Preparation of cyclic urea compounds

A method for preparing a cyclic urea compound of Formula (Ic) comprising the steps:

• (a) converting a compound of Formula (IIa) to a compound of Formula (IIb) by any of direct alkylation, reductive amination, or successive acylation and reduction,
• (b) converting the compound of Formula (IIb) from step (a) to a product comprising a cyclic urea compound of Formula (Ib),
• (c) purifying the product of step (b) by
• (i) washing the product of step (b) with an aqueous acid solution, resulting in a washed product, and
• (ii) eluting the washed product of step (c)(i) through a bed of silica gel to produce a substantially pure compound of Formula (Ib), and
• (d) converting the substantially pure compound of Formula (Ib) from step (c)(ii) to a cyclic urea compound of Formula (Ic),
• wherein,
• the compound of Formula (IIa) has the structure shown in Formula (II) with the proviso that R.sup.22 and R.sup.23 are hydrogen,
• the compound of Formula (IIb) has the structure shown in Formula (II) with the proviso that only one of R.sup.22 or R.sup.23 is hydrogen,
• the compound of Formula (Ib) has the structure shown in Formula (I) with the proviso that only one of R.sup.22 or R.sup.23 is hydrogen,
• the compound of Formula (Ic) has the structure shown in Formula (I) with the proviso that neither R.sup.22 nor R.sup.23 is hydrogen;
• compound (I) has a Formula:
• ##STR39## including a pharmaceutically acceptable salt or prodrug form thereof, and compound (II) has a Formula:
• ##STR40## wherein, for each compound of Formula (I) and Formula (II):
• each of R.sup.4 and R.sup.7 is independently:
• hydrogen, --O(R.sup.13), --S(R.sup.13), --C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11,
• C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.11,
• C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.11,
• a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-3 R.sup.11 or 0-3 R.sup.12, or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.12 ;
• each of R.sup.4A and R.sup.7A is independently:
• hydrogen, --O(R.sup.13), --S(R.sup.13), --C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.4 alkyl unsubstituted or substituted with halogen or C.sub.1 -C.sub.2 alkoxy, or
• phenylmethyl unsubstituted or substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
• R.sup.4 and R.sup.4A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R.sup.12 ;
• R.sup.7 and R.sup.7A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R.sup.12 ;
• each of R.sup.5 and R.sup.5A is independently:
• hydrogen, halogen, --N(R.sup.20).sub.2, --S(R.sup.20), --O(R.sup.20) or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
• R.sup.5 and R.sup.5A can alternatively join together to form a .dbd.O, .dbd.S or a ketal ring;
• each of R.sup.6 and R.sup.6A is independently:
• hydrogen, halogen, --N(R.sup.20).sub.2, --S(R.sup.20), --O(R.sup.21) or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
• R.sup.6 and R.sup.6A can alternatively join together to form a .dbd.O, .dbd.S or a ketal ring;
• R.sup.5 and R.sup.6 can alternatively join together to form an epoxide or aziridine ring;
• --OCH.sub.2 SCH.sub.2 O--, --OS(.dbd.O)O--, --OC(.dbd.O)O--, --OCH.sub.2 O--, --OC(.dbd.S)O--, --OC(.dbd.O)C(.dbd.O)O--, --OC(CH.sub.3).sub.2 O--, --OC((CH.sub.2).sub.3 NH.sub.2)(CH.sub.3)O--, --OC(OCH.sub.3)(CH.sub.2 CH.sub.2 CH.sub.3)O--, --OS(.dbd.O).sub.2 O--, --NHC(.dbd.O)NH--, --OC(.dbd.O)NH--, --NHC(.dbd.O)O--, --NHCH.sub.2 O--, --OCH.sub.2 NH--, --NHC(.dbd.S)O--, --OC(.dbd.S)NH--, --OS(.dbd.O)NH--, --NHS(.dbd.O)O--, --NHC(.dbd.O)C(.dbd.O)O--, --OC(.dbd.O)C(.dbd.O)NH--, --NHC(.dbd.O)C(.dbd.O)NH--, --NHC(CH.sub.3).sub.2 O--, --OC(CH.sub.3).sub.2 NH-- or any group that, when administered to a mammalian subject as part of a compound of Formula (I), cleaves to form a compound having two free hydroxyl groups, or two free amino groups, or one free hydroxyl group and one free amino group;
• each R.sup.11 is independently:
• hydrogen, keto, halogen, cyano, phenylmethyl, phenethyl, methylenedioxy, ethylenedioxy, hydroxamic acid, hydrazide, boronic acid, sulfonamide, azido, formyl, phenoxy, phenylmethoxy, nitro, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), --OCH.sub.2 C(.dbd.O)OH, --C(.dbd.O)O(R.sup.13), --OC(.dbd.O)(R.sup.13), --O(R.sup.13), C.sub.2 -C.sub.6 alkoxyalkyl, --S(.dbd.O).sub.m (R.sup.13), --NHC(.dbd.NH )NH (R.sup.13), --C(.dbd.NH)NH(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14)C(.dbd.O)(R.sup.13), .dbd.N--O(R.sup.14), --N(R.sup.14)C(.dbd.O)O(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14), --C(R.sup.14).dbd.N--O(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13)(R.sup.14), C.sub.1 -.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, 2-(1-morpholino)ethoxy, -(C.sub.1 -C.sub.3 alkyl)aryl substituted with 0-2 R.sup.12,
• a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12, or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R.sup.12 ;
• and
• - 3amino acids linked together via amide bonds, and linked to R.sup.4, R.sup.7, R.sup.20, or R.sup.21 via the amine or carboxylate terminus;
• m is:
• 0, 1 or 2;
• each R.sup.11A is independently:
• H, keto, halogen, cyano, --CH.sub.2 NH.sub.2, --NH.sub.2, --C(.dbd.O)OH, --OC(.dbd.O)(C.sub.1 -C.sub.3 alkyl), --OH, C.sub.2 -C.sub.6 alkoxyalkyl, --C(.dbd.O)NH.sub.2, --OC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NH.sub.2, --S(.dbd.O).sub.2 NH.sub.2, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NH.sub.2, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --OCH.sub.2 C(.dbd.O)OH, 2-(1-morpholino)ethoxy, azido, aryl(C.sub.1 -C.sub.3 alkyl), a C.sub.5 -C.sub.14 carbocyclic residue, or a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
• each R.sup.12 when a substituent on carbon, is independently:
• phenyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, C.sub.1 -C.sub.4 alkoxy, --C(.dbd.O)OH, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --O(R.sup.13), C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --S(.dbd.O).sub.m (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --NHS(.dbd.O).sub.2 (R.sup.14), --OCH.sub.2 C(.dbd.O)OH, 2-(1-morpholino)ethoxy, --C(R.sup.14).dbd.N--O(R.sup.14),
• a 5- to 10-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R.sup.15
• a 3- or 4-carbon aliphatic chain attached to an adjacent carbon on the ring to which it is appended to form a fused 5- or 6-membered ring, the 5- or 6-membered ring being optionally substituted on any of the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, --N(R.sup.13)(R.sup.14), or
• when R.sup.12 is a substituent on a saturated carbon atom, R.sup.12 may alternatively be .dbd.O or .dbd.S;
• each R.sup.12 when a substituent on nitrogen, is independently:
• phenyl, phenylmethyl, phenethyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --C(.dbd.O)OH, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl or --C(R.sup.14).dbd.N--O(R.sup.14);
• each R.sup.13 is independently:
• hydrogen,
• phenyl substituted with 0-3 R.sup.11A,
• phenylmethyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11A,
• C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11A,
• C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11A,
• an amine protecting group when R.sup.13 is bonded to N, or
• a hydroxy protecting group when R.sup.13 is bonded to O;
• each R.sup.14 is independently:
• hydrogen, hydroxy, trifluoromethyl, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyl, phenylmethyl, amino,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 groups selected from hydroxy, C.sub.1 -C.sub.4 alkoxy, halogen or amino,
• an amine protecting group when R.sup.14 is bonded to N, or
• a hydroxy protecting group when R.sup.14 is bonded to O;
• R.sup.13 and R.sup.14 can alternatively join to form:
• --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
• R.sup.15 is:
• hydrogen or methyl;
• each of R.sup.20 and R.sup.21 is independently:
• hydrogen,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11,
• C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11
• benzoyl substituted with 0-3 R.sup.12,
• phenoxycarbonyl substituted with 0-3 R.sup.12,
• phenylaminocarbonyl substituted with 0-3 R.sup.12,
• or any group that, when administered to a mammalian subject as part of a compound of Formula (I), cleaves to form a free hydroxyl, free amino or free sulfhydryl;
• each of R.sup.22 and R.sup.23 is independently:
• hydrogen,
• C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.31,
• C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.31,
• C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.31,
• a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-5 R.sup.31 or 0-5 R.sup.32 or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.32 ;
• alternatively, R.sup.22 can join with R.sup.4 or R.sup.4A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, R.sup.23 can join with R.sup.7 or R.sup.7A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, R.sup.22 or R.sup.23 can join with R.sup.5 or R.sup.6 to form a 0- to 7- membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R.sup.12 and the bridge containing 0-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, the atoms to which R.sup.22 and R.sup.4A are appended may be joined together with a double bond;
• alternatively, the atoms to which R.sup.23 and R.sup.7A are appended may be joined together with a double bond;
• Z is:
• O or S;
• each R.sup.31 is independently:
• keto, halogen, cyano, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), --C(.dbd.O)O(R.sup.13), --C(.dbd.O)(R.sup.11), --OC(.dbd.O)(R.sup.13), --O(R.sup.13), C.sub.2 -C.sub.6 alkoxyalkyl, --S(.dbd.O).sub.m (R.sup.13), --NHC(.dbd.NH)NH(R.sup.13), --C(.dbd.NH)NH(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14)C(.dbd.O)(R.sup.13), .dbd.N--O(R.sup.14), --N(R.sup.14)C(.dbd.O)O(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14) S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13 )(R.sup.14), C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 - C.sub.4 alkylcarbonylamino, --OCH.sub.2 C(.dbd.O)O(R.sup.13), 2-(1-morpholino)ethoxy, azido, --C(R.sup.14).dbd.N--O(R.sup.14),
• a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-5 R.sup.32,
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.32 or
• - 3amino acids, linked together via amide bonds, and linked to R.sup.22 or R.sup.23 via the amine or carboxylate terminus;
• each R.sup.32 when a substituent on carbon, is independently:
• phenethyl, phenoxy, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, hydrazide, oxime, C.sub.2 -C.sub.6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, --NHS(.dbd.O).sub.2 (R.sup.14), phenylmethoxy, halogen, 2-(1-morpholino)ethoxy, --C(.dbd.O)O(R.sup.13), hydroxamic acid, --C(.dbd.O)N(R.sup.13)N(R.sup.13)(R.sup.14), cyano, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.2 -C.sub.4 haloalkenyl, C.sub.2 -C.sub.4 haloalkynyl, --N(R.sup.13)(R.sup.14), --C(R.sup.14).dbd.N--O(R.sup.14), --NO.sub.2, --O(R.sup.13), --N(R.sup.40)(R.sup.41), --S(.dbd.O).sub.m (R.sup.13), --S(.dbd.O).sub.m N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --C(.dbd.O)(R.sup.11), --OC(.dbd.O)(R.sup.11), --OC(.dbd.O)O(R.sup.13), phenyl, --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)-N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.40)(R.sup.41), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)NH(R.sup.14), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)-N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)-R.sup.11, --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)(R.sup.14), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.4 alkoxy substituted with 0-4 groups selected from:
• R.sup.11, C.sub.3 -C.sub.6 cycloalkyl, --C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14) or hydroxyl,
• C.sub.1 -C.sub.4 alkyl substituted with 0-4 groups selected from:
• R.sup.11, .dbd.N(R.sup.14), .dbd.NN(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14) or --N(R.sup.13)(R.sup.14),
• C.sub.2 -C.sub.4 alkenyl substituted with 0-4 R.sup.11
• C.sub.2 -C.sub.4 alkynyl substituted with 0-4 R.sup.11
• a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur,
• a 3- or 4-carbon aliphatic chain attached to an adjacent carbon on the ring to which it is appended, to form a fused 5- or 6-membered ring, the 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxyl--N(R.sup.13)(R.sup.14), or
• when R.sup.32 is attached to a saturated carbon atom, R.sup.32 may be .dbd.O or .dbd.S;
• each R.sup.32 when a substituent on nitrogen, is independently:
• phenyl, phenylmethyl, phenethyl, hydroxyl, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --C(.dbd.O)OH, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl or --C(R.sup.14).dbd.N--O(R.sup.14);
• R.sup.40 is:
• hydrogen or C.sub.1 -C.sub.3 alkyl;
• R.sup.41 is:
• --C(.dbd.O)N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 .sup.N (R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)H, --C(.dbd.O)(R.sup.11), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)(R.sup.14), --C(.dbd.O)--(Cl.sub.1 -C.sub.4 alkyl)--N(R.sup.13)C(.dbd.O)O(R.sup.13) or 1-3 amino acids linked together via amide bonds and linked to the N atom via the carboxylate terminus;
• and
• n is:
• 0, 1 or 2;
• provided that:
• R.sup.4, R.sup.4A, R.sup.7 and R.sup.7A are not all hydrogen;
• when R.sup.4 and R.sup.4A are both hydrogen, R.sup.22 is not hydrogen, and
• when R.sup.7 and R.sup.7A are both hydrogen, R.sup.23 is not hydrogen.

A method for preparing and purifying a cyclic urea compound of Formula (Ib) comprising the steps:

• (a) converting a compound of Formula (IIa) to a compound of Formula (IIb) by any of direct alkylation, reductive amination, or successive acylation and reduction,
• (b) converting the compound of Formula (IIb) from step (a) to a product comprising a cyclic urea compound of Formula (Ib),
• (c) purifying the product of step (b) by
• (i) washing the product of step (b) with an aqueous acid solution, resulting in a washed product, and
• (ii) eluting the washed product of step (c)(i) through a bed of silica gel to produce a substantially pure compound of Formula (Ib)
• wherein,
• the compound of Formula (IIa) has the structure shown in Formula (II) with the proviso that R.sup.22 and R.sup.23 are hydrogen,
• the compound of Formula (IIb) has the structure shown in Formula (II) with the proviso that only one of R.sup.22 or R.sup.23 is hydrogen,
• the compound of Formula (Ib) has the structure shown in Formula (I) with the proviso that only one of R.sup.22 or R.sup.23 is hydrogen,
• compound (I) has a Formula:
• ##STR41## including a pharmaceutically acceptable salt or prodrug form thereof, and compound (II) has a Formula:
• ##STR42## wherein, for each compound of Formula (I) and Formula (II):
• each of R.sup.4 and R.sup.7 is independently:
• hydrogen, --O(R.sup.13), --S(R.sup.13), --C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11,
• C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.11,
• C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.11,
• a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-3 R.sup.11 or 0-3 R.sup.12 or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.12 ;
• each of R.sup.4A and R.sup.7A is independently:
• hydrogen, --O(R.sup.13), --S(R.sup.13), --C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.4 alkyl unsubstituted or substituted with halogen or C.sub.1 -C.sub.2 alkoxy, or
• phenylmethyl unsubstituted or substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
• R.sup.4 and R.sup.4A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R.sup.12 ;
• R.sup.7 and R.sup.7A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R.sup.12 ;
• each of R.sup.5 and R.sup.5A is independently:
• hydrogen, halogen, --N(R.sup.20).sub.2, --S(R.sup.20), --O(R.sup.20) or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
• R.sup.5 and R.sup.5A can alternatively join together to form a .dbd.O, .dbd.S or a ketal ring;
• each of R.sup.6 and R.sup.6A is independently:
• hydrogen, halogen, --N(R.sup.20).sub.2, --S(R.sup.20), --O(R.sup.21) or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
• R.sup.6 and R.sup.6A can alternatively join together to form a .dbd.O, .dbd.S or a ketal ring;
• R.sup.5 and R.sup.6 can alternatively join together to form an epoxide or aziridine ring;
• --OCH.sub.2 SCH.sub.2 O--, --OS(.dbd.O)O--, --OC(.dbd.O)O--, --OCH.sub.2 O--, --OC(.dbd.S)O--, --OC(.dbd.O)C(.dbd.O)O--, --OC(CH.sub.3).sub.2 O--, --OC((CH.sub.2).sub.3 NH.sub.2)(CH.sub.3)O--, --OC(OCH.sub.3)(CH.sub.2 CH.sub.2 CH.sub.3)O--, --OS(.dbd.O).sub.2 O--, --NHC(.dbd.O)NH--, --OC(.dbd.O)NH--, --NHC(.dbd.O)O--, --NHCH.sub.2 O--, --OCH.sub.2 NH--, --NHC(.dbd.S)O--, --OC(.dbd.S)NH--, --OS(.dbd.O)NH--, --NHS(.dbd.O)O--, --NHC(.dbd.O)C(.dbd.O)O--, --OC(.dbd.O)C(.dbd.O)NH--, --NHC(.dbd.O)C(.dbd.O)NH--, --NHC(CH.sub.3).sub.2 O--, --OC(CH.sub.3).sub.2 NH-- or any group that, when administered to a mammalian subject as part of a compound of Formula (I), cleaves to form a compound having two free hydroxyl groups, or two free amino groups, or one free hydroxyl group and one free amino group;
• each R.sup.11 is independently:
• hydrogen, keto, halogen, cyano, phenylmethyl, phenethyl, methylenedioxy, ethylenedioxy, hydroxamic acid, hydrazide, boronic acid, sulfonamide, azido, formyl, phenoxy, phenylmethoxy, nitro, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), --OCH.sub.2 C(.dbd.O)OH, --C(.dbd.O)O(R.sup.13), --OC(.dbd.O)(R.sup.13), --O(R.sup.13), C.sub.2 -C.sub.6 alkoxyalkyl, --S(.dbd.O).sub.m (R.sup.13), --NHC(.dbd.NH)NH(R.sup.13), --C(.dbd.NH)NH(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14)C(.dbd.O)(R.sup.13), .dbd.N--O(R.sup.14), --N(R.sup.14)C(.dbd.O)O(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14), --C(R.sup.14).dbd.N--O(R.sup.14), --N(R.sup.14) S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 C.sub.4 alkylcarbonyloxy, C.sub.1 C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, 2-(1-morpholino)ethoxy, --(C.sub.1 -C.sub.3 alkyl) aryl substituted with 0-2 R.sup.12,
• a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12, or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R.sup.12 ;
• and
• - 3amino acids linked together via amide bonds, and linked to R.sup.4 R.sup.7 R.sup.20 or R.sup.21 via the amine or carboxylate terminus;
• m is:
• 0, 1 or 2;
• each R.sup.11A is independently:
• H, keto, halogen, cyano, --CH.sub.2 NH.sub.2, --NH.sub.2, --C(.dbd.O)OH, --OC(.dbd.O)(C.sub.1 -C.sub.3 alkyl), --OH, C.sub.2 -C.sub.6 alkoxyalkyl, --C(.dbd.O)NH.sub.2, --OC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NH.sub.2, --S(.dbd.O).sub.2 NH.sub.2, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NH.sub.2, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --OCH.sub.2 C(.dbd.O)OH, 2-(1-morpholino)ethoxy, azido, aryl(C.sub.1 -C.sub.3 alkyl), a C.sub.5 -C.sub.14 carbocyclic residue, or a 5- to 10-membered heterocyclic ring system containing to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
• each R.sup.12 when a substituent on carbon, is independently:
• phenyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, C.sub.1 -C.sub.4 alkoxy, --C(.dbd.O)OH, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --O(R.sup.13), C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --S(.dbd.O).sub.m (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --NHS(.dbd.O).sub.2 (R.sup.14), --OCH.sub.2 C(.dbd.O)OH, 2-(1-morpholino)ethoxy, --C(R.sup.14).dbd.N--O(R.sup.14),
• a 5- to 10-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R.sup.15,
• a 3- or 4-carbon aliphatic chain attached to an adjacent carbon on the ring to which it is appended to form a fused 5- or 6-membered ring, the 5- or 6-membered ring being optionally substituted on any of the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, --N(R.sup.13)(R.sup.14), or
• when R.sup.12 is a substituent on a saturated carbon atom, R.sup.12 may alternatively be .dbd.O or .dbd.S;
• each R.sup.12 when a substituent on nitrogen, is independently:
• phenyl, phenylmethyl, phenethyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --C(.dbd.O)OH, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl or --C(R.sup.14).dbd.N--O (R.sup.14);
• each R.sup.13 is independently:
• hydrogen,
• phenyl substituted with 0-3 R.sup.11A,
• phenylmethyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11A,
• C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11A,
• C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11A,
• an amine protecting group when R.sup.13 is bonded to N, or
• a hydroxy protecting group when R.sup.13 is bonded to O;
• each R.sup.14 is independently:
• hydrogen, hydroxy, trifluoromethyl, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyl, phenylmethyl, amino,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 groups selected from hydroxy, C.sub.1 -C.sub.4 alkoxy, halogen or amino,
• an amine protecting group when R.sup.14 is bonded to N, or
• a hydroxy protecting group when R.sup.14 is bonded to O;
• R.sup.13 and R.sup.14 can alternatively join to form:
• --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
• R.sup.15 is:
• hydrogen or methyl;
• each of R.sup.20 and R.sup.21 is independently:
• hydrogen,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11,
• C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11
• C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11
• benzoyl substituted with 0-3 R.sup.12,
• phenoxycarbonyl substituted with 0-3 R.sup.12,
• phenylaminocarbonyl substituted with 0-3 R.sup.12,
• or any group that, when administered to a mammalian subject as part of a compound of Formula (I), cleaves to form a free hydroxyl, free amino or free sulfhydryl;
• each of R.sup.22 and R.sup.23 is independently:
• hydrogen,
• C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.31,
• C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.31,
• C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.31,
• a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-5 R.sup.31 or 0-5 R.sup.32, or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.32 ;
• alternatively, R.sup.22 can join with R.sup.4 or R.sup.4A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, R.sup.23 can join with R.sup.7 or R.sup.7A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12 the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, R.sup.22 or R.sup.23 can join with R.sup.5 or R.sup.6 to form a 0- to 7- membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R.sup.12 and the bridge containing 0-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, the atoms to which R.sup.22 and R.sup.4A are appended may be joined together with a double bond;
• alternatively, the atoms to which R.sup.23 and R.sup.7A are appended may be joined together with a double bond;
• Z is:
• O or S;
• each R.sup.31 is independently:
• keto, halogen, cyano, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), --C(.dbd.O)O(R.sup.13), --C(.dbd.O)(R.sup.11), --OC(.dbd.O)(R.sup.13), --O(R.sup.13), C.sub.2 -C.sub.6 alkoxyalkyl, --S(.dbd.O).sub.m (R.sup.13), --NHC(.dbd.NH)NH(R.sup.13), --C(.dbd.NH)NH(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14)C(.dbd.O)(R.sup.13), .dbd.N--O(R.sup.14), --N(R.sup.14)C(.dbd.O)O(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --OCH.sub.2 C(.dbd.O)O(R.sup.13), 2-(1-morpholino)ethoxy, azido, --C(R.sup.14).dbd.N--O(R.sup.14),
• a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-5 R.sup.32
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.32 or
• - 3amino acids, linked together via amide bonds, and linked to R.sup.22 or R.sup.23 via the amine or carboxylate terminus;
• each R.sup.32 when a substituent on carbon, is independently:
• phenethyl, phenoxy, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, hydrazide, oxime, C.sub.2 -C.sub.6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, --NHS(.dbd.O).sub.2 (R.sup.14), phenylmethoxy, halogen, 2-(1-morpholino)ethoxy, --C(.dbd.O)O(R.sup.13), hydroxamic acid, --C(.dbd.O)N(R.sup.13)N(R.sup.13)(R.sup.14), cyano, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C1--C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.2 -C.sub.4 haloalkenyl, C.sub.2 -C.sub.4 haloalkynyl, --N(R.sup.13)(R.sup.14), --C(R.sup.14).dbd.N--O (R.sup.14), --NO.sub.2, --O(R.sup.13), --N(R.sup.40)(R.sup.41), --S(.dbd.O).sub.m (R.sup.13), --S(.dbd.O).sub.m N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --C(.dbd.O)(R.sup.11), --OC(.dbd.O)(R.sup.11), --OC(.dbd.O)O(R.sup.13), phenyl, --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)-N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.40)(R.sup.41), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14 ), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)NH(R.sup.14), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)-N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)-R.sup.11, --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)(R.sup.14), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl) --N(R.sup.13)C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.4 alkoxy substituted with 0-4 groups selected from:
• R.sup.11, C.sub.3 -C.sub.6 cycloalkyl, --C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14) or hydroxyl,
• C.sub.1 -C.sub.4 alkyl substituted with 0-4 groups selected from:
• R.sup.11 .dbd.N(R.sup.14), .dbd.NN(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14) or --N(R.sup.13)(R.sup.14),
• C.sub.2 -C.sub.4 alkenyl substituted with 0-4 R.sup.11,
• C.sub.2 -C.sub.4 alkynyl substituted with 0-4 R.sup.11,
• a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur,
• a 3- or 4-carbon aliphatic chain attached to an adjacent carbon on the ring to which it is appended, to form a fused 5- or 6-membered ring, the 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxyl--N(R.sup.13)(R.sup.14), or
• when R.sup.32 is attached to a saturated carbon atom, R.sup.32 may be .dbd.O or .dbd.S;
• each R.sup.32, when a substituent on nitrogen, is independently:
• phenyl, phenylmethyl, phenethyl, hydroxyl, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --C(.dbd.O)OH, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl or --C(R.sup.14).dbd.N--O(R.sup.14);
• R.sup.40 is:
• hydrogen or C.sub.1 -C.sub.3 alkyl;
• R.sup.41 is:
• --C(.dbd.O)N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)NH (R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)H, --C(.dbd.O)(R.sup.11), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)(R.sup.14), C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)C(.dbd.O)O(R.sup.13) or 1-3 amino acids linked together via amide bonds and linked to the N atom via the carboxylate terminus;
• and
• n is:
• 0, 1 or 2;
• provided that:
• R.sup.4, R.sup.4A, R.sup.7 and R.sup.7A are not all hydrogen;
• when R.sup.4 and R.sup.4A are both hydrogen, R.sup.22 is not hydrogen, and
• when R.sup.7 and R.sup.7A are both hydrogen, R.sup.23 is not hydrogen.

A method for preparing and purifying a cyclic urea compound of Formula (Ib) comprising the steps:

• (a) converting a compound of Formula (IIb) to a product comprising a cyclic urea compound of Formula (Ib),
• (b) purifying the product of step (a) by
• (i) washing the product of step (a) with an aqueous acid solution, resulting in a washed product, and
• (ii) eluting the product of step (b)(i) through a bed of silica gel to produce a substantially pure compound of Formula (Ib), wherein,
• the compound of Formula (IIb) has the structure shown in Formula (II) with the proviso that only one of R.sup.22 and R.sup.23 is hydrogen,
• the compound of Formula (Ib) has the structure shown in Formula (I) with the proviso that only one of R.sup.22 and R.sup.23 is hydrogen,
• compound (I) has a Formula:
• ##STR43## including a pharmaceutically acceptable salt or prodrug form thereof, and compound (II) has a Formula:
• ##STR44## wherein for each compound of Formula (I) and Formula (II):
• each of R.sup.4 and R.sup.7 is independently:
• hydrogen, --O(R.sup.13), --S(R.sup.13), --C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11,
• C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.11,
• C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.11,
• a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-3 R.sup.11 or 0-3 R.sup.12 or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.12 ;
• each of R.sup.4A and R.sup.7A is independently:
• hydrogen, --O(R.sup.13), --S(R.sup.13), --C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.4 alkyl unsubstituted or substituted with halogen or C.sub.1 -C.sub.2 alkoxy, or
• phenylmethyl unsubstituted or substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
• R.sup.4 and R.sup.4A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R.sup.12 ;
• R.sup.7 and R.sup.7A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R.sup.12 ;
• each of R.sup.5 and R.sup.5A is independently:
• hydrogen, halogen, --N(R.sup.20).sub.2, --S(R.sup.20), --O(R.sup.20) or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
• R.sup.5 and R.sup.5A can alternatively join together to form a .dbd.O, .dbd.S or a ketal ring;
• each of R.sup.6 and R.sup.6A is independently:
• hydrogen, halogen, --N(R.sup.20).sub.2, --S(R.sup.20), --O(R.sup.21) or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
• R.sup.6 and R.sup.6A can alternatively join together to form a .dbd.O, .dbd.S or a ketal ring;
• R.sup.5 and R.sup.6 can alternatively join together to form an epoxide or aziridine ring;
• --OCH.sub.2 SCH.sub.2 O--, --OS(.dbd.O)O--, --OC(.dbd.O)O--, --OCH.sub.2 O--, --OC(.dbd.S)O--, --OC(.dbd.O)C(.dbd.O)O--, --OC(CH.sub.3).sub.2 O--, --OC((CH.sub.2).sub.3 NH.sub.2)(CH.sub.3)O--, --OC(OCH.sub.3)(CH.sub.2 CH.sub.2 CH.sub.3)O--, --OS(.dbd.O).sub.2 O--, --NHC(.dbd.O)NH--, --OC(.dbd.O)NH--, --NHC(.dbd.O)O--, --NHCH.sub.2 O--, --OCH.sub.2 NH--, --NHC(.dbd.S)O--, --OC(.dbd.S)NH--, --OS(.dbd.O)NH--, --NHS(.dbd.O)O--, --NHC(.dbd.O)C(.dbd.O)O--, --OC(.dbd.O)C(.dbd.O)NH--, --NHC(.dbd.O)C(.dbd.O)NH--, --NHC(CH.sub.3).sub.2 O--, --OC(CH.sub.3).sub.2 NH-- or any group that, when administered to a mammalian subject as part of a compound of Formula (I), cleaves to form a compound having two free hydroxyl groups, or two free amino groups, or one free hydroxyl group and one free amino group;
• each R.sup.11 is independently:
• hydrogen, keto, halogen, cyano, phenylmethyl, phenethyl, methylenedioxy, ethylenedioxy, hydroxamic acid, hydrazide, boronic acid, sulfonamide, azido, formyl, phenoxy, phenylmethoxy, nitro, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), --OCH.sub.2 C(.dbd.O)OH, --C(.dbd.O)O(R.sup.13), --OC(.dbd.O)(R.sup.13), --O(R.sup.13), C.sub.2 -C.sub.6 alkoxyalkyl, --S(.dbd.O).sub.m (R.sup.13), --NHC(.dbd.NH)NH(R.sup.13), --C(.dbd.NH)NH (R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), R.sup.14)C(.dbd.O)(R.sup.13), .dbd.N--O(R.sup.14), --N --N(R.sup.14)C(.dbd.O)O(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14), --C(R.sup.14).dbd.N--O(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13)(R.sup. 14), C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, 2-(1-morpholino)ethoxy, -(C.sub.1 -C.sub.3 alkyl) aryl substituted with 0-2 R.sup.12
• a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R.sup.12 ;
• and
• - 3amino acids linked together via amide bonds, and linked to R.sup.4 R.sup.7 R.sup.20, or R.sup.21 via the amine or carboxylate terminus;
• m is:
• 0, 1 or 2;
• each R.sup.11A is independently:
• H, keto, halogen, cyano, --CH.sub.2 NH.sub.2, --NH.sub.2, --C(.dbd.O)OH, --OC(.dbd.O)(C.sub.1 -C.sub.3 alkyl), --OH, C.sub.2 -C.sub.6 alkoxyalkyl, --C(.dbd.O)NH.sub.2, --OC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NH.sub.2, --S(.dbd.O).sub.2 NH.sub.2, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NH.sub.2, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --OCH.sub.2 C(.dbd.O)OH, 2-(1-morpholino)ethoxy, azido, aryl (C.sub.1 -C.sub.3 alkyl), a C.sub.5 -C.sub.14 carbocyclic residue, or a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
• each R.sup.12 when a substituent on carbon, is independently:
• phenyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, C.sub.1 -C.sub.4 alkoxy, --C(.dbd.O)OH, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --O(R.sup.13), C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --S(.dbd.O).sub.m (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --NHS(.dbd.O).sub.2 (R.sup.14), --OCH.sub.2 C(.dbd.O)OH, 2-(1-morpholino)ethoxy, --C(R.sup.14).dbd.N--O(R.sup.14),
• a 5- to 10-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R.sup.15,
• a 3- or 4-carbon aliphatic chain attached to an adjacent carbon on the ring to which it is appended to form a fused 5- or 6-membered ring, the 5- or 6-membered ring being optionally substituted on any of the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, --N(R.sup.13)(R.sup.14), or
• when R.sup.12 is a substituent on a saturated carbon atom, R.sup.12 may alternatively be .dbd.O or .dbd.S;
• each R.sup.12 when a substituent on nitrogen, is independently:
• phenyl, phenylmethyl, phenethyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --C(.dbd.O)OH, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl or --C(R.sup.14).dbd.N--O(R.sup.14);
• each R.sup.13 is independently:
• hydrogen,
• phenyl substituted with 0-3 R.sup.11A,
• phenylmethyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11A,
• C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11A,
• C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11A,
• an amine protecting group when R.sup.13 is bonded to N, or
• a hydroxy protecting group when R.sup.13 is bonded to O;
• each R.sup.14 is independently:
• hydrogen, hydroxy, trifluoromethyl, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyl, phenylmethyl, amino,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 groups selected from hydroxy, C.sub.1 -C.sub.4 alkoxy, halogen or amino,
• an amine protecting group when R.sup.14 is bonded to N, or
• a hydroxy protecting group when R.sup.14 is bonded to O;
• R.sup.13 and R.sup.14 can alternatively join to form:
• --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15)CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
• R.sup.15 is:
• hydrogen or methyl;
• each of R.sup.20 and R.sup.21 is independently:
• hydrogen,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11,
• C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11
• benzoyl substituted with 0-3 R.sup.12,
• phenoxycarbonyl substituted with 0-3 R.sup.12,
• phenylaminocarbonyl substituted with 0-3 R.sup.12,
• or any group that, when administered to a mammalian subject as part of a compound of Formula (I), cleaves to form a free hydroxyl, free amino or free sulfhydryl;
• each of R.sup.22 and R.sup.23 is independently:
• hydrogen,
• C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.31,
• C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.31,
• C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.31,
• a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-5 R.sup.31 or 0-5 R.sup.32 or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.32 ;
• alternatively, R.sup.22 can join with R.sup.4 or R.sup.4A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, R.sup.23 can join with R.sup.7 or R.sup.7A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, R.sup.22 or R.sup.23 can join with R.sup.5 or R.sup.6 to form a 0- to 7- membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R.sup.12 and the bridge containing 0-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, the atoms to which R.sup.22 and R.sup.4A are appended may be joined together with a double bond;
• alternatively, the atoms to which R.sup.23 and R.sup.7A are appended may be joined together with a double bond;
• Z is:
• O or S;
• each R.sup.31 is independently:
• keto, halogen, cyano, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), --C(.dbd.O)O(R.sup.13), --C(.dbd.O)(R.sup.11), --OC(.dbd.O)(R.sup.13), --O(R.sup.13), C.sub.2 -C.sub.6 alkoxyalkyl, --S(.dbd.O).sub.m (R.sup.13), --NHC(.dbd.NH)NH(R.sup.13), --C(.dbd.NH)NH(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14)C(.dbd.O)(R.sup.13), .dbd.N--O(R.sup.14), --N(R.sup.14)C(.dbd.O)O(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14) S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup. 13)(R.sup.14), C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --OCH.sub.2 C(.dbd.O)O(R.sup.13), 2-(1-morpholino)ethoxy, azido, --C(R.sup.14).dbd.N--O(R.sup.14),
• a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-5 R.sup.32,
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.32 or
• - 3amino acids, linked together via amide bonds, and linked to R.sup.22 or R.sup.23 via the amine or carboxylate terminus;
• each R.sup.32 when a substituent on carbon, is independently:
• phenethyl, phenoxy, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, hydrazide, oxime, C.sub.2 -C.sub.6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, --NHS(.dbd.O).sub.2 (R.sup.14), phenylmethoxy, halogen, 2-(1-morpholino)ethoxy, --C(.dbd.O)O(R.sup.13), hydroxamic acid, --C(.dbd.O)N(R.sup.13)N(R.sup.13)(R.sup.14), cyano, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.2 -C.sub.4 haloalkenyl, C.sub.2 -C.sub.4 haloalkynyl, --N(R.sup.13)(R.sup.14), --C(R.sup.14).dbd.N--O(R.sup.14), --NO.sub.2, --O(R.sup.13), --N(R.sup.40)(R.sup.41), --S(.dbd.O).sub.m (R.sup.13), --S(.dbd.O).sub.m N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --C(.dbd.O)(R.sup.11), --OC(.dbd.O)(R.sup.11), --OC(.dbd.O)O(R.sup.13), phenyl, --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)-N(R.sup.13)(R.sup. 14), --C(.dbd.O)N(R.sup.40)(R.sup.41), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)NH (R.sup.14), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)-N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)-R.sup.11, --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)(R.sup.14), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl) --N(R.sup.13)C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.4 alkoxy substituted with 0-4 groups selected from:
• R.sup.11 C.sub.3 -C.sub.6 cycloalkyl, --C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14) or hydroxyl,
• C.sub.1 -C.sub.4 alkyl substituted with 0-4 groups selected from:
• R.sup.11 .dbd.N(R.sup.14), .dbd.NN(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14) or --N(R.sup.13)(R.sup.14),
• C.sub.2 -C.sub.4 alkenyl substituted with 0-4 R.sup.11,
• C.sub.2 -C.sub.4 alkynyl substituted with 0-4 R.sup.11,
• a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur,
• a 3- or 4-carbon aliphatic chain attached to an adjacent carbon on the ring to which it is appended, to form a fused 5- or 6-membered ring, the 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxyl--N(R.sup.13)(R.sup.14), or
• when R.sup.32 is attached to a saturated carbon atom, R.sup.32 may be .dbd.O or .dbd.S;
• each R.sup.32 when a substituent on nitrogen, is independently:
• phenyl, phenylmethyl, phenethyl, hydroxyl, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --C(.dbd.O)OH, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl or --C(R.sup.14).dbd.N--O(R.sup.14);
• R.sup.40 is:
• hydrogen or C.sub.1 -C.sub.3 alkyl;
• R.sup.41 is:
• --C(.dbd.O)N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O) H, --C(.dbd.O)(R.sup.11), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)(R.sup.14), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)C(.dbd.O)O(R.sup.13) or 1-3 amino acids linked together via amide bonds and linked to the N atom via the carboxylate terminus;
• and
• n is:
• 0, 1 or 2;
• provided that:
• R.sup.4, R.sup.4A, R.sup.7 and R.sup.7A are not all hydrogen;
• when R.sup.4 and R.sup.4A are both hydrogen, R.sup.22 is not hydrogen, and
• when R.sup.7 and R.sup.7A are both hydrogen, R.sup.23 is not hydrogen.

A method for converting a compound of Formula (IIa) to a compound of Formula (IIb) by any of direct alkylation, reductive amination, or successive acylation and reduction,

• wherein,
• the compound of Formula (IIa) has the structure shown in Formula (II) with the proviso that R.sup.22 and R.sup.23 are hydrogen,
• the compound of Formula (IIb) has the structure shown in Formula (II) with the proviso that only one of R.sup.22 or R.sup.23 is hydrogen,
• compound (II) has a Formula:
• ##STR45## wherein, each of R.sup.4 and R.sup.7 is independently:
• hydrogen, --O(R.sup.13), --S(R.sup.13), --C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.11,
• C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.11,
• C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.11,
• a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-3 R.sup.11 or 0-3 R.sup.12 or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.12 ;
• each of R.sup.4A and R.sup.7A is independently:
• hydrogen, --O(R.sup.13), --S(R.sup.13), --C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.4 alkyl unsubstituted or substituted with halogen or C.sub.1 -C.sub.2 alkoxy, or
• phenylmethyl unsubstituted or substituted with halogen or C.sub.1 -C.sub.2 alkoxy;
• R.sup.4 and R.sup.4A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R.sup.12 ;
• R.sup.7 and R.sup.7A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R.sup.12 ;
• each of R.sup.5 and R.sup.5A is independently:
• hydrogen, halogen, --N(R.sup.20).sub.2, --S(R.sup.20), --O(R.sup.20) or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
• R.sup.5 and R.sup.5A can alternatively join together to form a .dbd.O, .dbd.S or a ketal ring;
• each of R.sup.6 and R.sup.6A is independently:
• hydrogen, halogen, --N(R.sup.20).sub.2, --S(R.sup.20), --O(R.sup.21) or C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11 ;
• R.sup.6 and R.sup.6A can alternatively join together to form a .dbd.O, .dbd.S or a ketal ring;
• R.sup.5 and R.sup.6 can alternatively join together to form an epoxide or aziridine ring;
• --OCH.sub.2 SCH.sub.2 O--, --OS(.dbd.O)O--, --OC(.dbd.O)O--, --OCH.sub.2 O--, --OC(.dbd.S)O--, --OC(.dbd.O)C(.dbd.O)O--, --OC(CH.sub.3).sub.2 O--, --OC((CH.sub.2).sub.3 NH.sub.2)(CH.sub.3)O--, --OC(OCH.sub.3)(CH.sub.2 CH.sub.2 CH.sub.3)O--, --OS(.dbd.O).sub.2 O--, --NHC(.dbd.O)NH--, --OC(.dbd.O)NH--, --NHC(.dbd.O)O--, --NHCH.sub.2 O--, --OCH.sub.2 NH--, --NHC(.dbd.S)O--, --OC(.dbd.S)NH--, --OS(.dbd.O)NH--, --NHS(.dbd.O)O--, --NHC(.dbd.O)C(.dbd.O)O--, --OC(.dbd.O)C(.dbd.O)NH--, --NHC(.dbd.O)C(.dbd.O)NH--, --NHC(CH.sub.3).sub.2 O--, --OC(CH.sub.3).sub.2 NH-- or any group that, when administered to a mammalian subject as part of a compound of Formula (I), cleaves to form a compound having two free hydroxyl groups, or two free amino groups, or one free hydroxyl group and one free amino group;
• each R.sup.11 is independently:
• hydrogen, keto, halogen, cyano, phenylmethyl, phenethyl, methylenedioxy, ethylenedioxy, hydroxamic acid, hydrazide, boronic acid, sulfonamide, azido, formyl, phenoxy, phenylmethoxy, nitro, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), --OCH.sub.2 C(.dbd.O)OH, --C(.dbd.O)O(R.sup.13), --OC(.dbd.O)(R.sup.13), --O(R.sup.13), C.sub.2 -C.sub.6 alkoxyalkyl, --S(.dbd.O).sub.m (R.sup.13), --NHC(.dbd.NH)NH(R.sup.13), --C(.dbd.NH)NH(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14)C(.dbd.O)(R.sup.13), .dbd.N--O(R.sup.14), --N(R.sup.14)C(.dbd.O)O(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14), --C(R.sup.14).dbd.N--O(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, 2-(1-morpholino)ethoxy, --(C.sub.1 -C.sub.3 alkyl) aryl substituted with 0-2 R.sup.12,
• a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-3 R.sup.12 or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R.sup.12 ;
• and
• - 3amino acids linked together via amide bonds, and linked to R.sup.4 R.sup.7 R.sup.20 or R.sup.21 via the amine or carboxylate terminus;
• m is:
• 0, 1 or 2;
• each R.sup.11A is independently:
• H, keto, halogen, cyano, --CH.sub.2 NH.sub.2, --NH.sub.2, --C(.dbd.O)OH, --OC(.dbd.O)(C.sub.1 -C.sub.3 alkyl), --OH, C.sub.2 -C.sub.6 alkoxyalkyl, --C(.dbd.O)NH.sub.2, --OC(.dbd.O)NH.sub.2, --NHC(.dbd.O)NH.sub.2, --S(.dbd.O).sub.2 NH.sub.2, C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --NH.sub.2, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --OCH.sub.2 C(.dbd.O)OH, 2-(1-morpholino)ethoxy, azido, aryl (C.sub.1 -C.sub.3 alkyl), a C.sub.5 -C.sub.14 carbocyclic residue, or a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur;
• each R.sup.12 when a substituent on carbon, is independently:
• phenyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, halogen, hydroxy, nitro, cyano, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, C.sub.1 -C.sub.4 alkoxy, --C(.dbd.O)OH, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, --O(R.sup.13), C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --S(.dbd.O).sub.m (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --NHS(.dbd.O).sub.2 (R.sup.14), --OCH.sub.2 C(.dbd.O)OH, 2-(1-morpholino)ethoxy, --C(R.sup.14).dbd.N--O(R.sup.14),
• a 5- to 10-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-3 R.sup.15,
• a 3- or 4-carbon aliphatic chain attached to an adjacent carbon on the ring to which it is appended to form a fused 5- or 6-membered ring, the 5- or 6-membered ring being optionally substituted on any of the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, --N(R.sup.13)(R.sup.14), or
• when R.sup.12 is a substituent on a saturated carbon atom, R.sup.12 may alternatively be .dbd.O or .dbd.S;
• each R.sup.12 when a substituent on nitrogen, is independently:
• phenyl, phenylmethyl, phenethyl, hydroxy, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --C(.dbd.O)OH, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl or --C(R.sup.14).dbd.N--O(R.sup.14);
• each R.sup.13 is independently:
• hydrogen,
• phenyl substituted with 0-3 R.sup.11A,
• phenylmethyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11A,
• C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11A,
• C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11A,
• C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11A,
• an amine protecting group when R.sup.13 is bonded to N, or
• a hydroxy protecting group when R.sup.13 is bonded to O;
• each R.sup.14 is independently:
• hydrogen, hydroxy, trifluoromethyl, C.sub.1 -C.sub.6 alkoxy, C.sub.2 -C.sub.6 alkenyl, phenylmethyl, amino,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 groups selected from hydroxy, C.sub.1 -C.sub.4 alkoxy, halogen or amino,
• an amine protecting group when R.sup.14 is bonded to N, or
• a hydroxy protecting group when R.sup.14 is bonded to O;
• R.sup.13 and R.sup.14 can alternatively join to form:
• --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 --, --CH.sub.2 CH.sub.2 N(R.sup.15) CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 --;
• R.sup.15 is:
• hydrogen or methyl;
• each of R.sup.20 and R.sup.21 is independently:
• hydrogen,
• C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11,
• C.sub.3 -C.sub.6 alkoxyalkyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkylcarbonyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkoxycarbonyl substituted with 0-3 R.sup.11,
• C.sub.1 -C.sub.6 alkylaminocarbonyl substituted with 0-3 R.sup.11,
• benzoyl substituted with 0-3 R.sup.12,
• phenoxycarbonyl substituted with 0-3 R.sup.12,
• phenylaminocarbonyl substituted with 0-3 R.sup.12,
• or any group that, when administered to a mammalian subject as part of a compound of Formula (I), cleaves to form a free hydroxyl, free amino or free sulfhydryl;
• each of R.sup.22 and R.sup.23 is independently:
• hydrogen,
• C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.31,
• C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.31,
• C.sub.2 -C.sub.8 alkynyl substituted with 0-3 R.sup.31,
• a C.sub.3 -C.sub.14 carbocyclic ring system substituted with 0-5 R.sup.31 or 0-5 R.sup.32, or
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.32 ;
• alternatively, R.sup.22 can join with R.sup.4 or R.sup.4A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, R.sup.23 can join with R.sup.7 or R.sup.7A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R.sup.12, the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, R.sup.22 or R.sup.23 can join with R.sup.5 or R.sup.6 to form a 0- to 7- membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R.sup.12 and the bridge containing 0-3 heteroatoms independently selected from nitrogen, sulfur or oxygen;
• alternatively, the atoms to which R.sup.22 and R.sup.4A are appended may be joined together with a double bond;
• alternatively, the atoms to which R.sup.23 and R.sup.7A are appended may be joined together with a double bond;
• Z is:
• O or S;
• each R.sup.31 is independently:
• keto, halogen, cyano, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), --C(.dbd.O)O(R.sup.13), --C(.dbd.O)(R.sup.11), --OC(.dbd.O)(R.sup.13), --O(R.sup.13), C.sub.2 -C.sub.6 alkoxyalkyl, --S(.dbd.O).sub.m (R.sup.13), --NHC(.dbd.NH)NH(R.sup.13), --C(.dbd.NH)NH(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14)C(.dbd.O)(R.sup.13), .dbd.N--O(R.sup.14), --N(R.sup.14)C(.dbd.O)O(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.14) S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.14)S(.dbd.O).sub.2 (R.sup.13), --S(.dbd.O).sub.2 N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, nitro, C.sub.7 -C.sub.10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 alkyl substituted with --N(R.sup.13)(R.sup.14), C.sub.1 -C.sub.4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.1 -C.sub.4 alkoxycarbonyl, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 - C.sub.4 alkylcarbonyl, C.sub.1 -C.sub.4 alkylcarbonylamino, --OCH.sub.2 C(.dbd.O)O(R.sup.13), 2-(1-morpholino)ethoxy, azido, --C(R.sup.14).dbd.N--O(R.sup.14),
• a C.sub.5 -C.sub.14 carbocyclic residue substituted with 0-5 R.sup.32,
• a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring system being substituted with 0-2 R.sup.32, or
• - 3amino acids, linked together via amide bonds, and linked to R.sup.22 or R.sup.23 via the amine or carboxylate terminus;
• each R.sup.32, when a substituent on carbon, is independently:
• phenethyl, phenoxy, C.sub.3 -C.sub.10 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, C.sub.7 -C.sub.10 arylalkyl, hydrazide, oxime, C.sub.2 -C.sub.6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C.sub.1 -C.sub.4 alkylcarbonyloxy, --NHS(.dbd.O).sub.2 (R.sup.14), phenylmethoxy, halogen, 2-(1-morpholino)ethoxy, --C(.dbd.O)O(R.sup.13), hydroxamic acid, --C(.dbd.O)N(R.sup.13)N(R.sup.13)(R.sup.14), cyano, boronic acid, sulfonamide, formyl, C.sub.3 -C.sub.6 cycloalkoxy, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 haloalkoxy, C.sub.2 -C.sub.4 haloalkenyl, C.sub.2 -C.sub.4 haloalkynyl, --N(R.sup.13)(R.sup.14), --C(R.sup.14).dbd.N--O(R.sup.14), --NO.sub.2, --O(R.sup.13), --N(R.sup.40)(R.sup.41), --S(.dbd.O).sub.m (R.sup.13), --S(.dbd.O).sub.m N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)(R.sup.14), --OC(.dbd.O)N(R.sup.13)(R.sup.14), --C(.dbd.O)(R.sup.11), --OC(.dbd.O)(R.sup.11), --OC(.dbd.O)O(R.sup.13), phenyl, --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)-N(R.sup.13)(R.sup. 14), --C(.dbd.O)N(R.sup.40)(R.sup.41), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)NH(R.sup.14), --C(.dbd.O)N(R.sup.13)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)--(C.sub.1 -C.sub.4 alkyl)--R.sup.11, --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl) --N(R.sup.13)(R.sup.14), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl) --N(R.sup.13)C(.dbd.O)O(R.sup.13),
• C.sub.1 -C.sub.4 alkoxy substituted with 0-4 groups selected from:
• R.sup.11, C.sub.3 -C.sub.6 cycloalkyl, --C(.dbd.O)O(R.sup.13), --C(.dbd.O)N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14) or hydroxyl,
• C.sub.1 -C.sub.4 alkyl substituted with 0-4 groups selected from:
• R.sup.11, .dbd.N(R.sup.14), .dbd.NN(R.sup.13)C(.dbd.O)N(R.sup.13)(R.sup.14) or --N(R.sup.13)(R.sup.14),
• C.sub.2 -C.sub.4 alkenyl substituted with 0-4 R.sup.11,
• C.sub.2 -C.sub.4 alkynyl substituted with 0-4 R.sup.11,
• a 5- or 6-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur,
• a 3- or 4-carbon aliphatic chain attached to an adjacent carbon on the ring to which it is appended, to form a fused 5- or 6-membered ring, the 5- or 6-membered ring being optionally substituted on the aliphatic carbons with halogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxyl --N(R.sup.13)(R.sup.14), or
• when R.sup.32, is attached to a saturated carbon atom, R.sup.32 may be .dbd.O or .dbd.S;
• each R.sup.32 when a substituent on nitrogen, is independently:
• phenyl, phenylmethyl, phenethyl, hydroxyl, C.sub.1 -C.sub.4 hydroxyalkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.6 cycloalkylmethylene, --CH.sub.2 N(R.sup.13)(R.sup.14), --N(R.sup.13)(R.sup.14), C.sub.2 -C.sub.6 alkoxyalkyl, C.sub.1 -C.sub.4 haloalkyl, C.sub.1 -C.sub.4 alkoxycarbonyl, --C(.dbd.O)OH, C.sub.1 -C.sub.4 alkylcarbonyloxy, C.sub.1 -C.sub.4 alkylcarbonyl or --C(R.sup.14).dbd.N--O(R.sup.14);
• R.sup.40 is:
• hydrogen or C.sub.1 -C.sub.3 alkyl;
• R.sup.41 is:
• --C(.dbd.O)N(R.sup.13)(R.sup.14), --C(.dbd.O)N(R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)NH(R.sup.14), --C(.dbd.O)C(R.sup.11).sub.2 N(R.sup.13)C(.dbd.O)O(R.sup.13), --C(.dbd.O) H, --C(.dbd.O)(R.sup.11), --C(.dbd.O)--(C.sub.1 -C.sub.4 alkyl)--N(R.sup.13)(R.sup.14), --C(.dbd.O)--(Cl--C.sub.4 alkyl)--N(R.sup.13)C(.dbd.O)O(R.sup.13) or 1-3 amino acids linked together via amide bonds and linked to the N atom via the carboxylate terminus;
• and
• n is:
• 0, 1 or 2;
• provided that:
• R.sup.4, R.sup.4A, R.sup.7 and R.sup.7A are not all hydrogen;
• when R.sup.4 and R.sup.4A are both hydrogen, R.sup.22 is not hydrogen, and
• when R.sup.7 and R.sup.7A are both hydrogen, R.sup.23 is not hydrogen.