NZ336613A

NZ336613A - Oxazoline, imidazoline or thiazoline derivatives useful for inhibiting beta-amyloid peptide

Info

Publication number: NZ336613A
Application number: NZ336613A
Authority: NZ
Inventors: Eugene D Thorsett; Warren J Porter; Jeffrey S Nissen; Lee H Latimer; James E Audia; James J Droste
Original assignee: Lilly Co Eli; Elan Pharm Inc
Priority date: 1997-02-28
Filing date: 1998-02-27
Publication date: 2001-10-26
Also published as: KR20000075767A; WO1998038177A1; PE59399A1; JP2001513107A; ZA981627B; AR011164A1; IL130851A0; CO4920244A1; EA199900778A1; PL335424A1; HRP980093A2; ID22873A; EP0968198A1; NO994016L; YU7998A; TR199902071T2; NO994016D0; CN1253554A; AU6662298A; CA2278674A1

Abstract

A compound has the formula A-B-D wherein: A is a group of formula (2); R1, R2, R5 and R6 are independently optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclic; Z is -CX'X"C(O)-, -T-CH2-C(O)-, -T-C(O)-C(O)- or -CX'X"-T-C(O)-; X' and X" are independently hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; T is oxygen, sulphur or -NR3; R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; m and p are independently is 0 or 1; T' is a bond covalently linking R' to -CX'X"-, oxygen, sulphur or -NR3; W and X are independently -(CR7R7)q-, oxygen, sulphur or -NR8; q is 1 or 2; each R7 and R8 is independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters or heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; R4 is hydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclic; B is (i) -C(O)-N(H)-CH(R5) or a group of formula 3 or when A is either formula (ii) or (iii) as defined above, then B can also be a covalent bond linking A to D; D is (i) -C(O)Y, (ii) -C(S)Y or (iii) a group of formula 4; Y is optionally substituted alkyl, alkoxy, thioalkoxy or is cycloalkyl, hydroxy, aryl, heteroaryl, heterocyclic, -NR'R", -NHSO2-R8, -NR9NR10R10, -ONR9[C(O)O]zR10, -CR11R11Y' R' and R" are independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic provided that one of R' or R" is hydroxy or alkoxy, or R' and R" are joined to form an optionally substituted cyclic group optionally containing 1 to 2 additional heteroatoms of oxygen, sulphur or nitrogen; R9 is hydrogen or alkyl; each R10 and R11 is independently hydrogen, optionally substituted alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclic; z is 0 or 1; Y' is hydroxyl, amino, thiol, optionally substituted alkoxy or thioalkoxy, -OC(O)R9, -SSR9 or -SSC(O)R9; A*, together with -C=N-, forms a heterocyclic group which is optionally fused to form a bi- or multi-fused ring system with one or more ring structures selected from optionally substituted cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl group limited by the provisos listed in the specification. A pharmaceutical composition thereof is useful for inhibiting the cellular release and/or synthesis of b-amyloid peptide, preventing the onset of Alzheimer's disease or inhibiting further deterioration in the condition.

Description

<div class="application article clearfix" id="description"> WO 98/38177 PCT/US98/03373 - 3 - State of the Art Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically "by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and 5 ultimately death AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three 10 million individuals in the United States alone. AD is at present incurable No treatment that effectively prevents AD or reverses its symptoms and course is currently known The brains of individuals with AD exhibit characteristic lesions termed 15 senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillaiy tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive 20 anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires 25 observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure The principal chemical constituent of the amyloid plaques and vascular 30 amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of Printed from Mimosa 07/26/1999 12:37:07 page -5- WO 98/38177 _ 4 - about 39-43 amino acids designated the /3-amyloid peptide (j8AP) or sometimes A/3, A/3P or 0/A4 /3-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S Patent No. 5 4,666,829*. Molecular biological and protein chemical analyses have shown that the /3-amyloid peptide is a small fragment of a much larger precursor protein (APP), that is normally produced by cells in many tissues of various animals, 10 including humans. Knowledge of the structure of the gene encoding the APP has demonstrated that /3-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). The precise biochemical mechanism by which the /3-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and m the walls of the 15 cerebral and meningeal blood vessels is currently unknown. Several lines of evidence indicate that progressive cerebral deposition of j3-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe3. 20 The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid lsoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al.4; Chartier Harlan, et al.5; and Murrell, et al.6) and is referred to as the Swedish variant. A double 25 mutation changing lysine595-methionine595 to asparagine595-leucine596 (with reference to the 695 isoform) found in a Swedish family was reported m 1992 (Mullan, et al.7). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families In addition, a 30 mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the /3-amyloid peptide deposition disease, HCHWA-D, Printed from Mimosa 07/26/1999 12:37:07 page -6- 336613 5 - and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its 3-amyloid peptide fragment can cause AD. 10 Despite the progress which has been made in understanding the underlying mechanisms of AD and other /S-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting /3-amyloid peptide release and/or its synthesis in vivo. 15 25 30 35 SUMMARY OF THE INVENTION This invention is directed to the discovery of a class of compounds which inhibit (3-amyloid peptide release and/.or its synthesis and, therefore, are useful in the prevention of AD in patients susceptable to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition. Accordingly, in a first aspect the present invention provides a compound of formula I: A-B-C wherein A is selected from the group consisting of: R2 (0 Jm u intellectual property office of n.z. 2 2 AUG 2001 RECEIVED where R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; 336613 - 6 - Z is selected from the group consisting of (a) a group having the formula -CX'X"C(0)- where X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; (b) a group having the formula -T-CH2C(0)- or -T-C(0)C(0)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; and (c) a group having the formula -CX'X"-T-C(0)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; R6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; m is an integer equal to 0 or 1; and p is an integer equal to 0 or 1; where Rl is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; intellectual property office of n.z. W X 2 2 AUG 2001 RECEIVED (ii) X* X" 33 6613 _7 - T' is selected from the group consisting of a bond linking R1 to -CX'X"-, oxygen, sulfur, and - NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group, with the proviso that when T' is oxygen, sulfur or -NR3 then X' and X" are hydrogen or X' and X" together form an oxo group; W and X are independently selected from the group consisting of -(CR7R7)?-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; ^ and with the further proviso that when W is oxygen, then X is not also oxygen; X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; R4 is selected from the group consisting of hydrogen, alkyl, substituted 20 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aiyl, heteroaryl and heterocyclic; and 10 R<-t'v N X «» A X- X" where R1 is selected from the group consisting of alkyl, alkenyl, 30 alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; Intellectual proper^ office of n.z. 2 2 AUG 2001 received 336613 - 8 - T' is selected from the group consisting of a bond linking R1 to -CX'X"-, oxygen, sulfur, and - NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group, with the proviso that when T' is oxygen, sulfur or -NR3 then X' and X" are hydrogen or X' and X" together form an oxo group; W and X are independently selected from the group consisting of -(CR7R7)?-, oxygen, sulfur and -NR8 where q is an integer equal to one or two and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; B is selected from the group consisting of: where R5 is selected from the group consisting of alkyl, substituted alkyl. alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; (i) H N W X intellectual property office of n.z. (ii) 2 2 AUG 2001 received 336613 „ 9 - W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfiir and -NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 -group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; and with the further proviso that when W is oxygen, then X is not also oxygen; R* is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to 1 or 2 and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl. heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated; .the remaining R7 group on each carbon atom participates in the unsaturation; N X (iii) intellectual property office of n.z. 2 2 AUG 2001 received 33 6613 -10 - R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; and (iv) when A is either formula (ii) or (iii) as defined above, then B can also be a covalent bond linking A to C; C is selected from the group consisting of: (i) -C(0)Y or -C(S)Y where Y is selected from the group consisting of: (a) alkyl or cycloalkyl, (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do" not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl, or a-0C(O)aryl groups, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, intellectual property office of n.z. 2 2 AUG 2001 received 336613 -- i I -- (j) -NHS02-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) .-NR9NR'°R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and (1) -ONR'fCCOJOJjR10 where z is zero or one, R9 and R10 are as defined above; (ii) -CRUR"Y' where each R" is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkoxy, substituted * thioalkoxy, -0C(0)R9, -SSR9, and -SSC(0)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic; and where A* together with -C=N-, forms a heterocyclic group which is optionally fused to form a bi- or multi-fused ring system with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, -NHC(0)R'°, -NHS02R10, -C(0)NH2, -C(0)NHR'°, -C(O)NR10R10, -S(0)R'°, -S(0);R'°, -S(O)2NHRt0 and intellectual property office of n.z. (iii) N 2 2 AUG 2001 RECEIVED - 12 -(followed by 12a) -S(O):NRl0R'° where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl, ammo, N-alkylammo, N,N-dialkylammo, N-substituted alkylammo, N,N-disubsntuted alkylamino, N-alkenylamino, N,N-dialkenylammo, N-subsututed alkenylamino, N,N-disubstituted alkenylamino, N-cycloalkylammo, N.N-dicycloalkylamino, N-substituted cycloalkylamino, N,N-disubstituted cycloaJkylammo, N-arylamino, N,N-diarylamino, N-heteroarylamino, N,N-diheteroarylamino, N-heterocyclic amino, N,N-diheterocycIic amino and mixed N,N-amino groups comprising a first and second substituent on said amino group which substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic provided that said first and second substituents are not the same; with the proviso that when A has structure (i) and B has structure (i), then C does not have structure (i) or (ii); with the further provisos that A. when A has structure (i) with Rl being phenyl, Z being -CH:0C(0)-, R2 being methyl and p being zero, B has structure (iii) with W being -NH-, X being -CH2-, and R4 being benzyl then C is not -C(0)0CH3; B. when A has structure (i) with R1 being 3,5-difluorophenyl, Z being -CH2C(0)-, R2 being methyl, and p being zero, B has structure (ii) with W being > NC(0)0C(CH3)3, X being -CHr, and R4 being phenyl, then C is not -C(0)0CH3; C. when A has structure (ii) wherein is 3,5-difluorophenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene and R4 is methyl, and B is a covalent bond linking A to C, then C is not -C(0)0CH3 ; D. when A has structure (ii) with R1 being phenyl, T' is a bond linking R' to -CX'X"-, X' and X" are hydrogen, W is oxygen, X is methylene and R4 is hydrogen, and B has structure (i) where R5 is iso-propyl then C is not -C(0)0H, or -C(0)0CH3, ^ (f'-s {£? o i/y -12a-(followed by 12b) E. when A has structure (ii) with R1 being phenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is oxygen, X is methylene and R4 is hydrogen, and B has structure (iv) then C is not -C(0)NHNH2, or -C(0)CH3; F. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyl or indole-3-CH2- and p being zero; B has structure (ii) where W is -NR8 - where R8 is hydrogen or te/t-butyloxycarbonyl, X is methylene and R4 is benzyl or w-butyl then C is not -C(0)0H or -C(0)0CH3; G. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyloxycarbonyl-NH-(CH2)4 - and p being zero; B has structure (ii) where W is -NH-, X is methylene and R4 is benzyloxycarbonyl-NH-(CH2)4- then C is not -C(0)0CH3; H. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyl and p being zero; B has structure (ii) where W is sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH3; I. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being methyl or sec-butyl and p being zero; B has structure (ii) where W is sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH2CH3 or -C(0)NH2; and J. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being methyl and p being zero; B has structure (ii) where W is oxygen or sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH3. intellectual property office of n.z. 2 2 AUG 2001 RECEIVED 336613 —12b— In one preferred embodiment, the compounds of formula I are further characterized by formula II below: II wherein R1, R:, R5, R6, A* Z, m and p are as defined above >NT^al PROPERTY OFFICE OF n.z. 2 2 AUG 2001 REC 98/38177 - 13 -- In formula II above, when m is one, Z is preferably -CX'X"C(0)-where X" is preferably hydrogen, X' is preferably hydrogen or fluoro or X' and X" form an oxo group In formula II above, preferred R1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like Preferred R1 substituted aryl groups in formula II include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not include more than 3 substituents Examples of substituted R1 phenyls preferred in formula II include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-z^o-propy lpheny 1, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3.4.5-trimethoxyphenyl, 3,4,5-tri-(tnfluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2.4.6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyI, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, Printed from Mimosa 07/26/1999 12:37:07 page -15- 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethy Iphenyl. Preferred R1 alkaryl groups in formula II include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like. Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formula II include, by way of example, wo-propyl, /i-propyl, /i-butyl, wo-butyl, sec-butyl, /-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH:-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, and the like. Preferred R1 heteroaryls and substituted heteroaryls in formula II include, by way of example, pynd-2-yl, pyrid-3-yl, pynd-4-yl, fluoropyridyls (including 5-fluoropynd-3-yl), chloropyndyls (including 5-chloropynd-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan- 2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-l,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like. Preferably, m formula II, R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Particularly preferred R2 substituents include, by way of example, methyl, ethyl, rc-propyl, wo-propyl, n-butyl, tso-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, -CH2CH2SCH3, and the like. As noted below, R2, as well as R^ and R6 are preferably the side chain of an L-araino acid _ intellectual property office of n.z. 2 2 AUG 2001 RECEIVED 336613 - 15 - Preferred R5 and/or R6 substituents in formula II are independently selected from the group consisting of include, for example, hydrogen, methyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, wo-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, /n-fiuorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxy benzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH20-benzyl, /?-(CH3)3C0C(0)CH20-benzyl, /?-(H00CCH20)-benzy 1, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH20)-benzyl, -CH2CH2C(0)NH2, -CH2-imidazol-4-yl, -CH:-(3-tetrahydrofuranyl), -CH:-thiophen-2-yl, -CH2(l-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH:-C(0)0-r-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH,N(CH3)2, -CH2C(CH3)=CH2i -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(0-r-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyndyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), -CH2-(N-morpholino), /7-(N-morpholino-CH2CH20)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo[b] thiophen-2-y 1, 4,5,6,7 -tetrahydrobenzo [b] thiophen-2-y 1, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH;CH2SCH3, thien-2-yl, thien-3-yl, and the like. ethyl, /i-propyl, wo-propyl, /i-butyl, /so-butyl, sec-butyl, /e/r-butyl, * In formula II, preferred groups are further N characterized by the following structures intellectual property office of n.z. 2 2 AUG 2001 received 33 6613 - 16 - \ N- where Y" is a heteroatom selected from oxygen, sulfur and >NR8 where R8 is as defined above and A', together with -Y"-C=N-, forms a heterocyclic group 10 which is optionally fused to form a bi- or multi-fused ring system with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, 15 alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamrao, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N.N-disubstituted alkylamino, aryl, heteroaryl, heterocyclic, -NHC(O)R!0, -NHS02R10, 20 -C(0)NH,, -C(0)NHR'°, -C(O)NR10R10, -S(0)R10, -S(0)2R10, -S(0)2NHR10 and -S(O)2NRl0R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl. Preferred heterocyclic structures include, by way of example, 3-methyl-25 l,2,4-oxadiazol-5-yl, thiazohn-2-yl, 3-phenyl-l,2,4-oxadiazol-5-yI, 3-(p-methoxy-benzyl)-l,2,4-oxadiazol-5-yl, and the like. Preferred compounds of formula II include the following. 30 35 (S)-5-[l-iV-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]amino]ethyl-3-ethyl-1,2,4-oxadiazole (S)-5-[l-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-pheny lethy 1] - 3 -methy I-1,2,4-oxadiazole 2 2 AUG 2001 WO 98/38177 PCT/US98/03373 - 17 ~ 2-[l-N-|7V-(3,5-difluorophenylacetyl)-L-alamnyl]amino-l-pHenyl]methyl-2-thiazolme (S)-5-[ 1 -N-[N-( 3, 5-difluorophenylacetyl)-L-alaninyl]amino-1-5 phenyl]methyl-3-methyl-l,2,4-oxadiazole (S)-5-[ 1 -iV-[7V-(3,5-difluoropheny lacetyl)-L-alaniny l]amino-1 -phenyl]methy 1-3-pheny 1-1,2,4-oxadiazole 10 (S)-5-[l-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-l- phenyl]methyl-3-(4-methoxyphenylmethyl)-l,2,4-oxadiazole In another preferred embodiment, the compounds of formula I are 15 further characterized by formula III and IV below 30 and 35 N X C(0)Y R4 IV 40 wherein R1, R2, R4, R6, W, X, Y, Z, m and p are as defined above. In formula III and IV above, when m is one, Z is preferably 45 -CX'X"C(0)- where X" is preferably hydrogen, X' is preferably hydrogen or fluoro and where X' and X" form an oxo group. Printed from Mimosa 07/26/1999 12:37:07 page -19- »1 » . ^ ".J -- 18 - In formula III and IV above, preferred R1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like. Preferred R1 substituted aryl groups in formula III and IV include, for 5 example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not include more than 3 substituents. 10 Examples of substituted R1 phenyls preferred in formula III and IV include, for instance, 2-chlorophenyI, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 15 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-wo-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-tnfluoromethylphenyl, 2,3-dichlorophenyl, 20 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl. 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 25 3,4,5-tnmethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-tnfluorophenyI. 2,4.6-tnmethylphenyl, 2,4.6-tn-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl. 2,4.5-trifluorophenyl, 2.5-difluorophenyl, 2-fluoro-3-tnfluoromethylphenyl, 4-fluoro-2-tnfluoromethylpheny 1, 2-fluoro-4-tnfluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 30 2.5-dimethylphenyl, 4-phenylphenyl and 2-fluoro- 3-tnfluoromethylphenyl intellectual property office of n.z. 2 2 AUG 2001 RECEIVED 98/38177 PCT/US98/03373 - 19 -- Preferred R1 alkaryl groups in formula III and IV include,-by way of example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formula III and IV include, by way of example, zso-propyl, rt-propyl, «-butyl, zso-butyl, sec-butyl, r-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, and the like. Preferred R1 heteroaryls and substituted heteroaryls in formula III and IV include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-l ,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like. Preferably, in formula III and IV, R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Particularly preferred R2 substituents include, by way of example, methyl, ethyl, n-propyl, jso-propyl, n-butyl, wo-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, -CH2CH2SCH3, and the like. As noted below, R2 (as well as R6) are preferably the side chain of an L-amino acid. Preferred R6 substituents in formula III and IV include, for example, hydrogen, methyl, ethyl, n-propyl, /so-propyl, w-butyl, wo-butyl, sec-butyl, Printed from Mimosa 07/26/1999 12:37:07 page -21- 98/38177 PCT/US98/03373 - 20 - rm-butyl, -CH2CH(CH2CH3)2, 2-methyl-/i-butyl, 6-fluoro-«-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, zso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, /?-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, /7-methoxyphenyl, phenethyl, benzyl, /n-hydroxybenzyl, /j-hydroxybenzyl, /7-nitrobenzyl, m-trifluoromethy lphenyl, />-(CH3)2NCH2CH2CH20-benzyl, p-(CH3)3C0C(0)CH20-benzy 1, />-(H00CCH20)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH20)-benzy 1, -CH2CH2C(0)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(l-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(0)0-/-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(0-f-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2i -CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyndyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), -CH2-(N-morpholino), p-(N-morpholmo-CH2CH20)-benzy 1, benzo[b] thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, thien-3-yl, and the like. Preferably Y in Formula III or IV is hydroxy, alkoxy, substituted alkoxy and -NR'R" where R' and R" are as defined above. Preferred alkoxy and substituted alkoxy groups include methoxy, ethyoxy, /i-propoxy, wo-propoxy, n-butoxy, wo-butoxy, r-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, and the like. Preferred -NR'R" groups include, by way of example, amino (-NH2), -NH(zso-butyl), -NH(sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, Printed from Mimosa 07/26/1999 12:37:07 page -22- WO 98/38177 PCT/US98/03373 -- 21 -- -NH-methallyl, -NHCH2-(furan-2-yl), -NHCH2-cyclopropyl, -NH<r-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3)2, -NHCH2C(CH3)3, -NHCH2-(pynd-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolindinyl, 5 -N(CH2CH2CH3)2, -NHOH, -NH(p-N02-4>), -NHCH2(p-N02-<«, -NHCH2(m-N02-tf>), -N(CH3)OCH3, -N(CH3)CH2-0, -NHCH2-(3,5-di-fluorophenyl), -NHCH2CH2F, -NHCH2(p-CH3O-0), -NHCH2(m-CH30-<«, -NHCH2(p-CF3-tf>), -N(CH3)CH2CH2OCH3, -NHCH2CH2<*>, -NHCH(CH3)0, -NHCH2-(p-F-<*>) , -N(CH3)CH2CH2N(CH3)2, -NHCH2-(tetrahydrofuran-2-yl), 10 and the like. Still another preferred Y group is an alkyl group such as -CH2CH2CH(CH3)2, and the like. 15 Preferred heterocyclic structures defined by W and X include, by way of example, 4,5-dihydrothiazoles, 3,4-dihydro-l,3-isodiazoles, 3,4-dihydro-3-N-t-butoxy-3-isodiazoles, 4,5-dihydrooxazoles, and the like. Preferred compounds of formula III and IV include the following 20 (S)-2-[l-(3,5-difluorophenylacetamido)ethyl]-4-ethoxycarbonyl-2-thiazoline 1-/erf-butoxycarbonyl-2-[l-(jV-carbobenzyloxy)aminoethyl]-4- 25 methoxycarbonyl-4-phenylmethyl-2-imidazoline 1 -rm-butoxy carbony 1-2- [ 1 -(3,5-difluoropheny lacetamido)ethyl] -4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 30 2-[l-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4- phenylmethyl-2-imidazoline 2-[l-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline 35 2-[ 1 -(3,5-difluorophenylacetamido)-1 -phenyl]methyl-4-ethoxycarbony 1-2-thiazoline Printed from Mimosa 07/26/1999 12:37:07 page -23- WO 98/38177 PCT/US98/03373 -- 22 - 1-rerr-butoxycarbonyl-2-[l-(jV-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline 2-[(S)-l-(3,5-dichloroanilino)ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine 5 (S)-2- [ 1 -(3,5 -difluoropheny lacetamido)ethy 1]-5 (R, S)-ethoxycarbony 1-2-oxazoline 2-[l-(3,5-difluorophenylacetamido)-l-phenyl]methyl-4-methoxycarbonyl-10 2-thiazoline [l-(Ar-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazolme 15 20 30 40 In another preferred embodiment, the compounds of formula I are further characterized by formula V and VI below: O R6 R"T>C^n^n^VY v / \ R4 H U 25 X' X" U N X II and O R6 R1^T V^Orr 35 / \ R4 X' X" VI where R1, R4, R6, T', X', X", W, X, and Y are as defined above. In formula V and VI above, when m is one, Z is preferably -CX'X"C(0)- where X" is preferably hydrogen, X' is preferably hydrogen or fluoro or where X' and X" form an oxo group. Printed from Mimosa 07/26/1999 12:37:07 page -24- 336613 - 23 -- In formula V and VI above, preferred R1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like. Preferred R1 substituted aryl groups in formula V and VI include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and trisubsututed phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not include more than 3 substituents. Examples of substituted R1 phenyls preferred in formula IV and VI include, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyI, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyI, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl. 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-wo-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-tnfluoromethylphenyl, 2,3-dichlorophenyl, 2.3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3.4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3.4.5-tnmethoxypheny 1, 3,4,5 -tri-(trifluoromethy l)pheny 1, 2,4,6-trifluoropheny 1, 2.4.6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-tnfluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-tnfluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl. 2-fluoro-6-chlorophenyl, 2.5-dimethylphenyl, 4-phenylphenyl and 2-fluoro- 3-trifluoromethylphenyl intellectual property office of n.z. 2 2 AUG 2001 received 98/38177 - 24 - PCT/US98/03373 Preferred R1 alkaryl groups m formula IV and VI include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-/i-propyl, and the like. Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups in formula V and VI include, by way of example, zso-propyl, n-propyl, n-butyl, wo-butyl, sec-butyl, r-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CHrcyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, and the like Preferred R1 heteroaryls and substituted heteroaryls in formula III and IV include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-l ,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like Preferred R4 substituents m formula III and IV include, for example, hydrogen, methyl, phenyl, benzyl and the like. Preferred R6 substituents in formula V and VI include, for example, hydrogen, methyl, ethyl, H-propyl, /so-propyl, «-butyl, /so-butyl, sec-butyl, tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-«-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, jso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, /?-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, w-hydroxybenzyl, /7-hydroxybenzyl, /7-nitrobenzyl, Printed from Mimosa 07/26/1999 12:37:07 page -26- 98/38177 PCT/US98/03373 - 25 - m-trifluoromethy lphenyl, />-(CH3)2NCH2CH2CH20-benzyl, />-(CH3)3C0C(0)CH20-benzyl, p-(H00CCH20)-benzyl, 2-arainopyrid-6-yl, p-(N-morp"holmo-CH2CH20)-benzyl, -CH2CH2C(0)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofiiranyl), -CH2-thiophen-2-yl, -CH2( 1 -methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CHr C(0)0-f-buty 1, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(0-r-butyl)CH3> -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e g., 1-naphthyl and 2-naphthyl), -CH2-(N-morphohno), p-(N-morpholino-CH2CH20)-benzy 1, benzo[b]thiophen-2-y 1, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, thien-3-yl, and the like. Preferably Y in Formula V or VI is hydroxy, alkoxy, substituted alkoxy and -NR'R" where R' and R" are as defined above. Preferred alkoxy and substituted alkoxy groups include methoxy, ethyoxy, n-propoxy, iso-propoxy, n-butoxy, /so-butoxy, /-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-/i-propoxy, 4-bromo-«-butoxy, and the like. Preferred -NR'R" groups include, by way of example, amino (-NH2), -NH(i'so-butyl), -NH(sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, -NH-methallyl, -NHCH2-(furan-2-yl), -NHCH2-cyclopropyl, -NH(r-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3)2, -NHCH2C(CH3)3, -NHCH2-(pyrid-2-yl), -NHCH2-(pyrid-3-y 1), -NHCHr(pyrid-4-yl), N-thiazolindinyl, -N(CH2CH2CH3)2, -NHOH, -NH(p-N02-<M, -NHCH2(p-NO2-0), Printed from Mimosa 07/26/1999 12:37:07 page -27- ^ u If - 26 - -NHCH,(m-N02-4>), -N(CH3)OCH3, -N(CH3)CHH>, -NHCH2-(3,5-di-fluorophenyl), -NHCH2CH2F, -NHCH2(p-CH30-<f>), -NHCH2(m-CH30-<t>), -NHCH2(p-CFr<fi), -N(CH3)CH2CH2OCH3, -NHCH2CH2<», -NHCH(CH3)^, -NHCHz-(p-F-<t>), -N(CH3)CH2CH2N(CH3)2, -NHCH2-(tetrahydrofuran-2-yl), 5 and the like. Still another preferred Y group is an alkyl group such as -CH2CH:CH(CH3)2, and the like. 10 Preferred heterocyclic structures defined by W and X include, by way of example, 4-methyIthiazolin-4-yl. Preferred compounds of formula V and VI include the following: 15 (4R)-4-[N-( 1 S)-( 1 -methoxycarbony 1-1 -pheny l)methyl] carbamoy l-2-(3,5- difluorophenylmethyl)-4-methyl-2-thiazohne 4-[./V-(S)-(l-methoxycarbonyl-l-pheny l)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-2-thiazolme 20 4-[W-(S)-(l-methoxycarbonyl-l-phenyI)methyl]carbamoyI-2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline In a further aspect the present invention provides a compound selected 25 from the group consisting of compounds of formula VII and VIII 30 35 Vll intellectual property office of n.z. 2 2 AUG 2001 received 336613 -27 - 10 R1^r\r JL. VIII 15 20 25 30 35. wherein R1, R4, R6, T', X', X", W and X are as defined above, W\ together with -C(H)SC(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably nc more than 5 fused lings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(0)R10, -NHSO2Ri0, -C(0)NH2, -C(0)NHR10, -C(O)NRl0R10, -S(0)Rl°, -S(0):R10, -S(0),NHRl° and -S(O):NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl, U is selected from the group consisting of oxo (=0), thiooxo (=S), hydroxyl (-H, -OH), thiol (H.-SH) and hydro (H,H), s is an integer equal to 0 or 1, and t is an integer equal to 0 or 1 intellectual property office of n.z. 2 2 AUG 2001 received 98/38177 PCT/US98/03373 - 28 - In formula VII and VIII above, X" is preferably hydrogen, X' is preferably hydrogen or fluoro or X' and X" form an oxo group, and T' is preferably"a covalent bond linking R1 to -CX'X"-. In formula VII and VIII above, preferred R1 unsubstituted aryl groups include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like Preferred R1 substituted aryl groups in formula VII and VIII include, for example, monosubstituted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not include more than 3 substituents Examples of substituted R1 phenyls preferred in formula VII and VIII include 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-zso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2.3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3.4-dichlorophenyl, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3.4.5-trimethoxypheny 1,3,4,5-tri-(trifluoromethyl)pheny 1,2,4,6-trifluoropheny 1, 2.4.6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-tnfluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, Printed from Mimosa 07/26/1999 12:37:07 page -30- - 29 - 4-fluoro-2-trifluoromethylpheny 1, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro- 3-trifluoromethy lpheny 1. Preferred R1 alkaryl groups in formula VII and VIII include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-/z-propyl, and the like. Preferred R1 alkyl, substituted alkyl, alkenyi, cycloalkyl and cycloalkenyl groups in formula VII and VIII include, by way of example, wo-propyl, rt-propyl, n-butyl, zso-butyl, sec-butyl, /-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyI, -CH2-cyclopentyl, -CH2CH2-cyclopropyI, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH:CH2-cyclopentyl, and the like. Preferred R1 heteroaryls and substituted heteroaryls in formula VII and VIII include, by way of example, pyrid-2-yl, pyrid-3-yl, pynd-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropynd-3-yI), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenyIbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-l,2,4-thiooxadiazol-5-yl, 2-phenyloxazol- 4-yl, and the like. Preferred R4 substituents m formula VII and VIII include, for example, hydrogen, methyl, phenyl, benzyl and the like. Preferred R6 substituents in formula VII and VIII include, for example, hydrogen, methyl, ethyl, ^-propyl, zso-propyl, n-butyl, jso-butyl, sec-butyl, intellectual property office of n.z. 2 2 AUG 2001 received WO 98/38177 PCT/US98/03373 -- 30 - 10 15 20 25 tert-butyl, -CH2CH(CH2CH3)2, 2-methyl-/j-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, wo-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, /?-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, /w-hydroxybenzyl, /^-hydroxy benzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH20-benzyl, /j-(CH3)3C0C(0)CH20-benzyl, p-(H00CCH20)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholino-CH2CH20)-benzyl, -CH2CH2C(0)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(l-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(0)0-r-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(0-r-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e g., 1-naphthyl and 2-naphthyl), -CH2-(N-morpholino), p-(N-morpholino-CH2CH20)-benzyl, benzo[b]thiophen-2-yl, 5-chlorobenzo [b] thiophen-2-y 1,4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, thien-3-yl, and the like. Preferred cyclic groups defined by W' and -C(H)SC(=U)- include cycloalkyl, lactone, lactam, benzazepinone, dibenzazepinone and benzodiazepine groups In one preferred embodiment, the cyclic group defined by W' and -C(H)SC(=U)-, forms a cycloalkyl group of the formula: CH T" Printed from Mimosa 07/26/1999 12:37:07 page -32- WO 98/38177 PCT/US98/03373 - 31 -- wherein T" is selected from the group consisting of alkylene and substituted alkylene. A preferred cycloalkyl group is represented by the formula- 5 (Ra)w 10 (V) t wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, 15 substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 20 0 to 4; and w is an integer from 0 to 3 Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1. 25 In another preferred embodiment, the cyclic group defined by W', together with -C(H)SC(=U)- is a ring of the formula: T- 30 CH OH Printed from Mimosa 07/26/1999 12:37:07 page -33- WO 98/38177 PCT/US98/03373 -- 32 - or 5 C(H), r Cm SH 10 wherein s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13-15 where Z is a substituent selected from the group consisting of -0-, -S- and >NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the 20 proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3. Particularly preferred alcohol or thiol substituted groups include 25 (V), 30 35 (Ra)w HO Printed from Mimosa 07/26/1999 12:37:07 page -34- WO 98/38177 PCT/US98/03373 - 33 - (V), -(Ra)w OH wherein each V is independently selected from the group consisting of hydroxy, 10 acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, ammo, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, 15 amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3. 20 Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1 Yet another preferred embodiment of the cyclic group defined by W', together with -C(H)SC(=U)-, is a ring of the formula; Printed from Mimosa 07/26/1999 12:37:07 page -35- WO 98/38177 PCT/US98/03373 - 34 -- S 10 wherein s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13-where Z is a substituent selected from the group consisting of -0-, -S- and >NR12, each R12 is independently selected from the group consisting of alkyl, 15 alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -0- or -S-, and q is 20 an integer of from 1 to 3. Particularly preferred cyclic ketone and thioketone groups include: Printed from Mimosa 07/26/1999 12:37:07 page -36- WO 98/38177 PCT/US98/03373 -- 35 - wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, 5 thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3. 10 Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1. In another preferred embodiment, the cyclic group defined by W', together with -C(H)SC(=U)-, forms a ring of the formula: 15 20 II O 25 T 30 35 O Printed from Mimosa 07/26/1999 12:37:07 page -37- WO 98/38177 PCT/US98/03373 - 36 - wherein s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13-where Z is a substituent selected from the group consisting of -0-, -S- and 25 >NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and 30 substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3. 35 Particularly preferred lactone and thiolactone groups include: (V), (Ra)w (Ra)w h and O Printed from Mimosa 07/26/1999 12:37:07 page -38- WO 98/38177 PCT/U S98/03373 -- 37 - wherein each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, 5 thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integer from 0 to 4; and w is an integer from 0 to 3. 10 Preferably t is an integer from 0 to 2 and, more preferably, is an integer equal to 0 or 1. In another preferred embodiment, the cyclic group defined by W' and -C(H)SC(=U)-, forms a lactam ring of the formula: 15 T C(H), 20 II O 25 or a thiolactam ring of the formula: 30 35 S 40 Printed from Mimosa 07/26/1999 12:37:07 page -39- WO 98/38177 PCT/US98/03373 -- 38 -- wherein s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13-where Z is a substituent selected from the group consisting of -0-, -S- and >NR12, each R12 is independently selected from the group consisting of alkyl, 5 alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -0- or -S-, and q is 10 an integer of from 1 to 3. Particularly preferred lactam and thiolactam groups include: 15 (V)t rS O 20 ,(Ra), (Ra)w 25 O Rb 30 O O Printed from Mimosa 07/26/1999 12:37:07 page -40- WO 98/38177 PCT/US98/03373 - 39 - (V), .Ra 'Rb (V)f .(V)v ><% r^>< 10 15 20 25 30 )w O XRb (V)t Rb °v^- JT x ^ rNx O Rb Printed from Mimosa 07/26/1999 12:37:07 page -41- WO 98/38177 - 40 - PCT/US98/03373 wherein A-B is selected from the group consisting of alkylene, alkenylene, 25 substituted alkylene, substituted alkenylene and -N=CH-; Q' is oxygen or sulfur; each V is independently selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, 30 thioalkoxy, substituted thioalkoxy, trihalomethyl and the like; Ra is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, Printed from Mimosa 07/26/1999 12:37:07 page -42- WO 98/38177 PCT/US98/03373 - 41 - amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; Rb is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl, heteroaryl, heterocyclic, and the like; Rc is selected from the group consisting of alkyl, substituted alkyl, 5 alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted cycloalkyl; t is an integer from 0 to 4; t' is an integer from 0 to 3; and w is an integer from 0 to 3. 10 equal to 0 or 1. In another preferred embodiment, the cyclic group defined by W', together with -C(H)SC(=U)-, forms a ring of the formula; 15 wherein s is zero or one, T" is selected from the group consisting of alkylene, 25 substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13-where Z is a substituent selected from the group consistmg of -O-, -S- and >NR12, each R12 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently 30 alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -0- or -S-, and q is an integer of from 1 to 3. Preferably t is an integer from 0 to 2 and, more preferably, is an integer 20 '2 Printed from Mimosa 07/26/1999 12:37:07 page -43- 42 -- A still further preferred embodiment is directed to a ring group defined by W, together with -C(H),C( = U)-, of the formula: 10 NR12R12 15 20 25 wherein s is zero or one, T" is selected from the group consisting of alkylene, substituted alkylene, alkenylene, substituted alkenylene, -(R13Z)qR13- and -ZR13-where Z is a substituent selected from the group consisting of -0-, -S- and >NR12, each R12 is independendy selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic, each R13 is independently alkylene, substituted alkylene, alkenylene and substituted alkenylene with the proviso that when Z is -O- or -S-, any unsaturation in the alkenylene and substituted alkenylene does not involve participation of the -O- or -S-, and q is an integer of from 1 to 3. In a still further aspect the present invention provides a compound selected from the group consisting of compounds of formula IX and X: 30 35 40 RU IX intellectual property office of n.z. 2 2 AUG 2001 received -43 - (followed by 43 a) H RVM"N w J m x R2 wherein R1, R2, R4, Z, U, W, W', X, m and s are as defined above, W', together with -C(H)SC(=U>, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substimted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more ±an 5 fused rings) with one or more ring. strucrures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino* -NHC(0)R10, -NHSOjR10, -C(0)NH2, -C(0)NHR10, -QOJNR"^0, -S(0)R"\ -S(0)2R10, -S(0)2NHR'° and -S(O);NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl; U is selected from the group consisting of oxo ( = 0), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); s is an integer equal to 0 or 1; and t is an integer equal to 0 or 1. intellectual property office of n.z. 2 2 AUG 2001 received JJ6613 -43a- (followed by 43b) Preferred Rl, R~, R4, Z, W and W' are also as defined above. In a yet further aspect the present invention provides a use, in the preparation of a medicament for inhibiting the cellular release and/or synthesis of P -amyloid peptide in a patient in need thereof, of a compound of formula I as defined above. In another aspect the present invention provides a use, in the preparation of a medicament for preventing the onset of AD in a patient at risk for developing AD, of a compound of formula I as defined above. In another aspect the present invention provides a use in the preparation of a medicament for treating a patient with AD in order to inhibit further deterioration in the condition of that patient, of a compound of formula I as defined above. In another aspect the present invention provides a use, in the preparation of a medicament for inhibiting the cellular release and/or synthesis of P-amyloid peptide in a patient in need thereof, of a compound selected from the group consisting of compounds of formula VII and VIII as defined above. In another aspect the present invention provides a use, in the preparation of a medicament for preventing the onset of AD in a patient at risk for developing AD, of a compound selected from the group consisting of compounds of formula VII and VIII as defined above. In another aspect the present invention provides a use, in the preparation of a medicament for treating a patient with AD in order to inhibit further deterioration in the condition of that patient, of a compound selected from the group consisting of compounds of formula VII and VIII as defined above. In another aspect the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the invention. £ Ui • CL N °-U-<° ID ui "Jul a a CD ui CM > CD — UI <C O c-~i ul ol ce --43b-- Described but not claimed is a method for inhibiting /3-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I, VII and VIII above effective in inhibiting the cellular release and/or synthesis of /3-amyloid peptide Because the in vivo generation of /3-amyloid peptide is associated with the pathogenesis of AD8-9, the compounds of formula I, VII and VIII can also be employed in conjunction with a pharmaceutical composition to prophylactically and/or therapeutically prevent and/or treat AD. Accordingly, described but not claimed is a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I, VII and VIII above. Also described but not claimed is a therapeutic method for treating a patient with AD m order to inhibit further deterioration in the condition of that patient which method comprises administering intellectual property office of n.z. 2 2 AUG 2001 RECEIVED 3366 - 44 - to said patient a pharaiaceutical composition comprising a phanaaceutically inert earner and an effective amount of a compound or a mixture of compounds of formula I,~VII and VIII above. As described above this invention provides for novel compounds of formula I, VII or VIII. Further preferred compounds of formula I are represented m the following Tables I-IV which illustrate preferred subsets of these structures: intellectual property office of n.z. 2 2 AUG 2001 received WO 98/38177 PCT/US98/03373 - 45 - TABLE I R2 R1' R2 R4 Y w X 3,5-di-F-$-CH2C(0)- -ch3 H -OCH2CH3 s -ch2- 0-ch2-oc(o)- -ch3 -CU24> -och3 -N-r-Boc -ch2- 3,5-di-F-0-CH2C(O)- -ch3 -CH20 -och3 -N-/-Boc -CH2- 3,5-di-F-<A-CH2C(0)- -ch3 -CH 2<j> -och3 NH -ch2- <t>-C H20C(0)- -ch3 -<t> -och3 -N-r-Boc -ch2- 3,5-di-F-<£-CH2C(0)- -ch3 -<t> -och3 NH -ch2- 3,5-di-F-<£-CH2C(0)- -ch3 H -och3 0 -ch2- 3,5-di-Cl-<£-CH2C(0)- -ch3 H -och3 0 -ch2- 3,5-di-F-4>-CH2C(0)- -<t> H -och3 s -ch2- Printed from Mimosa 07/26/1999 12:37:07 page -47- WO 98/38177 PCT/US98/03373 - 46 - TABLE II | r4 r2 R' R2 R4 Y w X 3,5-difluoro-4>-CH2-C(0)- X U 1 H -OCH2CH3 0 -ch2- 3,5-difluoro-0-CH2-C(O)- -ch3 -CH 2<A -och3 NH -ch2- 3,5-difluoro-4>-CH2-C(0)- -CH3 -4> -och3 NH -ch2- Printed from Mimosa 07/26/1999 12:37:07 page -48- WO 98/38177 PCT/US98/03373 - 47 - TABLE III R1' R2 m R6 V 3,5-di-F-</>-CH2C(0)- -ch3 1 -ch3 3-ethyl-l ,2,4-oxadiazol-5-yl 3,5-di-F-4>-CH2C(0)- -ch3 1 -CH2</> 3-methyl-1,2,4-oxadiazol-5-yl 3,5-di-F-0-CH2C(O)- — 0 -ch3 l-(methylhexano-2-yl)-tetrazol-5-yl 3, 5-di-F-<£-CH2C(0)- -ch3 1 -4> thiazolin-2-yl 5,5-di-F-0-CH2C(O>- -ch3 1 -4> 3-methyl-l,2,4-oxadiazol-5-yl 3, J-di-F-</>-CH2C(0)- -ch3 1 3-phenyl-l,2,4-oxadiazol-5-yl 5,5-di-F-0-CH2C(O)- -ch3 1 -4> 3-(p-methoxy-benzyl)-1,2,4-oxadiazol-5-yl Printed from Mimosa 07/26/1999 12:37:07 page -49- WO 98/38177 PCT/US98/03373 -- 48 - TABLE IV R1' T n R2 Y 3,5-di-F-0-CH2- 2-R'-thiazohn-4-yl 1 -OCHj 3,5-di-F-0-CH2- 2-R'-4-methyl-thiazolin-4-yl 1 -OCHj 3,5-di-F-0-CH2- 2-R'-4-methyl-imidazolin-4-yl 1 -4> -och3 Printed from Mimosa 07/26/1999 12:37:07 page -50- WO 98/38177 PCT/US98/03373 - 49 - DETAILED DESCRIPTION OF THE INVENTION As above, this invention relates to compounds which inhibit /J-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. However, prior to describing this invention in further detail, 5 the following terms will first be defined. Definitions The term "/3-amyloid peptide" refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to 10 the form of the protein described by Glenner, et al.1 including mutations and post-translational modifications of the normal /J-amyloid peptide In whatever form, the /3-amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the /3-amyloid precursor protein (APP). Its 43-ammo acid sequence is: 15 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 20 ii Glu Val His His Gin Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 25 31 lie lie Gly Leu Met Val Gly Gly Val Val 41 30 lie Ala Thr (SEQ ID NO: 1) or a sequence which is substantially homologous thereto. "Alkyl" refers to monovalent alkyl groups preferably having from 1 to 10 35 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, wo-propyl, /i-butyl, iso-butyl, w-hexyl, and the like. Printed from Mimosa 07/26/1999 12:37:07 page -51- WO 98/38177 PCT/US98/03373 - 50 - "Substituted alkyl" refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy,"substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxylalkyl, oxyacyl, 5 oxyacylammo, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, aryloxy, thioaryloxy, heteroaryloxy, thioheteroaryloxy, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylammo, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from 10 alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic. "Alkylene" refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the 15 propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-), and the like "Alkaryl" refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like "Alkoxy" refers to the group "alkyl-O-" Preferred alkoxy groups include, by way of example, methoxy, ethoxy, K-propoxy, wo-propoxy, H-butoxy, /er/-butoxy, sec-butoxy, w-pentoxy, M-hexoxy, 1,2-dimethylbutoxy, and the like. "Substituted alkoxy" refers to the group "substituted alkyl-O-" where substituted alkyl is as defined above. "Alkenyl" refers to alkenyl groups preferably having from 2 to 10 carbon 30 atoms and more preferably 2 to 6 carbon atoms and having at least 1 and Printed from Mimosa 07/26/1999 12:37:07 page -52- WO 98/38177 - 51 - PCT/US98/03373 preferably from 1 -2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-CH=CH2), «-propenyl (-CH2CH=CH2), wo-propenyl (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3), and the like. 5 "Substituted alkenyl" refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono-10 and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic. 15 "Alkenylene" refers to divalent alkenylene groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., -CH,CH=CH- and -C(CH3)=CH-) and the like 20 "Substituted alkenylene" refers to an alkenylene group, preferably of from 2 to 8 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono-25 and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic. Additionally, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form 30 one or more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Printed from Mimosa 07/26/1999 12:37:07 page -53- 98/38177 PCT/US98/03373 -- 52 - "Alkynyl" refers to alkynyl groups preferably having from-2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably "from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (-OCH), propargyl (-CH2C=CH) and the like. "Substituted alkynyl" refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkyoxy, aryl, heteroaryl, heterocyclic, nitro, and mono-and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic. "Acyl" refers to the groups alkyl-C(O)-, substituted alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)- where alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein "Acylamino" refers to the group -C(0)NRR where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein "Aminoacyl" refers to the group -NRC(0)R where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl. and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein Printed from Mimosa 07/26/1999 12:37:07 page -54- WO 98/38177 PCT/US98/03373 - 53 - "Oxyacyl" refers to the groups -0C(0)-alkyl, -0C(0)-aryi, -C(0)0-heteroaryl-, and -C(0)0-heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein. 5 "Oxyacylamino" refers to the groups -0C(0)NR-alkyl, -0C(0)NR- substituted alkyl, -0C(0)NR-aryl, -OC(0)NR-heteroaryl-, and -0C(0)NR-heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein. 10 "Aminocarboxy esters" refers to the groups -NRC(0)0-alkyl, -NRC(0)0-substituted alkyl, -NRC(0)0-aryl, -NRC(0)0-heteroaryl, and -NRC(0)0-heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, 15 cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein "Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g , phenyl) or multiple condensed rings (e g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like 20 Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino 25 aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, acylamino, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, tnhalomethyl, mono- and di-alkylamino, mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylammo, mono- and di-heterocyclic amino, and unsymmetric di-substituted 30 amines having different substituents selected from alkyl, substituted alkyl, aryl, Printed from Mimosa 07/26/1999 12:37:07 page -55- WO 98/38177 PCT/US98/03373 -- 54 -- heteroaryl and heterocyclic, and the like Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy "Aryloxy" refers to the group aryl-O- wherein the aryl group is as defined 5 above including optionally substituted aryl groups as also defined above. "Carboxyalkyl" refers to the groups -C(0)0-alkyl and -C(0)0-substituted alkyl where alkyl and substituted alkyl are as defined above. 10 "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring or multiple condensed rings which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1 -methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the 15 like, or multiple ring structures such as adamantanyl, and the like. "Substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted 20 alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy. substituted thioalkoxy, trihalomethyl and the like. "Cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 8 carbon atoms 25 having a single cyclic ring and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like 30 "Substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, Printed from Mimosa 07/26/1999 12:37:07 page -56- WO 98/38177 PCT/US98/03373 -- 55 - substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl and the like. "Halo" or "halogen" refers to fluoro, chloro, bromo and lodo and preferably is either chloro or bromo. "Heteroaryl" refers to a monovalent aromatic carbocyclic group of from 2 to 10 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 3 substituents 15 selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, ammo, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, mtro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono-20 and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di- heteroarylammo, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. 25 Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl. 30 "Heterocycle" or "heterocyclic" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 8 Printed from Mimosa 07/26/1999 12:37:07 page -57- WO 98/38177 -- 56 -- PCT/US98/03373 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring Unless otherwise constrained by the definition for the heterocyclic 5 substituent, such heterocyclic groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, ammo, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic, 10 oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylammo, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocychc amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like. Such heterocyclic groups can 15 have a single ring or multiple condensed rings Preferred heterocyclics include morpholino, piperidinyl, and the like. Examples of heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, mdolizine, 20 isoindole, indole, indazole, purine, quinolizine, isoquinohne, quinohne, phthalazine, naphthylpyridine, quinoxaline, quinazohne, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indohne, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-25 tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like "Oxyacyl" refers to the groups -0C(0)-alkyl, -0C(0)-aryl, -C(0)0-heteroaryl-, and -C(0)0-heterocychc where alkyl, aryl, heteroaryl and heterocyclic 30 are as defined herein. Printed from Mimosa 07/26/1999 12:37:07 page -58- WO 98/38177 PCT/US98/03373 -- 57 -- "Oxyacylamino" refers to the groups -0C(0)NH-alkyl, -0C(0)NH-substituted alkyl, -0C(0)NH-aryl, -OC(0)NH-heteroaryl-, and -0C(0)NH-heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein 5 "Thiol" refers to the group -SH. "Thioalkoxy" refers to the group -S-alkyl. "Substituted thioalkoxy" refers to the group -S-substituted alkyl. 10 "Thioaryloxy" refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above. "Thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl 15 group is as defined above including optionally substituted aryl groups as also defined above. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound of formula I, VII or VIII which salts are derived from a variety of 20 organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. 25 Comnound Preparation The compounds of formula I are readily prepared via several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, etc. 30 Printed from Mimosa 07/26/1999 12:37:07 page -59- WO 98/38177 PCT/U S98/03373 -- 58 -- The heterocyclic ring(s) in the compounds of formula I above can be prepared by use or adaptation of known chemical syntheses and methods, which synthesis and methods are well known in the art. For example, the synthesis of various heterocycles is illustrated in detail in the examples set forth below. Using 5 these procedures, other suitable heterocycles can be prepared by modifying the starting materials employed in these procedures. In certain cases, the compounds of formula I above are prepared by coupling a suitable heterocycle having one or more pendant functional groups to 10 the other components necessary to form the A-B-C structure of formula I. Typical functional groups used for such couplings include, by way of example, carboxylic acid and amino groups. The coupling reaction is generally conducted using conventional coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. 15 can be used to facilitate coupling The reaction is typically conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. The compounds of formula VII and VIII are readily prepared by 20 conventional amidation of a carboxylic acid as shown in reaction (1) below. Printed from Mimosa 07/26/1999 12:37:07 page -60- WO 98/38177 -- 59 - PCT/US98/03373 1a 10 or 15 1b 20 25 Reaction 1 VII (for la) or VIII (for lb) 30 wherein R1, R4, R6, T', X', X", W, X, W', U, t and s are as defined above. Printed from Mimosa 07/26/1999 12:37:07 page -61- WO 98/38177 PCT/US98/03373 - 60 -- The reaction is conventionally conducted by using at least a stoichiometric amount of carboxylic acid la or lb and amine 2. This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare compounds VII and "VIII. For 5 example, well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran 10 and the like. Alternatively, the acid halide of compound la or lb can be employed m reaction (1) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamme, N-methylmorpholme and the like. 15 Synthesis of Carboxylic Acid Starting materials Carboxylic acids la and lb can be prepared by several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, whether t 20 is zero or one One method for preparing these compounds (when t is one) is the hydrolysis of esters of compounds of formula V and VI above. Similar methods can be employed to prepare related compounds when 1 is zero. Carboxylic acids 1 having m equal to 1 and n equal to 1 or 2 can also be 25 prepared by use of polymer supported forms of carbodiimide peptide coupling reagents A polymer supported form of EDC, for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993))10 Additionally, a new carbodiimide coupling reagent, PEPC, and its corresponding polymer supported forms have been discovered and are very useful for the preparation of such compounds. 30 Printed from Mimosa 07/26/1999 12:37:07 page -62- WO 98/38177 PCT/US98/03373 -- 61 -- Polymers suitable for use in making a polymer supported coupling reagent are either commercially available or may be prepared by methods well known to the artisan skilled m the polymer arts. A suitable polymer must possess pendant sidechains bearing moieties reactive with the terminal amine of 5 the carbodiimide Such reactive moieties include chloro, bromo, iodo and methanesulfonyl Preferably, the reactive moiety is a chloromethyl group. Additionally, the polymer's backbone must be inert to both the carbodiimide and reaction conditions under which the ultimate polymer bound coupling reagents will be used. 10 Certain hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer supported coupling reagents. Examples of these hydroxylated resins include the 4-hydroxymethylphenylacetamidomethyl resin (Pam Resin) and 4-15 benzyloxybenzyl alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville, Kentucky, USA (see Advanced Chemtech 1993-1994 catalog, page 115). The hydroxymethyl groups of these resins may be converted into the desired chloromethyl groups by any of a number of methods well known to the skilled artisan. 20 Preferred resins are the chloromethylated styrene/divmylbenzene resins because of their ready commercial availability. As the name suggests, these resins are already chloromethylated and require no chemical modification prior to use. These resins are commercially known as Merrifield's resms and are 25 available from Aldrich Chemical Company of Milwaukee, Wisconsin, USA (see Aldrich 1994-1995 catalog, page 899). Methods for the preparation of PEPC and its polymer supported forms are outlined in the following scheme Printed from Mimosa 07/26/1999 12:37:07 page -63- WO 98/38177 PCT/US98/03373 - 62 - 10 H,N r> a sNCO N=C=N JL, 15 LG ©_/ Functionalized Resin where ~ an inert polymer and LG = CI, Br. I or 0S02CH3 20 a. (p)—-J cr N=C —N 25 Such methods are described more fully in U.S. Patent Application Serial No. 60/019,790 filed June 14, 1996 which application is incorporated herein by reference m its entirety. Briefly, PEPC is prepared by first reacting ethyl isocyanate with l-(3-aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer supported form 30 is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent. Printed from Mimosa 07/26/1999 12:37:07 page -64- WO 98/38177 PCT/US98/03373 - 63 - The carboxylic acid coupling reactions employing these reagents are performed at about ambient to about 45°C, for from about 3 to 120 hours. Typically,"the product may be isolated by washing the reaction with CHC13 and concentrating the remaining orgamcs under reduced pressure." As discussed 5 supra, isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure. Preparation of Cyclic Amino Compounds 10 Cyclic amino compounds 2 employed in reaction (1) above are generally aminolactams, aminolactones, aminothiolactones and aminocycloalkyl compounds which can be represented by the formula: 20 where U and s are as defined above, Q is preferably selected from the group consisting of -0-, -S-, >NR16, and >CR17R18 where each of R16, R17 and R18 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic with the proviso that if Q is -0-, -S- or >NR15, 25 then X is oxo or dihydro. The aminolactams, aminolactones and aminothiolactones of the formula above can be prepared by use or adaptation of known chemical syntheses which syntheses are well described in the literature. See, e.g., Ogliaruso and Wolfe, 30 Synthesis of Lactones and Lactams, Patai, et al. Editor, J. Wiley & Sons, New York, New York, USA, pp. 1085 et seq. (1993). Printed from Mimosa 07/26/1999 12:37:07 page -65- WO 98/38177 PCT/US98/03373 -- 64 ~ Specifically, 3-amino substituted lactams 13 with 5, 6 or 7 ring atoms may be prepared by the direct cyclization of a suitable alpha, omega-diamino acid ester"12 as shown in reaction (5) below. Q ,.o HN-—^ H2N—L—{ •- 1 _T Reaction (5) NH-Pr NH-Pr 12 12 10 wherein L is a linking group (typically an alkylene group) of from 2-4 atoms, Pr is a suitable protecting group such as /-butoxycarbonyl, carbobenzyloxy, or the like and R19 is an alkoxy or aryloxy group such as methoxy, ethoxy, 15 p-nitrophenoxy, N-succinimidoxy, and the like. The reaction may be earned out in a solvent such as water, methanol, ethanol, pyridine, and the like. Such reactions are exemplied by cyclization of a lysine ester to a caprolactam as described by Ugi, et al., Tetrahedron, 52(35). 11657-11664 (1996) Alternatively, such a cyclization can also be conducted in the presence of 20 dehydrating agents such as alumina or silica to form lactams as described by Blade-Font, Tetrahedron Lett., 21:2443 (1980) The preparation of aminolactams alkylated on the amino group of the cyclic lactam is described by Freidinger, et al., J. Org. Chem., 47-104-109 25 (1982) and illustrated in reaction (6) below O CH u a 1-Reductive Q I—( "V amination R®N—r u f/ Ntic- + X ,'J Reaction (6) 30 2 O 2. Cyclization Printed from Mimosa 07/26/1999 12:37:07 page -66- WO 98/38177 PCT/US98/03373 -- 65 - wherein L and R16 are as defined above. In reaction (6), reductive amination of 14 with aldehyde 15 and subsequent ring closure by methods using, for example, EDC "provides for 5 aminolactam 16. The preparation of six-membered lactams using this general procedure is described by Semple, et al., J. Med. Chem., 39:4531-4536 (1996). The internal cyclization of an amide anion with a halide or equivalent thereof can sometimes be used to particular advantage in the synthesis of 10 smaller ring lactams where the stereochemistry of the amino-lactam center is available from the standard amino-acid pool. This approach is illustrated in reaction (7) below 15 20 25 SMe r1" N-F BocHN'/^[ 0 12 where R16 is as defined above. r> 0 11 -R6 Reaction (7) The approach of reaction (7) is presented by Semple, et al., supra., and Freidinger, et al., J. Org. Chem., 47" 104-109 (1982) where a dimethylsulfonium leaving group is generated from methyl iodide treatment of an alkyl methyl sulfide 17 to provide for lactam 18. A similar approach using a Mitsunobu reaction on an omega alcohol is found Holladay, et al., J. Org Chem., 56:3900-3905 (1991). In another method, lactams 20 can be prepared from cyclic ketones 19 using either the well known Beckmann rearrangement (e g., Donaruma, et al., 30 Organic Reactions, U 1-156 (I960)) or the well known Schmidt reaction (Wolff, Organic Reactions, 3:307-336 (1946)) as shown in reaction (8) below: Printed from Mimosa 07/26/1999 12:37:07 page -67- WO 98/38177 PCT/US98/03373 - 66 - Beckmann rearrangement or h Schmidt reaction L~N Reaction (8) L>=o I 12 29l 0 wherein L is as defined above. 10 Application of these two reactions leads to a wide variety of lactams especially lactams having two hydrogen atoms on the carbon alpha to the lactam carbonyl which lactams form a preferred group of lactams in the synthesis of the compounds of formula I above. In these reactions, the L group can be highly variable including, for example, alkylene, substituted alkylene and hetero 15 containing alkylene with the proviso that a heteroatom is not adjacent to the carbonyl group of compound 19. Additionally, the Beckmann rearrangement can be applied to bicyclic ketones as described in Krow, et al., J. Org Chem., 61-5574-5580 (1996) 20 The preparation of lactones can be similarly conducted using peracids m a Baeyer-Vilhger reaction on ketones Alternatively, thiolactones can be prepared by cyclization of an omega -SH group to a carboxylic acid and thiolactams can be prepared by conversion of the oxo group to the thiooxo group by P2S5 or by use of the commercially available Lawesson's Reagent, 25 Tetrahedron, 35:2433 (1979). One recently reported route for lactam synthesis is a variation of the Schmidt reaction through the use of an alkyl azide, either intermolecularly or mtramolecularly, through a tethered alkylazide function that attacks a ketone 30 under acidic conditions. Gracias, et al., J. Am. Chem. Soc., 117:8047-8048 (1995) describes the mtermolecular version whereas Milligan, et al., 7. Am. Printed from Mimosa 07/26/1999 12:37:07 page -68- WO 98/38177 PCT/US98/03373 — 67 Chem. Soc., 117:10449-10459 (1995) describes the intramolecular"version. One example of the intramolecular version is illustrated in reaction (9) below: 10 Reaction (9) 15 20 where R10 is exemplified by alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic. In this reaction, ketone 21 is converted to an a-(w-alkyl)ketone 22 which is cyclized to form bicyclic lactam 23. Such intramolecular reactions are useful in forming bicyclic lactams having 5-7 members and the lactam ring of 6-13 members. The use of hetero atoms at non-reactive sites in these rings is feasible in preparing heterobicyclic lactams. 25 Still another recent approach to the synthesis of lactams is described by Miller, et al., J Am Chem. Soc., 118:9606-9614 (1996) and references cited and is illustrated in reaction (10) below: HN i P -Q r f V 21 Printed from Mimosa 07/26/1999 12:37:07 page -69- WO 98/38177 PCT/US98/03373 - 68 - where R6 and Pr are as defined above and R" is exemplified by halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic wherein the aryl, heteroaryl, cycloalkyl and heterocyclic group is optionally fused to the lactam ring structure. 5 Specifically, in reaction (10), lactam 26 is formed from an appropriate unsaturated amide (e.g., 24) through a ruthenium or molybdenum complexes catalysed olefin metathesis reaction to form unsaturated lactam 25 which can be used herein without further modification. However, the unsaturation in 25 10 permits a myriad of techniques such as hydroboration, Sharpless or Jacobsen epoxidations, Sharpless dihydroxylations, Diels-Alder additions, dipolar cycloaddition reactions and many more chemistries to provide for a wide range of substituents on the lactam ring. Moreover, subsequent transformations of the formed substitution leads to other additional substituents (e.g., mesylation 15 of an alcohol followed by nucleophilic substitution reactions). See, for example, March, et al Advanced Organic Chemistry, Reaction Mechanisms and Structure, 2nd Edition, McGraw-Hill Book Company, New York, New York, USA (1977) for a recitation of numerous such possible reactions. Saturated amides used in this reaction are conventional with amide 24 being commercially 20 available Related chemistry to cyclize amides to form lactams is disclosed by Colombo, et al., Tetrahedron Lett., 35(23):4031-4034 (1994) and is illustrated in reaction (11) below 25 30 AcHN V, J AcHN-X^n. , Reaction (11) CO2IBU 21 Printed from Mimosa 07/26/1999 12:37:07 page -70- WO 98/38177 PCT/US98/03373 - 69 - In this reaction, proline derivative 27 is cyclized via a tributyltin-radical cyclization to provide for lactam 28. Some of the lactams described above contain the requisite amino group 5 alpha to the lactam carbonyl whereas others did not. However, the introduction of the required amino group can be achieved by any of several routes delineated below which merely catalogue several recent literature references for this synthesis. 10 For example, in a first general synthetic procedure, azide or amine displacement of a leaving group alpha to the carbonyl group of the lactam leads to the alpha-aminolactams. Such general synthetic procedures are exemplified by the introduction of a halogen atom followed by displacement with phthalimide anion or azide and subsequent conversion to the amine typically by 15 hydrogenation for the azide as described in Rogriguez, et al., Tetrahedron, 52:7727-7736 (1996), Parsons, etal , Biochem. Biophys. Res. Comm , 117:108-113 (1983) and Watthey, et al , / Med Chem., 28:1511-1516 (1985). One particular method involves lodination and azide displacement on, for example, benzyllactams as described by Armstrong, et al., Tetrahedron Lett., 35'3239 20 (1994) and by King, et al., J Org. Chem., 58:3384 (1993) Another example of this first general procedure for the synthesis of alpha-aminolactams from the corresponding lactam involves displacement of a triflate group by an azido group as described by Hu, et al., Tetrahedron Lett., 25 36(21):3659-3662 (1995) Still another example of this first general procedure uses a Mitsunobu reaction of an alcohol and a nitrogen equivalent (either -NH2 or a phthalimido group) in the presence of an azodicarboxylate and a triarylphosphine as 30 descnbed in Wada, et al., Bull. Chem. Soc. Japan, 46:2833-2835 (1973) using an open chain reagent. Printed from Mimosa 07/26/1999 12:37:07 page -71- WO 98/38177 PCT/US98/03373 -- 70 - Yet another example of this first general procedure involves reaction of alpha-chlorolactams with anilines or alkyl amines in a neat mixture at 120°C to provide for 2-(N-aryl or N-alkyl)lactams as described by Gaetzi, Chem. Abs., 66:28690m. 5 In a second general synthetic procedure, reaction of an enolate with an alkyl nitrite ester to prepare the alpha oxime followed by reduction yields the alpha-aminolactam compound This general synthetic procedure is exemplified by Wheeler, et al., Organic Syntheses, Coll. Vol. VI, p 840 which describes 10 the reaction of isoamyl nitrite with a ketone to prepare the desired oxime. The reduction of the oxime methyl ester (prepared from the oxime by reaction with methyl iodide) is described in the J. Med Chem., 28(12): 1886 (1985) and the reduction of alpha-oximino caprolactams by Raney-nickel and palladium catalysts is described by Brenner, et al , U.S. Patent No. 2,938,029. 15 In a third general synthetic procedure, direct reaction of an enolate with an electrophilic nitrogen transfer agent can be used. The original reaction employed toluenesulfonyl azide but was improved as described by Evans, et al., J. Am. Chem. Soc , 112 4011-4030 (1990) Specifically, direct introduction of 20 an azido group which can be reduced to the amine by hydrogenation is described by Micouin, et al., Tetrahedron, 52 7719-7726 (1996). Likewise, the use of triisopropylbenzenesulfonyl azide as the azide transferring agent for reaction with an enolate is described by Evans, et al., supra. The use of triphenylphosphine to reduce the alpha-azidolactams to the corresponding 25 aminolactams in the benzodiazepine series is disclosed by Butcher, et al., Tetrahedron Lett., 32(37):6685-6688 (1996). Lastly, diazo transfer of beta-diketones and subsequent reduction of the diazo group to the amino group is exemplified by Hu, et al., Tetrahedron Lett., 36(21).3659-3662 (1995) who used Raney-nickel and hydrogen in acetic acid and acetic anhydride as the 30 solvent. Printed from Mimosa 07/26/1999 12:37:07 page -72- WO 98/38177 PCT/US98/03373 - 71 - In a fourth general procedure, ^-substituted lactams are first- converted to the 3-alkoxycarbonyl derivatives by reaction with a dialkyl carbonate and a base such as"sodium hydride. See, for example, M.L. Reupple, et al., J. Am Chem. Soc., 93:7021 et seq. (1971) The resulting esters serve"as starting 5 materials for conversion to the 3-amino derivatives. This conversion is achieved via the Curtius reaction as shown in reaction (12) below: h12 ,hu y2 L-N L-fjk L-N I L " J—^ ^ Reaction (12) RO,C 0 P*HN O 15 where Pr is as defined above and R12 is typically hydrogen, an alkyl or an aryl group. The Curtius reaction is described by P.A.S Smith, Organic Reactions, 3.337-449 (1946). Depending on the reaction conditions chosen, Pr = H or a 20 protecting group such as Boc For example, when R = H, treatment of the acid with diphenylphosphoryl azide in the presence of t-butanol provides the product wherein Pr = Boc. The alpha-aminolactams employed as the cyclic amino compounds 2 in 25 reaction (1) above include ring N-substituted lactams in addition to ring N-H lactams. Some methods for preparing ring N-substituted lactams have been described above. More generally, however, the preparation of these compounds range from the direct introduction of the substituent after lactam formation to essentially introduction before lactam formation. The former 30 methods typically employ a base and an primaiy alkyl halide although it is Printed from Mimosa 07/26/1999 12:37:07 page -73- WO 98/38177 PCT/US98/03373 - 72 -- contemplated that a secondary alkyl halide can also be employed although yields may suffer Accordingly, a first general method for preparing N-substituted lactams 5 is achieved via reaction of the lactam with base and alkyl halide (or acrylates in some cases). This reaction is quite well known and bases such as sodamide, sodium hydride, LDA, LiHMDS in appropriate solvents such as THF, DMF, etc are employed provided that the selected base is compatible with the solvent. See for example' K. Onto, et al., Tetrahedron, 36:1017-1021 (1980) 10 and J E. Semple, et al , J. Med. Chem , 39:4531-4536 (1996) (use of LiHMDS with either R-X or acrylates as electrophiles). A second general method employs reductive amination on an amino function which is then cyclized to an appropriate ester or other carbonyl 15 function A third general method achieves production of the N-substitution during lactam formation. Literature citations report such production from either photolytic or thermal rearrangement of oxaziridines, particularly of N-aryl 20 compounds See, for example, Krunm, Chem. Ber., 91:1057 (1958) and Suda, et al., J. Chem. Soc. Chem Comm., 949-950, (1994). Also, the use of methyl hydroxylamine for the formation of mtrones and their rearrangement to the N-methyl derivatives is reported by Barton, et al., J. Chem. Soc., 1764-1767 (1975). Additionally, the use of the oxaziridine process in chiral synthesis has 25 been reported by Kitagawa, et al., J. Am. Chem. Soc., 117.5169-5178 (1975). A more direct route to obtain N-phenyl substituted lactams from the corresponding NH lactams through the use of t-butyltetramethylguanidine and triphenylbismuth dichloride is disclosed by Akhatar, et al., J. Org Chem., 30 55 5222-5225 (1990) as shown in reaction (13) below. Printed from Mimosa 07/26/1999 12:37:07 page -74- WO 98/38177 PCT/US98/03373 - 73 -- 25 Reaction (13) 10 Given that numerous methods are available to introduce an alpha-ammo group onto a lactam (or lactone) ring, the following lactams (and appropriate corresponding lactones) are contemplated for use in the synthesis of compounds of formula I above Similar alcohol functions at the carbonyl position are 15 derivative of either amine ring opening of cyclic epoxides, ring opening of aziridines, displacement of appropriate halides with amine or alcohol nucleophiles, or most likely reduction of appropriate ketones These ketones are also of interest to the present invention 20 Monocyclic lactams as described by Nedenskov, et al., Acta Chem Scand., 12:1405-1410 (1958) and represented by the formula: (a" R 2 where R1 and R2 are exemplified by alkyl, aryl or alkenyl (e.g., allyl). Printed from Mimosa 07/26/1999 12:37:07 page -75- WO 98/38177 PCT/US98/03373 - 74 - Monocyclic lactams containing a second nitrogen ring atom as described by Sakakida, et al., Bull. Chem. Soc. Japan, 44.478-480 (1971) and represented by the formula: 0 i R where R is exemplified by CH3- or PhCH2-. Monocyclic lactams having hydroxyl substitution on the ring as described by Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995) and represented by the formula- 15 20 where R is exemplified by benzyl (includes both the cis and trans hydroxy lactams). The direct preparation A/-substituted lactams of 5-8 members from the 25 corresponding ketones is described by Hoffman, et al., Tet. Lett., 30:4207-4210 (1989). These lactams are represented by the formula: rf° XrR n , 4 30 L(CH*>" '"4 Printed from Mimosa 07/26/1999 12:37:07 page -76- WO 98/38177 PCT/US98/03373 -- 75 -- wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, or benzyl. N-methoxylactams prepared from cyclohexanone and dimethoxyamine are described by Vedejs, et al., Tet. Lett., 33:3261-3264 (1992). These 5 structures are represented by the formula. "Substituted 3-aminoazetidinone derivatives prepared by a variety of routes including those described by van der Steen, et al., Tetrahedron, 47, 7503-7524 (1991)56, Hart, et al., Chem Rev., 89:1447-1465 (1989) and 15 references cited therein are represented by the formula. h2n rI oW 2 o ft 20 where R1 and R2 are independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, heterocyclic or are fused to form a cyclic group. 25 Ring substituted lactams are described by Lowe, et al., Bioorg. Med. Chem. Lett., 4:2877-2882 (1994) and are represented by the formula: Printed from Mimosa 07/26/1999 12:37:07 page -77- WO 98/38177 PCT/US98/03373 - 76 -- 10 wherein R2 and R3 are exemplified by aryl and substimted aryl and R1 is exemplified by alkyl or hydrogen The synthesis of substimted 3-aminopyrrolidones from alpha-bromoketones is described by McKennis, Jr., et al., J. Org. Chem , 28:383-387 15 (1963) These compounds are represented by the formula: NH, 20 0 - RlA^Br Ri N 1 2 R where R1 is aryl or heteroaryl and R2 corresponds to any substituent for which the corresponding amine R2-NH2 exists. 25 Additional references for the synthesis of alpha aminolactams are as follows: 1 Shirota, et al., J. Med. Chem., 20:1623-1627 (1977) which describes the synthesis of a compound of the formula: Printed from Mimosa 07/26/1999 12:37:07 page -78- WO 98/38177 PCT/US98/03373 — 77 - H,N 2. Overberger, et al., J. Am. Chem. Soc., 85:3431 (1963) which 10 describes the preparation of optically active /3-methylcaprolactam of the formula: 15 20 3. Herschmann, Helv. Chim. Acta, 32:2537 (1949) describes the synthesis of a disubstituted caprolactam from the Beckmann rearrangement of menthone which is represented by the formula: 25 Printed from Mimosa 07/26/1999 12:37:07 page -79- WO 98/38177 PCT/US98/03373 - 78 -- 4. Overberger, et al., Macromolecules, 1:1 (1968) describes the synthesis of eight-membered lactams from 3-methylcycloheptanone as shown below: + O 10 5. The synthesis of benzolactams (benzazepinones) has been reported by Busacca, et al., Tet Lett., 33:165-168 (1992): 15 20 by Croisier, et al., U.S. Patent No. 4,080,449: 25 Printed from Mimosa 07/26/1999 12:37:07 page -80- WO 98/38177 PCT/US98/03373 - 79 -- and by J.A. Robl, et al., Tetrahedron Lett., 36(10): 1593-1596 (1995) who employed an internal Friedel-Crafts like cyclization to prepare the tricyclic benzyllactams shown below where Pht is the phthalimido protecting group: 10 Eta OEt C02Et 8 10 15 Another tricyclic lactam series is disclosed by Flynn, et al., J Med. Chem., 36:2420-2423 (1993) and references cited therein. 6 Onto, et al., Tetrahedron, 36:1017-1021 (1980) discloses phenyl substituted benzazepmones represented by the formula 20 wherein R = H or CH3-; 25 Kawase, et al., J.Org. Chem , 54:3394-3403 (1989) discloses a N-methoxy benzazepinone represented by the formula: 30 Printed from Mimosa 07/26/1999 12:37:07 page -81- WO 98/38177 PCT/US98/03373 - 80 - 7. Lowe, et al., J. Med. Chem., 37:3789-3811 (1994) describes several synthetic pathways to substituted benzazepinones of the formula: 10 where R1 is substituted aryl or cyclohexyl, X is a suitable substituent and R2 can be H or alkyl. The syntheses described m Lowe are, however, adaptable to form numerous R1 substituents. 15 8. Robl, et al., Bioorg. Med. Chem. Lett., 4.1789-1794 (1994) and references cited therein as well as Skiles, et al., Bioorg. Med. Chem. Lett., 3 773-778 (1993) disclose benzofused lactams which contain additional heteroatoms in the lactam ring. These compounds are represented by the formula: 25 where X is O and R2 = H or CH3 or X = S and R2 = H. In either case, R1 = H or alkyl Also, in Skiles, the thio group of the thiolactam can be oxided to the S02 group. These structures are also presented from Beckmann rearrangement in Grunewald, et al., J. Med. Chem., 39(18) 3539 (1996). 30 Printed from Mimosa 07/26/1999 12:37:07 page -82- WO 98/38177 PCT/US98/03373 - 81 - 9. Also syntheses for the benzoheterolactam series is presented in Thomas, et al., J. Chem. Soc., Perkin II, 747 (1986) which could lead to compounds of the formula: NH2 10 20 0*\.-N X = o, H2 R = C02R where X is O or H2 and R is C02R. 10. Further examples of benzazepinones are found in Warshawsky, et al., Bioorg. Med. Chem. Lett., 6:957-962 (1996) which discloses compounds of 15 the formula. The synthesis can be generalized to produce R = alkyl or aryl. 25 11. Ben-Ishai, et al., Tetrahedron, 43:439-450 (1987) describes syntheses which could lead to several benzolactams of the formula: 30 Printed from Mimosa 07/26/1999 12:37:07 page -83- WO 98/38177 PCT/US98/03373 -- 82 - wherein n = 0, 1, or 2 and R= -CH3, PhCH2- and H. 12. van Niel et al., Bioorg. Med. Chem. Lett., 5:1421-1426 (1995) 5 reports the synthesis of compounds of the formulas: wherein X is -OH, -NH2 or -NR6R6 where R6 is as defined above. The reported ketone is a versatile synthetic intermediate which can be modified by 15 conventional methods such as reductive amination, reduction, etc. 13. Kawase, et al., J. Org Chem., 54:3394-3403 (1989) describes a synthetic method for the preparation of: 20 oar OCH, 25 In addition to the above, saturated bicyclic alpha-aminolactams are also contemplated for use in the synthesis of compounds of formula I Such saturated bicyclic alpha-aminolactams are well known in the art. For example, Edwards, et al., Can. J. Chem., 49-1648-1658 (1971) describes several 30 syntheses of bicyclic lactams of the formula- Printed from Mimosa 07/26/1999 12:37:07 page -84- WO 98/38177 PCT/US98/03373 - 83 - Similarly, Milligan, et al., J. Am. Chem. Soc., 117:10449-10459 (1995) and references cited therein report the synthesis of lactams of the formula: R 15 wherein R1 and R2 are H or -CH3, ring A can have from 6-13 members and ring B can have from 5-7 members R can be alkyl, aryl, cycloalkyl and the like 20 The introduction of a heteroatom into the saturated cyclic structure fused to the lactam ring is disclosed by Curran et al., Tet Lett., 36:191-194 (1995), who describe a synthetic method which can be used to obtain a lactam of the formula: 30 by Slusarchyk, et al., Bioorg. Med. Chem. Lett., 5.753-758 (1995), who describe syntheses which could lead to a lactam of the formula: Printed from Mimosa 07/26/1999 12:37:07 page -85- WO 98/38177 PCT/US98/03373 - 84 -- H,N and by Wyvratt, et al., Eur. Pat. Appl. 61187 (1982), who describe a lactam of the formula- 10 Co H2N I 15 20 Lactams having further heteroatom(s) in the cyclic lactam structure (in addition to the nitrogen of the amido group of the lactam) are described by Comille, et al., J. Am. Chem. Soc., 117 909-917 (1995), who describe lactams of the formula. po H2N I 25 30 and J. Kolc, Coll. Czech. Chem. Comm., 34;630 (1969), who describes lysines suitable for cyclization to lactams which have a hetero lactam ring atom as shown by the formula: H NH, -oXJ N-/ H Printed from Mimosa 07/26/1999 12:37:07 page -86- WO 98/38J77 PCT/US98/03373 - 85 - where X=0, S and NR where R is, for example, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic, and the like. Similarly, each of Dickerman, et al., J. Org. Chem., (4:530 (1949)86, 5 Dickerman, et al., J. Org. Chem., 20:206 (1955), and Dickerman, et al., J. Org. Chem., 19:1855 (1954) used the Schmidt and Beckmann reactions on substituted 4-piperidones to provide for lactams of the formula: i H where R is acyl, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic 15 provided that R is not an acid labile group such as t-Boc; and R' is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclicoxy, halo, cyano, nitro, trihalomethyl, and the like 20 An internal cyclization of appropriate ethylenediamine amides onto a ketone or aldehyde is described by Hoffman, et al , J Org Chem., 27:3565 (1962) as follows. Printed from Mimosa 07/26/1999 12:37:07 page -87- WO 98/38177 PCT/US98/03373 - 86 - Ring expansion methodology based on beta lactams to provide for larger ring lactams containing an aza group has twice been reported m Wasserman, et al., J. Am. Chem. Soc., 103:461-2 (1981) and in Crombie, et al., Tetrahedron Lett., 27(42):5151-5154 (1986) Dieckmann methodology has been used to prepare aza caprolactams from unsymmetrical amines such as shown below by Yokoo, et al., Bull, Chem. Soc Jap., 29-631 (1956). 10 V-C02Et 15 where R is as defined in this reference. The dislosure of Yokoo, et al. can be extended to cover R being alkyl, substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic, alkenyl, substituted alkenyl, and 20 the like. The synthesis of various members of the oxalactam series has been reported by Burkholder, et al., Bioorg. Med. Chem. Lett., 2:231 (1993) and references cited therein which oxalactams are represented by the formula: 25 f R Printed from Mimosa 07/26/1999 12:37:07 page -88- WO 98/38177 PCT/US98/03373 -- 87 -- where 'R is as defined in the reference and R can be alkyl, substituted alkyl, aryl, alkoxy, substimted alkoxy, heteroaryl, cycloalkyl, heterocyclic, alkenyl, substimted" alkenyl, and the like. 5 The synthesis of thialactams (generally oxalactams can be made by the same methodology) has been reported by Freidinger, et al., J. Org. Chem , 42:104-109 (1982), who prepared thialactams of the formula O This reference provides a series of procedures having broad application for synthesis of lactams permitting R in the above formula to be derived from any 15 amine (alkyl, aryl, heteroaryl, etc.) with the restriction being that the R-group does not contain any functional groups reactive with formaldehyde (e.g., primary and secondary amines). The general synthetic scheme provided by Freidlinger, et al. is: Printed from Mimosa 07/26/1999 12:37:07 page -89- WO 98/38177 PCT/US98/03373 - 88 - The coupling agent is any standard reagent used in the formation of typical peptide or amide bonds, for example, carbodiimide reagents. See, also, Karanewsky, U.S. Patent No. 4,460,579 and Kametani, et al., Heterocycles, 9:831-840 (1978). 5 The Friedinger procedure can be extended to afford disubstituted thialactams of the following structure: S_R2 10 15 20 rr 0 R1 In this procedure, the thiolactam ring is prepared as follows: f^J j-m y S™ o o In practical terms, R2 will be limited to aryl and heteroaryl groups and sterically hindered alkyl groups such as t-butyl. R1 can be highly variable and 25 is limited only by subsequent reaction steps. Still further is the Kametani procedure which provides for lactams as follows Printed from Mimosa 07/26/1999 12:37:07 page -90- WO 98/38177 PCT/US98/03373 „ 89 - (VnXsh +Y o o 10 In principle, the Kametani procedure allows for a wide selection of Rl and R2 groups limited primarily by stability to the reaction conditions. See, for example, Yanganasawa, et al., J. Med. Chem., 30:1984-1991 15 (1987) and J. Das et al , Biorg. Med. Chem. Lett., 4:2193-2198 (1994) which describes general methods for the synthesis of isomeric 7-membered thialactams of the following structure: 20 H. O H 25 30 The first synthetic route is: jT • -BocHN^y-OH + O 1. Cyclization 2. Selective alkyl; ation H2N 1. N-methyl-morpholine N02 2. Reduction BocHN^y^OH R2 ° S^/R NH, Printed from Mimosa 07/26/1999 12:37:07 page -91- WO 98/38177 PCT/US98/03373 - 90 - R2 can be highly variable (e.g., alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic and the like) since a number of well documented routes exist for the synthesis "of nitroethylene derivatives from aldehydes and nitromethane (Henry reaction) followed by dehydration. R1 is limited to groups that can 5 undergo alkylation reactions. 10 (Vn-Th *V ^-OCHPh2 ^ 0 o .NHBoc *OMs 0 ,—( Cd>-Cs ' >-OCHPh2 O O NHBoc 1. Protecting group removal 15 2. Cyclization 3. Selective alkylation (R,) 4. Methylhydrazine H,N In this procedure, R2 can be highly variable. The starting component required 20 to introduce R2 can be readily derived by the reduction of any known alpha-BOC-amino acid to the alcohol derivative followed by formation of the mesylate. As noted above, the primary approaches to the preparation of lactams is 25 the Beckmann/Schmidt ring expansion reaction using either inter- or intramolecular approaches serves to prepare lactams of various ring sizes. The intramolecular approach generates bicyclic materials with the lactam nitrogen incorporated into the ring fusion. Additional approaches set forth above are at the base of the methodology are internal cyclization of omega-amino 30 acids/esters where the construction of the substituent pattern takes place prior to cyclization, and internal cyclization of an electrophilic center onto a Printed from Mimosa 07/26/1999 12:37:07 page -92- WO 98/38177 PCT/US98/03373 - 91 -- nucleophilic functional group as in the Fnedel Crafts type cyclization at the center of the Ben-Ishal procedure for making benzazepmones. This latter procedure is"applicable to a wide variety of heteroaromatics as well as benzenoid rings, and may also be applied to non-aromatic double or triple 5 bonds to generate a wide array of substituents or ring fusions. Deoxygenation of the lactam by reagents such as diborane, LiAlH4, and the like leads to azaheterocycles (=X is dihydro). 10 Similarly, for U = H, OH, such compounds can be prepared by epoxidation of cycloalkenyl groups followed by oxirane opening by, e.g., ammonia After formation of compounds of formula I, =U being H, OH can be oxidized to provide for cycloalkylones (=X being oxo). 15 Additionally, the 5,7-dihydro-6H-diben[b,d]azepin-6-one derivatives employed in this invention can be prepared using conventional procedures and reagents For example, an appropriately substituted N-/er/-Boc-2-amino-2'-methylbiphenyl compound can be cyclized to form the corresponding 5,7-dihydro-6H-diben[b,d]azepin-6-one derivative by first treating the biphenyl 20 compound with about 2.1 to about 2.5 equivalents of a strong base, such as sec-butyl lithium This reaction is typically conducted at a temperature ranging from about -80 °C to about -60°C in an inert diluent such as THF. The resulting diamon is then treated with dry carbon dioxide at a temperature of about -78°C to afford the 5,7-dihydro-6H-diben[b,d]azepin-6-one. This 25 procedure is described further in R. D. Clark et al., Tetrahedron, 49(7), 1351-1356 (1993) and references cited therein. After forming the 5,7-dihydro-6H-diben[b,d]azepin-6-one, the amide nitrogen can be readily alkylated by first treating the dibenazepinone with about 30 1.1 to about 1 5 equivalents of a strong base, such as sodium hydride, in an inert diluent, such as DMF. This reaction is typically conducted at a Printed from Mimosa 07/26/1999 12:37:07 page -93- WO 98/38177 PCT/US98/03373 - 92 - temperature ranging from about -10°C to about 80°C for about 0.5'to about 6 hours The resulting anion is then contacted with an excess, preferably about 1.1 to about"3.0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is conducted at a temperature of 5 about 0°C to about 100°C for about 1 to about 48 hours. An amino group can then be introduced at the 5-position of the 7-alkyl-5,7-dihydro-6H-diben[b,d]azepin-6-one using conventional procedures and reagents For example, treatment of 7-methyl-5,7-dihydro-6H-10 diben[b,d]azepin-6-one with an excess of butyl nitrite m the presence of a strong base, such as potassium 1,1,1,3,3,3-hexamethyldisilazane (KHMDS), affords 5-oximo-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Subsequent reduction of the oximo group by hydrogenation in the presence of a catalyst, such as palladium on carbon, then provides 5-ammo-7-methyl-5,7-dihydro-6H-15 diben[b,d]azepin-6-one. Other conventional amination procedures, such as azide transfer followed by reduction of the azido group, may also be employed. Similarly, various benzodiazepine derivatives suitable for use in this invention can be prepared using conventional procedures and reagents. For 20 example, a 2-aminobenzophenone can be readily coupled to a-(isopropylthio)-N-(benzyloxycarbonyl)glycine by first forming the acid chloride of the glycine derivative with oxayl chloride, and then coupling the acid chloride with the 2-aminobenzophenone in the presence of a base, such as 4-methylmorpholine, to afford the 2-[a-(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]-25 aminobenzophenone. Treatment of this compound with ammonia gas in the presence of an excess, preferably about 1.1 to about 1.5 equivalents, of mercury (II) chloride then affords the 2-[N-(a-ammo)-N'-(benzyloxycarbonyl)-glycinyl]aminobenzophenone. This intermediate can then be readily cychzed by treatment with glacial acetic acid and ammonium acetate to provide the 3-30 (benzyloxycarbonyl)amino-2,3-dihydro-5-phenyl-lH-l ,4-benzodiazepin-2-onel. Printed from Mimosa 07/26/1999 12:37:07 page -94- WO 98/38177 PCT/US98/03373 -- 93 - Subsequent removal of the Cbz group affords the 3-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one. Alternatively, 2,3-dihydro-5-phenyl-lH-l,4-benzodiazepin-2-ones can be 5 readily aminated at the 3-position using conventional azide transfer reactions followed by reduction of the resulting azido group to form the corresponding ammo group. The conditions for these and related reactions are described in the examples set forth below. Additionally, 2,3-dihydro-5-phenyl-lH-l,4-benzodiazepin-2-ones are readily alkylated at the 1-position using conventional 10 procedures and reagents. For example, this reaction is typically conducted by first treating the benzodiazepinone with about 1.1 to about 1.5 equivalents of a base, such as sodium hydride, potassium rert-butoxide, potassium 1,1,1,3,3,3-hexamethyldisilazane, cesium carbonate, in an inert diluent, such as DMF. This reaction is typically conducted at a temperature ranging from about -78°C 15 to about 80°C for about 0.5 to about 6 hours. The resulting anion is then contacted with an excess, preferably about 1.1 to about 3 0 equivalents, of an alkyl halide, typically an alkyl chloride, bromide or iodide. Generally, this reaction is conducted at a temperature of about 0°C to about 100°C for about 1 to about 48 hours 20 Additionally, the 3-amino-2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5-benzodiazepines employed in this invention are typically prepared by first coupling malonic acid with a 1,2-phenylenediamine. Conditions for this reaction are well known m the art and are described, for example, in PCT 25 Application WO 96-US8400 960603. Subsequent alkylation and amination using conventional procedures and reagents affords various 3-amino-l,5-bis(alkyl)-2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5-benzodiazepines. Such procedures are described in further detail in the example set forth below. 30 Accordingly, a vast number of lactams, lactones and thiolactones are available by art recognized procedures. Similarly, the art is replete with Printed from Mimosa 07/26/1999 12:37:07 page -95- WO 98/38177 PCT/US98/03373 .. 94 examples of aminocycloalkyl compounds for use in the synthesis of compounds of formula I above. In the synthesis of compounds of formula I using the synthetic methods 5 described above, the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixture of R,S enantiomers. Alternatively, a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained. Such reaction 10 protocols can involve inversion of the chiral center during synthesis. Accordingly, unless otherwise indicated, the products of this invention are a mixture of diastereomers or R,S enantiomers. Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid 15 derivative. Alternatively, chiral products can be obtained via purification techniques which separates diastereomers or enantiomers to provide for one or the other stereoisomer. Such techniques are well known in the art. Pharmaceutical Formulations 20 When employed as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such 25 compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I above 30 associated with pharmaceutically acceptable carriers In making the compositions of this invention, the active ingredient is usually mixed with an Printed from Mimosa 07/26/1999 12:37:07 page -96- WO 98/38177 PCT/US98/03373 - 95 - excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the 5 compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments contaimng, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders 10 In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh If the active 15 compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, 20 sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystallme cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents, emulsifying and 25 suspending agents; preserving agents such as methyl- and propylhydroxy- benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after admimstration to the patient by employing procedures known in the art. 30 Printed from Mimosa 07/26/1999 12:37:07 page -97- WO 98/38177 - 96 -- PCT/US98/03373 The compositions are preferably formulated in a unit dosage -form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg; of the active ingredient The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and 5 other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight 10 percent, with the balance being pharmaceutically inert carrier(s). The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered 15 will be determined by a physician, in the light of the relevant circumstances, - including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like 20 For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly 25 throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention. 30 Printed from Mimosa 07/26/1999 12:37:07 page -98- WO 98/38177 PCT/US98/03373 - 97 -- The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For'example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the 5 former. The two components can separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as 10 shellac, cetyl alcohol, and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and 15 flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or 20 mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions 25 may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner. 30 Printed from Mimosa 07/26/1999 12:37:07 page -99- WO 98/38177 PCT/US98/03373 - 98 - The following formulation examples illustrate the pharmaceutical compositions of the present invention. Formulation Example 1 5 Hard gelatin capsules containing the following ingredients are prepared: Quantity Ingredient Cmg/capsule) Active Ingredient 30.0 10 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in 15 340 mg quantities. Formulation Example 2 A tablet formula is prepared using the ingredients below. Quantity 20 Ingredient (mg/tablet) Active Ingredient 25 0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10 0 25 Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg 30 Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components: 35 Ingredient Weight % Active Ingredient 5 Lactose 95 Printed from Mimosa 07/26/1999 12:37:07 page -100- WO 98/38177 PCT/US98/03373 -- 99 -- The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance Formulation Example 4 5 Tablets, each containing 30 mg of active ingredient, are prepared as follows. Quantity Ingredient (mg/tablet) 10 Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in sterile water) 4 0 mg 15 Sodium carboxymethyl starch 4 5 mg Magnesium stearate 0.5 mg Talc 1 0 mg 20 Total 120 mg The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone 25 is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50° to 60°C and passed through a 16 mesh U S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U S. sieve, are then added to the granules which, after mixing, are compressed on a tablet 30 machine to yield tablets each weighing 150 mg. Formulation Example 5 Capsules, each containing 40 mg of medicament are made as follows- Printed from Mimosa 07/26/1999 12:37:07 page -101- WO 98/38177 PCT/US98/03373 - 100 - Quantity Ingredient (me/cansule'l Active Ingredient 40 0 mg Starch 109 0 mg Magnesium stearate 1.0 mg 10 Total 150.0 mg The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities. 15 Formulation Example 6 Suppositories, each containing 25 mg of active ingredient are made as follows: 20 Ingredient Amount Active Ingredient 25 mg Saturated fatty acid glycerides to 2,000 mg 25 30 The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool. Formulation Example 7 Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows: Printed from Mimosa 07/26/1999 12:37:07 page -102- WO 98/38177 PCT/US98/03373 - 101 -- Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg_ Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10 0 mg Flavor and Color q.v. Purified water to 5.0 ml The active ingredient, sucrose and xanthan gum are blended, passed 15 through a No 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. 20 Formulation Example 8 Quantity Ingredient (me/capsule") 25 Active Ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg 30 The active ingredient, starch, and magnesium stearate are blended, passed through a No 20 mesh U S. sieve, and filled into hard gelatin capsules in 560 mg quantities. Printed from Mimosa 07/26/1999 12:37:07 page -103- WO 98/38177 PCT/US98/03373 -- 102 -- Formulation Example 9 A subcutaneous formulation may be prepared as follows: Ingredient Ouantity- 5 Active Ingredient 1 0 mg corn oil 1 ml (Depending on the solubility of the active ingredient in corn oil, up to 10 about 5 0 mg or more of the active ingredient may be employed in this formulation, if desired) Formulation Example 10 A topical formulation may be prepared as follows- 15 Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g 20 White Soft Paraffin to 100 g The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active 25 ingredient is added and stirring is continued until dispersed The mixture is then cooled until solid. Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal 30 patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference Such patches may be constructed for 35 continuous, pulsatile, or on demand delivery of pharmaceutical agents Printed from Mimosa 07/26/1999 12:37:07 page -104- WO 98/38177 PCT/US98/03373 - 103 - Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system 5 used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,011,472 which is herein incorporated by reference. Indirect techniques, which are generally preferred, usually involve 10 formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier Alternatively, the dehveiy of 15 hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier. Other suitable formulations for use in the present invention can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, 20 PA, 17th ed (1985). Utility The compounds and pharmaceutical compositions of the invention are useful in inhibiting 0-amyloid peptide release and/or its synthesis, and, 25 accordingly, have utility in diagnosing and treating Alzheimer's disease in mammals including humans As noted above, the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to 30 enhance the in vivo serum half-life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, Printed from Mimosa 07/26/1999 12:37:07 page -105- WO 98/38177 PCT/US98/03373 - 104 -- prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated 5 herein by reference. The amount of compound administered to the patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, 10 and the like. In therapeutic applications, compositions are administered to a patient already suffering from AD in an amount sufficient to at least partially arrest further onset of the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as "therapeutically effective dose." Amounts effective for this use will depend on the judgment of the 15 attending clinician depending upon factors such as the degree or severity of AD in the patient, the age, weight and general condition of the patient, and the like. Preferably, for use as therapeutics, the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day. 20 In prophylactic applications, compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease. An amount adequate to accomplish this is defined as "prophylactically effective dose." Amounts effective for this use will depend on the judgment of the 25 attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like. Preferably, for use as prophylactics, the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day 30 As noted above, the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be Printed from Mimosa 07/26/1999 12:37:07 page -106- WO 98/38177 PCT/US98/03373 - 105 - sterilized by conventional sterilization techniques, or may be sterile-filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration The pH of the compound preparations typically will be 5 between 3 and 11, more preferably from 5 to 9 and most preferably from 7 and 8 It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts. The compounds described herein are also suitable for use in the 10 administration of the compounds to a cell for diagnostic and drug discovery purposes. Specifically, the compounds may be used in the diagnosis of cells releasing and/or synthesizing /3-amyloid peptide In addition the compounds described herein are useful for the measurement and evaluation of the activity of other candidate drugs on the inhibition of the cellular release and/or 15 synthesis of /3-amyloid peptide. 20 25 30 The following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. EXAMPLES In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. 35 BEMP Boc BOP bd bs d dd DIC 2-tert-butylimino-2-diethylamino-1,3-dimethy Iperhydro-1,3,2-diazaphosphonne Z-butoxycarbonyl benzotriazol-1 -y loxy-tris(dimethylamino)phosphomum hexafluorophosphate broad doublet broad singlet doublet doublet of doublets diisopropylcarbodiimide Printed from Mimosa 07/26/1999 12:37:07 page -107- WO 98/38177 PCT/US98/03373 -- 106 - 10 15 20 25 30 35 40 DCM DMF DMAP DMSO * EDC eq. EtOAc EtOH g HOBT Hunig's base L m M max meq mg mL mm mmol MOC N N/A ng nm od PEPC PP-HOBT psi <t> q quint. rpm s t TFA THF tic fih UV dichloromethane dimethylformamide dimethylaminopyridine dimethylsulfoxide ethyl-1 -(3-dimethy aminopropy l)carbodnmide equivalents ethyl acetate ethanol grams 1-hydroxybenzotriazole hydrate diisopropylethylamine liter multiplet molar maximum milliequivalent milligram milliliter millimeter millimole methoxyoxycarbonyl normal not available nanogram nanometers optical density l-(3-(l-pyrrolidinyl)propyl)-3-ethylcarbodumide pipendine-piperidine-1 -hy droxybenzotrizole pounds per square inch phenyl quartet quintet rotations per minute singlet triplet trifluoroacetic acid tetrahydrofuran thin layer chromatography microliter ultra-violet Additionally, the following abbreviations are used to indicate the commercial source for certain compounds and reagents- Printed from Mimosa 07/26/1999 12:37:07 page -108- WO 98/38177 PCT/U S98/03373 - 107 10 15 20 25 30 35 Aldrich Fluka Lancaster Sigma Chemservice Bachem Maybndge TCI Alfa Novabiochem Oakwood Advanced Chemtech Pfaltz & Bauer Aldrich Chemical Company, Inc., -1001 West Saint Paul Avenue, Milwaukee, WI 53233 USA Fluka Chemical Corp., 980 South 2nd Street, Ronkonkoma NY 11779 USA Lancaster Synthesis, Inc , P.O. Box 100 Windham, NH 03087 USA Sigma, P O. Box 14508, St. Louis MO 63178 USA Chemservice Inc., Westchester, PA Bachem Biosciences Inc., 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, PA 19406 USA Maybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW Umted Kingdom TCI America, 9211 North Harborgate Street, Portland OR 97203 Johnson Matthey Catalog Company, Inc 30 Bond Street, Ward Hill, MA 01835-0747 Calbiochem-Novabiochem Corp. 10933 North Torrey Pines Road, P O. Box 12087, La Jolla CA 92039-2087 Oakwood, Columbia, South Carolina Advanced Chemtech, Louisville, KY Pfaltz & Bauer, Waterbury, CT, USA In the examples below, all temperatures are in degrees Celsius (unless 40 otherwise indicated). Each of the compounds set forth in Examples 1- was prepared by one of the following General Procedures, unless otherwise indicated. Printed from Mimosa 07/26/1999 12:37:07 page -109- WO 98/38177 PCT/US98/03373 -- 108 - GENERAL PROCEDURE A EDC Coupling — Procedure I A carboxylic acid (1.0 eq.), 1-hydroxybenzotriazole hydrate (1.1 eq.) and an amine (1.0 eq.) were stirred in THF under a nitrogen atmosphere. To this 5 mixture was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1 eq.) followed by a suitable base, such as Hunig's base (1.1 eq. of base if a free amine is used, and 2.1 eq. of base if an amine hydrochloride is used). After stirring from about 4 h to 17 h at room temperature, the solvent was removed under reduced pressure. The residue was 10 partitioned between ethyl acetate and water and the organic layer was separated and washed sequentially with aqueous sodium bicarbonate, dilute aqueous hydrochloric acid and brine The organic layer was then dried (sodium sulfate) and concentrated under reduced pressure The product was either used without further purification or was purified using standard procedures, such as silica 15 gel chromatography and/or recrystallization. GENERAL PROCEDURE B EDC Coupling — Procedure II A carboxylic acid (1 eq.) was stirred in a suitable solvent (such as THF, 20 dioxane or DMF) and an alcohol or oxime (1 - 5 eq ) was added. To this mixture was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 eq.) and 1-hydroxybenzotriazole hydrate (1 eq.) followed by a suitable base, such as 4-methylmorpholine, tnethylamine, or Hunig's base (0 - 1 eq.). A catalytic amount (0.1 eq.) of 4-dimethylaminopyridine was then 25 added and the mixture was stirred at ambient temperature and under a dry atmosphere of nitrogen After 20 hours, the mixture was concentrated under reduced pressure and the resulting concentrate was partitioned between ethyl acetate and water The organic portion was separated and washed with aqueous sodium bicarbonate and brine, and then dried (sodium sulfate) and concentrated 30 under reduced pressure. The crude product was either used without further Printed from Mimosa 07/26/1999 12:37:07 page -110- WO 98/38177 PCT/US98/03373 -- 109 -- purification or was purified using standard procedures, such as silica gel chromatography and/or recrystalhzation GENERAL PROCEDURE C 5 EDC Coupling — Procedure III To a solution of the amine (1 eq.) in THF (0.08-0.06 M) at 0°C under an atmosphere of nitrogen was added 3,5-difluorophenylacetic acid (1 10 eq.), 1-hydroxybenzotriazole hydrate (1.15-1 20 eq ), 7V,7V-diisopropylethylamine (2.30 eq ), followed by l-(3-dimethylaminopropyl)-3-ethylcarbodnmide 10 hydrochloride (1.15-1.20 eq ). The cooling bath was removed and the mixture allowed to warm to ambient temperature with stirring for 12-14 hours. The solution was then diluted with ethyl acetate, washed with 0.2-0.5 M aqueous HC1 (2x), dilute aqueous NaHC03 (lx), and brine (lx), and then the organic phase was dried over Na2S04, filtered, concentrated in vacuo, and the residue 15 purified by flash chromatography to afford the product. GENERAL PROCEDURE D Removal of N-tert-BOC Protecting Group — Procedure I To the N-Boc-protected imidazoline (1 eq.) in a round-bottomed flask, 20 cooled to 0°C, was added trifluoroacetic acid (0 07-0 08 M) followed by anisole (6.2-8.0 eq.). The resulting solution was stirred at 0°C for 1 hour, then allowed to warm to ambient temperature with stirring for 1-1.5 hours. The solution was then concentrated in vacuo, EtjO was added and the mixture again concentrated in vacuo. The residue was dissolved m either CH2C12 or EtOAc 25 and washed with dilute aqueous NaHCOj (1 or 2x), and sometimes brine (lx), then the organic phase was dried over Na2S04, filtered, and concentrated in vacuo to afford the product. GENERAL PROCEDURE E 30 Removal of N-tert-BOC Protecting Group — Procedure II Printed from Mimosa 07/26/1999 12:37:07 page -111- WO 98/38177 PCT/US98/03373 - 110 - The iV-tert-Boc-amine was dissolved in a suitable dry solvent (such as 1,4-dioxane or ethyl acetate) and the solution was cooled in an ice bath. Gaseous HCl was introduced into the solution until the mixture was saturated with HCl and the mixture was then stirred until the starting material was consumed. The 5 resulting mixture was concentrated under reduced pressure to yield the amine hydrochloride. The amine hydrochloride was either used without further purification or was triturated in diethyl ether and the resulting solid collected by filtration. 10 GENERAL PROCEDURE F Thiazoline Synthesis — Procedure I To a stirred solution of a nitrile (1 eq.) in dry ethanol under an atmosphere of nitrogen was added 2-mercaptoethylamine (1 - 3 eq.) The reaction mixture was then heated at reflux until the nitrile was consumed. The mixture was then 15 concentrated under reduced pressure and the resulting product purified by chromatography and/or recrystallization. GENERAL PROCEDURE G Thiazoline Synthesis — Procedure II 20 To a stirred solution of a nitrile (1 eq.) in dry ethanol under an atmosphere of nitrogen were added L-cysteine ethyl ester hydrochloride (1 - 3 eq.) (Aldrich) and a stoichiometric amount of 7V,iV-dusopropylethylamine (based on the L-cysteine ethyl ester hydrochloride). The reaction mixture was heated at reflux for three hours and then concentrated under reduced pressure The 25 resulting product was purified by chromatography and/or crystallization. GENERAL PROCEDURE H Cyclization Using Burgess Reagent To a solution of jV-[jV-(3,5-dichlorophenyl)-L-alamnyl]-L-senne methyl 30 ester (178 mg, 0.5 mmol) in 2.5 mL of THF was added 147 mg (0.62 mmol, 1.2 eq.) of (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt Printed from Mimosa 07/26/1999 12:37:07 page -112- WO 98/38177 PCT/US98/03373 - Ill - (available from Aldrich Chemical Co., Milwaukee, Wisconsin). The solution was refluxed for 5 h and then stirred at room temperature for 36 h. The solvents were then removed and the residue purified by preparative tic using 3:2 hexanes/ethyl acetate as the eluent to afford 50 mg of 2-[(S)-l-(3,5-5 dichloroanilino)ethyl]-(S)-4-methoxycarbonyl-2-oxazolidme as a yellow oil. Various other (S)-4-alkoxycarbonyl-2-oxazolidines can be prepared from N-substituted (amino acid)-L-serine esters using this procedure. GENERAL PROCEDURE I 10 5-Aminoalkvl-l .2.4-Oxadiazole Synthesis An 7V-rm-Boc-protected amino acid and an amidoxime are reacted according to General Procedure B above to provide the corresponding O-acyloxime. The O-acyloxime is then heated at reflux in xylenes with the azeotropic removal of water to provide the /V-rm-Boc-protected 5-aminoalkyl-15 1,2,4-oxadiazole derivative, which is then typically purified by silica gel chromatography. The tert-Boc protecting group is then removed according to General Procedure E above to afford the 5-aminoalkyl-1,2,4-oxadiazole The following Examples A-L illustrate the synthesis of heterocyclic 20 intermediates which may be used to prepare the compounds of the present invention. Example A Synthesis of 25 (S)-5-(l-Aminoethyl)-3-ethyl-l,2,4-oxadiazole Hydrochloride Following General Procedure I above, the title compound was prepared using N-tert-Boc-L-alanine (Sigma) and propanamidoxime. Example B 30 Synthesis of (S)-5-(l-Amino-2-phenylethyl)-3-methyl-l,2,4-oxadiazole Hydrochloride Printed from Mimosa 07/26/1999 12:37:07 page -113- WO 98/38177 PCT/US98/03373 - 112 - Following General Procedure I above, the title compound was prepared using yV-fert-Boc-L-phenylalanine (Sigma) and acetamidoxime. Example C 5 Synthesis of (S)-5-(l-Amino-l-phenylmethyl)-3-methyl-l,2,4-oxadiazole Hydrochloride Following General Procedure I above, the title compound was prepared using 7V-rm-Boc-L-phenylglycine (Sigma) and acetamidoxime. 10 Example D Synthesis of (S)-5-(l-Amino-l-phenylmethyl)-3-phenyl-l,2,4-oxadiazole Hydrochloride Following General Procedure I above, the title compound was prepared using AT-tert-Boc-L-phenylglycine (Sigma) and benzamidoxime. 15 Example E Synthesis of (S)-5-(l-Amino-l-phenylmethyl)-3-(4-methoxyphenyImethyl)-l,2,4-oxadiazole Hydrochloride Following General Procedure I above, the title compound was prepared 20 using TV-tert-Boc-L-phenylglycine (Sigma) and 4-methoxyphenylacetamidoxime. Example F Synthesis of (2S)-2-(l-Aminoethyl)-5(R,S)-ethoxycarbonyl-2-oxazoline 25 Step A — Synthesis of yV-Carbobenzyloxy-L-alanine-D,L-isoserine Ethyl Ester Following General Procedure A above and using iV-carbobenzyloxy-L-alanine (Sigma) and D,L-isoserine ethyl ester hydrochloride, the title compound was prepared 30 Step B — Synthesis of (2S)-2-[l-(ALCarbobenzyloxy)aminoethyl]-5(R,S)-ethoxycarbonyl-2-oxazoline Printed from Mimosa 07/26/1999 12:37:07 page -114- WO 98/38177 PCT/US98/03373 - 113 - To a solution of iV-carbobenzyloxy-L-alanme-D,L-isoserme ethyl ester from Step A above in dry THF was added triphenylphosphine (2 eq.). The mixture was cooled to 0°C and a solution of diethyl azodicarboxylate (2 eq.) in THF was added dropwise. The resulting mixture was allowed to warm to room 5 temperature and, after 20 hours, the mixture was concentrated under reduced pressure The resulting oil was purified by silica gel chromatography to yield the title compound as an oil which was used without further purification. Step C — Synthesis of (2S)-2-(l-Aminoethyl)-5(R,S)-ethoxycarbonyl-2-10 oxazoline The crude oil from Step B above was dissolved in ethanol and the solution was degassed and stirred under an atmosphere of nitrogen Palladium on carbon (10%) was added and the atmosphere of nitrogen was replaced with hydrogen under balloon pressure. The mixture was stirred for 2 hours and then 15 filtered through Celite The filtrate was concentrated and the residue purified by silica gel chromatography to provide the title compound as an oil Example G Synthesis of 20 (S)-2-(l-Aminoethyl)-4(R,S)-ethoxycarbonyl-2-thiazoline Hydrochloride Step A — Synthesis of (S)-2-[l-(iV-terf-Butoxycarbonyl)aminoethyl]-4-ethoxycarbonyl-2-thiazoline The title compound was prepared according to the procedures described in C. D. J. Boden, et al., Synlett, 5, 417 (1995). 25 Step B — Synthesis of (S)-2-(l-Aminoethyl)-4(R,S)-ethoxycarbonyl-2-thiazoline Hydrochloride The N-tert-Boc protecting group was removed from the product of Step A above using General Procedure E above to afford the title compound. 30 Example H Synthesis of 2-(3,5-Difluorophenylmethyl)-4-carboxy-2-thiazoline Printed from Mimosa 07/26/1999 12:37:07 page -115- WO 98/38177 PCT/US98/03373 _ - 114 - Step A — Synthesis of 2-(3,5-Difluorophenylmethyl)-5-ethoxycarbonyl-2-thiazoline Following General Procedure G and using 3,5-difluorophenylacetonitrile and L-cysteine ethyl ester hydrochloride (Aldrich), the title compound was 5 prepared. Step B - Synthesis of 2-(3,5-Difluorophenyhnethyl)-5-carboxy-2-thiazoline The title compound was prepared by hydrolysis of the product from Step A 10 above using 1 equivalent of LiOH tn wet dioxane as described in General Procedure II-A, Method B. Example I Synthesis of 15 7V-(3,5-Difluorophenylacetyl)phenylglycinonitrile Following General Procedure A above and using 3,5-difluorophenylacetic acid (Aldrich) and 2-phenylglycmonitrile hydrochloride (Lancaster), the title compound was prepared. The crude product was purified by silica gel chromatography using 1:1 ethyl acetate/hexanes as the eluent, followed by 20 crystallization from 1-chlorobutane/acetomtrile. NMR data was as follows- 'H-nmr (CDC13, 250 MHz). 8 = 3.61 (s, 2H), 6.13 (d, 1H), 6.98 (m, 2H), 7.12 (m, 1H), 7.46 (m, 5H), 9.40 (d, 1H). CI6Hl2F2N20 (MW = 286.28); mass spectroscopy (M+) 286. 25 Example J Synthesis of 2-(l-Aminoethyl)-l-terf-butoxycarbonyl-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline Step A — Synthesis of l-[2-(7V-carbobcnzyloxy)amino-30 thiopropionyljpiperidine Following the procedures described in Gilbert, et al., Tetrahedron, 1995 51, 6315-6336 and using N-carbobenzyloxy-D,L-alanine (Sigma), the title compound was prepared in two steps (51% overall yield) as a solid having a melting point Printed from Mimosa 07/26/1999 12:37:07 page -116- WO 98/38177 PCT/US98/03373 - 115 - of 68-69°C. The final reaction was monitored by tic (Rf = 0.59 in 24:1 DCM/EtOAc) and the product was purified by flash column chromatography. NMR data was as follows: 'H-nmr (CDC13, 250 MHz): 8 = 7.37-7.29 (m, 5H), 6.46 (trd, 1H, J= 8.26 5 Hz), 5 10 (ABq, 2H, JAB= 12.38 Hz, Avab= 9.12 Hz), 4.92 (p, 1H, J= 7 07 Hz), 4.41-4.34 (m, 1H), 4.17-4.06 (m, 1H), 3.86-3.65 (m, 2H), 1.75-1.65 (bm, 6H), 1.35 (d, 3H, J= 6.75 Hz). C16H22N202S (MW = 306.43); mass spectroscopy (MH+) 306.2 10 Step B — Synthesis of Methyl 2,3-Diamino-2-phenylmethylpropionate Following the procedures described in Gilbert, et al., Tetrahedron, 1995 51, 6315-6336 and using L-phenylalanine methyl ester hydrochloride (Aldrich), the title compound was prepared in three steps (14% overall yield). The final reaction was monitored by tic (Rf = 0.26 in 9:1 DCM/MeOH) and the product 15 was purified by flash column chromatography, followed by recrystallization from cyclohexane/ethyl acetate (201). NMR data was as follows: 'H-nmr (CDC13, 250 MHz): 8 = 7.32-7.17 (m, 3H), 7 14-7.09 (m, 2H), 3.70 (s, 3H), 2.96 (ABq, 2H, JAB = 13.13 Hz, Avab= 114.63 Hz), 2.90 (ABq, 2H, JAB= 20 13.38 Hz, Avab= 86.35 Hz), 1.55 (bs, 4H). C,,H|6N202 (MW = 208.26); mass spectroscopy (MH+) 209.1. Step C — Synthesis of 2-[l-(7V-Carbobenzyloxy)aminoethyl)-4-mcthoxycarbonyl-4-phenylmethyl-2-imidazoline 25 The product from Step A above (1 equivalent) in iodomethane (35 equivalents) was heated to reflux under nitrogen for 8 hours. The dark yellow solution was concentrated in vacuo to a golden yellow foam, then azeotroped with methanol (2x) to remove any residual iodomethane The residue was dissolved in methanol (0.2 M) and the product from Step B above (1 equivalent) 30 was added. The resulting clear colorless solution was heated to reflux for 1 hour under nitrogen and then stirred at ambient temperature for 14 hours, and again heated to reflux for an additional 1 hour. The solution was allowed to Printed from Mimosa 07/26/1999 12:37:07 page -117- WO 98/38177 PCT/US98/03373 - 116 - cool to ambient temperature and then concentrated in vacuo. The reaction was monitored by tic (Rf = 0.27 in 95:5 DCM/MeOH) and the residue was purified by flash column chromatography to provide the title compound as a 1:1 mixture of diastereomers (75% yield). 5 NMR data was as follows: 'H-nmr (CDC13, 250 MHz). 5 = 7.36-7.20 (m, 8H), 7.14-7.08 (m, 2H), 5.84-5.74 (m, 1H), 5.15-5.02 (m, 2H), 4.96 (bs, 1H), 4.44-4.30 (m, 1H), 4.03-3 97 (m, 1H), 3.72-3 66 (m, 1H), 3.70 (s, 1.5H), 3.69 (s, 1.5H), 3.07 (ABq, 1H, JAB= 13.38 Hz, Avab= 54.25 Hz), 3.06 (ABq, 1H, JAB= 13.51 Hz, Avab= 52 03 10 Hz), 1.39 (d, 1.5H, J= 7 00 Hz), 1.35 (d, 1.5H, J= 7.00 Hz). C22H25N304 (MW = 395.46); mass spectroscopy (MH+) 396.1. Step D — Synthesis of l-ter/-ButoxycarbonyI-2-[l-(/V-carbobenzyloxy)aminocthyl]-4-methoxycarbony]-4-phenylmethyl-2-15 imidazoline To a 1:1 mixture of the product from Step C above (1.815 g, 1 eq.) in THF (9 mL)/H20 (9 mL) at ambient temperature was added NaHC03 (0.377 g, 1.50 eq ) and di-/er/-butyl dicarbonate (I 304 g, 2.00 eq.) (Aldrich) in THF (6 mL) The resulting pale yellow mixture was stirred at ambient temperature for 1 hour 20 and then additional NaHC03 (0.188 g, 0.75 eq.) and di-/er/-butyl dicarbonate (0.652 g, 1.00 eq.) in THF (3 mL) were added and the mixture was stirred for an additional hour. The mixture was then diluted with ethyl acetate, washed with brine (2x), dried over Na2S04, filtered, concentrated m vacuo, and purified by flash column chromatography using 3:2 hexanes/EtOAc as the eluent to 25 provide the title compound in 77% yield as a viscous oil (Rf = 0.31 in 3:2 hexanes/EtOAc). The racemic product was isolated as a 1.1 mixture of diastereomers. NMR data was as follows: 'H-nmr (DMSCW3, 250 MHz): 5 = 7.38-7.09 (m, 10H), 6.00 (bd, 1H, J= 30 7.75 Hz), 5.21-5.05 (m, 3H), 4.15 (d, 1H, J= 11.76 Hz), 4.08 (d, 1H, J= 11.26 Hz), 3.85-3.80 (m, 2H), 3.78 (s, 3H), 3.20-3.00 (m, 2H), 1.43 (s, 9H), 1.36 (d, 1.5H, J= 6.75 Hz), 1.24 (d, 1.5H, J= 6.75 Hz). Printed from Mimosa 07/26/1999 12:37:07 page -118- WO 98/38177 PCT/US98/03373 -- 117 - C27H33N3Og (MW = 495.58); mass spectroscopy (MH+) 496 4 - Step E -- Synthesis of l-te/*f-Butoxycarbonyl-2-(l-aminoethyl)-4-tnethoxycarbonyl-4-phenylmethyl-2-imidazoline 5 A mixture of the racemic N-Cbz-protected amine from Step D above and 20% Pd(OH)2 on carbon (20% weight eq.) in MeOH (0.010-0.015 M) under an atmosphere of hydrogen (35-40 psi) were shaken for 4 hours The catalyst was removed by filtration through a plug of Celite and the filtrate was concentrated in vacuo to provide the title compound as a viscous oil (Rf = 0.26 in 95:5 10 DCM/MeOH). NMR data was as follows: 'H-nmr (CDC13, 250 MHz). 5 = 7.32-7.15 (m, 5H), 4.19-4.05 (m, 2 H), 3.87-3.78 (m, 1H), 3.80 (s, 3H), 3 21-3.03 (m, 2H), 1.98 (bs, 2H), 1.43 (s, 9H), 1.33 (d, 1.5H, J= 7.00 Hz), 1.26 (d, 1.5H, J= 6.50 Hz). 15 C19H27N304 (MW = 361.44); mass spectroscopy (MH+) 361. Example K Synthesis of 2-(l-Aminoethyl)-l-terf-butoxycarbonyl-4-methoxycarbonyl-4-phcnyl-2-imidazoline 20 Step A — Synthesis of Methyl 2,3-Diamino-2-phenylpropionate Following the procedures described in Gilbert, et al., Tetrahedron, 1995 51, 6315-6336 and using (S)-(+)-2-phenylglycine methyl ester hydrochloride (Aldrich), the title compound was prepared in three steps (16% overall yield). The final reaction was monitored by tic (Rf = 0.34 in 9:1 CH2Cl2/MeOH) and 25 the product was purified by flash column chromatography. NMR data was as follows: 'H-nmr (CDC13, 250 MHz). 5 = 7.52-7.47 (m, 2H), 7.39-7.25 (m, 3H), 3.74 (s, 3H), 3.42 (d, 1H, J= 13.26 Hz), 2.89 (d, 1H, J = 13.26 Hz), 1.88 (bs, 4H). C,0Hl4N2O2 (MW = 194.23); mass spectroscopy (MH+) 195. 30 Step B — Synthesis of 2-[l-(jV-Carbobenzyloxy)aminoethyl)-4-methoxycarbonyl-4-phenyl-2-imidazoline Printed from Mimosa 07/26/1999 12:37:07 page -119- WO 98/38177 - 118 -- PCT/US98/03373 The product from Example J — Step A (5.206 g, 1.1 eq.) in iodomethane (36.5 mL, 38 eq.) was heated to reflux under nitrogen for 16 hours The dark yellow solution was concentrated in vacuo to a golden yellow foam, then azeotroped once with methanol (30 mL) to remove any residual iodomethane. 5 The residue was dissolved in methanol (30 mL) and the product from Step A above (3.00 g, 1 eq.) was added. The resulting pale yellow solution was heated to reflux under nitrogen for 3.5 hours. The solution was then allowed to cool to ambient temperature, concentrated in vacuo, and purified by flash chromatography to yield (5.08 g, 86%) of the title compound as a 10 1:1 mixture of racemic diastereomers. The reaction was monitored by tic (Rf = 0 32 in 95:5 CH2Cl2/MeOH) and the product was purified by flash column chromatography. NMR data was as follows: 'H-nmr (CDC13, 250 MHz): 5 = 7.38-7.28 (m, 10H), 6.09-6.00 (m, 1H), 15 5.11-5.04 (m, 2H), 4 10 (bs, 1H), 3.84-3.68 (m, 4H), 1 53 (d, 3H, J= 1 00 Hz). C2oH23N304 (MW = 381.43); mass spectroscopy (MH+) 382.4 Step C — Synthesis of l-terf-Butoxycarbonyl-2-[l-(iY-carbobenzyIoxy)aniinoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline 20 To product from Step B above (4 94 g, 1 eq.) in THF (35 mL)/H20 (35 mL) at ambient temperature was added NaHC03 (2.00 g, 1.84 eq ) and di-tert- butyl dicarbonate (7.50 g, 2.65 eq.) (Aldrich). The resultant pale yellow mixture was stirred at ambient temperature for 1 hour and then additional NaHC03 (0.45 g, 0.41 eq ) and di-/er/-butyl dicarbonate (0 98 g, 2 65 eq ) were added and the 25 mixture was stirred for an additional hour. The mixture was then diluted with ethyl acetate, washed with H20 (lx), brine (2x), dried over Na2S04, filtered, concentrated in vacuo, and purified by flash chromatography. The racemic diastereomeric products [R^ 0.38 (isomer A as a racemic mixture) and 0.28 (isomer B as a racemic mixture) eluting with 6:1 toluene/EtOAc] were separated 30 by flash chromatography using 6:1 toluene/EtOAc with a one step gradient to 5:1 toluene/EtOAc as the eluent to provide two sets of racemic enantiomer pairs Printed from Mimosa 07/26/1999 12:37:07 page -120- WO 98/38177 PCT/US98/03373 - 119 -- in 73% yield, isomer A (1.122 g) as a viscous oil and isomer B (1.G868 g) as a white solid. NMR data was as follows (isomer A): 'H-nmr (CDC13, 250 MHz): 8 = 7.39-7.27 (m, 10H), 6.20 (bd, 1H, J= 8.00 5 Hz), 5.40-5.30 (m, 1H), 5.13 (s, 2H), 4.84 (d, 1H, J= 11.26 Hz), 3.87 (d, 1H, J= 11.26 Hz), 3.70 (s, 3H), 1.52-1.50 (m, 12H). C26H31N306 (MW = 481 55); mass spectroscopy (MH+) 482.3. Step D — Synthesis of 1 -ter/-Butoxy carbonyI-2-( 1 -aminoethy])-4-10 methoxycarbonyl-4-phenyl-2-imidazoline Isomer A of Step C above and 20% Pd(OH)2 on carbon (20% weight eq.) m methanol (0.010-0.015 M) under an atmosphere of hydrogen (35-40 psi) were shaken for 4 hours. The catalyst was removed by filtration through a plug of Celite and the filtrate was concentrated in vacuo and purified by flash 15 chromatography to provide the title compound (88%) as a viscous oil (Rf = 0.28 in 95:5 DCM/MeOH) NMR data was as follows- 'H-nmr (CDC13, 250 MHz): 8 = 7.43-7.27 (m, 5H), 4.80 (d, 1H, J= 11.26 Hz), 4.41 (q, 1H, J= 6.75 Hz), 3.87 (d, 1H, J= 11.51 Hz), 3.73 (s, 3H), 2.02 (s, 20 2H), 1.49 (s, 9H), 1.45 (d, 3H, J= 6.75 Hz) ClgH25N304 (MW = 347.42); mass spectroscopy (MH+) 348.2. Example L Synthesis of 25 (4R)-4-Carboxy-2-(3,5-difIuorophenylmethyl)-4-methyl-2-thiazoIine Step A — Synthesis of Methyl 3,5-Difluorophenylacetimidate Hydrochloride The title compound was prepared according to the procedures described in S. C. Zimmerman, et al, J Org Chem. 1989, 54, 1256-1264, for the synthesis 30 of imidates. Specifically, a stream of anhydrous HCl gas was passed through a solution of 3,5-difluorophenylacetonitrile (5.045 g, 1 eq.) (Lancaster) and methanol (2.00 mL, 1.5 eq.) in diethyl ether (100 mL) at 0 °C for 20 minutes. Printed from Mimosa 07/26/1999 12:37:07 page -121- WO 98/38177 PCT/US98/03373 - 120 -- The solution was then allowed to warm to ambient temperature under nitrogen with stirring for 23 hours, during which time a white precipitate formed. The white precipitate was collected by filtration and rinsed with diethyl ether to yield the title compound (6.6756 g, 91%) as a solid having a melting point of 156 5-5 157.5°C. NMR data was as follows. 'H-nmr (CDC13, 300 MHz): 8 = 13.01 (bs, 1H), 11.93 (bs, 1H), 7.04-6 97 (m, 2H), 6.83-6 75 (m, 1H), 4 30 (s, 3H), 4 08 (s, 2H) 10 Step B — Synthesis of Methyl (R)-2-Methylcysteine Hydrochloride The title compound was prepared as a viscous oil in five steps (35% overall yield) from D-(S)-cysteine methyl ester hydrochloride as described in G. Pattenden, et al., Tetrahedron, 1993, 49, 2131-2138 and references cited therein D-(S)-cysteine methyl ester hydrochloride was prepared in one step (98% yield) 15 from D-cysteine hydrochloride monohydrate (Aldrich) as described in J. E. Baldwin, et al., Tetrahedron, 1989, 45, 4537-4550. NMR data was as follows: 'H-nmr (D20, 250 MHz)- 8 = 4.83 (bs, 4H), 3.92 (s, 3H), 3.27 (d, 1H, J= 15.26 Hz), 3.02 (d, 1H, J= 15.01 Hz), 1.69 (s, 3H). 20 Optical Rotation: [a]20 = 2.44 (c 1.15, 11,0) C5H|2N02SC1 (MW = 185.67); mass spectroscopy (MH+) 149.1. Step C — Synthesis of (4R)-2-(3,5-Difluorophenylmethyl)-4-methoxycarbonyl-4-methyl-2-thiazoline 25 The title compound was prepared according to the procedures described in G. Pattenden, et al., Tetrahedron, 1995, 51, 7313-7320, for the synthesis of thiazohnes. Specifically, to a solution of methyl (R)-2-methylcysteine hydrochloride (1.7109 g, 1 00 eq.) from Step B above in CH2C12 (55 mL) at ambient temperature under nitrogen was added the imidate hydrochloride (2.042 30 g, 1 00 eq.) from Step A above followed by the dropwise addition of triethylamine (1.28 mL, 1.00 eq.) over a period of 20 minutes. The resulting opaque pale yellow solution was stirred at ambient temperature for 40 hours, Printed from Mimosa 07/26/1999 12:37:07 page -122- WO 98/38177 PCT/US98/03373 -- 121 - during which time an off-white suspension formed The mixture was diluted with CH2C12, washed with IN aqueous HCl (lx), H20 (lx), and brine (lx); then the organic phase was dried over MgS04, filtered, concentrated in vacuo, and the residue purified by flash chromatography using 20:1 DCM/EtOAc as the 5 eluent to afford the title compound (1.6669 g, 63%) as a colorless oil (Rf = 0.34 in 20:1 DCM/EtOAc). NMR data was as follows: 'H-nmr (CDC13, 300 MHz): 5 = 6.85-6.79 (m, 2H), 6.74-6.67 (m, 1H), 3.81 (s, 2H), 3.80 (s, 3H), 3.79 (d, 1H, J= 11.30 Hz), 3.17 (d, 1H, J= 11 30 Hz), 1.56 10 (s, 3H). Optical Rotation: [a]20 = 3.71 (c 1.02, CHC13). C13H13N02SF2 (MW = 285.32); mass spectroscopy (MH+) 285.2. Step D -- Synthesis of (4R)-4-Carboxy-2-(3,5-difluorophenylmethyl)-4-15 methyl-2-thiazoline To the product from Step C above (0.7265 g, 1 0 eq.) in 1,4-dioxane (15 mL) at ambient temperature was added LiOH (0 0671 g, 1.1 eq ) in water (1 mL) dropwise over a period of 2 minutes Additional water (2 mL) was added and the resulting opaque colorless solution was stirred at ambient temperature 20 for 1.25 hours, during which time the solution became clear and colorless. The solution was concentrated in vacuo to a volume of approximately 5 mL and the concentrate was diluted with ethyl acetate and washed with 1 N aqueous HCl (2x), and water (lx); then dried over Na2S04, filtered, and concentrated in vacuo to a give the title compound (0.6111 g, 88% yield) as a white solid having a 25 melting point of 119.5-122.0°C NMR data was as follows: 'H-nmr (CDC13, 300 MHz)- 8 = 10.88 (bs, 1H), 6.86-6 78 (m, 2H), 6.76-6.69 (m, 1H), 3.89 (ABq, 2H, JAB = 15 14 Hz, Avab= 20.57 Hz), 3.84 (d, 1H, J= 11.48 Hz), 3.21 (d, 1H, J= 11.61 Hz), 1.61 (s, 3H). 30 Printed from Mimosa 07/26/1999 12:37:07 page -123- WO 98/38177 PCT/US98/03373 - 122 - The following General Procedures II-A to II-E and Examples II-A to II-S illustrate the synthesis of carboxylic acid intermediates which may be used to prepare the compounds of the present invention. 5 GENERAL PROCEDURE II-A Ester Hydrolysis to Free Acid Ester hydrolysis to the free acid was conducted by conventional methods. Below are two examples of such conventional de-esterification methods. 10 Method A: To a carboxylic ester compound in a 1.1 mixture of CH30H/H20 was added 2-5 equivalents of K2C03 The mixture was heated to 50°C for 0 5 to 1.5 hours until tic showed complete reaction The reaction was cooled to room temperature and the methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to ~2, and washed with saturated aqueous NaCl and dried over MgS04 The solution was stripped free of solvent on a rotary evaporator to yield the product. Method B: The amino acid ester was dissolved in dioxane/water (4:1) to 20 which was added LiOH (~2 eq.) that was dissolved in water such that the total solvent after addition was about 2:1 dioxane:water. The reaction mixture was stirred until reaction completion and the dioxane was removed under reduced pressure. The residue was dissolved in water and washed with ether. The layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer 25 was extracted with ethyl acetate. The ethyl acetate extracts were dried over Na2S04 and the solvent was removed under reduced pressure after filtration. The residue was purified by conventional methods (e g., recrystallization). 15 ethyl acetate was added to extract the product. The organic phase was then 30 GENERAL PROCEDURE II-B Acid Chloride Preparation Printed from Mimosa 07/26/1999 12:37:07 page -124- WO 98/38J77 PCT/US98/03373 - 123 -- 3,5-DifluorophenyIacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and this solution was cooled to 0°C DMF (0 5 mL, catalytic) was added followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction was stirred for 3 h and then 5 rotoevaporated at reduced pressure to give an oil which was placed on a high vacuum pump for 1 h to afford 3,5-difluorophenylacetyl chloride as a thin yellow oil. Other acid chlorides can be prepared in a similar manner. GENERAL PROCEDURE II-C 10 Schotten-Baumann Procedure 3,5-Difluorophenylacetyl chloride (from General Procedure II-B) was added dropwise to a 0°C solution of L-alanine (Aldrich) (16.7 g, 0.187 mol) in 2 N sodium hydroxide (215 mL, 0.43 mol) The reaction was stirred for 1 h at 0°C and then overnight at room temperature The reaction was diluted with water 15 (100 mL), then extracted with ethyl acetate (3 x 150 mL) The organic layer was then washed with brine (200 mL), dried over MgS04, and rotoevaporated at reduced pressure to a residue. Recrystallization of the residue from ethyl acetate/hexanes afforded the desired product (34.5 g, 82% yield) Other acid chlorides may be used in this procedure to provide for intermediates useful in 20 this invention. GENERAL PROCEDURE II-D Reductive Amination To a solution of the arylamine in ethanol in a hydrogenation flask was 25 added 1 equivalent of the 2-oxocarboxylic acid ester (e.g., pyruvate ester), followed by 10% palladium on carbon (25 weight percent based on the arylamine) The reaction was hydrogenated at 20 psi H2 on a Parr shaker until complete reaction was indicated by tic (30 minutes to 16 hours) The reaction mixture was then filtered through a pad of Celite 545 (available from Aldrich 30 Chemical Company, Inc ) and stripped free of solvent on a rotary evaporator. The crude product residue was then further purified via chromatography. Printed from Mimosa 07/26/1999 12:37:07 page -125- WO 98/38177 PCT/US98/03373 - 124 - GENERAL PROCEDURE II-E EDC Coupling Procedure To a 1:T mixture of the corresponding carboxylic acid and the corresponding amino acid ester or amide in CH2C12 at 0°C was" added 1.5 5 equivalents triethylamine, followed by 2.0 equivalents hydroxybenzotriazole monohydrate and then 1 25 equivalents of ethyl-3-(3-dimethylamino)propyl carbodiimideHCl. The reaction mixture was stirred overnight at room temperature and then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHC03, IN HCl and saturated aqueous 10 NaCl, and then dried over MgS04. The resulting solution was stripped free of solvent on a rotary evaporator to yield the crude product. Example II-A Synthesis of N-(PhenylacetyI)-L-alanine 15 Using General Procedure II-C, the title compound was prepared from phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solid having a melting point of 102-104°C NMR data was as follows. 'H-nmr (CDC13)' 5 = 9 14 (br s, 1H), 7.21-7.40 (m, 5H), 6 20 (d, J = 7.0 20 Hz, 1H), 4.55 (m, 1H), 3.61 (s, 2H), 1.37 (d, J = 7.1 Hz, 3H). 13C-nmr (CDC13): 5 = 176.0, 171.8, 134.0, 129.4, 127.5, 48.3, 43.2, 17 9. Example II-B Synthesis of N-(3,5-Difluorophenylacetyl)-L-aIanine 25 Using General Procedure II-C, the title compound was prepared from 3,5- difluorophenylacetyl chloride (General Procedure II-B) and L-alanine (Aldrich). NMR data was as follows: 'H-nmr (CD3OD)- 5 = 8.32 (br s, 0.3H), 6.71 (m, 2H), 6.60 (m, 1H), 4 74 (br s, 1.7H), 4.16 (m, 1H), 3.36 (s, 2H), 1.19 (d, J = 7.3 Hz, 3H). 30 ,3C-nmr (CD3OD): 5 = 175.9, 172.4, 164.4 (dd, J = 13.0, 245 3 Hz), 141.1, 113.1 (dd, J = 7.8, 17.1 Hz), 102.9 (t, J = 25.7 Hz), 49.5, 42.7, 17.5. Printed from Mimosa 07/26/1999 12:37:07 page -126- WO 98/38177 PCT/US98/03373 - 125 -- Example II-C Synthesis of N-(Cyclopentylacetyl)-L-phenylglycine Step A - Preparation of N-(Cvclopentvlacetvl)-L-phenvlglvcine Methvl Ester Following General Procedure II-E above using cyclopentylacetic acid 5 (Aldrich) and L-phenylglycine methyl ester hydrochloride (Novabiochem), the title compound was prepared as a solid having a melting point of 83-86°C. The reaction was monitored by tic on silica gel (Rf = 0.28 in 25% ethyl acetate/hexanes) and purification was by recrystallization from ethyl acetate/hexanes 10 NMR data was as follows: 'H-nmr (CDC13): 8 = 7 35 (s, 5H), 6 44 (bd, 1H), 5 6 (d, 1H), 3.72 (s, 3H), 2.24 (bs, 3H), 1.9-1 4 (m, 6H), 1.2-1 05 (m, 2H). 13C-nmr (CDC13). 8 = 172.3, 171.7, 136.7, 129.0, 128.6, 127.3, 56.2, 52.7, 42.5, 36.9, 32.40, 32.38, 24.8. 15 C16H21N03 (MW = 275.35); mass spectroscopy (M+Na) 298. Step B - Preparation of N-fCvclonentvlacetvlVL-phenvlglvcine Following General Procedure II-A above using N-(cyclopentylacetyl)-L-phenylglycine methyl ester (from Step A), the title compound was prepared as a 20 solid having a melting point of 155-158°C The reaction was monitored by tic on silica gel (Rf = 0.18 in 10% methanol/dichloromethane). NMR data was as follows. 'H-nmr (CDC13): 8 = 8.60 (d, J = 7.8 Hz, 1H), 7.45 (m, 5H0, 5 41 (d, J = 7.2 Hz, 1H), 2.20 (m, 3H), 1.8-1.1 (m, 8H).. 25 13C-nmr (CDC13): 8 = 172 3, 172.0, 137.5, 128.7, 128.1, 127 8, 56.2, 40.9, 36.8, 31.8, 24.5. C15H19N03 (MW = 261.32); mass spectroscopy (M+Na) 284. Example II-D 30 Synthesis of N-(CyclopentylacetyI)-L-alanine Step A - Preparation of N-fCvclopentvlacetvlVL-alanine Methvl Ester Printed from Mimosa 07/26/1999 12:37:07 page -127- WO 98/38177 PCT/US98/03373 -- 126 -- Following General Procedure II-E above using cyclopentylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as a solid having a melting point of 43-46°C. Purification was by recrystallization from ethyl acetate/hexanes. 5 NMR data was as follows. 'H-nmr (CDC13): 5 = 6.38 (d, 1H), 4.50 (m, 1H), 3 65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes d at 1.30, 3H), 11H). 13C-nmr (CDC13): 8 = 173.7, 172.5, 52 1, 47.6, 42.3, 36.8, 32.15, 32.14, 18.0. 10 CnH19N03 (MW = 213.28), mass spectroscopy (MH+) 214 Step B - Preparation of N-(Cvclopentvlacetvl)-L-alanine Following General Procedure II-A above using N-(cyclopentylacetyl)-L-alanine methyl ester (from Step A), the title compound was prepared The 15 reaction was monitored by tic on silica gel (Rf = 0.18 in 10% methanol/dichloromethane). NMR data was as follows' 'H-nmr (DMSO-d6) 8 = 12 45 (bs, 1H), 8 12 (d, J=7 2 Hz, 1H), 4.24 (quint, J = 7.2 Hz, 1H), 2.14 (m, 3H), 1.8-1.4 (m, 6H), 1.29 (d, J = 7.2 Hz, 20 3H), 1.2-1.0 (m, 3H). 13C-nmr (DMSO-d6)' 8 - 174 6, 171.9, 47.3, 41.1, 36 7, 31.8, 24.5, 17.2 C10HI7NO3 (MW = 199.25), mass spectroscopy (MH+) N/A. Example II-E 25 Synthesis of N-(Cyclopropylacetyl)-L-alanine Step A - Preparation of N-(Cvclopropylacetvl)-L-alanine Methvl Ester Following General Procedure II-E above using cyciopropylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as an oil The reaction was monitored by tic on silica gel (Rf = 30 0.15 m 25% ethyl acetate/hexanes) and purification was by flash column chromatography using 25% ethyl acetate/hexanes as the eluant. Printed from Mimosa 07/26/1999 12:37:07 page -128- WO 98/38177 PCT/US98/03373 - 127 - NMR data was as follows. 'H-nmr (CDC13): 8 = 6 60 (d, 1H), 4.55 (m, 1H), 3.69 (s, 3H), 2.10 (m, 2H), 1.34 (d; 3H), 0.95 (m, 1H), 0.58 (m, 2H), 0.15 (m, 2H). 13C-nmr (CDC13): 8 = 173.7, 172.3, 52.3, 47.7, 41 0, 18.2,-6.7, 4.27, 4.22. 5 C9H15N03 (MW = 185.22); mass spectroscopy (MH+) N/A. Step B - Preparation of N-fCvclopentvlacetvP-L-alanine Following General Procedure II-A above using N-(cyclopropylacetyl)-L-alanine methyl ester (from Step A), the title compound was prepared as an oil 10 The reaction was monitored by tic on silica gel (Rf = 0 27 in 10% methanol/dichloromethane). NMR data was as follows 'H-nmr (DMSO-d5)- 8 = 8 18 (d, 1H), 4.25 (m, 1H), 2.08 (m, 2H), 1 30 (d, 3H), 1 00 (m, 1H), 0.50 (m, 2H), 0.19 (m, 2H) 15 13C-nmr (DMSO-d6). 8 = 174.6, 171.7, 47 4, 17.3, 7.6, 4.12, 4.06. C8H13N03 (MW = 199.25); mass spectroscopy (MH+) N/A Example II-F Synthesis of N-(Cyclopropylacetyl)-L-phenylglycine 20 Step A - Preparation of N-fCvclopropvlacetvll-L-glvcine Methvl Ester Following General Procedure II-E above using cyclopropylacetic acid (Aldrich) and L-phenylglycine methyl ester, the title compound was prepared as a solid having a melting point of 74-76°C. The reaction was monitored by tic on silica gel (Rf = 0.61 in 50% ethyl acetate/hexanes) and purification was by 25 recrystallization from ethyl acetate/hexanes. NMR data was as follows. 'H-nmr (CDC13): 8 = 7.35 (m, 5H), 6.97 (bd, J=7.2 Hz, 1H), 5.59 (d, J=7.8 Hz, 1H), 3.71 (s, 3H), 2.17 (m, 2H), 1.05-0.95 (m, 1H), 0.62 (m, 2H), 0.20 (m, 2H). 30 13C-nmr (CDC13): 8 = 171.9, 174.6, 136 6, 129.0, 128.5, 127.2, 56.1, 52.7, 41.0, 6.9, 4.37, 4.33. Printed from Mimosa 07/26/1999 12:37:07 page -129- WO 98/38177 PCT/US98/03373 ^ - 128 - C14Hl7N03 (MW = 247.30); mass spectroscopy (MIT) N/A. Step B~- Preparation of N-CCvclonentvlacetvlVL-phenvlglvcine Following General Procedure II-A above using N-(cyclopropylacetyl)-L-5 phenylglycme methyl ester (from Step A), the title compound was prepared as a solid having melting point of 152-157°C The reaction was monitored by tic on silica gel (Rf = 0.23 in 10% methanol/dichloromethane) and purification was by recrystallization from ethyl acetate/hexanes. NMR data was as follows: 10 'H-nmr (CDC13)- 8 = 8.47 (d, J = 7 69 Hz, 1H), 7.35 (m, 5H), 5.34 (d, J = 7 69 Hz. 1H), 2.10 (m, 2H), 0.90 (m, 1H), 0.40 (m, 2H). 0.10 (m, 2H) 13C-nmr (CDC13): 8 = 172.3, 171.8, 137 6, 128.7. 56.2, 7.7, 4.0. C13H15N03 (MW = 233.27); mass spectroscopy (MH+) N/A. 15 Example II-H Synthesis of N-(2-Biphenyl)-D,L-aianine 2-Aminobiphenyl (2 g, 11.8 mmol, Aldrich), tnethylamine (1.2 eq.) and ethyl 2-bromopropionate (1.1 eq, Aldrich) were combined and heated to 85°C 20 with stirring After 7 days, the mixture was diluted with chloroform and washed with water The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography (1:1 CH2Cl2/hexanes). The resulting oil was dissolved in a 1:2 mixture of water/dioxane (200 mL) and LiOH (2 eq.) was added. After 2 hours, the mixture was concentrated to yield 25 an oil which was dissolved in water. The aqueous solution was washed with ether then was adjusted to pH 3 with 5N HCl and extracted with ethyl acetate. The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography (EtOAc) to yield the title compound 30 Example II-I Synthesis of N-(Phenyl-furazan-3-yl)-D,L-alanine Printed from Mimosa 07/26/1999 12:37:07 page -130- WO 98/38177 PCT/US98/03373 - 129 -- 4-Phenyl-furazan-3-ylamine (Maybridge) and ethyl pyruvate (Aldrich) were dissolved in dry ethanol. Platinum on sulfide carbon (5%) was added and the resulting mixture was hydrogenated (1000 psi, H2) at 150°C for 8 hours. The reaction mixture was then filtered through Celite and the filtrate" was 5 concentrated under reduced pressure. The residue was purified by silica gel chromatography using CHC13 as the eluent to provide the title compound as its ethyl ester. The ethyl ester was then hydrolyzed using General Procedure II-A, Method B (LiOH/HjO/dioxane) to provide the title compound. 10 Example II-L Synthesis of S-(+)-3,5-Difluoromandelic Acid Step A - Preparation of Methvl S-f+V3.5-difluoromandelate To a solution of 3,5-difluorobenzaldehyde (Aldrich) in CH2C12 (100 mL) 15 was added ZnCl2 (6.7 g, 21.1 mmol) to form a slurry. Tnmethysilyl cyanide (21.0 g, 211.2 mmol) dissolved in CH2C12 (100 mL) was slowly added to the slurry at 0°C. The resulting solution was stirred at room temperature for 4 h The reaction mixture was then diluted with water and the organic layer separated. The combined organic layers were concentrated to a residue. The 20 residue was dissolved with MeOH (200 mL) at 0°C and anhydrous HCl gas bubbled into the solution for 10 min. After stirring at room temperature for 18 h, the solution was concentrated to a solid. The solid was dissolved in CH2C12 / H20 and the aqueous portion extracted with CH2C12. The combined organics were washed with brine, dried over anhydrous MgS04 and concentrated to a 25 solid (37.4 g, 87.6%), mp = 77-78°C 'H NMR (300 MHz, CDC13): 8 = 6 97 (dd, J = 9.6 Hz, J = 1.79 Hz, 2H), 6.74 (dt, J = 8.82, J = 2.28 Hz, 1H), 5.14 (d, J = 4.64 Hz, 1H), 3.78 (s, 3H), 3 54 (d, J = 5.1 Hz, 1H). 30 Step B - Preparation of Methvl S-f+V3.5-difluoromandelate Methyl (±)-3,5-difluoromandelate was separated via preparative chiral HPLC to give a white solid having a melting point of 70-71°C Printed from Mimosa 07/26/1999 12:37:07 page -131- WO 98/38177 PCT/US98/03373 - 130 - C9H8F203 (MW = 202.17); mass spectroscopy found (M+NH/) -220.0. Anal, calcd for C9H8F,03- C, 53.47; H, 3 99. Found* C, 53.40; H, 3.89 Step C - Preparation of S-(+V3.5-Difluoromandelic acid 5 A solution of methyl S-(+)-3,5-difluoromandelate (1 eq.) in 74% aqueous THF was cooled to 0 °C and treated with lithium hydroxide. After 40 minutes at 0 °C the reaction was complete by TLC. The contents were transferred to a separatory funnel and partitioned between CH2C12 and saturated aqueous NaHC03 The aqueous layer was acidified with 0.5 N NaHS04 and extracted 10 thrice with ethyl acetate. The combined extracts were washed with brine, dried over Na2S04, filtered, and concentrated to a white solid having a melting point of 119-122 °C. The 'H NMR was consistent with known 3,5-difluoromandelic acid. 15 Example II-M Synthesis of 2-Azido-(3,5-difluorophenyl)acetic Acid Step A. To a three-necked flask equipped with a mechanical stirrer and a nitrogen inlet tube was added 3,5-difluorophenylacetic acid (Aldrich) and THF 20 The reaction mixture was cooled to -78°C and 1.2 eq. of triethylamine was added, followed by dropwise addition of trimethylacetyl chloride (1.05 eq.) (Aldrich). During the addition, the temperature was maintained at -78°C. The cold bath was then removed and replaced with an ice bath The temperature was allowed to warm to 0°C and stirring was continued for 1 hour. The 25 reaction mixture was then re-cooled to -78°C. To a second flask charged with THF, triphenylmethane (cat, 0 1 mole %) and (S)-(-)-4-benzyl-2-oxazolidione (1.1 eq.) (Aldrich) at -78°C was added an n-butyllithium solution dropwise until an orange color persisted. This reaction mixture was stirred at -78°C for 30 min. and then cannulated into the first reaction mixture. The resulting mixture 30 was allowed to stir at -78°C for 1 hour and then quenched with 2.2 eq. of acetic acid. The solvent was removed under reduced pressure and the residue was redissolved in dichloromethane and this solution washed with water, followed by Printed from Mimosa 07/26/1999 12:37:07 page -132- WO 98/38177 PCT/US98/03373 -- 131 -- 1M potassium carbonate. The organic layer was then dried over sodium sulfate, filtered and concentrated. The residue was purified by LC 2000 chromatography, elutmg with EtOAC/Hexane (15:85) The resulting oil was slurried in hexane to afford a white solid which was collected by filtration to 5 give (S)-(-)-3-(3,5-difluorophenyacetyl)-4-benzyl-2-oxazolidione Step B: To (S)-(-)-3-(3,5-difluorophenyacetyl)-4-benzyl-2-oxazolidione (3.0 mM) in 20 mL of dry THF cooled to -78°C was added LiHMDS (1.05 eq) dropwise while maintaining the temperature at -78°C The reaction mixture was 10 allowed to stir at -78°C for 15 min and then a pre-cooled (-60°C) solution of trisyl azide (1.12 eq.) in 10 mL of THF was added. The reaction mixture was allowed to stir an additional 10 min. and then was quenched with 4.4 eq. of acetic acid Using a warm water bath, the temperature was raised to 30-40°C for 6 hrs. The reaction mixture was then poured into a separatory funnel and 15 extracted into dichloromethane The organic layer was washed with bicarbonate solution, followed by brine, and then dried over sodium sulfate, filtered and solvent removed The residue was purified by LC 2000 chromatography to afford methyl 2-azido-2-(3,5-difluorophenyl)acetate. 20 Step C- To a solution of methyl 2-azido-2-(3,5-difluorophenyl)acetate in THF/H,0 (2 6:1) cooled to 0°C was added 1.7 eq. of lithium hydroxide The reaction mixture was stirred at room temperature for 3 hours and then poured into a separatory funnel The mixture was extracted into water and washed with ether. The aqueous layer was acidified with IN HCl and extracted with ethyl 25 acetate. The organic layer was then washed with water and bnne. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-azido-2-(3,5-difluorophenyl)acetic acid. Example 1I-N 30 Synthesis of (R)-N,N'-Di-BOC-2-Hydrazinopropionic Acid Step A: To (S)-(-)-4-benzyl-2-oxazolidanone (Aldrich) in THF cooled to Printed from Mimosa 07/26/1999 12:37:07 page -133- WO 98/38177 - 132 - PCT/US98/03373 -50°C was added M-butyllithium 1.1 eq. (1.6 M in hexane) dropwise-. The reaction mixture was allowed to warm to -20°C and then was re-cooled to -78°C and propionyl chloride (1.1 eq) was added in one portion. The reaction mixture was allowed to stir an additional 15 min. at -78°C and then was allowed to 5 warm to room temperature. The reaction was then quenched with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic extracts were washed with water, followed by brine and then dried over sodium sulfate, filtered and concentrated to give (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone. 10 Step B. To a solution of (S)-(-)-3-propionyl-4-benzyl-2-oxazolidanone in THF at -78°C was added KHMDS (1.05 eq.) (Aldrich) dropwise The reaction mixture was allowed to stir at -78°C for 30 min. and then a precooled solution of di-tert-butyl-azodicarboxylate (Aldrich) was added via a cannula. After 5 15 min. 2.6 eq of acetic acid was added The reaction mixture was then extracted with dichloromethane and the organic layer was washed with 1M potassium phosphate. The organic layer was then dried over sodium sulfate, filtered and concentrated to give (S)-(-)-3-[(R)-N,N'-di-BOC-2-hydrazinopropionyl]-4-benzyl-2-oxazolidanone. 20 Step C. To (S)-(-)-3-[(R)-N,N'-di-BOC-2-hydrazinopropionyl]-4-benzyl-2-oxazolidanone (0.49 moles) at 0°C m 8 mL of THF and 3 mL of water was added LiOH (1.7 eq) and H202 (3.0 eq ) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into a 25 seraratory funnel and diluted with water. The aqueous mixture was extracted with ethyl acetate and then acidified to pH 2.0 with IN HCl and extracted with ethyl acetate. The organic layer was then dried over sodium sulfate, filtered and solvent removed to give (R)-N,N'-di-BOC-2-hydrazinopropionic acid which was used without further purification. 30 Example II-O Printed from Mimosa 07/26/1999 12:37:07 page -134- WO 98/38177 PCT/US98/03373 -- 133 -- Synthesis of 3,5-Difluorophenyl-a-oxoacetic Acid Step A.- Ethvl 3,5-difluorophenyl-a-oxoacetate was prepared from 1-bromo- 3,5-difluorobenzene (Aldrich) according to the procedure described in J. Org 5 Chem., 45 (14), 2883-2887 (1980). Step B- Ethyl 3,5-difluorophenyl-a-oxoacetate was hydrolyzed using General Procedure II-A (Method B) to afford 3,5-difluorophenyl-a-oxoacetic acid. 10 Example II-P Synthesis of Cyclopentyl-a-hydroxyacetic Acid The title compound (CAS No. 6053-71-0) was prepared in two steps from 15 cyclopentylmethanal (CAS No. 872-53-7, Wiley) using the procedure described by Gibby, W. A.; Gubler, C J. Biochemical Medicine 1982, 27, 15-25. Example II-Q Synthesis of N-(3,4-dichlorophenyl)alanine 20 Using the procedure set forth in U.S Patent No. 3,598,859, the disclosure of which is incorporated herein by reference in its entirety, N-(3,4-dichlorophenyl)alanine was prepared. Specifically, to a solution of 3,4-dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mL per mL of isopropanol) 25 and 2-chloropropionic acid (2 equivalents) (Aldrich). This mixture is wanned to 40°C and sodium bicarbonate (0.25 equivalents) is added in successive portions before heating under reflux for 4-5 days. After cooling, the reaction mixture is poured into water and the unreacted 3,4-dichloroaniline is removed by filtration. The filtrate is acidified to pH 3-4 with concentrated hydrochloric acid and the 30 resultant precipitate is filtered, washed and dried to yield the title compound, mp. = 148-149°C. Printed from Mimosa 07/26/1999 12:37:07 page -135- WO 98/38177 PCT/US98/03373 - 134 - Example II-R Synthesis of N-(3,5-difluorophenyl)alanine Using the procedure set forth in U.S. Patent No. 3,598,859 and Example Q above, N-(3,5-difluorophenyl)alanine was prepared using 3,5-difluoroaniline 5 (Aldrich) and 2-chloropropionic acid (Aldrich). Example II-S Synthesis of a-Fluoro-3,5-difluorophenylacetic Acid 10 Step A - Synthesis of Methyl 3,5-Difluoromandelate To a solution of 3,5-difluoromandelic acid (Fluorochem) in methanol was bubbled HCl gas for 10 minutes. The reaction was refluxed overnight The mixture was then concentrated in vacuo and the residue was taken up in ethyl acetate and washed with saturated NaHC03 and brine The organic layer was 15 dried over Na2S04, filtered, and concentrated to give the title intermediate as a white solid. C9H8F203 (MW=202 17); mass spectroscopy 202. 'H NMR (300 MHz, CDC13). 5 = 7 00 (2H, d, J=6.58 Hz), 6 76 (1H, t, J=8.86 Hz), 5.16 (1H, d, J=5.29 Hz), 3.81 (3H, s), 3.54 (1H, d, J=5.39 Hz). , 20 Step B - Synthesis of Methyl a-FIuoro-3,5-difluorophenylacetate A solution of diethylaminosulfur trifluoride (DAST) (1.1 eq) in methylene chloride was cooled to 0°C and a pre-cooled solution of methyl 3,5-difluoromandelate (1 eq) in methylene chloride was added. The transfer flask 25 was rinsed with a small portion of methylene chloride After 15 minutes, the cooling bath was removed and the reaction mixture was stirred an additional 40 minutes at ambient temperature The mixture was poured over ice and the layers separated The organic phase was washed with saturated NaHC03 and brine. The organic layer was dried over Na2S04, filtered, and concentrated. 30 The residue was purified via HPLC eluting with 7% ethyl acetate/hexanes providing the title intermediate as a yellow oil. C9H7F302 (MW=204.16); mass spectroscopy 204 Printed from Mimosa 07/26/1999 12:37:07 page -136- WO 98/38177 PCT/US98/03373 -- 135 - Anal, calcd for C9H7F302- C, 52.95; H, 3.46 Found: C, 52.80; H, 3.73. Step C -* Synthesis of a-Fluoro-3,5-difluorophenylacetic Acid Following General Procedure II-A, Method B and using methyl a-fluoro-5 3,5-difluorophenylacetate, the title intermediate was prepared as a white solid having a melting point of 100-102°C. C8HsF302 (MW = 190.13); mass spectroscopy 190. Anal calcd for C8H5F302: C, 50.54; H, 2 65. Found: C, 50.47; H, 2.79. 10 The following Examples 1-20 illustrate the synthesis of compounds of the present invention. Example 1 Synthesis of 15 (S)-5-[l-7V-[Ar-(3,5-Difluorophenylacetyl)-L-alaninyl]amino- 2-phenylethyl]-3-methyl-l,2,4-oxadiazole Following General Procedure A above and using N-(3,5-difluorophenylacetyl)-L-alanine (Example II-B) and (S)-5-(l-amino-2-phenylethyl)-3-methyl-1,2,4-oxadiazole hydrochloride (Example B), the title 20 compound was prepared as a solid having a melting point of 159-162°C. The reaction was monitored by tic (Rf = 0.6 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 7% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane. NMR data was as follows: 25 'H-nmr (DMSO-4,): 5 = 4.30 (m, 1H), 5.26 (m, 1H) C2lH22F2N403 (MW = 428.44); mass spectroscopy (MH+) 428. Example 2 Synthesis of 30 (S)-2-[l-(3,5-Difluorophenylacetamido)ethyl]-4-ethoxycarbonyl-2-thiazoline Following General Procedure A above and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(l-aminoethyl)-4-ethoxycarbonyl-2-thiazohne Printed from Mimosa 07/26/1999 12:37:07 page -137- WO 98/38177 PCT/US98/03373 - 136 -- hydrochloride (Example G), the title compound was prepared as a semisolid. The reaction was monitored by tic (Rf = 0.2 in 1.1 EtOAc/hexanes) and the product was" purified by silica gel chromatography using 1:1 EtOAc/hexanes as the eluent. 5 NMR data was as follows: 'H-nmr (CDC13): 5 = 1.33 (t, 3H), 1.44 (t, 3H), 3.55 (s, 2H), 3.60 (m, 2H), 4.37 (m, 2H), 4.85 (m, 1H), 5.05 (m, 1H), 6.46 (t, 1H), 6.74 (t, 1H), 6.84 (d, 2H). CI6H,8F2N203S (MW = 356.39); mass spectroscopy (MH+) 356 10 Example 3 Synthesis of l-terf-Butoxycarbonyl-2-[l-(./V-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenylmcthyl-2-imidazoline 15 To a 1:1 mixture of the product from Example J, Step C (1.815 g, 1 eq.) in THF (9 mL)/H20 (9 mL) at ambient temperature was added NaHC03 (0.377 g, 1.50 eq ) and di-tert-butyl dicarbonate (1.304 g, 2 00 eq.) (Aldrich) in THF (6 mL). The resulting pale yellow mixture was stirred at ambient temperature for 1 hour and then additional NaHC03 (0.188 g, 0.75 eq.) and di-ferf-butyl 20 dicarbonate (0.652 g, 1 00 eq ) in THF (3 mL) were added and the mixture was stirred for an additional hour. The mixture was then diluted with ethyl acetate, washed with brine (2x), dried over Na2S04, filtered, concentrated in vacuo, and purified by flash column chromatography using 3.2 hexanes/EtOAc as the eluent to provide the title compound in 77% yield as a viscous oil (Rf = 0.31 in 3:2 25 hexanes/EtOAc). The racemic 1:1 mixture of diastereomers was inseparable by flash chromatography. NMR data was as follows- 'H-nmr (DMSO-J3, 250 MHz): 8 = 7.38-7.09 (m, 10H), 6.00 (bd, 1H, J= 7.75 Hz), 5.21-5 05 (m, 3H), 4.15 (d, 1H, J= 11.76 Hz), 4.08 (d, 1H, J= 11.26 30 Hz), 3.85-3.80 (m, 2H), 3.78 (s, 3H), 3.20-3 00 (m, 2H), 1.43 (s, 9H), 1.36 (d, 1.5H, J= 6 75 Hz), 1.24 (d, 1.5H, J= 6.75 Hz). C27H33N306 (MW = 495.58); mass spectroscopy (MH+) 496.4. Printed from Mimosa 07/26/1999 12:37:07 page -138- WO 98/3?177 PCT/US98/03373 -- 137 -- Example 4 Synthesis of l-/e/£-Butoxycarbonyl-2-[l-(3,5-difluorophenylacetaniido)ethyl]-4-methoxycarbonyl-4-phenylmethyI-2-imidazoline 5 Following General Procedure C above and using 3,5-difluorophenylacetic acid (Aldrich) and 1 -ter/-butoxycarbonyl-2-( 1 -aminoethyl)-4-methoxycarbonyl-4- phenylmethyl-2-imidazoline (Example J), the title compound was prepared as an amorphous solid. The reaction was monitored by tic (Rf = 0.34 in 2:1 hexanes/EtOAc) and the product was purified by flash column chromatography 10 NMR data was as follows: 'H-nmr (CDC13, 250 MHz): 8 = 7.28-7.20 (m, 3H), 7.16-7.12 (m, 1 H), 7.07-7.03 (m, IH), 6 91-6.80 (m, 3H), 6.77-6.67 (m, IH), 5.35-5.21 (m, IH), 4.17-4.05 (m, IH), 3.86-3.79 (m, IH), 3.79 (s, 3H), 3 55 (s, IH), 3.52 (s, IH), 3.18-2.99 (m, 2H), 1 43 (s, 4.5H), 1.41 (s, 4 5H), 1.33 (d, 1.5H, J= 6.75 Hz), 15 1.21 (d, 1.5H, J= 6.75 Hz). C27H3,F2N305 (MW = 515.56), mass spectroscopy (MH+) 516.2. Example 5 Synthesis of 20 2-| 1 -(3,5-Difluorophenylacetamido)ethyl]- 4-methoxycarbonyl-4-phenylmethyl-2-imidazoline Following General Procedure D above and using the product from Example 4 above, the title compound was prepared as a white solid (93%) having a melting point of 158-160°C. The reaction was monitored by tic (Rf = 0.31 in 25 95-5 DCM/MeOH). NMR data was as follows: 'H-nmr (DMSO-rf6 and CDC13, 250 MHz): 8 = 8.09 (bt, IH, J= 7.75 Hz), 7.28-7.19 (m, 3H), 7.14-7 09 (m, 2H), 6.89 (bd, 2H, J= 7.25 Hz), 6 74 (bt, IH, J= 9 13 Hz), 4.62-4 48 (m, IH), 3.88 (bd, IH, J= 12.51 Hz), 3.68 (s, 3H), 3.61-30 3.54 (m, IH), 3.50 (s, 2H), 3.11-2.92 (m, 2H), 1.31 (d, 1.5H, J= 6.75 Hz), 1 30 (d, 1.5H, J= 7.00 Hz). C22H20F2N3O3 (MW = 415.44); mass spectroscopy (MH+) 416.1. Printed from Mimosa 07/26/1999 12:37:07 page -139- WO 98/38177 -- 138 - PCT/US98/03373 Example 6 Synthesis of (S)-2-[ 1-(3,5-Difluoropheny lacetamido)ethy I]-5(R,S)-ethoxycarbonyl-2-oxazoline 5 Following General Procedure A and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(l-aminoethyl)-5(R,S)-ethoxycarbonyl-2-oxazoline (Example F), the title compound was prepared as a semisolid. The reaction was monitored by tic (Rf = 0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent. 10 NMR data was as follows: 'H-nmr (DMSO-4): 5 = 1.20 (t, 3H), 1 30 (d, 3H), 3.50 (s, 2H), 3.80 (m, IH), 4 05 (m, IH), 4.15 (q, 2H), 4.55 (m, IH), 5.10 (m, IH), 6.97 (d, 2H), 7.08 (m, IH), 8.60 (d, IH). C|6H18F2N204 (MW = 340.33); mass spectroscopy (MH+) 340. 15 Example 7 Synthesis of 2-[l-(3,5-Difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyI-2-imidazoline 20 Step A — Synthesis of l-ter/-ButoxycarbonyI-2-[l-(3,5- difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyI-2-imidazoline Following General Procedure C above and using 3,5-difluorophenylacetic acid (Aldrich) and 1 -/er/-butoxycarbonyl-2-( 1 -aminoethyl)-4-methoxycarbonyl-4-phenyl-2-imidazoline (Example K), the title compound was prepared as a white 25 foam (90%) The reaction was monitored by tic (Rf = 0.39 in 3:2 hexanes/EtOAc) and the product was purified by flash column chromatography. NMR data was as follows: 'H-nmr (CDC13, 250 MHz): 8 = 7.38-7.31 (m, 5H), 7.09 (d, IH, J= 7.50 Hz), 6.90-6.82 (m, 2H), 6.76-6.66 (m, IH), 5.57 (p, IH, J= 7.50 Hz), 4 83 (d, 30 IH, J= 11.26 Hz), 3.87 (d, IH, J= 11.26 Hz), 3.72 (s, 3H), 3.56 (s, 2H), 1 49 (s, 9H), 1 48 (d, 3H, J= 7.00 Hz). C26H29F2N305 (MW = 501.53); mass spectroscopy (MH+) 502. Printed from Mimosa 07/26/1999 12:37:07 page -140- WO 98/38177 PCT/US98/03373 - 139 - Step B — Synthesis of 2-[l-(3,5-Difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyI-2-imidazoline Following General Procedure D above and using the product from Step A above, the title compound was prepared as a white foam (89%).. The reaction 5 was monitored by tic (Rf = 0.24 in 95.5 DCM/MeOH) and the product was purified by flash column chromatography. NMR data was as follows 'H-nmr (DMSO-rf6, 300 MHz): 5 = 8.47 (d, IH, J= 7 89 Hz), 7.34-7.27 (m, 5H), 7.12-7.06 (m, IH), 7 03-7.00 (m, 2H), 4.55 (p, IH, J= 7.35 Hz), 4.34 (bm, 10 IH), 3.62 (s, 2H), 3.53 (s, 2H), 1.31 (d, 3H, J= 7.00 Hz).. C21H21F2N303 (MW = 401.41); mass spectroscopy (MH+) 402 Example 8 Synthesis of l-tert-Butoxycarbonyl-15 2-(3,5-difluorophenylmethyl)-4-ethoxycarbonyl-4-methyl-2-imidazoline Step A — Synthesis of Ethyl 2,3-Diamino-2-methylpropionate Following the procedures described in Gilbert, et al., Tetrahedron, 1995 51, 6315-6336, the title compound was prepared as an oil. Purification was by Kugelrohr distillation. 20 NMR data was as follows: 'H-nmr (DMSO-rf,,): 5 = 4.06 (m, 2H), 2.70 (d, IH), 2.46 (d, IH), 2.18 (bs, 4H), 1 18 (t, 3H), 1 10 (s, 3H). C6H)4N202 (MW = 146.19); mass spectroscopy (MH+) 147. 25 Step B ~ Synthesis of 2-(3,5-Difluorophenylmethyl)-4-ethoxycarbonyl-4- methyl-2-imidazoline In a round bottom flask fitted with an addition funnel was added 2.25 g (9.55 mmole) of the product from Example L ~ Step A above and 20 mL of ethanol. The flask was cooled to 0° C and stirring was initiated under an 30 atmosphere of nitrogen. The product from Step A above (1 40 g, 9.55 mmole) in 20 ml of ethanol was slowly added to the reaction via an addition funnel. The reaction was allowed to slowly warm to room temperature and stir Printed from Mimosa 07/26/1999 12:37:07 page -141- WO 98/38177 PCT/US98/03373 - 140 - overnight. The mixture was then filtered through a sintered glass funnel and the filtrate was concentrated on the rotary evaporator. The residue was partitioned between 50 mL of 1 0 N sodium hydroxide and 50 mL of dichloromethane. The organic phase was separated and the aqueous layer was washed twice with 5 50 mL of dichloromethane. The combined organic layers were washed with 50 mL of saturated brine and dried over sodium sulfate. Filtration followed by concentration on the rotary evaporator, yielded a yellow oil which was purified via flash chromatography on silica gel 60 (230-400 mesh) using 95:5 DCM/MeOH as the eluent. Concentration of the fractions gave 2 61 g (82% 10 yield) of the title compound (Rf = 0.17 in 95:5 DCM/MeOH). NMR data was as follows: 'H-nmr (DMSO-^)- 5 = 7.05 (m, 3H), 4.04 (m, 2H), 3.75 (d, J = 11.71 Hz, IH), 3 49 (s, 2H), 3.27 (d, J = 11.73 Hz, IH), 1.29 (s, 3H), 1.17 (t, 3H). C,4Hl6F2N202 (MW = 282.29); mass spectroscopy (MH+) 282 1. 15 Step C ~ Synthesis of l-/erf-ButoxycarbonyI-2-(3,5-difluorophenylmethyl)-4-ethoxycarbonyl-4-methyl-2-imidazoline In a round bottom flask fitted with an addition funnel was added the product from Step B above (2 00 g, 7.08 mmole), 0 743 g (8.85 mmole) of 20 sodium bicarbonate, 30 mL of water, and 30 mL of THF. Stirring was initiated under an atmosphere of nitrogen and di-Zerr-butyl dicarbonate (3.47 g, 15.90 mmole) (Aldrich) in 15 mL of THF was added to the reaction via the addition funnel. After stirring for 1 hour, an additional 627 mg (7.05 mmole) of sodium bicarbonate and 1.17 g (5.40 mmole) of di-ter/-butyl dicarbonate were added to 25 the reaction. The reaction was monitored using thm layer chromatography, and when the reaction was complete, the reaction mixture was partitioned between 250 mL of ethyl acetate and 250 mL of saturated brine. The organic layer was washed twice with a 250 mL of saturated brine and then dried over sodium sulfate. Filtration followed by concentration on the rotary evaporator yielded a 30 yellow oil which was purified by flash chromatography on silica gel 60 (230-400 mesh) using 15.85 ethyl acetate/dichloromethane as the eluent. Printed from Mimosa 07/26/1999 12:37:07 page -142- WO 98/38177 PCT/US98/03373 - 141 -- Concentration of the fractions gave 2 10 g (78 % yield) of the title compound (Rf = 0 15 in 15:85 EtOAc/hexanes). NMK data was as follows: 'H-nmr (DMSO-<4): 5 = 7.07 (m, IH), 6.94 (m, 2H), 4.05 (m, 5H), 3.57 5 (d, IH), 1.38 (d, 12H), 1.19 (t, 3H). ,3C-nmr (DMSO-rf6): 5 = 172.116, 163.599, 160.348, 157.624, 149.352, 140.855, 111.511, 101.584, 81.677, 69.950, 60.758, 55.442, 34.855, 27.423, 24.203, 13.581. C^H^FjNiO^ (MW = 382.41); mass spectroscopy (MH+) 382.1. 10 Example 9 Synthesis of 2-[l-7V-[iV-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-l-phenyl]methyl-2-thiazoline 15 Following General Procedure F above and using N-( 1 -cyano-1- phenylmethyl)-AT'-(3,5-difluorophenylacetyl)-L-alaninamide and 2-mercaptoethylamine, the title compound was prepared The reaction was monitored by tic (Rf = 0 3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent. 20 NMR data was as follows: 'H-nmr (CDC13). 8 = 1.31 (m, 3H), 3.31 (m, 2H), 3.50 (d, 2H), 4.24 (m, 2H), 4.55 (m, IH), 4.64 (d, IH), 6.30 (m, IH), 6 76 (m, 2H), 7 33 (d, 5H), 7.52 (m, IH). C21H21F2N302S (MW = 417.48); mass spectroscopy (MH+) 417. 25 Example 10 Synthesis of 2-[l-(3,5-Difluorophenylacetamido)-l-phenyl]methyl-4-ethoxycarbonyl-2-thiazoiine 30 Following General Procedure G above and using N-(3,5- difluorophenylacetyl)phenylglycinonitrile from Example I above and L-cysteine ethyl ester hydrochloride (Aldrich), the title compound was prepared as an amorphous solid. The reaction was monitored by tic (Rf = 0.5 in 1-1 Printed from Mimosa 07/26/1999 12:37:07 page -143- WO 98/38177 PCT/US98/03373 - 142 - EtOAc/hexanes) and the product was purified by silica gel chromatography using 40% EtOAc/hexanes as the eluent NMR'data was as follows 'H-nmr (CDC13): 8 = 1 36 (t, 3H), 3.6 (m, 4H), 4.30 (m, 2H), 5.10 and 5 5.20 (t, IH), 5.84 (d, IH), 6.72 (m, IH), 6.84 (m, 2H), 7.38 (m, 5H). C2lH20F2N2O3S (MW = 418.47); mass spectroscopy (MH") 418 Example 11 Synthesis of 10 2-[(S)-l-(3,5-dichIoroanilino)ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine Following General Procedure H above, the title compound was prepared as an oil The reaction was monitored by tic (Rf =05 in 3.2 hexanes/EtOAc) and the product was purified by preparative tic chromatography using 3.2 hexanes/EtOAc as the eluent. 15 NMR data was as follows. 'H-nmr (CDC13)- 8 = 1 5 (d, J = 7 Hz, 3H), 3.79 (s, 3H), 4.15-4.3 (m, IH), 4.3-4.65 (m, 3H), 4.7-4.85 (m, IH), 6 45 (s, 2H). 6.7 (s, IH). ,3C-nmr (CDC13). 8 = 14.2, 42 08, 42.15, 47.9, 62 9, 65.3, 106.67, 106.72, 113 0, 130.7, 143.3, 166.3. 20 C13H14C12N203 (MW = 317); mass spectroscopy (MH+) N/A. Example 12 Synthesis of (S)-5-[l-/V-[iV-(3,5-DifluorophenylacetyI)-L-aIaninyl]amino-25 l-phenyl]methy]-3-methyl-l,2,4-oxadiazole Following General Procedure A above and using N-(3,5-difluorophenylacetyl)-L-alanine (Example II-B) and (S)-5-(l-amino-1-phenylmethyl)-3-methyl- 1,2,4-oxadiazole hydrochloride (Example C), the title compound was prepared as a solid (3:2 mixture of diastereomers) The reaction 30 was monitored by tic (Rf = 0.6 in 7% MeOH/CHCl3) and the product was purified by silica gel chromatography using 7% MeOH/CHCl3, followed by recrystallization from 1-chlorobutane/acetonitrile. Printed from Mimosa 07/26/1999 12:37:07 page -144- WO 98/38177 PCT/US98/03373 - 143 -NMR data was as follows: 'H-nmr (DMSO-^): 5 = 1.21 (d, 3H), 2.32 (s, 3H), 3.53 (s, 2H), 4.43 (m, IH), 6.35 (d, IH), 6.97 (d, 2H), 7 07 (m, IH), 7.38 (broad s, 5H), 8.38 (d, IH), 9.27 (d, IH). 5 C20H20F2N4O3 (MW = 414.41); mass spectroscopy (MH+) 414. Example 13 Synthesis of (S)-5-[ 1-iV- [7V-(3,5-Difluorophenylacetyl)-L-alaninyl] amino-10 l-phenyl]methyl-3-phenyl-l,2,4-oxadiazole Following General Procedure A above and using #-(3,5-difluorophenylacetyl)-L-alanine (Example II-B) and (S)-5-(l-amino-l-phenylmethyl)-3-phenyl-1,2,4-oxadiazole hydrochloride (Example D), the title compound was prepared. The reaction was monitored by tic (Rf = 0.4 in 5% 15 MeOH/CHClj) and the product was purified by silica gel chromatography using 5% MeOH/CHCIj as the eluent NMR data was as follows. 'H-nmr (DMSO-</6). 8 = 131 (d, 3H), 3 51 (s, 2H), 4.47 (m, IH), 6.42 (d, IH), 6.97 (d, 2H), 7.07 (m, IH), 7.35-7 60 (m, 8H), 7.97 (d, 2H), 8.40 (d, 20 IH), 9.27 (d, IH). C26H22F2N403 (MW = 476 49); mass spectroscopy (MHT) 476. Example 14 Synthesis of 25 (S)-5-[l-iV-[jY-(3,5-Difluorophenylacetyl)-L-alaninyl}amino- l-phenyl]methyl-3-(4-methoxyphenylmethyl)-l,2,4-oxadiazole Following General Procedure A above and using #-(3,5-difluorophenylacetyl)-L-alanine (Example II-B) and (S)-5-(l-amino-1-phenylmethyl)-3-(4-methoxyphenylmethyl)-1,2,4-oxadiazole hydrochloride 30 (Example E), the title compound was prepared (1:2 mixture of diastereomers). The reaction was monitored by tic (Rf = 0.25 in 3.5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 3.5% MeOH/CHCl3) as the eluent Printed from Mimosa 07/26/1999 12:37:07 page -145- WO 98/38177 PCT/US98/03373 -- 144 -- NMR data was as follows 'H-nmr (DMSO-rf3): 5 = 1 22 (d, 3H), 3.49 (s, 2H), 3.72 (s, 3H), 3.98 (s, 2H), 4.42 (ffl, IH), 6 28 (d, IH), 6 86 (d, 2H), 6 96 (d, 2H), 7.07 (m, IH), 7.18 (d, 2H), 7.38 (broad s, 5H), 8.36 (d, IH), 9.18 (d, IH) 5 C28H26F2N404 (MW = 520.54); mass spectroscopy (MH~) 520. Example 15 Synthesis of (4R)-4- [AT-(1 S)-( 1-Methoxy carbonyl-1 -pheny l)methy 1] carbamoy 1-10 2-(3,5-difluorophenylmethyI)-4-methyl-2-thiazoline To a solution of (4R)-4-carboxy-2-(3,5-difluorophenylmethyl)-4-methyl-2-thiazohne (0.2509 g, 1 00 eq.) from Example L above in THF (20 mL) at 0°C under an atmosphere of nitrogen was added (S)-(+)-2-phenylglycine methyl ester hydrochloride (0.2052 g, 1.10 eq.) (Aldrich), 1 -hydroxybenzotriazole hydrate 15 (0.1437 g, 1.15 eq.) (Aldrich), M^V-diisopropylethylamine (0.371 mL, 2.30 eq.), followed by l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.2039 g, 1.15 eq.) (Aldrich) The cooling bath was removed and the mixture allowed to warm to ambient temperature with stirring for 19 hours The solution was diluted with ethyl acetate, washed with 0.5 M aqueous HCl (2x), 20 dilute aqueous NaHC03 (lx), and brine (lx); then the organic phase was dried over Na2S04, filtered, concentrated in vacuo, and the residue purified by flash column chromatography using 2:1 hexanes/EtOAc as the eluent to yield the title compound as a clear colorless viscous oil (0.3465 g, 90%) NMR data was as follows: 25 'H-nmr (CDC13, 300 MHz): 8 = 7.59 (d, IH, J= 7.25 Hz), 7.36-7.27 (m, 5H), 6.80-6 78 (m, 2H), 6.75-6.68 (m, IH), 5.51 (d, IH, J= 7.37 Hz), 3.78 (s, 2H), 3.74 (s, 3H), 2.63 (d, IH, J= 11.59 Hz), 2.22 (d, IH, J= 11.60 Hz), 1.55 (s, 3H). Optical Rotation. [a]20 = 65.3 (c 1.0, CHC13). 30 C21H20F2N2O3S (MW = 418.47); mass spectroscopy (MH+) 418.3. Example 16 Printed from Mimosa 07/26/1999 12:37:07 page -146- WO 98/38177 PCT/US98/03373 -- 145 -- Synthesis of 4-[7V-(S)-(l-Methoxycarbonyl-l-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-2-thiazoline Following General Procedure A above and using L-phenylglycine methyl 5 ester and 2-(3,5-difluorophenylmethyl)-4-carboxy-2-thiazoline from Example H above, the title compound was prepared as two separate diastereomeric isomers. The reaction was monitored by tic (Rf = 0.6 and 0.4 in 1:1 EtOAc/hexanes) and the products were purified by silica gel column chromatography using 40% EtOAc/hexanes as the eluent. 10 First Diastereomeric Isomer (amorphous solid)- NMR data was as follows: 'H-nmr (CDC13): 8 = 3.58-3.82 (m, 5H), 3 94 (s, 2H), 5.10 (t, IH), 5.57 (d, IH), 6.75 (m, IH), 6.90 (d, 2H), 7.35 (m, 5H), 7 84 (d, IH) C,9H18F2N203S (MW = 404.44); mass spectroscopy (MH+) N/A. 15 Second Diastereomeric Isomer (oil): NMR data was as follows: 'H-nmr (CDC13): 8 = 3.61 (d, 2H), 3.75 (s, 3H), 3 84 (s, 2H), 5 13 (t, IH), 5 56 (d, IH), 6.72 (m, IH), 6.80 (d, 2H), 7 33 (m, 5H), 7.66 (d, IH). 20 C19H)8F2N203S (MW = 404.44); mass spectroscopy (MH+) 404. Example 17 Synthesis of (S)-5-[l-A'-[A'-(3,5-Difluorophenylacetyl)-L-alaninyl]amino]ethyl-25 3-ethyl-l,2,4-oxadiazole Following General Procedure A and using yV-(3,5-difluorophenylacetyl)-L-alanine (Example II-B) and (S)-5-(l-aminoethyl)-3-ethyl-l,2,4-oxadiazole hydrochloride (Example A), the title compound was prepared as a solid having a melting point of 181-183°C. The reaction was monitored by tic (Rf = 0.3 in 7% 30 MeOH/CHCl3) and the product was purified by silica gel column chromatography using 7% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane. NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -147- WO 98/38177 PCT/US98/03373 - 146 - 'H-nmr (DMSO-J6): 8 = 1.20 (m, 6H), 1.45 (d, 3H), 2.70 (q; 2H), 3.51 (s, 2H), 4.32 (m, IH), 5.13 (m, IH), 6.98 (d, 2H), 7.10 (m, IH), 8.38 (d, IH), 8.73 (d, IH): Optical Rotation: [a]20 = +53.1 @ 589 nm (c 1.08, DMSO). 5 C17H20F2N4O3 (MW = 366 37); mass spectroscopy (MH+) 367. Example 18 Synthesis of 2-[l-(3,5-Difluorophenylacetamido)-l-phenyl]methyl-10 (4R)-4-methoxycarbonyl-2-thiazoline Following General Procedure G above and using N-(3,5- difluorophenylacetyl)phenylglycinonitrile from Example I above and (R)- cysteine methyl ester hydrochloride (CAS No. 2485-62-3), the title compound was prepared The product was purified by silica gel chromatography using 1.1 15 EtOAc/hexanes as the eluent, followed by crystallization from 1 -chlorobutane. First Diastereomeric Isomer (higher Rf). NMR data was as follows. 'H-nmr (CDC13): 8 = 5.08 (t, IH), 5 18 (t, IH), 5 47 (t, IH), 5.82 (m, IH). 20 C20H18F2N2O3S (MW = 404.44); mass spectroscopy (M+) 404. Second Diastereomeric Isomer (lower Rf): NMR data was as follows. 'H-nmr (CDC13): 8 = 5.12 (t, IH), 5.21 (t, IH), 5 47 (t, IH), 5.83 (m, 25 IH). C2oH18F2N203S (MW = 404 44), mass spectroscopy (M+) 404 Example 19 Synthesis of 30 2-[l-(3,5-Difluorophenylacetamido)-l-phenyl]methyl- (4S)-4-methoxycarbonyl-2-thiazoline Following General Procedure G above and using N-(3,5- difluorophenylacetyl)phenylglycinonitrile from Example I above and (S)-cysteine Printed from Mimosa 07/26/1999 12:37:07 page -148- WO 98/38177 PCT/US98/03373 - 147 - methyl ester hydrochloride (Aldrich), the title compound was prepared. The product was purified by silica gel chromatography using 2:3 EtOAc/hexanes as the eluent, followed by crystallization from 1-chlorobutane/hexanes. First Diastereomeric Isomer (higher Rf): 5 NMR data was as follows: 'H-nmr (CD3OD): 5 = 3.76 (s, 3H), 5.20 (t, IH), 5.85 (s, IH). C20H,8F2N2O3S (MW = 404.44); mass spectroscopy (M+) 404. Second Diastereomeric Isomer (lower Rf): 10 NMR data was as follows: 'H-nmr (CD3OD). 8 = 3.78 (s, 3H), 5.22 (t, IH), 5.83 (s, IH). C20HlgF2N,O3S (MW = 404.44); mass spectroscopy (M+) 404 Example 20 15 Synthesis of 7V-[2-(3,5-Difluorophenylmethyl)-4-inethyl-2-imidazoline-4-carboxamido]-L-phenylglycine Methyl Ester Step A — Synthesis of l-/er/-Butoxycarbonyl-2-(3,5-20 difluorophenylmethyl)-4-carboxy-4-methyl-2-imidazoline A round bottom flask containing a magnetic stir bar was charged with 150 mL of THF, 50 mL of a 0.1N aqueous solution of lithium hydroxide, and 1-/m-butoxycarbonyl-2-(3,5-difluorophenylmethyl)-4-ethoxycarbonyI-4-methyl-2-imidazoline (Example 8, Step C) (2.58 g, 6.75 mmole). The reaction mixture 25 was stirred for 1 hour and then an additional 75 mL of a 0.1N aqueous solution of lithium hydroxide was added and stirring was continued for 3.5 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was partitioned between ethyl acetate and a 0.5N aqueous solution of hydrochloric acid. The organic phase was separated and washed with an additional 0.5N 30 aqueous solution of hydrochloric acid. The organic phase was then dried over Na^O,, The drying agent was removed by filtration and the filtrate was partially concentrated in vacuo The resulting solid was isolated via vacuum Printed from Mimosa 07/26/1999 12:37:07 page -149- WO 98/38177 -- 148 -- PCT/US98/03373 filtration through a sintered glass funnel, followed by drying under -vacuo at 80°C. Mass spectroscopy data was as follows- Cl7H20N2O4 (MW - 354.36); mass spectroscopy (MH+) 255.2. 5 Step B — Synthesis of 7V-[l-fcrt-ButoxycarbonyI-2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline-4-carboxamido]-L-phenylglycine Methyl Ester Following General Procedure A above and using (S)-(+)-2-phenylglycine 10 methyl ester hydrochloride and the product of Step A, the title compound was prepared. The product was purified by flash silica gel chromatography (230-400 mesh) using 95:5 DCM/MeOH as the eluent. First Diastereomeric Isomer (viscous oil) NMR data was as follows: 15 'H-nmr (CDC13): 6 = 7/60 (bs, IH), 7.35 (s, 5H), 6.90 (m, 2H), 6.69 (m, IH), 5.49 (d, IH), 4.12 (m, 3H), 3.72 (s, 3H), 3.61 (d, IH), 1 46 (s, 9H), 1.41 (s, 3H). Second Diastereomeric Isomer (viscous oil). 20 NMR data was as follows: 'H-nmr (DMSO-rfJ: 5 = 7.55 (bs, IH), 7.31 (m, 5H), 6.84 (m, 2H), 6.67 (m, IH), 5 49 (d, IH), 4.08 (m, 3H), 3.72 (s, 3H), 3.56 (m, IH), 1.50 (s, IH), 1.43 (s, 9H). 25 Step C - Synthesis of Ar-[2-(3,5-Difluorophenylmethyl)-4-methyl-2- imidazoline-4-carboxamido)-L-phenylglycine Methyl Ester Following General Procedure D above and using the individual isomers from Step B, the title compound was prepared as two separate isomers. These products were purified by flash silica gel chromatography (230-400 mesh) using 30 97.5:2.5 DCM/MeOH as the eluent. First Diastereomeric Isomer: Mass spectroscopy data was as follows. Printed from Mimosa 07/26/1999 12:37:07 page -150- WO 98/38177 PCT/US98/03373 - 149 - C21H2lF2N203S (MW = 401 42); mass spectroscopy (MH ) 402 0 Second Diastereomeric Isomer: Mass spectroscopy data was as follows- C2|H21F2N203S (MW = 401.42); mass spectroscopy (MH') 402.0. Additionally, the following General Procedures and Examples provide various carboxylic acids (and carboxylic acid esters which can be hydrolyzed using General Procedures AC or BD below to afford the corresponding 10 carboxylic acids) which can be used to prepare additional compounds within the scope of this invention. GENERAL PROCEDURE AA Reductive Amination 15 To a solution of the arylamine in ethanol in a hydrogenation flask was added 1 equivalent of the 2-oxocarboxylic acid ester (e.g., pyruvate ester), followed by 10% palladium on carbon (25 weight percent based on the arylamine). The reaction was hydrogenated at 20 psi H2 on a Parr shaker until complete reaction was indicated by tic (30 minutes to 16 hours) The reaction 20 mixture was then filtered through a pad of Celite 545 (available from Aldrich Chemical Company, Inc.) and stripped free of solvent on a rotary evaporator. The crude product residue was then further purified via chromatography. GENERAL PROCEDURE AB 25 First Transesterification Technique A solution of 1-5 equivalents of the desired alcohol was added to 1 equivalent of sodium hydride in toluene. After off-gassing had ceased, the compound to be transesterified, dissolved in toluene, was added. After 0 5 hours, the reaction was either heated to 40°C and placed under house vacuum 30 (~20 mmHg), or nitrogen was bubbled through the solution while it was heated at 90°C. The reaction was followed by tic, and when the reaction was complete Printed from Mimosa 07/26/1999 12:37:07 page -151- WO 98/38177 PCT/US98/03373 - 150 - the solution was cooled and quenched with water or 1M HCl, and in smaller scale reactions diluted with ethyl acetate. The organic phase was extracted with saturated aqOeous NaHC03, then washed with saturated aqueous NaCl and dried over MgSOj The solution was stripped free of solvent on a rotary evaporator, 5 and the crude product residue was then further purified by chromatography. Alternatively, the reaction mixture was worked-up by evaporation of the solvents and direct chromatography of the crude mixture. This procedure is particularly useful in the case of costly and/or high 10 boiling alcohols. GENERAL PROCEDURE AC Second Transesterification Technique The compound to be transesterified was placed in a large excess of the 15 desired alcohol. A catalytic amount of dry NaH was added, and the reaction was followed by tic until the presence of starting material was no longer detected The reaction was quenched with a few milliliters of IN HCl, and after a few minutes of stirring saturated aqueous NaHCO; was added. The organic phase was washed with saturated aqueous NaCl and dried over MgS04. The 20 solution was stripped free of solvent on a rotary evaporator, and the crude product residue was then further purified by chromatography. GENERAL PROCEDURE AD Third Transesterification Technique 25 The compound to be transesterified was placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added, and the reaction was followed by tic until the presence of starting material was no longer detected. The reaction was quenched with a few milliliters of IN HCl, and after a few minutes of stirring saturated aqueous NaHC03 was added. The 30 volume of the reaction mixture was reduced on a rotary evaporator until the excess alcohol was removed and then the remaining residue was taken up in Printed from Mimosa 07/26/1999 12:37:07 page -152- WO 98/38177 PCT/US98/03373 - 151 - ethyl acetate and additional water was added The organic phase was washed with saturated aqueous NaCl and dried over MgS04 The solution was stripped free of solvent on a rotary evaporator, and the crude product residue was then further purified by chromatography 5 This procedure is particularly employed in the case of low boiling, inexpensive alcohols, miscible with water. GENERAL PROCEDURE AE 10 O-Alkvlation Technique To a carboxylic acid compound (prepared, for example, by reductive amination via General Procedure AA to provide for the iV-aryl amino acid ester, followed by hydrolysis via Procedure AF) in DMF was added 1.5 equivalents K2C03, followed by 1 equivalent of alkylating agent (e g , tert-butyl 15 bromoacetate). The reaction was stirred at room temperature for 2 hours, then was quenched with water and extracted into ethyl acetate. The organic phase was washed with saturated aqueous NaHC03, water, and saturated aqueous NaCl, and was then dried over MgSO„. The solution was stripped free of solvent on a rotary evaporator to yield the crude product. 20 GENERAL PROCEDURE AF Ester Hydrolysis to Free Acid To a carboxylic ester compound (prepared, for example, by reductive amination via General Procedure AA to provide for the N-aryl amino acid ester) 25 in a 1:1 mixture of CH30H/H20 was added 2-5 equivalents of K,CO,. The mixture was heated to 50°C for 0.5 to 1 5 hours until tic showed complete reaction The reaction was cooled to room temperature and the methanol was removed on a rotary evaporator. The pH of the remaining aqueous solution was adjusted to ~2, and ethyl acetate was added to extract the product. The organic 30 phase was then washed with saturated aqueous NaCl and dried over MgSO„. Printed from Mimosa 07/26/1999 12:37:07 page -153- WO 98/3&177 PCT/U S98/03373 - 152 - The solution was stripped free of solvent on a rotary evaporator to yield the crude product GENERAL PROCEDURE AG 5 yV-Heteroarvlation of Alanine A solution of 1 1 equivalents of L-alanme and 2 equivalents NaOH in DMSO was stirred at room temperature for 1 hour, then 1 equivalent of 2-chlorobenzothiazole was added The mixture was heated to 100°C for 4 hours, then cooled to room temperature and poured onto ice. The pH of the resulting 10 aqueous solution was adjusted to ~2, and the precipitated solid was removed by filtration. This solid was then dissolved in IN NaOH and the resulting solution was filtered through a pad of Celite 545 The pH of the filtrate was adjusted to ~2, and the white precipitate was removed by filtration and washed with water to yield the crude product. 15 GENERAL PROCEDURE AH EDC Coupling To a 1:1 mixture of the desired acid and alcohol in CH2C12 at 0°C was added 1.5 equivalents triethylamine, followed by 2 0 equivalents 20 hydroxybenzotriazole monohydrate, then 1.25 equivalents of ethyl-3-(3- dimethylamino)-propyl carbodiimide HCl (EDC). The reaction was stirred overnight at room temperature, then transferred to a separatory funnel and washed with water, saturated aqueous NaHCO,, IN HCl, and saturated aqueous NaCl, and was then dried over MgSO„. The solution was stripped free of 25 solvent on a rotary evaporator to yield the crude product. GENERAL PROCEDURE Al Oxime or Amine Coupling Technique The trichlorophenyl ester (1 eq) of a carboxylic acid was stirred in DMF 30 or THF The oxime or amine (1.2 eq) was added and the mixture was stirred at ambient temperature for 1-4 hours. In cases where the hydrochloride salt form Printed from Mimosa 07/26/1999 12:37:07 page -154- WO 98/38177 PCT/US98/03373 - 153 -- of an amine was used, a suitable base such as Af,Af-diisopropylethylamine (1 2 eq) was also added The resulting mixture was concentrated under reduced pressure to yield a crude product which was used without purification or was purified by silica gel chromatography and/or crystallization 5 GENERAL PROCEDURE AJ Alkylation Technique The amine (1 eq), the a-bromo ester (1 1 eq) and a suitable base (such as tnethylamine) (2 eq) were stirred in chloroform. The resulting solution was 10 heated at reflux for 4-12 hours After cooling, the mixture was diluted with chloroform and washed with water The organic portion was dried (sodium sulfate) and concentrated under reduced pressure The crude product was purified by silica gel chromatography. The carboxylic acid (1 eq) was stirred in a suitable solvent (such as THF, dioxane or DMF). An alcohol or oxime (1-5 eq) was added EDC hydrochloride (1.2 eq) and hydroxybenzotriazole hydrate (1 eq) were added. A 20 suitable base (such as 4-methylmorpholine or triethylamine) (0-1 eq) was added. A catalytic amount (0.1 eq) of 4-dimethylaminopyndine was added. The mixture was stirred at ambient temperature and under a dry atmosphere of nitrogen After 20 hours, the mixture was concentrated under reduced pressure. The resulting concentrate was partitioned between ethyl acetate and water. The 25 organic portion was separated and washed with aqueous sodium bicarbonate and brine. The organic portion was dried (sodium sulfate) and concentrated under reduced pressure. The crude product was used without purification or was purified by silica gel chromatography and/or crystallization 15 GENERAL PROCEDURE AK Oxime or Alcohol Coupling Technique 30 GENERAL PROCEDURE AL EDC Coupling Printed from Mimosa 07/26/1999 12:37:07 page -155- WO 98/38177 PCT/US98/03373 - 154 - The carboxylic acid was dissolved in methylene chloride. The amino acid (1 eq.), N-methylmorpholine (5 eq) and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. A cooling bath was applied to the round bottomed flask until the solution reached 0°C. At that time, 1.2 eq. of l-(3-5 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) was added. The solution was allowed to stir overnight and come to room temperature under nitrogen pressure The reaction mixture was worked up by washing the organic phase with saturated aqueous sodium carbonate, 0.1M citric acid, and brine before drying with sodium sulfate. The solvents were then removed to yield 10 crude product. Pure products were obtained by flash chromatography in an appropriate solvent. GENERAL PROCEDURE AM Triflate Displacement 15 To a 0°C solution of wo-butyl R-(+)-lactate in CH2C12 was added 1.1 equivalents of trifluoromethanesulfomc anhydride. After stirring at room temperature for 20 min, 1.1 equivalents of 2,6-lutidine was added and stirring was continued for 10 min. This solution was then transferred to a flask containing 1 equivalent the arylamine and 1 equivalent N,N-20 dnsopropylethylamine in CH2C12 or CH3NO, at 0°C The reaction was held overnight at room temperature and then stripped free of solvent on a rotary evaporator. The residue was dissolved in ethyl acetate, washed with 5% citric acid, followed by saturated aqueous NaCl, dried over magnesium sulfate or sodium sulfate and then the solution was stripped free of solvent on a rotary 25 evaporator to yield the crude product, which was then purified by chromatography. GENERAL PROCEDURE AN BOC Removal 30 The BOC-protected compound was added to a 1:1 mixture of CH2C12 and trifluoroacetic acid, and was stirred until tic indicated complete conversion, Printed from Mimosa 07/26/1999 12:37:07 page -156- WO 98/3S177 - 155 -- PCT/US98/03373 typically 2h. The solution was then stripped to dryness and the residue was taken up in ethyl acetate and extracted with dilute HCl. The acid reaction was neutralized and extracted with ethyl acetate The organic phase was washed with saturated aqueous NaCl and dried over MgS04. The solution was stripped 5 free of solvent on a rotary evaporator to yield the product. GENERAL PROCEDURE AO Synthesis of Pyruvate Esters To a mixture of pyruvic acid (8.8 g, 0 1 mol) (Aldrich) in 100 mL of 10 benzene was added /so-butanol (14.82 g, 0 2 mol) and a catalytic amount of /j-toluenesulfonic acid. The mixture was then refluxed using a Dean Stark apparatus. After 4 hours, the reaction appeared to be complete with the isolation of 1.8 g (0.1 mol) of water. The benzene and jso-butanol were removed on a rotary evaporator The residue (14 g, 0.1 mol), which was primarily the 15 pyruvate /so-butyl ester by nmr ['H-Nmr (CDC13): 8 = 4.0 (d, 2H), 2.5 (s, 3H), 2.0 (m, IH), 1.0 (d, 6H)], was used without further purification. By substituting other alcohols in place of wo-butanol (e.g., ethanol, isopropanol, n-butanol, benzyl alcohol and the like), other esters of pyruvic acid can be prepared in a similar manner. 20 GENERAL PROCEDURE AP Aromatic Nucleoohilic Substitution of Fluorobenzenes A mixture of 1.82 g (10 mmol) of D,L-alanine iso-butyl ester hydrochloride, the fluorobenzene (10 mmol) and 3 g of anhydrous potassium 25 carbonate in 10 mL of DMSO was stirred at 120°C for 2-5 hours. The reaction mixture was then cooled to room temperature and diluted with 100 mL of ethyl acetate. The ethyl acetate extract was washed with water (3x), dried over MgS04 and evaporated to dryness to afford the crude product, which was further purified by column chromatography. 30 GENERAL PROCEDURE AQ Printed from Mimosa 07/26/1999 12:37:07 page -157- WO 98/38177 PCT/US98/03373 - 156 - Fourth Transesterification Technique The ester to be transesterified was dissolved in a large excess of the alcohol and 0.3 equivalents of titanium(IV) isopropoxide (Aldrich) was added. The reaction was followed by tic until complete and then the volatiles were 5 removed at reduced pressure. The resulting crude material was then chromatographed to obtain the desired product. GENERAL PROCEDURE AR Synthesis of N-BOC Anilines 10 To a solution of the aniline in THF was added dropwise 1 equivalent of di-/er/-butyl dicarbonate (Aldrich) in THF and then 1.5 equivalents of ION aqueous sodium hydroxide at 0°C. After stirring at room temperature for 16 hours, or heating at 80°C for 3 hours, if needed, the reaction mixture was diluted with ether and washed with NaHCOj, brine, dried over sodium sulfate 15 and potassium carbonate, concentrated at reduced pressure and chromatographed to afford the Af-BOC aniline. GENERAL PROCEDURE AS Oxime Ester Formation 20 The trichlorophenyl ester (1 eq.) was stirred in DMF or THF. The oxime (1.2 eq.) was added and the mixture was stirred at ambient temperature for 1 to 4 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography and/or crystallization. 25 Example AA Synthesis of D,L-alanine uo-butyl ester hydrochloride A mixture of 35.64 g (0.4 mol) of D,L-alanine (Aldrich), 44 mL (0 6 mol) of thionyl chloride (Aldrich) and 200 mL of wo-butanol was refluxed for 1.5 hours. The volatiles were removed at reduced pressure at 90°C under 30 reduced pressure to give the title compound as an oil, which was used without further purification. Printed from Mimosa 07/26/1999 12:37:07 page -158- WO 98/38177 PCT/US98/03373 - 157 -- NMR data was as follows* 'H-nmr (CDC1,)" 8 = 8.72 (br s, 3H), 4 27 (q, J = 7.4 Hz, IH), 3.95 (m, 2H), 1.96 (s; IH), 1.73 (d, J = 7 2 Hz, 3H), 0.92 (d, J = 6.7 Hz, 6H). ,3C-nmr (CDC13): 8 = 170.0, 72.2, 49.2, 27.5, 18.9, 16.1. 5 Example AB Synthesis of N-(3,4-dichlorophenyl)alanine Using the procedure set forth in U.S. Patent No. 3,598,859, the disclosure of which is incorporated herein by reference in its entirety, N-(3,4-10 dichlorophenyl)alanine was prepared Specifically, to a solution of 3,4- dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about 500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mL per mL of isopropanol) and 2-chloropropionic acid (2 equivalents) (Aldrich) This mixture is warmed to 40°C and sodium bicarbonate (0.25 equivalents) is added in successive portions 15 before heating under reflux for 4-5 days. After cooling, the reaction mixture is poured into water and the unreacted 3,4-dichloroanilme is removed by filtration. The filtrate is acidified to pH 3-4 with concentrated hydrochloric acid and the resultant precipitate is filtered, washed and dried to yield the title compound, m.p = 148-149°C. 20 Alternatively, following General Procedure AF above and using N-(3,4-dichlorophenyl)alamne ethyl ester (from Example Al below), the title compound was prepared. 25 Example AC Synthesis of N-(3,5-difluorophenyl)aIanine Using the procedure set forth in U.S. Patent No. 3,598,859, N-(3,5-difluorophenyl)alanine was prepared using 3,5-difluoroanihne (Aldrich) and 2-chloropropionic acid (Aldrich) 30 Example AD Printed from Mimosa 07/26/1999 12:37:07 page -159- WO 98/38177 PCT/US98/03373 - 158 - Synthesis of Zso-butyl 2-bromopropionate To a mixture of /.vo-butanol and 1.0 equivalent of pyridine in dry diethyl ether was added dropwise 1 3 equivalents of 2-bromopropionyl bromide at 0°C After stirring at room temperature for 16 hours, the reaction was diluted with 5 diethyl ether, washed with IN HCl, water, aqueous NaHC03, brine and dried over magnesium sulfate or sodium sulfate. Removal of the solvents at reduced pressure gave the title compound as a clear oil. Example AE 10 Synthesis of N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester N-(2-Naphthyl)alanine methyl ester (5 0 g, 20 6 mmol) (from Example A44 below) was dissolved in dioxane (100 mL). NaOH (30 mL, IN) was added and the resulting solution was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. The resulting solid was dissolved in water 15 and the aqueous mixture was washed with ether. The aqueous portion was adjusted to pH 3 with IN HCl and extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate or sodium sulfate and concentrated under reduced pressure to yield a white solid (4.35 g, 98%) 20 The resulting solid (4.35 g, 20 mmol) was dissolved in dichloromethane (300 mL). 2,4,5-Trichlorophenol (4 9 g, 25 mmol) (Aldrich) was added followed by dicyclohexylcarbodiimide (25 mL, 1M in dichloromethane) (Aldrich) After stirring for 18 hours, the mixture was filtered and concentrated to provide an oil which was purified by chromatography on silica gel using 25 chloroform as the eluant (Rf = 0.6). The title compound was obtained as a thick oil which slowly crystallized Example Al Synthesis of N-(3,4-dichlorophenyl)alanine ethyl ester 30 Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared as an Printed from Mimosa 07/26/1999 12:37:07 page -160- WO 98/38177 PCT/US98/03373 - 159 - oil. The reaction was monitored by tic on silica gel (Rf = 0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant) NMR data was as follows: 5 'H-nmr (CDC13): 6 = 7 2 (d, IH), 6.7 (d, IH,); 6 4 (dd. IH); 4.30 (bs, IH); 4.2 (q, 2H); 4.1 (q, IH); 1.5 (d, 3H), 1.3 (t, 3H) l3C-nmr (CDC13): 5 = 175, 146.7; 133, 131; 121; 114 9; 112.6; 72.0; 52.4; 28.3; 19.5 CMH13C12N02 (MW = 262.14). 10 Example A2 Synthesis of N-(3-trifluoromethyl-4-chlorophenyl)alanine ethyl ester Following General Procedure AA above and using 4-chloro-3-(trifluoromethyl)aniline (Aldrich) and ethyl pyruvate (Aldrich), the title 15 compound was prepared. Analysis: Calc.: C, 48.74; H, 4.43; N, 4 74 Found: C, 48.48; H, 4.54; N, 4.94 C12H13F3C1N02 (MW = 295.69); mass spectroscopy (MH+) 295. 20 Example A3 Synthesis of N-(3,5-dichlorophenyI)alanine ethyl ester Following General Procedure AA above and using 3,5-dichloroanihne (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared. Analysis: Calc.: C, 50.40; H, 5.00; N, 5.34. Found. C, 50.50; H, 5.06, 25 N, 5.25. CnH13Cl2N02 (MW = 262.14); mass spectroscopy (MH+) NA. Example A4 Synthesis of N-(3,4-difluorophenyl)alanine ethyl ester 30 Following General Procedure AA above and using 3,4-difluoroanihne (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared. The Printed from Mimosa 07/26/1999 12:37:07 page -161- WO 98/38177 PCT/US98/03373 - 160 - reaction was monitored by tic on silica gel (Rf = 0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant) NMR data was as follows: 5 'H-nmr (CDC13): 5 = 7.4 (m, IH), 6.8 (d, IH), 6.5 (m, IH), 4.30 (bs, IH), 4 2 (q, 2H), 4.1 (q, IH), 1.5 (d, 3H), 1.3 (t, 3H). l3C-nmr (CDC13): 8 = 175, 146.7, 135, 132, 125, 116, 113, 72, 52, 28, 19. C,,H]3F2N02 (MW = 229.23); mass spectroscopy (MH") 230 10 Example A5 Synthesis of N-(3,4-dichlorophenyl)alanine benzyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and benzyl pyruvate (prepared by following General Procedure AO 15 above using benzyl alcohol in place of /so-butanol), the title compound was prepared as an oil The reaction was monitored by tic on silica gel (Rf = 0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant) NMR data was as follows-20 'H-nmr (CDC1,)- 8 = 7.18 (d, IH); 7 0 (m, 5H); 6 6 (d, IH,); 6.4 (dd, IH); 5.1 (s, 2H); 4.30 (bs, IH), 4.08 (q, IH), 1.94 (m, IH); 1.47 (d, 3H); 0.91 (d, 6H). ,3C-nmr (CDC13): 8 = 174.5; 146.7; 133.5; 131.3; 121.3; 120.1, 114.9; 113.6; 72.0; 60.1, 52.4; 28.3, 19.5; 19.3. 25 C16H15C12N02 (MW = 324.31); mass spectroscopy (MH+) 325. Example A6 Synthesis of N-(3,4-dichlorophenyl)alanine ivo-butyl ester Following General Procedure AA above and using 3,4-dichloroaniline 30 (Aldrich) and jjo-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored Printed from Mimosa 07/26/1999 12:37:07 page -162- WO 98/38177 PCT/US98/03373 - 161 - by tic on silica gel (Rf = 0 55 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). NMR data was as follows: 5 'H-nmr (CDC13): 8 = 7 18 (d, IH, J=8 7 Hz), 6.66 (d, IH, J=2.7 Hz), 6 43 (dd, IH, J = 8 7 Hz, J = 2.7 Hz), 4.30 (bs, IH), 4.08 (q, IH, J = 6.9 Hz), 1.94 (sept, IH, J = 6.7 Hz), 1.47 (d, 3H, J = 6.9 Hz), 0.91 (d, 6H, J = 6.6 Hz). l3C-nmr (CDC13) 8 = 174.5, 146 7, 133.5, 131.3, 121 3, 114.9, 113.6, 10 72.0, 52.4, 28.3, 19.5, 19.3 CI3H!7C1,N02 (MW = 290.19); mass spectroscopy (MH~) 290 Example A7 Synthesis of N-(3,4-dichlorophenyl)alanine wo-propyl ester 15 Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and isopropyl pyruvate (prepared by following General Procedure AO above using isopropanol in place of wo-butanol), the title compound was prepared as an oil The reaction was monitored by tic on silica gel (Rf = 0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography 20 (silica gel using 25% EtOAc/hexanes as the eluant). NMR data was as follows 'H-nmr (CDC1,): 8 = 7 18 (d, IH), 6.66 (d, IH,); 6.43 (dd, IH); 4.30 (bs, IH); 4.08 (m, IH); 1.94 (m, IH); 1 47 (d, 3H); 0.91 (d, 6H) ,3C-nmr (CDC13). 8 = 174.5; 146.7; 133.5; 131.3; 121.3; 114.9, 113.6; 25 72 0; 52.4; 19.5. C,2Hi5C12N02 (MW = 276.16); mass spectroscopy (MH) 277 Example A8 Synthesis of N-(3,4-dichlorophenyl)alanine n-butyl ester 30 Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and rc-butyl pyruvate (prepared by following General Procedure AO Printed from Mimosa 07/26/1999 12:37:07 page -163- WO 98/38177 PCT/US98/03373 -- 162 -- above using «-butanol in place of wo-butanol), the title compound was prepared. The reaction was monitored by tic on silica gel (Rf = 0.7 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant) 5 NMR data was as follows. 'H-nmr (CDC1,): 5 = 7.18 (d, IH); 6.66 (d, IH,); 6.43 (dd, IH), 4.30 (bs, IH); 4.2 (m, 2H); 4 08 (q, IH), 1.94 (m, IH); 1.47 (m, 4H); 0.91 (t, 3H). ,3C-nmr (CDClj): 6 = 174.5; 146 7; 133 5, 131 3; 121.3, 114 9, 113.6; 72.0, 52 4; 28.3; 20.2; 19.5. 10 CI3HI7C12N02 (MW = 290.19); mass spectroscopy (MH+) 291 Example A9 15 Synthesis of N-(3,4-dichlorophenyl)alanine methyl ester (R,S isomers) Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf = 0.55 in 25% 20 EtOAc/hexanes) and purification was by flash chromatography (silica gel using 25% EtOAc/hexanes as the eluant) NMR data was as follows- 'H-nmr (CDC13). S = 7.19 (d, J = 8 73 Hz, IH), 6.66 (d, J = 2.75 Hz, IH), 6.43 (dd, J = 8.73 Hz, 2.80 Hz, IH), 4.25 (bd, J = 8.25 Hz, IH), 4.08 (m, 25 IH), 3.76 (s, 3H), 1.47 (d, J = 6.90 Hz) 13C-nmr (CDC13) 5 = 174.35, 145.96, 132.87, 130.70, 120.76, 114.38, 112.90, 52.43, 51 70, 18.67. C10HnCl2NO2 (MW = 248.11); mass spectroscopy (MH+) 247. 30 Example A10 Synthesis of N-(3,4-dichlorophenyl)alanine cyclopentyl ester Following transesterification General Procedure AB above and using N-35 (3,4-dichlorophenyl)aianine methyl ester (from Example A9 above) and Printed from Mimosa 07/26/1999 12:37:07 page -164- WO 98/38177 PCT/U S98/03373 -- 163 -- cyclopentanol (Aldrich), the title compound was prepared as an oil The reaction was monitored by silica gel tic (Rf = 0.66 in 25% EtOAc/hexanes) Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). 5 NMR data was as follows 'H-nmr (CDC13): 5 = 7.19 (d, IH, J = 8.7 Hz), 6.66 (d, IH, J = 2 7 Hz), 6.43 (dd, IH, J = 8.7 Hz, J = 2 7 Hz), 5.22 (m, IH), 4.27 (d, IH, J = 8.1 Hz), 4.02 (quint, IH, J = 7.5 Hz), 1.74 (m, 8H), 1.43 (d, 3H, J = 6.9 Hz). 10 13C-nmr (CDC13): 5 = 174.3, 146 7, 133.4, 131 2, 121.2, 114.9, 113.7, 78.9, 52.5, 33.2, 24.2, 24.1, 19.1 C|4H)7C12N02 (MW = 302 20); mass spectroscopy (MHT) 301. Example Al 1 15 Synthesis of N-(3,4-dichlorophenyI)alanine /t-propyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and ^-propyl pyruvate (prepared by following General Procedure AO above using n-propanol in place of wo-butanol), the title compound was prepared as an oil The reaction was monitored by tic on silica gel (Rf = 0.5 in 20 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). NMR data was as follows: 'H-nmr (CDC1,): 8 = 7.2 (d, IH), 6.6 (d, IH); 6.4 (dd, IH); 4.30 (bs, IH); 4.2 (q, 2H); 4.08 (q, IH), 1.94 (m, 2H), 1.5 (d, 3H); 0.95 (t, 3H). 25 13C-nmr (CDC13): 8 = 178; 144.7; 130.2; 120.62; 115.11, 71.82; 52.90. C|2H15C12N02 (MW = 276.16); mass spectroscopy (MHT) 277 Example A12 30 Synthesis of N-(3,4-dichlorophenyl)alanine ally! ester Printed from Mimosa 07/26/1999 12:37:07 page -165- WO 98/38177 PCT/US98/03373 - 164 - Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and allyl alcohol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf = 0.62 in 25% EtOAc/hexanes)." Purification was 5 by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). NMR data was as follows: 'H-nmr (CDC13): 5 = 7.19 (d, IH, J = 8.7 Hz), 6.67 (d, IH, J = 2 8 Hz), 6.44 (dd, IH, J = 8.7 Hz, J=2.8 Hz), 5 90 (m, IH), 5.30 (m, 2H), 4.64 (m, 2H), 10 4 26 (m, IH, 4.10 (m, IH), 1.48 (d, 3H, J = 6.9 Hz). ,3C-nmr (CDClj): 5 = 174.1, 146.6, 133 5, 132.1, 131.3, 121 4, 119 6, 115.0, 113.6, 66 5, 52 4, 19.3. C12H,3C12N02 (MW = 274.15); mass spectroscopy (MH+) 273. 15 Example A13 Synthesis of N-(3,4-dichlorophenyl)alanine 4-methylpentyl ester Following transesterification General Procedure AB above and using N-20 (3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and 4-methylpentanol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf = 0.70 in 25% EtOAc/hexanes) Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). 25 NMR data was as follows: 'H-nmr (CDC13). 5 = 7.18 (d, IH, J = 8.7 Hz), 6.66 (d, IH, J = 2.7 Hz), 6.43 (dd, IH, J = 8.7 Hz, J = 2 7 Hz), 4.28 (m, IH), 4.10 (m, 3H), 1.55 (m, 6H), 1 19 (m, 2H), 0.87 (d, 3H, J = 6.6 Hz). 13C-nmr (CDC13): 8 = 174.6, 146.7, 133.4, 131.3, 121.3, 115.0, 113.6, 30 66.4, 52.4, 35.4, 28.2, 27.0, 23.0, 19 3. C]5H21C12N02 (MW = 318.25); mass spectroscopy (MH+) 317. Example A14 Printed from Mimosa 07/26/1999 12:37:07 page -166- WO 98/38177 PCT/US98/03373 -- 165 -- Synthesis of N-(3,4-dichlorophenyl)aIanine 2,2-dimethyl-l,3-dioxolane-4- methyl ester Following transesterification General Procedure AB above and using N-5 (3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and 2,2- dimethyl-l,3-dioxolane-4-methanol (solketal) (Aldrich), the title compound was prepared as a mixture of diastereomers The reaction was monitored by silica gel tic (Rf = 0.32 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). 10 NMR data was as follows 'H-nmr (CDC13): 5 = 7.19 (d, IH, J = 8.7 Hz), 6.66 (d, IH, 2 7 Hz), 6.43 (dd, IH, J = 8.7 Hz, J = 2.7 Hz), 4.22 (m, 6H), 3.70 (m, IH), 1.43 (m, 9H). l3C-nmr (CDC13): 8 = 174.34. 174 32, 146.5, 133.5, 131.3, 121.5, 115.0, 15 113 6, 110.52, 110 51, 73.97, 73.89, 66.6, 66.01, 65.95, 52.42, 52.37, 27.3, 25.8, 19.3 CI5HI9C12N04 (MW = 348.23), mass spectroscopy (MH+) 347. Example A15 20 Synthesis of N-(3,4-dichlorophenyl)alanine cyclohexylmethyl ester Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alamne methyl ester (from Example A9 above) and cyclohexylmethanol (Aldrich), the title compound was prepared NMR data was as follows: 25 'H-nmr (CDC1,): 8 = 7.19 (d, IH), 6.68 (d, IH), 6.45 (dd, IH), 4.26 (bd, IH), 4 10 (m, IH), 3.95 (d, 2H), 1.70-1.55 (m, 6H), 1.50 (d, 3H), 1.35-0.85 (m, 5H). l3C-nmr (CDC13): 8 = 174.58, 146.72, 133.48, 131.27, 121.34, 114 98, 113.72, 71 06, 52.52, 37.68, 30 10, 26.83, 26 17, 19.32. 30 C15H2iCl2N02 (MW = 318.25), mass spectroscopy (MH+) 317. Example A16 Printed from Mimosa 07/26/1999 12:37:07 page -167- WO 98/38177 - 166 - PCT/US98/03373 Synthesis of N-(3,4-dichlorophenyl)alanine ter/-butyloxycarbonylmethyl ester Following General Procedure AE above and using N-(3,4-5 dichlorophenyl)alanine (from Example AB above) and /erf-butyl bromoacetate (Aldrich), the title compound was prepared as a solid. The reaction was monitored by silica gel tic (Rf = 0 57 in 25% EtOAc/hexanes). Purification was by recrystallization from ethanol. NMR data was as follows: 10 'H-nmr (CDC1,): 8 = 7.19 (d, IH), 6.68 (d, IH), 6.45 (dd, IH), 4.55 (m, 2H), 4 20 (m, 2H), 1.55 (d, 3H), 1 45 (s, 9H) 13C-nmr (CDClj): 8 = 173.9, 166 9, 146.5, 133.5, 131.3, 115.1, 113.6, 83.4, 62 2, 52.2, 28 6, 19.3. C15H,9C12N04 (MW = 348.23); mass spectroscopy (MH+) 347. 15 Example A17 Synthesis of N-(3,4-dichlorophenyl)Ieucine iso-butyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and wo-butyl 4-methyl-2-oxopentanoate (prepared by following 20 General Procedure AO above using 4-methyl-2-oxovaleric acid (Fluka) and wo-butanol), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf = 0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). 25 NMR data was as follows: 'H-nmr (CDC1,). 8 = 7.2 (d, IH), 6 5 (d, IH); 6.4 (dd, IH); 4.30 (bs, IH); 4.08 (q, IH), 3.8(m, 2H); 1.8 (m, 3H); 0.91 (m, 12H). l3C-nmr (CDC13): 8 = 174 5; 146.7; 133 5; 131.3; 121.3; 114.9, 113 6; 72.0; 52, 28.3; 20.1; 19 5. 30 CI6H23C12N02 (MW = 332.27); mass spectroscopy (MH+) 333. Example A18 Printed from Mimosa 07/26/1999 12:37:07 page -168- WO 98/38177 PCT/US98/03373 - 167 - Synthesis of 2-[N-(3,4-dichlorophenyl)amino]pentanoic acid iso-butyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and wo-butyl 2-oxopentanoate (prepared by following General Procedure AO above using 2-oxovaleric acid (Fluka) and wo-butanol), the title 5 compound was prepared as an oil The reaction was monitored by tic on silica gel (Rf = 0.5 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant) NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.2 (d, IH), 6.6 (d, IH); 6 4 (dd, IH); 4.3 (d, IH); 10 3.8 (m, 3H); 1.9 (m, 6H), 1.0 (t, 3H), 0.9 (m, 6H). 13C-nmr (CDC13): 5 = 178; 144.7; 130.2; 120.62, 115.11; 71.82, 52.90, 28.30; 19.53. C^HjiCUNOj (MW = 318 3), mass spectroscopy (MH+) 319. 15 Example A19 Synthesis of N-(4-cyanophenyl)alanine /so-butyl ester Following General Procedure AP above and using 4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared as an oil. The product was recovered 20 by column chromatography on silica gel using 1.5 EtOAc/hexanes as the eluant. NMR data was as follows: 'H-nmr (CDC1,): 8 = 7.44 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 4 74 (d, J = 8.1 Hz, IH), 4.18 (t, J = 7.4 Hz, IH), 3.95 (m, 2H), 1.94 (m, IH), 1.51 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 6.7 Hz, 6H). 25 13C-nmr (CDC13): 8 = 173.4, 149.7, 133.8, 120.1, 112.7, 99.8, 71 6, 51.2, 27.7, 18.9, 18.6 C,4H,8N202 MW = 246.31; mass spectroscopy (MH+) 247. Example A20 30 Synthesis of N-(3-chloro-4-cyanophenyl)alanine /so-butyl ester Printed from Mimosa 07/26/1999 12:37:07 page -169- WO 98/38177 -- 168 -- PCT/US98/03373 Following General Procedure AP above and using 2-chloro-4-fluorobenzonitrile (Aldrich) and D,L-alanine /so-butyl ester hydrochloride (from Example AA above), the title compound was prepared The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as 5 the eluant. NMR data was as follows: 'H-nmr (CDC1,) 6 = 7.40 (d, J = 8.5 Hz, IH), 6.62 (d, J = 2.3 Hz, IH), 6.48 (dd, J = 2.4, 8.6 Hz, IH), 4.90 (d, J = 7.6 Hz, IH), 4.16 (quintet, J = 7.1 Hz, IH), 3.96 (dd, J = 2.2, 6.7 Hz, 2H), 1 97 (m, IH), 1.51 (d, J = 7.0 Hz, 3H), 10 0 93 (d, J = 6.7 Hz, 6H) uC-nmr (CDClj). 5 = 173 0, 150.4, 138.3, 134.9, 117.3, 112 8, 111.3, 100.6, 71.7, 51.1, 27.7, 18.9, 18 4 C]4H,7N202C1 MW = 280.76; mass spectroscopy (MH+) 281. 15 Example A21 Synthesis of N-(3,4-dichloro)aIanine iso-butyl ester (S isomer) Following General Procedure AM above and using 3,4-dichloroaniline 20 (Aldrich) and wo-butyl R-(+)-lactate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf = 0.55 in 25% EtOAc/hexanes). Purification was column chromatography NMR data was as follows 'H-nmr (CDC13): 5 = 7 19 (d, J = 8.73, IH), 6 67 (d, J = 2 75, IH), 6.45 25 (dd, J = 8.73, J = 2.75, IH), 4.28 (bd, J = 8.36, IH), 4.09 (quint, IH), 3.94 (d, J = 6.66, 2H), 1.95 (hept, J = 6.71, IH), 1.49 (d, J = 6.90, 3H), 0.92 (d, J = 6.04, 6H) l3C-nmr (CDC13): 5 = 174.57, 146.67, 133.47, 131.28, 121 29, 114.93, 113 63, 71.01, 52.43, 28.30, 19 55, 19.33 30 C,3H17C12N02 (MW - 290.19); mass spectroscopy (MH+) 290. Example A22 Printed from Mimosa 07/26/1999 12:37:07 page -170- WO 98/38177 PCT/US98/03373 - 169 - Synthesis of N-(3,4-dichloro)aIanine tetrahydrofuran-3-yl-methyl ester Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and 5 tetrahydro-3-furanmethanol (Aldrich), the title compound was prepared as an oil The reaction was monitored by silica gel tic (Rf = 0.33 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant) NMR data was as follows: 10 'H-nmr (CDC1,): S = 7.18 (d, IH, J = 8 7 Hz), 6 65 (d, IH, J = 2.7 Hz), 6.42 (dd, IH, J = 8.7 Hz, J = 2.7 Hz), 4 30 (m, IH), 4 09 (m, 3H), 3.78 (m, 3H), 3.53 (m, IH), 2.56 (m, IH), 1.94 (m, IH), 1.58 (m, IH), 1.46 (d, 3H, J = 6.9 Hz). l3C-nmr (CDC13): 5 = 174.5, 146.6, 133.5, 131.3, 121 4, 114.9, 113.6, 15 70.86, 70 83, 68 2, 67.31, 67.29, 52 4, 38.7, 29.36, 29 33, 19 2 C)4H17C12N03 (MW = 318.20); mass spectroscopy (MH) 318 Example A23 Synthesis of N-(3,5-dichlorophenyl)alanine w-propyl ester 20 Following General Procedure AA above and using 3,5-dichloroaniline (Aldrich) and w-propyl pyruvate (which can be prepared by following General Procedure AO above using «-propanol in place of zso-butanol), the title compound could be prepared. 25 Example A24 Synthesis of 2-[N-(3,4-dichIorophenyl)amino]butanoic acid iso-butyl ester Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and jso-butyl 2-oxobutanoate (prepared by following General Procedure AO above using 2-oxobutyric acid (Aldrich) and wo-butanol), the title 30 compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf = 0.3 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). Printed from Mimosa 07/26/1999 12:37:07 page -171- WO 98/38177 PCT/US98/03373 - 170 - NMR data was as follows: 'H-nmr (CDC1,): 8 = 7.2 (d, IH); 6 6 (d, IH); 6.4 (dd, IH); 4 3 (d, IH); 3.8 (m, 3H);~ 1 9 (m, 3H); 1 0 (t, 3H); 0.9(m, 6H). uC-nmr (CDC13): 5 = 178, 144.7, 130.2; 120.62, 115.11-, 71.82; 52.90; 5 28 30; 20.5; 19.53. C]4H19C12N02 (MW = 304.22); mass spectroscopy (MH+) 305. Example A25 Synthesis of N-(4-chlorophenyl)alanine uo-butyl ester 10 Following General Procedure AA above and using 4-chloroaniline (Aldrich) and wo-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf = 0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the 15 eluant) NMR data was as follows- 'H-nmr (CDC13) 8 = 7.18 (d, 2H), 6.66 (d, 2H), 4 30 (bs, IH), 4.08 (q, IH), 1 94 (sept, IH), 1.47 (d, 3H), 0 91 (d, 6H). l3C-nmr (CDC13): 8 =174 5, 146.7, 133.5, 131.3, 121.3, 114.9, 113.6, 20 72.0,52 4,28.3,19.5,19.3. C|3HI8C1N02 (MW = 255.75); mass spectroscopy (MH+) 256. Example A26 Synthesis of N-(3,5-dichlorophenyl)alanine iso-butyl ester 25 Following General Procedure AA above and using 3,5-dichloroaniline (Aldrich) and wo-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf = 0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the 30 eluant). NMR data was as follows- Printed from Mimosa 07/26/1999 12:37:07 page -172- WO 98/38177 ~ 171 _ PCT/U S98/03373 'H-nmr (CDC1,): 8 = 7.18 (d, 2H), 6.66 (m, IH), 4.30 (bs, IH), 4.08 (q, IH), 1.94 (m, IH), 1.47 (d, 3H). 0.91 (d, 6H) ,3C-nfnr (CDC13): 8 = 175; 146.7, 133, 131; 121; 114.9; 112 6; 72.0; 52.4; 28.3; 19.5. 5 C13H17C12N02 (MW = 290.2); mass spectroscopy (MH") 291. Example A27 Synthesis of N-(4-ethylphenyl)alanine methyl ester A solution of 0.68 g (5 mmol) of 4'-aminoacetophenone (Aldrich), 0.60 10 mL of 90% methyl pyruvate (Aldrich) and 0.05 g (0.25 mmol) of p- toluenesulfonic acid in ethanol was hydrogenated in the presence of a catalytic amount of 10% Pd/C at from 30 to 15 psi of hydrogen for 16 hours The catalyst was removed by filtering the reaction mixture through Celite and the solvent was evaporated to provide the crude product The product was purified 15 by column chromatography (silica gel using 1.9 EtOAc/hexanes as the eluant) to provide the title compound NMR data was as follows: 'H-nmr (CDC1,): 8 = 1 19 (t, J = 7.6 Hz, 3H), 1 47 (d, J = 6.8 Hz, 3H), 2.54 (q, J = 7 6 Hz, 2H), 3.74 (s, 3H), 4.04 (bs, IH), 4 13 (m, IH), 6.57 (d, J = 20 8.5 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H). 13C-nmr (CDC13)- 8 = 15.8, 18.0, 27 9, 52.17, 52 19, 113 5, 128.6, 134.1, 144.4, 175 3 C)2H]7N02 MW = 207.27; mass spectroscopy (MH+) 208. 25 Example A28 Synthesis of N-(4-(l-ethoxy)ethylphenyl)alanine methyl ester Following the procedure for Example A27 above, the title compound was isolated as another reaction product by column chromatography (silica gel using 1:9 EtOAc/hexanes as the eluant). 30 NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -173- WO 98/38177 - 172 - PCT/US98/03373 'H-nmr (CDC1,): 8 = 1.15 (t, J = 7 0 Hz, 3H), 1.40 (d, J = 6.5 Hz, 3H), 1 47 (d, J = 6.1 Hz, 3H), 3.31 (q, J = 5.1 Hz, 2H), 3.74 (s, 3H), 4.14 (m, 2H), 4.29 (q, J = 6.4 Hz, IH), 6.57 (d, J = 8.5 Hz, 2H), 7 12 (d, J = 8 4 Hz, 2H). '3C-nmr (CDC13): 8 = 15.4, 19.0, 23.9, 51.9, 52.2, 63.4. 77.3, 113.1, 5 127.3, 133.6, 145.8, 175.1. Ci4H21N03 MW = 251 33; mass spectroscopy (MH+) 251. Example A29 Synthesis of N-(3,4-dichloro)alanine 2,2-dimethylpropyl ester 10 (R,S isomers) Following transesterification General Procedure AQ above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and neopentyl alcohol (Aldrich), the title compound was prepared. The reaction was 15 monitored by silica gel tic (Rf = 0 72 in 25% EtOAc/hexanes). Purification was by flash chromatography (silica gel using 25% EtOAc/hexanes as the eluant). NMR data was as follows 'H-nmr (CDC1,): 8 = 7 19 (d, IH, J = 8 7 Hz), 6 68 (d, IH, J = 2 7 Hz), 6.45 (dd, IH, J = 8.7 Hz, J = 2.7 Hz), 4 29 (m, IH), 4 11 (m, IH), 3.85 (m, 20 2H), 1.49 (d, 3H, J = 6 9 Hz), 0.93 (s, 9H) 13C-nmr (CDC13): 8 = 174 6, 146.7, 133 5, 131.3, 121.3, 114.9, 113.7, 75.2, 52.4, 32.0, 26.9, 19.4. C14H19C12N02 (MW = 304.22); mass spectroscopy (MH") 303. 25 Example A30 Synthesis of N-(3,4-dichlorophenyl)glycine iso-butyl ester 3,4-Dichloroaniline (Aldrich) was treated with di-?er/-butyl dicarbonate (Aldrich) using conventional procedures to produce the N-BOC aniline. The N-BOC aniline was treated with sodium hydride in THF and then with wo-butyl 2-30 bromoacetate (from Example AD above) to produce the N-BOC N-(3,4- dichlorophenyl)glycine Ko-butyl ester The BOC group was then removed using General Procedure AN above to afford the title compound. The reaction was Printed from Mimosa 07/26/1999 12:37:07 page -174- WO 98/38177 PCMJS98/03373 -- 173 - monitored by tic on silica gel (Rf = 0.78 in 50% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 50% EtOAc/hexahes as the eluant). NMR data was as follows: 5 'H-nmr (CDC13): 6 = 7.19 (dd, J=4.1, 4 7, 3.4, IH); 6.65 (d, J=2 7, IH); 6 44 (dd, J=2.7, 4.5, 4.2, IH): 4.4 (m, IH): 3.97 (dd, J=3.6, 3.0, 2.3, 2H); 3.87 (s, 2H); 1.9 (m, IH); 0.93 (d, J=6.7, 6H). l3C-nmr (CDC13): 5 = 171.2, 147.0, 133 5, 131 3, 121.2, 114.5, 113.3, 72.2, 46.0, 28.2, 19.6. 10 C|2H,5C12N02 (MW = 276); mass spectroscopy (MH+) 277. Example A31 Synthesis of N-(3,4-dichlorophenyl)alanine 2-ethylbutyl ester Following General Procedure AA above and using 3,4-dichloroaniline 15 (Aldrich) and 2-ethylbutyl pyruvate (prepared by following General Procedure AO above using 2-ethylbutanol (Aldrich) in place of /.vo-butanol), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf = 0.6 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). 20 NMR data was as follows' 'H-nmr (CDC13): 8 = 7.2 (d, IH); 6.6 (d, IH), 6.4 (dd, IH); 4.2 (t, 2H), 4.1 (q, IH); 1.5 (d, 3H), 1 4 (m, 4H), 1 0 (m, 6H) ,3C-nmr (CDC13): 8 = 178, 144 7, 130.2; 120.62; 115.11; 70.7; 51.90; 26.3; 19.53, 18.5. 25 C1SH2IC12N02 (MW = 318.25); mass spectroscopy (MH+) 319. Example A32 Synthesis of N-(3-chloro-4-iodophenyl)alanine iso-butyl ester Following General Procedure AR above and using 3-chloro-4-iodoaniline 30 (Aldrich), Af-BOC-3-chloro-4-iodoaniline was prepared To a stirred slurry of 5.0 equivalents of sodium hydride in DMF was added 1.0 equivalent of N-BOC- Printed from Mimosa 07/26/1999 12:37:07 page -175- WO 98/38177 PCT/US98/03373 - 174 -- 3-chloro-4-iodoanihne and then 1 1 equivalents of M'o-butyl 2-bromopropionate (from Example AD above) were slowly added The reaction was heated to 100°C for 10 hours, cooled, diluted with dichloromethane and washed with cold IN HCl, water and brine. The solvents were removed at reduced pressure and 5 the residue was chromatographed to provide #-BOC-7V-(3-chloro-4- iodophenyl)alanine /so-butyl ester as a clear oil. Following General Procedure AN above, the BOC group was removed from vV-BOC-jV-(3-chloro-4-iodophenyl)alanine wo-butyl ester to provide the title compound. The BOC-removal reaction was monitored by tic on silica gel (Rf = 0.58 in 30% 10 EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 30% EtOAc/hexanes as the eluant). The compound was further purified by chromatography on an HPLC chiral column (Chiralcel OD) NMR data was as follows: "H-nmr (CDC13). 8 = 7.52 (d, J=8.7, IH); 6.72 ( d, J=2.7, IH); 6.25 (dd, 15 J=2.7, 5.9, 2 7, IH), 4 35 (d, J=6 6, IH): 4.08 (quintex, J=7.2, 6 7, IH); 3 93 (d, J=6.7, 2H): 1.94 (m, IH); 1.47 (d, J=6.9, 3H), 0.92 (d, J=6.9, 6H). l3C-nmr (CDC1S). 8 = 174.5, 148.3, 140.7, 139 5, 114.4, 114.3, 82.6, 72.0, 52.2, 28.3, 19.6, 19.3. C13H17C1IN02 (MW = 381.5); mass spectroscopy (MH+) 382. 20 Example A3 3 Synthesis of N-(4-azidophenyl)alanine /so-butyl ester Following General Procedure AA above and using 4-azidoaniline (Aldrich) and /so-butyl pyruvate (prepared by following General Procedure AO 25 above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf = 0.3 m 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). NMR data was as follows: 30 'H-nmr (CDC13): 8 = 7.3 (d, 2H), 6.8 (d, 2H), 4.30 (bs, IH), 4.08 (q, IH), 1.94 (sept, IH), 1.47 (d, 3H), 0.91 (d, 6H). Printed from Mimosa 07/26/1999 12:37:07 page -176- WO 98/38177 PCT/US98/03373 - 175 -- l3C-nxnr (CDC13): 8 = 174.5, 148.7, 131 5, 130.3, 121.3, 114.-9, 113.6, 72.0, 52 4, 28.3, 19 5, 19.3 C13Hf8N402 (MW = 262.31); mass spectroscopy (MH+) 263 5 Example A34 Synthesis of N-[(4-phenylcarbonyl)phenyl]alanine iso-butyl ester Following General Procedure AA above and using 4'-aminobenzophenone (Aldrich) and /so-butyl pyruvate (prepared by following 10 General Procedure AO above), the title compound was prepared as an oil The reaction was monitored by tic on silica gel (Rf = 0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant). NMR data was as follows: 15 'H-nmr (CDC1,). 8 = 7.7 (d, 2H), 7.1 (m, 5H), 6.9 (d, 2H), 4.30 (bs, IH), 4.08 (q, IH), 1 94 (sept, IH), 1 47 (d, 3H), 0.91 (d, 6H). 13C-nmr (CDC13). 5 = 199, 178.5, 149.7, 131.5, 130.3, 126, 121.3, 114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3. C20H23NO3 (MW = 325 41); mass spectroscopy (MH+) 326 20 Example A3 5 Synthesis of N-(3,5-difluorophenyl)alanine /so-butyl ester Following General Procedure AH above and using N-(3,5-difluorophenyl)alanine (from Example AC above) and iso-butanol, the title 25 compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf = 0.9 in 3% methanol/methylene chloride) and purification was by preparative plate chromatography (silica gel using 3% methanol/methylene chloride as the eluant). NMR data was as follows: 30 'H-nmr (CDC1,): 8 = 6.1 (m, 3H), 4.5 (bs, IH), 4.1 (d, IH), 3.95 (m, 2H), 2.0 (m, IH), 1.5 (d, J = 7 Hz, 3H), 0.95(d, J = 6 Hz, 6H). Printed from Mimosa 07/26/1999 12:37:07 page -177- WO 98/38177 PCT/US98/03373 - 176 - l3C-nmr (CDC13): 5 = 174.44, 166.40, 166.19, 163.16, 162 9-5, 149.43, 96.73, 96 60, 96.48, 96.35, 94.06, 93.72, 93.37, 72.03, 52.30, 28 29, 19.47, 19.23. C,3H17F2N02 (MW = 290.2); mass spectroscopy (MH+) 291. 5 Example A36 Synthesis of N-(3,4-dichlorophenyl)alanine O-acylacetamidoxime ester Following General Procedure AK above and using N-(3,4-dichlorophenyl)alamne (from Example AB above) and acetamide oxime 10 (prepared according to the procedures described in J Org Chem , 46, 3953 (1981)), the title compound was prepared as a semisolid The reaction was monitored by tic on silica gel (Rf = 0.4 in ethyl acetate) and purification was by preparative plate chromatography (silica gel using ethyl acetate as the eluant). NMR data was as follows. 15 'H-nmr (dmso-J6): 8 = 7 27 (d, IH), 6.81 (s, IH) 6 4 (broad s, 2H), 6.62 (d, IH), 6.45 (d, IH), 4.22 (m, IH), 1.74 (s, 3H), 1.40 (d, 3H). CnH,3Cl2N302 (MW = 290.15), mass spectroscopy (MH") 291. Example A3 7 20 Synthesis of N-(3,4-dichlorophenyl)alanine pyrrolyl amide Following General Procedure AL above and using N-(3,4-dichlorophenyl)alanine (from Example AB above) and pyrrole (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf = 0.28 in 10% ethyl acetate/hexanes) and purification was by preparative 25 plate chromatography (silica gel using 10% ethyl acetate/hexanes as the eluant). NMR data was as follows 'H-nmr (CDCl,): 8 = 7.36 (d, J=2.2, 2H); 7.20 (d, J=8.7, IH); 6.71 (d, J=2.7, IH); 6.5 (m, IH); 6.38 (t, J=2.4, 2H); 4.8 (m, IH); 4.57 (d, J=8.7, IH); 30 1.59 (d, J=6.8, 3H). Printed from Mimosa 07/26/1999 12:37:07 page -178- WO 98/38,177 PCT/US98/03373 ~ 177 - ,3C-nmr (CDCI3): 8 = 171.9, 146.1, 133.6, 131.5, 121.9, 119:6, 115.4, 114 7, 113.8, 51.8, 20 2. C]3H12C12N20 (MW = 283); mass spectroscopy (MH+) 284. 5 Example A3 8 Synthesis of N-(3,4-dichlorophenyl)alanine O-acylbutyramidoxime ester Following General Procedure Al above and using N-(3,4-dichlorophenyl)alanine 2,4,6-trichlorophenyl ester (prepared from N-(3,4-10 dichlorophenyl)alanine methyl ester (from Example A9) using essentially the same procedure as described in Example AE above) and butyramide oxime (prepared according to the procedures described in J Org Chem , 46, 3953 (1981)), the title compound was prepared as a semisolid. The reaction was monitored by tic on silica gel (Rf = 0.25 in 50% ethyl acetate/hexanes) and 15 purification was by preparative plate chromatography (silica gel using 50% ethyl acetate/hexanes as the eluant). NMR data was as follows: 'H-nmr (4,-DMSO): 8 = 7.27 (d, IH), 6 83 (s. IH) 6.38 (broad s, 2H), 6.61 (d, IH), 6.46 (d, IH), 4 25 (m, IH), 2.02 (t, 2H), 1.55 (m, 2H), 1 40 (d, 20 3H), 0.88 (t, 3H). C13H17C12N302 (MW = 318.20); mass spectroscopy (MH+) 319. Example A39 Synthesis of 2-[N-(naphth-2-y])amino]butanoic acid ethyl ester 25 Following General Procedure AJ above and using 2-aminonaphthalene (Aldrich) and ethyl 2-bromobutyrate (Aldrich), the title compound was prepared as a solid, m.p. 81-83°C. The reaction was monitored by silica gel tic (Rf =05 in CHClj). Purification was by chromatography (silica gel using chloroform as the eluant). 30 NMR data was as follows: 'H-nmr (d6-DMSO) 8 = 7.63 (m, 2H), 7.54 (d, IH), 7.3l(t, IH), 7.12 (t, IH), 7 03 (d, IH), 6.62 (s, IH), 6 32 (d, IH), 4.15 (m, 3H), 1.42 (d, 3H), 1.19 (t, 3H). Printed from Mimosa 07/26/1999 12:37:07 page -179- WO 98/38J 77 PCT/US98/03373 - 178 -- C16Hl9N02 (MW = 257 34); mass spectroscopy (MH+) 258. - Example A40 Synthesis of N-(2-naphthyl)alanine /so-butyl ester 5 Following General Procedure AA above and using 2-aminonaphthalene (Aldrich) and wo-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared as an oil. Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant) 10 NMR data was as follows- 'H-nmr (CDC1,): 8 = 7.65 (m, 3H), 7.38 (t, IH, J = 6.9 Hz), 7.23 (t, IH, J = 6.9 Hz), 6 93 (m, IH), 6 81 (d, IH, J = 2 3 Hz), 4 31 (q, IH, J = 6.9 Hz), 3.95 J = 6.7 Hz, J = 1.6 Hz), 1.96 (sept, IH, J = 6.7 Hz), 1.57 (d, 3H, J = 6.9 Hz), 0.93 (dd, 6H, J = 6.7 Hz, J = 1.6 Hz). 15 l3C-nmr (CDC13) 8 = 174.6, 144.2, 134.9, 129.1, 127.8, 127.6, 126.3, 126.0, 122.3, 118.1, 105 3, 71.2, 52.0, 27.7, 18.9, 18.8 Example A41 20 Synthesis of N-(2-methylquinolin-6-yl)alanine iso-butyl ester Following General Procedure AA above and using 6-ammo-2-methylquinoline (Lancaster) and wo-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared. The reaction 25 was monitored by silica gel tic (Rf = 0.44 in 50% EtOAc/hexanes) Purification was by flash chromatography (silica gel using 50% EtOAc/hexanes as the eluant). NMR data was as follows. 'H-nmr (CDC1,)- 8 = 7.90 (m, 2H), 7.10 (m, 2H), 6.66 (d, IH, J = 2.6), 30 4 50 (bd, IH), 4 24 (m, IH), 3.91 (d, 2H, J = 6.6 Hz), 2 64 (s, 3H), 1 91 (sept, IH, J = 6 7 Hz), 1 52 (d, 3H, J = 6 9 Hz), 0 87 (d, 6H, J = 6.7 Hz). !3C-nmr (CDC13) 8 = 175.0, 155.4, 144 6, 143.4, 134.9, 130.2, 128.4, 122.8, 121.8, 104.9, 71.8, 52.7, 28.3, 25.4, 19.5, 19.4. Printed from Mimosa 07/26/1999 12:37:07 page -180- WO 98/38177 PCT/US98/03373 - 179 „ C,7H22C12N202 (MW = 286.38); mass spectroscopy (MH+) 287. Example A42 Synthesis of N-(3,4-methylenedioxyphenyl)alanine /so-butyl ester 5 Following reductive amination General Procedure AA above and using 3,4-methylenedioxyamline (Aldrich) and methyl pyruvate (Aldrich), N-(3,4-methylenedioxyphenyl)alanme methyl ester was prepared. The methyl ester was then transesterified following General Procedure AQ above and using iso-10 butanol to provide the title compound as an oil. The reaction was monitored by silica gel tic (Rf = 0.61 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography with silica gel using 25% EtOAc/hexanes as the eluant. NMR data was as follows: 15 'H-nmr (CDC1,): 8 = 6 63 (d, IH, 8.3 Hz), 6.25 (d, IH, J = 2.3 Hz), 6 04 (dd, IH, J = 8.3 Hz, J = 2 3 Hz), 5.83 (s, 2H), 3.96 (m, 4H), 1.92 (sept, IH, J = 6.7 Hz), 1.44 (d, 3H, J = 6.9 Hz), 0.90 (d, 6H, J = 6.6 Hz). 13C-nmr (CDC13): 8 = 175 4, 148 9, 142 9, 140 8, 109.2, 105 8, 101.2, 97.4, 71.6, 53.6, 28.3, 19.6, 19.5. 20 C14H|9N04 (MW = 265.31); mass spectroscopy (MH+) 265. Example A43 Synthesis of N-(3,4-ethylenedioxyphenyl)alanine /so-butyl ester Following reductive amination General Procedure AA above and using 25 l,4-benzodioxa-6-amine (Aldrich) and methyl pyruvate (Aldrich), N-(3,4- ethylenedioxyphenyl)alamne methyl ester was prepared. The methyl ester was then transesterified following General Procedure AQ above using wo-butanol to provide the title compound. Purification was by preparative plate chromatography 30 NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -181- WO 98/38177 PCT/US98/03373 - 180 - 'H-nmr (CDC1,). 8 = 0.91 (d, J = 7Hz, 6H), 1.42 (d, J = 7Hz, 3H), 1.8-2.0 (m, IH), 3.8-3.95 (m, 3H), 4 0-4.1 (m, IH), 4.15-4.25 (m, 4H), 6.12-6 2 (m, 2H), 6.65-6.75 (m, IH). ,3C-nmr (CDC13): 8 = 19.55, 19.56, 19.67, 28.3, 53.4, 64.7, 65.3, 71.7, 5 103.1, 108.0, 118.3, 142.1, 144.6, 175.4. Ci5H2,N04 (MW = 279.34); mass spectroscopy (MH+) 280. 10 Example A44 Synthesis of N-(2-naphthyl)alanine methyl ester Following reductive amination General Procedure AA above and using 2-aminonaphthalene (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared. The reaction was monitored by silica gel tic (Rf = 0.50 in 25% EtOAc/hexanes). Purification was by flash chromatography with silica gel using 15 25% EtOAc/hexanes as the eluant NMR data was as follows 'H-nmr (CDC13). 8 = 7.65 (m, 3H), 7 48 (m, IH), 7.25 (m, IH), 6.91 (m, IH), 6.79 (m, IH), 4.31 (m, 2H), 3.76 (s, 3H), 1 55 (d, 3H) ,3C-nmr (CDC13): 8 = 175.66, 144.78, 135.55, 129.78, 128.47, 128.22, 20 126 96, 126 67, 123.01, 118.66, 105.88, 52.95, 52.51, 19.45. C14H]5N02 (MW = 229.28); mass spectroscopy (MH+) 229. Example A45 Synthesis of N-(benzothiazol-6-yl)alanine ethyl ester 25 To a solution of 6-aminobenzothiazole (Lancaster) m dichloromethane was added 1.2 equivalents of pyridine, followed by 1.5 equivalents of trifluoroacetic anhydride. The reaction was stirred at room temperature for 3 hours and then washed with 5% citric acid, dried over MgS04, and stripped free 30 of solvent on a rotary evaporator to yield 6-trifluoroacetamidothiazole. This material was dissolved in THF and then added to a suspension of KH in THF at 0°C. A catalytic amount of 18-crown-6 was added, followed by ethyl 2-bromopropionate (Aldrich). The reaction was held at room temperature for 1 Printed from Mimosa 07/26/1999 12:37:07 page -182- WO 98/38177 PCT/US98/03373 -- 181 -- hour, and then heated to reflux for 24 hours, and then cooled to room temperature. The reaction mixture was stripped free of solvent on a rotary evaporator and the resulting residue was dissolved in ether This solution was washed with water, saturated aqueous NaCl, and dried over MgS04 The 5 solution was stripped free of solvent on a rotary evaporator and the title compound was obtained by chromatography of the residue using 5% methanol/dichloromethane (Rf = 0.59) as the eluant. NMR data was as follows 'H-nmr (CDC13)- 8 = 8 69 (s, IH), 7.90 (d, IH, J = 8.8 Hz), 7.04 (d, 10 IH, J = 2.3 Hz), 6.84 (dd, IH, J = 8.8 Hz, J = 2.4 Hz), 4.41 (bd, IH, J = 7.5 Hz), 4.20 (m, 3H), 1 53 (d, 3H, J = 6 9 Hz), 1.27 (t, 3H, J = 7 1 Hz). l3C-nmr (CDC13): 8 = 174.9, 150.2, 147.1, 145.6, 136.3, 124.6, 115 7, 103.5, 61.9, 52 9, 19.4, 14.8. C!2H14N202S (MW = 250.32); mass spectroscopy (MH+) 251. 15 Example A46 Synthesis of N-(indoI-5-yI)alanine /.vo-butyl ester (S isomer) Following General Procedure AM and using 5-aminoindole (Aldrich) and 20 iso-butyl R-(+)-lactate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf = 0 46 in 33% EtOAc/hexanes). Purification was by preparative plate chromatography with silica gel using 33% EtOAc/hexanes as the eluant. NMR data was as follows: 25 'H-nmr (CDC13): 8 = 8.11 (bs, IH), 7.07 (d, J=8.8 Hz, IH), 6.98 (d, J=2.8 Hz, IH), 6.83 (d, J=2.2 Hz, IH), 6 61 (m, IH), 6.32 (m, IH), 4.18 (q, J=6.9 Hz, IH), 3 95 (bs, IH), 3.87 (d, J=6.7 Hz, 2H), 1 89 (hept, J=6.7 Hz, IH), 1.48 (d, J=6 96 Hz, 3H), 0.86 (dd, J=6.7 Hz, J=1.6 Hz, 6H) l3C-nmr (CDC13): 8 = 176.15, 141 06, 131 28, 129.24, 125.34, 113.34, 30 112.53, 104 21, 102.17, 71 65, 54.28, 28.36, 19.87, 19.62. C^HjoN^ (MW = 260.34); mass spectroscopy (MH+) 261. Printed from Mimosa 07/26/1999 12:37:07 page -183- WO 98/38177 PCT/US98/03373 - 182 -Example A47 Synthesis of N-(naphth-2-yl)alanine O-acylacetamidoxime ester Following General Procedure Al above using N-(naphth-2-yl)alamne 2,4,6-tnchlorophenyl ester (from Example AE above) and acetamide oxime 5 (prepared according to the procedures described in J Org Chem , 46, 3953 (1981)), the title compound was prepared as a semisolid. The reaction was monitored by tic on silica gel (Rf = 0.4 in ethyl acetate) and purification was by preparative plate chromatography (silica gel using ethyl acetate as the eluant) NMR data was as follows* 10 'H-nmr (d'-DMSo)* 8 = 7 64 (t, 2H), 7 54 (d, IH), 7 32 (t, IH), 7.13 (t, IH), 7.04 (d, IH), 6 78 (s, IH) 6.42 (broad s, 2H), 6.32 (d, IH), 4.33 (m, IH), 1.72 (s, 3H), 1.46 (d, 3H). C15HI7N302 (MW = 271.32); mass spectroscopy: 271. 15 Example A48 Synthesis of N-(2-naphthyl)alanine ethyl ester Following reductive amination General Procedure AA above and using 2-aminonaphthalene (Aldrich) and ethyl pyruvate (Aldrich), the title compound 20 was prepared as a solid having a melting point of 52-56°C. The reaction was monitored by silica gel tic (Rf = 0.50 in 25% EtOAc/hexanes). Purification was by flash chromatography with silica gel using 25% EtOAc/hexanes as the eluant. NMR data was as follows: 'H-nmr (CDC1,): 5 = 7.65 (m, 3H), 7.48 (m, IH), 7.25 (m, IH), 6 91 25 (m, IH), 6.79 (m, IH), 4.31 (m, 2H), 3.76 (s, 3H), 1.55 (d, 3H). ,3C-nmr (CDC13): 8 = 175.66, 144 78, 135.55, 129.78, 128.47, 128.22, 126.96, 126.67, 123.01, 118.66, 105.88, 52.95, 52.51, 19.45. C14H|5N02 (MW = 229.28); mass spectroscopy (MH+) 229. 30 Example A49 Synthesis of N-(3,4-dichlorophenyl)alanine O-acylpropionamidoxime ester Printed from Mimosa 07/26/1999 12:37:07 page -184- WO 98/38J77 PCT/US98/03373 -- 183 - Following General Procedure Al above using N-(3,4-dichlorophenyl)alanine 2,4,6-trichlorophenyl ester (prepared from N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9) using essentially the same procedure as described in Example AE above) and propionamide oxime 5 (prepared according to the procedures described in J Org Chem , 46, 3953 (1981)), the title compound was prepared as a semisolid. The reaction was monitored by tic on silica gel (Rf = 0.2 m 50% ethyl acetate/hexane) and purification was by preparative plate chromatography (silica gel using 50% ethyl acetate/hexane as the eluant). 10 NMR data was as follows- 'H-nmr (d'-DMSO): 8 = 7.27 (d, IH), 6.83 (s, IH), 6 64 (d, IH), 6 47 (d, IH), 6.38 (broad s, 2H), 4.24 (m, IH), 2.07 (q, 2H), 1 41 (d, 3H). Ci2HI5C12N302 (MW = 304.17); mass spectroscopy (MH") 305. 15 Example A50 Synthesis of N-(4-ethoxycarbonylphenyl)alanine iso-butyl ester (S isomer) Following General Procedure AM and using ethyl 4-aminobenzoate (Aldrich) and wo-butyl R-(+)-lactate (Aldrich), the title compound was prepared 20 as an oil. The reaction was monitored by silica gel tic (Rf = 0.21 in 10% EtOAc/hexanes) Purification was by preparative plate thin layer chromatography using 25% EtOAc/hexanes as the eluant. NMR data was as follows: 'H-nmr (CDC13): 8 = 7.82 (d, J = 8.73 Hz, 2H), 6 51 (d, J = 8 79 Hz, 25 2H), 4.81 (d, J = 7.82 Hz, IH), 4.25 (q, J = 7 14 Hz, 2H), 4.15 (quint, J = 7.40 Hz, IH), 3.87 (m, 2H), 1.87 (sept, J = 6.70 Hz, IH), 1.43 (d, J = 6 95 Hz, 3H), 1 30 (t, J = 7 14 Hz, 3H), 0.84 (d, J = 6.71 Hz, 6H). ,3C-nmr (CDC13): 8 = 174.5, 167.3, 151 0, 132.0, 119.9. 112.5, 71.9, 60.8, 51.9, 28.2, 19 5, 19.2, 15.0. 30 Ci6H23N04 (MW = 293.37), mass spectroscopy (MH+) 294. Example A51 Printed from Mimosa 07/26/1999 12:37:07 page -185- WO 98/35177 PCT/US98/03373 - 184 - Synthesis of N-[3,5-di(trifluoromethyl)phenyl]alanine iso-butyl ester (S isomer) Following General Procedure AM and using 3,5-5 di(trifluoromethyl)aniline (Aldrich) and wo-butyl R-(+)-lactate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf = 0.38 in 10% EtOAc/hexanes). Purification was by preparative plate thin layer chromatography using 10% EtOAc/hexanes as the eluant NMR data was as follows: 10 'H-nmr (CDC1,). 8 = 7.13 (s, IH), 6.91 (s, 2H), 4.97 (d, J = 8.24 Hz, IH), 4.18 (m, IH), 3.93 (d, J = 6.59 Hz, 2H), 1.93 (sept, J = 6.71 Hz, IH), 1 49 (d, J = 7 02 Hz, 3H), 0.89 (d, J = 6.59 Hz, 6H) 13C-nmr (CDC13)- 8 = 174.4, 147.9, 133 6, 133 2, 132.7, 132.3, 129.4, 125.8, 122 2, 118 6, 112.81, 112.76, 111.42, 111.37, 111.32, 111.27, 111.22, 15 72.2, 52.0, 32.1, 28.24, 28 17, 23.2, 19.5, 19.3, 19 2, 18.9, 14.6. C15HnF6N02 (MW = 357.30); mass spectroscopy (MH+) 358 Example A52 Synthesis of N-(3,5-dimethoxyphenyl)alanine iso-butyl 20 ester N-(3,5-dimethoxyphenyl)alanine (crude, 454 mg) (prepared according to the procedure described in U.S Patent No. 3,598,859 using 3,5-dimethoxyaniline (Aldrich) and 2-chloropropiomc acid (Aldrich)) was treated in dry /so-butanol 25 (10 mL) with 0 1 mL of chlorotrimethylsilane and the reaction mixture refluxed overnight. The excess alcohol was removed at reduced pressure and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous NaHC03, dried with Na2S04 and the solvent removed to provide the title compound. The reaction was monitored by silica gel tic (Rf = 0 3 in 20% 30 EtOAc/hexanes) Purification was by preparative thin layer chromatography using 20% EtOAc/hexanes as the eluant. NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -186- WO 98/38177 PCT/US98/03373 -- 185 - 'H-nmr (CDC1,): 8 = 0.9 (d, J = 7, 6H), 1.47 (d, J = 7, 3H); 1.9-2 0 (m, IH), 3 7 (s, 6H), 3 85-4 0 (m, 2H), 4.1-4.2 (m, IH), 4.3 (brs, IH), 5.8 (s, 2H), 5.9 (s, IH). " l3C-nmr (CDC13): 6 = 19.49, 19.52, 19.54, 28.3, 52.5, 55.6, 71.7, 91.1, 5 92 7, 149.2, 162.3, 175.2. C15H23N04 (MW = 281.35). Example A53 Synthesis of N-(2-napthyl)alanine O-acylpropionamidoxime ester 10 Following General Procedure AS and using N-(2-naphthyl)alamne 2,4,5-trichlorophenyl ester (from Example AE above) and propionamide oxime (prepared according to the procedures described in J Org Chem , 46, 3953 (1981)), the title compound was prepared. The reaction was monitored by silica 15 gel tic (Rf = 0 5 in EtOAc). Purification was by silica gel chromatography using 1.1 EtOAc/hexanes as the eluant NMR data was as follows: 'H-nmr (DMSO-4): 8 = 1.03 (t, 3H), 1.45 (d, 3H) C,6H19N302 (MW = 285.35); mass spectroscopy (M+) 285. 20 Example A54 Synthesis of N-(2-napthyl)alanine O-acylbutyramidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5- 25 trichlorophenyl ester (from Example AE above) and butyramide oxime (prepared according to the procedures described in J Org Chem , 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf = 0 6 in EtOAc). Purification was by silica gel chromatography using 1.1 EtOAc/hexanes as the eluant. 30 NMR data was as follows: 'H-nmr (DMSO-rf6): 8 = 0.86 (t, 3H), 1.46 (d, 3H). Ci7H21N302 (MW = 299 37); mass spectroscopy (MH+) 299. Printed from Mimosa 07/26/1999 12:37:07 page -187- WO 98/38177 - 186 - PCT/US98/03373 Example A55 Synthesis of N-(2-napthyI)alanine O-acylisovaleramidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5-5 trichlorophenyl ester (from Example AE above) and isovaleramide oxime (prepared according to the procedures described in J Org Chem , 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf =03 in T1 EtOAc/hexanes). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant. 10 NMR data was as follows- 'H-nmr (DMSO-J.): 5 = 0 86 (t, 3H), 1.45 (d, 3H) C,8H23N302 (MW = 313.40); mass spectroscopy (MH+) 313. Example A56 15 Synthesis of N-(2-napthyl)aIanine O-acylbenzamidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE above) and benzamide oxime (prepared according to the procedures described in J Org Chem., 46, 3953 (1981)), the 20 title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf = 0.3 in 1 1 EtOAc/hexanes). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant NMR data was as follows: 'H-nmr (DMSO-c/6). 6 = 4.42 (m, IH), 1.53 (d, 3H). 25 C20Hl9N3O2 (MW = 333.39); mass spectroscopy (MH+) 333. Example A57 Synthesis of N-(2-napthyl)alanine O-acylcyclopropanecarboxamidoxime ester 30 Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5-trichlorophenyl ester (from Example AE above) and cyclopropanecarboxamide oxime (prepared according to the procedures described in J Org Chem , 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was Printed from Mimosa 07/26/1999 12:37:07 page -188- WO 98/38177 - 187 - PCT/US98/03373 monitored by silica gel tic (Rf = 0 3 in 1:1 EtOAc/hexanes). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant. NMR data was as follows. 'H-nmr (DMSO-fiQ: 5 = 0.85 (m, 4H), 1.43 (d, 3H) -5 C)7H]9N302 (MW = 297 36); mass spectroscopy (MH+) 297. Example A58 Synthesis of N-(2-napthyl)alanine O-acylcyclopropylacetamidoxime ester 10 Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5- trichlorophenyl ester (from Example AE above) and cyclopropylacetamide oxime (prepared according to the procedures described in J Org Chem , 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf =0.3 in 1.1 EtOAc/hexanes) Purification was by silica gel 15 chromatography using 1:1 EtOAc/hexanes as the eluant. NMR data was as follows. 'H-nmr (DMSO-<): 5 = 1.43 (d, 3H), 1.91 (d, 2H) C18H21N302 (MW = 311.39), mass spectroscopy (MH+) 311 20 Example A59 Synthesis of N-(2-napthyl)alanine O-acylcyclopentanecarboxamidoxime ester Following General Procedure AS and using N-(2-naphthyl)alanine 2,4,5- 25 trichlorophenyl ester (from Example AE above) and cyclopentanecarboxamide oxime (prepared according to the procedures described in J Org Chem , 46, 3953 (1981)), the title compound was prepared as an oil. The reaction was monitored by silica gel tic (Rf = 0.3 in 1:1 EtOAc/hexanes). Purification was by silica gel chromatography using 1:1 EtOAc/hexanes as the eluant. 30 NMR data was as follows- 'H-nmr (DMSO-</6): 5 = 1.43 (d, 3H), 2.43 (m, IH) C,7Hl9N302 (MW = 297.36) Printed from Mimosa 07/26/1999 12:37:07 page -189- WO 98/38177 PCT/US98/03373 - 188 - GENERAL PROCEDURE BA Coupling of R1 CfX'YX"")C(OtCl with H,NCH(R2)C(Q)XR3 To a "stirred solution of (D,L)-alanine wo-butyl ester hydrochloride (from Example BB below) (4.6 mmol) in 5 mL of pyridine was added 4.6 mmol of an 5 acid chloride. Precipitation occurred immediately. The mixture was stirred for 3 5 h, diluted with 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated at reduced pressure to yield the product. Other amino acid esters may also be employed in this 10 procedure. GENERAL PROCEDURE BB Coupling of R'aX'¥X"')C(OK)H with H.NCHfR^CfO'lXR3 A solution of the acid (3.3 mmol) and CDI in 20 mL THF was stirred 15 for 2 h. L-alamne iso-butyl ester hydrochloride (from Example BB below) (3.6 mmol) was added, followed by 1.5 mL (10.8 mmol) of tnethylamine. The reaction mixture was stirred overnight The reaction mixture was diluted with 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once and brine once. The solution was dried over 20 magnesium sulfate, filtered, and evaporated at reduced pressure to yield the product. Other amino acid esters may also be employed in this procedure. GENERAL PROCEDURE BC Esterification of R'CrX'')rX",)C(0'>NHCHrR2)C(0)0H With HOR3 25 To a stirred solution of phenylacetylvaline (1.6470 g, 7.0 mmol) in 20 mL THF was added CDI (1.05 g, 6.5 mmol) and the mixture was stirred for 1.5 h. 2-Methylbutanol (0.53 g, 6 mmol) was added the mixture, followed by addition of NaH (0 16 g, 6.5 mmol) Bubbling occurred immediately. The reaction mixture was stirred overnight The reaction mixture was diluted with 30 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once and brine once The solution was dried over Printed from Mimosa 07/26/1999 12:37:07 page -190- WO 98/38177 PCMJS98/03373 - 189 - magnesium sulfate, filtered, and evaporated at reduced pressure to yield the product. Other N-acyl amino acids and alcohols may also be employed in this procedure. 5 GENERAL PROCEDURE BD Ester Hydrolysis to the Free Acid Ester hydrolysis to the free acid was conducted by conventional methods. Below are two examples of such conventional de-esterification methods 10 To the ester in a 1.1 mixture of CH,0H/H,0 was added 2-5 equivalents of K2CO,. The mixture was heated to about 50°C for about 0.5 to 1.5 hours until tic showed complete reaction. The reaction was cooled to room temperature and the methanol was removed at reduced pressure. The pH of the remaining aqueous solution was adjusted to about 2, and ethyl acetate was added 15 to extract the product. The organic phase was then washed with saturated aqueous NaCl and dried over MgSO„. The solution was stripped free of solvent at reduced pressure to yield the product The amino acid ester was dissolved in dioxane/water (4.1) to which was 20 added LiOH (~2 eq.) that was dissolved in water such that the total solvent after addition was about 2:1 dioxane:water. The reaction mixture was stirred until reaction completion and the dioxane was removed under reduced pressure. The residue was diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc, the 25 combined organics were dried over Na2S04 and the solvent was removed under reduced pressure after filtration. The residue was purified by conventional methods (e.g., recrystallization). The following exemplifies this later example. The methyl ester of 3-NO, 30 phenylacetyl alanine 9.27 g (0.0348 mols) was dissolved in 60 mL dioxane and 15 mL of H,0 and adding LiOH (3.06 g, 0.0731 mol) that has been dissolved in Printed from Mimosa 07/26/1999 12:37:07 page -191- WO 98/38177 -- 190 -- PCT/U S98/03373 15 mL of H,0. After stirring for 4 hours, the dioxane was removed under reduced pressure and the residue diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc (4 X 100 mL), the combined organics were dried over Na2S04 and 5 the solvent was removed under reduced pressure after filtration. The residue was recrystalhzed from EtOAc/isooctane giving 7 5 g (85%) of 3-nitrophenylacetyl alanine CnH12N205 requires C = 52 38, H = 4.80, and N = 1111. Analysis found C = 52.54, H = 4.85, and N = 11.08 [a]23 = - 29.9 @ 589 nm. 10 GENERAL PROCEDURE BE Low Temperature BOP Coupling of Acid and Alcohol A solution of methylene chloride containing the carboxylic acid (100M%) and N-methyl morpholine (150 M%) was cooled to -20°C under 15 nitrogen BOP (105 M%) was added in one portion and the reaction mixture was maintained at -20°C for 15 minutes. The corresponding alcohol (120 M%) was added and the reaction mixture was allowed to warm to room temperature and stirred for 12 hours The reaction mixture was then poured into water and extracted with ethyl acetate (3x). The combined ethyl acetate portions were 20 backwashed with saturated aqueous citric acid (2x), saturated aqueous sodium bicarbonate (2x), brine (lx), dried over anhydrous magnesium sulfate or sodium sulfate and the solvent removed under reduced pressure to yield the crude product. 25 GENERAL PROCEDURE BF EDC Coupling of Acid and Amine The acid derivative was dissolved in methylene chloride. The amine (1 eq), N-methylmorpholine (5 eq.), and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. The reaction was cooled to about 0°C and 30 then 1.2 eq, of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The solution was allowed to stir overnight and come to room Printed from Mimosa 07/26/1999 12:37:07 page -192- WO 98/38177 - 191 - PCT/US98/03373 temperature under N, pressure. The reaction mix was worked up by washing the solution with saturated, aqueous NaHCOj, 0.1M citric acid, and brine before drying with Na^SC), and removal of solvents to yield crude product. Pure products were obtained by flash chromatography in an appropriate solvent. 5 GENERAL PROCEDURE BG EDC Coupling of Acid and Amine A round bottom flask was charged with carboxylic acid (1.0 eq ), hydroxy-benzotriazole hydrate (1.1 eq.) and amine (1.0 eq.) in THF under 10 nitrogen atmosphere. An appropriate amount (1.1 eq. for free amines and 2.2 eq. for hydrochloride amine salts) of base, such as Hunig's base was added to the well stirred mixture followed by EDC (1.1 eq.). After stirring from 4 to 17 hours at room temperature the solvent was removed at reduced pressure, the residue taken up in EtOAc (or similar solvent)/water The organic layer was 15 washed with saturated aqueous sodium bicarbonate solution, IN HCl, brine and dried over anhydrous sodium sulfate. In some cases, the isolated product was analytically pure at this stage while, in other cases, purification via chromatography and/or recrystallization was required prior to biological evaluation 20 GENERAL PROCEDURE BH Coupling of R'CrX'¥X"-)CrO)Cl with H-NCHfR^aOVXR3 An excess of oxalyl chloride in dichloromethane was added to the acid derivative together with one drop of DMF. The resulting mixture was stirred for 25 about 2 hours or until bubbling ceases. The solvent was then removed under reduced pressure and rediluted with dry methylene chloride. To the resulting solution was added about 1.1 eq. of the appropriate amino acid ester and triethylamine (1.1 eq. in methylene chloride) The system was stirred at room temperature for 2 hours and then the solvent was removed under reduced 30 pressure. The residue was dissolved in ethyl acetate, washed with IN HCl followed by IN NaOH. The organic layer was dried over anhydrous soldium Printed from Mimosa 07/26/1999 12:37:07 page -193- WO 98/38177 - 192 - PCT/US98/03373 sulfate, filtered and the solvent removed under reduced pressure to provide for the desired product. GENERAL PROCEDURE BI 5 P-EPC coupling P-EPC coupling employs an amino acid ester and a substituted acetic acid compound. The acetic acid derivative is well known in the art and is typically commercially available The amino acid ester is prepared by conventional methods from the known and typically commercially available N-10 BOC amino acid as described in GENERAL PROCEDURE BJ below Specifically, the appropriate amino ester free base (0.0346 mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in 2.0 mL CHC13 (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and the reaction was 15 mixed for 4 days at 23 °C The reaction was filtered through a plug of cotton, rinsed with 2 0 mL of CHC13 and the filtrate evaporated under a stream of nitrogen. The purity of each sample was determined by 'H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg of final product was obtained from each reaction and was tested without additional purification. 20 GENERAL PROCEDURE BJ Synthesis of Amino Acid Esters From the Corresponding N-BOC Amino Acid A. Esterification of the Acid. The N-BOC amino acid was dissolved in dioxane and treated with an 25 excess of alcohol ( — 1.5 eq.) and catalytic DMAP (100 mg) at 0°C. Stirring was continued until reaction completion whereupon the product was recovered by conventional methods. B Removal of N-BOC Group. 30 The N-BOC protected amino acid was dissolved in methylene chloride (0.05M) and treated with 10 eq. of TFA at room temperature under a nitrogen Printed from Mimosa 07/26/1999 12:37:07 page -194- WO 98/38177 PCT/US98/03373 -- 193 - atmosphere. The reaction was monitored by tic until starting material was consumed usually within 1-5 hours. An additional 10 eq. of TFA was added to the reaction if the starting material was still present after 5 hours. The reaction was carefully neutralized with Na2C03, separated, the organic layer washed 5 with brine and dried over anhydrous Na2S04. The crude amine was then used without purification. Specific exemplification of these procedures are as follows: 1 Racemic (+/-)-N-BOC-a-amino butyric acid (Aldrich) (9.29 g, 10 0.0457 mol) was dissolved in 100 mL of dioxane and treated with wo-butyl alcohol (6.26 mL, 0.0686 mol), EDC (8.72 g, 0.0457) and catalytic DMAP (100 mg) at 0°C. After stirring for 17 hours, the organics were evaporated at reduced pressure, the residue diluted with EtOAc washed with NaHC03, brine and dried over Na2S04. Evaporation yields 8.42 g (71 %) of an oil. C13H25N04 15 requires: C = 60.21, H = 9.72, and N = 5.40. Anal found- C = 59.91, H = 9.89, and N = 5.67. The above N-BOC amino acid ester (8.00 g, 0.032 mol) was deprotected as above giving 3.12 g (61%) of the free base as a colorless oil which solidifies 20 upon standing 2. L-N-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) was dissolved in 100 mL of CH2C12, iso-butyl alcohol (21.9 mL, 0.238 mol) and treated with DMAP (100 mg) and EDC (10.0 g, 0.52 mol) at 0°C. The mixture was 25 stirred for 17 hours, diluted with H20, washed with 1.0 N HCl, NaHC03, then brine and the organics were dried over Na2S04 Filtration and evaporation yields 11.8 g (quantitative) of L-N-BOC alanine iw-butyl ester which is contaminated with a small amount of solvent. A sample was vacuum dried for analytical analysis. C12H23N04 requires: C = 58.79, H = 9.38, and N = 30 5.71. Anal found: C = 58 73, H = 9.55, and N = 5.96. Printed from Mimosa 07/26/1999 12:37:07 page -195- WO 98/38177 PCT/US98/03373 -- 194 - The above N-BOC amino acid ester (11.8 g, 0.0481 mol) was deprotected as above. The free base was converted to the corresponding HCl salt using saturated HCl (g)/EtOAc to give L-N-alanine iso-butyl ester hydrochloride Obtained 4.2 g (48%) of a colorless solid. C7H15N02. HCl 5 requires: C = 46.28, H = 8.88, and N = 7.71. Anal found: C = 46.01, H = 8.85, and N = 7 68 GENERAL PROCEDURE BK 10 Methvl ester formation from amino acids The amino acid (ammo acid or amino acid hydrochloride) is suspended in methanol and chilled to 0°C. HCl gas is bubbled through this solution for 5 minutes. The reaction is allowed to warm to room temperature then stirred for 4 hours. The solvents are then removed at reduced pressure to afford the 15 desired amino acid methyl ester hydrochloride This product is usually used without further purification Example BA Synthesis of free and polymer bound PEPC 20 N-ethvl-N '-3-( 1 -pvrrolidinvDpropvlurea To a solution of 27.7 g (0.39 mol) ethyl isocyanate in 250 mL chloroform was added 50 g (0.39 mol) 3-(l-pyrrolidinyl)propylamine dropwise with cooling. Once the addition was complete, the cooling bath was removed and the reaction mixture stirred at room temperature for 4 hours. The reaction 25 mixture was then concentrated under reduced pressure to give 74.5 g (96 4%) of the desired urea as a clear oil. 1 -(3-( 1 -pvrrolidinvl)propvl)-3-ethvlcarbodiimide (P-EPC) To a solution of 31.0 g (0.156 mol) N-ethyl-N'-3-(l-pyrrolidinyl)propyl-30 urea in 500 mL dichloromethane was added 62.6 g (0.62 mol) triethylamme and the solution was cooled to 0°C. To this solution were then added 59.17 g (0.31 Printed from Mimosa 07/26/1999 12:37:07 page -196- WO 98/38177 PCT/US98/03373 -- 195 - mol) 4-toluenesulfonyl chloride m 400 mL dichloromethane dropwise at such a rate as to maintain the reaction at 0-5°C After the addition was complete, the reaction mixture was warmed to room temperature and then heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was washed 5 with saturated aqueous potassium carbonate (3 x 150 mL). The aqueous phases were combined and extracted with dichloromethane. All organic phases were combined and concentrated under reduced pressure The resultant orange slurry was suspended in 250 mL diethyl ether and the solution decanted off from the solid. The slurry/decantation process was repeated 3 more times. The ether 10 solutions were combined and concentrated under reduced pressure to give 18.9 g (67%) of the desired product as a crude orange oil. A portion of the oil was distilled under vacuum to give a colorless oil distilling at 78-82°C (0 4 mm Hg). 15 Preparation of a polymer supported form of l-(3-(l-pvrrolidinvl')propvl'>-3-ethvlcarbodiimide (P-EPC) A suspension of 8.75 g (48 3 mmol) l-(3-(l-pyrrolidin-yl)propyl)-3-ethylcarbodnmide and 24.17 g (24.17 mmol) Merrifield's resin (2% cross-linked, 200-400 mesh, chloromethylated styrene/divinylbenzene copolymer, 1 20 meq. Cl/g) in dimethylformamide was heated at 100°C for 2 days. The reaction was cooled and filtered and the resulting resin washed sequentially with 1L DMF, 1L THF and 1L diethyl ether. The remaining resin was then dried under vacuum for 18 hours. 25 Example BB Preparation of alanine iso-butyl ester hydrochloride A mixture of 35.64 g (0.4 mol) of (D,L)-alanine (Aldrich) (or L-alamne (Aldrich)); 44 mL (0.6 mol) of thionyl chloride (Aldrich) and 200 mL of isobutanol was refluxed for 1.5 hours and the volatiles were removed 30 completely on a rotavapor of 90°C under reduced pressure to give (D,L)- Printed from Mimosa 07/26/1999 12:37:07 page -197- WO 98/38177 PCT/US98/03373 - 196 -- alanine iso-butyl ester hydrochloride (or L-alanine iso-butyl ester hydrochloride), which was pure enough to be used for further transformations. Example BC 5 Preparation of 3,5-dichlorophenylacetic acid To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol (Aldrich) in 75 mL of dichloromethane at 0°C was added 1.8 mL of methane sulfonylchloride followed by 3.5 mL of triethylamine added dropwise. After 2 hours the solution was diluted to 150 mL with dichloromethane, washed with 3N HCl, 10 saturated aqueous NaHCOa dried with Na2S04 and the solvents removed to yield the desired 3,5-dichlorobenzyl methanesulfonate as a yellow oil that was used without purification The crude sulfonate was dissolved in 50 mL of DMF at 0°C and then 3 g of KCN was added. After 2 hours an additional 50 mL of DMF was added 15 and the solution was stirred for 16 hours The red solution was diluted with 1 L of H20 and acidified to pH 3 with 3N HCl The aqueous solution was extracted with dichloromethane. The combined orgamcs were washed with 3N HCl, dried with Na2S04 and the solvents removed at reduced pressure to yield crude 3,5-dichlorophenylacetonitrile which was used without purification 20 The nitrile was added to a mixture of 40 mL of concentrated sulfuric acid and 50 mL H20 and heated to reflux for 48 hours, cooled to room temperature and stirred for 48 hours. The reaction was diluted into 1 L of crushed ice, warmed to toom temperature and extracted with 2 x 200 mL of dichloromethane and 2 x 200 mL of ethylacetate. Both sets of organics were 25 combined and washed with saturated aqueous NaHC03. The NaHC03 fractions were combined and acidified to pH 1 with 3N HCl. The white solid was too fine to filter and was extracted out with 2 X 200 mL of dichloromethane. The combined organics were dried with Na2S04 and the solvents removed at reduced presure to yield crude 3,5-dichlorophenylacetic acid as a white solid. The solid 30 was slurried with hexane and filtered to get 1.75g of white solid. NMR (CDC13): (in ppm) 3.61 (s, 2H), 7.19 (s,lH), 7.30 (s, IH) Printed from Mimosa 07/26/1999 12:37:07 page -198- WO 98/38177 PCT/US98/03373 - 197 -- Example BD Synthesis of N-(3-chlorophenylacetyl)alanine The title compound was prepared using L-alanine (Nova Biochem) and 3-chlorophenyl acetic acid (Aldrich) by following General Procedures BF or 5 BG, followed by hydrolysis using General Procedure BD Example BI Synthesis of N-(phenylacetyl)-D, L-alanine iso-butyl ester Following General Procedure BA above and using phenylacetyl chloride 10 (Aldrich) and D, L-alanine wo-butyl ester hydrochloride (from Example BB above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows. 15 'H-nmr (CDC13): 5 = 7.23-7.36 (m, 5H), 6.18 (d, IH), 4.58 (t, J = 7.3 Hz, IH), 3.87 (m, 2H), 3.57 (s, 2H), 1.90 (m, IH), 1.34 (d, J = 7 2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 6H). ,3C-nmr (CDC13): 8 = 172.7, 170.3, 134 5, 129.2, 128.8, 127 2, 71.3, 48.1,43.4, 27.5, 18.8, 18.3. 20 C15H2IN03 (MW = 263.34; Mass Spectroscopy (MH+ = 264)) Example B2 Synthesis of 7V-(3-phenylpropionyl)-D,L-alanine iso-butyl ester Following General Procedure BA above and using 3-phenylpropionyl 25 chloride (Aldrich) and D,L-alanine wo-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a meltmg point of from 51°-54°C The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. 30 NMR data was as follows. Printed from Mimosa 07/26/1999 12:37:07 page -199- WO 98/38177 PCT/US98/03373 -- 198 - 'H-nmr (CDC13): 8 = 7.25 (m, 2H), 7.19 (m, 3H), 6 28 (d, J-= 7.2 Hz, IH), 4.58 (quint., J = 7.2 Hz, IH), 3.89 (m, 2H), 2.95 (t, J= 7.7 Hz, 2H), 2.50 (m, 2H), 1.92 (m, IH), 1.33 (d, J = 7.1 Hz, 3H), 0 91 (d, J = 6 7 Hz, 6H). l3C-nmr (CDC13): 8 = 173.0, 171.5, 140.6, 128.3, 128.1," 126 0, 71.2, 5 47.8, 37.9, 31.4, 27.5, 18.79, 18.77, 18.3. C16H23N03 (MW = 277.37, Mass Spectroscopy (MH+ 278)) Example B3 Synthesis of 7V-(3-methylpentanoyl)-L-aIanine uo-butyl ester 10 Following General Procedure BB and using 3-methylpentanoic acid (Aldrich) and L-alanine z.ra-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl 15 NMR data was as follows- 'H-nmr (CDC13): 5 = 6.08 (d, 5.9 Hz, IH), 4.62 (quint., J = 7.3 Hz, IH), 3.92 (m, 2H), 2.22 (m, IH), 1.84-2.00 (m, 3H), 1 40 (d, J= 7.2 Hz, 3H), 1.35 (m, IH), 1.20 (m, IH), 0.85-0.96 (m, 12H). l3C-nmr (CDC13). 8 = 173.3, 172.1, 71.4, 47.9, 43.9, 32 3, 29.38, 29 35, 20 27.6, 19.10, 19.06, 18.93, 18.91, 18.72, 18.67, 11.3. C)3H25N03 (MW = 243.35, Mass Spectroscopy (MHf 244)) Example B4 Synthesis of Ar-[(4-chlorophenyl)acetyl]-L-alanine tso-butyl ester 25 Following General Procedure BB and using 4-chlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 111°-113°C. The reaction was monitored by tic on silica gel and purification was by extraction with Et,0 followed by washes with aqueous K2C03 and aqueous HCl 30 NMR data was as follows Printed from Mimosa 07/26/1999 12:37:07 page -200- WO 98/38177 PCT/US98/03373 -- 199 - 'H-nmr (CDC13). 5 = 7.30 (d,J= 8.2 Hz, 2H), 7.21 (d, J= 8 3 Hz, 2H), 6.18 (d, J= 5.5 Hz, IH), 4.57 (quint, J = 7.2 Hz, IH), 3.88 (m, 2H), 3.53 (s, 2H), 1.91 (in, IH), 1.36 (d, J= 7 1 Hz, 3H), 0.90 (d, J= 6.8 Hz, 6H). l3C-nmr (CDC13): 5 = 172.8, 169 8, 133.1, 133.0, 130.6," 128.9, 71.4, 5 48.2, 42.6, 27.6, 18.85, 18.82, 18.4 C]5H20NO3Cl (MW = 297.78, Mass Spectroscopy (MH+ 298)) Example B5 Synthesis of Ar-[(3,4-dichlorophenyl)acetyl]-L-alanine iso-butyl ester 10 Following General Procedure BB and using 3,4-dichlorophenylacetic acid (Aldrich) and L-alanine wo-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 81°-83°C The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. 15 NMR data was as follows: 'H-nmr (CDC13): S = 0.90 (d, J= 6.8 Hz, 6H), 1.38 (d, J= 7.1 Hz, 3H), 1.91 (m, IH), 3.50 (s, 2H), 3.90 (m, 2H), 4.57 (quint., J = 7 1 Hz, IH), 6.31 (d, J = 4 9 Hz, 1H),7.12 (m, IH), 7.38 (m, 2H). nC-nmr (CDC13)- 5 = 18.4, 18.8, 18.9, 27 6, 42.2, 48.3, 71.5, 128.6, 20 130 6, 131 2, 131.3, 132.6, 134.7, 169.2, 172 8. C15H]9N03C12 (MW = 332.23, Mass Spectroscopy (MH+ 332)) Example B6 Synthesis of iV-[(4-methylphenyl)acetyl]-D,L-alanine wo-butyl ester 25 Following General Procedure BB and using 4-methylphenylacetic acid (Aldrich) and D,L-alanine zso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 102°-104°C. The reaction was monitored by tic on silica gel (Rf =0.6 in 33% ethyl acetate/hexanes) and purification was by extraction with Et,0 followed by 30 washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -201- WO 98738177 PCT/US98/03373 -- 200 -- 'H-nmr (CDC13): 5 = 0.90 (d, J = 6.7 Hz, 6H), 1 35 (d, J = 7.2 Hz, 3H), 1.91 (m, IH), 2 34 (s, 3H), 3.55 (s, 2H), 3.88 (m, 2H). 4.58 (m, IH), 6.05 (bd, IH), 7.16 (s, 4H). 13C-nmr (CDC13): 8 = 18.5, 18.85, 18.87, 21.0, 27.6, 43.1, 48.1, 71.3, 5 129.2, 129.6, 131.3, 136.9, 170.6, 172.8. C16H23N03 (MW = 277.37, Mass Spectroscopy (MH+ 278)) Example B7 Synthesis of ./V-[(3-pyridyl)acetyl]-D,L-alanine iso-butyl ester 10 Following General Procedure BF and using 3-pyridylacetic acid hydrochloride (Aldrich) and D,L-alanine wo-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 62°-64°C. The reaction was monitored by tic on silica gel (Rf = 0.48 10% methanol/dichloromethane) and purification was by silica gel 15 chromatography. NMR data was as follows. 'H-nmr (CDC1,): 8 = 8 40 (d, J = 2.8, 2H); 7.6 (m, IH) 7 16 (m, 2H); 4.5 (quint., J = 7.2, 7.2, IH); 3.8 (m, 2H); 3.48 (s, 2H), 1.8 (m, IH); 1.30 (d, J = 7.2, 3H), 0.81 (d, J= 6.7, 6H). 20 l3C-nmr (CDC13): 8 = 173.4, 170.1, 150.6, 148.8, 137 4, 131 4, 124.1, 71.9, 48 9, 40 6, 28.1, 19.5, 19.4, 18.6. C|4H20N2O3 (MW = 264, Mass Spectroscopy (MH+ 265)) Example B8 25 Synthesis of 7V-[(l-naphthyl)acetyl]-L-alaninc iso-butyl ester Following General Procedure BB and using 1-naphthylacetic acid (Aldrich) and L-alanine /'so-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 69°-73°C. The reaction was monitored by tic on silica gel and purification was by 30 extraction with Et,0 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -202- WO 98/38177 PCT/US98/03373 - 201 -- 'H-nmr (CDC1,). 8 = 0.83 (m, 6H), 1.25 (d, J= 7 1 Hz, 3H); 1.81 (m, IH), 3.79 (m, 2H), 4.04 (2s, 2H), 4 57 (quint., J = 7.3 Hz, IH), 5.99 (d, J = 7.1 Hz, IH), 7.4*4 (m, 2H), 7.53 (m, 2H), 7.85 (m, 2H), 7 98 (m, IH). ,3C-nmr (CDC13): 8 = 18.2, 18.81, 18.83, 27.5, 41.5, 48.2, 71.3, 123.7, 5 125.6, 126.1, 126.6, 128.2, 128.5, 128.7, 130.7, 132.0, 133.9, 170.3, 172.5. Ci9H23N03 (MW = 313.40, Mass Spectroscopy (MH+ 314)) Example B9 Synthesis of 7V-|(2-naphthyl)acetyl]-L-alanine /so-butyl ester 10 Following General Procedure BB and using 2-naphthylacetic acid (Aldrich) and L-alanine wo-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 128°-129°C. The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl 15 NMR data was as follows: 'H-nmr (CDC1,): 8 = 0.86 (m, 6H), 1.35 (d, J= 7.1 Hz, 3H), 1.78 (m, IH), 3.76 (s, 2H), 3.87 (m, 2H), 4.62 (quint., J = 7.2 Hz, IH), 6.13 (d, J = 7.1 Hz, IH), 7.41 (m, IH), 7.48 (m, 2H), 7.74 (s, IH), 7.83 (m, 3H). 13C-nmr (CDC13): 8 = 18.4, 18.82, 18.85, 27.6, 43.7, 48 2, 71.4, 125.9, 20 126.3, 127.2, 127.6, 127.7, 128.2, 128.7, 132 0, 132.5, 133.5, 170.3, 172.8. Ci9H23N03 (MW = 313.40, Mass Spectroscopy (MH+ 314)). Example B10 Synthesis of Ar-(4-phenylbutanoyl)-L-alanine wo-butyl ester 25 Following General Procedure BB and using 4-phenylbutanoic acid (Aldrich) and L-alanine wo-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. 30 NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -203- WO 98/38177 -- 202 - PCT/US98/03373 'H-nmr (CDC13): 8 = 0.92 (d, J = 6.7 Hz, 6H), 1.38 (d, J= 7.1 Hz, 3H), 1.96 (m, 3H), 2 21 (t, J = 7.1 Hz, 2H), 2.64 (t, J= 7.3 Hz, 2H), 3.90 (m, 2H), 4.59 (quint,V = 7.2 Hz, IH), 6.31 (d, IH), 7.16 (m, 3H), 7.24 (m, 2H) !3C-nmr (CDC13): 8 = 18.3, 18 75, 18.78, 26.8, 27.5, 34:9, 35.3, 47 8, 5 71.2, 125.7, 128.2, 128.3, 141.3, 172.1, 173 0. CI7H25N03 (MW = 291.39, Mass Spectroscopy (MH+ 292)). Example BI 1 Synthesis of yV-(5-phenylpentanoyl)-L-alanine zso-butyl ester 10 Following General Procedure BB and using 5-phenylpentanoic acid (Aldrich) and L-alanine /so-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl 15 NMR data was as follows: 'H-nmr (CDC1,)- 8 = 7.23 (m, 2H), 7.17 (m, 3H), 6.30 (d, IH), 4.59 (quint., J = 7.3 Hz, IH), 3 91 (m, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.22 (t, J = 7.2 Hz, 2H), 1.93 (m, IH), 1.66 (m, 4H), 1.38 (d, J= 7.2 Hz, 3H), 0.92 (d, J = 6.7 Hz, 6H). 20 13C-nmr (CDC13): 8 = 173.1, 172 3, 142.0, 128.2, 128.1, 125.6, 71.2, 47.8, 36.1, 35.5, 30.8, 27.5, 25.0, 18.80, 18.77, 18.4 C18H27N03 (MW = 305.39, Mass Spectroscopy (MH+ 306)). Example B12 25 Synthesis of JV-[(4-pyridyl)acetyl]-D,L-alanine i.vo-butyl ester Following General Procedure BF and using 4-pyridylacetic acid hydrochloride (Aldrich) and (D,L)-alanine zso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a meltmg point of 64°-66°C The reaction was monitored by tic on silica gel (Rf 30 = 0.43 10% methanol/dichloromethane) and purification was by silica gel chromatography. Printed from Mimosa 07/26/1999 12:37:07 page -204- WO 98/38177 PCT/US98/03373 -- 203 - NMR data was as follows: 'H-nmr (CDC1,)' 8 = 8.51 (dd, J = 1 6, 2 8, 1 6, 2H), 7.23 (dd, J = 4 3, 1.6, 4.4, 2H)~; 6.71 (d, 7= 6.8, IH); 4.56 (quint, J = 7.3, 7.2, IH); 3.88 (m, 2H), 3 53 (s, 2H); 1 89 (m, IH); 1.36 (d, J = 7.2, 3H); 0.88 (d, J= 6.7, 6H). 5 IJC-nmr (CDC13)' 8 = 173.5, 169.3, 150.5, 144.4, 125.1, 72.1, 48.9, 43.0, 28.2, 19.5, 19.5, 18.9. CnH20N,O3 (MW = 264, Mass Spectroscopy (MH+ 265)) Example B13 10 Synthesis of N-(phenylacetyl)-L-alanine /so-butyl ester Following General Procedure BB and using phenylacetyl chloride (Aldrich) and L-alanine wo-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 45°-47°C. The reaction was monitored by tic on silica gel and purification was by 15 extraction with Et,0 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows. 'H-nmr (CDC13). 8 = 7.24-7.39 (m, 5H), 6.14 (d, IH), 4.58 (t, J= 7.3 Hz, IH), 3 88 (m, 2H), 3.58 (s, 2H), 1.90 (m, IH), 1 35 (d, J = 7 2 Hz, 3H), 0.89 (d, J = 6 7 Hz, 6H). 20 13C-nmr (CDC13): 8 = 172.8, 170.4, 134.5, 129 3. 128.9, 127.2, 71.3, 48.1, 43.5, 27.5, 18.9, 18.8, 18.4. C15H2iN03 (MW = 263.34, Mass Spectroscopy (MH+ 264)). Example B14 25 Synthesis of 2-[(3,4-dichlorophenyl)acetamido]butyric acid uo-butyl ester Following General Procedure BI above and using 3,4-dichlorophenylacetic acid (Aldrich) and /so-butyl 2-aminobutyrate (prepared following General Procedure BJ above) the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as 30 described in the general procedure. NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -205- WO 98/38177 PCT/US98/03373 -- 204 - 'H-nmr (CDC13): 8 = 7.36 (m, 3H), 6.03 (bd, IH), 4.54 (m, IH), 3.87 (m, 2H), 3.49 (s, 2H), 1.93 (m, 2H), 1.72 (m, IH), 0.88 (d, 6H), 0.80 (t, 3H). Example B15 5 Synthesis of 2- [(3-methoxyphenyl)acetamido] butyric acid /.w-butyl ester Following General Procedure BI above and using 3-methoxyphenylacetic acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared frollowing General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in 10 the general procedure. NMR data was as follows. 'H-nmr (CDC13) 8 = 6.75 (m, 4H), 5.93 (bd, 1H), 4 51 (m, IH), 3 83 (m, 2H), 3.75 (s, 2H), 3.52 (s, 2H), 1 82 (m, 2H), 1.60 (m, IH), 0.84 (d, 6H), 0.74 (t, 3H) 15 Ci7H25N04 (MW = 307.39, Mass Spectroscopy (MH+ 309)). Example B16 Synthesis of 2-[(4-nitrophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 4-nitrophenylacetic 20 acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 25 'H-nmr (CDC13): 8 = 8.16 (d, 2H), 7.44 (d, 2H), 6.04 (bd, IH), 4.55 (m, IH), 3.86 (m, 2H), 3 66 (s, 2H), 1.86 (m, 2H), 1.67 (m, IH), 0.85 (d, 6H), 0.81 (t, 3H). C16H22N205 (MW = 322.36, Mass Spectroscopy (MH+ 323)) 30 Example B17 Synthesis of 2-[(3,4-methylenedioxyphenyl)acetamido]butyric acid /so-butyl ester Printed from Mimosa 07/26/1999 12:37:07 page -206- WO 98/38177 PCT/US98/03373 -- 205 -- Following General Procedure BI above and using 3,4-(methylenedioxy)-phenyl acetic acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described 5 in the general procedure. NMR data was as follows- 'H-nmr (CDC13): 8 = 6.72 (m, 3H), 5.92 (bd, IH), 4.54 (m, IH), 3.86 (m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.66 (m, IH), 0.89 (d, 6H), 0.79 (t, 3H). 10 Example B18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid zso-butyl ester Following General Procedure BI above and using 3-thiopheneacetic acid (Aldrich) and /so-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic 15 on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDC13). 8 = 7.37 (m, IH), 7.16 (m, IH), 7 04 (m, IH), 6.05 (bd, IH), 4.57 (m, IH), 3.66 (s, 2H), 1.93 (m, 2H), 1 67 (m, IH), 0.91 (d, 6H), 20 0.86 (t, 3H). Example B19 Synthesis of 2-[(4-chlorophenyl)acetamido]butyric acid MO-butyl ester Following General Procedure BI above and using 4-chlorophenylacetic 25 acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -207- 98/38177 PCT/US98/03373 - 206 - 'H-nmr (CDCl,)- 8 = 7.22 (m, 2H), 7.11 (m, 2H), 5.80 (m, IH), 4.44 (m, IH), 3 78 (m, 2H), 3 43 (s, 2H), 1.77 (m, 2H), 1 56 (m, IH), 0.83 (d, 6H) 0.71 (t, 3H). / Example B20 Synthesis of 2-[(3-nitrophenyl)acetamido]butyric acid /so-butyl ester Following General Procedure BI above and using 3-nitrophenylacetic acid (Aldrich) and /so-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows. "H-nmr (CDCl,)- 8 = 8.15 (m, 2H), 7.65 (m, IH), 6.08 (m, IH), 4.46 (m, IH), 3 92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, IH), 0.98 (d, 6H) 0.71 (t, 3H). Example B21 Synthesis of 2-[(2~hydroxyphenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDCl,): 8 = 7.14 (m, IH), 7.01 (m, IH), 6.93 (m, IH), 6.79 (m, IH), 6.46 (m, IH), 4.51 (m, IH), 3.87 (m, 2H), 3.57 (s, 2H), 2 01 (m, 2H), 1 75 (m, IH), 0.89 (d, 6H), 0.85 (t, 3H) Example B22 Synthesis of 2-[(2-naphthyl)acetamido]butyric acid iso-butyl ester Printed from Mimosa 07/26/1999 12:37:07 page -208- WO 98/38177 PCT/US98/03373 -- 207 - Following General Procedure BI above and using 2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general 5 procedure. NMR data was as follows: 'H-nmr (CDCl,): 8 = 7.83 (m, 7H), 5 95 (m, IH), 4.58 (m, IH), 3.84 (m, 2H), 3.75 (s, 2H), 1.89 (m, 2H), 1 63 (m, IH), 0 91 (d, 6H), 0.81 (t, 3H). C20H25NO3 (MW = 327.42, Mass Spectroscopy (MH+ 328)). 10 Example B23 Synthesis of 2-[(2,4-dichlorophenyl)acetamido] butyric acid iso-butyl ester Following General Procedure BI above and using 2,4-dichlorophenylacetic acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared 15 following General Procedure BJ above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure NMR data was as follows 'H-nmr (CDC13): 8 = 7.49 (m, IH), 7.22 (m, 2H) 5.98 (m, IH), 4.52 (m, 20 IH), 3.86 (m, 2H), 3 61 (s, 2H), 1 84 (m, 2H), 1.62 (m, IH) 0 87 (d, 6H), 0.80 (t, 3H). Example B24 Synthesis of 2-[(4-bromophenyl)acetamido] butyric acid /so-butyl ester 25 Following General Procedure BI above and using 4-bromophenylacetic acid (Aldrich) and rso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure 30 NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -209- WO 98/38177 PCT/US98/03373 - 208 -- 'H-nmr (CDCl,): 8 = 7.43 (d, 2H), 7.19 (d, 2H) 5.85 (m, IH), 4 51 (m, IH), 3.81 (m, 2H), 3.47 (s, 2H), 1.84 (m, 2H), 1.61 (m, IH) 0.84 (d, 6H), 0.76 (t,3H). C,6H22N03Br (MW = 356.26, Mass Spectroscopy (MH+ 358)). 5 Example B25 Synthesis of 2-[(3-chlorophenyl)acetamido])butyric acid iso-butyl ester Following General Procedure BI above and using 3-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General 10 Procedure BJ above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure NMR data was as follows- 'H-nmr (CDC13): 8 = 7.25 (m, 3H), 7.12 (m, IH) 5.80 (m, IH), 4.52 (m, 15 IH), 3.86 (m, 2H), 3 50 (s, 2H), 1.87 (m, 2H), 1.67 (m, IH) 0.88 (d, 6H), 0.77 (t, 3H). C16H22N03C1 (MW = 311.81 Mass Spectroscopy (MH~ 313)). Example B26 20 Synthesis of 2-[(3-fIuorophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 3-fluorophenylacetic acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as described in 25 the general procedure. NMR data was as follows: 'H-nmr (CDCl,): 8 = 7.31 (m, IH), 7.01 (m, 3H) 5.95 (m, IH), 4.54 (m, IH), 3 84 (m, 2H), 3.54 (s, 2H), 1.88 (m, 2H), 1.65 (m, IH) 0 87 (d, 6H), 0.81 (t, 3H). 30 C16H22N03F (MW = 295.35 Mass Spectroscopy (MH+ 296)). Printed from Mimosa 07/26/1999 12:37:07 page -210- WO 98/38177 PCT/US98/03373 - 209 -- Example B27 Synthesis of 2-[(benzothiazol-4-yl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 4-benzothiazol-4-yl acetic acid (Chemservice) and jso-butyl 2-aminobutyrate (prepared following 5 General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDCl,): 5 = 7.82 (m, IH), 7.51-7.21 (m, 4H) 5.84 (m, IH), 4.51 10 (m, IH), 3.90 (s, 2H), 3.79 (m, 2H), 1.78 (m, 2H), 1.58 (m, IH) 0.80 (d, 6H), 0 66 (t, 3H). Example B28 Synthesis of 2-[(2-methyIphenyl)acetamido]butyric acid iso-butyl ester 15 Following General Procedure BI above and using 2-methylphenylacetic acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. 20 NMR data was as follows: 'H-nmr (CDCl,): 5 = 7.18 (m, 4H), 5.79 (m, IH), 4 54 (m, IH), 3 85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, IH) 0 87 (d, 6H), 0.77 (t, 3H) C|7H2jN03 (MW = 291.39 Mass Spectroscopy (M+ 291)). 25 Example B29 Synthesis of 2-[(2-fluorophenyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 2-fluorophenylacetic acid (Aldrich) and wo-butyl 2-aminobutyrate (prepared following General 30 Procedure BJ above), the title compound was prepared The reaction was Printed from Mimosa 07/26/1999 12:37:07 page -211- WO 98/38177 PCT/US98/03373 -- 210 -- monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDCl,): 8 = 7.28 (m, IH), 7.09 (m, 3H) 6.03 (m, IH), 4.54 (m, 5 IH), 3.87 (m, 2H), 3.57 (s, 2H), 1 89 (m, 2H), 1 64 (m, IH) 0.88 (d, 6H), 0.80 (t, 3H). Example B30 Synthesis of 2-[(4-fluorophenyl)acetamido]butyric acid m>-butyJ ester 10 Following General Procedure BI above and using 4-fluorophenylacetic acid (Aldrich) and zso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure 15 NMR data was as follows: 'H-nmr (CDCl,): 8 = 7 20 (m, 2H), 6 97 (m, 2H) 5.87 (m, IH), 4.492 (m, IH), 3.83 (m, 2H), 3.48 (s, 2H), 1 86 (m, 2H), 1.60 (m, IH) 0 87 (d, 6H), 0.78 (t, 3H). Ci6H22N03F (MW = 295.35 Mass Spectroscopy (MH+ 296)). 20 Example B31 Synthesis of 2-[(3-bromophenyI)acetamido]butyric acid /so-butyl ester Following General Procedure BI above and using 3-bromophenylacetic acid (Aldrich) and /so-butyl 2-aminobutyrate (prepared following General 25 Procedure BJ above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure NMR data was as follows: 'H-nmr (CDCl,): 8 = 7.45 (m, 2H), 7.23 (m, 2H) 5.95 (m, IH), 4.55 (m, 30 IH) 3.84 (m, 2H) 3 55 (s, 2H), 1.89 (m, 2H), 1.68 (m, IH) 0.91 (d, 6H), 0.81 (t, 3H) Printed from Mimosa 07/26/1999 12:37:07 page -212- WO 98/38177 - 211 - PCT/U S98/03373 C|6H22N03Br (MW = 356.26 Mass Spectroscopy (M+ 357)). - Example B32 Synthesis of 2-[(3-trifluoromethylphenyI)acetamido]butyric acid 5 iso-butyl ester Following General Procedure BI above and using 3-trifluoromethyl-phenylacetic acid (Aldrich) and Kobutyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described 10 in the general procedure NMR data was as follows- 'H-nmr (CDCl,): 8 = 7.52 (m, IH), 7.47 (m, 2H) 6.01 (m, IH), 4.56 (m, IH), 3 86 (m, 2H), 3 61 (s, 2H), 1.84 (m, 2H), 1.62 (m, IH) 0.87 (d, 6H), 0.80 (t, 3H). 15 C17H22N03F3 (MW = 345.36 Mass Spectroscopy (MH+ 345)). Example B33 Synthesis of 2-[(2-thienyl)acetamido]butyric acid iso-butyl ester Following General Procedure BI above and using 2-thiopheneacetic acid 20 (Aldrich) and jso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 25 'H-nmr (CDCl,)' 8 = 6.89 (m, 3H), 6.07 (bd, IH), 4.50 (m, IH), 3.82 (m, 2H), 3 71 (s, 2H), 1.85 (m, 2H), 1.62 (m, IH), 0 81 (d, 6H), 0.75 (t, 3H). C14H21N03S (MW = 283.39, Mass Spectroscopy (MH+ 284)). Example B34 30 Synthesis of 2-(phenylacetamido)butyric acid iso-butyl ester Following General Procedure BH above and using phenylacetic acid (Aldrich) and zso-butyl 2-aminobutyrate (prepared following General Procedure Printed from Mimosa 07/26/1999 12:37:07 page -213- WO 98/38177 - 212 - PCT/US98/03373 BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by chromatography on silica gel using 9:1 toluene :EtOAc as the eluant NMR data was as follows-5 'H-nmr (CDCl,): 5 = 7.17-7.28 (m, 5H), 6.23 (bd, IH), 4.51 (m, IH), 3 86 (m, 2H), 3.54 (s, 2H), 1 87 (m, 2H), 1.62 (m, IH), 0 87 (d, 6H), 0.78 (t, 3H) C,6H23N03 (MW = 277.36, Mass Spectroscopy (MH+ 277)) 10 Example B35 Synthesis of 7V-(phenylacetyl)valine 2-methylbutyl ester Step A. Preparation of N-(phenylacetyl) valine To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0°C was added dropwise 5.3 mL (40 mmol) 15 of phenylacetyl chloride (Aldrich) A colorless oil precipitated The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white precipitate formed was filtered off, washed thoroughly with water, followed by diethyl ether to give 7 1 g (30 mmol, 69% yield) of the title 20 compound. NMR data was as follows: 'H-nmr (DMSO-</6): 8 = 12 63 (s, IH), 8.25 (d, J = 8.6 Hz, IH), 7.27 (m, 5H), 4.15 (m, IH), 3.56 (d, J= 13.8 Hz, IH), 3 47 (d, J = 13.8 Hz, IH), 2.05 (m, IH), 0.87 (d, J = 6.8, Hz, 3H), 0.84 (d, J = 6.8 Hz, 3) 25 13C-nmr (DMSO-c/J: 8 = 173.2, 170.4, 136.6, 129.0, 128.2, 126.3, 57.1, 41 9, 30.0, 19.2, 18.0 C13H17N03 (MW=235.29; Mass Spectroscopy (MH+ = 236)) Step B. Synthesis of //-(phenylacetyl)valine 2-methylbutyl ester 30 Following General Procedure BC and using the N-(phenylacetyl) valine prepared in Step A above and 2-methylbutan-l-ol (Aldrich), the title compound Printed from Mimosa 07/26/1999 12:37:07 page -214- WO 98/38177 PCT/US98/03373 - 213 - was prepared as a diastereomeric mixture The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMK data was as follows. 'H-nmr (CDCl,). 8 = 7.25-7.40 (m, 5H), 5.95 (d, IH), 4.56 (m, IH), 5 3.84-4.00 (m, 2H), 3.61 (s, 2H), 2.10 (m, IH), 1.68 (m, IH), 1.38 (m, IH), 1.15 (m IH), 0.82-0.94 (m, 9H), 0.76 (d, 3H). !3C-nmr (CDC13): 8 = 171.84, 171.81, 170.7, 134.6, 129.31, 129.27, 128.9, 127.3, 69 8, 57.0, 43 7, 33.9, 31.3, 25.9, 25 8„ 18.9, 17.4, 16.34, 16.27, 11.12, 11.07 10 C18H27N03 (MW = 305.42, Mass Spectroscopy (MH 306)) Example B36 Synthesis of N-(phenylacetyl)-L-methionine iso-butyl ester L-Methionine (0.129g, 0.869 mmols) (Aldrich) was taken-up in dioxane 15 (5.0 mL) and treated with a saturated solution of sodium bicarbonate (5 0 mL) followed by phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmols) After stirring for 17 hours at room temperature the mixture was diluted with ethyl acetate, the layers separated and the aqueous layer acidified to pH 2 with 5N HCl. The crude product was extracted into ethyl acetate, dried over sodium 20 sulfate, vacuum dried and used without further purification. N-Phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolved in 3.0 mL dioxane and wo-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol), and catalytic DMAP (0.015g). After stirring for 17 hours at 25 23°C, the mixture was evaporated at reduced pressure to an oil, the residue was diluted m EtOAc and washed with 0 1 N HCl and saturated sodium bicarbonate. Chromatography on silica gel using 98.2 CHCl3/MeOH as eluant provided the pure product. NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -215- WO 98/38177 PCT/US98/03373 - 214 - 'H-nmr (CDC13): 8 = 7.4-7.23 (m, 5H), 6.14 (bd, IH), 4.70 (m, IH), 3.89 (d, 2H), 3.62 (s, 2H), 2 43 (m, 2H), 2.12 (m, IH), 1.93 (m, 2H), 0.94 (d, 6H). Cl7H35N03S (MW = 323.17, Mass Spectroscopy (M+ 323) 5 Example B37 Synthesis of N-(phenylacetyl)-L-leucine iso-butyl ester L-Leucine (Aldrich) (0.114g, 0.869 mmols) was taken-up in dioxane (5 0 mL) and treated with a saturated solution of sodium bicarbonate (5.0 mL) 10 followed by phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmols). After stirring for 17 hours at room temperature the mixture was diluted with ethyl acetate, the layers separated and the aqueous layer acidified to pH 2 with 5N HCl. The crude product was extracted into ethyl acetate, dried over sodium sulfate, vacuum dried and used without further purification. 15 N-Phenylacetyl-L-leucine (0 0081 g, 0.038 mmol) was dissolved in 2.0 ml. CHC13 (EtOH free) and iso-butyl alcohol (0.055 mL) and treated with P-EPC (100 mg, 0.87 milhequivalents) The mixture was rotated for 4 days, filtered through a plug of cotton and the filtrate evaporated at reduced pressure 20 to an oil which was sufficiently pure for testing. NMR data was as follows' 'H-nmr (CDCl,): 8 = 7.22 (m, 5H), 5.57 (d, IH), 4.35 (m, IH), 3 35 (m, 3H), 1.35 (m, 4H), 0.68 (m, 9H). C]8H27N03 (MW = 305.40, Mass Spectroscopy (M+ 305)). 25 Example B38 Synthesis of /V-[(3-chlorophenyl)acetyl]alaninc 3-methylbut-2-enyl ester Following General Procedure BC above and using N-(3-chlorophenylacetyl alanine (from Example BD above) and 3-methylbut-2-en-l-ol 30 (Aldrich), the title compound can be prepared. The reaction was monitored by Printed from Mimosa 07/26/1999 12:37:07 page -216- WO 98/38177 PCT/US98/03373 - 215 -- tic on silica gel and purification was by liquid chromatography using 30% EtOAc/hexane as the eluant. NMR data was as follows: 'H-nmr (CDCl,): 8 = 7.39-7.16 (m, 4H), 6.06 (bd, IH),-5.38-5.29 (m, 5 IH), 4.63 (d, J = 9Hz, 2H), 3.56 (s, 2H), 1.79 (s, 3H), 1.7 (s, 3H), 1.39 (d, J = 9Hz, 3H). Example B39 Synthesis of A4(3-chlorophenyl)acetyl] alanine cyclopropylmethyl ester 10 Following General Procedure BC above, and using N-(3- chlorophenylacetyl alanine (from Example BD above) and cyclopropylmethanol (Aldrich), the title compound can be prepared The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc'hexane as the eluant. 15 NMR data was as follows: 'H-nmr (CDCl,): 8 = 7.2-7.1 (m, 4H), 6 09 (bs, IH), 4.6 (dq, J= 9 Hz, IH), 3.96 (dd, J = 9Hz, 2H), 3 59 (s, 2H), 1.2 (d, J = 9Hz, 3H), 1.2-1.0 (m, IH), 0.603-0.503 (m, 2H), 0.300-0.203 (m, 2H). 20 Example B40 Synthesis of A^-[(3-chlorophcnyl)acetyl]alanine 2-thienylmethyl ester Following General Procedure BC above, and using N-(3-chlorophenylacetyl alanine (from Example BD above) and 2-thiophenemethanol (Aldrich) the title compound can be prepared. The reaction was monitored by 25 tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows: 'H-nmr (CDCl,). 8 = 7.37-6.97 (m, 7H), 5.97 (q, 7=14 Hz, 2H), 4 6 (dq, J = 9 Hz, IH), 3.76 (s, 2H), 1.38 (d, J = 9Hz, 3H) 30 Example B41 Printed from Mimosa 07/26/1999 12:37:07 page -217- WO 98/38177 PCT/US98/03373 - 216 - Synthesis of A^-[(3-chlorophenyl)acetyl] alanine (l-methylcyclopropyl)methyl ester Following General Procedure BC above, and using N-(3-chlorophenylacetyl alanine (from Example BD above) and (1-5 methylcyclopropyl)methanol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows: 'H-nmr (CDC13): 8 = 8.6 (bd, 7 = 9 Hz, IH), 3.86 (q, J= 14 Hz, 2H), 10 3.4 (s, 2H), 2.29 (q, J = 9 Hz, IH), 1.3 (d, J = 9Hz, 3H), 1.03 (s, 3H), 0.5-0.4 (m, 2H), 0 4-0.28 (m, 2H). Example B42 Synthesis of iV-[(3-chlorophenyl)acetyl] alanine 3-thienyImethyl ester 15 Following General Procedure BC above, and using N-(3- chlorophenylacetyl alanine (from Example BD above) and 3-thiophenemethanol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3 7 EtOAc:hexane as the eluant 20 NMR data was as follows. 'H-nmr (CDC13): 8 = 8.03 (bd, J = 9 Hz, IH), 7.56-7.5 (m, IH), 7 47 (bs, IH), 7 4-7.17 (m, 4H), 7.06 (d, J = 9 Hz, IH), 5 1 (s, 2H), 4.3 (dq, IH), 1 3 (d, J = 9 Hz, 3H). 25 Example B43 Synthesis of 7V-[(3-chlorophenyl)acetyl]alaninc 2-methylcyclopentyl ester Following General Procedure BC above, and using N-(3-chlorophenylacetyl alanine (from Example BD above) and 2-methylcyclopentanol (Aldrich) the title compound can be prepared. The reaction 30 was monitored by tic on silica gel and purification was by liquid chromatography using 3.7 EtOAc:hexane as the eluant. NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -218- WO 98/38177 PCT/US98/03373 -- 217 - 'H-nmr (CDCl,): 5 = 7.39-7.16 (m, 4H), 6.3 (bd, IH), 4.79-4.7 (m, IH), 4.6-4.25 (m, J= 9 Hz, IH), 3.577 (s, 2H), 2 09-1.8 (m, 2H), 1.74-1.6 (m, 2H), 1.39 (dd, /= 9 Hz, 3H), 1.2 (dt, J = 9 Hz, IH), 0.979 (dd, J = 9 Hz, 2H) C17H22N03C1 (MW = 323.82, Mass Spectroscopy (MH+ 323). 5 Example B44 Synthesis of JV-[(3-chIorophenyl)acetyl] alanine 2-methylprop-2-enyl ester Following General Procedure BC above, and using N-(3-chlorophenylacetyl alanine (from Example BD above) and 2-methylprop-2-en-l-10 ol (Aldrich) the title compound can be prepared The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant. NMR data was as follows. 'H-nmr (CDCl,). 8 = 7.39-7.16 (m, 4H), 6.03 (bs, IH), 4.77 (s, 2H), 4.7-15 4.29 (m, 3H), 2.59 (s, 2H), 1.73 (s, 3H), 1.43 (d, J = 9 Hz, 3H) C15HI8N03C1 (MW = 295.76, Mass Spectroscopy (MH+ 295)). Example B45 Synthesis of 7V-[(3-chlorophenyl)acetyl]alanine cyclohex-2-enyl ester 20 Following General Procedure BC above, and using N-(3- chlorophenylacetyl alanine (from Example BD above) and cyclohex-2-en-l-ol (Aldrich) the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc.hexane as the eluant. 25 NMR data was as follows: 'H-nmr (CDCl,): 8 = 8.6 (bd, J =9 Hz, IH), 7.4-7.2 (m, 4H), 6.0-5.8 (m, IH), 5.7-5.5 (m, IH), 5 1 (bs, IH), 4.13-4.29 (m, IH), 3.5 (s, 2H), 2.1-1.9 (m, 2H), 1.8-1 69 (m, IH), 1 69-1.49 (m, 4H), 1 3 (dd, J= 9 Hz, 3H) Cl7H20NO3Cl (MW = 321 8, Mass Spectroscopy (MH+ 321.2)). 30 Example B46 Printed from Mimosa 07/26/1999 12:37:07 page -219- WO 98/35177 PCT/US98/03373 -- 218 - Synthesis of JV-[(2-phenylbenzoxazol-5-yl)acetyl) alanine iso-butyl ester Following General Procedure BI above, and using 5-(2-phenylbenzoxazol)-yl-acetic acid (CAS# 62143-69-5) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was 5 prepared NMR data was as follows: 'H-nmr (CDCl,): 8 = 8 24 (m, 3H), 7.68 (m, IH), 7.51 (m, 5H), 6.04 (m, IH), 4.58 (m, IH), 3.85 (m, 2H), 3.68 (s, 2H), 1.9 (m, IH), 1.35 (d, 3H), 0.87 (d, 6H). 10 C22H24N2O4 (MW = 380, Mass Spectroscopy (MH+ 381)) Example B47 Synthesis of N- [(3-methylthiophenyl)acetyl] alanine iso-butyl ester Following General Procedure BI above, and using 3-15 methylthiophenylacetic acid (CAS# 18698-73-2) and alanine /so-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 20 'H-nmr (CDCl,): 8 = 7.14 (m, 2H), 7.01 (m, IH), 4.56 (m, IH), 3.88 (m, 2H), 3.54 (s, 2H), 2 46 (s, 3H), 1.89 (m, IH), 1 35 (d, 3H) 0.85 (d, 6H). Cl6H23N03S (MW = 309, Mass Spectroscopy (MH+ 310)). Example B48 25 Synthesis of AT-4-[(2-furyl)acetyl] alanine iso-butyl ester Following General Procedure BI above, and using 2-furylacetic acid (CAS# 2745-26-8) and alanine /so-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in 30 the general procedure. NMR data was as follows Printed from Mimosa 07/26/1999 12:37:07 page -220- WO 93/3JJ177 - 219 - PCT/US98/03373 'H-nmr (CDCl,): 6 = 7 36 (m, IH), 6 34 (m, IH), 6.21 (m, IH), 4.56 (m, IH), 3.91 (m, 2H), 3.61 (s, 2H), 1.92 (m, IH), 1.38 (d, 3H) 0.89 (d, 6H). C13H,9N04 (MW = 253, Mass Spectroscopy (MH* 254)). 5 Example B49 Synthesis of A^-[(benzofuran-2-yl)acetyl] alanine iso-butyl ester Following General Procedure BI above, and using benzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was 10 monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDCl,): 8 = 751 (m, IH), 7.44 (m, 1H),7.25 (m, 2H), 6.67 (s, IH), 4.60 (m, IH), 3.87 (m, 2H), 3.77 (s, 2H), 1 88 (m, IH), 1.38 (d, 3H), 0.87 15 (d, 6H). C)7H21N04 (MW = 303, Mass Spectroscopy (MH+ 304)) Example B50 Synthesis of JV-[(benzothiophen-3-yI)acetyl] alanine iso-butyl ester 20 Following General Procedure BI above, and using thianaphthen-3-ylacetic acid (Lancaster) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. 25 NMR data was as follows. 'H-nmr (CDCl,): 8 = 7.89 (m, IH), 7 76 (m, IH), 7.38 (m, 3H), 6.07 (m, IH), 4 57 (m, IH), 3.92 (m, 2H), 3.82 (s, 4H), 1.84 (m, IH), 1 32 (d, 3H) 0.85 (d, 6H). C17H2|N03S (MW = 319, Mass Spectroscopy (MH+ 320)). 30 Example B51 Printed from Mimosa 07/26/1999 12:37:07 page -221- WO 98/38177 PCT/US98/03373 - 220 -- Synthesis of iV-[(2-chloro-5-thienyl)acetyl)alanine iso-butyl ester Following General Procedure BI above, and using 5-chloro-2-thienyl)acetfc acid (CAS# 13669-19-7) and alanine 2so-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The 5 reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDCl,): 6 = 6.77 (m, IH), 6.68 (d, IH), 6.31 (bm, IH), 4.59 (m, IH), 3.91 (m, 2H), 3.38 (s, 2H), 1 90 (m, IH), 1 39 (d, 3H) 0.89 (d, 6H). 10 CI3HI8N03SC1 (MW = 303, Mass Spectroscopy (MH+ 303)). Example B52 Synthesis of 7V-[(3-methylisoxazol-5-yl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using (3-methyl-isoxazol-5-15 yl)acetic acid (CAS# 19668-85-0) and alanine /so-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure NMR data was as follows: 20 'H-nmr (CDCl,): 8 = 6.07 (s, 2H), 4.56 (m, IH), 3.92 (m, 2H), 3 68 (s, 2H), 2.29 (s, 3H), 1 94 (m, IH), 1.89 (d, 3H) 0 91 (d, 6H). Ci3H20N2O4 (MW = 268, Mass Spectroscopy (MH+ 269)). Example B53 25 Synthesis of ^[(l-phenylthiothienytyacetyl] alanine iso-butyl ester Following General Procedure BI above, and using (2-phenyl-thiothienyl)acetic acid and alanine /.yo-butyl ester (prepared following General Procedure BJ above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as described in 30 the general procedure. NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -222- WO 98/38177 PCT/US98/03373 - 221 - 'H-nmr (CDCl,). 8 = 7.21-7.11 (m, 6H), 6.92 (d, IH), 4.56(m, IH), 3.87 (m, 2H), 3.72 (s, 2H), 1.94 (m, IH), 1.38 (d, 3H) 0 89 (d, 6H). C19H23N03S2 (MW = 377, Mass Spectroscopy (MH+ 378)). 5 Example B54 Synthesis of ^-[(d-methoxybenzothiophen-Z-y^acetyl]alanine iso-butyl ester Following General Procedure BI above, and using (6-methoxythianaphthen-2-yl)acetic acid and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The 10 reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure NMR data was as follows 'H-nmr (CDCl,): 8 = 7.59 (d, IH), 7.33 (d, IH), 7.16 (s, IH), 7.03 (dd, IH), 4.56 (m, IH), 3.87(s, 3H), 3 84 (m, 2H), 3.76 (s, 2H),1.85 (m, IH), 1.30 15 (d, 3H) 0.86 (d, 6H). Cl8H23N04S (MW = 349, Mass Spectroscopy (MH+ 350)) Example B55 Synthesis of JV-[(3-phenyl-l,2,4-thiadiazol-5-yl)acetyl]alanine iso-butyl ester 20 Following General Procedure BI above, and using (3-phenyl-l,2,4- thiadiazol-5-yl)acetic acid (CAS# 90771-06-5) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. 25 NMR data was as follows. 'H-nmr (CDCl,): 8 = 7 47 (m, 5H), 4.66 (m, IH), 4.16 (s, 2H), 3.91 (m, 2H), 1 93 (m, IH), 1.48 (d, 3H) 0.93 (d, 6H). C)7H2iN303S (MW = 347, Mass Spectroscopy (MH+ 348)). 30 Example B56 Synthesis of 7V-[2-phenyloxazol-4-yl)acetyl]alanine iso-butyl ester Printed from Mimosa 07/26/1999 12:37:07 page -223- WO 98/38177 PCT/US98/03373 -- 222 - Following General Procedure BI above, and using (2-phenyloxazol-4-yl)acetic acid (CAS# 22086-89-1) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as described 5 in the general procedure. Example B57 Synthesis of N-[(3-methylphenyl)acetyl]alanine iso-butyl ester Following General Procedure BI above, and using 3-methylphenylacetic 10 acid (Aldrich) and alanine /so-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by filtration as.described in the general procedure. NMR data was as follows: 15 'H-nmr (CDCl,): 8 = 7.21 (m, IH), 7.07 (m, 3H), 4 54 (m, IH), 3.83 (m, 2H), 3.52 (s, 2H), 2.35 (s, 3H), 1.87 (m, IH), 1.32 (d, 3H), 0 88 (d, 6H) C16H23N03 (MW = 277, Mass Spectroscopy (MH+ 278)). Example B58 20 Synthesis of Ar-[(2,5-difluorophenyl)acetyI] alanine iso-butyl ester Following General Procedure BI above, and using 2,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as 25 described in the general procedure NMR data was as follows: 'H-nmr (CDCl,): 8 = 7.08-6.94 (m, 3H), 4.57 (m, IH), 3.91 (m, 2H), 3.56 (s, 2H), 1.92 (m, IH), 1.41 (d, 3H) 0.91 (d, 6H). C15H19N03F2 (MW = 299, Mass Spectroscopy (MH+ 300)). 30 Example B59 Printed from Mimosa 07/26/1999 12:37:07 page -224- WO 98/38177 -- 223 - PCT/US98/03373 Synthesis of iV-[(3,5-diflurophenyl)acetyl]alanine /so-butylester Following General Procedure BI above, and using 3,5-difluorophenylacetic acid (Aldrich) and alanine /so-butyl ester (prepared following General Procedure BJ above), the title compound way prepared. The 5 reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 'H-nmr (CDCl,): 5 = 6.81 (m, 2H), 6.74 (m, IH), 6.06 (m, IH), 4.57 (m, IH), 3.92 (m, 2H), 3.51 (s, 2H), 1.94 (m, IH), 1.36 (d, 3H) 0.87 (d, 6H). 10 C15H19N03F2 (MW = 299, Mass Spectroscopy (MH+ 300)). Example B60 Synthesis of 7V-[(3-thienyl)acetyl] alanine /so-butyl ester Following General Procedure BI above, and using 3-thiopheneacetic acid 15 (Aldrich) and alanine /so-butyl ester (prepared following General Procedure BJ above), the title compound was prepared The reaction was monitored by tic on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows. 'H-nmr (CDCl,): 5 = 7.33 (m, IH), 7.14 (m, IH), 7.01 (m, IH), 6.09 (m, 20 IH), 4 58 (m, IH), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, IH), 1 37 (d, 3H) 0.92 (d, 6H). Optical Rotation- [a]23 -52 (c 1 MeOH) @ 589 nm. C13Hl9N03S (MW = 269, Mass Spectroscopy (MH+ 269)). 25 Example B61 Synthesis of Ar-[(4-methylphenyl)acetyl]-L-alanine iso-butyl ester Following General Procedure BI above, and using 4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared The reaction was 30 monitored by tic on silica gel and purification was by filtration as described in the general procedure Printed from Mimosa 07/26/1999 12:37:07 page -225- WO 98/38177 PCT/US98/03373 - 224 -NMR data was as follows. 'H-nmr (CDCl,) 6 = 7.11 (s, 4H), 5.93 (m, IH), 4.58 (m, IH), 3.88 (m, 2H), 3 54 (s; 2H), 2.33 (s, 3H), 1.89 (m, IH), 1.32 (d, 3H), 0.89 (d, 6H) C16H,3N03 (MW = 277.35, Mass Spectroscopy (MH+ 278)) 5 Example B62 Synthesis of 7V-(phenylacetyI)-L-aIanine S-l-(methoxycarbonyl) /so-butyl ester Following General Procedure BK and using (S)-(+)-2-hydroxy-2-10 methylbutyric acid (Aldrich) in place of the amino acid, methyl (S)-(+)-2-hydroxy-2-methylbutyrate was prepared Methyl (S)-(+)-2-hydroxy-2-methylbiityrate was then coupled with carbobenzyloxy-L-alamne (Aldrich) using General Procedure BE to provide carbobenzyloxy-L-alanine S-l-(methoxycarbonyl) zso-butyl ester. 15 Carbobenzyloxy-L-alanine S-l-(methoxycarbonyl) ;.so-butyl ester (1.0 g) was then dissolved in 20 mL of methanol and 6N HCl (0.5 mL) and 10% palladium on carbon (0.1 g) were added This reaction mixture was hydrogenated at 40 psi of hydrogen on a Parr apparatus for 5 hours at room temperature and then filtered through a pad of Celite. The filtrate was 20 concentrated at reduced pressure to provide L-alanine S-l-(methoxycarbonyl) jso-butyl ester hydrochloride (98% yield). L-Alanine S-l-(methoxycarbonyl) /so-butyl ester hydrochloride was then coupled to phenylacetic acid using General Procedure BG to provide the title compound. 25 NMR data was as follows: 'H-nmr (CDCl,): 5 = 7 35 - 7.20 (m, 5H), 6.22 (bd, IH), 4.83 (d, IH), 4.65 (p, IH), 3.68 (s, 3H), 3.55 (s, 2H), 2.21 (m, IH), 1.40 (d, 3H), 0.97 (d, 3H), 0 93 (d, 3H). l3C-nmr (CDC13): 5 = 173.25, 171.18, 170 22, 135.11, 129.94, 129.50, 30 127.88, 52.67, 48 49, 43 98, 30 53, 19.21, 18.75, 17 58 Example B63 Printed from Mimosa 07/26/1999 12:37:07 page -226- WO 98/38177 PCT/US98/03373 - 225 - Synthesis of 7V-[(3-nitrophenyl)acetyl|-L-alanine iso-butyl ester Following General Procedure BH above and using 3-nitrophenylacetic acid (AldricH) and L-alanine wo-butyl ester hydrochloride (from Example BB above), the title compound was prepared. The reaction was monitored by tic on 5 silica gel and purification was by recrystallization from butyl chloride. NMR data was as follows: 'H-nmr (CDC13): 5 = 8.17 (m, 2H), 7.68 (d, IH), 7.52 (t, IH), 6.18 (m, IH), 4.48 (m, IH), 3.94 (m, 2H), 3 67 (s, 2H), 1.93 (m, IH), 1.42 (d, 3H), 0.91 (d, 3H). 10 Optical Rotation: [a],3 -49 (c 5, MeOH). Example B64 Synthesis of /V-[(3,5-difluorophenyl)acetyl] alanine ethyl ester Following General Procedure BG and using 3,5-difluorophenylacetic acid 15 (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93°-95°C. The reaction was monitored by tic on silica gel (Rf = 0 8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1 -chlorobutane. NMR data was as follows: 20 'H-nmr (DMSO-rf6): 5 = 1.30 (d, 3H), 3.52 (s, 2H). C13H,5N03F2 (MW = 271.26, Mass Spectroscopy (Mir 271)). Example B65 Synthesis of jV-[(3-nitrophenyl)acetyl]methionine ethyl ester 25 Following General Procedure BG above and using 3-nitrophenylacetic acid (Aldrich) and methionine ethyl ester hydrochlonde (Aldrich), the title compound was prepared. The reaction was monitored by tic on silica gel and purification was by recrystallization from butyl chloride NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -227- WO 98/38177 - 226 -- PCT/US98/03373 'H-nmr (CDCl,): 8 = 8.18 (s, IH), 8.15 (d, IH) 7 66 (d, IH); 7.48 (t, IH), 6.30 (m, IH), 4.67 (m, IH), 4.21 (t, 2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27 (t, 3H). Optical Rotation: [a]23 -30 (c 5, MeOH). 5 Example B66 Synthesis of JV-|(3-chlorophenyl)acetyl] alanine iso-butyl ester Following General Procedure BG above and using 3-chlorophenylacetic acid (Aldrich) and alanine wo-butyl ester (prepared following General Procedure 10 BJ above), the title compound was prepared The reaction was monitored by tic on silica gel NMR data was as follows: 'H-nmr (CDCl,): 5 = 7.29 (m, 3H), 7.18 (m, IH), 6.0 (m, IH), 4.56 (m, IH), 3.89 (m, 2H), 3.53 (s, 2H), 1.91 (m, IH), 1.39 (d, 3 H), 0.91 (d, 3H). 15 Optical Rotation: [<x]23 -45 (c 5, MeOH). C)5H2oNOjC1 (MW = 297.78, Mass Spectroscopy (MH+ 297)). Example B67 Synthesis of jV-[(3-chlorophenyi)acetyl]alanine 20 2-(Ar^V-dimethylamino)ethyl ester Following General Procedure BC above, and using N-(3-chlorophenyl-acetyl)alanine (from Example BD above) and 2-(N,N-dimethyl amino) ethanol (Aldrich), the title compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 0.1:2.0 79 25 NH4OH:EtOH:CHCl3 as the eluant. NMR data was as follows: 'H-nmr (CDCl,): 7.37 (s, IH), 7.33-7.2 (m, 3H), 4.675-4.6 (m, IH), 4.5-4.37 (m, IH), 4.25-4.13 (m, IH), 3.6 (d, J= 7 Hz, 2H), 2.86 (bs, 2H), 2.3 (s, 6H), 1.23 (d, J =9 Hz, 3H). 30 C15H21N,03C1 (MW = 313.799, Mass Spectroscopy (M+ 313)). Example B68 Printed from Mimosa 07/26/1999 12:37:07 page -228- WO 98/38177 - 227 -- PCT/US98/03373 Synthesis of 2-[(3,5-dichlorophenyl)acetamido]hexanoic acid methyl ester Following General Procedure BF above, an using 3,5-dichloropheriylacetic acid (from Example BC above) and L-norleucine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid having 5 a melting point of 77°-78°C The reaction was monitored by tic on silica gel (Rf = 0.70 in 40% EtOAC/hexanes) and purification was by flash chromatography on silica gel using 40% EtOAc/hexanes as the eluant NMR data was as follows. 'H-nmr (CDC13). 8 = 7.20 (s), 7.18 (s), 6.6 (m), 4.55 (m), 3.7 (s), 3.5 (s), 10 3 4 (s), 2.0 (s), 1.8 (m), 1 6 (m), 1.2 (m), 0.8 (t) l3C-nmr (CDC13): 5 = 173.54, 169.67, 138 43, 135.72, 128 33, 128 07, 78 04, 77.62, 77 19, 53 04, 52.90, 43.14, 32.57, 27 87, 22.81, 14.41. Example B69 15 Synthesis of 7V-[(3,5-diclorophenyl)acetyl]-L-alanine /so-butyl ester Following General Procedure BF above, and using 3,5-dichlorophenylacetic acid (from Example BC above) and L-alanine /so-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 115°-116°C The reaction was monitored 20 by tic on silica gel (Rf = 0.40 in 3% methanol/dichloromethane) and purification was by flash chromatography on silica gel using 3% methanol/dichloromethane as the eluant. NMR data was as follows. 'H-nmr (CDC13): 8 = 7.27 (d, J= 2 Hz, IH), 7.19 (s, 2H), 6.22 (d,J = 25 6 Hz, IH), 4 59 (quint., J= 7 Hz, IH), 3.9 (q, J= 4 Hz, 2H), 3.5 (s, 2H), 1.9 (m, IH), 1.4 (d, J= 7 Hz, 3H), 0.91 (d, J= 7 Hz, 6H). 13C-nmr (CDC13): 8 = 173.45, 169 37, 138.31, 135.75, 128.39, 128.11, 78.04, 77.61, 77.19, 72.19, 54 03, 48 97, 43 12, 28.24. 19.52, 19 49, 19.09 CI5H,9N03C12 (MW = 331.9, Mass Spectroscopy (MH+ 332)). 30 Example B70 Printed from Mimosa 07/26/1999 12:37:07 page -229- WO 98/38177 PCT/US98/03373 - 228 -- Synthesis of /V-(cyclohexylacetyl)-L-aIanine /so-butyl ester Following General Procedure BB above, and using cyclohexylacetic acid (Aldrich) arid L-alanine /so-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 92°C-5 93°C. The reaction was monitored by tic on silica gel (Rf = 0.39 in 1:3 EtOAc :hexane) and purification was by extraction with Et,0 followed by washes with aqueous K,C03 and aqueous HCl. NMR data was as follows: 'H-nmr (CDC13). S = 0.93 (d, 7= 6.7 Hz, 6H), 0.85-1.01 (m, 2H), 1.05-10 1 35 (m, 3H), 1.40 (d, 7 = 7.1 Hz, 3H), 1.60-1.85 (m, 6H), 1.95 (m, IH), 2.06 (d, 7 = 7.0 Hz, 2H), 3 92 (m, 2H), 4.61 (m, IH), 6.08 (bd, IH). 13C-nmr (CDC13) 5 = 18.7, 18 9, 26.0, 26.1, 27 6, 33.0, 35.3, 44 6, 47.9, 71.4, 171.8, 173.3. C15H27N03 (MW = 269.39, Mass Spectroscopy (MH+ 270)). 15 Example B71 Synthesis of 7V-(cyclopentyIacetyl)-L-alanine /so-butyl ester Following General Procedure BB above, and using cyclopentylacetic acid (Aldrich) and L-alanine /so-butyl ester hydrochloride (from Example BB above), 20 the title compound was prepared as a solid having a melting point of 62°C-64°C. The reaction was monitored by tic on silica gel (Rf = 0 37 in 1:3 EtOAc:hexane) and purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl. NMR data was as follows-25 'H-nmr (CDCl,): 8 = 0.87 (d, 7 = 6.8 Hz, 6H), 1.01-1.17 (m, 2H), 1.34 (d, J - 7.2 Hz, 3H), 1.40-1.62 (m, 4H), 1.70-1.83 (m, 2H), 1.89 (m, IH), 2.15 (m, 3H), 3.86 (m, 2H), 4.55 (m, IH), 6.30 (d, 7= 7.1 Hz, IH). l3C-nmr (CDC13): 8 = 18.4, 18.78, 18 80, 24.8 (very high), 27 5, 32.27, 32.32, 36.9, 42.5, 47 7, 71.2, 172.2, 173 2 30 Elemental Analysis-Calc (%). C, 65.85, H, 9.87, N, 5.49, Found (%): C, 66.01; H, 10.08; N, 5.49. Printed from Mimosa 07/26/1999 12:37:07 page -230- WO 98/38177 PCT/US98/03373 - 229 - C14H25NO3 (MW = 255.36, Mass Spectroscopy (MH+ 256)) ' Example B72 Synthesis of /V-[(cyclohex-l-enyl)acetyl]-L-alanine /so-butyl ester 5 Following General Procedure BB above, and using cyclohex-l-enyl acetic acid (Alfa) and L-alanine /so-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 49°C-51°C. The reaction was monitored by tic on silica gel (Rf = 0.40 in 1.3 EtOAc:hexane) and purification was by extraction with Et20 followed by washes 10 with aqueous K2C03 and aqueous HCl. NMR data was as follows. 'H-nmr (CDC13): 5 = 0.91 (d, J= 4.5 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 7.2 Hz, 3H), 1.52-1 70 (m, 4H), 1.97 (m, 3H), 2.06 (bs, 2H), 2.89 (s, 2H), 3.92 (m, 2H), 4.59 (m, IH), 5.65 (s, IH), 6.33 (d, J = 6.6 Hz, IH). 15 ,3C-nmr (CDC13): 8 = 18.7, 18.91, 18 93, 21.9, 22.7, 25.3, 27.6, 28.3, 46.1, 47.9, 71.4, 127.1, 132.5, 170.6, 173.1. Elemental Analysis-Calc (%). C, 67.38; H, 9.42; N, 5.24, Found (%)• C, 67.34; H, 9.54; N, 5.16 C,5H25N03 (MW = 267.37, Mass Spectroscopy (MH+ 268)). 20 Example B73 Synthesis of iV-[(3-chlorophenyl)acetyl]alanine 3-methylbut-2-enyl thioester Following General Procedure BC above, and using N-[(3-chlorophenyl)acetyl] alanine and 3-methyl-2-butene thioester (TCI), the title 25 compound can be prepared. The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3:7 EtOAc:Hexane as the eluant. NMR data was as follows: 'H-nmr (DMSO-rf6): 8 = 5.2-5.075 (m, IH), 4.37 (dq, J= 9 Hz, IH), 30 3.56 (s), 3.43 (d, J = 12 Hz, 2H), 1.266 (d, J = 12 Hz, 6H) 1.3 (d, J = 9 Hz, 3H). Printed from Mimosa 07/26/1999 12:37:07 page -231- WO 98/38177 PCT/US98/03373 -- 230 - C15H20NO2ClS (MW = 325.86, Mass Spectroscopy (M+ 325)). Example B74 Synthesis of 7V-[(2-phenyl)-2-fluoroacetyl]alanine ethyl ester 5 Following General Procedure BF above, and using a-fluorophenyl acetic acid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared The reaction was monitored by tic on silica gel (Rf = 0.75 in 1:1 EtOAc:hexane) and purification was by chromatography on silica gel using 1:2 ethyl acetate/hexanes as the eluent 10 NMR data was as follows: 'H-nmr (DMSO-</6)- 5 = 1 14 (q, 3H), 1.34 (d, 3H), 4 07 (m, 2H), 4.33 (m, IH), 5 84 (d, IH), 6.01 (d, IH), 7.40-7 55 (m, 5H), 8.87 (m, IH) C|3H,6N03F (MW = 253.27, Mass Spectroscopy (MH+ 253)). 15 Example B75 Synthesis of 7V-(3,5-difluorophenylacetyl)-L-phenylgIycine methyl ester Following General Procedure BF above, and using 3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared. 20 NMR data was as follows: 'H-nmr (CDC13): 5 =7.4-7.3 (m, 5H), 6.9-6.7 (m, 3H), 6.55 (d IH, 7 1 Hz), 5.56 (d IH 7 Hz), 3.72 (s 3H), 3.57 (s 2H) l3C-nmr (CDC13): 5 = 197.6, 177.6, 171.8, 169 3, 136.7, 129.6, 129.3, 127.8, 113.0, 112.9, 112.7, 111.4, 103.8, 103 5, 65.1, 57.2, 53.5, 45.1, 43.3, 25 43.3 C|7H15N03F2 (MW = 319.31, Mass Spectroscopy (MH +320)). Example B76 Synthesis of 7V-(3,5-difluorophenylacetyl)-L-phenylglycine iso-butyl ester 30 The 3,5-difluorophenylacetic acid (Aldrich) was EDC coupled to L- phenylglycine methyl ester hydrochloride (Bachem) via General Procedure BF Printed from Mimosa 07/26/1999 12:37:07 page -232- WO 98/38177 PCT/US98/03373 — 231 - above. The resulting compound was placed in a large excess of the desired alcohol A catalytic amount of dry NaH was added, and the reaction was followed by "tic until the presence of starting material was no longer detected. The reaction was quenched with a few milliliters of IN HCl, and after a few 5 minutes of stirring saturated aqueous NaHCO, was added The volume of the reaction mixture was reduced on a rotary evaporator until the excess alcohol was removed and then the remaining residue was taken up in ethyl acetate and additional water was added. The organic phase was washed with saturated aqueous NaCl and dried over MgSOj. The solution was stripped free of solvent 10 on a rotary evaporator, and the crude product residue was then further purified by chromatography NMR data was as follows 'H-nmr (CDC13)- 5 = 7.35-7.3 (m 5H), 6 8-6.7 (m 3H) 6 60 (d IH, 7 Hz), 5.55 (d IH 7.1 Hz), 3.9 (m 2H), 3 60 (s 2H), 1.85 (m IH 7 Hz), 0.8 (q 6H 15 7 Hz) ,3C-nmr (CDC13): 6 = 171.3, 169.3, 165 4, 138 5, 137.0, 129.5, 129.2, 127.6, 113 1, 113.0, 112.8, 112.7, 103.8, 103.5, 103.2, 75.5, 57.2, 43 4, 43.3, 28.2, 19.3 C20H21NO3F2 (MW = 361.39, Mass Spectroscopy (MH +362)). 20 Example B77 Synthesis of 7V-(cyclopentylacetyl)-L-phenylglycine methyl ester Following General Procedure BD above, and using cyclopentylacetic acid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem) the title 25 compound was prepared. NMR data was as follows: 'H-nmr (CDC13): 8 = 7.35 (s, 5H), 6.44 (bd, IH), 5.6 (d, IH). 3.72 (s, 3H), 2 24 (bs, 3H), 19-14 (m, 6H), 1.2-1.05 (m, 2H) ,3C-nmr (CDC13). 8 = 172.3, 171.7, 136.7, 129.0, 128.6, 127.3, 56.2, 30 52.7, 42.5, 36.9, 32.40, 32.38, 24.8 Printed from Mimosa 07/26/1999 12:37:07 page -233- -WO 98/38177 PCT/US98/03373 - 232 - Example B78 Synthesis of 7V-(cyclopentylacetyl)-L-alanine methyl ester Following General Procedure BD above, and using cyclopentylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma) the title compound 5 was prepared. NMR data was as follows: 'H-nmr (CDC13): 8 = 6.38 (d, IH), 4.50 (m, IH), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes d at 1.30, 3H), 11H) 13C-nmr (CDC13): 8 = 173.7, 172.5, 52.1, 47.6, 42.3, 36.8, 32.15, 32.14, 10 18.0 CmHwNOj (MW = 213.28, Mass Spectroscopy (MH* 214)). Example B79 Synthesis of 7V-(cyclopropylacetyl)-L-phenylglycine methyl ester 15 Following General Procedure BD above, and using cyclopropylacetic acid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared. NMR data was as follows: 'H-nmr (CDC13). 8 = 7.35 (m, 5H) 6 97 (bd, J = 12 Hz, IH) 5 59 (d, 20 J= 7.8 Hz, IH), 3.71 (s, 3H), 2.17 (m, 2H), 1.05-0.95 (m, IH), 0 62 (m, 2H), 0.02 (m, 2H) l3C-nmr (CDC13): 8 = 171.9, 174.6, 136.6, 129.0, 128 5, 127.2, 56.1, 52.7, 41.0, 6.9, 4.37, 4.33 25 Example B80 Synthesis of JV-(cyclopropylacetyl)-L-alanine methyl ester Following General Procedure BD above, and using cyclopropylacetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared 30 NMR data was as follows: Printed from Mimosa 07/26/1999 12:37:07 page -234- WO 98/38177 PCT/US98/03373 - 233 -- 'H-nmr (CDC13) 8 = 6.60 (d, IH), 4 55 (m, IH), 3.69 (s, 3H), 2 10 (m, 2H), 1.34 (d, 3H), 0.95 (m, IH), 0.58 (m, 2H) 0.15 (m, 2H) l3C-nmr (CDC13): 8 = 173.7, 172.3, 52.3, 47.7, 41 0, 18.2, 6 7, 4.27, 4.22 5 Example B81 Synthesis of AL[(3-nitrophenyl)acetyl]-L-methionine /so-butyl ester Following General Procedure BH above, and using nitrophenylacetic acid (Aldrich) -and L-methionine (Aldrich), the title compound was prepared as a tan oil. The reaction was monitored by tic on silica gel. 10 NMR data was as follows: 'H-nmr (CDC13). 8 = 8.16 (m,2H) 7.67 (d,lH) 7.32 (t, IH), 6.31 (bd, IH), 4.69 (m, IH), 3.90 (d, 2H), 3.68 (s, 2H), 2 47 (t, 2H), 2.15 (m, IH), 2 02 (s, 3H), 1.90 (m, 2H), 0.91 (d, 6H). C17H24N205S (MW = 368.4, Mass Spectroscopy (MH+ 368)). 15 The following General Procedures and Examples illustrate the synthesis of various lactams and related compounds which can be used to prepare, for example, compounds of formula VII and VIII above 20 GENERAL PROCEDURE III-A First EDC Coupling Procedure To a 1:1 mixture of the corresponding carboxylic acid and the corresponding amino acid ester or amide in CH2C12 at 0°C was added 1.5 equivalents triethylamme, followed by 2.0 equivalents hydroxybenzotriazole 25 monohydrate and then 1.25 equivalents of ethyl-3-(3-dimethylamino)propyl carbodiimide'HCl. The reaction mixture was stirred overnight at room temperature and then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHC03, IN HCl and saturated aqueous NaCl, and then dried over MgS04. The resulting solution was stripped free of 30 solvent on a rotary evaporator to yield the crude product. Printed from Mimosa 07/26/1999 12:37:07 page -235- WO 98/38177 PCT/US98/03373 — 234 - GENERAL PROCEDURE III-B Second EDC Coupling Procedure A mixture of the corresponding acid (1 eqv), N-l-hydroxybenzotriazole (1.6 eqv), the corresponding amine (1 eqv), N-methylmorpholine ( 3 eqv) and 5 dichloromethane (or DMF for insoluble substrates) was cooled in an ice-water bath and stirred until a clear solution was obtained. EDC (1.3 eqv) was then added to the reaction mixture. The cooling bath was then allowed to warm to ambient temperature over 1-2 h and the reaction mixture was stirred overnight. The reaction mixture was then evaporated to dryness under vacuum. To the 10 residue was added 20% aqueous potassium carbonate and the mixture was shaken throughly and then allowed to stand until the oily product solidified (overnight if necessary) The solid product was then collected by Alteration, washed thoroughly with 20% aqueous potassium carbonate, water, 10% HCl, and water to give the product, usually in pure state. No racemization was 15 observed. GENERAL PROCEDURE III-C Third EDC Coupling Procedure The carboxylic acid was dissolved in methylene chloride The 20 corresponding amino acid ester or amide (1 eq.), N-methylmorpholine (5 eq.) and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. A cooling bath was applied to the round bottomed flask until the solution reached 0°C At that time, 1.2 eq. of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The solution was allowed to stir overnight and come 25 to room temperature under nitrogen pressure The reaction mixture was worked up by washing the organic phase with saturated aqueous sodium carbonate, 0.1M citric acid, and brine before drying with sodium sulfate. The solvents were then removed to yield crude product. 30 GENERAL PROCEDURE III-D Fourth EDC Coupling Procedure Printed from Mimosa 07/26/1999 12:37:07 page -236- wo 98/38177 PCT/US98/03373 - 235 - A round bottom flask was charged with the corresponding carboxylic acid (1.0 eq.), hydroxybenzotriazole hydrate (1.1 eq.) and the corresponding amine (1.0 eq.) in THF under nitrogen atmosphere. An appropriate amount (1.1 eq for free amines and 2.2 eq. for hydrochloride amine salts) of base, such as 5 Hunig's base was added to the well stirred mixture followed by EDC (1.1 eq.). After stirring from 4 to 17 hours at room temperature the solvent was removed at reduced pressure, the residue taken up in ethyl acetate (or similar solvent) and water, washed with saturated aqueous sodium bicarbonate solution, 1 N HCl, brine, dried over anhydrous sodium sulfate and the solvent removed at reduced 10 pressure to provide the product GENERAL PROCEDURE III-E BOP Coupling Procedure To a stirred solution of jV-(3,5-difluorophenylacetyl)alanine (2 mmol) in 15 DMF, cooled in an ice-water bath, was added BOP (2.4 mmol) and N- methylmorphohne (6 mmol). The reaction mixture was stirred for 50 min. and then a solution of a-amino-y-lactam (2 mmol) in DMF cooled at 0 °C was added. The cooling bath was allowed to warm to ambient temperature over 1-2 h and the reaction mixture was then stirred overnight A 20% aqueous 20 potassium carbonate solution (60 mL) was added and this mixture shaken throughly. No solid formed. The mixture was then washed with ethyl acetate (150 mL) and evaporated to dryness under vacuum to give a white solid. Water (50 mL) was then added and this mixture shaken throughly. The precipitate that formed was collected by filtration, then washed thoroughly with water, followed 25 by 1 mL of diethyl ether to give the product (51 mg, 0.16 mmol, 7.8%). GENERAL PROCEDURE III-F Coupling of an Acid Chloride with an Amino Acid Ester To a stirred solution of (D,L)-alamne isobutyl ester hydrochloride (4.6 30 mmol) in 5 ml of pyridine was added 4.6 mmol of the acid chloride. Precipitation occurred immediately. The mixture was stirred for 3.5 h, dissolved Printed from Mimosa 07/26/1999 12:37:07 page -237- WO 98/38177 PCT/US98/03373 - 236 -- in 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once and brine once. The solution was dried over magnesium sulfate, filtered, and evaporated to yield the product Other amino acid esters may also be employed in this procedure. 5 GENERAL PROCEDURE III-G Coupling of a Carboxvhc Acid with an Amino Acid Ester A solution of the carboxylic acid (3.3 mmol) and l,l'-carbodiimidazole (CDI) in 20 mL THF was stirred for 2 h. (D,L)-alanme isobutyl ester 10 hydrochloride (3.6 mmol) was added, followed by 1 5 mL (10 8 mmol) of triethylamine. The reaction mixture was stirred overnight. The reaction mixture was dissolved in 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once and brine once The solution was dried over magnesium sulfate, filtered, and evaporated to yield the product. 15 Other amino acid esters may also be employed in this procedure GENERAL PROCEDURE III-H Fifth EDC Coupling Procedure In a round bottom flask was added a carboxylic acid (1.1 eq.) in THF, an 20 amine hydrochloride (1 0 eq.), 1-hydroxybenzotriazole hydrate (1.1 eq.), N,N-diisopropylethylamine (2.1 eq.), followed by l-(3-dimethylaminopropyI)-3-ethylcarbodiimide hydrochloride (EDC) (1.1 eq) The reaction mixture stirred at room temperature for 10-20 hours under an atmosphere of nitrogen. The mixture was diluted with EtOAc and washed with 0.1 M HCl (1 x 10 mL), 25 saturated NaHC03 (1x10 mL), H20 (1 x 10 mL), and brine and dried over MgS04. The drying agent was removed by filtration and the filtrate was concentrated in vacuo The residue was purified by flash column chromatography on silica gel followed by trituration from EtOAc and hexanes. 30 GENERAL PROCEDURE III-I Sixth EDC Coupling Procedure Printed from Mimosa 07/26/1999 12:37:07 page -238- WO 98/38177 PCT/US98/03373 - 237 - To a solution or suspension of the amine or amine hydrochloride (1.0 eq ) in THF (0.05-0.1 M) under N2 at 0°C was added the carboxylic acid (1.0-1.1 eq.), hydroxybenzotriazole monohydrate (1.1-1.15 eq.), Hunig's base (1 1 eq. for free amines and 1.1-2.3 eq. for hydrochloride amine salts), followed by l-(3-5 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.1-1.15 eq.). The cooling bath was removed and the mixture allowed to warm to room temperature for 10-24 hours. The solution or mixture was diluted with EtOAc, in a 3-5 volume multiple of the initial THF volume, and washed with 0 1-1.0 M aq. HCl (1 or 2x), dilute NaHC03 (1 or 2x), and brine (lx). Then, the organic 10 phase was dried over either MgSO„ or Na,S04, filtered, concentrated to provide the crude product, which was either further purified or utilized without further purification. GENERAL PROCEDURE III-J 15 EEDO Coupling Procedure To a solution of the amine in THF (1 0 eq., 0.05-0.08 M, final molarity) under N2 at room temperature was added the N-t-Boc protected amino acid (1.1 eq., either as a solid or in THF via cannula), followed by EEDQ (Aldrich, 1.1 eq.). The pale yellow solution was stirred at room temperature for 16-16 5 20 hours, then diluted with EtOAc (in a 3-5 volume multiple of the initial THF volume), and washed with 1M aq. HCl (2x), dilute aq. NaHC03 (2x), and brine (lx). The organic phase was dried over either NajSO,, or MgS04, filtered, and concentrated. 25 Example 2-A Synthesis of 5-Amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol Hydrochloride Step A - Synthesis of 5-Oximo-5.7-dihvdro-6H-30 dibenzo r a.clcvclohepten-6-one A round bottom flask was charged with 5,7-dihydro-6H- dibenzo[a,c]cyclohepten-6-one (1.0 g, 4 81 mmol)(CAS# 1139-82-8, prepared as Printed from Mimosa 07/26/1999 12:37:07 page -239- WD 98/38177 PCT/US98/03373 - 238 - described in Tetrahedron Letters, Vol. 28, No. 23, (1987), pp 2633-2636) and butyl nitrite (0.673 ml, 5.77 mmol) (Aldrich) in Et20. The solution was cooled to 0°C and treated drop-wise with a saturated solution of HCl(g)/Et20. After 5 h at 0°C the resulting precipitate was filtered, rinsed with cold Et,0 and vacuum 5 dried to give the title compound as a colorless solid NMR data was as follows: 'H-nmr (CDC13): S - 7.26-7 74 (m, 8H), 3.84 (m, 2H). C|5HnN02 (MW = 237.26); mass spectroscopy (MH+) 238. Anal. Calcd for C15HnN02; C, 75 93 H, 4.67 N, 5.90. Found: C, 75.67 10 H, 4.83 N, 5.67. Step B- Synthesis of 5-Amino-5.7-dihvdro-6H- dibenzora.clcvclohepten-6-ol Hydrochloride The compound isolated above (0 489 g, 2.04 mmol) was dissolved in 15 THF and added drop-wise to a well-stirred mixture of LAH (10.2 ml, 10.2 mmol)/THF. After heating to reflux for 25 h under N2 atmosphere the solution was quenched and worked-up according to Fieser's method. The resulting solid was rinsed with NH3 sat/CHCl3, the filtrate evaporated and the title compound purified by chromatography (SiO,, CHC13). 20 Cl5Hi5NO(MW = 225.290); mass spectroscopy (MH+) 226 Anal. Calcd for C15H15NO; C, 79.97 H, 6 71 N, 6.22. Found C, 80.19 H, 6.71 N, 5.91. GENERAL PROCEDURE 5-A 25 yV-AIkvlation of Lactams To a stirred solution of a BOC-protected a-aminocaprolactam (6.87 g, 30 mmol) in DMF (150 mL) was added in portions 97% NaH (1 08g, 45 mmol). Bubbling occured immediately and followed by heavy precipitation. After 10 min., benzyl bromide (3.93 mL, 33 mmol) was added. The precipitate dissolved 30 quickly and in about 10 min. a clear solution was obtained. The reaction mixture was stirred overnight and then evaporated as completely as possible on a rotovap at 30°C. Ethyl acetate (100 mL) was added to the residue and this Printed from Mimosa 07/26/1999 12:37:07 page -240- WO 98/38177 PCT/US98/03373 - 239 - mixture was washed with water, bnne, and dried over magnesium sulfate After filtration and concentration, a thick liquid (10 g) was obtained which was then chromatographed over silica gel with 1.3 ethyl acetate/hexane as the eluant to provide 5.51 g (58%) of the N-benzylated product as an oil. Other lactams and 5 alkylating agents may be used in this procedure to obtain a wide variety of N-alkylated lactams. Various bases, such as LiN(SiMe3), may also be employed. GENERAL PROCEDURE 5-B BOC Removal Procedure 10 The BOC-protected compound in a 1:1-2:1 mixture of CH2C1, and trifluoroacetic acid was stirred until tic indicated complete conversion, typically 2 hours. The solution was then stripped to dryness and the residue was taken up in ethyl acetate or CH2C12. The solution was washed with saturated aqueous NaHC03 and the aqueous phase was adjusted to a basic pH, then extracted with 15 ethyl acetate or CH2C12. The organic phase was washed with saturated aqueous NaCl and dried over MgS04. The solution was stripped free of solvent on a rotary evaporator to yield the product GENERAL PROCEDURE 5-C 20 Synthesis of a-Aminolactams The Schmidt reaction was conducted on 4-ethylcyclohexanone using hydroxyamine sulfonic acid as described in Olah, Org Synth. Collective, Vol VII, page 254, to provide 5-ethylcaprolactam in 76% yield Using the procedure described in Watthey, et al., J. Med. Chem., 1985, 28, 1511-1516, this lactam 25 was then dichlorinated with PC15 at the alpha position and reduced by hydrogenation to provide four isomeric monochlorides (two racemic mixtures). The two racemic mixtures were separated from each other by column chromatography using silica gel and each racemic mixture was reacted with sodium azide to yield the corresponding azide which was hydrogenated to 30 provide the corresponding a-aminolactams. Other cycloalkanones may be employed in this procedure to provide a wide variety of a-ammolactams. In Printed from Mimosa 07/26/1999 12:37:07 page -241- WO 98/38177 PCT/US98/03373 - 240 - some cases, such as when preparing the 9-membered ring a-aminolactam, longer reaction times, higher reaction temperatures and an excess of sodium azide may be required." For example, the 9-membered ring a-aminolactam required 5 equivalents of sodium azide, a reaction temperature of 120°C and a reaction 5 time of 4 days. Such conditions can be readily determined by those of ordinary skill in the art. GENERAL PROCEDURE 5-D Synthesis of 4-Amino-1.2.3.4-tetrahvdroisoauinoline-3-ones 10 The 4-amino-l,2,3,4-tetrahydroisoquinoline-3-one derivatives employed in this invention can be prepared by the following art-recognized procedures. The conditions for these reactions are further described in D. Ben-Ishai, et al., Tetrahedron, 43, 439-450 (1987). The following intermediates were prepared via this procedure: 15 3-amino-l ,2,3,4-tetrahydroisoquinolin-3-one 4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one 4-amino-l -phenyl-1,2,3,4-tetrahydroisoquinolin-3-one cis and /ra«s-4-amino-l -phenyl-1,2,3,4-tetrahydroisoquinolin-3-one 4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinohn-3-one 20 4-amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one 9-amino(fluoren-1 -yl)glycine 8-lactam-1,2,3,4-tetrahydroisoquinolin-3- one. Step A - Preparation of N-Bismethoxvcarbonvlaminoacetic Acid- To one 25 mole equivalent of glyoxylic acid in 2 liters of ethanol-free chloroform was added two mole equivalents of methyl carbamate and 0.1 mole equivalent of naphthalene sulfonic acid The reaction mixture was then brought to a reflux for 6 hours. Water was removed using an inverse Dean Stark trap. The reaction was then cooled and the product filtered and washed with chloroform The 30 white solid was recrystallized from ethyl acetate/hexanes to give a white powder in 65% yield. Printed from Mimosa 07/26/1999 12:37:07 page -242- WO 98/38.177 PCT/US98/03373 -- 241 - Step B - Coupling Procedure: To 0 0291 moles of N-bismethoxycarbonylaminoacetic acid (or the appropriate carboxcyclic acid) in 200 mL of THF was added one mole equivalent of EDC*HC1, a benzylamine, HOBT, and dnsopropylethylamine. The reaction was allowed to stir at room 5 temperature for 18 hours and then poured into a separatory funnel and extracted into ethyl acetate. The ethyl acetate solution was washed with 1 molar K2C03 and then 1 molar HCl. The organic layer was dried over Na2S04, filtered and solvent removed to give the crystalline benzylamide of N-bismethoxycarbonylaminoacetic acid. This material was used without further 10 purification. Typical yields range from 40 - 55%. Step C - Cyclization Procedure The benzylamide of N-bismethoxycarbonylaminoacetic acid (0.008 moles) was dissolved in 75 mL of methanesulfonic acid and allowed to stir over night at room temperature The 15 reaction mixture was poured over ice and extracted into ethyl acetate. The ethyl acetate extract was washed with 1 molar K2C03 and then 1 N HCl. The organic layer was dried over NajS04, filtered and the solvent removed to give the crystalline 4-methoxycarbonylamino-l,2,3,4-tetrahydroisoquinoline-3-one in 50-90% yield This material was used without further purification 20 Step D - Removal of the Methoxvoxvcarbonvl Group ("MOCV To the 4-methoxycarbonylamino-l,2,3,4-tetrahydroisoquinohne-3-one (3.4 mmoles) in 30 mL of acetonitnle was added 2 mole equivalents of trimethylsilyliodide (TMSI). The reaction mixture was heated to 50-80°C for 3 hrs and then cooled and 25 poured into a seperatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K2C03 and then with 5% NaHS03. The organic layer was dried over Na2S04 and filtered The solvent was removed under reduced pressure to give the 4-amino-l,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yields range from 50-87%. 30 Printed from Mimosa 07/26/1999 12:37:07 page -243- WO 98/38177 PCT/US98/03373 -- 242 - Step E - Alternative Procedure for Removal of the Methoxvoxvcarbonvl Group- To 3.8 mmoles of the MOC-protected compound was added 10 mL of 30% HBr in acetic acid and this reaction mixture was heated to 60°C for 3 hrs. The mixture was then cooled and hexanes were added. The hexanes layer was 5 decanted off and the residue as placed under reduced pressure to give a tan solid. This solid was slurried in ether and filtered to give the 4-amino-l,2,3,4-tetrahydroisoquinoline-3-one hydrobromide salt Typical yields range from 57-88%. 10 Example 5-A Synthesis of 3-Amino-l,2,3,4-tetrahydroquinolin-2-one Step A: Sodium (0.30g, 110M%) was added to anhydrous ethanol (45 mL) and the reaction mixture was stirred until homogenous Diethyl N-15 acetylaminomalonate (2.51 g, 100 M%) was added in one portion and this mixture was stirred for 1 h. 2-Nitrobenzyl bromide (2.5g, 100M%) was then added in one portion and the reaction mixture was stirred for 3 h The reaction was poured into water and extracted with ethyl acetate (3x) and then backwashed with water (3x) and brine (lx). Treatment with MgS04, 20 rotoevaporation, and chromotography (30% EtOAc/hexanes) yielded diethyl N-acetylamino-2-nitrobenzylmalonate in 82% yield Step B: Diethyl N-acetylamino-2-nitrobenzylmalonate (lg, 100M%) was dissolved in a minimum amount of EtOH Pd/C (10%, 0.05g) was added and 25 the reaction mixture was subjected to 50 psi of H, for 3 hours. The reaction was then filtered thru a pad of celite. Additional EtOH (25mL) and TsOH (catalytic amount, 0 Olg) were added and this mixture was refluxed for 2 hours. The reaction was rotoevaporated to a residue and then partitioned between water and ethyl acetate The water layer was extracted with ethyl acetate (3x) and the 30 combined ethyl acetate extracts were washed with water (3x) and then brine (lx) Treatment with MgS04 and rotoevaporation yielded pure 3-(N-acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (89% yield) Printed from Mimosa 07/26/1999 12:37:07 page -244- WO 98/38177 PCT/US98/03373 - 243 - Step C. 3-(N-Acetylamino)-3-carboethoxy-l,2.3,4-tetrahydroquinolin-2-one (0.75 g, 100M%) was suspended in 6N HCl (25 mL) and the mixture was heated to 100°C for 3 hours. The reaction was cooled, rotoevaporated to a residue and then partitioned between water and ethyl acetate. The water was 5 extracted with ethyl acetate (3x) and the combined ethyl acetate extracts were then washed with water (3x) and then brine (lx). Treatment with MgS04 followed by rotoevaporation yielded 3-(R,S)-amino-l,2,3,4-tetrahydroquinolin-2-one (72% yield). Example 5-B 10 Synthesis of 4-Amino-l-(pyrid-4-yl)-l,2,3,4-tetrahydroisoquinoIin-3-one Step A To a solution of 4-cyanopyridine (Aldrich) (0 150 moles) in 300 mL of dry ether was added 1.1 eq. of phenylmagnesium bromide (Aldrich) dropwise. The reaction was refluxed for 2 hours and then stirred overnight at 15 room temperature. Sodium borohydride (1.0 eq ) was added dropwise as a solution in 200 mL of methanol (CAUTION — very exothermic). The reaction was then heated to reflux for 6 hours, cooled and quenched with a saturated solution of ammonium chloride. The solution was decanted from the salt in the reaction mixture and acidified with IN HCl. After washing the aqueous layer 20 with ethyl acetate, the pH of aqueous layer was adjusted to about 9.0 with IN sodium hydroxide (cold) The aqueous layer was then extracted with ethyl acetate and the organic extracts washed with brine, dried over NajSO,,, filtered and concentrated to give 4-pyridyl-a-benzyl amine as a thick yellow oil. 25 Step B: Following General Procedure 5-D and using 4-pyridyl-a-benzyl amine, the title compound was prepared Example 5-C 30 Synthesis of 4-Amino-l-(pyrid-2-yl)-l,2,3,4-tetrahydroisoquinolin-3-one Printed from Mimosa 07/26/1999 12:37:07 page -245- WO 98/38177 PCT/US98/03373 - 244 - Step A 2-Pyndyl-a-benzyl amine was prepared by substituting 2-cyanopyridine (Aldrich) for 4-cyanopyridine in the procedure described in Example 5-B. 5 Step B: Following General Procedure 5-D and using 4-pyridyl-a-benzyl amine, the title compound was prepared Example 5-D Synthesis of 10 4-Amino-l-(pyrid-3-yl)-l,2,3,4-tetrahydroisoquinoIin-3-one Step A Following the procedure described in J. Med. Chem., 1982, 25, 1248, and using 3-benzoyl-pyridine (Aldrich), 3-pyridyl-a-benzyl amine was prepared 15 Step B- Following General Procedure 5-D and using 3-pyridyl-a-benzyl amine, the title compound was prepared. Example 5-E Synthesis of 20 4-Amino-7-benzyl-l ,2,3,4-tetrahydroisoquinolin-3-one Step A: To a Parr bottle containing 3-benzoylbenzoic acid (0.044 moles) (Aldrich) in 150 mL of ethyl acetate and 4.5 mL of concentrated H2S04 was added 10 grams of 5% Pd/C The mixture was hydrogenated on a Pan-apparatus under hydrogen (45 psi) overnight. The reaction mixture was then 25 filtered through Hyflo, washing with ethyl acetate. The filterate was dried over Na,S04, filtered and concentrated to give an oil. The oil was slurried in hexane and the resulting white solid was collected by filtration to afford 3-benzylbenzoic acid, which was used without further purification. 30 Step B: To the product from Step A (0.0119 moles) was added 150 mL of CH,C12, one drop of DMF, 10 mL of oxalyl chloride, and the mixture was stirred at room temperature for 3 hours. After cooling to 10°C, 30 mL of Printed from Mimosa 07/26/1999 12:37:07 page -246- WO 98/38177 PCT/US98/03373 - 245 -- NH4OH (exothermic) was added and the mixture was stirred for 30 min The reaction mixture was then concentrated and the resulting residue diluted with ethyl acetate" The organic layer was washed with IN NaOH, brine, dried over Na2S04, and concentrated to give the 3-(benzyl)benzamide as a white solid, 5 which was used without further purification. Step C: To a solution of 3-(benzyl)benzamide ( 0094 moles) from Step B in 70 of toluene was added 8 mL of Red-Al® (65+ wt. % solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene, Aldrich) (CAUTION — 10 reaction very exothermic) The reaction mixture was then heated at 60°C for 2 hours and then poured over ice. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with water and brine. The organic layer was extracted with IN HCl and the aqueous layer washed with ethyl acetate The pH of the aqueous layer was then adjusted to about 9.0 with 15 IN NaOH and extracted with ethyl acetate. The organic extracts were washed with water and brine and then concentrated to give 3-(benzyl)benzyl amine. Step D Following General Procedure 5-D and using 3-(benzyl)benzyl amine, the title compound was prepared 20 Example 5-F Synthesis of 4-Amino-6-phenyl-l,2,3,4-tetrahydroisoquinolin-3-one Step A: To a solution of 4-biphenylcarboxamide (Aldrich) (0.025 mole) 25 in 150 mL of THF cooled to 10°C was added a solution of 1.5 eq of LAH (1M m THF) dropwise. The reaction mixture turned from a white slurry to a green homogenous solution and then to a yellow homogeneous solution The reaction was then quenched with 2.5 mL of IN NaOH. The mixture was then filtered through Hyflo and extracted with ethyl acetate. The organic layer was then 30 washed with IN HCl. The pH of the resulting aqueous layer was adjusted to about 9 with IN NaOH and extracted with ethyl acetate The organic extracts Printed from Mimosa 07/26/1999 12:37:07 page -247- WO 98/38177 PCT/US98/03373 - 246 -- were washed with water and brine, and then dried over Na2S04, filtered and concentrated to give 4-(phenyl)benzyl amine as a white solid. Step B- Following General Procedure 5-D and using 4-(phenyl)benzyl 5 amine, the title compound was prepared. Example 5-G Synthesis of cis- and //-a«s-4-Amino-l-phenyl-l,2,3,4-tetrahydroisoquinolin-3-onc 10 Step A: Following General Procedure 5-D and using a- phenylbenzylamine (Aldrich), 4-amino-1 -phenyl-1,2,3,4-tetrahydroisoquinolin-3-one was prepared. Step B: To a solution of 4-amino-l-phenyl-l,2,3,4-tetrahydroisoquinolin-15 3-one (0 00158 moles) from Step A in 20 mL of CH2C12 was added 2.0 eq. of triethylamme and Boc anhydride (1.1 eq.). The reaction was stirred overnight at room temperature and then concentrated. The residue was diluted with ethyl acetate and water. The pH of the aqueous layer was adjusted to 3.0 with sodium bisulfate and the layers were separated. The organic layer was dried 20 over Na2S04, filtered and concentrated. The residue was purified by LC 2000, eluting with ethyl acetate/hexanes (70:30) to give a white solid containing a 1:1 mixture of cis- and /rans-4-(N-Boc-amino)-1 -phenyl-1,2,3,4-tetrahydroisoquinolin-3-one isomers This mixture was recrystalhzed from ethyl acetate to give the pure trans isomer and a cis isomer-enriched mixture of as 25 and trans isomers. This mixture was recrystalhzed again from ethyl acetate/hexanees (70:30) to give the pure cis isomer. Step C: The cis isomer and the trans isomer from Step B were separately deprotected using General Procedure 8-J to give m-4-amino-1 -30 phenyl-1,2,3,4-tetrahydroisoquinolin-3-one and /ram--4-amino-1 -phenyl-1,2,3,4-tetrahydroisoquinolin-3-one. Printed from Mimosa 07/26/1999 12:37:07 page -248- WO 98/38177 PCT/US98/03373 -- 247 - Example 5-H Synthesis of 4-Amino-7-phenyl-l,2,3?4-tetrahydroisoquinolin-3-one Step A: To a solution of 1-bromo-3-phenylbenzene (Aldrich) (0 0858 5 moles) in 300 mL of dry THF cooled to -78°C was added tert-butyl lithium (2 eq.) (1.7M in hexane) dropwise. The reaction mixture was stirred for 40 min. at -78°C and then quenched with 2 eq. of DMF (13.24 mL). The resulting mixture was stirred for 20 min and then poured into a separatory funnel and extracted with CH2C12 The organic extracts were washed with water, dried over Na2S04, 10 filtered and concentrated to give a brown oil. This oil was purified by LC 2000 chromatography, eluting with ethyl acetate/hexanes (5 95) to give 3-biphenylcarboxaldehyde Step B. To a solution of 3-biphenylcarboxaldehyde (0.011 eq ) in 30 mL 15 of methanol was added 10 eq. of 7N NH3/MeOH and NaCNBH4 (2 eq.) A yellow gum precipitated from solution. The solution was then heated at 60°C until gum dissolved and the solution was stirred at room temperature overnight The reaction mixture was then concentrated and the resulting residue diluted with ice water and ethyl acetate. The organic layer was then washed with brine 20 and extracted with 5N HCl The pH of the aqueous layer was then adjusted to 12 and the aqueous layer was extracted with cold ethyl acetate The organic layer was dried over Na2S04, filtered and concentrated to give 3-(phenyl)benzyl amine as an oil. 25 Step C: Following General Procedure 5-D and using 3-(phenyl)benzyl amine, the title compound was prepared. Example 5-1 Synthesis of 30 4-Amino-l-benzyl-l,2,3,4-tetrahydroisoquinolin-3-one Step A: To a solution of benzoyl chloride (0.123 moles) (Aldrich) in 600 mL of CH2C12 was added 2.0 eq of phenethylamine (Aldrich) dropwise Printed from Mimosa 07/26/1999 12:37:07 page -249- WO 98/38177 PCT/US98/03373 - 248 -- The reaction mixture was stirred at room temperature for 3 hours and then poured into a separatory and extracted with CH2C12. The organic extracts were washed with"water and IN HCl, and then dried over Na2S04, filtered and concentrated to give N-phenethyl benzamide. 5 Step B- Reduction of N-phenethyl benzamide using the procedure of Example 5-E, Step C afforded N-benzyl-N-phenethylamine as an oil. Step C. Following General Procedure 5-D and using N-benzyl-N-10 phenethylamine, the title compound was prepared. Example 5-J Synthesis of 3-Amino-l-methyl-2-indoIinone Monohydrochloride 15 Step A: (2,3-Dihydro-l-methyl-2-oxo-lH-indol-3-yl)carbamic acid methyl ester (CAS No. 110599-56-9) was prepared using the procedure described in Ben-Ishai, D.; Sataty, I.; Peled, N ; Goldshare, R. Tetrahedron 1987, 43, 439-450. The starting materials for this preparation were N-methylaniline (CAS# 100-61-8, Eastman Kodak Co ), glyoxylic acid (CAS# 298-20 12-4, Aldrich), and methyl carbamate (CAS# 598-55-0, Aldrich). Step B: The product from Step A (333.5 mg) in 31% HBr in AcOH (10 mL) was heated to 50-60°C for 2 hours. The resulting orange solution was concentrated to a thick orange oil which was dissolved in EtOAc (15 mL) and 25 the product extracted into 1 M aq. HCl (10 mL) The aqueous acid was neutralized with aq NaHCOj and the product extracted into CH2C12 (10 x 10 mL) HCl (gas) was passed through the combined CH2C12 extracts to form a purple solution. The solution was concentrated to provide the title compound (262.8 mg) as a purple solid. 30 Example 5-K Synthesis of Printed from Mimosa 07/26/1999 12:37:07 page -250- WO 98/38177 PCT/US98/03373 - 249 - 3-Amino-l-methyl-4-phenyl-3,4-fraws-dihydrocarbostyril/Tin Complex Step A: - Synthesis of 4-PhenyI-3,4-dihydrocarbostyriI 4-Phenyl-3,4-dihydrocarbostyril (CAS# 4888-33-9) was prepared in two steps using the procedure described by Conley, R. T.; Knopka, W. N. J Org. 5 Chem. 1964, 29, 496-497. The starting materials for this preparation were cinnamoyl chloride (Aldrich) and aniline (Aldrich). The title compound was purified by flash chromatography eluting with CH2Cl2/EtOAc (4:1) Step B - Synthesis of l-Methyl-4-phenyl-3,4-dihydrocarbostyriI 10 To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil) in THF (50 mL) under N2 at 0°C was added the product from Step A (1 0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5 minutes. The resulting pale yellow mixture was stirred at 0°C for 10 minutes, then Mel (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to slowly 15 (ice bath not removed) warm to ambient temperature with stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc (250 mL) were added and the phases partitioned The organic phase was washed with dilute NaHC03 (1 x 100 mL), brine (1 x 100 mL), then dried over MgS04, filtered, concentrated, and the residue purified by flash chromatography eluting with CH2Cl2/EtOAc (19.1 20 gradient to 15:1) to provide l-methyl-4-phenyl-3,4-dihydrocarbostyril. Step C: - Synthesis of 3-Azido-l-methyl-4-phenyl-3,4-/ra«s-dihydrocarbostyril Following General Procedure 8-K, 3-azido-1 -methyl-4-phenyl-3,4-/r<ms-25 dihydrocarbostyril was prepared as a white solid. The product was purified by flash chromatography eluting with CH2Cl2/hexanes/EtOAc 15:15:1. Selected 'H-NMR data for the title compound (CDC13): 8 = 4 46 (d, IH, J = 10.57 Hz), 4.18 (d, IH, J = 10.63 Hz). 30 Step D: - Synthesis of 3-Amino-l-methyl-4-phenyI-3,4-fra/is- dihydrocarbostyril/Tin Complex Printed from Mimosa 07/26/1999 12:37:07 page -251- WO 98/38177 PCT/US98/03373 - 250 - To a mixture of SnCl2 (350.7 mg) in MeOH (7 mL) under N2 at 0°C was added the product from Step C (257.4 mg) in MeOH/THF (5 mL/5 mL) via cannula over'a period of 1 minute The cooling bath was removed the solution allowed to warm to ambient temperature for 8 hours (No starting material by 5 TLC). The solution was concentrated to a yellow foam, THF (10 mL) was added and the mixture was re-concentrated and used without further purification. Example 5-L Synthesis of 10 3-Amino-l-methyI-4-phenyl-3,4-c/s-dihydrocarbostyril Step A- - Synthesis of 3-Amino-l-methyl-4-phenyl-3,4-/ra/is-dihydrocarbostyril 3-Amino-l -methyl-4-phenyl-3,4-/r<ms-dihydrocarbostyril was prepared following General Procedure 8-F using 3-azido-l-methyl-4-phenyl-3,4-fraw,s- 15 dihydrocarbostyril from Example 5-K, Step C The product was purified by L C 2000 eluting with EtOAc/hexanes (4:1) to yield a white solid. Selected 'H-NMR data for the title compound (CDC13): 5 = 4.03 (d, IH, J = 12 8 Hz), 3 92 (d, IH, J = 12.7 Hz). 20 Step B: - Synthesis of 3-(4-Chlorobenzylimine)-l-methyI-4- phenyl-3,4-/ro«s-dihydrocarbostyril To a solution of the product from Step A (1 eq.. 239.6 mg) in CH2C12 (10 mL) under N2 at ambient temperature was added 4-chlorobenzaldehyde (1.05 eq , 140 mg, Aldrich), Et3N (1.4 eq., 185 mL), and MgS04 (3.6 eq , 411 mg). 25 The resultant mixture was stirred at room temperature for 73 hours. The solids were removed by filtration through a plug of Celite, rinsing with CH2C12, and the filtrate concentrated to provide 3-(4-chlorobenzylimine)-l-methyl-4-phenyl-3,4-/ram-dihydrocarbostyril as a thick white foam. 30 Step C - Synthesis of 3-Amino-l-methyl-4-phenyI-3,4-cis- dihydrocarbostyril To a solution of dnsopropylamine (1 05 eq., 0 132 mL) in THF (5 mL) under N2 at -78°C was added a solution of n-BuLi (1.05 eq., 0.588 mL of a 1.6 Printed from Mimosa 07/26/1999 12:37:07 page -252- WO 98/38177 -- 251 - PCT/US98/03373 M solution in hexanes) and the result solution was stirred for 30 minutes. To this solution was added the product from Step B (1 0 eq., 336 mg) in THF (2 mL) via cannula. The solution was allowed to warm to 0°C, then quenched with 1 M aq. HCl (3 mL) and allowed to warm to room temperature with 5 stirring overnight. The product was extracted into H20 and washed with EtOAc (1 x), then the aqueous acid was basified with 1 M aq. K2C03 and the product extracted into EtOAc. The EtOAc extract was dried over Na2S04, filtered, and concentrated to give 3-amino-l-methyl-4-phenyl-3,4-c/5-dihydrocarbostyril. Selected 'H-NMR data for the title compound (CDC13): 6 = 4.31 (d, IH, 10 J = 6.6 Hz). Example 5-M Synthesis of 3-Amino-l-/erf-butoxycarbonyl-4-phenyl-15 3,4-/ra/is-dihydrocarbostyriI/Tin Complex Step A- - Synthesis of l-tert-Butoxycarbonyl-4-pheny 1-3,4-dihydrocarbostyril 1 -/er/-Butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyril was prepared from the product of Example 5-K, Step A (CAS# 4888-33-9) by the Boc procedure 20 for aryl amides described by Grehn, L.; Gunnarsson, K., Ragnarsson, U. Acta Chemica Scandinavica B 1986, 40, 745-750, employing (Boc)20 (Aldrich) and catalytic DMAP (Aldrich) in acetonitrile The product was purified by flash chromatography eluting with CH2C12 gradient to CH2Cl2/EtOAc (19:1) and isolated as a pale yellow oil 25 Step B - Synthesis of 3-Azido-l-ter/-butoxycarbonyl-4-phenyl-3,4-/rans-dihydrocarbostyril Following General Procedure 8-K using the product from Step A, the title compound was prepared as a 12.4:1 mixture of trans/cis isomers which 30 were separated by flash chromatography eluting with hexanes/Et20 (6:1 gradient to 4:1) in the first column and hexanes/EtOAc (12:1) in a second column. The pure trans isomer was used in Step C. Printed from Mimosa 07/26/1999 12:37:07 page -253- WO 98/38177 -- 252 -- PCT/US98/03373 Selected 'H-NMR data for the title compound (CDC13): 5 = 4.45 (d, IH, J = 11.1 Hz), 4 24 (d, IH, J = 11 2 Hz). Step C. - Synthesis of 3-Amino-l-terf-butoxycarbonyl-4-phenyl-5 3,4-//"a/is-dihydrocarbostyril/Tin Complex To a mixture of SnCl, (450.6 mg) in MeOH (9 mL) under N2 at 0°C was added the product from Part D (433 0 mg) in MeOH (15 mL) via cannula over a period of 1 minute. The cooling bath was removed the solution allowed to warm to ambient temperature for 17 hours The solution was concentrated to an 10 amorphous yellow solid and used without further purification. Example 5-N Synthesis of (S)-3-Amino-l-benzyl-5-valerolactam 15 Step A. - Synthesis of L-(+)-Ornithine Methyl Ester Hydrochloride Into a stirred suspension of L-(+)-ornithine hydrochloride (Aldrich) in methanol was bubbled anhydrous hydrochloric acid gas until the solution was saturated. The reaction mixture was capped with a rubber septum and stirring 20 was continued overnight at room temperature The solvent was then stripped under reduced pressure and the residue triturated with ether. The resulting solid was dried under reduced pressure to afford L-(+)-ornithine methyl ester hydrochloride as a white solid (97% yield). 25 Step B- - Synthesis of (S)-3-Amino-5-valerolactam Sodium spheres in oil (2.0 eq.) (Aldrich) were washed with hexanes (2x) and methanol (2 3 mL/mmol) was slowly added. The reaction mixture was stirred under nitrogen until the sodium dissolved and then L-(+)-ornithine methyl ester hydrochloride (1 eq ) in methanol (2.3 rnL/mmol) was added dropwise. 30 The reaction mixture was stirred for 16 hours and then diluted with diethyl ether (5 mL/mmol) and filtered to remove the solids. The solvent was then removed under reduced pressure and the residue was heated at 70°C for 3 hours under Printed from Mimosa 07/26/1999 12:37:07 page -254- WO 98/3&177 PCT/US98/03373 -- 253 - reduced pressure. The residue was then triturated with dichloromethane/ether, the solvent decanted and the resulting residue dried under reduced pressure to afford (S)-3-amino-8-valerolactam (44% yield). 5 Step C: - Synthesis of N-Boc-(S)-3-Amino-5-vaIerolactam (S)-3-Amino-8-valerolactam (1 eq.) was dissolved in dioxane and the solution was chilled to 0°C. BOC-anhydride (1.3 eq.) was added and the ice bath was removed allowing the solution to come to room temperature and stirring was continued for 16 hours. The solution was rotory evaporated to 10 afford N-Boc-(S)-3-amino-8-valerolactam. Step D: - Synthesis of (S)-3-Amino-l-benzyl-5-valerolactam Following General Procedure 5-A and using N-Boc-(S)-3-amino-S-valerolactam and benzyl bromide provided N-Boc-(S)-3-amino-l-benzyl-8-15 valerolactam. Removal of the Boc group using General Procedure 5-B afford the title compuound. Example 5-0 Synthesis of 20 4-Amino-2-aza-2-benzyl-3-oxobicyclo [3.2.1 J octane Hydrochloride Step A: - Synthesis of 2-Aza-3-oxobicyclo[3.2.1] octane and 3-Aza-2-oxobicycio[3.2.1]octane (9:1 Mixture) To (+)-norcamphor (Aldrich) in 1 mL/mmole of acetic acid was added 1 5 eq. of hydroylamine-O-sulfonic acid. The reaction mixture was 25 heated to reflux under nitrogen for 1 hour and then saturated sodium carbonate and dilute sodium hydroxide were added. The resulting mixture was extracted with dichloromethane and the organic extracts washed with brine, dried over sodium sulfate, and the solvent removed under reduced pressure Purification of the residue by column chromatography afforded a 9:1 mixture of 2-aza-3-30 oxobicyclo[3.2.1]octane and 3-aza-2-oxobicyclo[3.2 l]octane. Step B - Synthesis of 2-Aza-2-benzyl-3-oxobicyclo[3.2.1]octane Printed from Mimosa 07/26/1999 12:37:07 page -255- WO 98/38177 PCT/US98/03373 -- 254 - Following General Procedure 5-A and using the product for Step A and benzyl bromide, 2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane was prepared. Step C: - Synthesis of 2-Aza-2-benzyl-4-oximino-3-5 oxobicyc!o[3.2.1]octane To a solution of 2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane in THF was added 2 5 eq. of 1M t-BuOK/THF (Aldrich) and the resulting mixture was stirred for 30 minutes. Isoamyl nitrite (1 5 eq) was then added dropwise and the reaction mixture was stirred overnight. To the reaction mixture was added 10 3N HCl and this mixture was extracted with ethyl acetate and the organic extracts washed with water, dried, and concentrated under reduced pressure. The residue was triturated with ether/hexanes, the solvents decanted and the residue dried under reduced pressure to afford 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3.2 l]octane as a tan liquid (41% yield) This procedure is further 15 described in Y Kim, Tetrahedron Lett. 30(21), 2833-2636 (1989). Step D: - Synthesis of 2-Aza-2-benzyl-4-amino-3-oxobicyclo [3.2.1 ] octane A solution of 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3 2.1]octane in 10 20 mL/mmole of ethanol and 5.8 mL/mmole of 3N HCl containing 0.5 g/mmole of 10% Pd/C was saturated with hydrogen gas to 45 psi The mixture was shaken for 3 hours and then filtered through a layer of Celite. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as a solid (86% yield). This procedure is further described in E. 25 Reimann, Arch. Pharm 310,102-109 (1977). GENERAL PROCEDURE 6-A Alkylation of 1 -Amino-1.3.4.5-tetrahvdro-2H-3-benzazepin-2-one 30 Step A: l-Ethoxycarbonylamino-l,3,4,5-tetrahydro-2H-3-benzazepin-2- one was prepared according to the procedure of Ben-Ishai et al., Tetrahedron, 1987, 43, 430. Printed from Mimosa 07/26/1999 12:37:07 page -256- WO 98/38177 PCT/US98/03373 - 255 - Step B. 1 -Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (2.0 g, 100 M%) was dissolved in DMF (30 mL) and NaH (95%, 0.17 g, 100M%) was added in one portion. The reaction mixture was stirred for 1 hour and then the appropriate alkyl iodide (300M%) was added and the mixture was 5 stirred for 12 hours. The reaction was poured into water and extracted with ethyl acetate (3x). The ethyl acetate extracts were then washed with water (3x) and brine (lx) Treatment with MgS04, rotoevaporation, and chromotography (30% EtOAc/hexanes) yielded 1 -ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one in 87% yield 10 Step C 1 -Ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (l.Og, 100M%) was suspended m 30 mL of 30% HBr/HOAc and heated to 100°C The reaction mixture was stirred for 5 hours at this temperature and then the reaction was cooled and rotoevaporated to yield 1- 15 amino-3-alkyl-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one as the hydrobromide salt (100% yield) GENERAL PROCEDURE 6-B Alkylation of 20 3-Amino-1.3.4.5-tetrahvdro-2H-1 -benzazepin-2-one Step A. 3-Amino-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one was prepared from a-tetralone using the methods described in Armstrong et al. Tetrahedron Letters. 1994, 35, 3239. The following compounds were as prepared by this procedure for use in the following steps- 25 5-methyl-3-amino-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one (from 4- methyl-a-tetralone (Aldrich)); and 5,5-dimethyl-3-amino-l ,3,4,5-tetrahydro-2H-1 -benzazepin-2-one (from 4,4-dimethyul-a-tetralone (Aldrich)). 30 Step B. 3-Amino-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one (4.43 g, 100M%) was suspended in t-butanol (30mL) and BOC-anhydride (7.5 mL, 130M%) was added dropwise. The reaction was stirred for 2 hours and then it Printed from Mimosa 07/26/1999 12:37:07 page -257- WO 98/38177 PCT/US98/03373 - 256 - was rotoevaporated to a residue which was chromatographed with 60% ethyl acetate/hexanes to yield BOC-protected 3-amino-1,3,4,5-tetrahydro-2H-l-benzazepin-2-one in 87% yield 5 Step C: BOC-protected 3-amino-l,3,4,5-tetrahydro-2H-l-benzazepin-2- one (1.5 g, 100M%) was dissolved in DMF (20mL) and NaH (95%, 0.13g, 100M%) was added in one portion. The reaction mixture was stirred for 1 hour and then the appropriate alkyl iodide (300M%) was added and stirring was continued for 12 hours. The reaction was poured into water and extracted with 10 ethyl acetate (3x). The ethyl acetate extracts were washed with water (3x) and then brine (lx). Treatment with MgS04, rotoevaporation, and chromotography (30% EtOAc/hexanes) yielded a BOC-protected 3-amino-l-alkyl-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one in 80% yield. 15 Step D- The BOC-protected 3-amino-l-alkyl-l,3,4,5-tetrahydro-2H-l- benzazepin-2-one (1 Og, 100M%) was suspended in 30 mL of 1:1 CH2Cl2/triflouroacetic acid and the mixture was stirred for 4 hours. The reaction was then rotoevaporated to yield the 3-amino-l-alkyl-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one (100% yield). 20 Example 6-A Synthesis of 3-Amino-l,5-dimethyl-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one Step A: 3-Amino-5-methyl-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one 25 was prepared from 4-methyl-a-tetralone using the methods described in Armstrong et al. Tetrahedron Letters. 1994, 35, 3239. Step B: 3-Amino-5-methyl-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one (9.3g 100M%) was dissolved in dioxane (300mL) and the solution was chilled 30 to 0°C. BOC-anhydride (13.89g 130M%) was added and the ice bath was removed allowing the solution to come to room temperature and stirring was continued for 16 hours. The solution was rotory evaporated to remove dioxane Printed from Mimosa 07/26/1999 12:37:07 page -258- WO 98/38177 PCT/U S98/03373 -- 257 - to provide an off white solid. This solid was recrystalhzed from CHC13 to yield BOC-protected 3-amino-5-methyl-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one in 55%-yield. 5 Step C- BOC-protected 3-amino-5-methyl-l,3,4,5-tetrahydro-2H-l- benzazepin-2-one (100 M%) was dissolved in DMF (20mL) and NaH (95%, 100 M%) was added in one portion and the reaction mixture was stirred for 1 hour. Methyl iodide (300 M%) was added and this mixture was stirred for 12 hours. The reaction was then poured into water and extracted with ethyl 10 acetate (3x) then backwashed with water (3x) and then brine (lx). Treatment with MgS04, rotoevaporation, and chromotography (5% MeOH/CH2Cl2) yielded BOC-protected 3-ammo-l,5-dimethyl-l ,3,4,5-tetrahydro-2H-l-benzazepin-2-one in 75 % yield 15 Step D: BOC-protected 3-amino-l,5-dimethyl-l,3,4,5-tetrahydro-2H-l- benzazepin-2-one (100 M%) was suspended in 30 mL of 1:1 CH2Cl2/triflouroacetic acid. The reaction mixture was stirred for 4 hours. The reaction was then rotoevaporated to yield 3-amino-l,5-dimethyl-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one (100% yield). 20 Example 6-B Synthesis of 5-(L-Alaninyl)-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one Hydrochloride 25 Following the procedure of Example 7-1 and using 5-amino-3,3,7- trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example 6-C), the title compound was prepared Example 6-C 30 Synthesis of 5-Amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b] azepin-6-one Hydrochloride Printed from Mimosa 07/26/1999 12:37:07 page -259- WO 98/38177 PCT/US98/03373 — 258 -- Step A: Following General Procedure 5-A and using N-t-Boc-5-amino-3,3-dimethyl-5,7-dihydro-6H-benz[b]azepin-6-one (General Procedure 6-B, following by Boc protection) and methyl iodide, N-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepm-6-one was prepared. - Step B- Following General Procedure 8-N and using N-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one, the title compound was prepared. 10 Example 6-D Synthesis of 3-(S)-Amino-l-methyI-5-oxa-l,3,4,5-tetrahydro-2H- l-benzazepin-2-one Step A- 3-(S)-Amino-5-oxa-l,3,4,5-tetrahydro-2H-l-benzazepin-2-one 15 was prepared from N-Boc-serine (Bachem) and 2-fluoro-l-nitrobenzene (Aldrich) using the method of R. J. DeVita et al , Bioorgamc and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286 Step B Following General Procedure 5-A and using the product from 20 Step A, the title compound was prepared. Example 6-E Synthesis of 3-(S)-Amino-l-ethyl-5-oxa-l, 3,4,5-25 tetrahydro-2H-l-benzazepin-2-one Step A. 3-(S)-Amino-5-oxa-l ,3,4,5-tetrahydro-2H-l-benzazepin-2-one was prepared from N-Boc-serine (Bachem) and 2-fluoro-l-nitrobenzene (Aldrich) using the method of R. J. DeVita et al , Bioorgamc and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286. 30 Step B. Following General Procedure 5-A and using the product from Step A, the title compound was prepared. Printed from Mimosa 07/26/1999 12:37:07 page -260- WO 98/38177 -- 259 -- PCT/US98/03373 Example 6-F Synthesis of 3-(S)-Amino-l-methyl-5-thia-l, 3,4,5-tetrahydro-2H-l-benzazepin-2-one 5 The title compound was prepared from N-Boc-cystine (Novabio) and 2- fluoro-l-mtrobenzene (Aldrich) using the method of R. J. DeVita et al., Bioorgamc and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286, followed by General Procedure 5-A. 10 GENERAL PROCEDURE 7-A Preparation of 5-Amino-7-alkyl-5,7-dihydro-6H-dibenzrb.dlazepin-6-one Derivatives Step A: Following General Procedure 5-A and using 5,7-dihydro-6H- 15 dibenz[b,d]azepin-6-one and an alkyl halide, the 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared. Step B: The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq ) was dissolved in THF and isoamylnitrite (1.2 eq.) was added The mixture was 20 cooled to 0°C in an ice bath NaHMDS (1.1 eq., 1M in THF) was added dropwise. After stirring for 1 hour or until the reaction was complete, the mixture was concentrated then acidified with IN HCl and extracted with EtOAc. The organic portion was dried and concentrated to yield a crude product which was purified by silica gel chromatography. 25 Step C The resulting oxime was dissolved in EtOH/NH3 (20:1) and hydrogenated m a bomb using Raney nickel and hydrogen (500 psi) at 100°C for 10 hours. The resulting mixture was filtered and concentrated to provide an oil which was purified by silica gel chromatography to yield the title compound. 30 GENERAL PROCEDURE 7-B Preparation of Fluoro-substituted 5,7-dihydro-6H- Printed from Mimosa 07/26/1999 12:37:07 page -261- WO 98/38177 PCT/US98/03373 - 260 -- dibenzrb.dlazepin-6-one Derivatives A modification of the procedure of Robin D. Clark and Jahangir, Tetrahedron; Vol. 49, No. 7, pp. 1351-1356, 1993 was used Specifically, an appropriately substituted N-t-Boc-2-amino-2'-methylbiphenyl was dissolved in 5 THF and cooled to-78°C. s-Butyl lithium (1.3M in cyclohexane, 2.2 eq ) was added slowly so that the temperature remained below -65 °C The resulting mixture was allowed to warm to -25 °C and was stirred at that temperature for 1 hour. The mixture was cooled to -78 °C. Dry C02 was bubbled through the mixture for 30 seconds. The mixture was allowed to warm to ambient 10 temperature then was carefully quenched with water The mixture was concentrated under reduced pressure then was adjusted to pH 3 with IN HCl. The mixture was extracted with EtOAc and the organic portion was dried and concentrated to yield a crude material The crude material was dissolved in methanol and the solution was saturated with HCl. The mixture was heated at 15 reflux for 12 hours then was allowed to cool The mixture was concentrated to provide crude lactam which was purified by chromatography or crystallization. GENERAL PROCEDURE 7-C Resolution of 20 5-Amino-7-methvl-5.7-dihvdro-6H-dibenzrb.dlazepin-6-one In a round bottom flask was added the racemic freebase amine (1.0 eq.) in methanol followed by di-p-toluoyl-D-tartaric acid monohydrate (1.0 eq.). The mixture was concentrated in vacuo to a residue and redissolved in a moderate volume of methanol and allowed to stir at room temperature open to 25 the atmosphere (8-72 hours). The solid was removed by filtration. The enantiomeric excess was determined by chiral HPLC (Chiracel ODR) using 15% acetonitrile and 85% H20 with 0.1% trifluoroacetic acid and a flow rate of 1.0 mL/min at 35°C. The resolved di-p-toluoyl-D-tartaric salt was then dissolved in EtOAc and saturated NaHCOj until pH 9-10 was reached. The 30 layers were separated and the organic layer was washed again with saturated NaHCOj, H20, and brine. The organic layer was dried over MgS04 and the drying agent was removed by filtration. The filtrate was concentrated in vacuo. Printed from Mimosa 07/26/1999 12:37:07 page -262- WO 98/38177 - 261 - PCT/US98/03373 The free amine was dissolved in MeOH and HCl (12M, 1 0 eq.) was added. The salt was concentrated in vacuo and the resulting film was triturated with EtOAc. The HCl salt was filtered and rinsed with EtOAc The ee was determined by chiral HPLC. 5 Example 7-A Synthesis of 5-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride 10 Step A - Synthesis of 7-Methvl-5.7-dihvdro-6H-dibenzrb.dlazepin-6-one A round bottom flask was charged with sodium hydride (0.295 g, 7.46 mmol) in 9.0 ml of DMF and treated with 5,7-dihydro-6H-dibenz[b,d]azepm-6-one (1 3 g, 6.22 mmol) (CAS if 20011-90-9, prepared as described in Brown, et. al , Tetrahedron Letters. No. 8, 667-670, (1971) and references cited 15 therein). After stirring at 60°C for 1 h, the solution was treated with methyl iodide (1.16 ml, 18.6 mmol) and stirring continued for 17 h with the exclusion of light After cooling, the reaction was diluted with CH2C12/H20, washed with NaHS04 solution, H20, and dried over Na2S04 Evaporation and flash chromatography (Si02, CHC13) gave 0.885 g (63%) of the title compound as a 20 colorless solid. NMR data was as follows 'H-nmr (CDC13): 6 = 1 62 (d, 2H), 7.26-7.47 (m, 6H), 3.51 (m, 2H), 3.32 (s, 3H). Cl5H13NO(MW = 223.27); mass spectroscopy (MH+) 223. 25 Anal. Calcd for C15H13NO; C, 80.69 H, 5.87 N, 6.27. Found: C, 80 11 H, 5.95 N, 6.23 Step B - Synthesis of 7-Methvl-5-oximo-5.7-dihvdro-6H-dibenzlb.dlazepin-6-one 30 The compound isolated above (0.700 g, 3.14 mmol) was dissolved in 20 ml of toluene and treated with butyl nitrite (0.733 ml, 6.28 mmol). The reaction temperature was lowered to 0°C and the solution was treated with KHMDS Printed from Mimosa 07/26/1999 12:37:07 page -263- WO 98/38177 -- 262 - PCT/US98/03373 (9.42 ml, 0.5 M) under N2 atmosphere. After stirring for 1 h the reaction was quenched with a saturated solution of NaHS04, diluted with CH2C12 and separated. The organic layer was dried over Na2S04 and the title compound purified by chromatography (Si02, 98:2 CHCl3/MeOH) giving 0 59 g (80 %) as 5 a colorless solid. C,jH12N,0,(MW = 252.275), mass spectroscopy (MH+) 252. Anal. Calcd for C15H,,N202, C, 71.42 H, 4.79 N, 11.10 Found: C, 71.24 H, 4 69 N, 10.87. 10 Step C - Synthesis of 5-Ammo-7-Methvl-5.7-dihvdro-6H- dibenzrb.dlazepin-6-one Hydrochloride The oxime isolated above (0.99 g, 3.92 mmol) was hydrogenated in a Parr apparatus at 35 psi over 10 % Pd/C (0 46 g) in 3A ethanol. After 32 h the reaction mixture was filtered through a plug of celite, the filtrate evaporated to a 15 foam and treated with a saturated solution of HCl (g) in Et20. The resulting colorless solid was filtered, rinsed with cold Et20 and vacuum dried to give 0.66 g (61 %) of the title compound. NMR data was as follows- 'H-nmr (DMSOd6): S = 9.11 (bs, 3H), 7.78-7 41(m, 8H), 4.83 (s, IH), 20 3.25 (s, 3H) CI5HmN20 HCl (MW = 274 753); mass spectroscopy (MH+ free base) 238. Anal. Calcd for C15Hl4N20 HCl; C, 65.57 H, 5.50 N, 10.19 Found: C, 65 27 H, 5.67 N, 10.13. 25 Example 7-B Synthesis of (S)- and (R)-5-(L-Alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 30 Step A - Synthesis of (SV and (R)-5-(N-Boc-L-Alaninvl')-amino-7- methvl-5-7-dihvdro-6H-dibenzrb.d1azepin-6-one Boc-L-Alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.305 g, 2.26 mmol), and 5-amino-7-methyl-5,7- Printed from Mimosa 07/26/1999 12:37:07 page -264- WO 98/38177 PCT/US98/03373 - 263 - dihydro-6H-dibenz[b,d]azepin-6-one (0 45 g, 1.89 mmol) (Example 7-A). The temperature was lowered to 0°C and the reaction mixture treated with EDC (0 449 g, 2.26 mmol) (Alrich) and stirred 17 hours under N2. The reaction mixture was evaporated, the residue diluted with Et0Ac/H20, washed 1.0 N 5 HCl, sat. NaHCOj, brine and dried over Na2S04. The diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute. Isomer 1: Retention time 3.37 minutes. NMR data was as follows: "H-nmr (CDC13). 6 = 7.62-7.33 (m, 9H), 5.26 (d, IH), 5.08 (m, IH), 10 4.34 (m, IH), 3.35 (s, 3H), 1.49 (s, 9H), 1.40 (d, 3H). Optical Rotation: [a]20 = - 96 @ 589 nm(c= 1, MeOH). C23H27N304 (MW = 409.489); mass spectroscopy (MH+) 409. Anal. Calcd for C23H27N304; C, 67.46 H, 6.64 N, 10.26. Found: C, 68.42 H, 7.02 N, 9 81. 15 Isomer 2: Retention time 6.08 minutes. NMR data was as follows: 'H-nmr (CDC13): 6 = 7.74 (bd,1H), 7.62-7.32 (m, 8H), 5.28 (d, IH), 4.99 (m, IH), 4.36 (m, IH), 3.35 (s, 3H), 1 49 (s, 9H), 1.46 (d, 3H). Optical Rotation: [ct]20 = 69 @ 589 nm (c = 1, MeOH) 20 C23H27N304 (MW = 409.489), mass spectroscopy (MH+) 409 Anal. Calcd for C23H27N304; C, 67.46 H, 6.64 N, 10.26. Found. C, 67.40 H, 6.62 N, 10.02 Step B - Synthesis of (S">- and (RV5-CL-Alaninvl)-amino-7-methvl-25 5.7-dihvdro-6H-dibenzrb.dlazepin-6-one Hydrochloride The compounds isolated in Part A (each isomer separately) were dissolved in dioxane and treated with excess HCl (g). After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying. 30 Isomer 1: C,gH|9N302.HCl (MW = 345 832); mass spectroscopy (MH+ free base) 309. Printed from Mimosa 07/26/1999 12:37:07 page -265- WO 98/38177 -- 264 - PCT/US98/03373 Optical Rotation: [cr]20 = - 55 @ 589 nm(c= 1, MeOH) Isomer 2. C18HT9N302.HC1 (MW = 345.832); mass spectroscopy (MH+ free base) 309. 5 Optical Rotation: [o]20 = 80 @ 589 nm (c = 1, MeOH). Example 7-C Synthesis of (S)- and (R)-5-(L-VaIinyI)-amino-7-methyI-10 5,7-dihydro-6H-dibenz[b,d]azepin-6-one Step A - Synthesis of (S)- and fRV5-(N-Boc-L-ValinvD-amino-7-methvl-5.7-dihvdro-6H-dibenzfb.dlazepin-6-one Boc-L-Valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml, 6.05 mmol) 15 and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g, 2.75 mmol)(Example 7-A) The temperature was lowered to 0°C and the reaction mixture treated with EDC (0.601 g, 3.02 mmol)(Alrich) and stirred 17 hours under N,. The reaction mixture was evaporated, the residue diluted with Et0Ac/H20, washed 1.0 N HCl, sat. NaHC03, brine and dried over 20 Na2S04. The diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute. Isomer 1: Retention time 3.23 minutes Optical Rotation: [cr]20 = - 120 @ 589 nm (c = 1, MeOH). C25H31N304 (MW = 437.544); mass spectroscopy (MH+) 438 25 Isomer 2: Retention time 6.64 minutes. Optical Rotation: [ar]20 = 50 @ 589 nm (c = 1, MeOH). C25H3,N304 (MW = 437.544); mass spectroscopy (MH+) 438 Step B - Synthesis of (SI- and CR)-5-("L-Valinvl)-amino-7-methvl-30 5.7-dihvdro-6H-dibenzrb.dlazepin-6-one Hydrochloride The compounds isolated in Part A (each isomer separately) were dissolved in dioxane and treated with excess HCl (g). After stirring for 17 Printed from Mimosa 07/26/1999 12:37:07 page -266- WO 98/38177 PCT/US98/03373 -- 265 - hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying. Isomer 1: C2oH23N302.HC1 (MW = 373.88); mass spectroscopy (MH+ free base) 5 338 Optical Rotation: [o]20 = - 38 @ 589 nm (c = 1, MeOH). Isomer 2: C20H23N3O2.HCl (MW = 373.88); mass spectroscopy (MH+ free base) 338. 10 Optical Rotation: [cr]20 = 97 @ 589 nm (c = 1, MeOH). Example 7-D Synthesis of (S)- and (R)-5-(L-tert-Leucine)-amino-7-methyl-15 5,7-dihydro-6H-dibenz[b,d]azepin-6-one Step A - Synthesis of CSV and fR")-5-fN-Boc-L-tert-LeucinvlV amino-7-methvl-5.7-dihvdro-6H-dibenzfb.dlazepin-6-one Boc-L-tert-Leucine (0.698 g, 3.02 mmol) (Fluka) was dissolved in THF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml. 6.05 20 mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (0.75 g, 2.75 mmol)(Example 7-A) The temperature was lowered to 0°C and the reaction mixture treated with EDC (0.601 g, 3.02 mmol) (Alrich) and stirred 17 hours under N2. The reaction mixture was evaporated, the residue diluted with Et0Ac/H20, washed 1.0 N HCl, sat. NaHC03, brine and 25 dried over NajSO,, The diastereomers were separated on a Chiralcel OD column using 10% IPA/heptane at 1.5 ml/minute. Isomer 1: Retention time 3.28minutes. Optical Rotation [a]20 = - 128 @ 589 nm (c = 1, MeOH). C26H33N304 (MW = 451.571); mass spectroscopy (MH+) 452 30 Isomer 2: Retention time 5.52 minutes. Optical Rotation: [a]20 = 26 @ 589 nm (c = 1, MeOH) Printed from Mimosa 07/26/1999 12:37:07 page -267- WO 98/38177 PCT/US98/03373 - 266 - C26H33N304 (MW = 451 571); mass spectroscopy (MH+) 452 Step-B - Synthesis of (SI- and fR)-5-(L-tert-Leucinvl")-amino-7-methvl-5.7-dihvdro-6H-dibenzrb.dlazepin-6-one 5 Hydrochloride The compounds isolated in Part A (each isomer separately) were dissolved in dioxane and treated with excess HCl (g) After stirring for 17 hours, the title compounds were isolated as colorless solids after evaporation and vacuum drying 10 Isomer 1: C2|H25N30,.HC1 (MW = 387.91); mass spectroscopy (MH+ free base) 352. Optical Rotation: [cr]20 = - 34 @ 589 nm (c = 1, MeOH). 15 Isomer 2. C2]H25N302 HCl (MW = 387.91); mass spectroscopy (MH-f- free base) 352. Optical Rotation- [cr]20 = 108 @ 589 nm (c = 1, MeOH). 20 Example 7-E Synthesis of 5-(N-Boc-Amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one Step A - Synthesis of 5-Iodo-5.7-dihvdro-6H-dibenzrb.d1azepin-6-one 25 A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4 77 mmol) (Example 7-A) and Et3N ( 2.66 ml, 19.12 mmol) were stirred for 5.0 minutes at -15°C in CH2Cl2and treated with TMSI (1.36 ml, 9.54 mmol). After stirring for 15 minutes I, (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10°C over 3 h. The reaction was quenched with 30 sat. Na2S03, diluted with CH2C12 and separated. The organics were washed with Na2S03 and NaHS03 and dried over MgS04. After filtration, the organics were concentrated to approximately 20 ml and diluted with an additional 20 ml of hexanes. The title compound was isolated as a tan precipitate by filtration. Printed from Mimosa 07/26/1999 12:37:07 page -268- WO 98/38177 - 267 - PCT/US98/03373 Step B - Synthesis of 5-Azido-5.7-dihvdro-6H-dibenzrb.d1azepin-6-one The" -iodide isolate above was dissolved in DMF and treated with 1.2 equivalents of NaN3. After stirring 17 h at 23°C the mixture was diluted with 5 Et0Ac/H20, separated, washed with brine and dried over MgS04. The title compound was triturated from hot EtOAc as a tan powder. Step C - Synthesis of 5-CN-Boc-AminoV5.7-dihvdro-6H.7H-dibenzrb.dlazepin-6-one 10 The azide was dissolved in THF/H20 and stirred at 23°C for 17 h in the presence of 3 0 equivalents of Ph3P. The reaction was diluted with 50 % HOAc/toluene, separated, the aqueous layer extracted with toluene and evaporated to an oily residue This was taken to pH 7.0 by the addition of 1 N NaOH, the resulting HO Ac salt was collected and vacuum dried. Finally, the 15 compound was treated with Boc anhydride (1.05 equivalents) and Et3N (2.1 equivalents) in THF After stirring for 5 h at 23 °C the reaction was filtered and the title compound isolated as a colorless powder. Example 7-F 20 Synthesis of 5-Amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride Step A - Synthesis of 5-(N-Boc-Amino)-7-(2-methvlpropvl1-5.7-dihvdro-6H-dibenzrb.dlazepin-6-one 25 A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin- 6-one (0.2g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs2C03 (0.22 g, 0.678 mmol) and warmed to 60°C To the reaction mixture was added 1-iodo-2-methylpropane (0.078 ml, 0.678 mmol) and stirring continued for 17 h. After cooling to 23 °C the mixture was diluted with CH2C12, washed with 30 several portions of brine and dried over Na2S04. The title compound was purified by chromatography (Si02, CHCl3/MeOH 9:1). C23H28N203 (MW = 380.41), mass spectroscopy (MH+) 381 Printed from Mimosa 07/26/1999 12:37:07 page -269- WO 98/38177 PCT/US98/03373 -- 268 - Anal. Calcd for C23H28N203; C, 72.61 H, 7.42 N, 7.36. Found C, 72.31 H, 7 64 N, 7.17. Step B - Synthesis of 5-Amino-7-(2-methvlpropvl)-5.7-dihvdro-6H-5 dibenzfb.dl azepin-6-one Hydrochloride The compound isolated in Part A was deprotected in dioxane saturated with gaseous HCl The title compound was isolated as a slightly colored solid after evaporation and vacuum drying. 10 Example 7-G Synthesis of 5-Amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,djazepin-6-one Hydrochloride Step A- Synthesis of 5-fN-Boc-AminoV7-(methoxyacetvD-5.7-15 dihvdro-6H-dibenzrb.dlazepin-6-one A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.03, 3 08 mmol) (Example 7-E) in DMF was treated with Cs2C03 (1.10 g, 3.39 mmol) and warmed to 60°C To the reaction mixture was added bromomethyl acetate (0 321 ml, 3.39 mmol) (Aldrich) and stirring continued for 20 17 h. After cooling to 23 °C the mixture was diluted with CH2C12, washed with several portions of brine and dried over Na2S04. The title compound was purified by chromatography (Si02, CHC13). C22H24N205 (MW = 396.44); mass spectroscopy (MH+) 397 Anal. Calcd for C22H24N205; C, 66 65 H, 6.10 N, 7.07. Found: C, 66.28 25 H, 5.72 N, 6.50. Step B - Synthesis of 5-Amino-7-(methoxvacetvl")-5.7-dihvdro-6H-dibenzrb.dlazepin-6-one Hydrochloride The compound isolated in Part A was deprotected in dioxane saturated 30 with gaseous HCl. The title compound was isolated as a colorless solid after evaporation and vacuum drying. C17Hl6N203 HCl (MW = 332.78), mass spectroscopy (MH+ free base) 297. Printed from Mimosa 07/26/1999 12:37:07 page -270- WO 98/38177 PCT/US98/03373 - 269 - Example 7-H Synthesis of 5-Amino-7-(3,3-dimethyI-2-butanonyl)-5,7-dihydro-6H-dibenz|b,d] azepin-6-one Hydrochloride 5 Step A- Synthesis of 5-(N-Boc-Amino")-7-f3.3-dimethvl-butanonvl)- 5.7-dihvdro-6H-dibenzrb.d1azepin-6-one A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617 mmol) (Example 7-E) in DMF was treated with Cs2C03 (0.3 g, 0.925 mmol) and warmed to 60°C. To the reaction mixture was added 1-chloro-10 3,3-dimethyl-2-butanone (0.096 ml, 0.74 mmol) (Aldrich) and stirring continued for 17 h. After cooling to 23 °C, the mixture was diluted with CH2C12, washed with several portions of brine and dried over Na2S04 The title compound was isolated as a colorless solid. C25H30N2O4 (MW = 422.522); mass spectroscopy (MH+) 423 15 Step B - Synthesis of 5-Amino-7-(3.3-dimethvl-2-butanonvlV5.7-dihvdro-6H-dibenzrb.dlazepin-6-one Hydrochloride The compound isolated in Part A was deprotected in dioxane saturated with gaseous HCl. The title compound was isolated as a colorless solid after 20 evaporation and vacuum drying. Example 7-1 Synthesis of L-Alaninyl-5-amino-7-methyl-5,7-dihydro-25 6H-dibenz[b,d]azepin-6-one Hydrochloride Step A. Following General Procedure III-D and using N-t-Boc-L-alanme and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared. 30 Step B- Following General Procedure 8-N and using the N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared. Other substituted N-t-Boc-L-alaninyl-5-amino-7- Printed from Mimosa 07/26/1999 12:37:07 page -271- WO 98/38177 PCT/US98/03373 - 270 -- methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones can also be prepared by this procedure Example 7-J 5 Synthesis of L-ValinyI-5-amino-7-methyI-5,7-dihydro-6H-dibenz|b,d)azepin-6-one Hydrochloride Step A: Following General Procedure III-D and using N-t-Boc-L-valine and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, N-t-Boc-L- 10 valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared. Step B. Following General Procedure 8-N and using the N-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenztb,d]azepin-6-one, the title compound was prepared. Other substituted N-t-Boc-L-valinyl-5-amino-7- 15 methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-ones can also be prepared by this procedure. Example 7-K Synthesis of 20 5-Amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Following General Procedure 7-A and using 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters. No. 8, 667-670, (1971) and references cited therein) and l-chloro-4-phenylbutane (Aldrich), the title compound was prepared. 25 Example 7-L Synthesis of 5-Amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d] azepin-6-one 30 Following General Procedure 7-A and using 5,7-dihydro-6H- dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al, Tetrahedron Letters. No. 8, 667-670, (1971) and references cited therein) and (bromomethyl)cyclopropane (Aldrich), the title compound was prepared. Printed from Mimosa 07/26/1999 12:37:07 page -272- WO 98/38177 PCT/US98/03373 -- 271 - Example 7-M Synthesis of '. 5-Amino-7-(2%2',2'-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one 5 Following General Procedure 7-A and using 5,7-dihydro-6H- dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters. No. 8, 667-670, (1971) and references cited therein) and l-bromo-2,2,2- trifluoroethane (Aldrich), the title compound was prepared. 10 Example 7-N Synthesis of 5-Amino-7-cyclohexyl-5,7-dihydro-6H-dibenz| b,d J azepin-6-one Following General Procedure 7-A and using 5,7-dihydro-6H-15 dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters. No. 8, 667-670, (1971) and references cited therein) and bromocyclohexane (Aldrich), the title compound was prepared Example 7-0 20 Synthesis of 5-(L-Alaninyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Step 1: 2-Bromo-5-fluorotoluene was stirred in THF at -78C s-BuLi (1.05 eq., 1.3 M in cyclohexane) was slowly added and the mixture was stirred 25 for 45 minutes. Trimethylborate (1.5 eq) was added and the mixture was allowed to warm to ambient temperature After stirring for 1 hour, pinacol (2 eq.) was added. The mixture was stirred for 16 hours then was concentrated under reduced pressure The resulting residue was slurried in CH2C12 and filtered through Cehte. The filtrate was concentrated to yield an oil which was 30 purified by chromatography on deactivated silica gel (Et3N) to yield the arylboronate ester. Printed from Mimosa 07/26/1999 12:37:07 page -273- WO 98/38177 PCT/US98/03373 - 272 - Step 2- 2-Bromoaniline (1 eq ) and di-t-butyl-dicarbonate (l-.l eq.) were stirred at 80°C for 20 hours. The resulting mixture was allowed to cool and was directly distilled using house vacuum to provide N-t-Boc-2-bromoaniline 5 Step 3: N-t-Boc-2-bromoaniline (Step 2, 1 eq.), the arylboronate ester (Step 1,1.1 eq.), K2C03 (1.1 eq.) and tetrakis(triphenylphosphme)palladium(0) (0.02 eq) were stirred in 20% water/dioxane under nitrogen. The solution was heated at reflux for 10 hours The mixture was allowed to cool then was concentrated. The resulting residue was partitioned between water and 10 chloroform The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography using 1 • 1 CH2CI2/hexanes. Step 4 Following General Procedure 7-B and using the substituted biphenyl from step 3, the 9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was 15 prepared Step 5- 9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq., Step 4), cesium carbonate (1.1 eq , Aldrich) and methyl iodide (1.1 eq., Aldrich) were stirred in dry DMF at ambient temperature for 16 hours. The mixture was 20 concentrated under reduced pressure to provide a residue which was partitioned between EtOAc and water. The organic portion was dried and concentrated to yield an oil which was purified by silica gel chromatography to 9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one. 25 Step 6: Following General Procedure 7-A, Step B and 9-fluoro-7- methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step 5, 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared. Step 7: Following the procedure of Example 7-1 and using 5-amino-9-30 fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step 6, the title compound was prepared. Printed from Mimosa 07/26/1999 12:37:07 page -274- WO 98/38177 PCT/US98/03373 - 273 -- Example 7-P Synthesis of 5-(L-Alaninyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride 5 Following the procedure of Example 7-0 and using 2-bromo-4- fluoroaniline (Step 2, Lancaster) and o-tolylboronic acid (Step 3, Aldrich), the title compound was prepared. 10 Example 7-Q Synthesis of 5-(L-Alaninyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibcnz[b,d]azcpin-6-onc Hydrochloride Following the procedure of Example 7-0 and using 2-bromo-4- 15 fluorotoluene (Step 1), the title compound was prepared. Example 7-R Synthesis of 5-(L-AlanyI)-araino-7-cycIopropylmethyl-20 5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-1 and using 5-amino-7- cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the title compound was prepared. 25 Example 7-S Synthesis of 5-(L-AIaninyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-1 and using 5-amino-7-phenbutyl- 30 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-K), the title compound was prepared. Example 7-T Synthesis of Printed from Mimosa 07/26/1999 12:37:07 page -275- WO 98/38177 - 274 - 5-(L-Valinyl)amino-7-cycIopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-J and using 5-amino-7- cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-L), the 5 title compound was prepared Example 7-U Synthesis of 5-(L-Valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz|b,d]azepin-6-one Hydrochloride Following the procedure of Example 7-J and using 5-amino-7-phenbutyI- 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-U), the title compound was prepared Example 7-V Synthesis of 5-(L-Vaiinyl)amino-7-hexyI-5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride Step A Following General Procedure 7-A and using 5,7-dihydro-6H- dibenz[b,d]azepin-6-one (prepared as described in Brown, et. al., Tetrahedron Letters. No. 8, 667-670, (1971) and references cited therein) and 1-bromohexane (Aldrich), 5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared 25 Step B- Following the procedure of Example 7-J and using 5-amino-7- hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the title compound was prepared Example 7-W Synthesis of 30 5-(L-Valinyl)amino-10-fluoro-7-methyl- 5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride Following the procedure of Example 7-J and using 5-amino-10-fluoro-7- methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (as prepared in Example 13-QQ), the title compound was prepared. 15 20 Printed from Mimosa 07/26/1999 12:37:07 page -276- WO 98/38177 PCT/US98/03373 - 275 - Example 7-X Synthesis of 5-(L-Valinyl)amino-13-f1uoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride 5 Following the procedure of Example 7-J and using the 5-ammo-13- fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (as prepared in Example 7-P), the title compound was prepared. Example 7-Y 10 Synthesis of 5-(L-Valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d] azepin-6-one Hydrochloride Following the procedure of Example 7-J and using the 5-ammo-9-fluoro- 7-methyl-5,7-dihydro-6H-dibenz[b,d]azepm-6-one (as prepared in Example 7-0), 15 the title compound was prepared. Example 7-Z Synthesis of (5-Amino-7-methyl-l,2,3,4,5,7-hexahydro-20 6H-dicyclohexyl [b,d] azepin-6-one The 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-A) was dissolved in a 1:1 mixture of EtOAc/HOAc. 5% Rh/C was added and the mixture was stirred at 60°C under 60 psi of hydrogen. After 3 days, the mixture was filtered and the filtrate was 25 concentrated to provide an oil which was purified by SCX-cation exchange chromatography to yield the title compound Example 7-AA Synthesis of 30 5-(S)-Amino-7-methyl-5,7-dihydro- 6H-dibenz[b,d]azepin-6-one Hydrochloride Following General Procedure 7-C using racemic 5-amino-7-methyl-5,7- dihydro-6H-dibenz[b,d]azepin-6-one (1.0 eq.) and di-/?-toluoyl-D-tartaric acid monohydrate (1.0 eq.) in methanol, the title compound was prepared as a solid Printed from Mimosa 07/26/1999 12:37:07 page -277- WO 98/38177 PCT/US98/03373 -- 276 - The product was collected by filtration. Enantiomeric excess was determined by chiral HPLC. Desired enantiomer 1 • retention time of 9.97 minutes Undesired enantiomer 2- retention time of 8.62 minutes. 5 NMR data was as follows: 'H-nmr (CDC13)- 6 = 9.39 (s, 2H), 7.75-7.42 (m, 8H), 4.80 (s, IH), 3.30 (s, 3H) CI5H15C1N20 (MW = 274.75); mass spectroscopy (MH+) 239.1. Anal Calcd for C15H15C1N203; C, 65.57; H, 5.50, N, 10.20; Found: C, 10 65 51, H, 5.61; N, 10.01. GENERAL PROCEDURE 8-A N-l-Methvlation of Benzodiazepines A solution of benzodiazepine (1 eq.) in DMF (0 1 M concentration) at 15 0°C was treated with potassium tert-butoxide (1.0 eq., 1.0 M solution in THF). After stirring for 30 minutes at 0°C, iodomethane (1.3 eq.) was added and stirring continued for 25 minutes. The mixture was diluted with methylene chloride and washed with water and brine. The organic phase was dried over Na2S04, filtered, and concentrated. The crude product was then either purified 20 by trituration with 1:1 ether/hexanes or chromatographed via HPLC using ethyl acetate/hexanes as the eluent GENERAL PROCEDURE 8-B Cbz Removal Procedure 25 A flask was charged with the Cbz-protected 3-aminobenzodiazepine (1 eq). To this was added HBr (34 eq.; 30% solution in acetic acid). Within 20 minutes all of the starting material dissolves The reaction was stirred for 5 hours at ambient temperature. Ether was added to the orange solution causing the HBr*amine salt to precipitate. The mixture was decanted This process of 30 adding ether and decanting was repeated thrice in an effort to remove acetic acid and benzyl bromide. Toluene was added and the mixture concentrated in vacuo. Printed from Mimosa 07/26/1999 12:37:07 page -278- WO 98/38177 PCT/US98/03373 -- 277 - This step was also repeated The HBr salt was partitioned between-ethyl acetate and 1 M K2C03. The aqueous layer was back-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2S04, filtered, and concentrated. 5 GENERAL PROCEDURE 8-C Boc Removal Procedure A solution of Boc-protected amine (1 eq.) in methylene chloride (0.15 M concentration) was cooled to 0°C and treated with trifluoroacetic acid (30 eq.) 10 After 10 minutes at 0°C, the cooling bath was removed and stirring continued at ambient for 20 minutes to 1 hour The mixture was concentrated in vacuo to remove excess trifluoroacetic acid The residue was dissolved in methylene chloride and washed with saturated aqueous NaHC03 or 1 M K2C03 and brine. The organic layer was dried over Na2S04, filtered, and concentrated. 15 GENERAL PROCEDURE 8-D Azide Transfer Reaction Using KHMDS The azido derivative was prepared using the procedure described in John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996). 20 GENERAL PROCEDURE 8-E Azide Transfer Reaction Using LDA To a solution of diisopropylamine (1.1 eq) in 1 mL of dry THF cooled to -78°C was added n-butyl lithium (1.6M in hexane) (1.1 eq.) dropwise 25 maintaing the reaction temperature at -78°C. The reaction mixture was stirred for 30 min. at -78°C and then the lactam (0 471 mM) was added dropwise as a solution in 1 mL of dry THF. The reaction mixture was stirred at -78°C for 30 min. and then a pre-cooled solution of trisyl azide (1.2 eq.) was added as a solution in 1 mL of dry THF. The reaction mixture was stirred at -78°C for 20 30 min. and then quenched with acetic acid (4.0 eq.). The reaction mixture was then stirred at 40°C for 2 hrs. The reaction was then poured into EtOAc and Printed from Mimosa 07/26/1999 12:37:07 page -279- WO 98/38177 PCT/US98/03373 -- 278 - washed with water, sodium bicarbonate and brine, and then dried over sodium sulfate, filtered and concentrated. The residue was purified by LC 2000 chromatography. 5 GENERAL PROCEDURE 8-F Azido Group Reduction The azido group was reduced to the corresponding primary amine using the procedure described in John W. Butcher et al, Tel Lett, 37, 6685-6688 (1996). 10 GENERAL PROCEDURE 8-G N-Alkylation of Amides or Lactams Using Sodium Hydride or Potassium tert-Butoxide To a slurry of sodium hydride or potassium tert-butoxide (1.1 eq) in 15 15 mL of dry DMF was added the appropriate amide (0.0042 moles) as a solution in 10 mL of DMF. The alkyl iodide was then added and a thick slurry resulted. The reaction became less thick as time elapsed and when complete by TLC the reaction had become homogeneous. The reaction mixture was poured over ice and extracted into ethyl acetate. The organic layer was washed with water, 20 followed by brine The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure The residue was purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane system GENERAL PROCEDURE 8-H 25 N-Alkylation of Amides or Lactams Using KHMDS To the appropriate amide or lactam in THF cooled to -78°C was added KHMDS dropwise and the reaction mixture was stirred for 30 min. at -78°C. The alkyl iodide was then added dropwise while maintaining the temperature at 30 -70°C. The cooling bath was then removed and reaction was allowed to warm to room temperature and stirring was continued for 2 hours. The reaction mixture was then poured over ice and extracted into ethyl acetate The organic Printed from Mimosa 07/26/1999 12:37:07 page -280- WO 98/38177 PCT/US98/03373 -- 279 - extracts were washed with water, followed by brine. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane system. 5 GENERAL PROCEDURE 8-1 N-Alkvlation of Amides or Lactams Using Cesium Carbonate To a solution of the amide or lactam in DMF was added cesium carbonate (1.05 eq) and an alkyl iodide (1 1 eq) The mixture was allowed to 10 stir overnight at room temperature and then the reaction mixture was dilluted with ethyl acetate and washed with water, followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC (LC 2000), eluting with an ethyl acetate/hexane system. 15 GENERAL PROCEDURE 8-J BOC Removal Procedure To an N-Boc protected compound was added CH2C12/TFA (4:1) at room temperature. The reaction mixture was stirred at room temperature for 3 hours 20 and then concentrated The residue was extracted into dichloromethane and washed with water, saturated sodium bicarbonate, dried over Na2S04, filtered and concentrated to give the free amine. GENERAL PROCEDURE 8-K 25 Azide Transfer Procedure This azide transfer procedure is a modification of the procedure described m Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J Am Chem. Soc. 1990, 112, 4011-4030. To a solution of the lactam substrate (1.0 eq.) in THF (~0 1 M) under N2 at -78 °C was added a solution of KN(TMS)2 (1.1 eq. of 0.5 30 M in Toluene, Aldrich) dropwise over a period of 2-10 minutes. A slight exotherm was often observed by an internal thermometer, and the resulting Printed from Mimosa 07/26/1999 12:37:07 page -281- WO 98/38177 PCT/US98/03373 - 280 - solution was stirred for 5-15 minutes, while re-cooling to -78°C. Then, trisyl azide (1 1-1.5 eq., CAS No 36982-84-0, prepared as described by references in the Evans reference above) in THF (~0.5 M), either precooled to -78°C or at room temperature, was added via cannula over a period of 0.5-5 minutes. 5 Again, a slight exotherm was generally noted. The resulting solution was stirred for from 5-10 minutes, while re-cooling to -78°C. Then, AcOH (4.5-4.6 eq., glacial) was added, the cooling bath removed and the mixture allowed to warm to room temperature with stirring for 12-16 hours. The mixture was diluted with EtOAc, in a 2-5 volume multiple of the initial THF volume, and washed 10 with dilute aq NaHC03 (l-2x), 0.1-1 0 M aq. HCl (0-2x), and brine (lx). The organic phase was then dried over MgS04, filtered, concentrated to provide the crude product GENERAL PROCEDURE 8-L 15 Azide Reduction to an Amine A mixture of the azide in absolute EtOH (0.03-0.07 M) and 10% Pd/C (-1/3 by weight of the azide) was shaken in a Parr apparatus under H2 (35-45 psi) at room temperature for 3-6 hours. The catalyst was removed by filtration through a plug of Celite, rinsing with absolute EtOH, and the filtrate 20 concentrated to provide the crude amine product GENERAL PROCEDURE 8-M Amide Alkylation Using Cesium Carbonate This procedure is a modification of the procedure described in Claremon, 25 D. A.; et al, PCT Application: WO 96-US8400 960603. To a mixture of 2,4-dioxo-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine (CAS No. 49799-48-6) in DMF (1.0 eq., 0.7 M) under N2 at room temperature was added Cs2C03 (2 2 eq.) and the appropriate alkyl halide (2.2 eq.) The mixture was stirred at room temperature for 5 5-16 hours. The mixture was partitioned between EtOAc and 30 sat NaHC03. The aqueous layer was extracted with EtOAc (l-2x) and the Printed from Mimosa 07/26/1999 12:37:07 page -282- WO 98/38177 PCT/US98/03373 -- 281 - combined EtOAc extracts were dried over Na2S04, filtered, and concentrated to provide the crude product. GENERAL PROCEDURE 8-N 5 BOC Removal Procedure A stream of anhydrous HCl gas was passed through a stirred solution of the N-t-Boc protected amino acid in 1,4-dioxane (0.03-0.09 M), chilled in a ice bath to ~10°C under N2, for 10-15 minutes. The solution was capped, the cooling bath removed, and the solution was allowed to warm to room 10 temperature with stirring for 2-8 hours, monitoring by TLC for the consumption of starting material The solution was concentrated (and in some instances dissolved in CH2C1, then re-concentrated and placed in vacuum oven at 60-70°C to remove most of the residual dioxane) and used without further purification. 15 Example 8-A Synthesis of 3-Amino-l,3-dihydro-5-(l-piperidinyl)-2H-l,4-benzodiazepin-2-one Step A - Preparation of 1.2-Dihvdro-3H-1 -methv 1-5-f 1 -piperidinvl)-1.4-benzodiazepin-2-one 20 A solution of phosphorous pentachloride (1.2 eq) in methylene chloride was added dropwise to a solution of l-methyl-l,2,3,4-tetrahydro-3H-l,4-benzodiazepin-2,5-dione (Showell, G. A.; Bourrain, S.; Neduvehl, J G.; Fletcher, S. R.; Baker, R.; Watt, A. P.; Fletcher, A. E.; Freedman, S. B.; Kemp, J. A.; Marshall, G. R.; Patel, S.; Smith, A. J.; Matassa, V. G. J Med. Chem. 25 1994, 37, 719.) in methylene chloride The resultant yellowish-orange solution was stirred at ambient temperature for 2.5 hours; the solvent was removed in vacuo The orange residue was redissolved in methylene chloride, cooled to 0 °C, and treated with a solution of piperidine (2 eq) and triethylamine (2 eq) in methylene chloride The cooling bath was removed and the reaction stirred for 30 18 hours. The reaction mixture was washed with saturated aqueous NaHC03 (back-extracted with methylene chloride) and brine. The organic phase was dried over Na2S04, filtered, and concentrated. The residue was purified via Printed from Mimosa 07/26/1999 12:37:07 page -283- WO 98/38177 PCT/US98/03373 - 282 - HPLC eluting with a gradient of 4 to 10% methanol/methylene chloride affording the title intermediate as a yellow solid having a melting point of 103-105°C. C,5H|9N30 (MW 257.37), mass spectroscopy 257. 5 Anal. Calcd for Cl5H19N30: C, 70.01; H, 7.44; N, 16.33. Found: C, 69.94; H, 7.58; N, 16.23. Step B - Preparation of 1.2-Dihvdro-3H-l-methvl-3-oximido-5-n-piperidinvD-1.4-benzodiazepin-2-one 10 Potassium tert-butoxide (2.5 eq) was added in two portions to a -20°C solution of 1,2-dihydro-3H-1 -methyl-5-( 1 -piperidinyl)-1,4-benzodiazepin-2-one (1 eq) in toluene) After stirring at - 20°C for 20 min, isoamyl nitrite (1.2 eq.; Aldrich) was added to the red reaction mixture. The reaction was stirred at -20 °C for 5 hours at which time the reaction was done by TLC. The cooling bath 15 was removed and the reaction quenched with 0.5 M citric acid. After stirring for 10 minutes, diethyl ether was added. The suspension was stirred at ambient temperature overnight then filtered washing with ether The resultant cream colored solid had a melting point of 197-200°C. 'H NMR data of the E/Z isomers was as follows: 20 'H NMR (300 MHz, CDC13): 8 = 7.64 (IH, bs), 7.48 (2H, d, J=7 4 Hz), 7.35-7.20 (6H, m), 6.75 (IH, bs), 3.8-3.2 (8H, m), 3.46 (3H, s), 3.42 (3H, s), 1.90-1.40 (12H, m). C]5H|8N402 (MW = 286.37); mass spectroscopy 286. 25 Step C - Preparation of 1.2-dihvdro-3H-l-methvl-3-fO- fethvlaminocarbonvl)oximidol-5-f 1 -piperidinvD-1.4-benzodiazepin-2-one A mixture of l,2-dihydro-3H-l-methyl-3-oximido-5-(l-piperidinyl)-l,4-benzodiazepin-2-one (1 eq) in THF was treated with ethyl isocyanate (1 7 eq) 30 and triethylamine (0 6 eq) The mixture was heated to 64°C for 4 hours The mixture was concentrated and the residue purified by HPLC eluting with 5% methanol/methylene chloride. Printed from Mimosa 07/26/1999 12:37:07 page -284- WO 98/38177 - 283 - PCT/U S98/03373 'H NMR data of the E/Z isomers was as follows: 'H NMR (300 MHz, CDC13): 5 = 7.50 (2H, dd, J=8.4, 1.5 Hz), 7.35-7.22 (6H, m), 6.42 (IH, bt), 6.20 (IH, bt), 3.7-3.4 (8H, m), 3.46 (3H, s), 3 44 (3H, s), 3.25 (4H, m), 1.9-1.4 (12H, m), 1.12 (3H, t, J=6.3 Hz), 1.10 (3H, t, J=6.3 5 Hz). C18H23N503 (MW = 357.46), mass spectroscopy 357. Step D - Preparation of 3-Amino-1.3-dihvdro-2H-l-methvl-5-n-piperidinvD-1.4-benzodiazepin-2-one 10 The 1,2-dihydro-3H-1 -methy l-3-[0-(ethylaminocarbonyl)oximido]-5-( 1 - piperidinyl)-1,4-benzodiazepin-2-one (1 eq) was hydrogenated in methanol over 5% palladium on carbon (0.15 eq) at 43 psi for 3.25 hours. The reaction was filtered through celite and concentrated in vacuo. The residue was taken up in methylene chloride and filtered a second time through celite. The filtrate was 15 concentrated and the resultant foam was used immediately. Example 8-B Synthesis of 3-(L-AlaninyI)-amino-2,3-dihydro-20 l-methyI-5-phenyl-lH-l ,4-benzodiazepin-2-one Step A - Preparation of (S")-3-amino-1.3-dihvdro-l-methvl-5-phenvl-2H-1,4-benzodiazepin-2-one. (1 SV7.7-dimethvl-2-oxobicvclo[2.2 1 Iheptane-1 -methanesulfonate The title intermediate was prepared according to Reider, P. J.; Davis, P., 25 Hughes, D. L.; Grabowski, E. J. J. J Org. Chem. 1987, 52, 955 using 3-amino- l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one (Bock M. G.; DiPardo, R. M., Evans, B. E.; Rittle, K. E; Veber, D. F.; Freidinger, R. M.; Hirshfield, J.; Springer, J. P. J Org Chem 1987, 52, 3232.) as the starting material. 30 Step B - Preparation of 3-fN,-(tert-Butvlcarbamate')-L-alaninvll-amino-2.3-dihvdro-1 -methvl-5-phenvl-1H-1.4-benzodiazepin-2-one Printed from Mimosa 07/26/1999 12:37:07 page -285- WO 98/38177 PCT/US98/03373 -- 284 -- (S)-3-Amino-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one, (lS)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-l-methanesulfonate was free based by partitioning between methylene chloride and 1M potassium carbonate. The free amine was then coupled with N-Boc-alanine following General Procedure 5 III-D C24H28N404 (MW = 436.56); mass spectroscopy 436. Anal Calc. for C24H2SN404: C, 66.03; H, 6.47, N, 12.84. Found: C, 65.79; H, 6.68; N, 12.80 10 Step C - Preparation of 3-(L-Alaninvl1-amino-2.3-dihvdro-l-methvl- 5-phenvl-1H-1.4-benzodiazepin-2-one Following General Procedure 8-C using 3-[N'-(tert-butylcarbamate)-L- alaninyl]-amino-2,3-dihydro-1 -methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, the title compound was prepared as a white foam. 15 Anal. Calc. for C19H19N402: C, 69.21; H, 6.64; N, 15.37 Found- C, 70.11; H, 6.85; N, 15 01. Example 8-C Synthesis of 20 3-(L-Alaninyl)-amino-7-chloro-2,3-dihydro- l-methyl-5-phenyl-lH-l,4-benzodiazepin-2-one Step A - Preparation of 3-(BenzvloxvcarbonvIY-amino-7-chloro-2.3-dihvdro-1 -methvl-5-phenvl-1H-1.4-benzodiazepin-2-one A solution of 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-25 phenyl-lH-l,4-Benzodiazepin-2-one (1 eq; Neosystem) in DMF was cooled to 0°C and treated with potassium /erf-butoxide (1 eq, l.OM solution in THF). The resultant yellow solution was stirred at 0°C for 30 minutes then quenched with methyl iodide (1.3 eq). After stirring an addition 25 minutes the reaction was diluted with methylene chloride and washed with water and brine. The organic 30 phase was dried over Na2S04, filtered, and concentrated. The residue was purified via HPLC chromatography eluting with a gradient of 20-»30% ethyl acetate/hexanes. C24H20ClN3O3 (MW = 433.92); mass spectroscopy 433 Printed from Mimosa 07/26/1999 12:37:07 page -286- WO 98/38177 PCT/US98/03373 - 285 -- Anal, calcd for C24H20ClN3O3: C, 66.44; H, 4.65; N, 9.68. Found: C, 66.16; H, 4.50; N, 9.46. Step B - Preparation of 3-Amino-7-chloro-1.3-dihvdro-l-methvl-5-5 phenvl-2H-1.4-benzodiazepin-2-one Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1 -methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C. 10 Step C - Preparation of 3-rN1-tert-Butvlcarbamate)-L-alaninvl1-amino-7-chloro-1.3-dihvdro-l-methvl-5-phenvl-2H-1.4-benzodiazepin-2-one Following General Procedure III-D using N-Boc-L-alamne and 3-amino-15 7-chloro-1,3-dihydro-1 -methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam. C24H28C1N404 (MW = 471.18); mass spectroscopy 471 Anal, calcd for C24H28C1N404: C, 61.21; H, 5 78; N, 11.90 Found- C, 61.24; H, 5.59; N, 11.67. 20 Step D - Preparation of 3-(L-Alaninvl')amino-7-chloro-1.3-dihvdro-1 -methvl-5-phenvl-2H-1,4-benzodiazepin-2-one Following General Procedure 8-C using 3-[N'-tert-butylcarbamate)-L-alaninyl]-amino-7-chloro-l,3-dihydro-l-methyl-5-phenyl-2H-l,4-benzodiazepin-25 2-one, the title intermediate was prepared as a white foam. The crude material was used immediately. Example 8-D Synthesis of 30 3-(L-AIaninyl)amino-7-bromo-2,3-dihydro- 1 -methy l-5-(2-fluorophenyl)-1 H-l ,4-benzodiazepin-2-one Step A - Preparation of 3-(Benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1 -methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one Printed from Mimosa 07/26/1999 12:37:07 page -287- WO 98/38177 -- 286 - PCT/US98/03373 Following General Procedure 8-A using 3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (Neosystem), the title intermediate was prepared as a white foam C24H19BrFN303 (MW = 496.36); mass spectroscopy 497.-5 Anal, calcd for C24H19BrFN303- C, 58.08; H, 3.86; N, 8.47. Found: C, 57.90; H, 4.15; N, 8.20. Step B - Preparation of 3-Amino-7-bromo-1.3-dihvdro-l-methvl-5-(2-fluorophenvl1-2H-1.4-benzodiazepin-2-one 10 Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-7- bromo-2,3 -dihydro-1 -methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C. 15 Step C - Preparation of 3-rN'-(7ert-ButvlcarbamateVL-alaninvll- amino-7-bromo-l .3-dihvdro-1 -methvl-5-f2-fluorophenvD-2H-1.4-benzodiazepin-2-one Following General Procedure III-D using N-Boc-L-alanine (Novo) and 3-amino-7-bromo-1,3-dihydro-1 -methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin- 20 2-one, the title intermediate was prepared as a white foam. C24H26BrFN404 (MW = 533.12); mass spectroscopy 533.2. Anal, calcd for C24H26BrFN404: C, 54.04; H, 4.91; N, 10.50. Found: C, 53.75; H, 4.92; N, 10.41. 25 Step D - Preparation of 3-CL-Alaninvl'>-amino-7-bromo-1.3-dihvdro- 1 -methvl-5-(2-fluorophenvlV2H-1.4-benzodiazepin-2-one Following General Procedure 8-C using 3-[N'-(fer/-butylcarbamate)-L-alaninyl]-amino-7-bromo-1,3-dihydro-1 -methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam. The 30 crude material was used immediately. Example 8-E Synthesis of Printed from Mimosa 07/26/1999 12:37:07 page -288- WO 98/38177 - 287 - PCT/US98/03373 3-(N'-Methy!-L-aIaninyl)-amino-2,3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepin-2-one Step .A - Preparation of 3-fN'-(tert-ButvlcarbamateVN'-methvl-L-alaninvll-amino-2.3-dihvdro-1 -methvl-5-phenvl-1H-1.4-5 benzodiazet)in-2-one Following General Procedure III-D and using (S)-3-amino-l,3-dihydro-l-methyl-5-phenyI-2H-l,4-benzodiazepin-2-one (Example 8-B) and N-/er/-Boc-N-methyl-alanine (Sigma), the title intermediate was obtained as a white solid. C25H30N4O4 (MW = 450.2); mass spectroscopy (M+l) 451.2. 10 Anal, calcd for C25H30N4O4: C, 66.65; H, 6.71; N, 12.44 Found: C, 66.66; H, 6.89; N, 12.21. Step A - Preparation of 3-(N,-Methvl-L-alaninvl)-amino-2,3- dihvdro-1 -methvl-5-phenvl-1H-1,4-benzodiazepin-2-one 15 Following General Procedure 8-C and using 3-[N'-(/e/V-butylcarbamate)- N' -methyl-L-alaninyl]-amino-2,3-dihydro-1 -methyl-5-phenyl-1H-1,4- benzodiazepin-2-one, the title intermediate was prepared as a white foam. C2oH22N402 (MW =350.46); mass spectroscopy (M+l) 351.4. Anal calcd for C20H22N4O2: C, 68.55, H, 6.33; N, 15.99. Found, C, 20 68.36; H, 6.20; N, 15.79. Example 8-F Synthesis of 3-(L-Alaninyl)amino-7-chloro-2,3-dihydro-25 l-methyl-5-(2-chlorophenyI)-lH-l,4-benzodiazepin-2-one Step A - Preparation of 3-(BenzvloxvcarbonvlVamino-7-chloro-2.3-dihvdro-1 -methvl-5-(2-chlorophenvl')-1H-1.4-benzodiazepin-2-one Following General Procedure 8-A using 3-(benzyloxycarbonyl)-amino-7-30 chloro-2,3-dihydro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one (Neosystem), the title intermediate was prepared as a white solid having a melting point of 232-233°C. C24H19C12N303 (MW = 468.36); mass spectroscopy 468. Printed from Mimosa 07/26/1999 12:37:07 page -289- WO 98/38177 - 288 - PCT/US98/03373 'H NMR (300 MHz, CDC13): 5 = 7.67 (IH, m), 7.52-(lH, -dd, J=2.4, 8 7 Hz), 7.42-7.26 (9H, m), 7.07 (IH, d, J=2.4 Hz), 6 70 (IH, d, J=8.3 Hz), 5.35 (IH, d, J=8 4 Hz), 5.14 (2H, ABq, J=19.6 Hz), 3.47 (3H, s). I3C NMR (75 MHz, CDC13): 5 = 166.66, 165.65, 155.72, 140.52, 136.99, 5 136.0, 132.87, 131.99, 131.47, 131.40, 131 38, 131.16, 130.54, 130.06, 128.45, 128.08, 128 03, 127.72, 127.22, 123.28, 122.01, 68.95, 67.02, 35.32. Step B - Preparation of 3-Amino-7-chloro-1.3-dihvdro-l-methvl-5-(2-chlorophenvl'>-2H-1.4-benzodiazepin-2-one 10 Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-7- chloro-2,3-dihydro-1 -methyi-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C. 15 Step C - Preparation of 3-FN'-(7ert-Butvlcarbamate1-L-alaninvl 1 - amino-7-chloro-1.3-dihvdro-l-methvl-5-(2-chlorophenvD-2H-1.4-benzodiazepin-2-one Following General Procedure III-D using N-Boc-L-alanme and 3-amino- 7-chloro-1,3-dihydro- l-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one, 20 the title intermediate was prepared as a white foam. C24H26C12N404 (MW = 505.44); mass spectroscopy 505.2. Step D - Preparation of 3-CL-AlaninvD-amino-7-chloro-1.3-dihvdro-1 -methvl-5-(2-chlorophenvl'>-2H-1,4-benzodiazepin-2-one 25 Following General Procedure 8-C using 3-[N'-(/6r/-butylcarbamate)-L- alaninyl]-amino-7-chloro-1,3-dihydro-1 -methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam. The crude material was used immediately. 30 Example 8-G Synthesis of 3-(L-Alaninyl)amino-5-cyclohexyI-2,3-dihydro-l-methyl-lH-l,4-Benzodiazepin-2-one Printed from Mimosa 07/26/1999 12:37:07 page -290- WO 98/38177 PCT/US98/03373 - 289 -- Step A - Preparation of 3-(Benzvloxvcarbonvls)-amino-5- cvlclohexvl-2.3-dihvdro-1 -methvl-1H-1,4-benzodiazepin-2-one Following General Procedure 8-A using 3-(benzyloxycarbonyl)-amino-5-5 cyclohexyl-2,3-dihydro-lH-l,4-benzodiazepin-2-one (Neosystem), the title intermediate was prepared as a white solid having a melting point of 205-206°C. C24H27N303 (MW = 405.54); mass spectroscopy 405. 'H NMR (300 MHz, CDC13): 5 = 7.54 (IH, d, J=7.9 Hz), 7.48 (IH, d, J=7.7 Hz), 7.36-7.26 (7H, m), 6.54 (IH, d, J= 8.3 Hz), 5.15 (IH, d, J=8.0 Hz), 10 5 09 (2H, ABq, J=I7.1 Hz), 3.39 (3H, s), 2 77 (IH, m), 2.01 (IH, bd, J=13.6 Hz), 1.85 (IH, bd, J=12.4 Hz), 1.68-1.49 (4H, m), 1.34-1.02 (4H, m). Step B - Preparation of 3-Amino-5-cvclohexvl-1.3-dihvdro-l-methvl-2H-1.4-benzodiazepin-2-one 15 Following General Procedure 8-B using 3-(benzyloxycarbonyl)-amino-5- cyclohexyl-2,3-dihydro-1 -methyl-1H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam which was used immediately in Step C. C,6H2,N30 (MW+H = 272.1763); mass spectroscopy 272.1766 20 Step C - Preparation of 3-rN,-Oer/-ButvIcarbamate')-L-alaninvll-amino-5-cvclohexvl-1.3 -dihvdro-1 -methvl-2H-1.4-benzodiazepin-2-one Following General Procedure III-D using N-Boc-L-alanine and 3-amino-25 5-cyclohexyl-l,3-dihydro-l-methyl-2H-l,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam. C;4H34N404 (MW = 442.62); mass spectroscopy (M+H) 443.2. Step D - Preparation of 3-(L-AlamnvDamino-5-cvclohexvl-1.3-30 dihvdro-1 -methvl-2H-l .4-benzodiazepin-2-one Following General Procedure 8-C using 3-[N'-(/m-butylcarbamate)-L-alaninyl]-amino-5-cyclohexyl-1,3-dihydro-1 -methyl-2H-1,4-benzodiazepin-2-one, Printed from Mimosa 07/26/1999 12:37:07 page -291- WO 98/38177 PCT/US98/03373 -- 290 -- the title intermediate was prepared as a white foam. The crude material was used immediately C19H26N402 (M+H = 343.2136), mass spectroscopy found 343.2139. 5 Example 8-H Synthesis of 3-(L-Alaninyl)amino-2,3-dihydro-l-methyl-7-nitro-5-phenyl-lH-l,4-benzodiazepin-2-one Step A - Preparation of 2-rN-fa-IsopropvlthioVN'-10 fbenzvloxvcarbonviyglvcinvll-amino-5-nitrobenzoDhenone A solution of a-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq; prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975, 31, 863.) in dry THF was cooled to 0 °C and treated with oxalyl chloride (1 eq) and 3 drops of DMF. After stirring for 15 minutes at 0°C, the cooling bath was removed 15 and stirring continued at ambient temperature for 40 minutes. The solution was recooled to 0°C. A solution of 2-amino-5-nitrobenzophenone (0 9 eq ; Acros) and 4-methylmorpholine (2.0 eq.) in dry THF was added via cannulation to the acid chloride. The cooling bath was removed and the reaction stirred at ambient for 5 hours. The reaction was diluted with methylene chloride and washed with 20 0 5 M citric acid, saturated aqueous NaHCOj, and brine. The organic phase was dried over Na2S04, filtered, and concentrated. The residue was purified via preparative LC2000 eluting with a gradient of 15—»20% ethyl acetate/hexanes giving an off-white foam. C26H25N306S (MW = 507.61), mass spectroscopy found 507.9. 25 Anal, calcd for C26H25N306S" C, 61.53; H, 4.96; N, 8.28. Found: C, 61.70; H, 4.99; N, 8.22. Step B - Preparation of 2-rN-(q-Amino')-N'-(benzvloxvcarbonvn-glvcinvll-amino-5-nitrobenzophenone 30 Ammonia gas was bubbled into a solution 2-[N-(a-isopropylthio)-N'- (benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone (1 eq) in THF at 0°C. After 35 minutes mercury(II) chloride (1.1 eq) was added. The ice bath was removed and ammonia gas was continued to bubble through the suspension for 4 Printed from Mimosa 07/26/1999 12:37:07 page -292- WO 98/38177 - 291 - PCT/US98/03373 hours The bubbler was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite washing with THF. The filtrate was concentrated-/^ vacuo. The crude solid was used in step C without further purification. 5 Step C - Preparation of 3-(BenzvIoxvcarbonvD-amino-2.3-dihvdro-7-nitro-5-phenvl-1H-1.4-benzodiazepin-2-one 2-[N-(a-Amino)-N'-(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone (1 eq) was treated with glacial acetic acid and ammonium 10 acetate (4.7 eq). The suspension was stirred at ambient temperature for 21 hours. After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and 1 N NaOH. The aqueous layer was back-extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified via flash 15 chromatography eluting with a gradient of 2-»3% isopropyl alcohol/methylene chloride. C23Hl8N405 (MW = 430.45); mass spectroscopy found (M+H) 431.2. Anal calcd for C23Hi8N405: C, 64.18, H, 4.22, N, 13.02. Found. C, 64.39; H, 4.30; N, 13.07. 20 Step D - Preparation of 3-CBenzvloxvcarbonvl')-amino-2.3-dihvdro-1 -methvl-7-nitro-5-phenvl-1H-1.4-benzodiazepin-2-one Following General Procedure 8-A and using 3-(benzyloxycarbonyl)-amino-2,3 -dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepm-2-one, the title 25 intermediate was prepared as a yellow foam C24H20N4O5 (MW = 444.48); mass spectroscopy found (M+H) 445.2. Anal, calcd for C24H20N4O5: C, 64.86; H, 4.54; N, 12.60 Found- C, 65.07; H, 4.55; N, 12.46. 30 Step E - Preparation of 3-Amino-1.3-dihvdro-l-methvl-7-nitro-5- phenvl-2H-1.4-benzodiazepin-2-one Printed from Mimosa 07/26/1999 12:37:07 page -293- WO 98/38177 - 292 - PCT/US98/03373 Following General Procedure 8-B and using 3-(benzyloxycarbonyl)-amino-2,3-dihydro-1 -methyl-7-nitro-5-phenyI-1H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow foam which was used immediately in Step F. 5 Step F - Preparation of 3-rN'-(fer/-Butvlcarbamate1-L-alaninvll-amino-2.3-dihvdro-l -methvl-7-nitro-5-phenvl-lH-l .4-benzodiazepin-2-one Following General Procedure III-D using N-Boc-L-alanine and 3-amino-10 l,3-dihydro-l-methyl-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow solid. C24H27N506 (MW = 481.56); mass spectroscopy found (M+H) 482.3. Anal, calcd for C24H27N506: C, 59 88; H, 5.61; N, 14.55. Found- C, 60.22; H, 5.75; N, 13.91. 15 Step G - Preparation of 3-('L-Alaninvl'l-amino-2.3-dihvdro-l-methvl-7-nitro-5-phenvl-1H-1.4-benzodiazepin-2-one Following General Procedure 8-C using 3-[N'-(terf-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1 -methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-20 one, the title intermediate was prepared as a yellow foam. The crude material was used immediately. Example 8-1 Synthesis of 25 3-(L-Alaninyl)amino-2,3-dihydro-l-methyl- 5-(2-fluorophenyl)-lH-l,4-benzodiazepin-2-one Step A - Preparation of 3-Amino-1.3-dihvdro-l-methvl-5-(2-fluorophenvl')-2H-1.4-benzodiazepm-2-one A flask was charged with 3-(benzyloxycarbonyl)-amino-7-bromo-2,3-30 dihydro-l-methyl-5-(2-fluorophenyl)-lH-l,4-benzodiazepin-2-one (1 eq.; Example 8-D, Step A) and 10% palladium on carbon Methanol was added, and the flask was placed under a balloon of H2. The reaction was stirred for 21 Printed from Mimosa 07/26/1999 12:37:07 page -294- WO 98/38177 - 293 -- PCT/U S98/03373 hours. The mixture was filtered through celite washing with methanol The filtrate was concentrated to a white solid. C,6Hl4FN30 (MW = 283.33); mass spectroscopy found (M+H) 284.1 5 Step B - Preparation of 3-l~N' /err-ButvlcarbamateVL-alaninvll- amino-1,3-dihvdro-1 -methvl-5-(2-fluorophenvl')-2H-1.4-benzodiazepin-2-one Following General Procedure III-D using N-Boc-L-alanine and 3-amino-l,3-dihydro-l-methyl-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-one, the title 10 intermediate was prepared as a white solid C24H27FN404 (MW = 454.50); mass spectroscopy found (M+H) 455.4. Anal, calcd for C24H27FN404- C, 63 44; H, 5.95; N, 12.33. Found: C, 63.64; H, 6.08; N, 12.16. 15 Step C - Preparation of 3-(L-AlaninvD-amino-7-bromo-1.3-dihvdro- 1 -methvl-5-f2-fluorophenvO-2H-1.4-benzodiazepin-2-one Following General Procedure 8-C using 3-[N'-(ter/-butylcarbamate)-L-alaninyl]-amino-l,3-dihydro-l-methyl-5-(2-fluorophenyl)-2H-l,4-benzodiazepin-2-one, the title intermediate was prepared as a white foam. The crude material 20 was used immediately. Example 8-J Synthesis of 3-(L-Alaninyl)-amino-2,3-dihydro-25 l-methyl-5-(3-fluorophenyl)-lH-l,4-benzodiazepin-2-one Step A - Preparation of 2-Amino-3'-fluorobenzophenone A solution of 3-bromofluorobenzene (1 eq.) in THF was cooled to -78°C under nitrogen and treated with /m-butyllithium (2 05 eq., 1.6 M solution in pentane) at a rate of 40 ml/h. The internal temperature did not rise above -30 74°C The orange solution was stirred at -78°C for 30 minutes prior to the addition of anthranilonitrile (0.6 eq.) as a solution in THF. The reaction was warmed to 0°C and stirred for 2 hours. 3N HCl was added to the mixture and stirring continued for 30 minutes. The reaction was diluted with ethyl acetate Printed from Mimosa 07/26/1999 12:37:07 page -295- WO 98/38177 - 294 and the layers were separated. The aqueous layer was back-extracted thrice with ethyl acetate The combined extracts were washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified via HPLC eluting with 93 7 hexanes/ethyl acetate. 5 C13H10FNO (MW = 215.24); mass spectroscopy found (M+H) 216.3. "H NMR (300 MHz, CDC13) d 7.44-7.19 (6H, m), 6.74 (IH, d, J=8 0 Hz), 6.61 (IH, dd, J=0.94, 7.9 Hz), 6.10 (2H, bs). Step B - Preparation of 2-rN-fq-Isopropvlthio')-N'-10 (benzvloxvcarbonvl'l-glvcinvll-amlno-3,- fluorobenzophenone A solution of a-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq; prepared according to Zoller, V ; Ben-Ishai, D Tetrahedron 1975, 31, 863.) in dry THF was cooled to 0°C and treated with oxalyl chloride (1 eq.) and 3 drops 15 of DMF. After stirring for 15 minutes at 0°C, the cooling bath was removed and stirring continued at ambient temperature for 40 minutes. The solution was recooled to 0°C. A solution of 2-amino-3'-fluorobenzophenone (0.9 eq.) and 4-methylmorpholine (2.0 eq) in dry THF was added via cannulation to the acid chloride. The cooling bath was removed and the reaction stirred at ambient for 20 5 hours. The reaction was diluted with methylene chloride and washed with 0.5 M citric acid, saturated aqueous NaHC03, and brine. The organic phase was dried over Na2S04, filtered, and concentrated. The residue was purified via preparative LC2000 eluting with a gradient of 15->20% ethyl acetate/hexanes giving an off-white foam. 25 C26H25N204S (MW = 480.60); mass spectroscopy found (M+NH/) 498.3. 'H NMR (300 MHz, CDC13) d 11.39 (IH, s), 8.59 (IH, d, J=6.0 Hz), 7.63-7.55 (2H, m), 7.48-7.27 (9H, m), 7.14 (IH, dt, J=1.2, 8.4 Hz), 5.94 (IH, d, J=7.2 Hz), 5.58 (IH, d, J=8.7 Hz), 5.17 (2H, ABq, J=14.7 Hz), 3.25 (IH, sep, J=6.6 Hz), 1.44 (3H, d, J=6.0 Hz), 1.28 (3H, d, J=6.6 Hz). 30 Step C - Preparation of 2-rN-(a-Amino)-N,-(benzvloxvcarbonvl'>-glvcinvll-amino-3' -fluorobenzophenone PCT/US98/03373 Printed from Mimosa 07/26/1999 12:37:07 page -296- WO 98/38177 - 295 -- PCT/US98/03373 Ammonia gas was bubbled into a solution 2-[N-(a-isopropykhio)-N'-(benzyloxycarbonyl)-glycinyl]-amino-3'-fluorobenzophenone (1 eq) in THF at 0°C. After 35 minutes mercury(II) chloride (l.l eq) was added. The ice bath was removed and ammonia gas was continued to bubble through the suspension 5 for 4 hours. The bubbler was removed and the reaction continued to stir for 16 hours The mixture was filtered through celite washing with THF. The filtrate was concentrated in vacuo. The crude solid was used in step D without further purification. 10 Step D - Preparation of 3-fBenzvloxvcarbonvO-amino-2.3-dihvdro- 5-C3 -fluorophenvl-)-1H-1.4-benzodiazepin-2-one 2-[N-(a-Amino)-N'-(benzyloxycarbonyl)-glycinyl]-amino-3'-fluorobenzophenone (1 eq) was treated with glacial acetic acid and ammonium acetate (4 7 eq) The suspension was stirred at ambient temperature for 21 15 hours. After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and 1 N NaOH. The aqueous layer was back-extracted with ethyl acetate. The combined organics were washed with brine, dried over NajSO,,, filtered, and concentrated. The residue was purified via flash chromatography eluting with a gradient of 2—»3% isopropyl alcohol/methylene 20 chloride. C23H,8FN303 (MW = 403.44), mass spectroscopy found (M+H) 404.4. Anal, calcd for C23H18FN303»0.5H20. C, 66.98; H, 4.64; N, 10.18. Found: C, 67.20, H, 4.64; N, 9.77. 25 Step E - Preparation of 3-(BenzvloxvcarbonvlVamino-2.3-dihvdro- 1 -methvl-5-f 3-fluorophenvD-1H-1.4-benzodiazepin-2-one Following General Procedure 8-A and using 3-(benzyloxycarbonyl)-amino-2,3-dihydro-5-(3-fluorophenyl)-lH-l,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow foam 30 C24H20FN3O3 (MW = 417 47); mass spectroscopy found (M+H) 418 3. Anal, calcd for C24H20FN3O3 C, 69.06; H, 4.83; N, 10 07. Found- C, 69.33; H, 4.95; N, 9.82. Printed from Mimosa 07/26/1999 12:37:07 page -297- WO 98/38177 - 296 - PCT/US98/03373 Step F - Preparation of 3-Amino-1.3-dihvdro-1 -methvl-5-(3-fluorophenvl")-2H-1.4-ben2odiazepin-2-one Following General Procedure 8-B and using 3-(benzyloxycarbonyl)- amino-2,3-dihydro-l-methyl-5-(3-fluorophenyl)-lH-l,4-benzodiazepin-2-one, the 5 title intermediate was prepared as a yellow foam which was used immediately in Step G. Step G - Preparation of 3-fN'-(7e;-/-Butvlcarhamate')-L-alaninvn-amino-2.3-dihvdro-1 -methvl-5-(3-fluorophenvl)-1H-1.4-10 benzodiazepm-2-one Following General Procedure III-D using N-Boc-L-alanine and 3-amino- 1,3-dihydro-1 -methyl-5-(3-fluoropheny 1)-2H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow solid. C24H27FN404 (MW = 454.50)', mass spectroscopy found (M+H) 455.3. 15 Anal, calcd for C24H27FN404: C, 63.42; H, 5.99; N, 12.33. Found. C, 63.34; H, 6 01; N, 12.08. Step H - Preparation of 3-(L-Alaninvl1-amino-2.3-dihvdro-l-methvl-5-O-fluorophenvD-1H-1,4-benzodiazepin-2-one 20 Following General Procedure 8-C using 3-[N'-(ter/-butylcarbamate)-L- alaninyl]-amino-2,3-dihydro-1 -methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin- 2-one, the title intermediate was prepared as a yellow foam. The crude material was used immediately. 25 Example 8-K Synthesis of 3-(L-Alaninyl)amino-2,3-dihydro-l-methyl-5-(4-fluorophenyl)-lH-l,4-benzodiazepin-2-one Step A - Preparation of 2-Amino-4,-fluorobenzophenone 30 A solution of 4-bromofluorobenzene (1 eq.) in THF was cooled to -78°C under nitrogen and treated with /er/-butyllithium (2 05 eq., 1.6 M solution in pentane) at a rate of 40 ml/h. The internal temperature did not rise above - 74°C. The orange solution was stirred at -78°C for 30 minutes prior to the Printed from Mimosa 07/26/1999 12:37:07 page -298- WO 98/38177 PCT/US98/03373 - 297 -- addition of anthranilonitrile (0 6 eq.) as a solution in THF. The reaction was warmed to 0°C and stirred for 2 hours. 3N HCl was added to the mixture and stirring continued for 30 minutes. The reaction was diluted with ethyl acetate and the layers were separated. The aqueous layer was back-extracted thrice with 5 ethyl acetate The combined extracts were washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified via HPLC eluting with 93 7 hexanes/ethyl acetate. CnH)0FNO (MW = 215.24); mass spectroscopy found (M+H) 216.3. Anal calcd for CI3H10FNO: C, 72.55; H, 4.68; N, 6 51. Found- C, 10 72.80, H, 4.51; N, 6.74. Step B - Preparation of 2-rN-Ca-IsopropvlthioVN'-(benzvloxvcarbonvlVglvcinvll-amino-4'-fluorobenzophenone 15 A solution of a-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1 eq; prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975, 31, 863.) in dry THF was cooled to 0°C and treated with oxalyl chloride (1 eq.) and 3 drops of DMF. After stirring for 15 minutes at 0°C, the cooling bath was removed and stirring continued at ambient temperature for 40 minutes. The solution was 20 recooled to 0°C. A solution of 2-amino-4'-fluorobenzophenone (0.9 eq.) and 4-methylmorpholine (2.0 eq.) in dry THF was added via cannulation to the acid chloride The cooling bath was removed and the reaction stirred at ambient for 5 hours. The reaction was diluted with methylene chloride and washed with 0.5 M citric acid, saturated aqueous NaHCOj, and brine The organic phase was 25 dried over Na2S04, filtered, and concentrated. The residue was purified via preparative LC2000 eluting with a gradient of 15-»20% ethyl acetate/hexanes giving an off-white foam. C26H25N204S (MW = 480.60); mass spectroscopy found (M+NH4+) 498.2. 'H NMR (300 MHz, CDC13) d 11 28 (IH, s), 8.56 (IH, d, J=8.4 Hz), 30 7.78-7.73 (2H, m), 7.61-7 53 (2H, m), 7.36-7.32 (5H, m), 7.20-7.14 (3H, m), 5.98 (IH, d, J=7.5 Hz), 5.57 (IH, d, J=7 8 Hz), 5.16 (2H, ABq, J=14.7 Hz), 3.25 (IH, sep, J=6.0 Hz), 1.43 (3H, d, J=6.3 Hz), 1.27 (3H, d, J=6.6 Hz). Printed from Mimosa 07/26/1999 12:37:07 page -299- WO 98/38177 PCT/US98/03373 - 298 -- Step C - Preparation of 2-rN-(a-Amino')-N,-fbenzvloxvcarbonvl1-glvcinvn-amino-4'-fluorobenzophenone Ammonia gas was bubbled into a solution 2-[N-(a-isopropylthio)-N'-(benzyloxycarbonyl)-glycinyl]-amino-3'-fluorobenzophenone (1 eq) m THF at 5 0°C. After 35 minutes mercury(II) chloride (1.1 eq) was added. The ice bath was removed and ammonia gas was continued to bubble through the suspension for 4 hours. The bubbler was removed and the reaction continued to stir for 16 hours. The mixture was filtered through celite washing with THF. The filtrate was concentrated in vacuo. The crude solid was used in step D without further 10 purification Step D - Preparation of 3-(BenzvloxvcarbonvlN)amino-2.3-dihvdro-5-(4-fluorophenvP-1H-1.4-benzodiazepin-2-one 2-[N-(a-Amino)-N'-(benzyloxycarbonyl)-glycmyl]-amino-4'-15 fluorobenzophenone (1 eq) was treated with glacial acetic acid and ammonium acetate (4.7 eq). The suspension was stirred at ambient temperature for 21 hours. After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and 1 N NaOH. The aqueous layer was back-extracted with ethyl acetate The combined organics were washed with brine, dried over 20 Na2S04, filtered, and concentrated. The residue was purified via flash chromatography eluting with a gradient of 2-»3% isopropyl alcohol/methylene chloride. C23HI8FNA (MW = 403.44); mass spectroscopy found (M+H) 404.4. Anal, calcd for C23H18FN303»1.25H20: C, 64.85; H, 4.85. Found: C, 25 64.80; H, 4 55. Step E - Preparation of 3-(Benzvloxvcarbonvl)-amino-2.3-dihvdro-1 -methvl-5-( 4-fluorophenvlV 1H-1.4-benzodiazepin-2-one Following General Procedure 8-A and using 3-(benzyloxycarbonyl)- 30 amino-2,3-dihydro-5-(4-fluorophenyl)-lH-l,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow foam. C24H20FN3O3 (MW = 417.47); mass spectroscopy found (M+H) 418.2. Printed from Mimosa 07/26/1999 12:37:07 page -300- WO 98/38177 PCT/US98/03373 - 299 - Anal, calcd for C24H20FN3O3: C, 69.06; H, 4.83; N, 10.07. Found: C, 69.35; H, 4.93; N, 9.97. Step F - Preparation of 3-Amino-1,3-dihvdro-1 -methvl-5-(4-5 fluorophenvl')-2H-1.4-benzodiazepin-2-one Following General Procedure 8-B and using 3-(benzyloxycarbonyl)-amino-2,3-dihydro-1 -methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow foam which was used immediately in Step G. 10 Step G - Preparation of 3-l"N'-(7ert-Butvlcarbamate")-L-alaninvll-amino-2.3-dihvdro-1 -methvl-5-G-fluorophenvn-1H-1.4-benzodiazepin-2-one Following General Procedure III-D using N-Boc-L-alanine and 3-amino- 15 l,3-dihydro-l-methyl-5-(3-fluorophenyl)-2H-l,4-benzodiazepin-2-one, the title intermediate was prepared as a yellow solid. C24H27FN404 (MW = 454.50); mass spectroscopy found (M+H) 455.4. Anal, calcd for C24H27FN404*1.5H20. C, 59 86; H, 6.28; N, 11.64. Found: C, 60.04; H, 5.62; N, 11.27. 20 Step H - Preparation of 3-(L-AlaninvlVamino-2.3-dihvdro-l-methvl-5-( 4-fluorophenvl')-1H-1.4-benzodiazepin-2-one Following General Procedure 8-C using 3-[N' -(/er/-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1 -methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin- 25 2-one, the title intermediate was prepared as a yellow foam. The crude material was used immediately. Example 8-L Synthesis of 30 3-(N '-L- Alaniny l)amino-2,3-dihy dro-1 -isobutyl- 5-phenyl-lH-l,4-benzodiazepin-2-one Step A: l,3-Dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one (prepared according to the procedure of M. G. Bock et al., J. Org Chem 1987, 52, 3232- Printed from Mimosa 07/26/1999 12:37:07 page -301- WO 98/38177 -- 300 - PCT/US98/03373 3239) was alkylated with isobutyl iodide using General Procedure 8-G to afford 1,3-dihydro-1 -isobuty l-5-phenyl-2H-1,4-benzodiazepin-2-one. Step B: Following General Procedures 8-D and 8-F and using the 5 product from Step A, 3-amino-l,3-dihydro-l-isobutyl-5-phenyl-2H-l,4-benzodiazepin-2-one was prepared. Step C- The product from Step B and N-Boc-L-alanine (Sigma) were coupled using General Procedure III-D, followed by removal of the Boc group 10 using General Procedure 8-J, to afford 3-(N'-L-alaninyl)amino-l,3-dihydro-l-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one. By substituting isopropyl iodide, n-propyl iodide, cyclopropylmethyl iodide and ethyl iodide for isobutyl iodide in Step A above, the following 15 additional intermediates were prepared: 3-(N'-L-alaninyl)amino-1,3-dihydro-1 -isopropyl-5-phenyl-2H-1,4-benzodiazepin-2-one 3-(N'-L-alaninyl)amino-1,3-dihydro-1 -propyl-5-phenyl-2H-1,4-benzodiazepin-2-one 20 3-(N'-L-alaninyl)amino-1,3-dihydro-1 -cyclopropy lmethyl-5-pheny 1-2H- 1,4-benzodiazepin-2-one 3 -(N'-L-alaninyl)amino-1,3 -dihydro-1 -ethyl-5-pheny 1-2H-1,4-benzodiazepin-2-one. 25 Example 8-M Synthesis of 3-(N'-L-Alaninyl)amino-l-methyl-5-phenyl-l,3,4,5-tetrahydro-2H-l,5-benzodiazepin-2-one Step A l,3,4,5-Tetrahydro-5-phenyl-2H-l,5-benzodiazepin-2-one (CAS 30 No. 32900-17-7) was methylated using General Procedure 8-1 to afford 1- methyl-5-phenyl-l,3,4,5-tetrahydro-2H-l,5-benzodiazepin-2-one Printed from Mimosa 07/26/1999 12:37:07 page -302- WO 98/38177 PCT/US98/03373 - 301 - Step B: Following General Procedures 8-E and 8-F and using the product from Step A, 3-amino-l-methyl-5-phenyl-l,3,4,5-tetrahydro-2H-1,5-benzodiazepfn-2-one was prepared. 5 Step C: The product from Step B and N-Boc-L-alanine (Sigma) were coupled using General Procedure III-D, followed by removal of the Boc group using General Procedure 8-N, to afford 3-(N'-L-alaninyl)amino-l-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one. 10 Example 8-N Synthesis of 3-(N'-L-AIaninyl)amino-2,4-dioxo-l-methyl-5-phenyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine 15 3-Amino-2,4-dioxo-l-methyl-5-phenyl-2,3,4,5-tetrahydro-lH-l,5- benzodiazepine (CAS No. 131604-75-6) was coupled with N-Boc-L-alanine (Sigma) using General Procedure III-D, followed by removal of the Boc group using General Procedure 8-N, to afford the title compound. 20 Example 8-0 Synthesis of 3-((R)-Hydrazinopropionyl)amino-2,3-dihydro-l-methyI-5-phenyI)-lH-l,4-benzodiazepin-2-one 25 3-Amino-2,3-dihydro-1 -methyl-5-phenyl-1H-1,4-benzodiazepm-2-one was coupled to (R)-N,N'-di-BOC-2-hydrazinopropionic acid (Example N) using General Procedure III-D. Removal of the Boc group using General Procedure 5-B afforded the title compound. 30 Example 8-P Synthesis of 3-Amino-2,4-dioxo-l,5-bis-(l-methylethyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Step A. - Synthesis of 2,4-Dioxo-2,3,4,5-tetrahydro-lH-l,5-35 benzodiazepine Printed from Mimosa 07/26/1999 12:37:07 page -303- WO 98/38177 PCT/US98/03373 - 302 - 2,4-Dioxo-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine (CAS No. 49799-48-6) was prepared from 1,2-phenylenediamine (Aldrich) and malonic acid (Aldrich) using the procedure of Claremon, D A.; et al, PCT Application: WO 96-US8400 960603. 5 Step B: - Synthesis of 2,4-Dioxo-l,5-bis-(l-methylethyl)-2,3,4,5-tetrahydro-lH-1,5-benzodiazepine 2,4-Dioxo-1,5-bis-( 1 -methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No 113021-84-4) was prepared following General 10 Procedure 8-M using the product from Step A and 2-iodopropane (Aldrich). Purification was by flash chromatography eluting with EtOAc/hexanes (3.7 gradient to 1:1), then recrystalization from EtOAc/hexanes Step C: - Synthesis of 3-Azido-2,4-dioxo-l,5-bis-(l-methylethyl)-15 2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Following General Procedure 8-K using the product from Step B, 3-azido-2,4-dioxo-l ,5-bis-( 1 -methylethyl)-2,3,4,5-tetrahydro-l H-l ,5-benzodiazepine (CAS No 186490-50-6) was prepared as a white solid The product was purified by flash chromatography eluting with hexanes/EtOAc (41) to provide a 20 separable 23 1 mixture of pseudo-axial/pseudo-equatorial azides. The pure pseudo-axial azide was used in the next step. Step D: - Synthesis of 3-Amino-2,4-dioxo-l,5-bis-(l-methylethyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine 25 Following General Procedure 8-L using the product from Step C, 3- amino-2,4-dioxo-l,5-bis-(l-methylethyl)-2,3,4,5-tetrahydro-lH-l,5- benzodiazepine (CAS No 186490-51-7) was prepared as a white solid. Purification was by flash chromatography eluting with CH2Cl2/MeOH (98.2 gradient to 95:5) The isolated pseudo-axial amine atropisomer was completely 30 converted to the pseudo-equatorial amine atropisomer by heating in toluene to 100-105 °C for 15 minutes, and the pseudo-equatorial amine atropisomer was used in the next step. The isomers were distinguished by 'H-NMR in CDC13. Printed from Mimosa 07/26/1999 12:37:07 page -304- WO 98/38177 PCT/US98/03373 - 303 - Selected 'H-NMR (CDC13): Pseudo-axial amine 4 40 (s, IH); Pseudo-equatorial amine 3.96 (s, IH). Example 8-Q 5 Synthesis of 3-(R-2-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-( 1 -m ethylethyl)-2,3,4,5-tetrahydro-1 H-l ,5-benzodiazepine Hydrochloride Step A: - Synthesis of N-(/-Butoxycarbonyl)-R-2-thienylglycine 10 N-(f-Butoxycarbonyl)-R-2-thienylglycine (CAS No. 74462-03-1) was prepared from L-a-(2-thienyl)glycme (Sigma) by the procedure described in Bodansky, M. et al, The Practice of Peptide Synthesis', Springer Verlag; 1994, p 17. 15 Step B. - Synthesis of 3-[N'-(f-Butoxycarbonyl)-R-2- thienylglycinyl] -amino-2,4-dioxo-1,5-bis-( 1 -methylethyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Following General Procedure III-J above using the product from Example 8-P and the product from Step A above, 3-[N'-(/-butoxycarbonyl)-R-2-20 thienylglycinyl]-amino-2,4-dioxo-1,5-bis-( 1 -methylethyl)-2,3,4,5-tetrahydro-l H-1,5-benzodiazepine was prepared as a white foam. Purification was by flash chromatography eluting with CH2Cl,/EtOAc (9 1 gradient to 5.1). Step C- - Synthesis of 3-(R-2-ThienylgIycinyl)amino-2,4-dioxo-25 l,5-bis-(l-methylethyl)-2,3,4,5-tetrahydro-lH-l,5- benzodiazepine Hydrochloride Following General Procedure 8-N above using the product from Step B, the title compound was prepared as a white solid 30 Example 8-R Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo-l,5-bis-methyl-2,3,4,5-tetrahydro-lH-l ,5-benzodiazepine Hydrochloride Step A. - Synthesis of 2,4-Dioxo-l,5-bis-methyl-2,3,4,5-35 tetrahydro-lH-l,5-benzodiazepine Printed from Mimosa 07/26/1999 12:37:07 page -305- WO 98/38.177 PCT/US98/03373 - 304 - 2,4-Dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No 23954-54-3) was prepared following General Procedure 8-M using the product front Example 8-P, Step A and iodomethane (Aldrich). The white solid product precipitated during partial concentration of the reaction after work-up, 5 and was isolated by filtration. Step B. - Synthesis of 3-Azido-2,4-dioxo-l,5-bis-methyl-2,3,4,5-tetrahydro- IH-1,5-benzodiazepine For this substrate, General Procedure 8-K was modified in the following 10 manner. Initially the product from Step A was suspended (not a solution) in THF at -78°C, and following addition of the KN(TMS), solution, this suspension was allowed to warm to -35°C over a period of 12 minutes, during which the suspension became a solution, and was re-cooled to -78°C; then treated as described in the General Procedure. 3-Azido-2,4-dioxo-l,5-bis-methyl-2,3,4,5-15 tetrahydro-lH-l,5-benzodiazepme was purified by flash chromatography eluting with CHClj/EtOAc (7:1), then trituration from hot CHClj with hexanes and cooled to -23 °C. The product was isolated as a white solid. Step C: - Synthesis of 3-Amino-2,4-dioxo-l,5-bis-methyl-2,3,4,5-20 tetrahydro-lH-l,5-benzodiazepine Following General Procedure 8-L using the product from Step B, 3-amino-2,4-dioxo-l,5-bis-methyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine was prepared as a white solid. The crude product was used without further purification. 25 Step D: - Synthesis of 3-[N' -(/-Butoxycarbonyl)-L-alaniny 1] - amino-2,4-dioxo-l, 5-bis-methyl-2,3,4,5-tetrahydro-lH-1,5-benzodiazepine Following General Procedure III-I above using N-Boc-L-alanine 30 (Novabiochem) and the product from Step C, 3-[N'-(/-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepme was prepared as a white foam Purification was by flash chromatography eluting with CH;Cl2/EtOAc (2:1 gradient to 1:1) Printed from Mimosa 07/26/1999 12:37:07 page -306- WO 98/38177 - 305 -- PCT/US98/03373 Step E. - Synthesis of 3-(L-aIaninyl)-amino-2,4-dioxo-l,5-bis-methyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Hydrochloride Following General Procedure 8-N above using the product from Step D, 5 the title compound was prepared as an off-white amorphous solid. Example 8-S Synthesis of 3-(L-Alaninyl)amino-2,4-dioxo-l,5-bis-(2-methylpropyI)-10 2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Hydrochloride Step A - Synthesis of 2,4-Dioxo-l,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine 2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5- benzodiazepine was prepared following General Procedure 8-M using the 15 product from Example 8-P, Step A and l-iodo-2-methylpropane (Aldrich). Purification was by flash chromatography eluting with EtOAc/hexanes (3.7 gradient to 1:1), then recrystalization from EtOAc/hexanes. Step B: - Synthesis of 3-Azido-2,4-dioxo-l,5-bis-(2-methylpropyl)-20 2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Following General Procedure 8-K (a precipitate formed during the addition of the KN(TMS)2, but dissolved upon addition of the trisyl azide) using the product from Step A, 3-azido-2,4-dioxo-l,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine was prepared as a white solid. The product 25 was purified by flash chromatography eluting with hexanes/EtOAc (4:1) and a second flash chromatography eluting with CH2Cl2/hexanes/EtOAc (10:10.1 gradient to 8:6:1). Step C: - Synthesis of 3-Amino-2,4-dioxo-l,5-bis-(2-30 methylpropyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Following General Procedure 8-L using the product from Step B, 3-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1 H-l ,5-benzodiazepine was prepared as a white solid. Purification was by flash Printed from Mimosa 07/26/1999 12:37:07 page -307- WO 98/38177 - 306 - PCT/US98/03373 chromatography eluting with CH3Cl2/MeOH (98.2 gradient to 95 5, with 5% NH3 in the MeOH). Step D: - Synthesis of 3-[N'-(/-Butoxycarbonyl)-L-alaninyl]-5 amino-2,4-dioxo-l ,5-bis-(2-methylpropyl)-2,3,4,5- tetrahydro-lH-l,5-benzodiazepine Following General Procedure III-I above using N-Boc-L-alanine (Novabiochem) and the product from Step C, 3-[N'-(/-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-l H-1,5-10 benzodiazepine was prepared as a white foam. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (3.1 gradient to 3:2). Step E: - Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo-l,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepinc 15 Hydrochloride Following General Procedure 8-N above using the product from Step D, the title compound was prepared as an amorphous white solid. Example 8-T 20 Synthesis of 3-(S-Phenylglycinyl)amino-2,4-dioxo-l,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine Hydrochloride Step A: - Synthesis of 3-[N'-(/-Butoxycarbonyl)-S-phenylglycinyl]-25 amino-2,4-dioxo-l, 5-bis-(2-methylpropyl)-2,3y4,5- tetrahydro-lH-l,5-benzodiazepine Following General Procedure III-J above using the product from Example 8-S, Step C and the Boc-L-phenylglycine (Novabiochem, CAS No. 2900-27-8), 3-[N'-(/-butoxycarbonyl)-S-phenylglycinyl]-amino-2,4-dioxo-l,5-bis-30 (2-methylpropyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine was prepared as a white foam Purification was by flash chromatography eluting with CH2Cl2/EtOAc (9:1 gradient to 5.1). Printed from Mimosa 07/26/1999 12:37:07 page -308- WO 98/38177 PCT/US98/03373 - 307 - Step B- - Synthesis of 3-(S-Phenylglycinyl)-amino-2,4-dioxo-l,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Hydrochloride Following General Procedure 8-N above using the product from Step A, 5 3-(S-phenylglycinyl)-ammo-2,4-dioxo-l,5-bis-(2-methylpropyl)-2,3,4,5- tetrahydro-lH-l,5-benzodiazepine hydrochloride was prepared as an off-white solid. Example 8-U 10 Synthesis of 3-(L-Alaninyl)amino-2,4-dioxo-l,5-bis-(cycIopropylmethyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Hydrochloride Step A. - Synthesis of 2,4-Dioxo-l,5-bis-(cycIopropylmethyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine 15 2,4-Dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5- benzodiazepine was prepared following General Procedure 8-M using the product from Example 8-P, Step A, and (bromomethyl)cyclopropane (Lancaster). Purification was by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to straight EtOAc), then recrystalization from EtOAc/hexanes. 20 Step B- - Synthesis of 3-Azido-2,4-dioxo-l,5-bis- (cyclopropylmethyl)-23,4,5-tetrahydro-lH-l,5-benzodiazepine For this substrate General Procedure 8-K was modified in the following 25 manner. Initially the product from Step A was suspended (not a solution) in THF at -78°C, and following addition of the KN(TMS)2 solution, this suspension was allowed to warm to -30°C, during which the suspension became a solution, and was re-cooled to -78°C. Upon re-cooling to -78°C a precipitate began to form, therefore the reaction flask containing the mixture was partially raised 30 above the cooling bath until the internal temperature rose to -50°C; then the trisyl azide solution was added. The cooling bath was removed and the mixture allowed to warm to -20°C whereupon the mixture had become a nearly homogenous solution, and the AcOH was added. Then, treated as described in the general procedure. 3-Azido-2,4-dioxo-l,5-bis-(cyclopropylmethyl)-2,3,4,5- Printed from Mimosa 07/26/1999 12:37:07 page -309- WO 98/38177 - 308 - PCT/US98/03373 tetrahydro-lH-l,5-benzodiazepine was purified by trituration with hot to room temperature EtOAc, followed by recrystaiization from hot to -23°C CHClj/EtOAc/EtOH (5:5.1) and isolated as a white solid. 5 Step C: - Synthesis of 3-Amino-2,4-dioxo-l,5-bis- (cyclopropylmethyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Following General Procedure 8-L using the product from Step B, 3-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-10 benzodiazepine was prepared as a white solid Purification was by flash chromatography eluting with CH2Cl2/MeOH (98:2 gradient to 95:5, with 5% NH3 in the MeOH) followed by recrystaiization from warm CH2Cl2/hexanes (1:1) to -23°C. 15 Step D: - Synthesis of 3-[N'-(f-Butoxycarbonyl)-L-alaninyl]- amino-2,4-dioxo-l,5-bis-(cycIopropylmethyl)-2,3,4,5-tetrahydro-1 H-l ,5-benzodiazepine Following General Procedure III-I above using N-Boc-L-alanine (Novabiochem) and the product from Step C, 3-[N'-(f-butoxycarbonyl)-L- 20 alaninyl]-amino-2,4-dioxo-l,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-lH-l,5- benzodiazepine was prepared as a white foam. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (3:1 gradient to 2:1). Step E: - Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo-l,5-bis-25 (cyclopropylmethyl)-2,3,4,5-tetrahydro-lH-l,5- benzodiazepine Hydrochloride Following General Procedure 8-N above using the product from Step D, the title compound was prepared as an off-white solid. 30 Example 8-V Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo-l,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Hydrochloride Printed from Mimosa 07/26/1999 12:37:07 page -310- WO 98/38177 PCT/US98/03373 - 309 -- Step A: - Synthesis of 2,4-Dioxo-l,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine To a stirred suspension of the product from Example 8-P, Step A (1.0 eq., 17.08 g) in DMSO (500 mL) at room temperature was added neopentyl 5 iodide (43.01 g, 2.24 eq , Aldrich) and CS2CO3 (72.65 g, 2.3 eq , Aldrich). The resulting mixture was heated to 75°C for 30 minutes, then additional Cs^COj (31.59 g, 1.0 eq ) was added and the mixture rapidly stirred at 75°C for 6 hours The mixture was allowed to cool and H20 (500 mL) and EtOAc (1000 mL) were added The phases were partitioned and the organic phase washed with 10 H20 (1x500 mL), 1 M aq. HCl (2x500 mL), and brine (1x500 mL). Then, the organic phase was dried over MgS04, filtered, concentrated, and purified by flash chromatography eluting with hexanes/EtOAc (3 2 gradient to 2:3) to provide 2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-l H-1,5-benzodiazepine as a white solid. 15 Step B: - Synthesis of 3-Azido-2,4-dioxo-l,5-bis-(2,2-dimethylpropyI)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Following General Procedure 8-K using the product from Step A, 3-20 azido-2,4-dioxo-l,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-l H-l,5- benzodiazepine was prepared as a white solid The product was purified by flash chromatography eluting with hexanes/CH2Cl2/EtOAc (10.5*1 gradient to 5.5-1) to provide a separable 13:1 mixture of pseudo-axial/pseudo-equatorial azides. The pure pseudo-axial azide was used in the next step. Selected 'H-25 NMR (CDCI3): Pseudo-axial azide 5.12 (s, IH), Pseudo-equatorial azide 4.03 (s, IH). Step C: - Synthesis of 3-Amino-2,4-dioxo-l,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-lH-l,5-30 benzodiazepine Following General Procedure 8-L using the product from Step B, 3-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1 H-l ,5-benzodiazepine was prepared as a white solid. Purification was by flash Printed from Mimosa 07/26/1999 12:37:07 page -311- WO 98/38177 -- 310 -- PCT/US98/03373 chromatography eluting with CH2Cl2/MeOH (98.2 gradient to 95:5, with 5% NH3 in the MeOH). The isolated white solid product was identified as a ~4.1 mixture of pseudo-axial and pseudo-equatorial amines atropisomers by 'H-NMR The mixture was heated in toluene to 100 °C for 20 minutes, then re-5 concentrated to provide the pure pseudo-equatorial amine atropisomer, as a white solid, and this was for the next step. Selected 'H-NMR (CDC13). Pseudo-axial amine 4 59 (s, IH); Pseudo-equatorial amine 4.03 (s, IH) Step D: - Synthesis of 3-[N'-(/-Butoxycarbonyl)-L-alaninyl]-10 amino-2,4-dioxo-l ,5-bis-(2,2-dimethylpropyl)-2,3,4,5- tetrahydro-lH-l,5-benzodiazepine Following General Procedure III-I above using N-Boc-L-alanine (Novabiochem) and the product from Step C, 3-[N'-(/-butoxycarbonyl)-L- alaninyl]-amino-2,4-dioxo-l,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-lH- 15 1,5-benzodiazepine was prepared as a white foam Purification was by flash chromatography eluting with CH2Cl2/EtOAc (4:1 gradient to 5:2) Step E- - Synthesis of 3-(L-AlaninyI)-amino-2,4-dioxo-l,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-lH-l,5-20 benzodiazepine Hydrochloride Following General Procedure 8-N above using the product from Step D, the title compound was prepared as an off-white solid Example 8-W 25 Synthesis of 3-(L-AIaninyl)amino-2,4-dioxo-l,5-bis-phenyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine hydrochloride Step A: - Synthesis of 2,4-Dioxo-l,5-bis-phenyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine 30 This procedure is a modification of the procedure described in Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013-9016. A mixture of the product from Example 8-P, Step A (1.0 eq., 7.50 g), Ph3Bi (2.2 eq., 41.26 g, Aldrich), Cu(OAc)2 (2 0 eq., 15 48 g, Aldrich), Et3N (2.0 eq., 8.62 g) in CH2C12 (100 mL) was stirred under N2 at room temperature for 6 days (monitoring by TLC). The Printed from Mimosa 07/26/1999 12:37:07 page -312- WO 98/38177 PCT/US98/03373 - 311 - solids were removed by filtration through a plug of Celite rinsing with CH2Cl2/MeOH (3x75 mL). The filtrate was concentrated, dissolved in hot CH2Cl2/MeOH (9:1) and filtered through a large plug of silica gel eluting with CH2Cl2/MeOH (9:1, 2L). The filtrate was concentrated and the residue purified 5 by flash chromatography eluting with straight CH2C12 gradient to CH2Cl2/MeOH (9:1). 2,4-Dioxo-1,5-bis-phenyI-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine crystallized during concentration of the fractions containing the product, and was isolated by filtration as a white solid. 10 Step B: - Synthesis of 3-Azido-2,4-dioxo-l,5-bis-phenyl-2,3,4,5- tetrahydro-lH-l,5-benzodiazepine For this substrate, General Procedure 8-K was modified in the following manner. Initially the product from Step A was suspended (not a solution) in THF at -70°C, and following addition of the KN(TMS), solution, this suspension 15 was allowed to warm to -20°C over a period of 10 minutes, during which the suspension became a solution, and was re-cooled to -70°C; then treated as described in the general procedure. The title compound was purified by trituration with hot CHCl3/hexanes (1:1) to yield 3-azido-2,4-dioxo-l,5-bis-phenyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine as a white solid. 20 Step C: - Synthesis of 3-Amino-2,4-dioxo-l,5-bis-phenyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Following General Procedure 8-L using the product from Step B, 3-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine was 25 prepared as a white solid. Purification was by flash chromatography eluting with CH2Cl2/MeOH (98:2 gradient to 95:5, with 5% NH3 in the MeOH). Step D - Synthesis of 3-[N'-(f-Butoxycarbonyl)-L-alaninylj- amino-2,4-dioxo-l,5-bis-phenyI-2,3,4,5-tetrahydro-lH-30 1,5-benzodiazepine Following General Procedure III-I above using N-Boc-L-alanine (Novabiochem) and the product from Step C, 3-[N'-(/-butoxycarbonyl)-L- alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5- Printed from Mimosa 07/26/1999 12:37:07 page -313- WO 98/38177 PCT/US98/03373 - 312 -- benzodiazepine was prepared as a white foam. Purification was by -flash chromatography eluting with CH2Cl2/EtOAc (4 1 gradient to 3:1) Step E. - Synthesis of 3-(L-Alaninyl)-amino-2,4-dioxo-l,5-bis-5 phenyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Hydrochloride Following General Procedure 8-N above using the product from Step D, the title compound was prepared as a white amorphous solid 10 Example 8-X Synthesis of 3-Amino-2,3-dihydro-l-methyl-5-phenyl-l/f-l,4-benzodiazepin-2-one Following the method of R. G. Sherrill et al, J Org Chem , 1995, 60, 730-734 and using glacial acetic acid and HBr gas, the title compound was 15 prepared. Example 8-Y Synthesis of 3-(L-Valinyl)-amino-2,3-dihydro-l-methyl-20 5-pheny 1-1 H-l ,4-benzodiazepin-2-one Step A - Synthesis of 3-[N'-(terf-Butylcarbamate)-L-valinyl]-amino-2,3-dihydro-l-methyl-5-phenyI-lH-l,4-benzodiazepin-2-one (S)-3-Amino-1,3-dihydro-1 -methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 25 (lS)-7,7-dimethyl-2-oxobicyclo[2.2 l]heptane-l-methanesulfonate (Example 8-B, Step A) was free based by partitioning between methylene chloride and 1M potassium carbonate. The free amine was then coupled with N-Boc-valine following General Procedure III-D to give the title compound C26H32N404 (MW 464.62); mass spectroscopy 464.3 30 Anal. Calcd for C26H32N404- C, 67.22; H, 6.94; N, 12.06. Found: C, 67.29, H, 6.79, N, 11.20. Step B - Synthesis of 3-(L-valinyl)-amino-2,3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepin-2-one Printed from Mimosa 07/26/1999 12:37:07 page -314- WO 98/38177 PCT/US98/03373 - 313 - Following General Procedure 8-C and using 3-[N'-(/e/7-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1 -methyl-5-phenyl-1 H-l ,4-benzodiazepine-2-one, the title compound was prepared as a white foam. C2,H23N402(MW 363.48); mass spectroscopy (M+H) 364.2. 5 Example 8-Z Synthesis of 3-(L-ter/-Leucinyl)-amino-2,3-dihydro-l-methyl-5-phenyI-lH-l,4-benzodiazepin-2-one 10 Step A - Synthesis of 3-[N'-(te/*/-Butylcarbamate)-L-ter/- leucinyl]-amino-2,3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepin-2-one (S)-3-amino-1,3-dihydro-1 -methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, (1 S)-7,7-dimethyl-2-oxobicyclo[2.2.1 ]heptane-1 -methanesulfonate (Example 8-B, 15 Step A) was free based by partitioning between methylene chloride and 1M potassium carbonate. The free amine was then coupled with N-Boc-fe/7-leucine following General Procedure III-D to give the title compound. C27H35N404 (MW 479.66), mass spectroscopy 479. 20 Step B - Synthesis of 3-(L-/erf-Leucinyl)-amino-2,3-dihydro-l- methyl-5-phenyl-lH-l,4-benzodiazepin-2-one Following General Procedure 8-C and using 3 - [N' -(butylcarbamate)-L-/erMeucinyl]-amino-2,3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepine-2-one, the title compound was prepared as a white foam. 25 Anal. Calcd for C22H25N402'0.5H20: C, 68.19; H, 7.02; N, 14.40. Found: C, 68.24; H, 7.00; N, 14.00. Example 8-AA Synthesis of 30 3-(L-Alaninyl)-amino-2,3-dihydro-l,5-dimethyl- 1 H-l ,4-benzodiazepine 2,3-Dihydro-l,5-dimethyl-lH-l,4-benzodiazepine was prepared following General Procedures 8-1 (using methyl iodide), 8-D and 8-F. Coupling of this intermediate with Boc-L-alanine (Novo) using General Procedure III-D, followed Printed from Mimosa 07/26/1999 12:37:07 page -315- WO 98/38177 PCT/US98/03373 -- 314 -- by deprotection using General Procedure 5-B afforded the title compound which was used without further purification Example 8-AB 5 Synthesis of 3-(L-3-ThienyIglycinyI)amino-2,4-dioxo-l,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Step A - Synthesis of N-(/-Butoxycarbonyl)-L-3-thienylglycine 10 N-(/-Butoxycarbonyl)-L-3-thienylglycine was prepared from L-a-(3- thienyl)glycine (Sigma) by the procedure described in Bodansky, M. et al, The Practice of Peptide Synthesis; Springer Verlag; 1994, p. 17. Step B - Synthesis of 3-[N'-(/-ButoxycarbonyI)-L-3-15 thienylglycinyl]-amino-2,4-dioxo-l, 5-bis-(2,2- dimethylpropyI)-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine Following General Procedure III-D above using the product from Example 8-V, Step C and the product from Step A above, 3-[N'-(/-20 butoxycarbonyl)-L-3-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(2,2- dimethylpropyl)-2,3,4,5-tetrahydro-lH-1,5-benzodiazepine was prepared. Step C- - Synthesis of 3-(L-3-Thienylglycinyl)amino-2,4-dioxo-l,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-lH-l,5-25 benzodiazepine Following General Procedure 8-N above using the product from Step B, the title compound was prepared. Example Bio-1 30 Cellular Screen for the Detection of Inhibitors of /J-Amyloid Production Numerous compounds of formula I above were assayed for their ability to inhibit (3-amyloid production in a cell line possessing the Swedish mutation. This screening assay employed cells (K293 = human kidney cell line) which were stably transfected with the gene for amyloid precursor protein 751 Printed from Mimosa 07/26/1999 12:37:07 page -316- WO 98/38177 -- 315 - PCT/US98/03373 (APP751) containing the double mutation Lys65,Met65:! to Asn651Leu652 (APP751 numbering) in the manner described in International Patent Application Publication No. 94/10569s and Citron et al.12. This mutation is commonly called the Swedish mutation and the cells, designated as "293 751 SWE", were plated 5 in Corning 96-well plates at 2-4 x 104 cells per well in Dulbecco's minimal essential media (Sigma, St. Louis, MO) plus 10% fetal bovine serum Cell number is important in order to achieve p-amyloid ELISA results within the linear range of the assay (~0.2 to 2.5 ng per mL). 10 Following overnight incubation at 37°C in an incubator equilibrated with 10% carbon dioxide, media were removed and replaced with 200 /xL of a compound of formula I (drug) containing media per well for a two hour pretreatment period and cells were incubated as above Drug stocks were prepared in 100% dimethyl sulfoxide such that at the final drug concentration 15 used in the treatment, the concentration of dimethyl sulfoxide did not exceed 0.5% and, in fact, usually equaled 0.1%. At the end of the pretreatment period, the media were again removed and replaced with fresh drug containing media as above and cells were incubated for 20 an additional two hours. After treatment, plates were centrifuged in a Beckman GPR at 1200 rpm for five minutes at room temperature to pellet cellular debris from the conditioned media. From each well, 100 /nL of conditioned media or appropriate dilutions thereof were transferred into an ELISA plate precoated with antibody 266 [P. Seubert, Nature (1992) 359.325-327] against amino acids 25 13-28 of p-amyloid peptide as described in International Patent Application Publication No. 94/105698 and stored at 4°C overnight. An ELISA assay employing labelled antibody 3D6 [P. Seubert, Nature (1992) 359:325-327] against ammo acids 1-5 of (3-amyloid peptide was run the next day to measure the amount of p-amyloid peptide produced. 30 Printed from Mimosa 07/26/1999 12:37:07 page -317- WO 98/38)77 PCT/US98/03373 - 316 - Cytotoxic effects of the compounds were measured by a modification of the method of Hansen, et al13 To the cells remaining in the tissue culture plate was added~25 /xL of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma, St. Louis, MO) stock solution (5 mg/mL) to a final 5 concentration of 1 mg/mL. Cells were incubated at 37°C for one hour, and cellular activity was stopped by the addition of an equal volume of MTT lysis buffer (20% w/v sodium dodecylsulfate in 50% dimethylformamide, pH 4.7) Complete extraction was achieved by overnight shaking at room temperature. The difference in the OD562nm and the OD6S0nm was measured in a Molecular 10 Device's UVmax microplate reader as an indicator of the cellular viability. The results of the p-amyloid peptide ELISA were fit to a standard curve and expressed as ng/mL p-amyloid peptide In order to normalize for cytotoxicity, these results were divided by the MTT results and expressed as a 15 percentage of the results from a drug free control. All results are the mean and standard deviation of at least six replicate assays. The test compounds were assayed for P-amyloid peptide production inhibition activity in cells using this assay. The results of this assay demonstrate 20 that the compounds of formula I inhibit p-amyloid peptide production by at least 30% as compared to control. Example Bio-2 In Vivo Suppression of /J-Amyloid Release and/or Synthesis 25 This example illustrates how the compounds of this invention could be tested for in vivo suppression of p-amyloid release and/or synthesis. For these experiments, 3 to 4 month old PDAPP mice are used [Games et al., (1995) Nature 373:523-527] Depending upon which compound is being tested, the compound is usually formulated at between 1 and 10 mg/mL. Because of the 30 low solubility factors of the compounds, they may be formulated with various vehicles, such as corn oil (Safeway, South San Francisco, CA); 10% ethanol in Printed from Mimosa 07/26/1999 12:37:07 page -318- WO 98/38177 -- 317 -- PCT/US98/03373 corn oil; 2-hydroxypropyl-p-cyclodextrin (Research Biochemicals International, Natick MA); and carboxy-methyl-cellulose (Sigma Chemical Co., St. Louis MO) 5 The mice are dosed subcutaneously with a 26 gauge needle and 3 hours later the animals are euthanized via CO, narcosis and blood is taken by cardiac puncture using a 1 cc 25G 5/8" tuberculin syringe/needle coated with solution of 0.5 M EDTA, pH 8.0. The blood is placed in a Becton-Dickinson vacutamer tube containing EDTA and spun down for 15 minutes at 1500 xg at 5°C. The 10 brains of the mice are then removed and the cortex and hippocampus are dissected out and placed on ice 1. Brain Assay To prepare hippocampal and cortical tissue for enzyme-linked 15 immunosorbent assays (ELISAs) each brain region is homogenized in 10 volumes of ice cold guanidine buffer (5.0 M guanidine-HCl, 50 mM Tris-HCl, pH 8.0) using a Kontes motorized pestle (Fisher, Pittsburgh PA) The homogenates are gently rocked on a rotating platform for three to four hours at room temperature and stored at -20°C prior to quantitation of p-amyloid. 20 The brain homogenates are diluted 1:10 with ice-cold casein buffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodium azide, 20 ng/ml aprotinin, 5 mM EDTA, pH 8.0, 10 fxg/ml leupeptin], thereby reducing the final concentration of guanidine to 0.5 M, before centrifugation at 16,000 xg for 20 25 minutes at 4°C. Samples are further diluted, if necessary, to achieve an optimal range for the ELISA measurements by the addition of casein buffer with 0.5 M guanidine hydrochloride added. The P-amyloid standards (1-40 or 1-42 amino acids) were prepared such that the final composition equaled 0.5 M guanidine m the presence of 0.1% bovine serum albumin (BSA) 30 Printed from Mimosa 07/26/1999 12:37:07 page -319- WO 98/38177 -- 318 - PCT/US98/03373 The total p-amyloid sandwich ELISA, quantitating both p-amyloid (aa 1 -40) and P-amyloid (aa 1-42) consists of two monoclonal antibodies (mAb) to p-amyloid. The capture antibody, 266 [P Seubert, Nature (1992) 359:325-327], is specific to amino acids 13 - 28 of P-amyloid The antibody 3D6 [Johnson-5 Wood et al., PNAS USA (1997) 94:1550-1555], which is specific to amino acids 1 - 5 of p-amyloid, is biotinylated and served as the reporter antibody in the assay. The 3D6 biotinylation procedure employs the manufacturer's (Pierce, Rockford IL) protocol for NHS-biotin labeling of immunoglobulins except that 100 mM sodium bicarbonate, pH 8.5 buffer is used. The 3D6 antibody does not 10 recognize secreted amyloid precursor protein (APP) or full-length APP but detects only p-amyloid species with an amino terminal aspartic acid The assay has a lower limit of sensitivity of ~50 pg/ml (11 pM) and shows no cross-reactivity to the endogenous murine p-amyloid peptide at concentrations up to 1 ng/ml 15 The configuration of the sandwich ELISA quantitating the level of P-amyloid (aa 1-42) employs the mAb 21F12 [Johnson-Wood et al., PNAS USA (1997) 94:1550-1555] (which recognizes amino acids 33-42 of P-amyloid) as the capture antibody. Biotinylated 3D6 is also the reporter antibody in this assay 20 which has a lower limit of sensitivity of -125 pg/ml (28 pM). The 266 and 21F12 capture mAbs are coated at 10 ng/ml into 96 well immunoassay plates (Costar, Cambidge MA) overnight at room temperature The plates are then aspirated and blocked with 0.25% human serum albumin in 25 PBS buffer for at least 1 hour at room temperature, then stored desiccated at 4°C until use. The plates are rehydrated with wash buffer (Tris-buffered saline, 0.05% Tween 20) prior to use. The samples and standards are added to the plates and incubated overnight at 4°C. The plates are washed > 3 times with wash buffer between each step of the assay. The biotinylated 3D6, diluted to 30 0.5 |ag/ml in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4) is incubated in the well for 1 hour at room temperature. Avidin-HRP Printed from Mimosa 07/26/1999 12:37:07 page -320- WO 98/38177 PCT/US98/03373 -- 319 - (Vector, Burlingame CA) diluted 1 4000 in casein incubation buffer is added to the wells for 1 hour at room temperature The colorimetric substrate, Slow TMB-ELISA (Pierce, Cambridge MA), is added and allowed to react for 15 minutes, after which the enzymatic reaction is stopped with addition of 2 N 5 H,S04. Reaction product is quantified using a Molecular Devices Vmax (Molecular Devices, Menlo Park CA) measuring the difference in absorbance at 450 nm and 650 nm. 2. Blood Assay 10 The EDTA plasma is diluted 1:1 in specimen diluent (0.2 gm/1 sodium phosphate»H20 (monobasic), 2.16 gm/1 sodium phosphate«7H20 (dibasic), 0.5gm/l thimerosal, 8.5 gm/1 sodium chloride, 0.5 ml Triton X-405, 6.0 g/1 globulin-free bovine serum albumin; and water). The samples and standards in specimen diluent are assayed using the total P-amyloid assay (266 capture/3D6 15 reporter) described above for the brain assay except the specimen diluent was used instead of the casein diluents described. Formulations other than those described above can also be used for oral delivery and intravenous delivery to a mammal. For oral delivery, the 20 compound can be mixed with either 100% corn oil or, alternatively, in a solution comtaining 80% corn oil, 19.5% oleic acid and 0.5% labrafil. The compound can be mixed with the above solutions in concentrations ranging from 1 mg/mL to 10 mg/mL. The compound in solution is preferably administered orally to the mammal at a dose volume of 5 mL/kg of body weight. For IV 25 delivery, the compound is preferably mixed with a solution of 3% ethanol, 3% solutol HS-15 and 94% saline The compound is preferably mixed with the above solution m concentrations ranging from 0.25 mg/mL to 5 mg/mL. The compound in solution is preferably administered by IV to the mammal at a dose volume of 2 mL/kg of body weight 30 Printed from Mimosa 07/26/1999 12:37:07 page -321- WO 98/38177 PCT/US98/03373 - 320 - From the foregoing description, various modifications and changes in the composition and method will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein. Printed from Mimosa 07/26/1999 12:37:07 page -322- - 321 - 336613 WHAT IS CLAIMED IS: 1. A use, in the preparation of a medicament for inhibiting the cellular release and/or synthesis of P -amyloid peptide in a patient in need thereof, of a compound of formula I: 10 A-B-C 15 20 25 (i) wherein A is selected from the group consisting of: R2 R H N, Re J intellectual property office of n.z. 2 2 AUG 2001 received where R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; Z is selected from the group consisting of (a) a group having the formula -CX'X"C(0)- where X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; a group having the formula -T-CH2C(0)- or -T-C(0)C(0)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; and (b) 35 (c) a group having the formula -CX'X"-T-C(0)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is 336613 -- 322 - 10 15 hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; R6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; m is an integer equal to 0 or 1, and p is an integer equal to 0 or 1; R1 (ii) C / \ X' X" W X N R4 intellectual property office of n.z. 2 2 AUG 2001 RECEIVED 20 where Rl is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; T' is selected from the group consisting of a bond linking R1 to -CX'X"-, 25 oxygen, sulfur, and - NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group, with the proviso that when T' is oxygen, sulfur or -NR3 then X' and X" are hydrogen or X' and X" together form an oxo group; W and X are independently selected from the group consisting of 30 -(CR7R7)?-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the </div>

Claims

<div class="application article clearfix printTableText" id="claims">



10 

$3 ft 11 

\ ' ><_>• i if ^ 

v_ - 

-- 323 -- 

proviso that when unsaturated, the remaining R7 group on each carbon atom participates m the unsaturation; 

and with the further proviso that when W is oxygen, then X is not also oxygen, 

X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, 

substituted cycloalkyl, aryl, heteroaryl and heterocyclic; and 

N X 

i V «• 

intellectual property office of n.z. 

2 2 AUG 2001 RECEIVED 

where Rl is selected from the group consisting of alkyl, alkenyl, 

alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, 20 heteroaryl and heterocyclic; 

T' is selected from the group consisting of a bond linking R1 to -CX'X"-, 

oxygen, sulfur, and - NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group, with the proviso that when T' is oxygen, sulfur or -NR3 then X' and X" are hydrogen or X' and X" together form an oxo group; 

25 

W and X are independently selected from the group consisting of -(CR7R7)?-, oxygen, sulfur and -NR8 where q is an integer equal to one or two and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, 30 carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; 

X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

WO 98/38177 PCT/US98/03373 

-- 324 -- 

R4 is selected from the group consisting of hydrogen, alkyl", substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 

5 B is selected from the group consisting of: 

15 

(i) 

1 

H N. 

R5 

10 where R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 

W X 

(ii) 

N' -OA 

R4 

20 W and X are independently selected from the group consisting of 

-(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 25 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; 

and with the further proviso that when W is oxygen, then X is not also 30 oxygen; 

R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic, 

35 

Printed from Mimosa 07/26/1999 12:37:07 page -326- 

WO 98/38177 PCT/US98/03373 

- 325 - 

N X 

(iii) 

W 

5 R4 

W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to 1 or 2 and each R7 and R8 is independently selected from the group consisting of 10 hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the 15 unsaturation; 

R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; and 

(iv) when A is either formula (ii) or (iii) as defined above, then B can 20 also be a covalent bond linking A to C, 

C is selected from the group consisting of: 

(i) -C(0)Y or -C(S)Y 

where Y is selected from the group consisting of: 

25 (a) alkyl or cycloalkyl, 

(b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl, or a-0C(0)aryl groups, 

(c) alkoxy or thioalkoxy, 

30 (d) substituted alkoxy or substituted thioalkoxy, 

(e) hydroxy, 

(f) aryl, 

(g) heteroaryl, 

Printed from Mimosa 07/26/1999 12:37:07 page -327- 

336613 

-- 326 - 

(h) heterocyclic, 

(i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, 

0) -NHSOj-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, 

(k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and 

(1) -0NR9[C(0)0]zR10 where z is zero or one, R9 and R10 are as defined above; 

where each R" is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -0C(0)R9, -SSR9, and -SSC(0)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic; and 

(ii) 

-CRnRuY' 

(iii) 

2 2 AUG 2001 

received where A* together with -C = N-, forms a heterocyclic group which is optionally fused to form a bi- or multi-fused ring system 

33 6613 

- 327 -- 

with one 01 more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, m turn, each of sucfi ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted 5 alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, -NHC(0)R'°, -NHS02R10, -C(0)NH2, -C(O)NHR10> -C(O)NR10R10, -S(0)R10, -S(0)2R10, -S(0),NHR10 and -S(O)2NR10R10 where each R10 is independently selected from the group 10 consisting of alkyl, substituted alkyl, or aryl, ammo, N-alkylammo, N,N-dialkylammo, N-substituted alkylamino, N,N-disubstituted alkylamino, N-alkenylamino, N,N-dialkenylammo, N-substituted alkenylamino, N.N-disubstituted alkenylamino, N-cycloalkylamino, N,N-dicycloalkylamino, N-substituted cycloalkylamino, N,N-disubstituted cycloalkylammo, 15 N-arylamino, N,N-diarylamino, N-heteroarylamino, N,N-diheteroarylamino, 

N-heterocychc ammo, N,N-diheterocyclic amino and mixed N,N-ammo groups comprising a first and second substituent on said amino group which substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, 20 and heterocyclic provided that said first and second substituents are not the same; 

with the proviso that when A has structure (1) and B has structure (i), then C does not have structure (i) or (ii); 

with the further provisos that 25 A. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, 

R2 being methyl and p being zero, B has structure (iii) with W being -NH-, X being -CH2-, and R4 being benzyl then C is not -C(0)0CH3; 

B. when A has structure (i) with R1 being 3,5-difluorophenyl, Z being -CH2C(0)-, R2 being methyl, and p being zero, B has structure (ii) with W 30 being >NC(0)0C(CH3)3, X being -CHr, and R4 being phenyl, then C is not -C(0)0CH3; 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

10 

25 

-- 328 -- 

(followed by 328a) 

336613 

C. when A has structure (ii) wherein R1 is 3,5-difluorophenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene 2nd R4 is methyl, and B is a covalent bond linking A to C, then C is not -C(0)0CH3 , 

D. when A has structure (ii) with R1 being phenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is oxygen, X is methylene and R4 is hydrogen, and B has structure (i) where R5 is iso-propyl then C is not -C(0)0H, or -C(0)0CH3, 

E. when A has structure (ii) with R1 being phenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is oxygen, X is methylene and R4 is hydrogen, and B has structure (iv) then C is not -C(0)NHNH2, or -C(0)CH3, 

2o F. when A has structure (i) with R1 being phenyl, Z being 

-CH20C(0)-, R2 being benzyl or indole-3-CH2- and p being zero, B has structure (ii) where W is -NR8 - where R8 is hydrogen or tert-butyloxycarbonyl. X is methylene and R4 is benzyl or tf-butyl then C is not -C(0)0H or -C(0)0CH3; 

G when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyloxycarbonyl-NH-(CH2)4 - and p being zero; B has structure (ii) where W is -NH-, X is methylene and R4 is benzyloxycarbonyl-NH-(CH2)4- then C is not -C(0)0CH3; 

H. when A has structure (i) with R1 being phenyl, Z being -CH,0C(0)-, R2 being benzyl and p being zero; B has structure (ii) where W is sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH3, 

I. when A has structure (i) with R1 being phenyl, Z being -CH-,0C(0)-, R2 being methyl or sec-butyl and p being zero; B has structure (ii) where W is sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH;CH3 or -C(0)NH2, and 

336613 

--328a-- 

J. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being methyl and p being zero; B has structure (ii) where W is oxygen or sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH3.
2. A use, in the preparation of a medicament for preventing the onset of AD in a patient at risk for developing AD, of a compound of formula I: 

where R1 is selected from the group consisting of alkyl, alkenyl, 

alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substimted alkynyl, substimted cycloalkyl, substimted cycloalkenyl, aryl, heteroaryl and heterocyclic; 

Z is selected from the group consisung of 

(a) a group having the formula -CX'X"C(0)- where X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

(b) a group having the formula -T-CH2C(0)- or -T-C(0)C(0)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; and 

A-B-C 

wherein A is selected from the group consisting of: 

R2 

(i) 

INTELLECTUAL property office of n.z. 

2 2 AUG 2001 

received 

-- 329 -- 

(c) a group having the formula -CX'X"-T-C(0)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen or fluoro, X" is hydrogen, hydroxy or fluoro, "or X' and X" together form an oxo group; 

R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; 

R6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; 

m is an integer equal to 0 or 1; and p is an integer equal to 0 or 1; 

W X 

where R1 is selected from the group consisting of alkyl, alkenyl, 

alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substimted alkenyl, substituted alkynyl, substimted cycloalkyl, substimted cycloalkenyl, aryl, heteroaryl and heterocyclic; 

T' is selected from the group consisting of a bond linking R1 to -CX'X"-, oxygen, sulfur, and - NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group, with the proviso that when T' is oxygen, sulfur or -NR3 then X' and X" are hydrogen or X' and X" together form an oxo group; 

W and X are independently selected from the group consisting of -(CR'R7)^-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, and each R7 and Rg is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, 

-- 330 -- 

heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates" in the unsaturation; 

and with the further proviso that when W is oxygen, then X is not also oxygen; 

X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; and 

<iio 

/ \ R4 

X' X" 

where R1 is selected from the group consisting of alkyl, alkenyl, 

alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; 

T' is selected from the group consisting of a bond linking R1 to -CX'X"-, oxygen, sulfur, and - NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group, with the proviso that when T' is oxygen, sulfur or -NR3 then X' and X" are hydrogen or X' and X" together form an oxo group; 

W and X are independently selected from the group consisting of -(CR7R7)9-, oxygen, sulfur and -NR8 where q is an integer equal to one or two and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation, 

intellectual property office of n.z. 

2 2 AUG 2001 RECEIVED 

WO 98/38177 

PCT/US98/03373 

15 

- 331 -- 

X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 

B is selected from the group consisting of: 

10 (i) 

R5 

where R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 

W X 

(H) J* 

20 R4 

W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of 25 hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom 30 participates in the unsaturation; 

and with the further proviso that when W is oxygen, then X is not also oxygen; 

R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, 35 substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 

Printed from Mimosa 07/26/1999 12:37:07 page -333- 

WO 98/38177 

PCT/US98/03373 

- 332 -- 

R4 

5 

W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to 1 or 2 and each R7 and R8 is independently selected from the group consisting of 10 hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the 15 unsaturation; 

R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic, and 

(iv) when A is either formula (ii) or (iii) as defined above, then B can 20 also be a covalent bond linking A to C, 

C is selected from the group consisting of 

(i) -C(0)Y or -C(S)Y 

where Y is selected from the group consisting of: 

25 (a) alkyl or cycloalkyl, 

(b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl, or a-0C(0)aryl groups, 

(c) alkoxy or thioalkoxy, 

30 (d) substituted alkoxy or substituted thioalkoxy, 

(e) hydroxy, 

(f) aryl, 

(g) heteroaryl, 

Printed from Mimosa 07/26/1999 12:37:07 page -334- 

33 6 6 7 

- 333 -- 

(h) heterocyclic, 

(i) -NR'R" where R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one t»f R' or R" is 

5 hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, 

(j) -NHS02-Rs where R8 is selected from alkyl, substituted alkyl, 10 alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and 

(1) -ONR'tQOjOljR10 where z is zero or one, R9 and R10 are as defined 

15 above; 

(ii) -CRuRnY' 

where each R11 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, 20 heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkoxy, substituted thioalkoxy, -0C(0)R9, -SSR9, and -SSC(0)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic; and 

30 

25 riNTELLECTUAL property 

OFFICE OF N.Z. 

2 2 AUG 2001 

(ui) 

received where Altogether with -C = N-, forms a heterocyclic group which is optionally fused to form a bi- or multi-fused ring system 

336613 

-- 334 - 

with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy,-substituted 5 alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, -NHC(0)R10, -NHS02R'°, -C(0)NH2, -C(0)NHR10, -C(O)NR10R10, -S(0)R10, -S(O)2R!0, -S(0)2NHR10 and -S(O)2NR10R10 where each R10 is independently selected from the group 10 consisting of alkyl, substituted alkyl, or aryl, amino, N-alkylamino, N,N-dialkylammo, N-substituted alkylamino, N,N-disubstituted alkylamino, N-alkenylammo, N,N-dialkenylamino, N-substituted alkenylamino, N,N-disubstituted alkenylamino, N-cycloalkylammo, N,N-dicycloalkylamino, N-substituted cycloalkylamino, N,N-disubstituted cycloalkylamino, 15 N-arylamino, N,N-diarylammo, N-heteroarylammo, N,N-diheteroarylamino, 

N-heterocyclic ammo, N,N-diheterocyclic ammo and mixed N,N-ammo groups comprising a first and second substituent on said amino group which substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, 20 and heterocyclic provided that said first and second substituents are not the same; 

with the proviso that when A has structure (i) and B has structure (i), 

then C does not have structure (i) or (ii); 

with the further provisos that 25 A. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, 

R2 being methyl and p being zero, B has structure (iii) with W being -NH-, X being -CH2-, and R4 being benzyl then C is not -C(0)0CH3; 

B. when A has structure (i) with R1 being 3,5-difluorophenyl, Z being -CH2C(0)-, R2 being methyl, and p being zero, B has structure (ii) with W 30 being > NC(0)0C(CH3)3, X being -CH2-, and R4 being phenyl, then C is not -C(0)0CH3; 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

336613 

- 335 --(followed by 335a) 

C. when A has structure (u) wherein R1 is 3,5-difluorophenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene "and R4 is methyl, and B is a covalent bond linking A to C, then C is not -C(0)0CH3; 

D. when A has structure (ii) with R1 being phenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is oxygen, X is methylene and R4 is hydrogen, and B has structure (i) where R5 is iso-propyl then C is not -C(0)0H, or -C(0)0CH3; 

E. when A has structure (ii) with R1 being phenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is oxygen, X is methylene and R4 is hydrogen, and B has structure (iv) then C is not -C(0)NHNH2, or -C(0)CH3; 

F when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyl or indole-3-CH2- and p being zero; B has structure (ii) where W is -NR8 - where R8 is hydrogen or re/Y-butyloxycarbonyl, X is methylene and R4 is benzyl or «-butyl then C is not -C(0)0H or -C(0)0CH3, 

G. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyloxycarbonyl-NH-(CH2)4 - and p being zero; B has structure (ii) where W is -NH-, X is methylene and R4 is benzyloxycarbonyl-NH-(CH2)4- then C is not -C(0)0CH3; 

H. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyl and p being zero, B has structure (ii) where W is sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH3; 

I. when A has structure (i) with R1 being phenyl, Z being 

-CH20C(0)-, R2 being methyl or sec-butyl and p being zero; B has structure (ii) 

where W is sulfur, X is methylene and R4 is hydrogen then C is not 

-C(0)0CH:CH3 or -C(0)NH2; and 

--335a- 

<^0 0 iQ) ^ 

-v s a 

J. when A has structure (i) with R1 being phenyl, Z being 

-CH20C(0)-, R2 being methyl and p being zero; B has structure (ii) where W is oxygen or sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH3.
3. A use in the preparation of a medicament for treating a patient with AD in order to inhibit farther deterioration in the condition of that patient, of a compound of formula I: 

where Rl is selected from the group consisting of alkyl, alkenyl, 

alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; 

Z is selected from the group consisting of 

(a) a group having the formula -CX'X"C(0)- where X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

(b) a group having the formula -T-CH2C(0)- or -T-C(0)C(0)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; and 

A-B-C 

wherein A is selected from the group consisting of: 

r2 

r h 

(0 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

- 336 -- 

TV -\ 

wO D j 

(c) " a group having the formula -CX'X"-T-C(0)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; 

R6 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; 

m is an integer equal to 0 or 1; and p is an integer equal to 0 or 1; — 

where Rl is selected from the group consisting of alkyl, alkenyl, 

alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substimted alkynyl, substimted cycloalkyl, substimted cycloalkenyl, aryl, heteroaryl and heterocyclic; 

T' is selected from the group consisting of a bond linking R1 to -CX'X"-, oxygen, sulfur, and - NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group, with the proviso that when T' is oxygen, sulfur or -NR3 then X' and X" are hydrogen or X' and X" together form an oxo group; 

W and X are independently selected from the group consisting of -(CR7R7)?-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, 

intellectual property office of n.z. 

(ii) 

W X 

2 2 AUG 2001 received 

X' X" 

33 661 

-- 337 - 

carboxyl, carboxyl esters and heterocyclic and further, when q is-2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl; heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsamration, 

and with the further proviso that when W is oxygen, then X is not also oxygen; 

X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

R4 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, heteroaryl and heterocyclic; and where R1 is selected from the group consisting of alkyl, alkenyl, 

alkynyl, cycloalkyl, cycloalkenyl, substimted alkyl, substimted alkenyl, substimted alkynyl, substimted cycloalkyl, substimted cycloalkenyl, aryl, heteroaryl and heterocyclic; 

T' is selected from the group consisting of a bond linking R1 to -CX'X"-, oxygen, sulfur, and - NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group, with the proviso that when T' is oxygen, sulfur or -NR3 then X' and X" are hydrogen or X' and X" together form an oxo group; 

W and X are independently selected from the group consisting of -(CR7R7)?-, oxygen, sulfur and -NR8 where q is an integer equal to one or two and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the 

N X 

(iii) 

X' X 

WO 98/38177 

PCT/US98/03373 

- 338 - 

proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; 

X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

5 R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 

B is selected from the group consisting of: 

where R5 is selected from the group consisting of alkyl, substituted 15 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 

W X 

W and X are independently selected from the group consisting of 25 -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, 30 heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; 

and with the further proviso that when W is oxygen, then X is not also oxygen; 

Printed from Mimosa 07/26/1999 12:37:07 page -340- 

WO 98/38177 

PCT/US98/03373 

-- 339 - 

R4 is selected from the group consisting of hydrogen, alkyi, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted*cycloalkyl, aryl, heteroaryl and heterocyclic; 

W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to 1 or 2 and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, 

15 and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation, 

20 R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; and 

(iv) when A is either formula (n) or (iii) as defined above, then B can also be a covalent bond linking A to C; 

25 C is selected from the group consisting of: 

5 

N X 

(iii) 

10 

(0 

-C(0)Y or -C(S)Y 

30 

where Y is selected from the group consisting of 

(a) alkyl or cycloalkyl, 

(b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl, or a-0C(0)aryl groups, 

(c) alkoxy or thioalkoxy, 

(d) substituted alkoxy or substituted thioalkoxy, 

Printed from Mimosa 07/26/1999 12:37:07 page -341- 

- 1 " ;7 

\ 

- 340 - 

(e) hydroxy, 

(f) aryl, 

(g) heteroaryl, 

(h) heterocyclic, 

5 (i) -NR'R" where R' and R" are independently selected from hydrogen, 

alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional 10 heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxylalkyl groups, 

(j) -NHSO:-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, (k) -NR9NR'°R10 where R9 is hydrogen or alkyl, and each R10 is 15 independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and 

(1) -0NR9[C(0)0]zR'° where z is zero or one, R9 and R10 are as defined above, 

20 (n) -CRUR"Y' 

where each R" is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, alkoxy, amino, thiol, substituted alkoxy, thioalkoxy, substituted 25 thioalkoxy, -0C(0)R9, -SSR9, and -SSC(0)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic; and 

30 

(ui> -c'- 1 

2 2 AUG 2001 

received. 

1 

-- 341 -- 

10 

15 

20 

25 

where At together with -C=N-, forms a heterocyclic group which-is optionally fused to form a bi- or multi-fused ring system with'one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl. substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, -NHC(0)R'°, -NHSO;R10, -C(0)NH2, -C(0)NHR'°, -C(O)NR10R10, -S(0)R10, -S(0)2R'°, -S(0)2NHR'° and -S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N,N-disubstituted alkylamino, N-alkenylamino, N,N-dialkenylamino, N-substituted alkenylamino, N,N-disubstituted alkenylamino, N-cycloalkylammo, N,N-dicycloalkylammo, N-substituted cycloalkylamino, N,N-disubstituted cycloalkylamino, 

N-arylamino, N,N-diarylamino, N-heteroarylammo, N,N-diheteroarylamino, N-heterocychc ammo, N,N-diheterocyclic ammo and mixed N,N-amino groups comprising a first and second substituent on said ammo group which substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl. substituted cycloalkyl, aryl, heteroaryl, and heterocyclic provided that said first and second substituents are not the same; 

with the proviso that when A has structure (i) and B has structure (i), then C does not have structure (i) or (ii), 

with the further provisos that 

A. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R: being methyl and p being zero, B has structure (in) with W being -NH-, X being -CH:-, and R4 being benzyl then C is not -C(0)0CH3, 

B. when A has structure (i) with R1 being 3,5-difluorophenyl, Z being intellectual property office of n.z. 

2 2 AU6 2001 

received 

- 342 -(followed by 342a) 

336613 

-CH2C(0)-, R2 being methyl, and p being zero, B has structure (h) with W being >NC(0)0C(CH3)3, X being -CH2-, and R4 being phenyl, then C is not -C(0)0CH3; 

C. when A has structure (ii) wherein Rl is 3,5-difluorophenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene and R4 is methyl, and B is a covalent bond linking A to C, then C is not -C(0)0CH3; 

D. when A has structure (ii) with R1 being phenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is oxygen, X is methylene and R4 is hydrogen, and B has structure (i) where R5 is iso-propyl then C is not -C(0)0H, or -C(0)0CH3; 

E. when A has structure (ii) with R1 being phenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is oxygen, X is methylene and R4 is hydrogen, and B has structure (iv) then C is not -C(0)NHNH2, or -C(0)CH3; 

F. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyl or indole-3-CH2- and p being zero; B has structure (ii) where W is -NR8 - where R8 is hydrogen or tert-butyloxycarbonyl, X is methylene and R4 is benzyl or «-butyl then C is not -C(0)0H or -C(0)0CH3; 

G. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyloxycarbonyl-NH-(CH2)4 - and p being zero; B has structure (ii) where W is -NH-, X is methylene and R4 is benzyloxycarbonyl-NH-(CH2)4- then C is not -C(0)0CH3; 

H. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyl and p being zero; B has structure (ii) where W is sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH3; 

-342a- 

I. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being methyl or sec-butyl and p being zero; B has structure (ii) where W is sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH2CH3 or -C(0)NH2; and 

J. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being methyl and p being zero; B has structure (ii) where W is oxygen or sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH3.
4. The use according to any one of claims 1,2 and 3 wherein the compound of formula I is selected from the group consisting of compounds of formula II below: 

wherein R1, R2, R5, R6, A,*Z, m and p are as defined in Claim 1.
5. The use according to Claim 4 wherein m is one, Z is -CX'X"C(0)-, X" is hydrogen, X' is hydrogen or fluoro or X' and X" form an oxo group.
6. The use according to Claim 5 wherein R( is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl.
7. The use according to Claim 5 wherein Rt is a substituted aryl group selected from the group consisting of monosubstituted phenyls, disubstituted phenyls, and trisubstituted phenyls. 

- 343 - 

336613
8 The use according to Claim 7 wherein said suostituted R, phenyl group is selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-mtrophenyl, 2-methylphenyl, 

2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, -4-fluorophenyl, 5 4-chlorophenyl, 4-bromophenyl, 4-mtrophenyl, 4-methylphenyl, 

4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-/so-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 

3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 10 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 

2.3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 

3.4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 

3.5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 15 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5- 

trifluorophenyl, 3,4,5-tnmethoxypheny 1, 3,4,5-tri-(trifluoromethyl)pheny 1, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(tnfluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-20 trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.
9 The use according to Claim 4 wherein R1 is an alkaryl group 25 selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-rz- 

propyl.
10. The use according to Claim 4 wherein R1 is selected from alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups. 

30 

i intellectual property 

1 office of n.2. 

I 2 2 AUG 2001 

received 

-- 344 --
11. The use according to Claim 10 wherein R1 is selected from the group consisting of /sopropyl, n-propyl, /z-butyl, /so-butyl, sec-butyl, r-butyl, -CH2CH="CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH:-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, and -CH2CH2-cyclopentyl.
12. The use according to Claim 4 wherein R1 is a heteroaryl or substituted heteroaryls selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6- " methoxythionaphthen-2-yl, 3-phenyl-l,2,4-thiooxadiazol-5-yl, and 2- 

pheny loxazol-4-y 1.
13. The use according to Claim 4 wherein R2 is selected from the group consisting of methyl, ethyl, /i-propyl, /so-propyl, /i-butyl, /so-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, and -CH2CH2SCH3.
14. The use according to Claim 4 wherein R5 and R6 substituents are independently selected from the group consisting of hydrogen, methyl, 

ethyl, /i-propyl, /so-propyl, /i-butyl, /so-butyl, sec-butyl, rerr-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, 

m-fluorophenyl, p-fluorophenyl, /^-methoxyphenyl, p-methoxyphenyl, 

phenethyl, benzyl, m-hydroxy benzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH20-benzyl, 

intellectual property office of n.z. 

2 2 AUG 2001 received 

-- 345 - 

/?-(CH3)3C0C(0)CH20-benzyl, /?-(H00CCH;0)-benzyl, 2-aminopyrid-6-yl, p-(N-morpholmo-CH2CH20)-benzyl, -CH2CH2C(0)NH2, -CH,-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(l-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(0)0-r-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3) = CH2, -CH2CH=CHCH3 (cis and trans), -CH,OH, -CH(OH)CH3, -CH(0-/-butyI)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH^NH,, -CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), -CH2-(N-morpholino), /?-(N-morphohno-CH2CH20)-benzyl, benzo[b]thiophen-2-yl, 

5-chlorobenzo[b]thiophen-2-yl, 4,5,6.7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 

6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl, thien-3-yl.
15. The use according to Claim 4 wherein the wherein Y" is a heteroatom selected from oxygen, sulfur and >NR8 where R8 is as defined above and A', together with -Y"-C=N-, forms a heterocyclic group which is optionally fused to form a bi- or multi-fused ring system group is of the following heterocyclic structure: 

intellectual property office of n.z. 

2 2 AUG 2001 received with one or more ring structures 

< t <?/ 

hJ ij [J jj ) v I ^ 

-- 346 - 

selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, 

aryl and heteroaryl group which, m turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, 

alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, ammo, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, aryl, heteroaryl, heterocyclic, -NHC(0)R'°, -NHSOjR10, -C(0)NH2, -C(0)NHR10, -C(O)NRI0R10, -S(0)R10, -S(0)2R10, -S(0)2NHR'° and -S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl.
16. The use according to Claim 15 wherein the heterocyclic structure is selected from 3-methyl-l,2,4-oxadiazol-5-yl, thiazolin-2-yl, 3-15 phenyl-1,2,4-oxadiazol-5-yl and 3-(/?-methoxy-benzyl)-l,2,4-oxadiazol-5-yl
17 The use according to Claim 4 wherein the compound of formula II is selected from the group consisting of- 

(S)-5-[l-N-[/V-(3,5-difluorophenylacetyl)-L-alaninyl]amino]ethyl-3-ethyl-1,2,4-oxadiazole 

(S)-5-[l-N-[N-(3,5-difluorophenylacetyl)-L-alanmyl]amino-2-phenylethyl]-3-methyl-1,2,4-oxadiazole 

2-[l-A''-[A'-(3,5-difluorophenylacetyl)-L-alaninyl]amino-l-phenyl]methyl-2-thiazoline 

(S)-5-[ 1 -A^-[jV-(3 ,5-difluorophenylacety l)-L-alaninyl]ammo-1 -30 phenyl]methyl-3-methyl-l,2,4-oxadiazole 

(S)-5-[l-A^-[Ar-(3,5-difluorophenylacetyl)-L-alanmyl]amino-l-phenyl]methyl-3-phenyl-l,2,4-oxadiazole; and 

35 (S^-fl-N-fN-O.S-difluorophenylacetyO-L-alaninyllamino-l- 

phenyl]methyl-3-(4-methoxyphenylmethyl)-l,2,4-oxadiazole. 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

336613 

-- 347 -
18. The use according to any one of claims 1,2 and 3 wherein the compound of formula I is selected from the group consisting of compounds of formula III and IV below: 

10 

111 

15 

20 

25 

R2 

R1 

^2ts 

N- 

R6 J 

C(0)Y 

R4 

IV 

30 

wherein R1, R2, R\ R6, W, X, Y, Z, m and p are as defined in claim 1.
19. The use according to Claim 18 wherein m is one, Z is -CX'X"C(0)-, X" is hydrogen, X' is hydrogen or fluoro and where X' and X" form an oxo group.
35 20. The use according to Claim 19 wherein R1 is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl
21. The use according to Claim 19 wherein R1 is a substituted aryl 40 group selected from the group consisting of monosubstituted phenyls, disubstituted phenyls, and trisubstituted phenyls intellectual property office of n.z. 

2 2 AUG 2001 

received 

-wy - 

c* c, 

p 

-- 348 --
22. The use according to Claim 21 wherein said substituted R1 phenyl group is selected from the group consisting of 2-chlorophenyl, 2-fluoropheriyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 

2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl; 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-wopropy lphenyl, 4-phenoxyphenyl, 4-tnfluoromethylphenyl, 

4-hydroxymethy lphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 

3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-tnfluoromethylphenyl, 

2.3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 

3.4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 

3.5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyI, 3,4,5-tnfluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-tnfluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.
23. The use according to Claim 18 wherein R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-rt-propyl.
24. The use according to Claim 18 wherein R1 is selected from alkyl, substituted alkyl alkenyl, cycloalkyl and cycloalkenyl groups 

INTELLECTUAL property office of n.z. 

2 2 AUG 2001 

received 

- 349 -
25 The use according to Claim 24 wherein R1 is selected from the group consisting of wo-propyl, ^-propyl, fl-butyl, /so-butyl, sec-butyl, /-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3. cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH;-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl and -CH2CH2-cyclopentyl.
26. The use according to Claim 18 wherein R' is a heteroaryl or substituted heteroaryls selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyndyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl. benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl. 6-methoxythionaphthen-2-yl, 3-phenyl-l,2,4-thiooxadiazol-5-yl, and 2-phenyloxazol-4-yl.
27. The use according to Claim 18 wherein R: is selected from the group consisting of methyl, ethyl, /i-propyl, wo-propyl, n-butyl, /so-butyl, sec-butyl , phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, and -CH2CH2SCH3
28. The use according to Claim 18 wherein R4 is selected from the group consisting of hydrogen, methyl, phenyl and benzyl.
29. The use according to Claim 18 wherein R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, uo-propyl, n-butyl, /so-butyl, sec-butyl, /ert-butyl, -CH2CH(CH2CH3)2, 2-methyl-fl-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, wo-but-2-enyl, 3-methylpentyl, -CH:-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-mdol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl. 

intellectual property office of n.z. 

2 2 AU6 2001 

received 

- 350 - 

336613 

p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH20-benzyI, p-(CH3)3C0C(0)CH20-benzyl, p-(H00CCH20)-benzyl, 2-aminopynd-6-yl, p-(N-morpholino-CH2CH20)-benzy 1, -CH2CH2C(0)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofurany 1), -CH2-thiophen-2-yl, -CH2( 1 -methyl)cyclopropy 1, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(0)0-/-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(0-r-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), -CH:-(N-morpholino), p-(N-morpholmo-CH2CH20)-benzyl, benzo[b]thiophen-2-yl, 

5-chlorobenzo[b]thiophen-2-y 1, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-y 1, benzo[b]thiophen-3-yl. 5-chlorobenzo[b]thiophen-3-y 1, benzo[b]thiophen-5-y 1, 

6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl and thien-3-yl.
30. The use according to Claim 18 wherein Y is hydroxy, alkoxy, substituted alkoxy and -NR'R".
31. The use according to Claim 30 wherein Y is selected from the group consisting of methoxy, ethyoxy, /z-propoxy, zso-propoxy, n-butoxy, iso-butoxy, /-butoxy, /zeopentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-/z-propoxy, 3-iodo-/i-propoxy, 4-bromo-/z-butoxy, amino (-NH2), -NH(w<?-butyl), -NH(sec-butyl), N-methylammo, N,N-dimethylammo, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-pipendinyl, N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, -NH-methallyl, -NHCH2-(furan-2-yl), -NHCH2-cyclopropyl, -NH(r-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3)2, -NHCH2C(CH3)3, -NHCH2-(pyrid-2-yl), -NHCH2-(pyrid-3-y 1), -NHCH2-(pyrid-4-yl), N-thiazolindinyl, 

intellectual property office of n.z. 

2 2 AUG 2001 received 

- 351 - 

-N(CH2CH2CH3)2, -NHOH, -NHO-N02-4>), -NHCH2(p-NO2-0), -NHCH2(m-N02-<*>), -N(CH3)OCH3i -N(CH3)CH2-<£, -NHCH2-(3,5-di-fluorophenyl), -NHCH2CH2F, -NHCH2(p-CH30-<A), -NHCH2(m-CH30-4>), -NHCH2(p-CF3-4>), -N(CH3)CH2CH2OCH3, -NHCH2CH20, -NHCH(CH3)<*>, -NHCH2-(p-F-*). -N(CH3)CH2CH2N(CH3)2, -NHCH2-(tetrahydrofuran-2-yl), and -CH;CH2CH(CH3)2.
32. The use according to Claim 18 wherein the heterocyclic structures defined by W and X are selected from the group consisting of 4,5-dihydrothiazoles, 3,4-dihydro-l,3-isodiazoles, 3,4-dihydro-3-N-t-butoxy-3-lsodiazoles, and 4,5-dihydrooxazoles
33 The use according to Claim 18 wherein the compound of formula II is selected from the group consisting of: 

(S )-2- [ 1 - (3,5-difluoropheny lacetamido)ethy 1 ] -4-ethoxy carbony 1-2 -thiazoline 

1 -terr-butoxycarbonyl-2-[ 1 -(/V-carbobenzyloxy)aminoethyl]-4-methoxycarbony 1-4-pheny Imethy 1 -2 - imidazoline 

1-rerr-butoxycarbonyl-2-[l-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 

2-[ l-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 

2-[l-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenyl-2-lmidazoline 

2-[ l-(3,5-difluoropheny lacetamido)-1 -phenyl]methyl-4-ethoxycarbonyl-2-thiazoline 

1 -rerr-butoxycarbony 1-2-[ 1 - (N-carbobenzy lo xy )aminoethy I] -4-methoxycarbonyl-4-phenyl-2-imidazoline 

2-[(S)-l-(3,5-dichloroanilino)ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine 

(S)-2-[l-(3,5-difluoropheny lacetamido )ethy 1] -5 (R, S)-ethoxycarbony 1-2-oxazohne 

INTELLECTUAL PROPERTY OFFICE OF N.Z. 

2 2 AUG 2001 received 

^ ^ ;A ; 

20 

-- 352 

2-[l-(3,5-difluorophenylacetamido)-l-phenyl]methyI-4-methoxycarbonyl-2-thiazoline, and 

[l-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-umdazohne. 

sU 

15
34. The use according to any one of claims 1, 2 and 3 wherein the compound of formula I is selected from the group consisting of compounds of formula V and VI below: 

0 

R« 

R1" 

■T 

W X 

\ 

C / \ X' X" 

"N 

R4 

'N H 

Y 

0 

V 

25 

30 

R1' 

•T' 

o R6 

—X II 

>MYy' 

X' X" 

VI 

where R1, R4, R6, T', X', X", W, X, and Y are as defined in claim 1. 

35
35. The use according to Claim 34 wherein m is one, Z is -CX'X"C(0)-, X" is hydrogen, X' is hydrogen or fluoro and X' and X" form an oxo group. 

40
36. The use according to Claim 35 wherein R1 is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl. 

intellectual property! office of n.z. 

2 2 AUG 2001 

received 

- 353 - 

336613
37 The use according to Claim 35 wherein R1 is a substituted aryl group selected from the group consisting of monosubstituted phenyls, disubstituted phenyls, and tnsubstituted phenyls
38. The use according to Claim 37 wherein said substituted R1 phenyl group is selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 

2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 

3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 

3-thiomethoxyphenyl, 3-methylphenyl. 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl. 3,4-dichloropheny 1,3,4-difluoropheny 1,3,4-methy lenedioxypheny 1, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyDpheny 1, 3,5-dimethoxypheny 1, 2,4-dichloropheny 1, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 

3.4.5-trimethoxypheny 1, 3,4,5-tri-(trifluoromethyl)pheny 1, 2,4,6-trifluoropheny 1, 

2.4.6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-tnfluoromethylphenyl, 

4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxypheny 1, 2-chloro-6-fluoropheny 1, 2-fluoro-6-chloropheny 1, 

2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro- 

3-trifluoromethylphenyl.
39. The use according to Claim 34 wherein R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-n-propyl. 

intellectual property office of n.z. 

2 2 AUG 2001 received 

^ i K' L* 

~vJ ii <Q; 

-- 354 --
40 The use according to Claim 34 wherein R1 is selected from alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups.
41 The use according to Claim 40 wherein R1 is selected from the group consisting of iso-propyl, ^-propyl, /i-butyl, iso-butyl, sec-butyl, /-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl and -CH2CH2-cyclopentyl.
42. The use according to Claim 34 wherein R1 is a heteroaryl or substituted heteroaryls selected from the group consisting of pynd-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropynd-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-l,2,4-thiooxadiazol-5-yl, and 2-phenyloxazol-4-yl.
43. The use according to Claim 34 wherein R4 is selected from the group consisting of hydrogen, methyl, phenyl and benzyl.
44. The use according to Claim 34 wherein R6 is selected from the group consisting of hydrogen, methyl, ethyl, /i-propyl, /so-propyl, n-butyl, {jo-butyl, sec-butyl, rerr-butyl, -CH2CH(CH2CH3)2, 2-methyl-rt-butyl, 6-fluoro-/z-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, /so-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxy phenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, /7-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylpheny 1, /?-(CH3)2NCH2CH2CH20-benzyl, 

intellectual property office of n.z. 

2 2 AUG 2001 received 

33661 

- 355 - 

p-(CH3)3C0C(0)CH20-benzyl, /?-(H00CCH20)-benzyl, 2-am;nopyrid-6-yl, />-(N-morpholino-CH2CH20)-benzyl, -CH2CH2C(0)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(l-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(0)0-r-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (CIS and trans), -CH2OH, -CH(OH)CH3, -CH(0-r-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 

3-pyridyl and 4-pyndyl), pyridyl (2-pyridyl, 3-pyndyl and 4-pyridyl), -CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), -CH2-(N-morpholino), p-(N-morpholino-CH2CH20)-benzyl, benzo[b] thiophen-2-yl, 

5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl", 

6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl and thien-3-yl
45. The use according to Claim 34 wherein Y is hydroxy, alkoxy, substituted alkoxy and -NR'R".
46. The use according to Claim 45 wherein Y is selected from the group consisting of methoxy, ethyoxy, n-propoxy, wo-propoxy, n-butoxy, /so-butoxy, r-butoxy, zieo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-«-propoxy, 3-iodo-/i-propoxy, 4-bromo-/i-butoxy, amino (-NH2), 

-NH(wo-butyl), -NH(sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorphohno, N-piperidinyl, N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, 

-NH-methallyl, -NHCH2-(furan-2-yl), -NHCH2-cyclopropyl, -NH(r-butyl), -NH(p-methylphenyl), -NHOCH3, -NHCH2(/?-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3)2, -NHCH2C(CH3)3, -NHCH2-(pynd-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolindmyl, 

-N(CH2CH2CH3)2, -NHOH, -NH(p-NOr4>), -NHCH2(p-N02-4>), 

intellectual property office of n.z, 

2 2 AUG 2001 RECEIVED 

-- 356 - 

15 

20 

25 

30 

-NHCH2(m-N02-<£), -N(CH3)OCH3, -N(CH3)CH2-0, -NHCH2-(3,5-di-fluorophenyl), -NHCH2CH2F, -NHCH2(/?-CH30-<£), -NHCH2(m-CH30-4>), -NHCH2(p-CF3-<*>), -N(CH3)CH2CH2OCH3, -NHCH2CH24>, -NHCH(CH3)<£, -NHCH2-(p-F-</>), -N(CH3)CH:CH2N(CH3)2 and -NHCH2-(tetrahydrofuran-2-yl).
47. The use according to Claim 34 wherein the heterocyclic structures defined by W and X are selected from the group consisting of 4,5-dihydrothiazoles, 3,4-dihydro-l,3-isodiazoles, 3,4-dihydro-3-N-t-butoxy-3-isodiazoles, and 4,5-dihydrooxazoles.
48. The use according to Claim 34 wherein said compound of formula V and VI are selected from the group consisting of 

(4R)-4-[iV-( 1 S)-( 1 -methoxycarbonyl-1 -phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyI-2-thiazoline 

4-[Ar-(S)-(i-methoxycarbonyl-l-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-2-thiazoline; and 

4-[yV-(S)-(l-methoxycarbonyl-l-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline.
49. A use, in the preparation of a medicament for inhibiting the cellular release and/or synthesis of P-amyloid peptide in a patient in need thereof, of a compound selected from the group consisting of compounds of formula VII and VIII: 

/ \ 

X1 X" 

w— 

Vll intellectual property office of n.z. 

U 

2 2 AUG 2001 

received 

33661 

- 357 -- 

10 

VIII 

15 wherein R1, R4, R6, T', X', X", W and X are as defined in claim 1. 

W\ together with -C(H)SC( = U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused 20 ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, 25 substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(0)R10, -NHS02R10, -C(0)NH2, -C(0)NHR'°, -C(O)NR10R10, -S(0)R10, 30 -S(0)2R10, -S(0)2NHR10 and -S(O)2NRl0R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl; 

U is selected from the group consisting of oxo (=0), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); 

s is an integer equal to 0 or 1; and 35 t is an integer equal to 0 or 1. 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

- 358 --
50. A use, in the preparation of a medicament for preventing the onset of AD in a patient at risk for developing AD, of a compound selected from the group consisting of compounds of formula VII and VIII- 

10 

15 

Vll 

20 

25 

30 

35 

40 

VIII 

wherein Rl, R\ R6, T', X', X", W and X are as defined in claim 1; 

W', together with -C(H)SC(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the 

INTELLEaUAL PROPER office of n.z. 

2 2 AUG 2001 

received 

O W " '-1 ^ 

' " "v.- \ a, , 

-- 359 -- 

10 

group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, cyano. carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, ammo, N-alkylamino, N,N-dialkylammo, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(0)R10, -NHS02R10, -C(0)NH2, -C(0)NHR10, -C(O)NRI0R10, -S(0)R10, -S(0):R'°, -S(0)2NHR'° and -S(O)2NRl0R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl; 

U is selected from the group consisting of oxo (=0), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); 

s is an integer equal to 0 or 1; and t is an integer equal to 0 or 1. 

15
51. A use, in the preparation of a medicament for treating a patient with AD in order to inhibit further deterioration in the condition of that patient, of a compound selected from the group consisting of compounds of formula VII and VIII: 

20 

25 

30 

Vll 

35 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

- 360 -- 

33 6 615 

o R6 

R'-^cJL 

/ \ X' X' 

N X 

W 

-x i h /W 

^ YVV« ^ 

R4- -6 \ J 

1 c —^ 

VIII 

u 

10 

0 

15 

20 

30 

wherein Rl, R4, R6, T', X', X", W and X are as defined in claim 1; 

W', together with -C(H),C(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, ammo, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(0)Rl°, -NHS02Rl°, -C(0)NH2, -C(0)NHRl°, -C(O)NRl0R10, -S(0)R10, -S(0)2R'°, -S(0)2NHR'° and -S(O)2NRl0R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl; 

U is selected from the group consisting of oxo (=0), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); 

s is an integer equal to 0 or 1; and / is an integer equal to 0 or 1.
52. A compound of formula I: 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

3366f5 

A-B-C 

10 

15 

20 

(0 

wherein A is selected from the group consisting of. 

R2 

R'^zt-s yN 

where R1 is selected from the group consisting of alkyl, alkenyl, 

alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; 

Z is selected from the group consisting of 

(a) a group having the formula -CX'X"C(0)- where X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

(b) a group having the formula -T-CH2C(0)- or -T-C(0)C(0)- where T is selected from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; and 

(c) a group having the formula -CX'X"-T-C(0)- where T is selected 

25 from the group consisting of oxygen, sulfur and -NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group; X' is hydrogen or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" 

together form an oxo group; 

R2 is selected from the group consisting of alkyl, substituted alkyl, 

30 alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, 

heteroaryl and heterocyclic; 

R6 is selected from the group consisting of alkyl, substituted alkyl, 

alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, 

heteroaryl and heterocyclic, INTELLECTUAL PROPERTY 

OFFICE OF N.Z. 

2 2 AUG 2001 

received 

-- 362 - 

33 6 13 

10 

m is an integer equal to 0 or 1; and p is an integer equal to 0 or 1; 

W X 

,« ""Vv 

X' X" 

where Rl is selected from the group consisting of alkyl, alkenyl, 

alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; 

T' is selected from the group consisting of a bond linking R1 to -CX'X"-, oxygen, sulfur, and - NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group, with the proviso that when T' is oxygen, sulfur or -NR3 then X' and X" are hydrogen or X' and X" together form an oxo group; 

2q W and X are independently selected from the group consisting of 

-(CR7R7)?-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; 

and with the further proviso that when W is oxygen, then X is not also 3Q oxygen; 

X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; and intellectual property office of n.z. 

2 2 AUG 2001 

A P A P I It ^ m 

33661 

where R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic; 

T' is selected from the group consisting of a bond linking R1 to -CX'X"-, oxygen, sulfur, and - NR3 where R3 is hydrogen, acyl, alkyl, aryl or heteroaryl group, with the proviso that when T' is oxygen, sulfur or -NR3 then X' and X" are hydrogen or X' and X" together form an oxo group; 

W and X are independently selected from the group consisting of -(CR7R7)9-, oxygen, sulfur and -NR8 where q is an integer equal to one or two and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; 

X' is hydrogen, hydroxy or fluoro, X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group; 

R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 

-- 363 - 

(iii) 

R1' 

-T' 

C / \ X' X" 

N X 

-vr 

\ R4 

B is selected from the group consisting of: 

H 

intellectual property office of n.z. 

1 2 AUG 2001 

received 

WO 98/38177 

-- 364 - 

PCT/US98/03373 

where R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted .cycloalkyl, aryl, heteroaryl and heterocyclic; 

5 W X 

10 

W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to one or two, and each R7 and R8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, 

15 carboxyl, carboxyl esters, and heterocyclic and further, when q is 2, an R7 group on each of the carbon atoms can optionally be fused to form an aiyl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated, the remaining R7 group on each carbon atom participates in the unsaturation; 

20 and with the further proviso that when W is oxygen, then X is not also oxygen; 

R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic; 

25 

W and X are independently selected from the group consisting of -(CR7R7)q-, oxygen, sulfur and -NR8 where q is an integer equal to 1 or 2 and each R7 and R8 is independently selected from the group consisting of 35 hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, acyl, acyloxy, and heterocyclic and further, when q is 2, an R7 group on each of the carbon 

Printed from Mimosa 07/26/1999 12:37:07 page -366- 

WO 98/38177 

PCTAJS98/03373 

- 365 - 

atoms can optionally be fused to form an aryl, heteroaryl, heterocyclic or cycloalkyl group with the ethylene group with the proviso that when unsaturated-, .the remaining R7 group on each carbon atom participates in the unsaturation; 

5 R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic, and 

(iv) when A is either formula (ii) or (iii) as defined above, then B can also be a covalent bond linking A to C; 

10 C is selected from the group consisting of. 

(i) -C(0)Y or -C(S)Y 

where Y is selected from the group consisting of: 

(a) alkyl or cycloalkyl, 

15 (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include a-haloalkyl, a-diazoalkyl, a-0C(0)alkyl, or a-0C(0)aryl groups, 

(c) alkoxy or thioalkoxy, 

(d) substituted alkoxy or substituted thioalkoxy, 20 (e) hydroxy, 

(f) aryl, 

(g) heteroaryl, 

(h) heterocyclic, 

(i) -NR'R" where R' and R" are independently selected from hydrogen, 25 alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R' or R" is hydroxy or alkoxy, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally 30 substituted with one or more alkyl, alkoxy or carboxylalkyl groups, 

Printed from Mimosa 07/26/1999 12:37:07 page -367- 

-- 366 - 

(j) -NHS02-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic, 

(k) .-NR9NR10R10 where R9 is hydrogen or alkyl, and each R'° is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and 

(1) -0NR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above; 

(ii) -CR"RI1Y' 

where each Ru is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, alkoxy, ammo, thiol, substituted alkoxy, thioalkoxy, substituted • thioalkoxy, -0C(0)R9, -SSR9, and -SSC(0)R9 where R9 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic; and where A* together with -C=N-, forms a heterocyclic group which is optionally fused to form a bi- or multi-fused ring system with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substimted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, heterocyclic, -NHC(0)R'°, -NHS02R10, -C(0)NH2, -C(0)NHR10, -C(O)NR10R10, -S(0)R10, -S(0)2R10, -S(0)2NHR10 and 

(iii) 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

^ O (,'/ 1 •< 

30 

- 367 -(followed by 367a) 

-S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl, ammo, N-alkylammo, N.N-dialkylammo, N-substituted alkylamino, N,N-disubstituted alkylamino, N-alkenylamino, N,N-dialkenylammo, N-substituted alkenylamino, N,N-5 disubstituted alkenylamino, N-cycloalkylammo, N,N-dicycloalkylamino, N-substituted cycloalkylamino, N,N-disubstituted cycloalkylamino, 

N-arylammo, N,N-diarylamino, N-heteroarylamino, N,N-diheteroarylamino, N-heterocyclic ammo, N,N-diheterocyclic amino and mixed N,N-ammo groups comprising a first and second substituent on said amino group which 10 substituents are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic provided that said first and second substituents are not the same; 

with the proviso that when A has structure (i) and B has structure (i), 15 then C does not have structure (i) or (ii); 

with the further provisos that 

A when A has structure (i) with Rl being phenyl, Z being -CH20C(0)-, R2 being methyl and p being zero, B has structure (iii) with W being -NH-, X being -CH2-, and R4 being benzyl then C is not -C(0)0CH3, 20 B. when A has structure (i) with R1 being 3,5-difluorophenyl, Z bemg 

-CH2C(0)-, R2 being methyl, and p being zero, B has structure (ii) with W being >NC(0)0C(CH3)3, X being -CH2-, and R4 being phenyl, then C is not -C(0)0CH3; 

C. when A has structure (ii) wherein is 3,5-difluorophenyl, T' is a 25 bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is sulfur, X is methylene and R4 is methyl, and B is a covalent bond linking A to C, then C is not -C(0)0CH3; 

D when A has structure (ii) with R1 being phenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is oxygen, X is methylene and R4 is hydrogen, and B has structure (i) where R5 is iso-propyl then C is not -C(0)0H, or -C(0)0CH3; 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

336613 

-367a™ 

E. when A has structure (ii) with R1 being phenyl, T' is a bond linking R1 to -CX'X"-, X' and X" are hydrogen, W is oxygen, X is methylene and R4 is hydrogen, and B has structure (iv) then C is not -C(0)NHNH2, or -C(0)CH3; 

F. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyl or indole-3-CH2- and p being zero; B has structure (ii) where W is -NR8 - where R8 is hydrogen or /ert-butyloxycarbonyl, X is methylene and R4 is benzyl or «-butyl then C is not -C(0)0H or -C(0)0CH3; 

G. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyloxycarbonyl-NH-(CH2)4 - and p being zero; B has structure (ii) where W is -NH-, X is methylene and R4 is benzyloxycarbonyl-NH-(CH2)4 - then C is not -C(0)0CH3; 

H. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being benzyl and p being zero; B has structure (ii) where W is sulfur, X is methylene and R4is hydrogen then C is not -C(0)0CH3; 

I. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being methyl or sec-butyl and p being zero; B has structure (ii) where W is sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH2CH3 or -C(0)NH2; and 

J. when A has structure (i) with R1 being phenyl, Z being -CH20C(0)-, R2 being methyl and p being zero; B has structure (ii) where W is oxygen or sulfur, X is methylene and R4 is hydrogen then C is not -C(0)0CH3.
53. The compound according to Claim 52 wherein the compound of formula I is selected from the group consisting of compounds of formula II below. 

intellectual property office of n.z. 

2 2 AUG 2001 

DCPCIUEn 

- 368 - 

336613 

R1 

m U 

wherein Rl, R\ R3, R6, A* z, m and p are as defined in Claim 52.
54 The compound according to Claim 53 wherein m is one, Z is -CX'X"C(0)-, X" is hydrogen, X' is hydrogen or fluoro or X' and X" form an oxo group.
55 The compound according to Claim 53 wherein R( is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl.
56. The compound according to Claim 53 wherein Rt is a substituted aryl group selected from the group consisting of monosubstituted phenyls, disubstituted phenyls, and trisubstituted phenyls.
57. The compound according to Claim 56 wherein said substituted R, phenyl group is selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 

2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-/so-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 

3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 

intellectual property i office of n.z. 

2 2 AUG 2001 

received 

-- 369 -- 

2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl, 

3.4-methy lenedioxypheny 1, 3,4-d imethoxypheny 1,3,5 -difluoropheny 1, 

3.5-dichlorophenyl, 3.5-di-(tnfluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.
58 The compound according to Claim 53 \yherein R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyI-fl-propyl.
59. The compound according to Claim 53 wherein R1 is selected from alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups.
60. The compound according to Claim 59 wherein R1 is selected from the group consisting of iso-propyl, /z-propyl, n-butyl, iso-butyl, sec-butyl, r-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, and -CH2CH2-cyclopentyl.
61'. The compound according to Claim 53 wherein R1 is a heteroaryl or substituted heteroaryls selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (includmg 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2- 

intellectual property office of n.z. 

2 2 AUG 2001 received 

336613 

- 370 - 

chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl. 6-methoxythionaphthen-2-yl, 3-phenyl-l,2,4-thiooxadiazol-5-yl, and 2-phenyloxazol-4-yl 

5
62.The compound according to Claim 53 wherein R2 is selected from the group consisting of methyl, ethyl, /z-propyl, /'so-propyl, n-butyl, /so-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, and -CH2CH2SCH3.
63- The compound according to Claim 53 wherein R5 and R6 10 substituents are independently selected from the group consisting of hydrogen, methyl, ethyl, w-propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, rerr-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, /so-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-15 cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, 

m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxy benzyl, p-hydroxybenzyl, p-nitrobenzyl, /w-trifluoromethy lphenyl, p-(CH3)2NCH2CH2CH20-benzyl, p-(CH3)3C0C(0)CH20-benzyl, p-(H00CCH20)-benzyl, 2-aminopyrid-6-yl, p-20 (N-morphoiino-CH2CH20)-benzyl, -CH2CH2C(0)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(l-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(0)0-r-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, 25 -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(0-r-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CHr naphthyl (e.g , 1-naphthyl and 2-naphthyl), -CH2-(N-morpholino), p-(N-morpholino-CH2CH20)-benzyl, benzo[b]thiophen-2-yl, 30 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, 

benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

b iq | g 

-- 371 - 

6-methoxynaphth-2-yl, -CH;CH2SCH3, thien-2-yl, thien-3-yl.
64 . The compound according to Claim 53 v/herem the 

5 

/' 

\ 

A 

) 

—c group is of 

10 

N 

the following heterocyclic structure: 

15 

A' 

C 

20 

wherein Y" is a heteroatom selected from oxygen, sulfur and >NR8 where R8 is as defined above and A', together with -Y"-C=N-, forms a heterocyclic group which is optionally fused to form a bi- or multi-fused ring system selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, 

aryl and heteroaryl group which, in turn, each of such ring structures are optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted 30 thioalkoxy, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, 

alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, ammo, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, aryl, heteroaryl, heterocyclic, -NHC(0)R'°, -NHS02R10, -C(0)NH2, -C(0)NHR10, -C(O)NR10R10, -S(0)R'°, -S(0)2R10, 35 -S(0)2NHR'° and -S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl. 

25 

with one or more ring structures intellectual property office of n.z. 

2 2 AUG 2001 

received 

~ 372 -- 

336613
65 The compound according to Claim 64 wherein the heterocyclic structure is selected from 3-methyl-l,2,4-oxadiazol-5-yl, thiazolin-2-yl, 3-phenyl-1,2,4_-oxadiazol-5-yl and 3-(p-methoxy-benzyI)-l,2,4-oxadiazol-5-yl.
66 The compound according to Claim 53 wherein the compound of formula II is selected from the group consisting of: 

10 

15 

(S)-5-[l-M[iV-(3,5-difluorophenylacetyl)-L-alaninyl]amino]ethyI-3-ethyl-1,2,4-oxadiazole 

(S)-5-[l-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2-phenylethy 1] -3-methy 1-1,2,4-oxadiazole 

2-[ 1 -N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]ammo-1 -phenyl]methyl-2-thiazoline 

20 

25 

(S)-5-[ 1 -N-[N-(3,5-difluorophenylacetyl)-L-alaninyl] ammo-1 -phenyl]methyl-3-methyl-l,2,4-oxadiazole 

(S)-5-[l-A^-[7V-(3,5-difluorophenylacetyl)-L-alaninyl]amino-l-phenyl]methyl-3-phenyl-l,2,4-oxadiazole; and 

(S)-5-[l-N-[Af-(3,5-difluoropheny lacety l)-L-alaninyl]amino-1-phenyl]methyl-3-(4-methoxyphenylmethyl)-l,2,4-oxadiazole. 

30
67. The compound according to Claim 52 wherein the compound of formula I is selected from the group consisting of compounds of formula III and IV below: 

35 

R1 

"> H 

W X 

R4 

R6 J 

III 

40 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

-- 373 -- 

7 

R2 

R 

m H 

N X 

R6 J 

C(0)Y 

R4 

IV 

wherein R1, R2, R4, R6, W, X, Y, Z, m and p are as defined in Claim 52.
68. The compound according to Claim 67 wherein m is one, Z is -CX'X"C(0)-, X" is hydrogen, X' is hydrogen or fluoro and where X' and X" form an oxo group.
69. The compound according to Claim 67 wherein R1 is an unsubstituted aryl group selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl.
70 The compound according to Claim 67 wherein R1 is a substimted aryl group selected from the group consisting of monosubstituted phenyls, disubstituted phenyls, and trisubstituted phenyls.
71. The compound according to Claim 70 wherein said substituted R1 phenyl group is selected from the group consisting of 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-mtrophenyl, 2-methylphenyl, 

2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethy lphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-/so-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 

3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

y 

%j ■ 

H 

- 374 

2,5-dimethoxyphenyl, 3,4-dichloropheny 1, 3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimeihoxyphenyl, 3,5-difluorophenyl, 3,5 -dichloropheny 1, 3,5 -di-(trifluoromethyl)pheny 1,3,5-dimethoxypheny 1, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl, 2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro-3-trifluoromethylphenyl.
72. The compound according to Claim 67 wherein R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-Ai-propyl.
73 The compound according to Claim 67 wherein Rl is selected from alkyl, substituted alkyl alkenyl, cycloalkyl and cycloalkenyl groups.
74 . The compound according to Claim 73 wherein R1 is selected from the group consisting of /so-propyl, /i-propyl, /z-butyl, /so-butyl, sec-butyl, r-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl and -CH2CH2-cyclopentyl.
75. The compound according to Claim 67 wherein R1 is a heteroaryl or substituted heteroaryls selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2- 

intellectual property office of n.z. 

2 2 AUG 2001 RECEIVED 

33 66)3 

chlorothiophen-5-yl, 3-methyhsoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-l,2.4-thiooxadiazol-5-yl, and 2-pheny loxazol-4-yl. 

5
76 The compound according to Claim 67 wherein R2 is selected from the group consisting of methyl, ethyl, /i-propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, and -CH2CH2SCH3. 

10
77 . The compound according to Claim 67 wherein R4 is selected from the group consisting of hydrogen, methyl, phenyl and benzyl.
78 The compound according to Claim 67 wherein R6 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, /so-propyl, /i-butyl, 15 /so-butyl, sec-butyl, rerr-butyl, -CH2CH(CH2CH3)2, 2-methyl-/i-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, z'so-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, 20 p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH20-benzyl, p-(CH3)3C0C(0)CH20-benzyl, p-(H00CCH20)-benzyl, 2-aminopynd-6-yl, p-(N-morpholino-CH2CH20)-benzyl, -CH2CH2C(0)NH2, -CH2-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(l-methyl)cyclopropyl, 25 -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(0)0-r-butyl, 

-CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopentyl, -cyclohex-2-enyl, -CH[CH(CH3)2]COOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3, -CH(0-r-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 30 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), -CH2-(N-morpholino), 

intellectual property office of n.z. 

1 2 AUG 2001 

ncPCIUFn 

33 6 6 "j 

- 376 -- 

/?-(N-morpholino-CH2CH20)-benzyl, benzo[b]thiophen-2-yl, 

5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiGphen-3-yl, 5-chlorobenzo[b]thiophen-3-yI, benzo[b]thiophen-5-yl, 

6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl and thien-3-yl.
79. The compound according to Claim 67 wherein Y is hydroxy, alkoxy, substituted alkoxy and -NR'R".
80 The compound according to Claim 79 wherein Y is selected from 10 the group consisting of methoxy, ethyoxy, /i-propoxy, /so-propoxy, n-butoxy, wo-butoxy, f-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, amino (-NH2), -NH(z'so-butyl), -NH(sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-15 hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, -NH-methallyl, -NHCH2-(furan-2-yl), -NHCH2-cyclopropyl, -NH(r-butyl), -NH(/?-methylphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3)2, -NHCH2C(CH3)3, -NHCH2-(pyrid-2-yl), -NHCH2-(pynd-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolmdinyl, 20 -N(CH2CH2CH3)2, -NHOH, -NH(p-N02-</>), -NHCH2(p-NOr<*>), -NHCH2(m-NO2-«/>), -N(CH3)OCH3, -N(CH3)CH2-<£, -NHCH2-(3,5-di-fluorophenyl), -NHCH2CH2F, -NHCH2(p-CH3O-0), -NHCH2(/n-CH30-</>), -NHCH2(P-CF3-0), -N(CH3)CH2CH2OCH3, -NHCH2CH20, -NHCH(CH3)4>, -NHCH2-O-F-0), -N(CH3)CH2CH2N(CH3)2, -NHCH2-(tetrahydrofuran-2-yl), and 25 -CH2CH2CH(CH3)2. 

30
81. The compound according to Claim 67 wherein the heterocyclic structures defined by W and X are selected from the group consisting of 4,5-dihydrothiazoles, 3,4-dihydro-l,3-isodiazoles, 3,4-dihydro-3-N-t-butoxy-3-isodiazoles, and 4,5-dihydrooxazoles. 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

5 

10 

15 

20 

25 

30 

35 

40 

45 

- 377 -
82 The compound according to Claim 67'wherein the compound of formula II is selected from the group consisting of: 

(S)-2-[l-(3,5-difluorophenylacetamido)ethyl]-4-ethoxycarbonyl-2-thiazoline 

1-rerr-butoxycarbonyl-2-[l-(N-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 

1 -/e/t-butoxycarbonyl-2-[ 1 -(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 

2-[l-(3,5-difluorophenylacetamido)ethyl]-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline 

2-[l-(3,5-difluoropheny lacetamido)ethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline 

2-[ 1 -(3,5-difluorophenylacetamido)-1 -phenyl]methyl-4-ethoxycarbonyl-2-thiazoline 

1 -rm-butoxycarbonyl-2-[ 1 -(Ar-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline 

2-[(S)-1-(3,5-dichloroanilino)ethyl]-(S)-4-methoxycarbonyl-2-oxazolidine 

(S)-2-[ 1-(3,5-difluoropheny lacetamido)ethy 1]-5(R, S)-ethoxycarbony 1-2-oxazohne 

2-[ 1 -(3,5-difluorophenylacetamido)-1 -pheny ljmethy 1-4-methoxycarbony 1-2-thiazoline; and 

[l-(jV-carbobenzyloxy)aminoethyl]-4-methoxycarbonyl-4-phenyl-2-imidazoline.
83 The compound according to Claim 52 wherein the compound of formula I is selected from the group consisting of compounds of formula V and VI below: 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

>iSi£ 

- 378 - 

V/ 

10 

o R6 

-T>MYr 

Y 

VI 

15 / \ R4 

X' X" 

where R1, R4, R6, T', X', X", W, X, and Y are as defined in Claim 52. 

20
84. The compound according to Claim 83 wherein m is one, Z is -CX'X"C(0)-, X" is hydrogen, X' is hydrogen or fluoro and X' and X" form an oxo group. 

25
85 The compound according to Claim 83 wherein R1 is an unsubstituted aryl group selected from the group consisting of phenyl, 

1-naphthyl and 2-naphthyl.
86- The compound according to Claim 83 wherein R1 is a substituted 30 aryl group selected from the group consisting of monosubstituted phenyls, disubstituted phenyls, and trisubstituted phenyls.
87. The compound according to Claim 86 wherein said substituted R1 phenyl group is selected from the group consisting of 2-chlorophenyl, 2-35 fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 

2-methoxyphenyl, 2-phenoxyphenyl, 2-trifluoromethy lphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-mtrophenyl, 4-methylphenyl, 

i intellectual propers 

1 OFFICE OF N.Z. 

1 2 2 AUG 2001 i dfCEIVED 

33 661 j 

- 379 -- 

4-hydroxypheriyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl, 

4-hydroxymethy lphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-mtrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl, 

3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichloropheny 1, 3,4-difluoropheny 1, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 

2,4-difluorophenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 

3.4.5-tnmethoxyphenyl, 3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl, 

2.4.6-trimethylphenyl ,2,4,6-tri-(trifluoromethyl)pheny 1, 2,3,5-trifluoropheny 1, 2,4,5-trifluorophenyl, 2,5-difluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 

4-fluoro-2-trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 

4-benzyloxyphenyl, 2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl, 

2,5-dimethylphenyl, 4-phenylphenyl and 2-fluoro- 

3-trifluoromethylphenyl.
88. The compound according to Claim 83 wherein R1 is an alkaryl group selected from the group consisting of benzyl, 2-phenylethyl and 3-phenyl-/j-propyl.
89. The compound according to Claim 83 wherein R1 is selected from alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups.
90. The compound according to Claim 89 wherein R1 is selected from the group consisting of wo-propyl, /i-propyl, /i-butyl, /so-butyl, sec-butyl, 

r-butyl, -CH2CH=CH2, -CH2CH=CH(CH2)4CH3, cyclopropyl, cyclobutyl, 

cyclohexyl, cyclopentyl, cyclohex-l-enyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl and -CH2CH;-cyclopentyl. 

intellectual property office of n.z. 

2 2 AUG 2001 RECEIVED 

-- 380 -- 

<T 7 €: „ 

^0 <J (') 

w B
91' The compound according to Claim 83 wherein R1 is a heteroaryl or substituted heteroaryls selected from the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyndyls (including 5-chloropyrid-3-yl), thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 

2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazoI-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-l,2,4-thiooxadiazol-5-yl, and 2-phenyloxazol-4-y 1.
92. The compound according to Claim 83 wherein R4 is selected from the group consisting of hydrogen, methyl, phenyl and benzyl.
93. The compound according to Claim 83 wherein R6 is selected from the group consisting of hydrogen, methyl, ethyl, /i-propyl, /so-propyl, /i-butyl, /so-butyl, sec-butyl, rerr-butyl, -CH2CH(CH2CH3)2, 2-methyl-n-butyl, 6-fluoro-/7-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl, allyl, /so-but-2-enyl, 3-methylpentyl, -CH2-cyclopropyl, -CH2-cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclohexyl, -CH2-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl, p-(CH3)2NCH2CH2CH20-benzyl, p-(CH3)3C0C(0)CH20-benzyl, p-(H00CCH20)-benzyl, 2-ammopyrid-6-yl, p-(N-morpholino-CH2CH20)-benzyl, -CH2CH2C(0)NH2, -CH;-imidazol-4-yl, -CH2-(3-tetrahydrofuranyl), -CH2-thiophen-2-yl, -CH2(l-methyl)cyclopropyl, -CH2-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl, -CH2-C(0)0-r-butyl, -CH2-C(CH3)3, -CH2CH(CH2CH3)2, -2-methylcyclopenty 1, -cyclohex-2-enyl, -CH[CH(CH3)JCOOCH3, -CH2CH2N(CH3)2, -CH2C(CH3)=CH2, -CH2CH=CHCH3 (cis and trans), -CH2OH, -CH(OH)CH3> -CH(0-r-butyl)CH3, -CH2OCH3, -(CH2)4NH-Boc, -(CH2)4NH2, -CH2-pyridyl (e.g., 2-pyridyl, 

3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), -CH2-naphthyl (e.g , 1-naphthyl and 2-naphthyl), -CH2-(N-morpholino), 

intellectual property office of n.z. 

2 2 AUG 2001 RECEIVED 

33 6 6 f 

-- 381 -- 

p-(N-morphol ino-CH2CH20)-benzy 1, benzo [b] thiophen-2-y 1, 

5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 

6-methoxynaphth-2-yl, -CH2CH2SCH3, thien-2-yl and thien-3-yl.
94. The compound according to Claim 83 wherein Y is hydroxy, alkoxy, substituted alkoxy and -NR'R".
95 The compound according to Claim 94 wherein Y is selected from 10 the group consisting of methoxy, ethyoxy, n-propoxy, /so-propoxy, /i-butoxy, iso-butoxy, r-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-/i-propoxy, 4-bromo-n-butoxy, amino (-NH2), 

-NH(wo-butyl), -NH(sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, 15 N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, 

-NH-methallyl, -NHCH2-(furan-2-yl), -NHCH2-cyclopropyl, -NH(r-butyl), -NH(p-methy lphenyl), -NHOCH3, -NHCH2(p-fluorophenyl), -NHCH2CH2OCH3, -NH-cyclohexyl, -NHCH2CH2N(CH3)2, -NHCH2C(CH3)3, -NHCH2-(pynd-2-yl), -NHCH2-(pyrid-3-yl), -NHCH2-(pyrid-4-yl), N-thiazolindinyl, 20 -N(CH2CH2CH3)2, -NHOH, -NH(p-N02-<A), -NHCH2(p-N02-<*>), 

-NHCH2(m-N02-<*>), -N(CH3)OCH3, -N(CH3)CH2-<*>, -NHCH2-(3,5-difluoropheny 1), -NHCH2CH2F, -NHCH2(p-CH30-</>), -NHCH2(m-CH30-<£), -NHCH2(p-CF3-0), -N(CH3)CH2CH2OCH3, -NHCH2CH20, -NHCH(CH3)<fr, -NHCH2-(p-F-<£), -N(CH3)CH2CH2N(CH3)2 and -NHCH2-(tetrahydrofuran-2-yl). 

25 

30
96. The compound according to Claim 83 wherein the heterocyclic structures defined by W and X are selected from the group consisting of 4,5-dihydrothiazoles, 3,4-dihydro-1,3-isodiazoles, 3,4-dihydro-3-N-t-butoxy-3-isodiazoles, and 4,5-dihydrooxazoles. 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

- 382 -- 

336e1
97. The compound according to Claim 83 wherein said compound of formula V and VI are selected from the group consisting of 

10 

(4R)-4-[N-( ISM 1 -methoxycarbonyl-1 -pheny l)methyl]carbamoy l-2-(3,5-difluorophenylmethyl)-4-methyl-2-thiazoline 

4-[jV-(S)-( 1 -methoxycarbonyl- l-phenyl)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-2-thiazoline; and 

4-[jV-(S)-( 1 -methoxycarbonyl-1 -pheny l)methyl]carbamoyl-2-(3,5-difluorophenylmethyl)-4-methyl-2-imidazoline. 

15 

20 

25
98. A compound selected from the group consisting of compounds of formula VII and VIII 

Vll 

30 

35 

40 

VIII 

wherein R1, R\ R6, T', X', X", W and X are as defined in claim 52; 

W\ together with -C(H)SC(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substimted cycloalkenyl group wherein intellectual property office of n.z. 

2 2 AUG 2001 

-- 383 -- 

each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fused rings) with one or more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, 

structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, 

10 substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(0)R10, -NHS02R10, -C(0)NH2, -C(O)NHRt0, -C(O)NR10R10, -S(0)R10, -S(0)2R10, -S(0):NHR10 and -S(O)2NRl0R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl; 

15 U is selected from the group consisting of oxo (=0), thiooxo (=S), 

5 heterocyclic, aryl and heteroaryl group which, in turn, each of such ring hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); s is an integer equal to 0 or 1; and t is an integer equal to 0 or 1. 

20
99. A compound selected from the group consisting of compounds of formula IX and X: 

25 

IX 

30 

U 

35 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

- 384 - 

wherein R\ R\ R6, T', X', X", W and X are as defined in claim 52; 

W', together with -C(H),C(=U)-, forms a cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl, or substituted cycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkyl or substituted cycloalkenyl group is optionally fused to form a bi- or multi-fused ring system (preferably no more than 5 fased rings) with one or.more ring structures selected from the group consisting of cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which, in turn, each of such ring structures is optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxyl, halo, alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino, N,N-dialkylammo, N-substituted alkylamino, N-alkyl N-substituted alkylamino, N,N-disubstituted alkylamino, -NHC(0)R10, -NHS02R'°, -C(0)NH2, -C(0)NHR10, -C(O)NRl0R10, -S(0)Rl°, -S(0)2R10, -S(0),NHR10 and -S(O)2NR10R10 where each R10 is independently selected from the group consisting of alkyl, substituted alkyl, or aryl; 

U is selected from the group consisting of oxo ( = 0), thiooxo (=S), hydroxyl (-H, -OH), thiol (H,-SH) and hydro (H,H); 

s is an integer equal to 0 or 1; and x is an integer equal to 0 or 1. 

intellectual property office of n.z. 

11 AUG 2001 

received 

3366 

- 385 -
100. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of Claims 52 - 99.
101. A use as defined in any one of claims 1, 2 and 3 substantially as herein described with reference to any example thereof.
102. A use as claimed in any one of claims 49, 50 and 51 substantially as herein described with reference to any example thereof.
103. A compound as defined in claim 52 substantially as herein described with reference to any example thereof.
104. A compound as claimed in claim 98 or claim 99 substantially as herein described with reference to any example thereof.
105. A pharmaceutical composition as claimed in claim 100 substantially as herein described with reference to any example thereof. 

intellectual property office of n.z. 

2 2 AUG 2001 

received 

END 



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