --NHC(O)NH.sub.2, --NHC(O)NZ.sub.1, --NHC(O)NZ.sub.1 Z.sub.2, --C(O)OH, --C(O)NH.sub.2, --C(O)NHZ.sub.1, --C(O)OZ.sub.1, --P(O).sub.3 H, --P(O).sub.3 H.sub.2, --P(O).sub.3 (Z.sub.1).sub.2, --S(O).sub.3 H , --S(O).sub.m Z.sub.1, --Z.sub.1, --OZ.sub.1, --OH, --NH.sub.2, --NHZ.sub.1, and --NZ.sub.1 Z.sub.2, wherein m is 0, 1 or 2, and Z.sub.1 and Z.sub.2 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms, or(ii) Y.sub.1 and Y.sub.2 are selected together to be --OC(Z.sub.3)(Z.sub.4)O--, wherein Z.sub.3 and Z.sub.4 are independently selected from the group consisting of hydrogen, alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms, with the proviso that if X is not a direct link, then R.sub.1 is not hydrogen,(c) R.sub.2 is selected from the group consisting of hydrogen, alkyl of 1 to about 4 carbon atoms, and alkenyl of about 2 to about 4 carbon atoms,(d) R.sub.3 is selected from the group consisting of ##STR232## where W is nitrogen or carbon; (e) Het is ##STR233## wherein (1) R.sub.4 is selected from the group consisting of(a) R.sub.1, --OR.sub.1, --NHR.sub.1, --S(O).sub.n R.sub.1, and halogen, wherein n is 0, 1 or 2, and R.sub.1 is independently selected, with the proviso that R.sub.4 is not a camphor derivative or ##STR234## heterocyclo group, (b) alkyl of 1 to about 12 carbon atoms substituted with Z.sub.5 wherein Z.sub.5 is selected from the group consisting of hydroxy, halogen, --C(O)OH, --C(O)OR.sub.8, --S(O).sub.3 OH, and --S(O).sub.p R.sub.8 wherein R.sub.8 is alkyl of 1 to about 6 carbon atoms and p is 0, 1 or 2, and(c) alkenyl of about 3 to about 6 carbon atoms;(2) R5 is selected from the group consisting of(a) hydrogen,(b) alkyl of 1 to about 10 carbon atoms,(c) alkyl of 1 to about 3 carbon atoms substituted with cyclic alkyl of about 3 to about 8 carbon atoms,(d) cyclic alkyl of 3 to about 6 carbon atoms,(e) heterocycloalkyl of 4 to about 6 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen and --S(O).sub.i -- wherein i is independently 0, 1 or 2,(f) heterocyclo of 4 to about 6 ring atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen and --S(O).sub.i -- wherein i is independently 0, 1 or 2 and which is attached to Het by a ring carbon atom,(g) alkenyl of 2 to about 6 carbon atoms which is optionally substituted with cyclic alkyl of 3 to about 5 carbon atoms,(h) aryl which is optionally mono-, di- or tri- substituted with Y.sub.1, Y.sub.2 and/or Y.sub.3 respectively,(i) heteroaryl of 5 to 6 atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and --S(O).sub.i -- wherein i is independently 0, 1 or 2 and which is optionally mono-, di- or tri- substituted with Y.sub.1, Y.sub.2 and/or Y.sub.3,(j) aralkyl of about 7 to about 10 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y.sub.1, Y.sub.2 and/or Y.sub.3 ;(k) heteroaralkyl of 6 to 9 atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen and --S(O).sub.i -- wherein i is independently 0, 1 or 2 and which is optionally mono-, di- or tri- substituted on the ring with Y.sub.1, Y.sub.2 and/or Y.sub.3,(l) aralkenyl of 8 carbon atoms which is optionally mono-, di- or tri- substituted on the aryl ring with Y.sub.1, Y.sub.2 and/or Y.sub.3,(m) heteroaralkenyl of 7 to 8 atoms with the ring atoms selected from carbon atoms and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and --S(O).sub.i -- wherein i is independently 0, 1 or 2, and which is optionally mono-, di- or tri-substituted on the ring with Y.sub.1, Y.sub.2 and/or Y.sub.3,(n) halogen,(o) difluoromethyl or perfluoroalkyl of 1 to 3 carbon atoms,(p) perfluorophenyl,(q) perfluoroaralkyl of 7 to about 9 carbon atoms, and(r) alkoxy of 1 to about 10 carbon atoms;(3) R.sub.6 is selected from the group consisting of(a) R.sub.1, --OR.sub.1, --NHR.sub.1, --S(O).sub.n R.sub.1, or halogen, wherein n is 0, 1 or 2, and R.sub.1 is independently selected, with the proviso that R.sub.6 is not a camphor derivative or ##STR235## heterocycle group, and (b) alkyl of 1 to about 12 carbon atoms substituted with Z.sub.6, wherein Z.sub.6 is selected from the group consisting of hydroxy, halogen, --OR.sub.9, --NHR.sub.9, --C(O)OH, --C(O)OR.sub.9, --S(O).sub.2 OH and --S(O).sub.p R.sub.9 wherein R.sub.9 is selected from alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 10 carbon atoms optionally mono-, di or tri-substituted on the ring with Y.sub.1, Y.sub.2 and/or Y.sub.3, aralkyl of about 7 to about 12 carbon atoms optionally mono-, di- or tri-substituted on the ring with Y.sub.1, Y.sub.2 and/or Y.sub.3, heteroaryl of 1 to about 9 carbon atoms with the ring atoms selected from carbon and heteroatoms selected from the group consisting of oxygen, nitrogen and --S(O).sub.p -- and optionally mono-, di- or tri-substituted on the ring with Y.sub.1, Y.sub.2 and/or Y.sub.3 ; and heteroaralkyl of about 2 to about 10 carbon atoms with the ring atoms selected from carbon and heteroatoms selected from the group consisting of oxygen, nitrogen and --S(O).sub.p -- and optionally mono-, di- or tri-substituted on the ring with Y.sub.1, Y.sub.2 and/or Y.sub.3 ; and(4) R7 is independently selected from the R5 group of substituents, provided that R7 is not halogen; and pharmaceutically acceptable salts thereof.