US5508400A — Preparation of cyclic urea compounds

Claim 1

Independent Claim 3094 words

A method for preparing a cyclic urea compound of Formula (Id) 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), (d) converting the substantially pure compound of Formula (Ib) from step (c)(ii) to a cyclic urea compound of Formula (Ic), and (e) converting the compound of Formula (Ic) from step (d) to a cyclic urea compound of Formula (Id), wherein, the compound of Formula (IIa) has the structure shown in Formula (II) with the proviso that R 22 and R 23 are hydrogen, the compound of Formula (IIb) has the structure shown in Formula (II) with the proviso that only one of R 22 or R 23 is hydrogen, the compound of Formula (Ib) has the structure shown in Formula (I) with the proviso that only one of R 22 or R 23 is hydrogen, the compound of Formula (Ic) has the structure shown in Formula (I) with the proviso that neither R 22 nor R 23 is hydrogen, the compound of Formula (Id) has the structure shown in Formula (I) with the provisos that neither R 22 nor R 23 is hydrogen and none of the hydroxyl, sulfhydryl or amine groups which may be present in the compound of Formula (Id) are protected by a hydroxyl, sulhydryl or amine protecting group, compound (I) has a Formula: ##STR37## including a pharmaceutically acceptable salt or prodrug form thereof, and compound (II) has a Formula: ##STR38## wherein, for each compound of Formula (I) and Formula (II): each of R 4 and R 7 is independently: hydrogen, --O(R 13 ), --S(R 13 ), --C(═O)O(R 13 ), C 1 -C 8 alkyl substituted with 0-3 R 11 , C 2 -C 8 alkenyl substituted with 0-3 R 11 , C 2 -C 8 alkynyl substituted with 0-3 R 11 , a C 3 -C 14 carbocyclic ring system substituted with 0-3 R 11 or 0-3 R 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 12 ; each of R 4A and R 7A is independently: hydrogen, --O(R 13 ), --S(R 13 ), --C(═O)O(R 13 ), C 1 -C 4 alkyl unsubstituted or substituted with halogen or C 1 -C 2 alkoxy, or phenylmethyl unsubstituted or substituted with halogen or C 1 -C 2 alkoxy; R 4 and R 4A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R 12 ; R 7 and R 7A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R 12 ; each of R 5 and R 5A is independently: hydrogen, halogen, --N(R 20 ) 2 , --S(R 20 ), --O(R 20 ) or C 1 -C 6 alkyl substituted with 0-3 R 11 ; R 5 and R 5A can alternatively join together to form a ═O, ═S or a ketal ring; each of R 6 and R 6A is independently: hydrogen, halogen, --N(R 20 ) 2 , --S(R 20 ), --O(R 21 ) or C 1 -C 6 alkyl substituted with 0-3 R 11 ; R 6 and R 6A can alternatively join together to form a ═O, ═S or a ketal ring; R 5 and R 6 can alternatively join together to form an epoxide or aziridine ring; --OCH 2 SCH 2 O--, --OS(═O)O--, --OC(═O)O--, --OCH 2 O--, --OC(═S)O--, --OC(═O)C(═O)O--, --OC(CH 3 ) 2 O--, --OC((CH 2 ) 3 NH 2 )(CH 3 )O--, --OC(OCH 3 )(CH 2 CH 2 CH 3 )O--, --OS(═O) 2 O-- , --NHC(═O)NH--, --OC(═O)NH--, --NHC(═O)O--, --NHCH 2 O--, --OCH 2 NH--, --NHC(═S)O--, --OC(═S)NH--, --OS(═O)NH--, --NHS(═O)O--, --NHC(═O)C(═O)O--, --OC(═O)C(═O)NH--, --NHC(═O)C(═O)NH--, --NHC(CH 3 ) 2 O--, --OC(CH 3 ) 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 11 is independently: hydrogen, keto, halogen, cyano, phenylmethyl, phenethyl, methylenedioxy, ethylenedioxy, hydroxamic acid, hydrazide, boronic acid, sulfonamide, azido, formyl, phenoxy, phenylmethoxy, nitro, --CH 2 N (R 13 )(R 14 ), --N(R 13 )(R 14 ), --OCH 2 C(═O)OH, --C(═O)O(R 13 ), --OC(═O)(R 13 ), --O(R 13 ), C 2 -C 6 alkoxyalkyl, --S(═O) m (R 13 ), --NHC(═NH)NH(R 13 ), --C(═NH)NH(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 14 )C(═O)(R 13 ), ═N--O(R 14 ), --N(R 14 )C(═O)O(R 14 ), --OC(═O)N(R 13 )(R 14 ), --N(R 13 )C(═O)N(R 13 )(R 14 ), --C(R 14 )═N--O(R 14 ), --N(R 14 )S(═O) 2 N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 --C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --N(R 13 )(R 14 ), C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, 2-(1-morpholino)ethoxy, --(C 1 -C 3 alkyl)aryl substituted with 0-2 R 12 , a C 5 -C 14 carbocyclic residue substituted with 0-3 R 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 12 ; and - 3amino acids linked together via amide bonds, and linked to R 4 , R 7 , R 20 , or R 21 via the amine or carboxylate terminus; m is: 0, 1 or 2; each R 11A is independently: H, keto, halogen, cyano, --CH 2 NH 2 , --NH 2 , --C(═O)OH, --OC(═O)(C 1 -C 3 alkyl), --OH, C 2 -C 6 alkoxyalkyl, --C(═O)NH 2 , --OC(═O)NH 2 , --NHC(═O)NH 2 , --S(═O) 2 NH 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C 7 -C 10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --NH 2 , C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, --OCH 2 C(═O)OH, 2-(1-morpholino) ethoxy, azido, aryl (C 1 -C 3 alkyl), a C 5 -C 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 12 , when a substituent on carbon, is independently: phenyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, halogen, hydroxy, nitro, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, C 1 -C 4 alkoxy, --C(═O)OH, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, --O(R 13 ), C 1 -C 4 alkyl substituted with --N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, --S(═O) m (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), --NHS(═O) 2 (R 14 ), --OCH 2 C(═O)OH, 2-(1-morpholino) ethoxy, --C(R 14 )═N--O(R 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 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 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, --N(R 13 )(R 14 ), or when R 12 is a substituent on a saturated carbon atom, R 12 may alternatively be ═O or ═S; each R 12 , when a substituent on nitrogen, is independently: phenyl, phenylmethyl, phenethyl, hydroxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxycarbonyl, --C(═O)OH, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl or --C(R 14 )═N--O(R 14 ); each R 13 is independently: hydrogen, phenyl substituted with 0-3 R 11A , phenylmethyl substituted with 0-3 R 11A , C 1 -C 6 alkyl substituted with 0-3 R 11A , C 2 -C 4 alkenyl substituted with 0-3 R 11A , C 1 -C 6 alkylcarbonyl substituted with 0-3 R 11A , C 1 -C 6 alkoxycarbonyl substituted with 0-3 R 11A , C 1 -C 6 alkylaminocarbonyl substituted with 0-3 R 11A , C 3 -C 6 alkoxyalkyl substituted with 0-3 R 11A , an amine protecting group when R 13 is bonded to N, or a hydroxy protecting group when R 13 is bonded to O; each R 14 is independently: hydrogen, hydroxy, trifluoromethyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, phenylmethyl, amino, C 1 -C 6 alkyl substituted with 0-3 groups selected from hydroxy, C 1 -C 4 alkoxy, halogen or amino, an amine protecting group when R 14 is bonded to N, or a hydroxy protecting group when R 14 is bonded to O; R 13 and R 14 can alternatively join to form: --(CH 2 ) 4 --, --(CH 2 ) 5 --, --CH 2 CH 2 N(R 15 )CH 2 CH 2 -- or --CH 2 CH 2 OCH 2 CH 2 --; R 15 is: hydrogen or methyl; each of R 20 and R 21 is independently: hydrogen, C 1 -C 6 alkyl substituted with 0-3 R 11 , C 3 -C 6 alkoxyalkyl substituted with 0-3 R 11 , C 1 -C 6 alkylcarbonyl substituted with 0-3 R 11 , C 1 -C 6 alkoxycarbonyl substituted with 0-3 R 11 , C 1 -C 6 alkylaminocarbonyl substituted with 0-3 R 11 benzoyl substituted with 0-3 R 12 , phenoxycarbonyl substituted with 0-3 R 12 , phenylaminocarbonyl substituted with 0-3 R 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 22 and R 23 is independently: hydrogen, C 1 -C 8 alkyl substituted with 0-3 R 31 , C 2 -C 8 alkenyl substituted with 0-3 R 31 , C 2 -C 8 alkynyl substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring system substituted with 0 5 R 31 or 0-5 R 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 32 ; alternatively, R 22 can join with R 4 or R 4A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 12 the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, R 23 can join with R 7 or R 7A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 12 the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, R 22 or R 23 can join with R 5 or R 6 to form a 0- to 7- membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R 12 and the bridge containing 0-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, the atoms to which R 22 and R 4A are appended may be joined together with a double bond; alternatively, the atoms to which R 23 and R 7A are appended may be joined together with a double bond; Z is: O or S; each R 31 is independently: keto, halogen, cyano, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), --C(═O)O(R 13 ), --C(═O)(R 11 ), --OC(═O)(R 13 ), --O(R 13 ), C 2 -C 6 alkoxyalkyl, --S(═O) m (R 13 ), --NHC(═NH)NH(R 13 ), --C(═NH)NH(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 14 )C(═O)(R 13 ), ═N--O(R 14 ), --N(R 14 )C(═O)O(R 14 ), --OC(═O)N(R 13 )(R 14 ), --N(R 13 )C(═O)N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, nitro, C 7 -C 10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --N(R 13 )(R.sup. 14), C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 - C 4 alkylcarbonylamino, --OCH 2 C(═O)O(R 13 ), 2-(1-morpholino)ethoxy, azido, --C(R 14 )═N--O(R 14 ), a C 5 -C 14 carbocyclic residue substituted with 0-5 R 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 32 , or - 3amino acids, linked together via amide bonds, and linked to R 22 or R 23 via the amine or carboxylate terminus; each R 32 , when a substituent on carbon, is independently: phenethyl, phenoxy, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, hydrazide, oxime, C 2 -C 6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 alkylcarbonyloxy, --NHS(═O) 2 (R 14 ), phenylmethoxy, halogen, 2-(1-morpholino)ethoxy, --C(═O)O(R 13 ), hydroxamic acid, --C(═O)N(R 13 )N(R 13 )(R 14 ), cyano, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 2 -C 4 haloalkenyl, C 2 -C 4 haloalkynyl, --N(R 13 )(R 14 ), --C(R 14 )═N--O(R 14 ), --NO 2 , --O(R 13 ), --N(R 40 )(R 41 ), --S(═O) m (R 13 ), --S(═O) m N(R 13 )(R 14 ), --C(═O)N(R 13 )(R 14 ), --OC(═O)N(R 13 )(R 14 ), --C(═O)(R 11 ), --OC(═O)(R 11 ), --OC(═O)O(R 13 ), phenyl, --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-N(R 13 )(R 14 ), --C(═O)N(R 40 )(R 41 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )NH(R 14 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-N(R 13 )C(═O)O(R 13 ), --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-R 11 , --C(═O)C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )NH(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O)--(C 1 -C 4 alkyl) --N(R 13 )(R 14 ), --C(═O)--(C 1 -C 4 alkyl)--N(R 13 )C(═O)O(R 13 ), C 1 -C 4 alkoxy substituted with 0-4 groups selected from: R 11 , C 3 -C 6 cycloalkyl, --C(═O)O(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 13 )(R 14 ) or hydroxyl, C 1 -C 4 alkyl substituted with 0-4 groups selected from: R 11 , ═N(R 14 ), ═NN(R 13 )C(═O)N(R 13 )(R 14 ) or --N(R 13 )(R 14 ), C 2 -C 4 alkenyl substituted with 0-4 R 11 , C 2 -C 4 alkynyl substituted with 0-4 R 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 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl--N(R 13 )(R 14 ), or when R 32 is attached to a saturated carbon atom, R 32 may be ═O or ═S; each R 32 , when a substituent on nitrogen, is independently: phenyl, phenylmethyl, phenethyl, hydroxyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxycarbonyl, --C(═O)OH, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl or --C(R 14 )═N--O(R 14 ); R 40 is: hydrogen or C 1 -C 3 alkyl; R 41 is: --C(═O)N(R 13 )(R 14 ), --C(═O)N(R 13 )NH(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )NH(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O) H, --C(═O)(R 11 ), --C(═O)--(C 1 -C 4 alkyl)--N(R 13 )(R 14 ), --C(═O)--(C 1 -C 4 alkyl)--N(R 13 )C(═O)O(R 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 4 R 4A R 7 and R 7A are not all hydrogen; when R 4 and R 4A are both hydrogen, R 22 is not hydrogen, and when R 7 and R 7A are both hydrogen, R 23 is not hydrogen.

Claim 2

Independent Claim 3094 words

A method for preparing a cyclic urea compound of Formula (Id) 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), (d) converting the substantially pure compound of Formula (Ib) from step (c)(ii) to a cyclic urea compound of Formula (Ic), and (e) converting the compound of Formula (Ic) from step (d) to a cyclic urea compound of Formula (Id), wherein, the compound of Formula (IIa) has the structure shown in Formula (II) with the proviso that R 22 and R 23 are hydrogen, the compound of Formula (IIb) has the structure shown in Formula (II) with the proviso that only one of R 22 or R 23 is hydrogen, the compound of Formula (Ib) has the structure shown in Formula (I) with the proviso that only one of R 22 or R 23 is hydrogen, the compound of Formula (Ic) has the structure shown in Formula (I) with the proviso that neither R 22 nor R 23 is hydrogen, the compound of Formula (Id) has the structure shown in Formula (I) with the provisos that neither R 22 nor R 23 is hydrogen and none of the hydroxyl, sulfhydryl or amine groups which may be present in the compound of Formula (Id) are protected by a hydroxyl, sulhydryl or amine protecting group, compound (I) has a Formula: ##STR37## including a pharmaceutically acceptable salt or prodrug form thereof, and compound (II) has a Formula: ##STR38## wherein, for each compound of Formula (I) and Formula (II): each of R 4 and R 7 is independently: hydrogen, --O(R 13 ), --S(R 13 ), --C(═O)O(R 13 ), C 1 -C 8 alkyl substituted with 0-3 R 11 , C 2 -C 8 alkenyl substituted with 0-3 R 11 , C 2 -C 8 alkynyl substituted with 0-3 R 11 , a C 3 -C 14 carbocyclic ring system substituted with 0-3 R 11 or 0-3 R 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 12 ; each of R 4A and R 7A is independently: hydrogen, --O(R 13 ), --S(R 13 ), --C(═O)O(R 13 ), C 1 -C 4 alkyl unsubstituted or substituted with halogen or C 1 -C 2 alkoxy, or phenylmethyl unsubstituted or substituted with halogen or C 1 -C 2 alkoxy; R 4 and R 4A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R 12 ; R 7 and R 7A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R 12 ; each of R 5 and R 5A is independently: hydrogen, halogen, --N(R 20 ) 2 , --S(R 20 ), --O(R 20 ) or C 1 -C 6 alkyl substituted with 0-3 R 11 ; R 5 and R 5A can alternatively join together to form a ═O, ═S or a ketal ring; each of R 6 and R 6A is independently: hydrogen, halogen, --N(R 20 ) 2 , --S(R 20 ), --O(R 21 ) or C 1 -C 6 alkyl substituted with 0-3 R 11 ; R 6 and R 6A can alternatively join together to form a ═O, ═S or a ketal ring; R 5 and R 6 can alternatively join together to form an epoxide or aziridine ring; --OCH 2 SCH 2 O--, --OS(═O)O--, --OC(═O)O--, --OCH 2 O--, --OC(═S)O--, --OC(═O)C(═O)O--, --OC(CH 3 ) 2 O--, --OC((CH 2 ) 3 NH 2 )(CH 3 )O--, --OC(OCH 3 )(CH 2 CH 2 CH 3 )O--, --OS(═O) 2 O-- , --NHC(═O)NH--, --OC(═O)NH--, --NHC(═O)O--, --NHCH 2 O--, --OCH 2 NH--, --NHC(═S)O--, --OC(═S)NH--, --OS(═O)NH--, --NHS(═O)O--, --NHC(═O)C(═O)O--, --OC(═O)C(═O)NH--, --NHC(═O)C(═O)NH--, --NHC(CH 3 ) 2 O--, --OC(CH 3 ) 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 11 is independently: hydrogen, keto, halogen, cyano, phenylmethyl, phenethyl, methylenedioxy, ethylenedioxy, hydroxamic acid, hydrazide, boronic acid, sulfonamide, azido, formyl, phenoxy, phenylmethoxy, nitro, --CH 2 N (R 13 )(R 14 ), --N(R 13 )(R 14 ), --OCH 2 C(═O)OH, --C(═O)O(R 13 ), --OC(═O)(R 13 ), --O(R 13 ), C 2 -C 6 alkoxyalkyl, --S(═O) m (R 13 ), --NHC(═NH)NH(R 13 ), --C(═NH)NH(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 14 )C(═O)(R 13 ), ═N--O(R 14 ), --N(R 14 )C(═O)O(R 14 ), --OC(═O)N(R 13 )(R 14 ), --N(R 13 )C(═O)N(R 13 )(R 14 ), --C(R 14 )═N--O(R 14 ), --N(R 14 )S(═O) 2 N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 --C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --N(R 13 )(R 14 ), C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, 2-(1-morpholino)ethoxy, --(C 1 -C 3 alkyl)aryl substituted with 0-2 R 12 , a C 5 -C 14 carbocyclic residue substituted with 0-3 R 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 12 ; and - 3amino acids linked together via amide bonds, and linked to R 4 , R 7 , R 20 , or R 21 via the amine or carboxylate terminus; m is: 0, 1 or 2; each R 11A is independently: H, keto, halogen, cyano, --CH 2 NH 2 , --NH 2 , --C(═O)OH, --OC(═O)(C 1 -C 3 alkyl), --OH, C 2 -C 6 alkoxyalkyl, --C(═O)NH 2 , --OC(═O)NH 2 , --NHC(═O)NH 2 , --S(═O) 2 NH 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C 7 -C 10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --NH 2 , C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, --OCH 2 C(═O)OH, 2-(1-morpholino) ethoxy, azido, aryl (C 1 -C 3 alkyl), a C 5 -C 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 12 , when a substituent on carbon, is independently: phenyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, halogen, hydroxy, nitro, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, C 1 -C 4 alkoxy, --C(═O)OH, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, --O(R 13 ), C 1 -C 4 alkyl substituted with --N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, --S(═O) m (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), --NHS(═O) 2 (R 14 ), --OCH 2 C(═O)OH, 2-(1-morpholino) ethoxy, --C(R 14 )═N--O(R 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 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 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, --N(R 13 )(R 14 ), or when R 12 is a substituent on a saturated carbon atom, R 12 may alternatively be ═O or ═S; each R 12 , when a substituent on nitrogen, is independently: phenyl, phenylmethyl, phenethyl, hydroxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxycarbonyl, --C(═O)OH, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl or --C(R 14 )═N--O(R 14 ); each R 13 is independently: hydrogen, phenyl substituted with 0-3 R 11A , phenylmethyl substituted with 0-3 R 11A , C 1 -C 6 alkyl substituted with 0-3 R 11A , C 2 -C 4 alkenyl substituted with 0-3 R 11A , C 1 -C 6 alkylcarbonyl substituted with 0-3 R 11A , C 1 -C 6 alkoxycarbonyl substituted with 0-3 R 11A , C 1 -C 6 alkylaminocarbonyl substituted with 0-3 R 11A , C 3 -C 6 alkoxyalkyl substituted with 0-3 R 11A , an amine protecting group when R 13 is bonded to N, or a hydroxy protecting group when R 13 is bonded to O; each R 14 is independently: hydrogen, hydroxy, trifluoromethyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, phenylmethyl, amino, C 1 -C 6 alkyl substituted with 0-3 groups selected from hydroxy, C 1 -C 4 alkoxy, halogen or amino, an amine protecting group when R 14 is bonded to N, or a hydroxy protecting group when R 14 is bonded to O; R 13 and R 14 can alternatively join to form: --(CH 2 ) 4 --, --(CH 2 ) 5 --, --CH 2 CH 2 N(R 15 )CH 2 CH 2 -- or --CH 2 CH 2 OCH 2 CH 2 --; R 15 is: hydrogen or methyl; each of R 20 and R 21 is independently: hydrogen, C 1 -C 6 alkyl substituted with 0-3 R 11 , C 3 -C 6 alkoxyalkyl substituted with 0-3 R 11 , C 1 -C 6 alkylcarbonyl substituted with 0-3 R 11 , C 1 -C 6 alkoxycarbonyl substituted with 0-3 R 11 , C 1 -C 6 alkylaminocarbonyl substituted with 0-3 R 11 benzoyl substituted with 0-3 R 12 , phenoxycarbonyl substituted with 0-3 R 12 , phenylaminocarbonyl substituted with 0-3 R 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 22 and R 23 is independently: hydrogen, C 1 -C 8 alkyl substituted with 0-3 R 31 , C 2 -C 8 alkenyl substituted with 0-3 R 31 , C 2 -C 8 alkynyl substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring system substituted with 0 5 R 31 or 0-5 R 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 32 ; alternatively, R 22 can join with R 4 or R 4A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 12 the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, R 23 can join with R 7 or R 7A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 12 the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, R 22 or R 23 can join with R 5 or R 6 to form a 0- to 7- membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R 12 and the bridge containing 0-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, the atoms to which R 22 and R 4A are appended may be joined together with a double bond; alternatively, the atoms to which R 23 and R 7A are appended may be joined together with a double bond; Z is: O or S; each R 31 is independently: keto, halogen, cyano, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), --C(═O)O(R 13 ), --C(═O)(R 11 ), --OC(═O)(R 13 ), --O(R 13 ), C 2 -C 6 alkoxyalkyl, --S(═O) m (R 13 ), --NHC(═NH)NH(R 13 ), --C(═NH)NH(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 14 )C(═O)(R 13 ), ═N--O(R 14 ), --N(R 14 )C(═O)O(R 14 ), --OC(═O)N(R 13 )(R 14 ), --N(R 13 )C(═O)N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, nitro, C 7 -C 10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --N(R 13 )(R.sup. 14), C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 - C 4 alkylcarbonylamino, --OCH 2 C(═O)O(R 13 ), 2-(1-morpholino)ethoxy, azido, --C(R 14 )═N--O(R 14 ), a C 5 -C 14 carbocyclic residue substituted with 0-5 R 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 32 , or - 3amino acids, linked together via amide bonds, and linked to R 22 or R 23 via the amine or carboxylate terminus; each R 32 , when a substituent on carbon, is independently: phenethyl, phenoxy, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, hydrazide, oxime, C 2 -C 6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 alkylcarbonyloxy, --NHS(═O) 2 (R 14 ), phenylmethoxy, halogen, 2-(1-morpholino)ethoxy, --C(═O)O(R 13 ), hydroxamic acid, --C(═O)N(R 13 )N(R 13 )(R 14 ), cyano, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 2 -C 4 haloalkenyl, C 2 -C 4 haloalkynyl, --N(R 13 )(R 14 ), --C(R 14 )═N--O(R 14 ), --NO 2 , --O(R 13 ), --N(R 40 )(R 41 ), --S(═O) m (R 13 ), --S(═O) m N(R 13 )(R 14 ), --C(═O)N(R 13 )(R 14 ), --OC(═O)N(R 13 )(R 14 ), --C(═O)(R 11 ), --OC(═O)(R 11 ), --OC(═O)O(R 13 ), phenyl, --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-N(R 13 )(R 14 ), --C(═O)N(R 40 )(R 41 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )NH(R 14 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-N(R 13 )C(═O)O(R 13 ), --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-R 11 , --C(═O)C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )NH(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O)--(C 1 -C 4 alkyl) --N(R 13 )(R 14 ), --C(═O)--(C 1 -C 4 alkyl)--N(R 13 )C(═O)O(R 13 ), C 1 -C 4 alkoxy substituted with 0-4 groups selected from: R 11 , C 3 -C 6 cycloalkyl, --C(═O)O(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 13 )(R 14 ) or hydroxyl, C 1 -C 4 alkyl substituted with 0-4 groups selected from: R 11 , ═N(R 14 ), ═NN(R 13 )C(═O)N(R 13 )(R 14 ) or --N(R 13 )(R 14 ), C 2 -C 4 alkenyl substituted with 0-4 R 11 , C 2 -C 4 alkynyl substituted with 0-4 R 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 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl--N(R 13 )(R 14 ), or when R 32 is attached to a saturated carbon atom, R 32 may be ═O or ═S; each R 32 , when a substituent on nitrogen, is independently: phenyl, phenylmethyl, phenethyl, hydroxyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxycarbonyl, --C(═O)OH, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl or --C(R 14 )═N--O(R 14 ); R 40 is: hydrogen or C 1 -C 3 alkyl; R 41 is: --C(═O)N(R 13 )(R 14 ), --C(═O)N(R 13 )NH(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )NH(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O) H, --C(═O)(R 11 ), --C(═O)--(C 1 -C 4 alkyl)--N(R 13 )(R 14 ), --C(═O)--(C 1 -C 4 alkyl)--N(R 13 )C(═O)O(R 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 4 R 4A R 7 and R 7A are not all hydrogen; when R 4 and R 4A are both hydrogen, R 22 is not hydrogen, and when R 7 and R 7A are both hydrogen, R 23 is not hydrogen.

Claim 3

Dependent Claim 138 words

The method according to claim 1, wherein the direct alkylation of step (a) comprises treating a compound of Formula (IIa) with a base and an alkylating agent, where the alkylating agent has the Formula R 16 X 1 , wherein R 16 is: C 1 -C 8 alkyl substituted with 0-3 R 31 , C 2 -C 8 alkenyl substituted with 0-3 R 31 , C 2 -C 8 alkynyl substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring system substituted with 0-5 R 31 or 0-5 R 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 32 ; and X 1 is a leaving group susceptible to displacement with an amino nitrogen.

Claim 4

Dependent Claim 16 words

The method according to claim 2, wherein the leaving group is halide, tosylate, mesylate or acetate.

Claim 5

Dependent Claim 35 words

The method according to claim 2, wherein the compound of Formula (IIa) and the alkylating agent of Formula R 16 X 1 are contacted in a molar ratio of between about 1:0.9 and about 1:1.5

Claim 6

Dependent Claim 23 words

The method according to claim 2, wherein the base is potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate or sodium bicarbonate.

Claim 7

Dependent Claim 20 words

The method according to claim 2, wherein the direct alkylation is conducted in the presence of a phase transfer agent.

Claim 8

Dependent Claim 17 words

The method according to claim 6, wherein the phase transfer agent is tetrabutylammonium iodide and potassium iodide.

Claim 9

Dependent Claim 72 words

The method according to claim 2, wherein the direct alkylation is conducted in a solvent selected from the group consisting of acetonitrile and tetrahydrofuran, and wherein the compound of Formula (IIa) is present in the solvent at a concentration of about 0.03 molar to about 3.0 molar, and wherein the base is potassium carbonate, and wherein about two equivalents of base are present for each equivalent of the compound of Formula (IIa).

Claim 10

Dependent Claim 147 words

The method according to claim 1, wherein the reductive amination of step (a) comprises reacting a compound of Formula (IIa) with a carbonyl compound to form an intermediate oxime, and reacting the intermediate oxime with a reducing agent to form a compound of Formula (IIb), wherein the carbonyl compound is C 1 -C 8 alkane substituted with 0-3 R 31 , C 2 -C 8 alkene substituted with 0-3 R 31 , C 2 -C 8 alkyne substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring substituted with 0-5 R 31 or 0-5 R 32 and a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring being substituted with 0-2 R 32 , with the proviso that at least one methylene group (--CH 2 --) is replaced with a carbonyl group (--C(═O)--).

Claim 11

Dependent Claim 85 words

The method according to claim 9, wherein the reducing agent is NaBH 4 , lithium aluminum hydride (LiAlH 4 ), sodium cyanoborohydride (NaBH 3 CN), borane complexes including BH 3 .THF, BH 3 .SMe 2 , BH 3 .amine including pyridine, and other borane compounds including BH(OAc) 3 , BH(O 2 CCF3) 2 , NaBH(OAc) 3 , (t-butyl)NH 2 BH 3 , LiBH(Et) 3 , LiBH(t-butyl) 3 , NaAlH 2 (O(CH 2 ) 2 OCH 3 ), LiBH(sec-butyl) 3 or Zn(BH 3 CN) 2 .

Claim 12

Dependent Claim 23 words

The method according to claim 9, wherein the molar ratio of the carbonyl compound to the compound of Formula (IIa) is about 1:1.

Claim 13

Dependent Claim 102 words

The method according to claim 1, wherein the successive acylation and reduction of step (a) comprises reacting a compound of Formula (IIa) with an acylating agent of Formula R 17 (C═O)X 2 to form an amide compound, and the amide compound is reacted with a reducing agent to form a compound of Formula (IIb), wherein R 17 is: C 1 -C 7 alkyl substituted with 0-3 R 31 , C 2 -C 7 alkenyl substituted with 0-3 R 31 , C 2 C 7 alkynyl substituted with 0-3 R 31 , or --R 31 ; and X 2 is a leaving group.

Claim 14

Dependent Claim 20 words

The method according to claim 12 wherein the leaving group X 2 is halide, --OR 17 or --OC(═O)R 17 .

Claim 15

Dependent Claim 23 words

The method according to claim 12 wherein the molar ratio of the acylating agent to the compound of Formula (IIa) is about 1:1.

Claim 16

Dependent Claim 71 words

The method according to claim 12, wherein the reducing agent is lithium aluminum hydride (LiAlH 4 ), BH 3 .THF, BH 3 .SMe 2 , B 2 H 6 , NaBH 4 and MeSO 3 H in DMSO, (Bu) 4 NBH 4 in methylene chloride, NaBH 4 --TiCl 4 in dimethoxyethane, NiCl 2 in methanol, heterogeneous catalytic hydrogenation with Cu chromite, Ba/Cu chromite, Raney nickel, Raney cobalt, or rhenium on carbon.

Claim 17

Dependent Claim 43 words

The method according to claim 1, wherein step (b) comprises reacting a compound of Formula (IIb) with either carbonyl diimidazole, thereby forming a cyclic urea of Formula (Ib) having Z=O, or thiocarbonyl diimidazole, thereby forming a cyclic urea of Formula (Ib) having Z=S.

Claim 18

Dependent Claim 27 words

The method according to claim 1, wherein the aqueous acid solution of step (c)(i) is an aqueous hydrochloric acid, nitric acid, phosphoric acid or citric acid solution.

Claim 19

Dependent Claim 20 words

The method according to claim 1, wherein the aqueous acid solution of step (c)(i) is an aqueous citric acid solution.

Claim 20

Dependent Claim 124 words

The method according to claim 1, wherein step (d) comprises treating the product of step (c)(ii) with an alkylating agent of Formula R 16 X 1 in the presence of a base, wherein R 16 is: C 1 -C 8 alkyl substituted with 0-3 R 31 , C 2 -C 8 alkenyl substituted with 0-3 R 31 , C 2 -C 8 alkynyl substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring system substituted with 0-5 R 31 or 0-5 R 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 32 ; and X 1 is a leaving group.

Claim 21

Dependent Claim 18 words

The method according to claim 19, wherein the leaving group X 1 is halide, mesylate, tosylate or acetate.

Claim 22

Dependent Claim 12 words

The method according to claim 19, wherein the base is sodium hydride.

Claim 23

Dependent Claim 23 words

The method according to claim 19, wherein the molar ratio of the product of step (c)(ii) to the alkylating agent is about 1:1.

Claim 24

Dependent Claim 45 words

The method according to claim 1, wherein step (e) comprises subjecting the cyclic urea compound of Formula (Ic) as produced in step (d) to an acidic or basic condition, so as to remove at least one protecting group if such a protecting group is present.

Claim 25

Dependent Claim 21 words

The method according to claim 23, wherein the acidic condition comprises subjecting the product of step (d) to aqueous hydrochloric acid.

Claim 26

Independent Claim 3018 words

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

Claim 27

Independent Claim 3018 words

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

Claim 28

Dependent Claim 135 words

The method according to claim 25, wherein the direct alkylation of step (a) comprises treating a compound of Formula (IIa) with a base and an alkylating agent, where the alkylating agent has the Formula R 16 X 1 wherein R 16 is: C 1 -C 8 alkyl substituted with 0-3 R 31 C 2 -C 8 alkenyl substituted with 0-3 R 31 C 2 -C 8 alkynyl substituted with 0-3 R 31 a C 3 -C 14 carbocyclic ring system substituted with 0-5 R 31 or 0-5 R 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 32 ; and X 1 is a leaving group susceptible to displacement with an amino nitrogen.

Claim 29

Dependent Claim 18 words

The method according to claim 26, wherein the leaving group X 1 is halide, tosylate, mesylate or acetate.

Claim 30

Dependent Claim 35 words

The method according to claim 26, wherein the compound of Formula (IIa) and the alkylating agent of Formula R 16 X 1 are contacted in a molar ratio of between about 1:0.9 and about 1:1.5.

Claim 31

Dependent Claim 23 words

The method according to claim 26, wherein the base is potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate or sodium bicarbonate.

Claim 32

Dependent Claim 20 words

The method according to claim 26, wherein the direct alkylation is conducted in the presence of a phase transfer agent.

Claim 33

Dependent Claim 17 words

The method according to claim 30, wherein the phase transfer agent is tetrabutylammonium iodide and potassium iodide.

Claim 34

Dependent Claim 72 words

The method according to claim 26, wherein the direct alkylation is conducted in a solvent selected from the group consisting of acetonitrile and tetrahydrofuran, and wherein the compound of Formula (IIa) is present in the solvent at a concentration of about 0.03 molar to about 3.0 molar, and wherein the base is potassium carbonate, and wherein about two equivalents of base are present for each equivalent of the compound of Formula (IIa).

Claim 35

Dependent Claim 148 words

The method according to claim 25, wherein the reductive amination of step (a) comprises reacting a compound of Formula (IIa) with a carbonyl compound to form an intermediate oxime, and reacting the intermediate oxime with a reducing agent to form a compound of Formula (IIb), wherein the carbonyl compound is C 1 -C 8 alkane substituted with 0-3 R 31 , C 2 -C 8 alkene substituted with 0-3 R 31 , C 2 -C 8 alkyne substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring substituted with 0-5 R 31 or 0-5 R 32 , and a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring being substituted with 0-2 R 32 , with the proviso that at least one methylene group (--CH 2 --) is replaced with a carbonyl group (--C(═O)--).

Claim 36

Dependent Claim 89 words

The method according to claim 33, wherein the reducing agent is NaBH 4 , lithium aluminum hydride (LiAlH 4 ), sodium cyanoborohydride (NaBH 3 CN), borane complexes including BH 3 .THF, BH 3 .SMe 2 , BH 3 .amine including pyridine, and other borane compounds including BH (OAc) 3 , BH (O 2 CCF3) 2 , NaBH(OAc) 3 , (t-butyl)NH 2 BH 3 , LiBH(Et) 3 , LiBH(t-butyl) 3 , NaAlH 2 (O(CH 2 ) 2 OCH 3 ), LiBH (sec-butyl) 3 or Zn (BH 3 CN) 2 .

Claim 37

Dependent Claim 23 words

The method according to claim 33, wherein the molar ratio of the carbonyl compound to the compound of Formula (IIa) is about 1:1.

Claim 38

Dependent Claim 101 words

The method according to claim 25, wherein the successive acylation and reduction of step (a) comprises reacting a compound of Formula (IIa) with an acylating agent of Formula R 17 (C═O)X 2 to form an amide compound, and the amide compound is reacted with a reducing agent to form a compound of Formula (IIb), wherein R 17 is: C 1 -C 7 alkyl substituted with 0-3 R 31 , C 2 -C 7 alkenyl substituted with 0-3 R 31 C 2 -C 7 alkynyl substituted with 0-3 R 31 , or --R 31 ; and X 2 is a leaving group.

Claim 39

Dependent Claim 21 words

The method according to claim 36 wherein the leaving group X 2 is halide, --OR 17 or --OC(═O) R 17 .

Claim 40

Dependent Claim 23 words

The method according to claim 36 wherein the molar ratio of the acylating agent to the compound of Formula (IIa) is about 1:1.

Claim 41

Dependent Claim 71 words

The method according to claim 36, wherein the reducing agent is lithium aluminum hydride (LiAlH 4 ), BH 3 .THF, BH 3 .SMe 2 , B 2 H 6 , NaBH 4 and MeSO 3 H in DMSO, (Bu) 4 NBH 4 in methylene chloride, NaBH 4 -TiCl 4 in dimethoxyethane, NiCl 2 in methanol, heterogeneous catalytic hydrogenation with Cu chromite, Ba/Cu chromite, Raney nickel, Raney cobalt, or rhenium on carbon.

Claim 42

Dependent Claim 43 words

The method according to claim 25, wherein step (b) comprises reacting a compound of Formula (IIb) with either carbonyl diimidazole, thereby forming a cyclic urea of Formula (Ib) having Z=O, or thiocarbonyl diimidazole, thereby forming a cyclic urea of Formula (Ib) having Z=S.

Claim 43

Dependent Claim 19 words

The method according to claim 25, wherein the aqueous acid solution of step (c)(i) is an organic carboxylic acid.

Claim 44

Dependent Claim 20 words

The method according to claim 25, wherein the aqueous acid solution of step (c)(i) is an aqueous citric acid solution.

Claim 45

Dependent Claim 124 words

The method according to claim 25, wherein step (d) comprises treating the product of step (c)(ii) with an alkylating agent of Formula R 16 X 1 in the presence of a base, wherein R 16 is: C 1 -C 8 alkyl substituted with 0-3 R 31 , C 2 -C 8 alkenyl substituted with 0-3 R 31 , C 2 -C 8 alkynyl substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring system substituted with 0-5 R 31 or 0-5 R 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 32 ; and X 1 is a leaving group.

Claim 46

Dependent Claim 18 words

The method according to claim 43, wherein the leaving group X 1 is halide, mesylate, tosylate or acetate.

Claim 47

Dependent Claim 12 words

The method according to claim 43, wherein the base is sodium hydride.

Claim 48

Dependent Claim 23 words

The method according to claim 43, wherein the molar ratio of the product of step (c)(ii) to the alkylating agent is about 1:1.

Claim 49

Independent Claim 2970 words

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 22 and R 23 are hydrogen, the compound of Formula (IIb) has the structure shown in Formula (II) with the proviso that only one of R 22 or R 23 is hydrogen, the compound of Formula (Ib) has the structure shown in Formula (I) with the proviso that only one of R 22 or R 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 4 and R 7 is independently: hydrogen, --O(R 13 ), --S(R 13 ), --C(═O)O(R 13 ), C 1 -C 8 alkyl substituted with 0-3 R 11 , C 2 -C 8 alkenyl substituted with 0-3 R 11 , C 2 -C 8 alkynyl substituted with 0-3 R 11 , a C 3 -C 14 carbocyclic ring system substituted with 0-3 R 11 or 0-3 R 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 12 ; each of R 4A and R 7A is independently: hydrogen, --O(R 13 ), --S(R 13 ), --C(═O)O(R 13 ), C 1 -C 4 alkyl unsubstituted or substituted with halogen or C 1 -C 2 alkoxy, or phenylmethyl unsubstituted or substituted with halogen or C 1 -C 2 alkoxy; R 4 and R 4A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R 12 ; R 7 and R 7A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R 12 ; each of R 5 and R 5A is independently: hydrogen, halogen, --N(R 20 ) 2 , --S(R 20 ), --O(R 20 ) or C 1 -C 6 alkyl substituted with 0-3 R 11 ; R 5 and R 5A can alternatively join together to form a ═O, ═S or a ketal ring; each of R 6 and R 6A is independently: hydrogen, halogen, --N(R 20 ) 2 , --S(R 20 ), --O(R 21 ) or C 1 -C 6 alkyl substituted with 0-3 R 11 ; R 6 and R 6A can alternatively join together to form a ═O, ═S or a ketal ring; R 5 and R 6 can alternatively join together to form an epoxide or aziridine ring; --OCH 2 SCH 2 O--, --OS(═O)O--, --OC(═O)O--, --OCH 2 O--, --OC(═S)O--, --OC(═O)C(═O)O--, --OC(CH 3 ) 2 O--, --OC((CH 2 ) 3 NH 2 )(CH 3 )O--, --OC(OCH 3 )(CH 2 CH 2 CH 3 )O--, --OS(═O) 2 O--, --NHC(═O)NH--, --OC(═O)NH--, --NHC(═O)O--, --NHCH 2 O--, --OCH 2 NH--, --NHC(═S)O--, --OC(═S)NH--, --OS(═O)NH--, --NHS(═O)O--, --NHC(═O)C(═O)O--, --OC(═O)C(═O)NH--, --NHC(═O)C(═O)NH--, --NHC(CH 3 ) 2 O--, --OC(CH 3 ) 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 11 is independently: hydrogen, keto, halogen, cyano, phenylmethyl, phenethyl, methylenedioxy, ethylenedioxy, hydroxamic acid, hydrazide, boronic acid, sulfonamide, azido, formyl, phenoxy, phenylmethoxy, nitro, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), --OCH 2 C(═O)OH, --C(═O)O(R 13 ), --OC(═O)(R 13 ), --O(R 13 ), C 2 -C 6 alkoxyalkyl, --S(═O) m (R 13 ), --NHC(═NH)NH(R 13 ), --C(═NH)NH(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 14 )C(═O)(R 13 ), ═N--O(R 14 ), --N(R 14 )C(═O)O(R 14 ), --OC(═O)N(R 13 )(R 14 ), --N(R 13 )C(═O)N(R 13 )(R 14 ), --C(R 14 )═N--O(R 14 ), --N(R 14 ) S(═O) 2 N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --N(R 13 )(R 14 ), C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 C 4 alkylcarbonyloxy, C 1 C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, 2-(1-morpholino)ethoxy, --(C 1 -C 3 alkyl) aryl substituted with 0-2 R 12 , a C 5 -C 14 carbocyclic residue substituted with 0-3 R 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 12 ; and - 3amino acids linked together via amide bonds, and linked to R 4 R 7 R 20 or R 21 via the amine or carboxylate terminus; m is: 0, 1 or 2; each R 11A is independently: H, keto, halogen, cyano, --CH 2 NH 2 , --NH 2 , --C(═O)OH, --OC(═O)(C 1 -C 3 alkyl), --OH, C 2 -C 6 alkoxyalkyl, --C(═O)NH 2 , --OC(═O)NH 2 , --NHC(═O)NH 2 , --S(═O) 2 NH 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C 7 -C 10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --NH 2 , C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, --OCH 2 C(═O)OH, 2-(1-morpholino)ethoxy, azido, aryl(C 1 -C 3 alkyl), a C 5 -C 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 12 when a substituent on carbon, is independently: phenyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, halogen, hydroxy, nitro, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, C 1 -C 4 alkoxy, --C(═O)OH, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, --O(R 13 ), C 1 -C 4 alkyl substituted with --N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, --S(═O) m (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), --NHS(═O) 2 (R 14 ), --OCH 2 C(═O)OH, 2-(1-morpholino)ethoxy, --C(R 14 )═N--O(R 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 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 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, --N(R 13 )(R 14 ), or when R 12 is a substituent on a saturated carbon atom, R 12 may alternatively be ═O or ═S; each R 12 when a substituent on nitrogen, is independently: phenyl, phenylmethyl, phenethyl, hydroxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxycarbonyl, --C(═O)OH, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl or --C(R 14 )═N--O (R 14 ); each R 13 is independently: hydrogen, phenyl substituted with 0-3 R 11A , phenylmethyl substituted with 0-3 R 11A , C 1 -C 6 alkyl substituted with 0-3 R 11A , C 2 -C 4 alkenyl substituted with 0-3 R 11A , C 1 -C 6 alkylcarbonyl substituted with 0-3 R 11A , C 1 -C 6 alkoxycarbonyl substituted with 0-3 R 11A , C 1 -C 6 alkylaminocarbonyl substituted with 0-3 R 11A , C 3 -C 6 alkoxyalkyl substituted with 0-3 R 11A , an amine protecting group when R 13 is bonded to N, or a hydroxy protecting group when R 13 is bonded to O; each R 14 is independently: hydrogen, hydroxy, trifluoromethyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, phenylmethyl, amino, C 1 -C 6 alkyl substituted with 0-3 groups selected from hydroxy, C 1 -C 4 alkoxy, halogen or amino, an amine protecting group when R 14 is bonded to N, or a hydroxy protecting group when R 14 is bonded to O; R 13 and R 14 can alternatively join to form: --(CH 2 ) 4 --, --(CH 2 ) 5 --, --CH 2 CH 2 N(R 15 )CH 2 CH 2 -- or --CH 2 CH 2 OCH 2 CH 2 --; R 15 is: hydrogen or methyl; each of R 20 and R 21 is independently: hydrogen, C 1 -C 6 alkyl substituted with 0-3 R 11 , C 3 -C 6 alkoxyalkyl substituted with 0-3 R 11 , C 1 -C 6 alkylcarbonyl substituted with 0-3 R 11 C 1 -C 6 alkoxycarbonyl substituted with 0-3 R 11 , C 1 -C 6 alkylaminocarbonyl substituted with 0-3 R 11 benzoyl substituted with 0-3 R 12 , phenoxycarbonyl substituted with 0-3 R 12 , phenylaminocarbonyl substituted with 0-3 R 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 22 and R 23 is independently: hydrogen, C 1 -C 8 alkyl substituted with 0-3 R 31 , C 2 -C 8 alkenyl substituted with 0-3 R 31 , C 2 -C 8 alkynyl substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring system substituted with 0-5 R 31 or 0-5 R 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 32 ; alternatively, R 22 can join with R 4 or R 4A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 12 , the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, R 23 can join with R 7 or R 7A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 12 the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, R 22 or R 23 can join with R 5 or R 6 to form a 0- to 7- membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R 12 and the bridge containing 0-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, the atoms to which R 22 and R 4A are appended may be joined together with a double bond; alternatively, the atoms to which R 23 and R 7A are appended may be joined together with a double bond; Z is: O or S; each R 31 is independently: keto, halogen, cyano, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), --C(═O)O(R 13 ), --C(═O)(R 11 ), --OC(═O)(R 13 ), --O(R 13 ), C 2 -C 6 alkoxyalkyl, --S(═O) m (R 13 ), --NHC(═NH)NH(R 13 ), --C(═NH)NH(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 14 )C(═O)(R 13 ), ═N--O(R 14 ), --N(R 14 )C(═O)O(R 14 ), --OC(═O)N(R 13 )(R 14 ), --N(R 13 )C(═O)N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, nitro, C 7 -C 10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --N(R 13 )(R 14 ), C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, --OCH 2 C(═O)O(R 13 ), 2-(1-morpholino)ethoxy, azido, --C(R 14 )═N--O(R 14 ), a C 5 -C 14 carbocyclic residue substituted with 0-5 R 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 32 or - 3amino acids, linked together via amide bonds, and linked to R 22 or R 23 via the amine or carboxylate terminus; each R 32 when a substituent on carbon, is independently: phenethyl, phenoxy, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, hydrazide, oxime, C 2 -C 6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 alkylcarbonyloxy, --NHS(═O) 2 (R 14 ), phenylmethoxy, halogen, 2-(1-morpholino)ethoxy, --C(═O)O(R 13 ), hydroxamic acid, --C(═O)N(R 13 )N(R 13 )(R 14 ), cyano, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, C1--C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 2 -C 4 haloalkenyl, C 2 -C 4 haloalkynyl, --N(R 13 )(R 14 ), --C(R 14 )═N--O (R 14 ), --NO 2 , --O(R 13 ), --N(R 40 )(R 41 ), --S(═O) m (R 13 ), --S(═O) m N(R 13 )(R 14 ), --C(═O)N(R 13 )(R 14 ), --OC(═O)N(R 13 )(R 14 ), --C(═O)(R 11 ), --OC(═O)(R 11 ), --OC(═O)O(R 13 ), phenyl, --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-N(R 13 )(R 14 ), --C(═O)N(R 40 )(R 41 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )NH(R 14 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-N(R 13 )C(═O)O(R 13 ), --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-R 11 , --C(═O)C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )NH(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O)--(C 1 -C 4 alkyl)--N(R 13 )(R 14 ), --C(═O)--(C 1 -C 4 alkyl) --N(R 13 )C(═O)O(R 13 ), C 1 -C 4 alkoxy substituted with 0-4 groups selected from: R 11 , C 3 -C 6 cycloalkyl, --C(═O)O(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 13 )(R 14 ) or hydroxyl, C 1 -C 4 alkyl substituted with 0-4 groups selected from: R 11 ═N(R 14 ), ═NN(R 13 )C(═O)N(R 13 )(R 14 ) or --N(R 13 )(R 14 ), C 2 -C 4 alkenyl substituted with 0-4 R 11 , C 2 -C 4 alkynyl substituted with 0-4 R 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 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl--N(R 13 )(R 14 ), or when R 32 is attached to a saturated carbon atom, R 32 may be ═O or ═S; each R 32 , when a substituent on nitrogen, is independently: phenyl, phenylmethyl, phenethyl, hydroxyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxycarbonyl, --C(═O)OH, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl or --C(R 14 )═N--O(R 14 ); R 40 is: hydrogen or C 1 -C 3 alkyl; R 41 is: --C(═O)N(R 13 )(R 14 ), --C(═O)N(R 13 )NH(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )NH (R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O)H, --C(═O)(R 11 ), --C(═O)--(C 1 -C 4 alkyl)--N(R 13 )(R 14 ), C(═O)--(C 1 -C 4 alkyl)--N(R 13 )C(═O)O(R 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 4 , R 4A , R 7 and R 7A are not all hydrogen; when R 4 and R 4A are both hydrogen, R 22 is not hydrogen, and when R 7 and R 7A are both hydrogen, R 23 is not hydrogen.

Claim 50

Independent Claim 2970 words

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 22 and R 23 are hydrogen, the compound of Formula (IIb) has the structure shown in Formula (II) with the proviso that only one of R 22 or R 23 is hydrogen, the compound of Formula (Ib) has the structure shown in Formula (I) with the proviso that only one of R 22 or R 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 4 and R 7 is independently: hydrogen, --O(R 13 ), --S(R 13 ), --C(═O)O(R 13 ), C 1 -C 8 alkyl substituted with 0-3 R 11 , C 2 -C 8 alkenyl substituted with 0-3 R 11 , C 2 -C 8 alkynyl substituted with 0-3 R 11 , a C 3 -C 14 carbocyclic ring system substituted with 0-3 R 11 or 0-3 R 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 12 ; each of R 4A and R 7A is independently: hydrogen, --O(R 13 ), --S(R 13 ), --C(═O)O(R 13 ), C 1 -C 4 alkyl unsubstituted or substituted with halogen or C 1 -C 2 alkoxy, or phenylmethyl unsubstituted or substituted with halogen or C 1 -C 2 alkoxy; R 4 and R 4A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R 12 ; R 7 and R 7A can alternatively join to form a 5- to 7-membered carbocyclic ring substituted with 0-2 R 12 ; each of R 5 and R 5A is independently: hydrogen, halogen, --N(R 20 ) 2 , --S(R 20 ), --O(R 20 ) or C 1 -C 6 alkyl substituted with 0-3 R 11 ; R 5 and R 5A can alternatively join together to form a ═O, ═S or a ketal ring; each of R 6 and R 6A is independently: hydrogen, halogen, --N(R 20 ) 2 , --S(R 20 ), --O(R 21 ) or C 1 -C 6 alkyl substituted with 0-3 R 11 ; R 6 and R 6A can alternatively join together to form a ═O, ═S or a ketal ring; R 5 and R 6 can alternatively join together to form an epoxide or aziridine ring; --OCH 2 SCH 2 O--, --OS(═O)O--, --OC(═O)O--, --OCH 2 O--, --OC(═S)O--, --OC(═O)C(═O)O--, --OC(CH 3 ) 2 O--, --OC((CH 2 ) 3 NH 2 )(CH 3 )O--, --OC(OCH 3 )(CH 2 CH 2 CH 3 )O--, --OS(═O) 2 O--, --NHC(═O)NH--, --OC(═O)NH--, --NHC(═O)O--, --NHCH 2 O--, --OCH 2 NH--, --NHC(═S)O--, --OC(═S)NH--, --OS(═O)NH--, --NHS(═O)O--, --NHC(═O)C(═O)O--, --OC(═O)C(═O)NH--, --NHC(═O)C(═O)NH--, --NHC(CH 3 ) 2 O--, --OC(CH 3 ) 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 11 is independently: hydrogen, keto, halogen, cyano, phenylmethyl, phenethyl, methylenedioxy, ethylenedioxy, hydroxamic acid, hydrazide, boronic acid, sulfonamide, azido, formyl, phenoxy, phenylmethoxy, nitro, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), --OCH 2 C(═O)OH, --C(═O)O(R 13 ), --OC(═O)(R 13 ), --O(R 13 ), C 2 -C 6 alkoxyalkyl, --S(═O) m (R 13 ), --NHC(═NH)NH(R 13 ), --C(═NH)NH(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 14 )C(═O)(R 13 ), ═N--O(R 14 ), --N(R 14 )C(═O)O(R 14 ), --OC(═O)N(R 13 )(R 14 ), --N(R 13 )C(═O)N(R 13 )(R 14 ), --C(R 14 )═N--O(R 14 ), --N(R 14 ) S(═O) 2 N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --N(R 13 )(R 14 ), C 1 -C 4 hydroxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 C 4 alkylcarbonyloxy, C 1 C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, 2-(1-morpholino)ethoxy, --(C 1 -C 3 alkyl) aryl substituted with 0-2 R 12 , a C 5 -C 14 carbocyclic residue substituted with 0-3 R 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 12 ; and - 3amino acids linked together via amide bonds, and linked to R 4 R 7 R 20 or R 21 via the amine or carboxylate terminus; m is: 0, 1 or 2; each R 11A is independently: H, keto, halogen, cyano, --CH 2 NH 2 , --NH 2 , --C(═O)OH, --OC(═O)(C 1 -C 3 alkyl), --OH, C 2 -C 6 alkoxyalkyl, --C(═O)NH 2 , --OC(═O)NH 2 , --NHC(═O)NH 2 , --S(═O) 2 NH 2 , C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C 7 -C 10 arylalkyl, hydroxamic acid, hydrazide, boronic acid, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --NH 2 , C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, --OCH 2 C(═O)OH, 2-(1-morpholino)ethoxy, azido, aryl(C 1 -C 3 alkyl), a C 5 -C 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 12 when a substituent on carbon, is independently: phenyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, halogen, hydroxy, nitro, cyano, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, C 1 -C 4 alkoxy, --C(═O)OH, hydroxamic acid, hydrazide, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, --O(R 13 ), C 1 -C 4 alkyl substituted with --N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, --S(═O) m (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), --NHS(═O) 2 (R 14 ), --OCH 2 C(═O)OH, 2-(1-morpholino)ethoxy, --C(R 14 )═N--O(R 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 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 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, --N(R 13 )(R 14 ), or when R 12 is a substituent on a saturated carbon atom, R 12 may alternatively be ═O or ═S; each R 12 when a substituent on nitrogen, is independently: phenyl, phenylmethyl, phenethyl, hydroxy, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxycarbonyl, --C(═O)OH, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl or --C(R 14 )═N--O (R 14 ); each R 13 is independently: hydrogen, phenyl substituted with 0-3 R 11A , phenylmethyl substituted with 0-3 R 11A , C 1 -C 6 alkyl substituted with 0-3 R 11A , C 2 -C 4 alkenyl substituted with 0-3 R 11A , C 1 -C 6 alkylcarbonyl substituted with 0-3 R 11A , C 1 -C 6 alkoxycarbonyl substituted with 0-3 R 11A , C 1 -C 6 alkylaminocarbonyl substituted with 0-3 R 11A , C 3 -C 6 alkoxyalkyl substituted with 0-3 R 11A , an amine protecting group when R 13 is bonded to N, or a hydroxy protecting group when R 13 is bonded to O; each R 14 is independently: hydrogen, hydroxy, trifluoromethyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, phenylmethyl, amino, C 1 -C 6 alkyl substituted with 0-3 groups selected from hydroxy, C 1 -C 4 alkoxy, halogen or amino, an amine protecting group when R 14 is bonded to N, or a hydroxy protecting group when R 14 is bonded to O; R 13 and R 14 can alternatively join to form: --(CH 2 ) 4 --, --(CH 2 ) 5 --, --CH 2 CH 2 N(R 15 )CH 2 CH 2 -- or --CH 2 CH 2 OCH 2 CH 2 --; R 15 is: hydrogen or methyl; each of R 20 and R 21 is independently: hydrogen, C 1 -C 6 alkyl substituted with 0-3 R 11 , C 3 -C 6 alkoxyalkyl substituted with 0-3 R 11 , C 1 -C 6 alkylcarbonyl substituted with 0-3 R 11 C 1 -C 6 alkoxycarbonyl substituted with 0-3 R 11 , C 1 -C 6 alkylaminocarbonyl substituted with 0-3 R 11 benzoyl substituted with 0-3 R 12 , phenoxycarbonyl substituted with 0-3 R 12 , phenylaminocarbonyl substituted with 0-3 R 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 22 and R 23 is independently: hydrogen, C 1 -C 8 alkyl substituted with 0-3 R 31 , C 2 -C 8 alkenyl substituted with 0-3 R 31 , C 2 -C 8 alkynyl substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring system substituted with 0-5 R 31 or 0-5 R 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 32 ; alternatively, R 22 can join with R 4 or R 4A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 12 , the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, R 23 can join with R 7 or R 7A to form a 5- or 6- membered fused heterocyclic ring or carbocyclic ring substituted with 0-2 R 12 the heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, R 22 or R 23 can join with R 5 or R 6 to form a 0- to 7- membered bridge to form a carbocyclic or heterocyclic ring, said bridge being substituted with 0-2 R 12 and the bridge containing 0-3 heteroatoms independently selected from nitrogen, sulfur or oxygen; alternatively, the atoms to which R 22 and R 4A are appended may be joined together with a double bond; alternatively, the atoms to which R 23 and R 7A are appended may be joined together with a double bond; Z is: O or S; each R 31 is independently: keto, halogen, cyano, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), --C(═O)O(R 13 ), --C(═O)(R 11 ), --OC(═O)(R 13 ), --O(R 13 ), C 2 -C 6 alkoxyalkyl, --S(═O) m (R 13 ), --NHC(═NH)NH(R 13 ), --C(═NH)NH(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 14 )C(═O)(R 13 ), ═N--O(R 14 ), --N(R 14 )C(═O)O(R 14 ), --OC(═O)N(R 13 )(R 14 ), --N(R 13 )C(═O)N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 N(R 13 )(R 14 ), --N(R 14 )S(═O) 2 (R 13 ), --S(═O) 2 N(R 13 )(R 14 ), C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, nitro, C 7 -C 10 arylalkyl, hydroxamic acid, hydrazide, oxime, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with --N(R 13 )(R 14 ), C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, --OCH 2 C(═O)O(R 13 ), 2-(1-morpholino)ethoxy, azido, --C(R 14 )═N--O(R 14 ), a C 5 -C 14 carbocyclic residue substituted with 0-5 R 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 32 or - 3amino acids, linked together via amide bonds, and linked to R 22 or R 23 via the amine or carboxylate terminus; each R 32 when a substituent on carbon, is independently: phenethyl, phenoxy, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethylene, C 7 -C 10 arylalkyl, hydrazide, oxime, C 2 -C 6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 alkylcarbonyloxy, --NHS(═O) 2 (R 14 ), phenylmethoxy, halogen, 2-(1-morpholino)ethoxy, --C(═O)O(R 13 ), hydroxamic acid, --C(═O)N(R 13 )N(R 13 )(R 14 ), cyano, boronic acid, sulfonamide, formyl, C 3 -C 6 cycloalkoxy, C1--C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 2 -C 4 haloalkenyl, C 2 -C 4 haloalkynyl, --N(R 13 )(R 14 ), --C(R 14 )═N--O (R 14 ), --NO 2 , --O(R 13 ), --N(R 40 )(R 41 ), --S(═O) m (R 13 ), --S(═O) m N(R 13 )(R 14 ), --C(═O)N(R 13 )(R 14 ), --OC(═O)N(R 13 )(R 14 ), --C(═O)(R 11 ), --OC(═O)(R 11 ), --OC(═O)O(R 13 ), phenyl, --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-N(R 13 )(R 14 ), --C(═O)N(R 40 )(R 41 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )NH(R 14 ), --C(═O)N(R 13 )C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-N(R 13 )C(═O)O(R 13 ), --C(═O)N(R 13 )--(C 1 -C 4 alkyl)-R 11 , --C(═O)C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )NH(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O)--(C 1 -C 4 alkyl)--N(R 13 )(R 14 ), --C(═O)--(C 1 -C 4 alkyl) --N(R 13 )C(═O)O(R 13 ), C 1 -C 4 alkoxy substituted with 0-4 groups selected from: R 11 , C 3 -C 6 cycloalkyl, --C(═O)O(R 13 ), --C(═O)N(R 13 )(R 14 ), --N(R 13 )(R 14 ) or hydroxyl, C 1 -C 4 alkyl substituted with 0-4 groups selected from: R 11 ═N(R 14 ), ═NN(R 13 )C(═O)N(R 13 )(R 14 ) or --N(R 13 )(R 14 ), C 2 -C 4 alkenyl substituted with 0-4 R 11 , C 2 -C 4 alkynyl substituted with 0-4 R 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 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxyl--N(R 13 )(R 14 ), or when R 32 is attached to a saturated carbon atom, R 32 may be ═O or ═S; each R 32 , when a substituent on nitrogen, is independently: phenyl, phenylmethyl, phenethyl, hydroxyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethylene, --CH 2 N(R 13 )(R 14 ), --N(R 13 )(R 14 ), C 2 -C 6 alkoxyalkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxycarbonyl, --C(═O)OH, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl or --C(R 14 )═N--O(R 14 ); R 40 is: hydrogen or C 1 -C 3 alkyl; R 41 is: --C(═O)N(R 13 )(R 14 ), --C(═O)N(R 13 )NH(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )(R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )NH (R 14 ), --C(═O)C(R 11 ) 2 N(R 13 )C(═O)O(R 13 ), --C(═O)H, --C(═O)(R 11 ), --C(═O)--(C 1 -C 4 alkyl)--N(R 13 )(R 14 ), C(═O)--(C 1 -C 4 alkyl)--N(R 13 )C(═O)O(R 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 4 , R 4A , R 7 and R 7A are not all hydrogen; when R 4 and R 4A are both hydrogen, R 22 is not hydrogen, and when R 7 and R 7A are both hydrogen, R 23 is not hydrogen.

Claim 51

Dependent Claim 139 words

The method according to claim 47, wherein the direct alkylation of step (a) comprises treating a compound of Formula (IIa) with a base and an alkylating agent, where the alkylating agent has the Formula R 16 X 1 , wherein R 16 is: C 1 -C 8 alkyl substituted with 0-3 R 31 , C 2 -C 8 alkenyl substituted with 0-3 R 31 , C 2 -C 8 alkynyl substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring system substituted with 0-5 R 31 or 0-5 R 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 32 ; and X 1 is a leaving group susceptible to displacement with an amino nitrogen.

Claim 52

Dependent Claim 16 words

The method according to claim 48, wherein the leaving group is halide, tosylate, mesylate or acetate.

Claim 53

Dependent Claim 35 words

The method according to claim 48, wherein the compound of Formula (IIa) and the alkylating agent of Formula R 16 X 1 are contacted in a molar ratio of between about 1:0.9 and about 1:1.5.

Claim 54

Dependent Claim 23 words

The method according to claim 48, wherein the base is potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate or sodium bicarbonate.

Claim 55

Dependent Claim 20 words

The method according to claim 48, wherein the direct alkylation is conducted in the presence of a phase transfer agent.

Claim 56

Dependent Claim 17 words

The method according to claim 52, wherein the phase transfer agent is tetrabutylammonium iodide and potassium iodide.

Claim 57

Dependent Claim 72 words

The method according to claim 48, wherein the direct alkylation is conducted in a solvent selected from the group consisting of acetonitrile and tetrahydrofuran, and wherein the compound of Formula (IIa) is present in the solvent at a concentration of about 0.03 molar to about 3.0 molar, and wherein the base is potassium carbonate, and wherein about two equivalents of base are present for each equivalent of the compound of Formula (IIa).

Claim 58

Dependent Claim 148 words

The method according to claim 47, wherein the reductive amination of step (a) comprises reacting a compound of Formula (IIa) with a carbonyl compound to form an intermediate oxime, and reacting the intermediate oxime with a reducing agent to form a compound of Formula (IIb), wherein the carbonyl compound is C 1 -C 8 alkane substituted with 0-3 R 31 , C 2 -C 8 alkene substituted with 0-3 R 31 , C 2 -C 8 alkyne substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring substituted with 0-5 R 31 or 0-5 R 32 , and a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring being substituted with 0-2 R 32 , with the proviso that at least one methylene group (--CH 2 --) is replaced with a carbonyl group (--C(═O)--).

Claim 59

Dependent Claim 91 words

The method according to claim 55, wherein the reducing agent is NaBH 4 , lithium aluminum hydride (LiAlH 4 ), sodium cyanoborohydride (NaBH 3 CN), borane complexes including BH 3 .THF, BH 3 .SMe 2 , BH 3 .amine including pyridine, and other borane compounds including BH (OAc) 3 , BH (O 2 CCF 3 ) 2 , NaBH(OAc) 3 , (t-butyl)NH 2 BH 3 , LiBH(Et) 3 , LiBH(t-butyl) 3 , NaAlH 2 (O(CH 2 ) 2 OCH 3 ), LiBH (sec-butyl) 3 or Zn (BH 3 CN) 2 .

Claim 60

Dependent Claim 23 words

The method according to claim 55, wherein the molar ratio of the carbonyl compound to the compound of Formula (IIa) is about 1:1.

Claim 61

Dependent Claim 101 words

The method according to claim 47, wherein the successive acylation and reduction of step (a) comprises reacting a compound of Formula (IIa) with an acylating agent of Formula R 17 (C═O)X 2 to form an amide compound, and the amide compound is reacted with a reducing agent to form a compound of Formula (IIb), wherein R 17 is: C 1 -C 7 alkyl substituted with 0-3 R 31 , C 2 -C 7 alkenyl substituted with 0-3 R 31 , C 2 -C 7 alkynyl substituted with 0-3 R 31 or --R 31 ; and X 2 is a leaving group.

Claim 62

Dependent Claim 21 words

The method according to claim 58 wherein the leaving group X 2 is halide, --OR 17 or --OC(═O) R 17 .

Claim 63

Dependent Claim 23 words

The method according to claim 58 wherein the molar ratio of the acylating agent to the compound of Formula (IIa) is about 1:1.

Claim 64

Dependent Claim 71 words

The method according to claim 58, wherein the reducing agent is lithium aluminum hydride (LiAlH 4 ), BH 3 .THF, BH 3 .SMe 2 , B 2 H 6 , NaBH 4 and MeSO 3 H in DMSO, (Bu) 4 NBH 4 in methylene chloride, NaBH 4 --TiCl 4 in dimethoxyethane, NiCl 2 in methanol, heterogeneous catalytic hydrogenation with Cu chromite, Ba/Cu chromite, Raney nickel, Raney cobalt, or rhenium on carbon.

Claim 65

Dependent Claim 43 words

The method according to claim 47, wherein step (b) comprises reacting a compound of Formula (IIb) with either carbonyl diimidazole, thereby forming a cyclic urea of Formula (Ib) having Z=O, or thiocarbonyl diimidazole, thereby forming a cyclic urea of Formula (Ib) having Z=S.

Claim 66

Dependent Claim 27 words

The method according to claim 47, wherein the aqueous acid solution of step (c)(i) is an aqueous hydrochloric acid, nitric acid, phosphoric acid or citric acid solution.

Claim 67

Dependent Claim 20 words

The method according to claim 47, wherein the aqueous acid solution of step (c)(i) is an aqueous citric acid solution.

Claim 68

Independent Claim 2919 words

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

Claim 69

Independent Claim 2919 words

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

Claim 70

Dependent Claim 43 words

The method according to claim 65, wherein step (a) comprises reacting a compound of Formula (IIb) with either carbonyl diimidazole, thereby forming a cyclic urea of Formula (Ib) having Z=O, or thiocarbonyl diimidazole, thereby forming a cyclic urea of Formula (Ib) having Z=S.

Claim 71

Dependent Claim 27 words

The method according to claim 65, wherein the aqueous acid solution of step (b)(i) is an aqueous hydrochloric acid, nitric acid, phosphoric acid or citric acid solution.

Claim 72

Dependent Claim 20 words

The method according to claim 65, wherein the aqueous acid solution of step (b)(i) is an aqueous citric acid solution.

Claim 73

Independent Claim 2844 words

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

Claim 74

Independent Claim 2844 words

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

Claim 75

Dependent Claim 136 words

The method according to claim 69, wherein the direct alkylation comprises treating a compound of Formula (IIa) with a base and an alkylating agent, where the alkylating agent has the Formula R 16 X 1 , wherein R 16 is: C 1 -C 8 alkyl substituted with 0-3 R 31 , C 2 -C 8 alkenyl substituted with 0-3 R 31 , C 2 -C 8 alkynyl substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring system substituted with 0-5 R 31 or 0-5 R 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 32 ; and X 1 is a leaving group susceptible to displacement with an amino nitrogen.

Claim 76

Dependent Claim 18 words

The method according to claim 70, wherein the leaving group X 1 is halide, tosylate, mesylate or acetate.

Claim 77

Dependent Claim 35 words

The method according to claim 70, wherein the compound of Formula (IIa) and the alkylating agent of Formula R 16 X 1 are contacted in a molar ratio of between about 1:0.9 and about 1:1.5.

Claim 78

Dependent Claim 23 words

The method according to claim 70, wherein the base is potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate or sodium bicarbonate.

Claim 79

Dependent Claim 20 words

The method according to claim 70, wherein the direct alkylation is conducted in the presence of a phase transfer agent.

Claim 80

Dependent Claim 17 words

The method according to claim 74, wherein the phase transfer agent is tetrabutylammonium iodide and potassium iodide.

Claim 81

Dependent Claim 72 words

The method according to claim 70, wherein the direct alkylation is conducted in a solvent selected from the group consisting of acetonitrile and tetrahydrofuran, and wherein the compound of Formula (IIa) is present in the solvent at a concentration of about 0.03 molar to about 3.0 molar, and wherein the base is potassium carbonate, and wherein about two equivalents of base are present for each equivalent of the compound of Formula (IIa).

Claim 82

Dependent Claim 145 words

The method according to claim 69, wherein the reductive amination comprises reacting a compound of Formula (IIa) with a carbonyl compound to form an intermediate oxime, and reacting the intermediate oxime with a reducing agent to form a compound of Formula (IIb), wherein the carbonyl compound is C 1 -C 8 alkane substituted with 0-3 R 31 , C 2 -C 8 alkene substituted with 0-3 R 31 , C 2 -C 8 alkyne substituted with 0-3 R 31 , a C 3 -C 14 carbocyclic ring substituted with 0-5 R 31 or 0-5 R 32 , and a 5- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur, the heterocyclic ring being substituted with 0-2 R 32 , with the proviso that at least one methylene group (--CH 2 --) is replaced with a carbonyl group (--C(═O)--).

Claim 83

Dependent Claim 88 words

The method according to claim 77, wherein the reducing agent is NaBH 4 , lithium aluminum hydride (LiAlH 4 ), sodium cyanoborohydride (NaBH 3 CN), borane complexes including BH 3 .THF, BH 3 .SMe 2 , BH 3 .amine including pyridine, and other borane compounds including BH(OAc) 3 , BH(O 2 CCF 3 ) 2 , NaBH(OAc) 3 , (t-butyl)NH 2 BH 3 , LiBH(Et) 3 , LiBH(t-butyl) 3 , NaAlH 2 (O(CH 2 ) 2 OCH 3 ), LiBH(sec-butyl) 3 or Zn (BH 3 CN) 2 .

Claim 84

Dependent Claim 23 words

The method according to claim 77, wherein the molar ratio of the carbonyl compound to the compound of Formula (IIa) is about 1:1.

Claim 85

Dependent Claim 100 words

The method according to claim 69, wherein the successive acylation and reduction comprises reacting a compound of Formula (IIa) with an acylating agent of Formula R 17 (C═O) X 2 to form an amide compound, and the amide compound is reacted with a reducing agent to form a compound of Formula (IIb), wherein R 17 is: C 1 -C 7 alkyl substituted with 0-3 R 31 , C 2 -C 7 alkenyl substituted with 0-3 R 31 , C 2 -C 7 alkynyl substituted with 0-3 R 31 , or --R 31 ; and X 2 is a leaving group.

Claim 86

Dependent Claim 21 words

The method according to claim 80 wherein the leaving group X 2 is halide, --OR 17 or --OC(═O) R 17 .

Claim 87

Dependent Claim 23 words

The method according to claim 80 wherein the molar ratio of the acylating agent to the compound of Formula (IIa) is about 1:1.

Claim 88

Dependent Claim 71 words

The method according to claim 80, wherein the reducing agent is lithium aluminum hydride (LiAlH 4 ), BH 3 .THF, BH 3 .SMe 2 , B 2 H 6 , NaBH 4 and MeSO 3 H in DMSO, (Bu) 4 NBH 4 in methylene chloride, NaBH 4 -TiCl 4 in dimethoxyethane, NiCl 2 in methanol, heterogeneous catalytic hydrogenation with Cu chromite, Ba/Cu chromite, Raney nickel, Raney cobalt, or rhenium on carbon.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	1999-04-16	1999-10-16	2000-04-16	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2003-04-16	2003-10-16	2004-04-16	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2007-04-16	2007-10-16	2008-04-16	$7700.00	Window Closed / Lapsed

Preparation of cyclic urea compounds

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