HIV PROTEASE INHIBITORS CONTAINING GUANIDINE

Abstract: Compounds of formula (I) wherein R<1> and A are amino terminal groups: Z is O or N-R<2>; M is a dipeptide isostere; and D1 and D2 are optionally absent or amino acids; and pharmaceutically acceptable salts thereof, are potent inhibitors of the HIV-1 protease and are useful in the treatment of viral diseases such as Acquired Immune Deficiency Syndrome (AIDS).

Description: TITLE HIV PROTEASE INHIBITORS CONTAINING GUANIDINE. FIELD OF THE INVENTION This invention relates to inhibitors of proteases encoded in retroviruses, in particular, to inhibitors cf the virally encoded protease of the Human Immunodeficiency Virus BACKGROUND Retroviruses, that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than deoxyribonucleic acid. Also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals. They are believed to be the causative agents in pathological states associated with infection by Rous sarcoma virus (RSV) , murine leukemia virus (MLV) , mouse mammary tumor virus (MMTV) , feline leukemia virus (FeLV) , bovine leukemia virus (BLV) , Mason-Pfizer monkey virus (MPMV) , simian sarcoma virus (SSV) , simian acquired immunodeficiency syndrome (SAIDS) , human T- lymphotropic virus (HTLV-I, -II) and human immunodeficiency virus (HIV-1, HIV-2) , which is the etiologic agent of AIDS (acquired immunodeficiency syndrome) and AIDS related complexes, and many others. Although the pathogens have, in many of these cases, been isolated, no effective method for treating this type of infection has been developed. Current treatments for retroviral diseases generally involve administration of compounds which inhibit reverse transcriptase, such as 3'-azido-3'-deoxythymidine and 2',3'- dideoxycytidine. These treatments have proven useful to reduce viral titers and retard the disease process, but, in general, have not proven useful to arrest or reverse the disease. In addition, they may have adverse side effects, and lose their efficacy over time. Accordingly, new treatments for viral disease are needed. Virally-encoded proteases function in many retroviruses to hydrolyze viral polyprotein precursors and to yield functional viral proteins. The proteolytic activity provided by the virally-encoded protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus. It has been demonstrated that retroviruses which lack a protease or contain a mutated form of it, lack infectivity. See Katoh et al . , Virology, 145, 280-92(1985), Crawford et al . , J. Virol . , 53, 899-907(1985) and Debouck et al . , Proc. Natl . Acad. Sci . USA, 84, 8903-6(1987) . Inhibition of retroviral protease, therefore, presents a method of therapy for retroviral disease. Methods to express retroviral proteases in E. coli have been disclosed by Debouck et al., Proc. Natl . Acad. Sci . USA, 8903-06 (1987) and Graves et al. r Proc. Natl . Acad. Sci . USA, 85, 2449-53 (1988) for the HIV-1 virus. The crystal structure of an HIV-1 protease has been disclosed by Miller et al . , Science, 246, 1149 (1989) . The method of isosteric replacement has been disclosed as a strategy for the development of protease inhibitors for HIV-1. Published European Patent applications EP-A 337 714, EP-A 352 000 and EP-A 357 332, EP-A 346 847, EP-A 342 541 and EP-A 393 445 are .representative. Similar strategies have also been reported for inhibition of renin in U.S. Patents 4,713,445 and 4,661,473. Other inhibitors of the HIV protease, which contain a symmetrical isostere are reported in EP-A 402 646. There remains a need for protease- inhibiting compounds which have a favorable balance of potency and pharmacokinetic properties. SUMMARY OF THE INVENTION This invention comprises compounds, hereinafter, of the formula (I), which inhibit the retroviral protease of HIV-1, and are useful for treating infection by the human immunodeficiency virus and Acquired Immunodeficiency Syndrome (AIDS) . This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier. This invention further constitutes a method for treating retroviral disease, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) - • DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are given by formula ( I ) : (I) wherein ■ R 1 is R 7 , R 7 C0, R 7 0C0, R 7 OCH(R 8 )CO or A-NR'CH (R 5 ) CO; Z is O or N-R 2 , where R 2 is H, CN or R'CO; Di and V>2 are or are absent; Q 1 , Q 2 and Q 3 are H, NH 2 or OH; V is N or C; Y is N, O or S; R 3 and R 4 are H or Ci-βalkyl, C 2 -6alkenyl, C3- 7 cycloalkyl, T, T-Ci-βalkyl, T-C2-6alkenyl or T-C3_ 7 cycloalkyl, optionally substituted with R 16 ; T is Ar, Het or C3- 7 cycloalkyl; R 5 and R 6 are Cχ- 6 alkyl, (CHR')n-T or (CHR')p-U, where U is NR' 2 , SR', OR', imidazole or CONR'2/ R 7 and R 8 are independently H, Cι_galkyl, C3- 7 cycloalkyl, T-(CHR 13 ) ra -, T-(CH 2 ) m CH(T) (CH 2 ) m ; R 9 is 0, S or (H,H) ; R' is H, Cχ- 4 alkyl or CH 2 Ph; k is 0 or 1; m is 0-6; n is 0-2; p is 1-4; A is H, or Ar, Het, R 10 (R 1:L R 12 C) m , Ar- , Het-W or R 10 (R 11 R 12 C) m —W, optionally substituted by one to three groups chosen from R 13 or Ci-βalkyl-R 13 ; is C=0, OC(=0), NR'C(=0), SC(=0) , NR * C(=S), SO, SO 2 , NR 8 Sθ 2 or P(=0) (OR 1 ^) ; R 10 , R 11 and R 12 are independently: i) H, R 13 or Cι_ 4 alkyl, C2-6alken l, phenyl, naphthyϊ, C3_6cycloalkyl or Het, each optionally substituted by one to three R 13 or R 13 -C 1 _ 6 alkyl groups, or ii) R 10 is as above and (R 11 R 12 C) are joined together to form a phenyl, naphthyl, C3_6Cycloalkyl or Het ring, or iii) R 10 is as above and R 11 and R 12 together are =0; R 13 is H, nitro, Cι_ 6 alkoxy, Cχ_ 6 alkylthio, 0(C=0)R 14 , C=0R 15 , C0 2 R 15 , CON(R 1 ) 2 , N(R 15 ) 2 , NHC(=N)NH-A, I, Br, Cl, F, OR 7 , or OH, provided that when R 13 is a substituent of the carbon adjacent to , R 13 is not halogen or OH when is 0C(=0) or NHCO; R 14 is H or C _ 6 alkyl; R 15 is H, C _ 6 alkyl, phenyl or phenyl-Cι_ 4 alkyl; R 16 is -X'-R\ -X'-(CH 2 ) q NR 17 R 18 , X" [ ( (CH 2 ) r O) s ]R 19 , CH2X" [ ( (CH 2 ) r 0) s ]R 19 , or benzofuryl, indolyl, azacycloalkyl, azabicyclo C 7 _ncycloalkyl or benzopiperidinyl, optionally substituted with Cχ_ 4 alkyl; q is 2-5; s is 1-6 and r is 1-3 within each repeating unit s; X' is CH 2 , 0, S or NH; X" is CH 2 , NR', 0, S, SO or S0 2 ; R 17 and R 18 are i) Cχ- 6 alkyl, optionally substituted by OH, Cχ_3alkoxy, or N(R') 2 , ϋ) the same or different and joined together to form a 5-7 member heterocycle containing up to two additional heteroatoms selected from NR, O, S, SO, S0 2 , said heterocycle optionally substituted with Ci-aalkyi, iii) aromatic heterocycle, optionally substituted with Cχ_ 4 alkyl or N(R' ) 2 ; R" is H or Ci-^alkyl; R 19 is H, Cι_ 4 alkyl, C(=0)R 20 , C (=0) U [ (CH 2 ) m 0] n R' / P (=0) (0M*) 2 , C0 2 R 20 , C(=O)NR 20 R 21 , where M * is a mono or divalent metal ion, and U is NR' or 0; R 20 is Cχ- 6 alkyl or Ar, optionally substituted with one or more hydroxy, carboxy, halo, Cχ_3alkoxy, C0NR' 2 , NR' 2 , C0 2 R', S0 2 NR' 2 , CH 2 NR 2 , NR'COR", NR'S0 2 R', X" [ (CH 2 ) r 0] S R' or CH 2 X" [ ( CH 2 )rO]s R ' ; and R 21 is H, Cχ_ 6 alkyl or together with R 20 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, O and S; or a pharmaceutically acceptable salt thereof. Suitably Z is NH. Suitably M is Suitably R 1 is H, R 7 CO or R 7 OCO. Suitably R 7 is Cχ-6alkyl or Ar-CH 2 or Het-CH2- In particular, R 1 is H, pyridylmethyloxycarbonyl, benzyloxycarbonyl or butyloxycarbonyl. Suitably R 3 and R 4 " are Cχ-6alkyl, Ar-Cχ_ 4 alkyl, Ar-C2- 4 alkenyl or Ar-C 2 - 4 alkynyl, optionally substituted by R 13 . Preferably R 3 and R 4 are benzyl. Suitably R 5 is Cχ-6alkyl and Jx is NH. Suitably Dx is Ala. Preferably Dx and D2 are absent. Preferably R 6 is Cχ-6alkyl and J 2 is NH. Most favorably, E is (S)-Val. Preferably Q 1 is OH. Suitably Q 2 or Q 3 is H. Preferably Q 2 and Q 3 are both H. Suitably A is H or R 10 (R 1:L R 12 C) m - , optionally substituted by one to three groups chosen from R 13 or Cχ-6alky1-R 13 ; and is 0 or OCO. For instance, A is H, methyl, acetyl, benzoyl, butyloxycarbonyl, benzyloxycarbonyl, 3-quinolinylmethyl-oxycarbonyl or pyridinylmethyloxycarbonyl. Preferably, A is butyloxycarbonyl or benzyloxycarbonyl. Representataive compounds of this invention are: N-benzyloxycarbonyl, N'-[ (2R,4S,5S)-2-phenylmethyl-4- hydroxy)-5- (t-butyloxycarbonyl)amino-6-phenylhexanoyl- (S) - valyl]-guanidine; N-[ (2R,4S,5S>-2-phenylmethyl-4-hydroxy)-5-(t-butyloxy¬ carbonyl)amino-6-phenylhexanoyl-(S)-valyl]-guanidine; N-acetyl, N'~[ (2R,4S,5S)-2-phenylmethyl-4-hydroxy-5- (t-butyloxycarbonyl)amino-6-phenylhexanoyl-valyl]-guanidine; N-t-butyloxycarbonyl, N*-[ (2R, S,5S)-2-ρhenylmethyl-4- hydroxy-5-(t-butyloxycarbonyl)amino-6-phenylhexanoyl-(S)- valyl]-guanidine; N-methoxycarbonyl, N l -[ (2R, S,5S)-2-phenylmethyl-4-hydroxy-5- (t-butyloxycarbonyl)amino-6-phenylhexanoyl-(S) -valyl]- guanidine; N-(4-pyridyl)methyloxycarbonyl, N'-[ (2R, S, 5S)-2- phenylmethyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6- phenylhexanoyl- (S)-valyl]-guanidine; N-benzyloxycarbonyl, N'- [ (2R, 4S, 5S) -2-methyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoy1- (S) -valyl]- guanidine; and N-benzyloxycarbonyl, N'- [ (2R, 4S, 5S)-2-propyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (S) -valyl]- guanidine. Preferred compounds are N-benzyloxycarbonyl, N' " - [ (2R, 4S, 5S) -2-phenylmethyl-4-hydroxy) -5- (t-butyloxy¬ carbonyl)amino-6-phenylhexanoyl- (S) -valyl]-guanidine, and N- (4-pyridyl)methyloxycarbonyl, N'- [ (2R, 4S, 5S) -2-phenylmethyl- 4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (S) - valyl]-guanidine; According to this invention, it has been found that a moiety of the formula -NH-C(=N-Z)NHR 1 constitutes a surprisingly useful substituent for incorporation into HIV-1 protease inhibitors based upon the non-hydrolyzable dipeptide isostere concept. When this substituent is located in the P3 ' position in a mimetic of a peptide substrate for the HIV-1 protease enzyme, greatly enhanced potency is realized. The compounds of this invention have favorable pharmacokinetic properties, and are useful, in particular, for the treatment of infections by the human immunodeficiency virus . Also included in this invention are pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo . The definition of any substituent moiety which may occur more than once in formula (I) is independent of any other occurrence. Formula (I) is intended to encompass all unique nonracemic stereoisomers which may occur due to the presence of asymmetric carbon atoms in the molecule. Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three Cχ_ 4 alkyl, Cχ_ 4 alkoxy, Cχ_ 4 alkthio, trifluoroalkyl, guanidino, amidino, hydroxyCχ_ 4 alkyl, amino, mono- or di-Cχ_ 4 alkylamino, carboxy, amino-Cχ- 4 alkyl, Cχ_galkoxycarbonyl, aminocarbonyl, carboxyCχ_6alkyl, aminocarbon lCχ- 6 alky1, alkoxycarbonylCx-βalkyl, HetCχ_ 4 alkoxy, HetCχ_ 4 alkyl, OH, Cl, Br or I. Het, or heteroaryl, indicates a five membered ring containing 0-2 double bonds, or a six membered ring containing 0-3 double bonds, or a nine membered ring containing 0-4 double bonds or a ten membered ring containing 0-5 double bonds, each ring having one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which, are stable and available by conventional chemical synthesis. Illustrative heterocycles are orpholine, tetrazole, imidazole, benzimidazole, pyrrole, indole, pyridine, pyrimidine, pyrimidone, quinoline, benzofuran, furan, benzothiophene or thiophene. The Het ring may optionally be substituted on the carbon or heteroatom by one to three Cχ_ 4 alkyl, C 2 - 4 alkenyl, Cχ_ 4 alkoxy, Cχ_ 4 alkthio, trifluoroalkyl, guanidino, amidino, amino, mono- or di- Cχ_ 4 alkylamino, amino-Cχ- 4 alkyl, hydroxyCχ_ 4 alkyl, aminocarbonyl, Cχ_ 6 alkoxycarbonyl, carboxy, carboxyCχ_gaikyl, aminocarbonylCχ_ 6 alkyl, alkoxycarbonylCx-βalkyl, or a phenylCx-ςalkyl group substituted by one to three Cχ_ 4 alkyl, Cχ- 4 alkoxy, Ci-aalkthio, trifluoroalkyl, OH, F, Cl, Br or I grou s. C3- 7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalklyl ring may be optionally substituted by one to three Cχ- 4 alkyl, Cχ- 4 alkoxy, Cχ_ 4 alkthio, trifluoroalkyl, guanidino, amidino, hydroxyCχ_ 4 alkyl, amino, mono- or di-Cχ_ 4 alkylamino, carboxy, amino-Cχ_ 4 alkyl, Cx-ςalkoxycarbonyl, aminocarbonyl, carboxyCχ_6alkyl, aminocarbonylCχ-6alkyl, alkoxycarbonylCχ_6alkyl, Ar-Cχ_6alkyl, HetCχ_4alkoxy, HetCχ_ 4 alkyl, OH, Cl, Br or I. Any accessible combination of up to three substituents on the phenyl, naphthyl, C3_6cyc oalkyl or Het ring which is available by conventional chemical synthesis and is stable are within the scope of this invention. C _ alkyl as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl. Ci-g lkyl includes, additionally, pentyl, isopentyl and hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1- methylpentyl, 2-ethylbutyl, and 1-ethylbutyl. C2-6 l enyl as applied herein means C2-6 a Uyl wherein one carbon-carbon single bond is replaced by a carbon-carbon double bond. C2-6 a lkenyl includes ethylenyl, propenyl, butenyl, pentenyl, hexenyl and the isomers thereof. C 2 -6 alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. C 2 - 6 alkynyl includes acetylene, propyne, butyne, pentyne, hexyne, and the isomers thereof. Ar-C _galkyl, Ar-C2-6 a lkenyl and Ar-Cχ- 6 alkynyl mean Ci-galkyl, C2-ςalkenyl or Ci-ςalkynyl wherein a carbon- hydrogen bond is replaced by a carbon-Ar bond. Het- C ] __5alkyl, Het-C2- β alkenyl and Ar-Ci-βalkynyl mean Cχ_galkyl, C2-6al enyl and Ci-βalkynyl wherein a carbon-hydrogen bond is replaced by a carbon-Het bond. Halogen indicates a fluorine, chlorine, bromine and iodine atom. M* indicates a mono- or divalent alkaline or earth metal ion, such as potassium, sodium, lithium, calcium or magnesium. Azacycloalkyl indicates a C3- 7 cycloalkyl group wherein a carbon atom is replaced by a nitrogen atom, such as aziridine, azetidine, pyrrolidine, piperidine or tetrahydroazepine . Azabicyclo-C 7 -χχcycloalkyl indicates a C 7 -ncycloalkyl group wherein one of the carbon atoms is replaced by a nitrogen atom. C 7 _χicycloalkyl indicates a stable mono- or bi-cyclic ring of 7 to 11 carbon atoms, which may be saturated or unsaturated, and may be substituted with one to three Cχ- 4 alkyl, Cχ- 4 alkoxy, Cχ- 4 alkthio, trifluoroalkyl, guanidino, amidino, OH, NR' , Cl, Br or I groups. C 7 -χicycloalkyl includes cycloheptyl, cyclooctyl, tetralinyl, indanyl, phenyl and naphthyl. Amino acid means the D- or L- isomer of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, ' isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine. Typically Dx and D2, if present, and E, may be amino acids. Usually lipophilic amino acids of the L-configuration are preferred, for instance, Ala and Val. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984). When E is an amino acid it is attached to the carbonyl of the isostere through its amino terminus. When Dx is an amino acid it is attached to the amino group of the isostere through its carbox 1 terminus. Boc refers to the t-butyloxycarbonyl radical, Cbz refers to the benzyloxycarbonyl radical, Bzl refers to the benzyl radical, Ac refers to acetyl, Ph refers to phenyl, EDTA is ethylenediamine tetraacetic acid, DIEA is diisopropyl ethylamine, DBU is 1,8 diazobicyclo[5.4.0]undec-7-ene, DMSO is dimethylsulfoxide, DMF is dimethyl formamide, MeOH is methanol, pyr is pyridine, DMAPEC is 1- (3-dimethylamino- propyl)-3-ethylcarbodiimide hydrochloride, DMAP is 4- dimethylamino pyridine, DTT is dithiothreitol, HOBT is N- hydroxy-benzotriazole, EDTA is ethylenediamine tetraacetic acid, DIEA is diisopropyl ethylamine, Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-1,3-dithia-2, 4-diphosphetane-2,4- disulfide, NMM is N-methylmorpholine, TBAF is tetrabutyl ammonium fluoride, and THF is tetrahydrofuran. DCC refers to dicyclohexylcarbodiimide, BOP refers to benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate, PPA refers to 1-propanephosphonic acid cyclic anhydride, and EDC refers to N-ethyl-N' (dimethylaminopropyl)-carbodiimide. When compounds of formula (I) are administered to an animal infected or potentially infected with a virus, which is dependent upon a virally encoded protease for processing of viral polyproteins, viral replication is inhibited, hence, disease progression is retarded. The compounds of this invention are prepared by conventional methods of organic chemistry. The compounds of formula (I) : (I) may be prepared by: (1) reacting a compound of the formula: A-Dι-D 2 -M-OH (ID wherein A, Dχ f D 2 and M are as defined for formula (I) , with any reactive groups protected, with a compound of the formula: H 2 NC(=Z)NR'-R 1 wherein Z, R' and R 1 are as defined for formula (I), and a coupling reagent, and optionally removing any protecting groups, or (2) reacting a compound of the formula: ' H-Dχ-D2-M-NR'C (=Z)NR'R 1 wherein Dx, D 2 , M, Z, R' and R 1 are as defined for formula (I) , with any reactive groups protected, with a compound of the formula : A-L' wherein A is as defined for formula (I) and L' is a leaving group, such as halogen or OH, and, if necessary, a coupling reagent if necessary, and optionally removing any protecting groups . Coupling reagents which are used to couple an amino group with a carboxyl group are well known in the art, such as DCC and other carbodiimides, DMAPEC, BOP and PPA, and they may optionally be used with other reagents, such as HOBT, NMK and DMAP, which may facilitate the reaction. Coupling reagents may be also be reagents which are used to convert a poor leaving group, such as OH, to an activated ester or a halogen. Thionyl chloride or bromide, oxallyl chloride, or phosphorousoxychloride may be used to form a halogen leaving group; and nitrophenol, N-hydroxy-succinimide and HOBT may be used to form an activated ester. Suitable protecting groups for the amino and hydroxyl group, and reagents for deprotecting these functional groups are disclosed in Greene et al . , PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Second Edition, John Wiley and Sons, New York, 1991. Deprotection indicates the removal of the protecting group and replacement with an hydrogen atom. In particular, suitably substituted acetyl and silyl groups are useful for protecting the hydroxyl group. The acetyl group is commonly removed by reacting the compound with a base, such as an alkali metal hydroxide, in a mixture of an alcohol and water. The silyl group, such as trimethyl silyl, dimethyl-t-butyl silyl, and t-butyl-diphenyl silyl may be removed by a fluoride reagent, such as a tetra-alkyl ammonium fluoride, or by acid hydrolyis. Suitable protecting groups for the amino group are those disclosed by Greene et al . , as indicated previously. The benzyloxycarbonyl and t-butoxycarbonyl groups are especially useful amino protecting groups. If the protecting group is not the desired group R 1 , the protecting group may be removed, and the amino group may be alkylated or acylated to append the desired group as described hereinafter. Compounds of formula (II), wherein M is , are prepared according to Scheme 1, by either reacting a compound of formula (IV) .with a compound of formula (V), and a coupling reagent; or reacting a compound of formula (VI) with a compound of formula (VII) , and coupling reagent, wherein A, Dχ D2, E, Q 1 , Q 2 , Q 3 , R 3 and R 4 are as defined in formula (I) , with any reactive groups protected, and J 2 is NH or O. Scheme 1 (VI) (VII) The isostere adducts (IV) and (VII) are similarly prepared by coupling reactions to add the A-Dχ-D 2 - and -E moieties respectively. Methods for preparing the isostere (VIII) (VIII) , where R 30 and R 31 are H, or amino and carboxyl protecting groups respectively, are well known to the art . For instance, methods for preparing protected 5-aιr.inc-4- hydroxy-2, 5-disubstituted-pentanoate esters and acids cf the general structure (IX) , and the corresponding γ-lactoneε (X) , are disclosed by Szelke et al . , U.S. Patent 4,713,455; Boger et al., U.S. Patent 4,661,473; Dreyer et al . , EP-A 0 352 000; Evans et al., J. Org. Chem. , 50, 4615 (1985); Kempf, J. Org . Chem. , 51, 3921 (1986); Fray et al . , J. Org. Chem., 51, 4828 (1986) ; Halladay et al., Tett . Lett., 24, 4401 (1983) ; Wuts et al., J. Org. Chem., 53, 4503 (1988); and Szelke et al . , WO 84/03044, all of which are incorporated herein by reference. Methods for preparing protected 5-amino-3, 4-dihydroxy- 2,5-disubstituted-pentanoate esters and acids of the general structure (XI) , have been disclosed, for example, by (XI) Thaisrivongs et al. , J. Med. Chem. , 30, 976 (1987) , WO87/05302 and WO89/01488, which are incorporated herein by reference . Methods for preparing protected 5-amino-2, 4-hydroxy-2 , 5- substituted esters and acids of the general formula (XII) , (XII) have been disclosed by Metternich et al., Tet . Lett . , 29, 3923 (1988), and Dellaria et al., WO 87/04349, which are incorporated herein by reference. Methods for preparing protected 4, 5-diamino-2,5- disubstituted acids and esters of the general formula (XIII) , (XIII) have been disclosed in WO87/02986 and WO89/0374, which are incorporated herein by reference. Compounds wherein Q 1 is amino may also be prepared from the corresponding 4-hydroxy intermediate by methods common in the art for converting a hydroxyl group into an amino group, such as by oxidation of the hydroxyl group, and subsequent reductive amination. For example, the alcohol may be oxidized via the Swern method, with DMSO, trifluoroacetic anhydride and triethylamine in methylene chloride solution, and the corresponding ketone reduced with sodium cyanoborohydride and ammonium bromide in an alcohol/water solution. Compounds of formula (II) wherein M is are prepared from the corresponding compound (XIV) : wherein the heterocyclic ring is derived from the carboxyl group of the isostere (IX), previously described. For instance, a hydroxyethylene isostere of formula (X) or (XI) , above, may be converted to a heterocycle via a thioamide, which may be prepared according to Scheme 2. Scheme 2 (XXI) (XXII ) To prepare a thiazole, wherein W is S and V is C, the thioamide may be reacted according to Scheme 3. Accordingly, Scheme 3 (XXII) (XXIII) the thioamide (XXII) is reacted with N, -dimethylformamide dimethyl acetal to yield the thioamidino intermediate (XXIII) . This intermediate is subsequently reacted with a suitably substituted halomethyl carbonyl reagent of the formula, RCO-CH 2 -X, where X is a displaceable group such as halogen and R is a carboxylate ester or a group which may be converted by common synthetic methods into a carboxylic acid, to yield the corresponding 5-acyl thiazole. If R 30 is a protecting group, but is not the desired substituent A-Dχ-D2~, R 30 may be removed and the desired substituent may be appended by common methods of acylation or alkylation as described hereinafter. Typical halomethyl carbonyl reagents useful in the reaction are chloroacetaldehyde, iodoacetamide, methyl 3- bromopyruvate and the like. Hydrolysis or oxidation, as appropriate, yields the corresponding thiazole carboxylic acid. The halomethyl carbonyl compounds, RCO-CH2-X, of this invention are commercially available or available by common synthetic methods. Compounds of formula (XIV), wherein W is N-R' and V is CH, are imidazoles and are prepared according to Scheme 4. Scheme 4 (XXV) (XXVII) (XXVIII) Preparation of the substituted thioamide (XXV) proceeds according to Scheme 3, where R 22 is a protecting group or an incipient imidazole substituent . The thioamide (XXV) is treated with an alkylating agent, such as methyl iodide, to yield a thioimide (XXVI), which is further reacted with ammonium acetate to yield the substituted amidine (XXVII) . Reaction of the amidine with a halomethyl ketone of the ' formula R-CO-CH 2 -X, wherein X is a suitable displaceable group and R is a carboxylate ester or a group which may be converted by common synthetic methods into a carboxylic acid, causes cyclization to yield the imidazole ring. Methyl 3- bromopyruvate is a suitable reagent for producing the 4- substituted imidazole, which may be hydrolyzed to yield a carboxylic acid. An alternate method for preparing the imidazoles of formula (XIV) is given by Scheme 5. An amino-protected, hydroxy-protected isostere, such as the protected Scheme 5 (XXXIV) (XXXIII) hydroxyethylene isostere (X) , is coupled to a 3-substituted- 4-amino-isoxazole (XXXI) to yield an acylaminoisoxazole (XXXII) , wherein R 24 is hydrogen or an incipient acyl substituent capable of being converted to a carboxylic acid and R 25 is a hydroxyl protecting group, such as the t-butyldimethylsilyl group. Hydrogenation of the isoxazole yields an iminoketone, which may be cyclized under basic conditions to yield an acylimidazole. If R 24 is a substituent such as hydrogen, the product is a 3-formyl-imidazole, which may be oxidized to a carboxylic acid, and optionally protected, to yield a compound of formula (XXXIV) . A compound of formula (III) wherein W is NH and V is N is a triazole and is prepared according to Scheme 6. Scheme 6 (XXI) (XLI) (XLII) Carboxamide (XXI), prepared as described in Scheme 2, is treated with a substituted dimethylamide dimethyl acetal (XL) , wherein R 25 is a substituent which may be converted into a carboxylic acid, to yield the carboximidate (XLI) . The carboximidate is subsequently treated with hydrazine which, in the presence of an acid, cyclizes to yield the triazine ring. Conversion of the substituent R 25 to a carboxylic acid completes the preparation of a compound of formula (XIV) , wherein V and Y are nitrogen. If a group other than the protecting group is desired for the moiety A-Dχ-D 2 ~, then the protecting group R 30 is removed and the amino group is reacted with an appropriate alkylating or acylating reagent. Alkyl halideε, acyl halides, sulfonyl halides, anhydrides, activated esters, and the like, of the appropriate group A, A-Dχ or A-Dχ-D 2 are useful for this purpose. Alternatively, a suitable carboxylic acid may also be used with an appropriate coupling reagent . If a final compound (I) of this invention contains a basic group, an acid addition salt may be prepared. Acid addition salts of the compounds are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. If the final compound contains an acidic group, cationic salts may be prepared. Typically the parent compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation. Cations such as Na + , K + , Ca ++ and NH + are examples of cations present in pharmaceutically acceptable salts . Certain of the compounds form inner salts or zwitterions which may also be acceptable. The compounds of formula (I) are used in the manufacture of a medicament to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatment . The method of treatment comprises the administration orally, parenterally, buccally, trans- dermally, intra-vaginally, rectally or by insufflation, of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical carrier. Dosage units of the active ingredient are generally selected from the range of 0.1 to 25 g/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic infection. The compounds of this invention are particularly useful for the treatment of HIV-1. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention. Pharmaceutical compositions of the compounds of this invention, or derivatives thereof, may be formulated as- solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a etered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternately, these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solubilizing agents, such as dimethylsulfoxide, ethanol or formamide, may also be added. Carriers, such as oils, optionally with solubilizing excipients, are especially suitable. Oils include any natural or synthetic non-ionic water-immiscible liquid, or low melting solid, which is capable of dissolving lipophilic compounds. Natural oils, such as triglycerides are representative. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule. A suitable dosage form for oral administration may be prepared by dissolving the peptide of Example 1 (312.5 mg) in dimethyl sulfoxide (1 mL) and diluting to a concentration of 12.5 mg/mL with soybean oil. A suitable dosage form for intravenous administration may be prepared by dissolving the compound of Example 1 (0.02 g) in dimethyl sulfoxide (1 mL) and diluting to 20 mL with a 70% propylene glycol/30% ethanol solution. Dosing may be adjusted by varying the volume of administration or the initial quantity of drug dissolved in the carrier. For intra-vaginal or rectal administration, a pulverized powder of the compounds of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository. The pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch. These and other pharmaceutically acceptable formulations are found in REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Edition, Alfonso R. Gennaro (ed.), Mack Publishing Company, Easton, Pennsylvania (1990) . Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of this invention. Examples of anti-viral agents include nucleoside analogues, phosphonoformate, rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen. Nucleoside analogues, which are reverse transcriptase inhibitors and include 2',3'- dideoxycytidine(ddC) , 2*,3'-dideoxyadenine(ddA) and 3'-azido- 2',3'-dideoxythymide(AZT) , are especially useful. AZT is one preferred agent. Suitably pharmaceutical compositions comprise an anti-viral agent, a protease inhibiting compound of this invention and a pharmaceutically acceptable carrier. The protease inhibiting properties of the compounds of this invention, are demonstrated by their ability to inhibit the hydrolysis of a peptide substrate by rHIV protease in the range of about 1 to 1000 nM, preferably less than 100 nM. The compound of Example 1 shows an IC 50 of less than IG nM. The Examples which follow serve to illustrate this invention. The Examples are intended to in no way limit the scope of this invention, but are provided to show how to make and use the compounds of this invention. ENZYME ACTIVITY The ability of the compounds of this invention to inhibit the HIV—1. protease enzyme may be demonstrated by using the assay disclosed by Dreyer et al . , Proc. Natl . Acad. Sci. , U.S.A. , 86, 9752 (1989), Grant et al . , Biochemistry, 30 8441 (1992), and EP-A 352 000. The Ki for the compounds of this invention are in the range of about 0.1 nM to about 2.5 μM. Preferred compounds have Ki of less than 0.5 μM. Preferred compounds have Ki of less than 1 nM. INFECTIVITY The ability of the compounds of this invention to gain entry to cells infected with the human immunodeficiency virus, and to inhibit viral replication in vitro may be demonstrated using the assay described by Meek et al . , Nature, 343, 90 (1990), and Petteway et al . , Trends Pharmacol . Sci, 12, 28 (1991) . Representative IC50 for the compounds of this invention are in the range of about 1 nM to about 20 μM. Preferred compounds have IC50 of less than 20 nM. The Examples which follow serve to further illustrate this invention. The Examples are intended to in no way limit the scope of this invention, but are provided to show how to make and use the compounds of this invention. In the Examples, all temperatures are in degrees Centigrade. RT indicates room temperature. FAB indicates fast atom bombardment mass spectrometry. ESMS indicates electrospray ionization mass spectrometry. NMR were recorded at 250 MHz using a Bruker AM 250 spectrometer. Celite® is filter aid composed of acid washed diatomaceous silica, and is a registered trademark of Mansville Corp., Denver, Colorado. ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. Microsorb is a silica gel packing made by Rainin Instruments Co, Woburn, Mass., having a nominal particle size of 5μ. Zorbax is a silica gel or octadecylsilyl silica gel packing, having a nominal particle size of 5μ, manufactured by the DuPont Corp., Wilmington, Delaware. Multiplicities for NMR spectra are indicated as: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets etc. and br indicates a broad signal. PREPARATION OF INTERMEDIATES Preparation 1 Preparation of (2R, 4S, 5S) -2-propyl-4- (t-butyldimethyl siloxy 5 (t-butyloxy-carbonyl) amino-6-phenylhexanoic acid a) t-butyloxycarbonyl-phenylalanine N,0-dimethylhydroxyl- a ide N-methyl piperidine (24.4 ml, 0.206 mol) was added via addition funnel to a stirring suspension of N,0- dimethylhydroxylamine hydrochloride (19.56 g, 0.2 mol) in methylene chloride (118 mL) at 0°C, forming a clear solution, A. Boc-phenylalanine (53 g, 0.2 mol), THF (230 mL) and methylene chloride (900 mL) were combined and cooled to -20°C, and N-methyl piperidine (2 .4 mL) was added dropwise with stirring. Methyl chloroformate (15.5 mL, 0.2 mol) was then added rapidly via addition funnel with good stirring, the temperature being maintained below -10°C. Two minutes later solution A was added. The solution was allowed to warm to room temperature with stirring overnight. The mixture was cooled to 5°C and extracted with two 250 mL portions of cold 0.2 N HC1, two 250 mL portions of 0.5 N NaOH, and 250 mL brine, the solution was dried over MgSθ 4 and concentrated to give the title compound (60.37 g) . [0C] 3 65 = 31° (c = 0.958, ethanol; 20°C) . b) t-butyloxycarbonyl-phenylalar.al To a fine suspension of LiAlH 4 (0.912 g, 24.0 mmol) in ether (80 mL) at -45°C under Ar was added a solution of the amide of Preparation 1(a) (6.16 g, 20.0 mmol) in ether (20 mL) in a steady stream. After 5 min the mixture was allowed to warm to +10°C over 30 min, then was recooled ' to -45°C and a solution of KHSO 4 (5.30 g, 39 mmol) in water (15 mL) was added cautiously with stirring. The cooling bath was removed and the thick mixture was stirred for 30 min. Ether (100 mL) and methylene chloride (100 mL) were added, the mixture was filtered through Celite®, and the filter cake was rinsed with 100 mL each of ether and methylene chloride. The filtrate was washed with three 50-mL portions of ice cold 1 N HC1, two 50-mL portions of ice cold 5% Na 2 C03, and 100 mL brine, then dried over MgS0 4 , filtered and concentrated by rotary evaporation at 30°C to provide the title compound as a white solid (4.18 g, 84%). mp: 82-83.5°C; [α] D = +35.3° (c=1.00, CH 2 C1 2 , 25°C) ; NMR(CDC1 3 ) : δ 9.62 (IH, s), 7.33-7.17 (5H, m) , 5.07 (IH, br) , 4.42 (IH, q) , 3.12 (2H, d) , 1.45 (9H, s) . c) (5RS, 6S)-7-phenyl-6- (tert-butyloxycarbonylamino) -5- hydroxyhept-1-ene A 200 mL flask fitted with reflux condenser under Ar was charged with dry ether (35 mL) and Mg turnings (2.16 g, 90 mmol) . 4-bromo-l-butene (7.61 mL, 75 mmol) was added over 25 min to a stirred suspension of Mg, causing vigorous reflux. After the reflux had subsided, the mixture was heated to gentle reflux for an additional 20 min, then cooled to 0°C. A solution of the aldehyde of Preparation 1(b) (5.26 g, 21.1 mmol) in dry toluene (40 mL) was added over 10 min. After 1.5 h at 0°C the clear, homogeneous reaction mixture was quenched cautiously with 3N HC1. The ether layer was separated, the aqueous layer was extracted once with ethyl acetate, the combined organic layers were washed with water and concentrated. The resulting yellow solid was dissolved in methanol (50 mL) and stirred with NaBHa (200 mg) for 10 min. The mixture was diluted with 3N HC1 and water, extracted with methylene chloride and concentrated. The residue was dissolved in a minimal volume of methylene chloride and purified by flash chromatography (150 g silica gel, 20%-40% ethyl acetate/hexane) to provide the title compound as a white solid (5.03 g, 78%) . d) (5S) - ( (1 'S) - (t-butyloxycarbonyl) amino-2 '-phenylethyl) - tetrahydrofuran-2-one To a solution of the alcohols of Preparation 1 (c) (5.00 g, 16.4 mmol) in ethyl acetate (50 mL) were added triethylamine (4.56 mL, 32.8 mmol), acetic anhydride (3.09 mL, 32.8 mmol), and 4-dimethylaminopyridine (50 mg, 0.41 mmol) . After 3 h excess ethanol was added, and several minutes later the mixture was washed with 3N HC1, 5% NaHCθ 3 , and water, and concentrated to a thick residue. The crude acetates were dissolved in benzene (35 mL) , and stirred rapidly at 0°C with water (35 mL) and acetic acid (7 mL) . Tetra-n-butylammonium bromide (160 mg, 0.5 mmol) and KMnθ (7.9 g, 50 mmol) were added. The mixture was allowed to warm to room temperature with vigourous stirring and intermittent cooling. After 2 h, the thick black mixture was cooled to 0°C and saturated aqueous NaHS0 3 (75 mL) was added. After 15 min stirring, the resulting white mixture was filtered through Celite®, the aqueous layer was separated and extracted with ether. The combined organic layers were washed with water and concentrated to a foam (6.9 g) . The resulting crude 4-acetoxy acids were dissolved in 100 L methanol and sodium methoxide (ca. 10 g) was added. The mixture was stirred at 25°C for two days then at 60°C for 18 h. The thick mixture was concentrated, diluted with methylene chloride and extracted with 10% HCl. The aqueous layers were extracted with methylene chloride, washed with water, dried over MgSθ 4 , and filtered. The resulting solution of 4-hydroxy acids was stirred with p-toluenesulfonic acid (80 mg) and several grams of 3 A molecular sieves for 24 h. The mixture was filtered through Celite® and concentrated to a thick oil. Flash chromatography (silica gel, 20%-30% ethyl acetate/hexane) provided the title lactone (2.59 g, 52% yield) . NMR(CDCl3) δ 7.25 (5H, m) , 4.68 (IK, d; J = 9.7 Hz), 4.47 (IH, dt) , 4.01 (IH, q), 2.91 (2H, m) , 2.51 (2H, m) , 2.14 (2H, m) , 1.38 (9K, s) . e) (3R,5S)-( (1'S)-(t-butyloxycarbonyl)amino-2'-phenylethyl)- 3-allyl-tetrahydrofuran-2-one To a solution of lithium diisopropyl amide (1.2 mL, 1.5 M solution) in tetrahydrofuran (1 mL) was added the lactone of Preparation 1(d) (0.250 g, 0.82 mmol) in anhydrous THF (2 mL) at -78°C. After stirring for 15 min at -78°C, hexamethyl-phosphoramide (0.285 mL, 1.64 mmol) was added to the solution. The solution was stirred for several min and allyl bromide (0.142 mL, 1.8 mmol) was added. After 2 h, the reaction mixture was quenched with a 10% solution of HCl and extracted with diethyl ether. The organic extracts were combined and evaporated to a clear oil. The oil was chromatographed (silica gel, 4:1 hexane:ethyl acetate) to give the title compound as a white foam. (0.175 g, 62%) . NMR(CDC13) δ 7.35-7.10 (5H, m) , 5.80-5.55 (IH, m) , 5.09 (IH, d) , 5.00 (IH, s), 4.62 (IH, d(br)), 4.45 (IH, dd) , 3.95 (IH, dd), 2.87 (2H, d) , 2.70 (IH, m) , 2.46 (IH, m) , 2.21 (2H, m) , 1.90 (IH, m) , 1.31 (9H, s); MS(DCI/NH3) m/z [M+NH4] + 363.3; 307.2; 290.2; 246.2; 154.1; 120.1. f) (3R, 5S)- ( (l'S)- (t-butyloxycarbonyl)amino-2 '-phenylethyl) - 3-propyl-tetrahydrofuran-2-one To a solution of the lactone of Preparation 1(e) (0.175 g, .507 mmol) in methanol (5 mL) was added 10% Pd on activated carbon (.020 g) . Hydrogen gas was bubbled through the solution for 1 h and the solution was then maintained under a hydrogen atmosphere for 12 h. The mixture was filtered through a pad of Celite® with methanol and the solvents evaporated to give the title compound as a white solid (0.166 g, 94%) . NMR(CDCl3) : δ 7.20-7.05 (5H, m) , 5.37 (IH, d) , 4.35 (IH, dd) , 3.70 (IH, dd) , 2.73 (2H, d) , 2.48 (IH, m) , 2.15 (IH, m) , 1.76 (IH, m) , 1.58 (IH, m) , 1.41-1.05 (12H, m) , 0.72 (3H, t) . g) (2R, 4S, 5S)-2-propyl-4- (t-butyldimethyi) siloxy-5 (t- butyloxycarbonyl) amino-6-phenylhexanoic acid The lactone of Preparation 1(f) (0.166 g, .45 mmol) was dissolved in 1,4-dioxane (2 mL) and distilled water (1 mL) . To this cloudy solution was added 1 N NaOH (0.523 mL, 1.1 eq.) dropwise over 5 min. The solution cleared after addition, and after 30 min the reaction was quenched with a 10% citric acid solution. The solution was extracted with diethyl ether and the combined organic extracts were washed with water, dried over magnesium sulfate, filtered, and evaporated to a white foam (0.197 g) . The white foam was stirred in dimethylformamide (1.5 mL) at 25°C, and tert-butyl dimethylsilylchloride (0.407 g, 5 eq.) and imidazole (0.367 g, 10 eq.) were added. The mixture was stirred under argon for 16 h, diluted with 10% aq. citric acid and extracted with diethyl ether. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and evaporated to an oil. The resultant oil was stirred- in tetrahydrofuran (9 mL) , acetic acid (9 mL) , and water (3 mL) for 3 h. The THF was evaporated in vacuo and the remaining solution diluted with water and extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give a white foam, which was chromatographed (silica gel, 50:1 dichloromethane:methanol) . The title compound was isolated as a white solid (0.135 g, 59%) . NMR(CDC13) : δ 7.35-7.08 (5H, m) , 4.70 (IH, d) , 3.91 (IH, dd) , 3.70 (2H, ), 2.95-2.60 (2H, m) , 2.42 (2H, m) , 1.70 (IH, m) , 1.51 (2H, m), 1.35-1.10 (12H, m) , 0.90 (9H, s) , 0.79 (3H, t) , 0.07 (6H, d) ; MS(DCI/NH3) : (M+H) + 480.4; 441 3; 424.3; 380.3; 362.3; 322.2; 248.2. Ereparation.2 By the procedure set forth in Preparation 1, except substituting for allyl bromide in step 1(e) either: (a) methyl iodide, (b) benzyl bromide, (c) methallyl bromide, (d) isobutyl bromide, or (e) n-propyl bromide, the following compounds were prepared: (a) (2R, 4S, 5S)-2-methyl-4-(tert-butyldimethylsilyloxy)- 5- (tert-butyloxycarbonyl)amino-6-phenylhexanoic acid; (b) (2R,4S, 5S)-2-phenylmethy1-4-(tert-butyldimethyl¬ silyloxy) -5-(tert-butyloxycarbonyl)amino-6-phenylhexanoic acid; (c) (2R,4S,5S)-2-methallyl-4-(tert-butyldimethyl¬ silyloxy)-5- (tert-butyloxycarbonyl) amino-6-phenylhexanoic acid; (d) (2R,4S, 5S)-2-isobutyl-4-(tert-butyldimethyl¬ silyloxy)-5-(tert-butyloxycarbonyl)amino-6-phenylhexanoic acid; and (e) (2R,4S,5S)-2-propyl-4-(tert-butyldimethyl-silyloxy) - 5-(tert-butyloxycarbonyl)amino-6-phenylhexanoic acid. Preparation 3 Preparation of (2R, 4S, 5S)-2-phenylmethyl-4- (tert- butyldimethylsilyloxy)-5- (t-butyloxycarbonyl-amino) -6- phenylhexanoyl-valine methyl ester To a solution of (2R, 4S, 5S)-2-phenylmethyl-4- (tert- butyldimethylsilyloxy) -5- (tert-butyloxycarbonyl)amino-6- phenylhexanoic acid (0.167 mmol) in tetrahydrofuran (1 mL) at -40°C under argon was added N-methyl morpholine (.027 mL, 0.25 mmol) and isobutyl chloroformate (0.022 mL, 0.167 mmol) . After stirring for 15 min at -40°C, N-methyl morpholine (0.027 mL, 0.25 mmol) and valine methyl ester hydrochloride (.049 g, 0.183 mmol) were added. The mixture was warmed to 25°C and allowed to stir under argon for 14 h. The mixture was diluted with ethyl acetate and washed successively with 5% HCl, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and evaporated to a semi-solid residue. The residue was chromatographed (silica gel, dichloromethane:methanol) to give the title compound. EXAMPLES Example Preparation of N-benzyloxycarbonyl, N'- f (2R, 4S, 5S) -2- phenylmethyl-4-hydroxy) -5- (t-butyloxycarbonyl) amino-6- phenylhexanoyl- (S) -valyllguanidine a) (2R, 4S, 5S)-2-phenylmethyl-4- (t-butyldimethylsilyloxy) -5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl-valine To a solution of (2R, 4S, 5S) -2-4- (t-butyldimethyl- silyloxy)-5- (t-butyloxycarbonyl)amino-6-phenylhexanoyl-valine (0.183 g, 0.285 mmol) (1) in 1:1 MeOH:H 2 0 (7 mL) , 2.5 M NaOH (0.120 mL) was added. The reaction mixture was allowed to stir for 20 h at RT. The solution was concentrated in vacuo to a wet solid and 0.05 N HCl was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over MgS0 4 , and concentrated to a colorless oil (0.175 g, 98%) . b) N-benzyloxycarbonyl, N'-[ (2R,4S,5S)-2-phenylmethyl-4-(t- butyldimethylsilyloxy)-5-(t-butyloxycarbonyl) amino-6- phenylhexanoyl-valyl]guanidine To a solution of the compound of Example 1(a) (0.175 g, 0.28 mmol) in methylene chloride (10 L) was added Cbz- guanidine (0.065 g, 0.335 mmol), HOBT (0.010 g) , and l-(3- dimethylaminopropyl)-3—ethylcarbodiimide hydrochloride (0.065 g, 0.335 mmol) . The reaction mixture was allowed to stir 20 h at RT, then diluted with methylene chloride and washed with NaHC03, brine, dried over K2CO3, and concentrated to a colorless oil. Chromatography (silica gel, 2:1 hexane:ethyl acetate) afforded the title compound as a colorless oil (0.18 g, 80%) . H 1 NMR (250 MHz, CDCI3) δ 0.1 (s, 6H) , 0.82 (d, J=2.6 Hz, 3H), 0.89 (d, J=2.6 Hz, 3H) , 0.93 (s, 9H) , 1.31 (s, 9H), 1.4-2.1 (m, 4H) , 2.4-2.95 ( , 4H) , 3.7 (m, IH) , 3.92 (m, IH), 4.15 (m, IH) , 5.17 (s, 2H) , 6.19 ( , IH) , 6.95-7.4 (m, 15H) . c) N-benzyloxycarbonyl, N'-[ (2R, S,5S)-2-phenylmethyl-4- hydroxy)-5-(t—butyloxycarbonyl) amino-6-phenylhexanoyl-valyl]- guanidine To a solution of the compound cf Example 1(b) (0.117 g, 0.146 mmol) in THF (7 mL) was added TBAF (1.0 M in THF, 0.17 mL) . The reaction mixture was heated gently to 50° C for 5 h and then ' cooled to RT and allowed to stir at RT for 20 h. The reaction mixture was diluted with ethyl acetate and washed with water, brine, dried over K 2 CO 3 and concentratd to a colorless oil. This was chromatographed (silica gel, 3% Me0H/CH 2 Cl2) to afford the title compound as a white solid (0.032 g, 35%) . MS m/e 688 [M+H] + ; H 1 NMR (250 Mhz, CDCI3) δ 0.8 (t, J=2.5 Hz, 6H) , 1.38 (s, 9H) , 1.5-2.2 (m, 4H) , 2.55- 3.0 (m, 4H) , 3.55 (m, IH) , 3.7 (m, IH) , 4.29 (m, IH) , 4.93 (m, IH), 5.13 (s, 2H), 6.09 (m, IH) , 6.9-7.35 (m, 15H) , 8.7 (br m, IH) . Example 2 Preparation of N- f (2R.4S.5S) -2-phenylmethyl-4-hvdroxy) -5- (t-butyloxycarbonyl)amino-6-phenylhexanoyl- (S)-valyll- guanidine (5) 10% Pd/C (0.015 g) was added to a solution of the compound of Example 1(c) (0.015 g, 0.0218 mmol) in ethanol (2 mL) . The reaction mixture was placed under H 2 at balloon pressure and allowed to stir overnight at RT. The mixture was filtered through Celite® and concentrated to a white solid (0.01 g, 82%) . The title compound was purified by preparative HPLC (Microsorb Si0 2 , gradient, 0%-25% isopropanol/methylene chloride) . H 1 NMR (250 Mhz, ' CDCI 3 ) δ 0.62 (d, J=2.8 Hz, 3H) , 0.76 (d, J=2.8 Hz, 3H) , 1.36 (s, 9H) , 1.7 (m, 2H) , 2.05 (m, IH) , 2.8 (4H) , 3.7 (m, 3H) , 4.08 (m, IH) , 5.02 (m, IH) , 7.2 (m, 10H) . Example 3 Preparation of N-acetyl. N'- r (2R.4S.5S) -2-phenylmethyl-4- hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (S) - valyl1-σuanidine a) N- [ (2R, S, 5S) -2-phenylmethyi-4-t-butyldimethylsiloxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl-valyl]-guanidine To a solution of the compound of Example 1(b) (0.57 g, 0.71 mmol) in EtOAc, was added Pd/C (10%, 0.5 g) . The mixture was placed under 1 atmosphere of hydrogen and allowed to stir for 20 h at RT. The mixture was filtered through Celite® and concentrated to a colorless oil. The oil was used without further purification. b) N-acetyl, N'- [ (2R, 4S, 5S)-2-phenylmethyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl-valyl]-guanidine To . a solution of the compound of Example 3(a) (0.115 g, 0.17 mmol) in CH 2 C1 2 was added triethylamine (0.019 g, 0.19 mmol) and acetic anhydride (0.019 g, 0.19 mmol) . The reaction mixture was allowed to stir 2 h at RT. The mixture was diluted with CH C1 , washed with NaHC03, water, and brine. This solution was concentrated and chromatographed (silica gel, 2:1 hexane:EtOAc) to afford two fractions. The higher Rf containing a mixture, and the lower Rf is >95% single isomer by HPLC and NMR. The lower Rf isomer (0.035 g, 0.049 mmol) was treated with TBAF (1 M in THF, 1 mL) and allowed to stir for 4 h at RT. The mixture was diluted with CH 2 CI2, washed with water and brine, dried over K 2 CO 3 and concentrated to an off white solid. The solid was chromatographed (silica gel, step gradient, 2:1 hexane:EtOAc, EtOAc) to yield the title compound (0.015 g) . Isomeric purity by HPLC and NMR is >95% (Microsorb ODS, 20% water/methanol) . H 1 NMR (250 Mhz, CDCI3) δ 0.81 (d, J=2.8 Hz, 3H) , 0.88 (d, J=2.8 Hz, 3H) , 1.38 (s, 9H), 1.8 (m, IH), 2.2 (m, 4H) , 2.8 (4H) , 3.7 ( , 3H) , 4.47 (m, IH) , 4.96 ( , IH) , 6.37 (m, IH) , 7.2 (m, 10H) ; MS m/e 596.4 [m+H] + . Example 4 Preparation of N-t-butyloxycarbonyl, N'-r (2R, 4S,5S) -2- phenylmethyl-4-hydroxy-5-(t-butyloxycarbonyl)amino-6- phenylhexanoyl-(R)-valyl1-guanidine; and N-t-butyloxycarbonyl. N'-f (2R.4S.5S)-2-phenylmethyl-4- hydroxy-5-(t-butyloxycarbonyl) amino-6-phenyIhexanoyl- (S) - valyl1-guanidine To a solution of the compound of Example 3(a) (0.045 g, 0.0674 mmol) in THF was added t-butyloxycarbonyl- pyrocarbonate (0.015 g, 0.07 mmol), and allowed to stir for 6 h at RT. The mixture was diluted with EtOAc, washed with NaHC03, brine, dried over K 2 CO3 and concentrated to an oil. The oil was chromatographed (silica gel, 4:1 hexane:EtOAc) and concentrated. The resulting oil was then treated with TBAF (1M in THF, lmL) and allowed to stir for 2 h at RT. The mixture was diluted with EtOAc, washed with water and brine, dried over K2CO3, and concentrated. The residue was dissolved in MeOH and filtered through an octadecyl silica gel column, and concentrated. The residue was chromatographed (preparatory silica gel TLC 1:1 hexane:EtOAc) to afford 2 fractions. The higher Rf value fraction corresponding to R-Valine, the lower Rf to S-Valine (absolute stereochemistry of the Valine position tenatively assigned) . HPLC analysis shows each isomer to be > 95% (Zorbax ODS, 25% water/ ethanol) . isomer 1 (R-Val) : H 1 NMR (250 MHz, CDCI 3 ) δ 0.52 (d, J=2.8 Hz, 3H) , 0.55 (d, J=2.8 Hz, 3H) , 1.39 (s, 9H) , 1.43 (s, 9H) , 1.58 (m, 2H) , 2.25 (m, IH) , 2.8 (4H) , 3.5-3.8 (m, 2H) , 4.33 (m, IH) , 4.97 (m, IH) , 5.58 (m, IH) , 7.2 (m, 10H) . isomer 2 (S-Val) : H 1 NMR (250 MHz, CDCI 3 ) δ 0.75 (d, J=2.8 Hz, 3H) , 0.85 (d, J=2.8 Hz, 3H) , 1.33 (s, 9H) , 1.52 (s, 9H) , 1.7 im, 2H) , 2.15 (m, IH) , 2.8 (4H) , 3.6-3.8 (m, 2H) , 4.25 (m, IH) , 4.95 (m, IH) , 6.12 (m, IH) , 7.2 (m, 10H) . The stereochemical assignment is tentative based upon bioactivity, the more active isomer being presumed to have the S-configuration. Example 5 Preparation of N-methoxycarbonyl. N'- r (2R, 4S, 5S) -2- phenylmethyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6- phenylhexanoyl- (S)-valyl!-guanidine; and N-methoxycarbonyl, N'- (2R 4S, 5S)-2-phenylmethyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (R) -valyl! - guanidine To a solution of the compound of Example 3(a) (0.049 g, 0.073 mmol) in CH 2 C1 2 was added triethylamine (0.007 g, 0.07 mmol), followed by methyl chloroformate (0.007 g, 0.07 mmol) and the mixture allowed to stir for 2 h at RT. The mixture was diluted with CH C1 2 , washed with NaHCθ 3 and brine, dried over K 2 C0 3 and concentrated to an oil. The oil was chromatographed (silica gel, 2:1 hexane:EtOAc) and concentrated. The resulting oil was treated with TBAF (IM in THF, lmL) and allowed to stir for 2 h at RT. The mixture was diluted with CH 2 C1 , washed with water and brine, dried over K 2 Cθ3, and concentrated. The residue was dissolved in MeOH, filtered through an octadecyl silica gel column, and concentrated. The residue was chromatographed (preparatory silica gel TLC, 1:1 hexane:EtOAc) to afford 2 fractions. The higher Rf value fraction corresponding to R-Valine, the lower Rf to S-Valine (absolute stereochemistry of the valine position tenatively assigned) . HPLC analysis shows each isomer to be > 95% pure (Zorbax ODS, 25% water/methanol) . isomer 1 (R-Val) : H 1 NMR (250 MHz, CDC1 3 ) δ 0.46 (d, J=2.8 Hz, 3H) , 0.59 (d, J=2.8 Hz, 3H) , 1.32 (s, 9H) , 1.55 ( , 2H) , 2.25 (m, IH), 2.8 (4H) , 3.6-3.9 (m, 3H) , 3.69 (s, 3H) , 4.32 ( , IH), 5.00 (m, IH) , 5.43 (m, IH) , 7.2 (m, 10H) ; MS m/e 612.4 [M+H] + - isomer 2 (S-Val) : H 1 NMR (250 MHz, CDCI 3 ) δ 0.8 (d, J=2.8 Hz, 3H), 0.82 (d, J=2.8 Hz, 3H) , 1.38 (s, 9H) , 1.9 (m, 2H) , 2.2 (m, IH) , 2.8 (4H) , 3.6-3.9 (m, 3H) , 3.75 (s, 3H) , 4.37 (m, . IH), 4.9 (m, IH), 6.00 (m, IH) , 7.2 (m, 10H) ; MS m/e 612.4 [m+H] + . The stereochemical assignment is tentative based upon bioactivity, the more active isomer being presumed to have the S-configuration. Example 6 Preparation of N-(4-pyridyl)methyloxycarbonyl, N'- r (2R.4S.5S -2-phenylmethyl-4-hydroxy-5- (t-butγloxycarbonyl) amino-6-phenylhexanoyl- (R) -valyl!- guanidine; and N-f -pyridyl>methyloxycarbonyl. N'-T f2R.4S.5Si -2- phenylmethyI-4-hydroxy-5-(t-butyloxycarbonyl)amino-6- phenylhexanoyl-(S)-valyl!-guanidine To a solution of the compound of Example 3(a) (0.061 g, 0.0913 mmol) in CH 2 CI 2 was added O-pyridyl-O-(p-nitrophenyl)- carbonate (0.038 g, 0.0913 mmol) and triethylamine (0.0092 g, 0.0913 mmol) . The reaction was allowed to stir overnight at room temperature. The reaction was diluted with CH 2 CI 2 and washed with NaHCθ3, water and brine, and dried over K2CO 3 . This was concentrated to an oil and chromatographed (silica gel, 95:5 CH2Cl 2 /MeOH) to afford a colorless oil. To this oil was added THF (2 mL) and TBAF in THF (2 mL of a 1M solution) . The reaction was allowed to stir for 4 h, and diluted with EtOAc. The solution was washed with NaHCθ3, water and brine, dried over K2CO3, and concentrated to a yellow oil. Chromatography (preparatory silica gel TLC, 95:5 CH 2 Cl 2 :MeOH) afforded a colorless oil. This material was then purified on a prep HPLC (ϋltrasphere ODS, 22% water/methanol) . Concentration of the appropriate fractions gave two compounds, both as white solids. isomer 1 (S-Val) : H 1 NMR (250 MHz, CDCI3) δ 0.8 (m, 6H) , 1.27 (s, 9H) , 1.68 (m, 2H) , 1.95 (m, IH) , 2.5-3.0 (m, 5H) , 3.58 (m, 2H) , 4.08 (m, IH) , 5.13 (s, 2H) , 7.1 (m, 10H) , 7.32 (d, J=6Hz, 2H) , 8.38 (d, J=6Hz 2H) ; MS m/e 689.2 [m+H] + . isomer 2 (R-Val) : H 1 NMR (250 Mhz, CDCI 3 ) δ 0.6 (m, 6H) , 1.23 (s, 9H) , 1.55 (m, IH) , 1.69 (m, IH) , 1.92 (m, IH) , 2.5-3.0 (m, 5H) , 3.43 (m, IH) , 3.6 (m, IH) , 4.08 (m, IH) , 5.14 (s, 2H) , 7.1 (m, 10H) , 7.35 (d, J=5.4Hz, 2H) , 8.41 (d, J=5.4Hz, 2H) . The stereochemical assignment is tentative based upon bioactivity; the more active isomer being presumed to have the S-configuration . Example 7 Preparation of N-benzyloxycarbonyl, N'- f (2R, 4S, 5S) -2-methyl- 4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (S) - valyl!-guanidine; and N-benzyloxycarbonyl, N'- (2R, 4S, 5S) -2-methyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (R) -valyl1 - guanidine a) (2R, 4S, 5S) -2-methyl-4-hydroxy-5- (t-butyloxycarbonyl) amino- 6-phenylhexanoyl- (R) -valine methyl ester The compound cf Preparation 2(a) (136.0 mg, 0.3 mmol) was dissolved in dry DMF and successively treated with 1- hydroxybenzotriazole (44.6 mg, 0.33 mmol), L-valine-O-methyl ester hydrochloride (50.3 mg, 0.3 mmol), 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (57.5 mg, 0.3 mmol), and N,N-Diisopropylethylamine (38.8 mg, 0.3 mmol) . The reaction mixture was stirred overnight at ambient temperature under argon. DMF was removed in vacuo and the residue was dissolved in EtoAc, washed with H2O, 1.0 NHC1, H2O, 5% NaHC03, saturated NaCl, dried over MgSO.}, filtered, and concentrated to a yellow, sticky solid residue. The residue was purified by flash chromatography (silica gel, 4:1 hexane:EtoAc) to afford the title compound as a sticky white solid (65.0 mg, 39%) . 1 H NMR (CDCI3, 250 MHz) δ 7.35-7.15 (m, 5H) , 6.15 (d, IH) , 4.7 (d, IH) , 4.45 (m, IH) , 3.95 (br m, IH), 3.7 (s, 3H), 2.8 (d, 2H) , 2.45 (br m, IH) , 2.1 (m, IH) , 1.8 (m, 2H), 1.55 (m, IH) , 1.35 (s, 9H) , 1.25 (d, 3H) , 0.95 (s, 9H) , 0.85 (2d, 6H) , 0.1 (d, 6H) ; TLC R f 0.23 (4:1 hexane:EtoAc) . b) (2R, S,5S)-2-methyl-4-hydroxy-5-(t-butyloxycarbonyl)amino- 6-phenylhexaπoyl-(R)-valine The compound of Example 7(a) (65.0 mg, 0.115 mmol) was dissolved in MeOH (4.0 mL) and to this was added 0.18 mL of 2.5 N NaOH (18.4 mg, 0.46 mmol) . The reaction mixture was stirred overnight at RT and concentrated to a white semi- solid. The semi-solid was redissolved in H2O, acidified to pH 3.5 with 3.0 NHC1, extracted into EtoAc, washed with saturated NaCl, dried over MgSO.j, filtered and concentrated to a white solid (64.6 mg, 100%) . NMR (CDCI3, 250 MHz) δ 7.5 (d, IH), 7.35-7.15 (m, 5H) , 5.15 (d, IH) , 4.7 (m, IH) , 3.85 (m, IH), 3.65 (m, IH) , 2.9 (m, IH) , 2.7 (m, IH) , 2.25 (br , 2H) , 1.7 (m, IH) , 1.6 (m, IH) , 1.35 (s, 9H) , 1.2 (d, 3H), 0.95 (s, 9H) , 0.85 (d, 3H) , 0.75 (d, 3H) , 0.1 (d, 6H) . c) N-benzyloxycarbonyl, N'-[ (2R,4S,5S)-2-propyl-4-hydroxy-5- (t-butyloxycarbonyl)amino-6-ph'enylhexanoyl-(R,S)-valyl]- guanidine The compound of Example 7(b) (64.6 mg, 0.117 mmol) was dissolved in dry DMF and successively treated with 1- hydroxybenzotriazole (19.0 mg, 0.14 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.7 mg, 0.117 mmol), carbobenzyloxyguanidine (22.6 mg, 0.117 mmol) and N,N-diisopropyl-ethylamine (15.1 mg, 0.117 mmol) . The reaction mixture was stirred overnight at ambient temperature under argon. DMF was removed in vacuo and the residue was dissolved in EtoAc, washed with H2O, 1.0 NHC1, H2θ, 5% NaHC03, saturated NaCl, dried over MgSO_ι, filtered, and concentrated to a white solid (70.2 mgs, 83%) . ^-H NMR (CDCI3, 250 MHz) δ 7.4-7.05 (m, 10H) , 6.45 (d, IH) , 5.15. (s, 2H) , 4.8 (m, IH) , 4.4 (br , IH) , 3.95 (m, IH) , 3.7 (m, IH) , 2.8 (d, 2H) , 2.5 (m, IH) , 2.15 (m, IH) , 1.85 (m, IH) , 1.55 (m, IH) , 1.30 (s, 9H) , 1.25 (d, 3H) , 0.95 (s, 9H) , 0.9 (d, 3H) , 0.85 (d, 3H) , 0.1 (d, 6H) ; TLC R f 0.65 (1:1 hexane:EtoAc) . d) N-benzyloxycarbonyl, N'- [ (2R, 4S, 5S) -2-methyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (S) -valyl] - guanidine; and N-benzyloxycarbonyl, N'- [ (2R,4S, 5S) -2-methyl-4-hydroxy-5- (t-butyloxycarbonyl)amino-6-phenylhexanoyl- (R) -valyl] - guanidine The compound of Example 7(c) (70.2 mg, 0.097 mmol) was dissolved in THF (2.0 mL) and treated with tetrabutyl ammonium fluoride (1M in THF, 2 mL, 2.0 mmol) . The reaction mixture was stirred at ambient temperature overnight under argon. The mixture was diluted with EtoAc, washed with 5% NaHC03, H2O, and saturated NaCl, dried over MgSθ4, filtered, and concentrated to a slightly colored solid. The residue was purified by flash chromatography (silica gel, 4% CH3OH/CH2CI2) to yield the title diastereomeric compound. isomer 1: ^-H NMR (CDCI3, 250 MHz) δ 7.35-7.1 (m, 10H) , 7.05 (m, 2H) , 6.0 (m, IH) , 5.1 (d, 2H) , 4.95 (d, IH) , 4.5 (m, IH) , 3.75 (m, 2H) , 2.7 (m, 2H) , 2.45 (br, IH) , 1.75 ( , IH) , 1.55 (br, IH) , 1.3 (s, 9H) , 1.25 (d, 2E) , 1.15 (d, 3H) , 1.0 (c, 3H) , 0.9 (d, 3H) ; TLC R f 0.57 (5% CH3OH : CH 2 C1 2 ) ; MS m /e 612 [M+H] + isomer 2: ^-H NMR (CDCI3, 250 MHz) 6 7.4-7.05 (m, 10H) , 6.3 (br s, IH) , 5.1 (d, 2H) , 5.0 (d, IH) , 4.35 (m, IH) , 3.7 (m, 2H) , 2.8 (d, IH) , 2.7 (m, 2H) , 2.3 (m, IH) , 2.0 (m, IH) , 1.65 (m, 2H) , 1.4 (s, 9H), 1.15 (d, 3H) , 0.95 (d, 3H) , 0.9 (d, 3H) ; TLC R f 0.41 (5% CH3OH/CH2CI2) ; MS m/e 612 [M+H] + . Sterochemical assignments made on the basis of bioactivity, the more potent isomer being presumed to be the S-Val isomer. Example 8 Preparation of N-benzvloxycarbonyl, N'- r (2R, 4S, 5S) -2-propvl- 4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (S) - valyl!-σuanidine; and N-benzyloxycarbonyl, N'-r (2R,4S,5S)-2-propyl-4-hydroxy-5- (t.-butvloxvcarbonvl)amino-6-phenvlhexanovl-(R) -valvl!- σuanidine a) (2R,4S,5S)-2-propγl-4-hydroxy-5-(t-butyloxycarbonyl)amino- 6-phenylhexanoyl-(S)-valine methyl ester The compound of Preparation 2(e) (136.6 mg, 0.285 mmol) was dissolved in dry DMF and successively treated with 1- hydroxybenzotriazole (46.2 mg, 0.342 mmol), L-valine-O-methyl ester hydrochloride (47.8 mg, 0.285 mol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (54.7 mg, 0.285 mmol), and N,N-diisopropylethylamine (36.8 mg, 0.285 mmol) . The reaction mixture was stirred overnight at ambient temperature under argon. DMF was removed in vacuo and the residue was dissolved in EtoAc, washed with H2O,. 1.0 M NH4CI, H 0, 5% NaHC03, saturated NaCl, dried over gS04, filtered and concentrated to yield a solid. The white solid was purified by flash chromatography (silica gel, 4:1 hexane:EtoAc) to afford the title compound as a white solid (36.7 mg, 22%) . 3-H NMR (CDCI3, 250 MHz) δ 7.35-7.1 ( , 5H) , 6.05 (d, IH), 4.75 (d, IH) , 4.5 (m τ IH) , 3.95 ( , IH) , 3.7 (s, 3H), 2.8 (m, 2H) , 2.25 (m, IK), 2.1 ( , IH) , 1.75 (m, IH), 1.6 (m, IH) , 1.35 (s, 9H) , 1.3 (m, 3H) , 1.1 (m, 2H) , 0.95 (s, 9H), 0.9 (d, 2H) , 0.85 (d, 3H) , 0.8 (t, 3H) , C.15 (d, 6H) ; TLC R f = 0.32 (4:1 hexane:EtoAc) . b) (2R,4S,5S)-2-propyl-4-hydroxy-5-(t-butyloxycarbonyl)amino- 6-phenylhexanoyl- (S)-valine The compound of Example 8(a) (33.0 mg, 0.056 mmol) was dissolved in MeOH (3.0 mL) and to this was added 0.09 mL of 2.5 N NaOH (8.9 mg, 0.22 mmol) . The reaction was stirred overnight at room temperature and concentrated to a white solid. The solid was dissolved in water, acidified to pH = 3.5 with 3.0 M NH4CI, extracted into EtoAc, washed with saturated NaCl, dried over MgS0 4 , filtered and concentrated to yield the title compound as a white solid (29.5 mg, 92%) . NMR (CDCI3, 250 MHz) δ 7.5 (d, IH) , 7.35-7.1 (m, 5H) , 5.2 (d, IH), 4.7 (m, IH) , 3.9 (m, IH) , 3.7 (m, IH) , 2.9 ( , IH) , 2 . 7 (m, IH) , 2 . 2 (m, 2H ) , 1 . 6 (m, 2H ) , 1 . 35 ( s , 9H ) , 1 . 3 (m, 3H) , 1 . 1 (m, 2H) , 0 . 95 ( s , 9H) , 0 . 9 ( d, 3H ) , 0 . 8 (d , 3H) , 0 . 65 (m, 3H) , 0 . 15 (d, 6H) . c) N-benzyloxycarbonyl, N'- [ (2R, 4S, 5S) -2-propyl-4-hydroxy-5- (t-butyloxycarbonyl)amino-6-phenylhexanoyl- (R, S) -valyl] - guanidine The compound of Example 8(b) (29.5 mg, 0.05 mmol) was dissolved in dry DMF and successively treated with 1- hydroxybenzotriazole (8.1 mg, 0.06 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.6 mg, 0.05 mmol), carbobenzyloxyguanidine (9.7 mg, 0.05 mmol), and N,N-diisopropylethylamine (6.5 mg, 0.05 mmol) . The reaction was stirred overnight at ambient temperature under argon. DMF was removed in vacuo and the residue was dissolved in EtoAc, washed with H2O, 1.0 M NH4CI, H 2 0, 5% NaHCθ3, saturated NaCl, dried over MgS04, filtered, and concentrated to yield the title compound as a white solid (25.0 mg, 66%) . λ H NMR (CDCI3, 250 MHz) δ 7.4-7.1 (m, 10H) , 6.4 (m, IH) , 5.15 (s, 2H) , 4.8 (d, IH) , 4.35 (m, IH) , 3.95 (m, IH) , 3.7 (m, IH) , 2.75 (m, 2H) , 2.35 - 2.05 (m, 2H) , 1.8 (m, IH) , 1.55 (m, IH) , 1.35 (d, 9H) , 1.25 (m, 3H) , I.C5 ( , 2H) , 0.90-0.85 (m, 6H) , 0.8 (m, 3H) , 0.1 (d, 6H) ; TLC R f 0.71 (1:1 hexane :EtoAc) . d) N-benzyloxycarbonyl, N 1 - [ (2R, 4S, 5S)-2-propyl-4-hydroxy-5- (t-butyloxycarbonyl)amino-6-phenylhexanoyl- (S) -valyl]- guanidine; and N-benzyloxycarbonyl, N'- [ (2R, 4S, 5S) -2-propyl-4-hydroxy-5- (t-butyloxycarbonyl)amino-6-phenylhexanoyl- (R) -valyl]- guanidine The compound of Example 8(c) (25.0 mg, 0.033 mmol) was dissolved in THF (1.5 mL) and treated with 1.5 mL of 1.0 M tetrabutylammonium fluoride (392.0 mg, 1.5 mmol) . The reaction mixture was stirred at ambient temperature overnight under argon. The mixture was diluted with EtoAc, washed with 5% NaHC03, H2O, and saturated NaCl, dried over MgS0 , filtered, and concentrated to a tan solid. The solid was purified by flash chromatography (silica gel, 4% CH3OH/CH2CI2) to yield the title diastereomers as pure compounds. isomer 1 (S-Val) : E NMR (CDCI3, 250 MHz) δ 7.4- 7.1 ( , 10H), 6.3 (d, IH) , 5.15 (d, 2H) , 5.0 (d, IH) , 4.4 (m, IH), 3.65 (d, 2H) , 2.85 (d, 2H) , 2.55 ( , IH) , 2.25 (m, IH) , 1.85 (m, IH), 1.65 (m, IH), 1.35 (s, 9H) , 1.35-1.15 (m, 5H) , 0.95 (d, 3H), 0.90 (d, 3H) , 0.85 (t, 3H) ; TLC R f 0.43 (silica gel, 4% CH3OH/CH2CI2); MS m/e 640 [M+H1+. isomer 2 (R-Val) : ^-H NMR (CDCI3, 250 MHz) δ 7.4-7.1 (m, 10H), 7.0 (m, 2H), 5.95 ( , IH) , 5.1 (m, 2H) , 4.85 (d, IH) , 4.6 ( , IH), 3.75 (m, 2H> , 2.75 (d, 2H) , 2.5 (m, 2H) , 1.75 ( , IH), 1.6 (m, IH), 1.35 (s, 9H) , 1.25 (m, 2H) , 1.0 (d, 3H), 0.95 (d, 3H) , 0.9 (t, 3H) ; TLC R f 0.56 (silica gel, 4% CH3OH/CH2CI2) ; MS m/e 640 [M+H] + . Sterochemical assignments made on the basis of bioactivity, the more potent isomer being presumed to be the S-Val isomer. Example 9 Parenteral Dosage Unit Composition A preparation which contains 25 mg of a compound of this invention is prepared as follows: 25 mg of the compound is dissolved in 15 mL of distilled water. The solution is filtered under sterile conditions into a 25 mL multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 mL of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume. This solution is also suitable for use in other methods for administration, such as addition to a bottle or bag for IV drip infusion. Examp e 1Q Oral Dosage Unit Composition A capsule for oral administration is prepared by mixing and milling 200 mg of the compound with 450 mg of lactose and 30 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule. The above description fully discloses how to make and use this invention. This invention, however, is not limited to the precise embodiments described herein, but encompasses all modifications within the scope of the claims which follow.

Claims: What is claimed is: 1. A compound of the formula: (I) wherein R 1 is R 7 , R 7 CO, R 7 OCO, R 7 0CH(R 8 )C0 or A-NR'CH(R 5 )CO; Z is O or N-R 2 , where R 2 is H, CN or R'CO; R 5 Di and D 2 are O or are absent; Q 1 , Q 2 and Q 3 are H, NH 2 or OH; V is N or C; Y is N, O or S; R 3 and R 4 are H or Cι_galkyl, C 2 _ 6 alkenyl, C3_7cycloalkyl, T, T-Cι_6alkyl, T-C 2 -6alkenyl or T-C3_7Cycloalkyl, optionally substituted with R 16 ; T is Ar, Het or C3_7cycloalkyl; R 5 and R 6 are Cι_ 6 alkyl, (CHR')n-T or (CHR')p-ϋ, where U is NR* 2 , SR r , OR', imidazole or C0NR' 2 ; R 7 and R 8 are independently H, Cχ_6alkyl, C3_7cycloalkyl, T-(CHRl3) m -, T-(CH 2 ) m CH(T) (CH 2 ) m ; R 9 is O, S or (H,H) ; R' is H, Cι_ alkyl or CH 2 Ph; k is 0 or 1; m is 0-6; n is 0-2; p is 1-4 ; A is H, or Ar, Het, R 10 (R 1:L R 12 C) m , Ar-W, Het-W or R 10 (R 1:L R 12 C)m-W, optionally substituted by one to three groups chosen from R 13 or Cι_ 6 alkyl-R 13 . Suitably R 13 is OH. W is C=0, OC(=0), NR'C(=0), SC(=0), NR'C(=S), SO, S0 2 , NR 8 S0 2 or P(=0) (OR 15 ) ; R 10 , R 11 and R 12 are independently: i) H, R 13 or Cι- 4 alkyl, C 2 -6alkenyl, phenyl, naphthyl, C3_6Cycloalkyl or Het, each optionally substituted by one to three R 13 or R 13 -C 1 _galkyl groups, or ii) R 10 is as above and (R 11 R 1 C) are joined together to form a phenyl, naphthyl, C 3 -6cycloalkyl or Het ring, or iii) R 10 is as above and R 11 and R 12 together are =0; R 13 is H, nitro, Ci-βalkoxy, C^galkylthio, 0(C=0)R 14 , C=OR 15 , C0 2 R 15 , CON(R 1 ) 2 , N(R 15 ) 2 , NHC(=N)NH-A, I, Br, Cl, F, OR 7 , or OH, provided that when R 13 is a substituent of the carbon adjacent to W, R 13 is not halogen or OH when W is 0C(=0) or NHCO; R 14 is H or Cι_6alkyl; R 15 is H, C^galkyl, phenyl or phenyl-Cι_ 4 alkyl; R 16 is -X'-R', -X'-(CH 2 ) q NR 1 R 18 , X" [ ( (CH 2 ) r O) s ]R 19 , CH 2 X" [ ( (CH 2 ) r O) s ]R 19 , or benzcfuryl, indolyi, azacycloalkyl, azabicyclo C 7 -ncycloalkyl or benzopiperidinyl, optionally substituted with Cι_ 4 alkyl; q is 2-5; s is 1-6 and r is 1-3 within each repeating unit s; X' is CH 2 , 0, S or NH; X" is CH 2 , NR', O, S, SO or S0 2 ; R 17 and R 18 are i) Ci-βalkyl, optionally substituted by OH, Cι-3alkoxy, or N(R') , ii) the same or different and joined together to form a 5-7 member heterocycle containing up to two additional heteroatoms selected from NR, 0, S, SO, S0 2 , said heterocycle optionally substituted with Cι_ 4 alkyl, iii) aromatic heterocycle, optionally substituted with Cι- 4 alkyl or N(R') ; R" is H or Cι_ 4 alkyl; R 19 is H, C 1 _ alkyl, C(=0)R 20 , C(=0)U[ (CH 2 ) m O] n R' , P(=0) (OM*)2 r CO2R 20 , C.(=O)NR 20 R 21 , where M* is a mono or divalent metal ion, and D is NR" or 0; R20 i s Ci-βalkyl or Ar, optionally substituted with one or more hydroxy, carboxy, halo, Cι_3alkoxy, C0NR' 2 , NR* 2 , C0 2 ', S0 NR' 2 , CH 2 NR 2 , NR'COR', NR'S02R', X" [ (CH 2 ) r 0] S R' or CH2X"[ ( CH 2 ) r01s R '; and R 21 is H, Ci—galkyl or together with R 20 forms a 5-7 membered heterocycle or a 6 membered heterocycle containing a heteroatom selected from N, O and S; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 in which Z is NH. 3. A compound according to claim 1 in which R 1 is H, R 7 CO or R 7 OCO. 4. A compound according to claim 1 in which M is 5. A compound according to claim 4 in which R 3 is benzyl and R 4 is Ci-galkyl, Ar-Cχ_ 4 alkyl, Ar-C 2 - 4 alkenyl or Ar- C 2 - 4 alky yl, optionally substituted by R 13 . 6. A compound according to claim 5 in which E is Val. 7. A compound according to claim 1 which is: N-benzyloxycarbonyl, N*-[ (2R,4S,5S)-2-phenylmethyl-4- hydroxy)-5-(t-butyloxycarbonyl)amino-6-phenylhexanoyl-(S)- valyl]-guanidine; N-[ (2R, S,5S)-2-phenylmethyl-4-hydroxy)-5-(t-butyloxy¬ carbonyl)amino-6-phenylhexanoyl-(S)-valyl]-guanidine; N-acetyl, • -[ (2R,4S,5S)-2-phenylmethyl-4-hydroxy-5- (t-butylox carbonyl)amino-6-phenylhexanoyl-valyl]-guanidine; N-t-butyloxycarbonyl, N'- [ (2R, 4S, 5S) -2-phenylmethyl-4- hydroxy-5- (t-butyloxycarbonyl)amino-6-phenylhexanoyl- (S) - valyl]-guanidine; N-methoxycarbonyl, N'- [ (2R, 4S, 5S) -2-phenylmethyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (S) -valyl]- guanidine; N-(4-pyridyl)methyloxycarbonyl, N*- [ (2R, 4S, 5S) -2- phenylmethyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6- phenylhexanoyl- (S)-valyl]-guanidine; N-benzyloxycarbonyl, N'- [ (2R, 4S, 5S)-2-methyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (S) -valyl]- guanidine; or N-benzyloxycarbonyl, N'- [ (2R, 4S, 5S) -2-propyl-4-hydroxy-5- (t-butyloxycarbonyl) amino-6-phenylhexanoyl- (S) -valyl]- guanidine. 8. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier. 9. A compound according to claim 1 for use in the manufacture of a medicament. 10. A method of treating disease states associated with infection by a retrovirus which comprises administering an effective amount of a compound according to claim 1. 11. A method of treating disease states associated with HIV ■ infection which comprises administering an effective amount of a compound according to claim 1. 12. The use of a compound according to claim 1 in the manufacture of a medicament for treating infection by HIV. 13. A method of treating disease states associated with HIV infection which comprises administering an effective amount of a compound according to claim 1 and a reverse transcriptase inhibitor. 14. A process for preparing a compound of the formula: (I) wherein A, Dχ r D 2 , M, Z, R' and Rl are as defined in claim 1, which comprises (1) reacting a compound of the formula: A-D ! -D 2 -M-0H wherein A, Di, 2 and M are as defined for formula (I) , with any reactive groups protected, with a compound of the form la: H 2 NC(=Z)NR'-R 1 wherein Z, R' and R 1 are as defined in claim 1, and a coupling reagent, and optionally removing any protecting groups, or (2) reacting a compound of the formula: H-D ! -D 2 -M-NR*C(=Z)NR'R 1 wherein Di, D 2 , M, Z, R 1 and R 1 are as defined for formula (I) , with any reactive groups protected, with a compound of the formula: A-L' wherein A is as defined in claim 1 and L 1 is a leaving group, and, if necessary, a coupling reagent, and optionally removing any protecting groups.

Inventors: GLEASON JOHN GERALD, LUM ROBERT THOMAS, GLEASON, JOHN, GERALD, LUM, ROBERT, THOMAS
Applicants: SMITHKLINE BEECHAM CORP, SMITHKLINE BEECHAM CORPORATION
Application year: 1992
Main classification: C07K5
IPC codes: A61K31, A61P31, C07C275, C07C279, C07C311, C07C317, C07C327, C07C329, C07C333, C07D233, C07D249, C07D263, C07D271, C07D277, C07D285, C07F9, C07K1, C07K5, C07K14