NZ265753A - Preparation of platelet glycoprotein iib/iiia inhibitors containing methylarginine - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £65753 M- New Zealand No. 265753 International No. PCT/US94/03222 Priority Date(s): 23.11^1.3.3.

Complete Specification f ,ijd : aeUis.hf......

Class: (6) Col.| !P+ Qbl ConK S /pfe; cco.K,ni.Q3, sb\. <5oicass Publication Date: 2 6 MO V. .1996-,.

P.O. Journal No: (Jrlr.A.Q NO NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: A process and intermediate compounds useful for the preparation of platelet glycoprotein llb/llla inhibitors containing NSlpha-methylarginine Di^VvO — Name, address and nationality of applicant(s) as in international application form: THE DU PONT MERCK PHARMACEUTICAL CO, of 1007 Market Street, Wilmington, Delaware 19898, United States of America ? e\ ia 5 i~a PCX/US94/03222 26 5 7 5 3 -m- TITLE A Process And Intermediate Compounds Useful For The 5 Preparation Of Platelet Glycoprotein Ilb/IIIa Inhibitors Containing Na-methylarginine FTF.T.n OF* THF. TNVKNTTON This invention relates to processes for the synthesis of platelet glycoprotein Ilb/IIIa inhibitors, and to intermediate compounds useful in said processes.

BArKCjftOTTNn OF THF TNVKNTTON Activation of platelets and the resulting platelet aggregation and secretion of factors by the platelets have been associated with different pathophysiological conditions including cardiovascular and cerebrovascular 20 thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes 25 stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.

Platelets are known to play an essential role in the maintenance of hemostasis and in the pathogenesis of 30 arterial thrombosis. Platelet activation has been shown to be enhanced during coronary thrombolysis which can lead to delayed reperfusion and reocclusion. Clinical studies with aspirin, ticlopidine and a monoclonal antibody for platelet glycoprotein Ilb/IIIa provide 35 biochemical evidence for platelet involvement in unstable angina, early stage of acute myocardial a. infarction, transient ischemic attack, cerebral ischemia/ and stroke.

Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion 5 of granular contents and aggregation. Aggregation of . platelets serves to further focus clot formation by concentrating activated clotting factors in one site. Several endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, 10 thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than 15 currently available antiplatelet drugs, which are agonist-specific.

Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts 20 against ADP; thromboxane A2 synthetase inhibitors or receptor antagonists, which act against thromboxane A2; and hirudin, which acts against thrombin.

Recently, a common pathway for all known agonists has been identified, namely platelet glycoprotein 25 Ilb/IIIa complex (GPIIb/IIIa), which is the membrane protein mediating platelet aggregation. A recent review of GPIIb/IIIa is provided by Phillips et al. (1991) Cell 65: 359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet 30 therapy. Recent studies in man with a monoclonal antibody for GPIIb/IIIa indicate the antithrombotic benefit of a GPIIb/IIIa antagonist.

There is presently a need for a GPIIb/IIIa-specific antiplatelet agent which inhibits the activation and 35 aggregation of platelets in response to any agonist.

Such an agent should represent a more efficacious antiplatelet therapy than the currently available agonist-specific platelet inhibitors.

GPIIb/IIIa does not bind soluble proteins on unstimulated platelets, but GPIIb/IIIa in activated 5 platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in 10 part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.

Several RGD-containing peptides and -related compounds have been reported which block fibrinogen binding and prevent the formation of platelet thrombi. 15 For example, see Cadroy et al. (1989) J. Clin. Invest. 84: 939-944; Klein et al. U.S. Patent 4,952,562, issued 8/28/90; European Patent Application EP 0319506 A; European Patent Application EP 0422938 Al; European Patent Application EP 0422937 Al; European Patent 20 Application EP 0341915 A2; PCT Patent Application WO 89/07609; PCT Patent Application WO 90/02751; PCT Patent Application WO 91/04247; and European Patent Application EP 0343085 Al.

Compounds of formula (I) below are difficult to 25 prepare. A key difficulty in the synthesis of this class of compounds is the preparation of a derivative of Arg (or another analogue of this amino acid), which is methylated exclusively on the a-amino group. Previous attempts to make peptides containing this amino acid 30 have involved the synthesis of derivatives of MeArg which require relatively expensive starting materials, and multi-step syntheses. For example, the process described in United States Patent Application 07/949,085 uses N-a methyl Tosyl protected Arginine as the initial starting material. Thus, Boc-MeArg protected at the guanidino function with a tosyl group has been prepared 4" starting with tosyl-arginine in a 4-step procedure.

This derivative can then be incorporated into peptides by the solution phase or solid phase method. This method is very expensive and is not easily amenable to 5 bulk preparation. Alternatively, MeArg can be introduced into peptide? via a N^-phthalyl-protected Orn intermediate using the general approach described for Lys derivatives in R. M. Freidinger, J. S. Hinkle, D. S. Perlow, B. H. Arison, J. Org. Chem. (1983), 48: 77-81, 10 and the guanidino group introduced at a later point in the synthesis as described in Z. Tian, R. W. Roeske, • Int. J. Pept. Prot. Res. (1991), 37: 425-429 and references therein. However, this procedure requires many steps resulting in an expensive process. 15 Thus, there is a need for a process capable of providing these compounds that utilizes inexpensive, readily available starting materials and intermediates, cheaper coupling reagents, techniques for cyclizing the compound that do not require high dilution in solvents 20 which are difficult to remove and which result in higher outputs. The present invention involves the use of a protected form of Gin which is dehydrated to give a derivative of 2-amino-4-cyano-butyric acid. Such derivatives of 2~amino-4-cyano-butyric acid have been 25 prepared starting with Gin as described in Z. Grzonka, B. Liberek, Bull. Acad. Pol. Sci. Ser. Sci. Biol. (1969), 17: 219-22; T. Yoneta, S. Shibahara, S. Fukatsu, S. Seki, Bull. Chem. Soc. Jpn. (1978); and M. Wilchek, S. Ariely, A. Patchornik, J. Org. Chem. (1968), 33: 30 1258-9, and these derivatives have also been used to prepare Orn as described in I. Mezo, M. Havranek, I. Teplan, J. Benes, B. Tanacs, Acta Chim. Acad. Sci. Hung. (1975), 85: 201-13. However, derivatives of 2-amino-4-cyano-butyric acid have not been used as synthetic 35 intermediates to produce the selective and efficient methylation of the a-amino group of Orn or Arg, nor the incorporation of these into peptides. Thus, insertion of an alkylation reaction into the reaction scheme (Gin to methyl-2-amino-4-cyano-butyric acid to Ntt-MeOrn)/ provides a novel entree into N^mono-alkyl derivatives of Orn and Arg. This invention involves the novel and more efficient approach to the problem of selectively methylating the a-amino group of Orn or Arg and incorporating N°-MeArg or Na-MeOrn into peptides.

ST1MMARY OF THE INVENTION It is an objective of the present invention to provide processes for the preparation of platelet 15 glycoprotein Ilb/IIIa inhibitors of Formula (I). It is also an objective of the present invention to provide intermediate compounds (of Formulae (II, III, IV, V, and VI) useful in said processes for the preparation of platelet glycoprotein Ilb/IIIa inhibitors. Finally, it 20 is an objective of this invention to provide processes for the preparation of said intermediate compounds. nETATT.r.n description of the tnvf.ntton This invention is directed to a process for the preparation of compounds of formula (1): 26 5 7 5 3 NH 1W f?^xa s - r R».J V-r'-n ° O " H Formula (I) comprising the steps of: (a) alkylating the a-amino group of an aminonitrile of the formula: Nq (CH2)m %hV° OH with an alkylating agent containing the group R3 (provided R3 is not H) to produce a compound of the formula (IV): /CN (CH8)m W i> °n Formula (IV) and coupling with amino acid derivatives to produce a nitrile tripeptide of the formula: N.2. PATENT OFFICE 2 8 MAY 1996 KSCSiVEO PCT /TJS94/03222 265753 (b) reducing the nitrile group from the product of step (a) to form the ;compound of the formula: NH, (c) reacting the amino group of the product of step (b) with a guanylating agent of the formula: N-XX XX-N~\ 2 , to produce the compound of the formula: N-XX XX-N-^ ^NH (CH2>n O I f O W-N N Y^°*Y I, O 7 CN / (CHa) R12 _ (CHa) m ? O \ N r O-Y (d) deprotecting the carboxyl and a-amino groups of the product from step (c) to form the compound of the formula: » 265 7 5 XX-N-\ yHH (?«,)„ ■y \) N-XX f o I * o ■vtrr OH and coupling the compound of the above formula with a carboxylic acid derivative of formula: ho-S^nh-V^ R» to produce a protected linear peptide of formula: N-XX XX-N-\ NH V o ?11 o^Rl-N-^rN-G 10 A R* • (e) removing the protecting group (G) of the product of Step (d) to produce a deprotected linear peptide of formula (III): 26 5 7 5 3 (f) cyclizing the deprotected linear peptide of formula (III) to produce a cyclic peptide of formula (II): . NXX XXN«^ NH / (CHa), * I J ' \ /R12 N R2 N-R11 R6 L d^^R1 I/T H Formula (II) f and (g) then, provided XX is not H when R® is CH2CO2H, converting the 10 : cyclic peptide of the formula (II) by a series of deprotecting and/or alkylating steps to a compound of formula (I): WO 94/22911 PCT/US94/03222 nh 285 7 5 3 "aN NH ^(CHa)n J~cM°c°tR4 Formula (I) wherein: R1 is Ri. pie fjir R18/ wherein: p and p1 are 0 or 1; Rl9 is a C6-C14 saturated/ partially saturated/ or aromatic carbocyclic ring system or heterocyclic ring system composed of carbon atoms and 1- 3 heteroatoms selected from N/ O, S; all t these ring systems being optionally substituted with 1 or 2 R7; R17 and R16 are independently selected from the group: hydrogen/ C1-C4 alkyl, optionally substituted with halogen, C1-C2 alkoxy, and benzyl; 265 R15 and R18 are independently selected from the group: hydrogen, C1-C8 alkyl substituted with 0-2 R8, C2-C8 alkenyl substituted with 0-2 R8, C2-C8 alkynyl substituted with 0-2 R8, c3-c8 cycloalkyl substituted with 0-2 R8, C6"Cio bicycloalkyl substituted with 0-2 R8, Ci-C4 alkoxy' aryl substituted with 0-2 R13, and a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoins with the remaining atoms being carbon, optionally substituted with 1 or 2 R13; R15 and R17 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R13; or R18 and R16 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R13; or R7 is independently selected at each occurrence from the group: H";-phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, Ci-Cs alkyl, C3-C6 cycloalkyl, 265 75 3 C^-Cy cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -C02R20, sulfonamide, formyl, C3-C6 cycloalkoxy, -OC (=0) R2", -C (=0) R20, -OC <»0) OR20®, -OR20, -CH2OR20, and C1-C4 alkyl optionally substituted with -NR20R21; R8 is independently selected at each occurrence from the group: «0, F, CI, Br, I, -CF3, -CN, -CO2R20, -C(»O)NR20R2:L, -CH2OR20, —OC (c0) R20, -CH2NR20R21, and -NR20r21; R13 is independently selected at each occurrence from the group: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C4-C6 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2R20, sulfonamide, formyl, C3-C6 cycloalkoxy, -0C(»0)R20, -C(»O)R20,-OC (=O)OR20a, -OR20, -CH2OR20, and C1-C4 alkyl optionally substituted with -NR20R21; R20 is independently selected at each occurrence from the group: H, C1-C8 alkyl, aryl, -(C1-C6 alkyl)aryl, and C3-C6 alkoxyalkyl; O A R20a is ag defined for R with the exception of H; R21 is independently selected at each occurrence from the group: f r c V.X WO 94/22911 PCT/US94/03222 i2> 26 5 7 5 3 H, C1-C4 alkyl, and benzyl; R12 is H or C^-Cg alkyl; R2 is H, C1-C8 alkyl, c3-c6 cycloalkyl, cycloalkylmethyl, C5-C~ cycloalkylethyl, phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3, CH2SCH3, CH2CH2SCH3, (CH2)sNH2, (CH2)sNHC (»NH) (nh2), Or (ch2)aNHR21, wherein s is 3-5; or R12 and R2 can be taken together to form -(ch2)t~ / or -ch2sc(ch3)2~ t wherein t is 2-4; R3 is H or Ci-Ce alkyl or C1-C4 alkylphenyl; R9 is H or alkyl; R5 is H or C^-Cp alkyl; R11 is H or Ci-Cs alkyl; R4 is independently from: H; ' C1-C8 alkyl; C2-Ce alkenyl; C2-C8 alkynyl; C3-C8 cycloalkyl; Ci-Ca alkyl substituted with aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-c5 alkyl, C1-c5 alkoxy, N02, -S (0) 0-2 (C1-c5 alkyl), OH, 1H. 265 7 5 3 N (R22) 2, C02R22, CON(R22)2 and -CvFw where v = 1 to 3 and « » 1 to (2v+l); C3-C8 cycloalkyl; or *-C (chz) N' lM R aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-C5 alkyl, C3.-C5 alkoxy, NO2, -S (0)0-2 (Cl~ 10 C5 alkyl), OH, N(r22)2/ CO2R22, C0N(R22)2 and -CvFw where v ■ 1 to 3 and w « 1 to (2v+l); C2-C8 alkyl, alkenyl or alkynyl; substituted with 1-2 substituents independently selected from C1-c4 alkyl, c3-c3 cycloalkyl, C1-c5 alkoxy, 15 phenoxy, benzyloxy, halogen, N02, CN, C02R22, CON(R22)2, N(R24)COR24, morpholino, 2- <1-morpholino) ethoxy, N(R22)2, N+(R22)3, OCOCH3, CF3, and s;('oy0_2R22; ' -CH(R24)0R26; -CH(R24)0C(»0)R25; -CH (R24) OC (*0) OR2^; -CH (R24) OC (=0) N (R25) 2; -CH (R24) N (R24) C (»0) R24; -CH(R24)C02R25; -CH (R24) CON (R22) 2; -CH(R24)N(R22)2; A kH, >27 26 5 7 5 3 ; wherein R22 is selected independently at each occurrence ' from: H, C<|-C-|o alkyl, C3-C10 cycloalkyl, C4-C12 alkylcycloalkyl, aryl, (C1-C10 alkyl) aryl, and C3-C10 alkoxyalkyl; or when two R22 groups are bonded to a single N, said R22 groups may alternatively be taken together to form -!CH2)2-5~ or -(CH2)0(CH2)-; R24 is selected independently at each occurrence from: H, C-j-Cs alkyl, C3-C10 cycloalkyl, pheryl an# benzyl; r25 iS selected from: H; IS" O A o o ,27 CH(R24; o >fc 265 75 3 Ci-Cs alkyl or C3-C8 cycloalkyl/ said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: C1-C4 alkyl; c3-C8 cycloalkyl; C1-c5 alkoxy; and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Cj.-C6 alkyl, C1-C6 alkoxy, NO2, -S (C1-c5 alkyl), —SO(C1-c5 alkyl), -SO2(C1-c5 alkyl), -OH, -N(R22)2, -C02R22, —C (=0) N (R22) 2, and -C F where v = 1 v w to 3 and w = 1 to (2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, N02, -S(C1-C5 alkyl), -S0(Ci-C5 20 alkyl), -S02(Ci-C5 alkyl), -OH, -N(r22)2, -co2R22, -C(«0)N(R22)2, and -CVFW where v = 1 to 3 and w » 1 to (2v+l); R26 is selected from: Ci-Ce alkyl or c3-c8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: C3.-c4 alkyl; C3-C8 cycloalkyl; C1-c5 alkoxy; and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-Cg alkyl, C3.-C6 n 26 5 7 5 3 alkoxy, no2, -S (C3.-c5 alkyl), -SO (C1-c5 alkyl),. —SO2 (Cj,—c5 alkyl), -OH, —N (R22) 2, -C02R22, -C (=0) N (R22) 2, -C P where v = 1 v w to 5 and « « 1 to (2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, Ci-Cg alkoxy, N02, -S(Ci-C5 alkyl), -S0(Ci-Cs alkyl), -S02(Ci-C5 alkyl), -OH, -N (R22) 2, -C02R22, -C (=0) N (R22) 2, and -CVFW where v = 1 to 3 a.nd w ® 1 to (2v+l) ; is selected front: h; C3.-C8 alkyl or C3-Ce cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: (i) C1-C6 alkyl; (ii) C1-C6 alkoxy; and (iii) aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Cj-C6 alkyl, C1-C6 alkoxy, no2, -S(C1-c5 alkyl), -SO(C1-C5 alkyl), -S02(Ci-Cs alkyl), -OH, —N (R22) 2, -C02R22, -C («0)N (R22) 21 and where v = 1 to 3 and w ■ 1 to (2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-Cg alkyl, Cj.-C$ alkoxy, NO2, -S(Ci-C5 alkyl), -S0(Ci-C5 alkyl), -SO2(C1-c5 alkyl), -OH, -N (R22) 2, -C02R22, -C(-0)N(R22)2, and wo 94/22911 pct/US94/03222 ,s 265 7 5 3 -CvFw where v = l to 3 and w « 1 to (2v+l); and r28 is selected from: H, C1-c5 alkyl, or 5 benzyl; and R6 is CH2CO2* or CH2C02R4y n is 1 to 4; in is 0 to 3; W and G are amino protecting gtoups and are independently selected from the group 15 consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), - substituted benzyloxycarbonyls, l-(p-20 biphenyl)-1-methylethoxycarbonyl, 9- fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, 25 allyloxycarbonyl, cyclopentyloxyc'arbonyl, adamantyloxycarbonyl triphenylmethyl, benzyl, trimethylsilane, 30 pheriylthiocarbonyl, dithiasuccinoylalkyl-urethane, O-nitrophenylsulfenyl (NPS) and O-nitropyridylsulfenyl (NPYS); Y is H a suitable carboxylate protecting group and can be selected from the group i n 26 5 7 5 3 consisting of: C]_ to Cg alkyl, C5 to Cg eyeloalkylalkyl, benzyl, substituted benzyl, triphenylmethyl, diphenylmethyl, CH2CH2CN' trialkylsilyl, phthalimidomethyl, anthrylmethyl, phenylfluorenyl, 4-picolyl and phenacyl; or any other group which can be cleaved by acidolysis, mild base treatment or mild reductive means.

XX is H or a suitable amino protecting group and is selected from the group consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, phenylthiocarbonyl, dithiasuccinoylalkyl -urethane, O-nitrophenylsulfenyl (NPS), nitropyridylsulfenyl (NPYS), 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr-NR.2), 2,4,S- ^ 265 75 3 trimethoxybenzenesulfonamide (Mtb-NR2), 2,6-dimethyl-4-raethoxybenzenesulfonamide (Mds-NR2), pentamethylbenzenesulfonamide (Pme-NR2), 2, 3, 5,6-tetramethyl-4-methoxybenzene-5 sulfonamide (Mte-NR2), 4-methoxybenzene- sulfonamide (Mbs-NR2), 2,4,6-trimethylbenzenesulfonamide (Mts-NR2), 2,6-dimethoxy-4-methoxybenzenesulfonamide (iMds-NR2), 2,2,5,7,8-pentamethylchroman-6-10 sulfonamide (Pmc-NR2),i and fluorenylphenyl; and Z is a leaving group such as S03~, S-alkyl, 0-alkyl or an O-substituted derivative of hydroxylamine.

The present invention also provides for the process for the preparation of compounds of Formula (I) : nh x «2n nh r3 . Xt'AR" ° j—ch2co2r4 r12-n V Rl-I H Formula (I) comprising the steps of: (a) alkylating an aminonitrile of the formula: ^ 265 75 3 Nq (CH2)m NH OH w with an alkylating agent containing the group R3 (provided R3 is not H) to produce a compound of the formula (IV): CN / (CH2)m w Formula (IV) / converting formula (IV) above through a series of deprotecting steps and coupling with amino acid derivatives to produce a protected nitrile tripeptide of the formula (V): CN R12 o lC\*" \" O w R3 Formula (V) (b) removing the protecting groups of the compound of formula (V) and coupling with a carboxylic acid derivative of the formula: 8 O R11 ho^R1^ nh t WO 94/22911 PCT/US94/03222 265 75 3 wherein G is a suitable amine protecting group, to produce a protected linear peptide of formula: cn P* O (C^a) m ' O '• ' * 1 o J t T (c) removing the protecting group G of the product of Step (b) to produce a deprotected linear peptide of formula: CN / pS Q (CH2) m ' O V-oH r«./ > 0 .V-r; "iV (d) cycli2ing the deprotected linear peptide of the product of step (c) to produce a cyclic peptide of formula (VI): 265 7 5 3 Formula (VI) f (e) reducing the nitrile from the product of step (d) to form the, compound of formula: NH2 / (CHj) „ n a n—< ,P A " " I \ p12 N-R1n -W: ■ H (f) reacting the product of step (e) with a guanylating agent of the formula: N-XX XX-N-\ Z , leading directly to a compound of Formula I, or via a series of deprotecting and/or alkylating steps converting to a compound of formula (I): 26 5 7 5 3 nh jr "a* -V R»Y^0 ( o TP**" —chjcojr* 0 o h Formula (I) wherein R1 to R28 and all other groups are as defined above.

In a preferred embodiment/ the above described processes provide compounds of formula (I) wherein: n is 3/ R19 is selected from: WO 94/22911 PCT/US94/03222 pec y p ^ R15 and R18 are independently selected * ^ from H, C1-C4 alkyl, phenyl, benzyl, alkoxy; benzyl, phenyl- (C2-C4)alkyl, and c,-c, 1 4 R17 and R16 are independently H or C1-c4 alkyl; R7 is H, C1-C0 alkyl, phenyl, halogen, or 10 C1-c4 alkoxy; R11 is H or C1-c3 alkyl; R12 is H or CH3; R3 is H or C^-Cg alkyl; R9 is H or C1-c3 alkyl; R5 is H or Cj-Cg alkyl; R4 is selected ffrom: h;; Ci-Cb alkyl; C2-C8 alkenyl; C2-C8 alkynyl; C3-C8 cycloalkyl; Ci-Ca alkyl substituted with aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-c5 alkyl, C1-c5 alkoxy, N02, -S (0) 0-2 (C1-c5 alkyl) , OH, N (R22) 21 C02R22, C0N(R22)2 and -c f where v w v » 1 to 3 and w «= 1 to (2v+l) ; 35 C3-C8 cycloalkyl; or !■ WO 94/22911 PCT/US94/03222 ~2-& 26 5 7 5 3 (ch2) n" R aryl, optionally substituted with 1-2 substituents 5 independently selected from halogen, phenyl, C1-C5 alkyl, C1-c5 alkoxy, NO2/ -S (0) 0-2 <ci*"c5 alkyl), OH, N(R22)2# C02R22, C0N(R22)2 and -CvFw where v « 1 to 3 and w ■ 1 to (2v+l); C2~C8 alkyl, alkenyl or alkynyl; substituted with 10 1-2 substituents independently selected from C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy, phenoxy, benzyloxy, halogen, NO2, CN, C02R22/ CON (R22) 2/ N(R24)COR24, morpholino, 2-<l-morpholino) ethoxy, N(R22)2/ N+(R22)3, OCOCH3, 15 CF3, and S(0)Q_2R22; -CH (R24)OR26; -CH (R24)OC(=0)R25; -CH (R24) OC (*0) OR2®; -CH (R24) OC (=0) N (R2*) 2; -CH (R24)C02R25; <A< R27 ; and -CH(R^)0-Q t and R 2, R2^, R2^, R^, R27 and R28 are as defined earlie: PCT /US94/03222 ^ 26 5 7 5 3 In the most preferred embodiment, the above-described processes provide compounds of formula (I) wherein: R2 is H or C1-c4 alkyl; R5, R9, R16, R17 and R18 are H; R11 and R12 are H or CH3; R15 is H/ C3.-C4 alkyl, phenyl, benzyl, or phenyl-(C2-C4)alkyl; and R3 is H or C1-c3 alkyl; R4 is selected from: H'j -CH(R24)0C(=0)R25, -CH(R24)0C(=0)0R26, 20 -CH20C(=0)N(R25)2, -CH2CH2N(R22)2/ -CH (R24)C02R25f and A R27 n ; wherein R24.is selected from: H, C.-CQ J. . 8 alkyl, phenyl, and benzyl; and R27 is selected from: C1-c5 alkyl, benzyl and phenyl; and 22 25 27 R , R and R are as defined earlier. •>\ c 28 265 In the specifically preferred embodiment, the above described process provides compounds of formula (I) wherein: n is 3; p is 0, p' is 1; R» is phenyl; R5, R9, R11, and R12 are H; r2 is ethyl; R3 is methyl; and R4 is selected from: H, -CH(R24)0C(«=0)R25, -CH(R24)0C(=0)0R26, and cAo R27 ri ; wherein R24 is C1-c4 linear alkyl or H; and R27 is C1-c4 alkyl, benzyl, or phenyl , and and are as defined earlier., This invention also provides a process wherein the intermediate compound of formula (IV): "Z°\ 265 7 5 3 /CN (CH2)m r° Formula (IV) is prepared by the steps of: (a) dehydrating the carboxamide group of the formula: H*N;=o (cha) rn Wv V/° h oh to the corresponding nitrile to produce the 10 formula: Nq (CHjJm %hy.

OH (b) then selectively alkylating the product of step (a) at the a-amino group using a suitable alkylating agent 3 3 containing the group R (provided R is not H) to produce • formula (IV) above, wherein: R3 is H or Ci-Cb alkyl; m is 0 to 3; and selected from the group consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulf onyl benzyloxycarbonyl (Cbz) , benzyloxycarbonyls/ 1-(p-biphenyl)-1-methylethoxycarbonyl/ 9-fluorenylmethyloxycarbonyl (Fmoc); tert-butyloxycarbonyl ! (Boc), ethoxycarbonyl/ diisopropylmethoxycarbonyl/ allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, phenylthiocarbonyl and dithiasiiccinoylalkyl-urethane.

Further this invention provides a process for preparation of an intermediate compound of the formula: XXN^ NXX \ nh / (CH2)„ Formula (II) 31 26 5 75 3 comprising the steps of cyclizing a compound of formula (III) : n-xx xx-n-\ ^NH (CHa)„ .

O \ R* O I R» ° * ".N r12-n r" O o R rT Formula (ill) wherein: n is 1 to 4; R1 is \v/RVV' 7v cc r" r" r17 R,\ wherein: p and p1 are 0 or 1; r19 is a C6-C14 saturated, partially saturated, or aromatic carbocyclic ring system or heterocyclic ring system composed of carbon atoms and 1-20 3 heteroatoms selected from N, 0, S; these ring systems being optionally 7 substituted with 1 or 2 R ; PCTAJS94/03222 33- 265 75 3 R17 and R16 are independently selected from the group: hydrogen# C1-C4 alkyl, optionally substituted with halogen, C3.-C2 alkoxy, and benzyl; R1^ and R18 are independently selected from the group: hydrogen, C1-C8 alkyl substituted with 0-2 R8, C_ Ca alkenyl substituted with 0-2 R8, C2-C8 alkynyl substituted with 0-2 R8, C3-C8 cycloalkyl substituted with 0-2 C6-C10 bicycloalkyl substituted with 0-2 R8, cI~c4 ^^oxy, aryl substituted with 0-2 R13, and a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms with the remaining atoms being carbon, optionally substituted with 1 or 2 R13; R15 and R17 can alternatively join to form a 5-1 membered carbocyclic ring substituted with 0-2 R13; or R8, WO 94/22911 PCT/US94/03222 33 26 5 7 5 3 R18 and R16 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R13; i R7 is independently selected at each occurrence from the group: H, phenyl# benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy/ nitro, 10 cyano/ Ci-Cs alkyl, C3-C6 cycloalkyl, C4-c^ cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2R20, sulfonamide, formyl, C3-C6 cycloalkoxy, -0C(»0)R20, -C(=O)R20,-OC(«O)OR2°a, 15 -OR20, -CH2OR20, and C1-c4 alkyl optionally substituted with -Nr20r21.

R8 is independently selected at each occurrence from the group: =0, F, CI/ Br/ 1/ -CF3, -CN, -CO2R20, -C(»O)NR20R21, -CH2OR20, -OC(=0)R20, -CH2NR20R21., and -NR20R21/ R13 is independently selected at each occurrence from the group: phenyl, benzyl, phenethyl, phenoxy/ benzyloxy, halogen, hydroxy, nitro, 30 cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C4-C^ cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2R20/ sulfonamide, formyl, C3-C6 cycloalkoxy, -0C(«0)R20, -C(=O)R20/-OC(«O)OR20a, WO 94/22911 PCT/US94/03222 34- 265 7 5 3 -OR20/ -ch2or20/ and C1-c4 alkyl optionally substituted with -nr20r21; R20 is independently selected at each 5 occurrence from the group: H, Ci-Ca alkyl, aryl, -(Ci-Cfi alkyl)aryl, and C3-C6 alkoxyalkyl; « A R20a is as defined for R with the exception of H; R^l is independently selected at each occurrence from the group: H, C1-C4 alkyl, and benzyl; R12 is H or C1-C8 alkyl; R2 is H, C1-C8 alkyl/ C3-C6 cycloalkyl, C4~C.7 cycloalkylmethyl, C^-Cg cycloalkylethyl, phenyl, phenylmethyl, CH2OH/ CH2SH/ CH2OCH3/ 20 CH2SCH3/ CH2CH2SCH3, (CH2)aNH2/ (CH2)sNHC(»NH) {NH2) / or (CH2)aNHR21, wherein s is 3-5; or R12 and R2 can be taken together to form -(CH2)t~ / 25 or -CH2SC(CH3)2- / wherein t is 2-4; r3 is H or Ci-Ca alkyl; R9 is H or C^-Cg alkyl; R5 is H or ci""cg alkyl; R11 is H or Ci-Ce alkyl; R6 is CH2C02* or CH2C02R4;.

WO 94/22911 PCT/US94/03222 3S 265 753 Y is a suitable carboxylate protecting group and can be selected from the group consisting of: to Cg alkyl, C5 to Cg cycloalkylalkyl, benzyl, substituted benzyl, triphenylmethyl, diphenylmethyl, CH2CH2CN, 10 trialkylsilyl, phthalimidomethyl, anthrylmethyl, phenylfluorenyl, 4-picolyl and phenacyl; or any other group which can be cleaved by acidolysis, mild base treatment or mild reductive means; and XX is H or a suitable amino protecting group and is selected from the group consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, allyloxycarbonyl, eyelopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, phenylthiocarbonyl, dithiasuccinoylalkyl -urethane, O-nitrophenylsulfenyl (NPS), 26 5 7 5 3 nitropyridylsulfenyl (NPYS) / 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr-NR2)/ 2,4,6-trimethoxybenzenesulfonamide (Mtb-NR2)/ 2,6-dimethyl-4-ntethoxybenzenesulfonaraide (Mds-NR2)/ pentamefchylbenzenesulfonamide (Pme-NR2), 2/3,5/6-tetramethyl-4-methoxybenzene-sulfonamide (Mte-NR2), 4-methoxybenzene-sulfonamide (Mbs-NR2), 2,4,6-trimethylbenzenesulfonamide (Mts-NR2), 2,6-dimethoxy-4-methoxybenzenesulfonamide (iMds-NR2) / 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc-NR2), and fluorenyiphenyl.

In a preferred embodiment/ the above described 15 process provides an intermediate compound of formula (II) wherein: n is 3; R19 is selected from: and r>V WO 94/22911 1 TH'rtJfffflil/fn??,?; 26 575 3 37 R15 and R18 are independently selected from H, c3.-c4 alkyl, phenyl, benzyl, phenyl-(c2-c4)alkyl, C1-c4 alkoxy; R17 and R16 are independently H or C1-c4 alkyl; R7 is H, Ci-Cs alkyl, phenyl, halogen, or 10 C1-c4 alkoxy; R11 is H or C1-c3 alkyl; R12 is H or CH3; R9 is H or alkyl; R5 is H or alkyl; and XX is selected from the group consisting of: t-Boc, acyl, o-nitrophenylsulfenyl, Cbz, Fmoc, and fluorenylphenyl.

In a more preferred embodiment, the above- described process provides intermediate compounds of formula (II) wherein: R2 is H or C1-C4 alkyl; r5, r9, r16; pi7 and r18 are h; R11, and R12 are H or CH3; 35 or R2 and R12 together are -(CH2)3~; N.Z. PATENT OFFICE 2 S HAY 1996 3B R15 is H, C1-C4 alkyl, phenyl, benzyl* or phenyl-(C2-C4)alkyl; and R3 is H or C1-c3 alkyl.

The above-described process specifically provides intermediate compounds of formula (II) wherein: p is 0, p' is 1; n is 3; R19 is phenyl; R5, R9, R11, and Rl2 are H; R2 is ethyl; R3 is methyl; R^ is CH2-OBn, CH2~OtBu, or CH2~0-tBoc; and XX is Cbz or Boc.

This invention also provides intermediate compounds useful in the claimed processes for the preparation of compounds of formula (I). Said 30 intermediate compounds have formulae: WO 94/22911 PCT/US94/03222 3^ , nxx XXN^^ \ nh / (CHa) 265 r3.

N o cps\ o12 n- r11 * Formula (II) # Formula (111) cn /CN R« o (C\"m f <? "■h^rr>5r ~ if °n Formula (IV) Formula (V) cn / (CHa) m y a, v oK- o r — Formula (VI) , and wherein: PCT/US94/Q3222 to 26 5 7 5 S R1 is w r" r" r17 R18, wherein: p and p' are 0 or 1; R19 is a Cfi-Ci4 saturated, partially saturated, or aromatic carbocyclic ring system or heterocyclic ring system composed of carbon atoms and 1-3 10 ' heteroatoms selected from N, 0, S; these ring systems being optionally 7 substituted with 1 or 2 R ; R17 and R16 are independently selected from 15 the group: hydrogen, C1-c4 alkyl, optionally substituted with halogen, C1-c2 alkoxy, and benzyl; r!5 and R*® are independently selected from the group: hydrogen, C1-C8 alkyl substituted with 0-2 R8, C2-C8 alkenyl substituted with 0-2 R8, C2-C8 alkynyl substituted with 0-2 R8, 30 C3-c8 cycloalkyl substituted with 0-2 r®, C6-C10 bicycloalkyl substituted with 0-2 R8/ C1~C4 al^oxY' WO 94/22911 PCT/US94/03222 ^ 265 7 5 3 aryl substituted with 0-2 and a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, 5 or sulfur heteroatoins with the remaining atoms being carbon, optionally substituted with 1 or 2; or R15 and R17 can alternatively join to form a 10 5-7 membered carbocyclic ring substituted with 0-2 R13; or R18 and R16 can alternatively join to form a 5-7 membered carbocyclic ring 15 substituted with 0-2 R13; or R7 is independently selected at each occurrence from the group: H,phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, Ci-Cg alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2R20, 25 sulfonamide, formyl, C3-C6 cycloalkoxy, -0C(«0)R20, -C(«O)R20,-OC(»O)OR20b/ -OR20, -ch2or20, and C1-c4 alkyl optionally substituted with -Nr20r21; R8 is independently selected at each occurrence from the group: «0, F, CI, Br, I, -CF3, ~CN, -CO2R20, -C(»0)NR20R21, -CH2OR20, -OC(«0)R20, -CH2NR20R21, and -NR20R21; PCT/US94/G3222 43- 26 5 7 5 3 Rl3 is independently selected at each occurrence from the group:• phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C4-C^ cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2R20r 10 sulfonamide, formyl, c3-c6 cycloalkoxy, -OC (»0) R20, -C («=0) R20, -OC (=0) OR20a, -OR20, -CH20R20, and C1-c4 alkyl optionally substituted with -NR2^r21; R20 is independently selected at each occurrence from the group: H, C1-C8 alkyl, aryl, -(Ci-Cg alkyl)aryl, and C3-C6 alkoxyalkyl; R20a as defined for with the exception of H; r21 is independently selected at each occurrence from the group: H, C1-C4 alkyl, and benzyl; R12 is H or C£-Cjj alkyl; R2 is H, C1-C8 alkyl, C3-C6 cycloalkyl, C4-c7 cycloalkylmethyl, C5-C8 cycloalkylethyl, 30 phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3, CH2SCH3, CH2CH2SCH3, (CH2)sNH2, <CH2) SNHC <»NH) (NH2), or <CH2) 8NHR21, wherein s is 3-5; or R12 and R2 can be taken together to form -(CH2)t~ / or -CH2SC(ch3)2~ r wherein t is 2-4; WO 94/22911 PCT/US94/03222 4.3 26 5 7 5 3 % R3 is H or Ci-Ce alkyl; R9 is H, Ci-Cb alkyl; R5 is H, C1-C8 alkyl; R11 is H or Ci-Cfl alkyl; R6 is CH2CO2Y or CH2CO2R4; R4 is selected from: H ; Ci-Ce alkyl, C2-C8 alkenyl, C2-CB alkynyl, c3-c8 cycloalkyl, Ci-Ce alkyl substituted with aryl, optionally substituted with 1-2 substituents independently selected from halogen/ phenyl, C1-C5 alkyl, C1-C5 alkoxy, no2, -S(0)0-2(C1-c5 alkyl), OH, N (R22) 2/ C02R22, CON (R22) 2 and -C F where v w v ■ 1 to 3 and w «= 1 to (2v+l); C3-C8 cycloalkyl, or (ch2) (m n R $ aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-c5 alkyl, C1-c5 alkoxy, NO2/ -S(0)0-2 (C1-c5 WO 94/22911 PCT/US94/03222 ^ 265 75 3 alkyl), OH, N<R22)2, C02R22, CON(R22)2 and -C F v w where v ■ 1 to 3 and w » 1 to (2v+l); C2-Ca alkyl, alkenyl or alkynyl; substituted with 1-2 substituents independently selected from 5 C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy, phenoxy, benzyloxy, halogen, N02, CN, C02R22, CON (R22) 2, N<R24)COR24, morpholino, 2-(l- morpholino)ethoxy, N(R22)2, N+(R22)3, 0C0CH3, no CF3, and S (O)'0_2R ; CH(R24)OR'*, CH(R24)OC(«0)R25, CH(R24)0C(=0)0R26, CH(R24)0C(«0)N(R25)2, CH (R24) N <R24) C (-0) R24, CH(R24)C02R25, CH(R24)C0N(R22)2/ CH(R24)N(R22)2, O o-N >27 1 o o b27 -CH(R24)0 o PCT AJS94/03222 265 75 3 r22 is selected independently at each occurrence froii H, ci~cio alky1/ c3~ci0; cycloalkyl, C4~C12 alkylcycloalkyl, aryl, (C^C.^ alkyl) aryl, or C^-C^ alkoxyalkyl; or when two R22 groups are bonded to a single N, said R22 groups may alternatively be taken together to form -(CH2>2-5~ or -<CH2)0(CH2)-; r24 is selected independently at each occurrence froi H, C^-Cg alkyl, C3_C^Q cycloalkyl, phenyl, and benzyl;, r25 is selected from: H; Ci-Cs alkyl or C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: C1-c4 alkyl; C3-C8 cycloalkyl; C1-c5 alkoxy; and aryl substituted with 0-2 groups independently selected from: 265 halogen, phenyl, C1-C6 alkyl, Ci-Ce alkoxy, NO2, -S(Ci-Cs alkyl), -SO(C1-c5 alkyl), -SO2(C1-c5 alkyl), -OH, -N(R22)2/ -C02R22, -C(»0)N(R22)2/ and -C F where v = 1 V w to 3 and w » 1 to (2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C2.-C6 alkyl, Ci-Cfi alkoxy, NO2/ ~S (C1-C5 alkyl), —SO{C1-C5 alkyl), -S02(Ci-Cs alkyl), -OH, -N (R22) 2, -co2r22, —C (=0) N (R22) 2/ or -CVFW" where v"= 1 to 3 and w = 1 to (2v+l); R26 is selected from: C1-C8 alkyl or C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: C1-c4 alkyl; c3-c8 cycloalkyl; C1-C5 alkoxy; and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-C$ alkyl, C1-C6 alkoxy, N02, -S<Ci-Cs alkyl), -SO(Ci-C5 alkyl), -S02(Ci-C5 alkyl), -OH, —N (R22) 2, -co2r221 -C («0) N (R22) 2, and -C F where v = 3 v w to 3 and w « 1 to (2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-Cg alkyl, Ci-Cg alkoxy, N02, -S(Ci-C5 alkyl), -S0(Ci-C5 alkyl), -S02(Ci-C5 alkyl), -OH, WO 94/22911 PCT/US94/Q3222 4-1 265 7 5 3 —N (R22) 2t -C02R22/ -C{«0)N(R22)2,and -CVFW where v « 1 to 3 and w = 1 to (2v+l); R2"7 is selected from: H ; Ci-C8 alkyl or C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: (i) C1-C6 alkyl; <ii) C1-C6 alkoxy; and ' (iii) aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-C« alkyl, C3.-C6 alkoxy, N02, -S(C1-C5 alkyl), -SO(Ci-C5 alkyl), -S02(Ci-C5 alkyl), -OH, —N(R22) 2/ -C02R22, -C (»0)N (R22) 2/ and -C F where v = 1 v w to 3 and w ■ 1 to <2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C3.-C6 alkyl, C1-C6 alkoxy, N02, -S(Ci-C5 alkyl), -SO(Ci-C5 25 alkyl), -S02(Ci-Cs alkyl), -OH, —N (R22) 2/ -CO2R22, -C(»0)N(R22)2, and -CvFw where v ■ 1 to 3 and w « 1 to (2v+l); R28 is selected from: H, C3.-C5 alkyl, or benzyl; n is 1 to 4; m is 0 to 3; 26 5 753 Y is a suitable carboxylate protecting group and can be selected from the group consisting of: to Cg alkyl, C5 to Cg cycloalkylalkyl, benzyl, substituted benzyl, triphenylmethyl, diphenylmethy1, CH2 CH2 CN, trialkylsilyl, phthalimidomethyl, anthrylmethyl, phenylfluorenyl, 4-picolyl and phenacyl; or any other group which can be cleaved by acidolysis, mild base treatment or mild reductive means; W is an amino protecting group and is selected from the group consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, phenylthiocarbonyl, dithiasuccinoylalkyl -urethane, f # wo 94/22911 PCT/US94/03222 W 265753 0-nitrophenylsulfenyl (NPS) and * ** ** nitropyridylsulfenyl (NPYS); and XX is H or a suitable amino protecting group 5 and is selected from the group consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, 10 9-fluorenylmethyloxycarbonyl (Fmoc) , tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, 15 phenylthiocarbonyl, dithiasuccinoylalkyl -urethane, O-nitrophenylsulfenyl (NPS), nitropyridylsulfenyl (NPYS), 2,3,6-trimethyl-4 -methoxybenzenesulfonamide (Mtr-NR-2) , 2,4,6-trimethoxybenzenesulfonamide (Mtb-NR.2) , 2,6-20 dimethyl-4-methoxybenzenesulfonamide (Mds- NR2) / pentamethylbenzenesulfonamide (Pme-NR2) / 2,3,5,6-tetramethyl-4-methoxybenzene-sulfonamide (Mte-NR2), 4-methoxybenzenesulf onamide (Mbs-NR^), 2,4,6-25 trimethylbenzenesulfonamide (Mts-NR2)/ 2,6- dimethoxy-4-methoxybenzenesulfonamide (iMds-NR2)/ and pentamethylchroman-6-sulfonamide (Pmc-NR2).

So 26 5 7 5 3 Preferred-intermediate compounds of formulae II, IV and V are those wherein: W and XX are independently Cbz, or t-Boc; r19 is selected from: R15 and R18 are independently selected from H, C1-C4 alkyl, phenyl, benzyl, phenyl-(C2-C4)alkyl, C1-C4 alkoxy; R17 and R16 are independently H or C3.-C4 alkyl; R7 is H, Ci-Ca alkyl, phenyl, halogen, or C\-C4 alkoxy; R11 is H or C1-C3 alkyl; R12 is H or CH3; R9 is H, or C^-C^ alRyl; / / 26575, R5 is H or C1-C3 alkyl; R4 is selected from: H, Ci-Ca alkyl, C2~Cb alkenyl, C2-C0 alkynyl, c3-C0 cycloalkyl, Ci-Ca alkyl substituted with aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-c5 alkyl, C1-c5 alkoxy, NO2/ -S (0) 0-2 (C1-c5 alkyl), OH, N (R22) 2/ C02R22, CON (R22) 2 and -CvFw-where v ■ 1 to 3 and w « 1 to (2v+l); C3-C8 cycloalkyl; or aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-c5 alkyl, c3.-c5 alkoxy, N02, -S (0) 0-2 (C1-C5 alkyl), OH, N(R22)2, C02R22, C0N(R22)2 and -CvFw where v « 1 to 3 and w « 1 to (2v+l); C2-C8 alkyl, alkenyl or alkynyl; substituted with 1-2 substituents independently selected from C1-C4 alkyl, C3-Cs cycloalkyl, C1-c5 alkoxy, phenoxy, benzyloxy, halogen, N02/ CN, co2r22, CON (R22) 2/ K(R24)COR24, xnorpholino, 2-(l-morpholino) ethoxy, N(R22)2/ N+(R22)3, OCOCH3, cf3, •and S(0)Q-2R22; -CH(R24)OR26, S3- -ch(r24)OC(=o)R25, 26 5 7 5 3 -CH(R24)0C(=0)0R26, -CH (R24) OC («0) N (R25) 2/ -CH (R24) C02R25, A R 27 and -CH(R24)0 u ; and m is 2/ and n is 3., and 'R22, R24, R25, R27, and R28 are as defined earlier.

Most preferred intermediate compounds of formulae II, III, IV and V are those preferred compounds wherein: R2 is C1-C4 alkyl; R5, R9, R16, R17 and R18 are H; R11, and R12/ are H or CH3; R15 is H, C1-C4 alkyl, phenyl, benzyl, or phenyl-(C2~C4)alkyl; R3 is H or C1-c3 alkyl; R4 is selected from: H, -CH(R24)0C(«0)R25' -CH (R24)OC(«O)0R2S, WO 94/22911 PCT/US94/03222 53 -CH20C<»0)N{R25)2, 26 5 75 3 -CH2CH2N(R22)2, -CH(R24)C02R25, and u <A R27 n ; wherein R24 is H, Ci-Ca alkyl, phenyl/ or benzyl; R27 is C1-C5 alkyl/ benzyl or phenyl; and m is 2, and n is 3, and 27 25 26 R , R and R are as defined in claim 14.

Specifically preferred compounds of formulae II/ III, IV/ and V are those wherein: p is 0, p' is 1; Rl9 is phenyl R5, R9, R11, and R12 are H? R2 is ethyl; r3 is methyl; m is 2/ and n is 3 R^ is CH2-OBn/ CH2~OtBu, or CH2-0-tBoc; R4 is selected from: H, -CH(R24)0C(«0)R25, 26 5 > 5 -CH(R24)0C<«O)OR26' A R27 ; wherein R24 is c3.-c4 linear alkyl or H; and R2"7 is C1-c4 alkyl, benzyl, or phenyl; XX is Cbz or Boc, and _25 "i, 26 R and R are as defined earlier.

The compounds of Formula (I) are described in PCT Publication No'. W09 4/22910 whiGh is hereby incorporated by reference. ••'•ii ■ ' ■ . i .

The compounds herein described may have stereogenic centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the 20 present invention. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Two distinct isomers (cia and trans) of the peptide bond are 25 known to occur; both can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Unless otherwise specifically noted, the L-isomer of the amino acid is the preferred stereomer of the present 30 invention. The D and L-isomers of a particular amino acid are designated herein using the conventional 3- PCT AJS94/03222 *5 letter abbreviation of the amino acid, as indicated by the following examples: d-Leu, or L-Leu.

When any variable (for example, R1 through R0, m, n, p, W, Y, etc.) occurs more than one time in any 5 constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen 15 bridge; "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; and "biycloalkyl" is intended to include saturated bicyclic ring groups such as 13.3.0]bicyclooctane, 20 [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any 25 stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, 30 such as ethynyl, propynyl and the like. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like. 35 As used herein, "aryl" is intended to mean phenyl or naphthyl; "carbocyclic" is intended to mean any PCT /US94/03222 SG stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are 5 not limited to cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heterocyclic ring system" is intended to mean a stable 10 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of N, O and S and 15 wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.' The heterocyclic ring may be 20 attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen, atom if the resulting compound is stable. Examples of such heterocycles 25 include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-30 pyrrolidonyi, pyrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl.

By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive 35 isolation to a useful degree of purity from a reaction PCT /US94/03222 ^7 mixture, and formulation into an efficacious therapeutic agent.

The term "substituted", as used herein, means that one or more hydrogen on the designated atom is replaced 5 with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.

As used herein and in the claims, the term "amine protecting group" means any group known in the art of 10 organic synthesis for the protection of amine groups. Such amine protecting groups include those listed in Greene, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1981); and Geiger and K5nig, "The Peptides: Analysis, Sythesis, Biology, Vol. 3, 15 Academic Press, New York (1981), the disclosures of which are hereby incorporated by reference. Any amine protecting group known in the art can be used. . Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, 20 trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-25 butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) 30 trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.

As used herein and in the claims, "carboxylate protecting groups" means any group known in the art of 35 organic synthesis for the protection of carboxylate groups. Such carboxylate protecting groups include PCT /US94/03222 se those listed in R. W. Roeske, in The Peptides, Vol 3/ Protection of functional groups in peptide synthesis/ (1981), pp 1-99; Academic Press, the disclosures of which are hereby incorporated by reference. Tiny 5 carboxylate protecting group known in the art can be used. Examples of carboxylate protecting groups include, but are not limited to, the following: alkyl esters such as Ci to Cs alkyl, C5 to Cs cycloalkylalkyl and t-butyl; aryl esters such as benzyl/ substituted 10 benzyl, triphenylmethyl, diphenylmethyl, pentamethylbenzyl,tetramethylbenzyl, and trimethylbenzyl; or esters which can be cleaved by acidolysis, mild base treatment or mild reductive means such as trichloroethyl and phenacyl esters; other 15 protecting groups can be CH2CH2CN, trialkylsilyl, phthalimidomethyl, anthrylmethyl/ phenylfluorenyl, 4-picolyl and phenacyl.

As used herein, "pharmaceutically acceptable salts and prodrugs" refer to derivatives of the disclosed 20 compounds that are modified by making acid or base salts/ or by modifying functional groups present in the compounds in such a way that the modifications are cleaved/ either in routine manipulation or in vivo. to the parent compounds. Examples include, but are not 25 limited to: mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; esters of carboxylates; acetate, formate and benzoate derivatives of alcohols and amines; and the like. 30 Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the 35 two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmarpntiral Sff^nnas. 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The term "amino acid" as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are modified and unusual amino acids,such as those disclosed in, for example, Roberts and Vellaccio (1983) The 10 Peptides. 5: 342-429, the teaching of which is hereby incorporated by reference.

The term "amino acid residue" as used herein means that portion of an amino acid (as defined herein) that is present in a peptide or pseudopeptide. The term 15 "peptide" as used herein means a linear compound that consists of two or more amino acids (as defined herein) that are linked by means of peptide or pseudopeptide bonds.

Synthesis The following abbreviations are used herein: D-Abu o-2-aminobutyric acid P-Ala or bAla 3-aminopropionic acid Boc t-butyloxycarbonyl Boc-iodo-Mamb t-butyloxycarbonyl-3-aminomethyl-4-iodo- benzoic acid Boc-Mamb t-butyloxycarbonyl-3-aminomethylbenzoic acid Boc-ON [ 2-(tert-butyloxycarbonyloxylimino)-2- phenylacetonitrile BOP benzotriazole-l-yl-oxy-tris- (dimethylaminophosphonium- hexafluorophosphate) cc> CI2B2I CBZ DCC DIEA di-NMeOrn DMAP HBTU KHMDS K-O-t-Bu LDA LiHMDS NaHMDS Na-O-t-Bu NMeArg or Me Arg NMeAmf NMeAsp NMeGly or MeGly NMe-Mamb NMM OcHex OBzl PyBOP PyBrOP TBTU TOS dichlorobenzyl Carbobenzyloxy dicyclohexylcarbodiimide diisopropylethylamine N-aMe-N-YMe-ornithine 4-dimethylaminopyridine 2-(IH-Benzotriazol-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate potassium bis(trimethylsilyl)amide potassium tert-butoxide lithium isopropylamide lithium bis(trimethylsilyl)amide sodium bis(trimethylsilyl)amide sodium tert-butoxide a-N-methyl arginine N-Methylaminomethylphenylalanine a-N-methyl aspartic acid N-methyl glycine N-rnethyl-3-aminomethylbenzoic acid N-methylmorpholine O-cyclohexyl O-benzyl benzotriazole-l-yl-oxy-tris-(pyrolidino phosphonium hexafluorophosphate) Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate 2-(lH-Benzotriazol-l-yl)-l,1, 3,3-tetramethyluronium tetrafluoroborate tosyl The following conventional three-letter amino acid abbreviations are used herein; the conventional one-letter amino acid abbreviations are not used herein: 6t Ala = alanine Arg = arginine Asn = asparagine Asp = aspartic acid Cys = cysteine Gin = glutamine Glu = glutamic acid Gly = glycine His - histidine He = isoleucine Leu = leucine Lys = lysine Met « methionine Nle « norleucine Orn «s ornithine Phe ■ phenylalanine Phg « phenylglycine Pro « proline Ser = serine Thr ■ threonine Trp « tryptophan Tyr « tyrosine Val = valine The present invention provides a process for the synthesis of compounds of formula (I). The provided process is accomplished using inexpensive, simple 30 starting materials and a more efficient approach to the problem of incorporating NMeArg into peptides. The overall process is novel: it utilizes novel reaction steps, novel reaction sequences, and novel reaction intermediates. In practicing the provided invention, 35 knowledge of a number of standard techniques known to PCT /US94/03222 (o~L those in the art is required. The following discussion and references are offered to provide such knowledge.

Generally, peptides are elongated by deprotecting the a-amine of the C-terminal residue and coupling the next suitably protected amino acid through a peptide • linkage using the methods described. This deprotection and coupling procedure is repeated until the desired sequence is obtained. This coupling can be performed with the constituent amino acids in a stepwise fashion, 10 or condensation of fragments (two to several amino acids), or combination of both processes, according to the methods described by Merrifield, J. Am. Chem. Soc., 85: 2149-2154 (1963); "The Peptides", Vol. 1, 2, 3, 5, and 9, (19*79-1987), E. Gross and J. Meienhofer, eds, 15 Academic Press, , Academic Press, New York; Bodanszky, "Peptide Chemistry: A Practical Textbook", Springer-Verlag, New York (3 988); Bodanszky et al. "The Practice of Peptide Sythesis" Springer-Verlag, New York (1984) ; the disclosures of which are hereby incorporated by 20 reference.

The coupling of two amino acid derivatives, an amino acid and a peptide, two peptide fragments, or the cyclization of a peptide can be carried out using standard coupling procedures such as the azide method, 25 mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimides) method, active ester (p-nitrophenyl ester, N-hydroxysuccinic imido ester) method, Woodward reagent K 30 method, carbonyldiimidazole method, phosphorus reagents such as BOP-C1, or oxidation-reduction method. Some of these methods (especially the carbodiimide) can be enhanced by the addition of 1-hydroxybenzotriazole. These coupling reactions may be performed in either 35 solution (liquid phase) or solid phase.

PCT /US94/03222 C3 The functional groups of the constituent, amino acids must be protected during the coupling reactions to avoid undesired bond formation. The protecting groups that can be used, methods of using them to protect amino 5 acids, and methods to remove them are listed as above.

The a-carboxyl group of the C-terminal residue is usually protected by an ester that can be cleaved to give the carboxylic acid. These protecting groups include but are not meant to be limited to: 1) alkyl 10 esters such as methyl and t-butyl, 2) aryl esters such as benzyl and substituted benzyl/ or 3) esters which can . be cleaved by mild base treatment or mild reductive means such as trichloroethyl and phenacyl esters. In the solid phase case, the C-terminal amino acid is 15 attached to an insoluble carrier (usually polystyrene). These insoluble carriers contain a group which will react with the carboxyl group to form a bond which is stable to the elongation conditions but readily cleaved later. Examples of which are: oxime resin (DeGrado and 20 Kaiser (1980) J. Org. Chem. 45: 1295-1300) chloro or bromomethyl resin, hydroxymethyl resin, and aminomethyl resin. Many of these resins are commercially available with the desired C-terminal amino acid already incorporated.

The a-amino group of each amino acid must be protected. Any amine protecting group known in the art can be used. Examples of these are: 1) acyl types such as formyl, trifluoroacetyl/ phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as 30 benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1- methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, 35 diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as £>4- cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and 5 dithiasuccinoyl. The preferred a-amino protecting group is either Cbz, Boc or Fmoc. Many amino acid derivatives suitably protected for peptide synthesis are commercially available.

The a-amino protecting group is cleaved prior to the coupling of the next amino acid. When the Cbz group is used, the reagents of choice are hydrogenation - conditions using hydrogen at atmospheric pressure or in a Parr apparatus at elevated hydrogen pressure, or cyclohexene or ammonium formate over palladium/ 15 palladium hydroxide on charcoal or platinum oxide in methanol/ ethanol or tetrahydrofuran, or combination of these solvents (P. N. Rylander, Hydrogenation Methods, Acedemic Press, 1985). When the Boc group is used, the methods of choice are trifluoroacetic acid, neat or in 20 dichloromethane, or HC1 in dioxane. The resulting ammonium salt is then neutralized either prior to the coupling or in situ with basic solutions such as aqueous buffers, or tertiary amines in dichloromethane or dimethylformamide. When the Fmoc group is used, the 25 reagents of choice are piperidine or substituted piperidines in dimethylformamide, but any secondary amine or aqueous basic solutions can be used. The deprotection is carried out at a temperature between 0°C and room temperature.

Any of the amino acids bearing side chain functionalities must be protected during the preparation of the peptide using any of the above-identified groups. Those skilled in the art will appreciate that the selection and use of appropriate protecting groups for 35 these side chain functionalities will depend upon the (oS amino acid and presence of other protecting groups in the peptide. The selection of such a protecting group is important in that it must not be removed during the deprotection and coupling of the a-amino group. For 5 example, when Cbz is chosen for the a-amine protection the following protecting groups are acceptable: p-toluenesulfonyl (tosyl) moieties for arginine; t-butyloxycarbonyl, phthalyl, or tosyl for lysine or ornithine; alkyl esters such as cyclopentyl for 10 glutamic and aspartic acids; alkyl ethers for serine and threonine/ and the indole of tryptophan can either be left unprotected or protected with a formyl group.

When Boc is chosen for the a-amine protection the following protecting groups are acceptable: p-15 toluenesulfonyl (tosyl) moieties and nitro for arginine; benzyloxycarbonyl/ substituted benzyloxycarbonyls, or tosyl for lysine; benzyl or alkyl esters such as cyclopentyl for glutamic and aspartic acids; benzyl ethers for serine and threonine; benzyl ethers, 20 substituted benzyl ethers or 2-bromobenzyloxycarbonyl for tyrosine; p-methylbenzyl, p-methoxybenzyl, acetamidomethyl/ benzyl, or t-butylsulfonyl for cysteine; and the indole of tryptophan can either be left unprotected or protected with a formyl group. 25 When Fmoc is chosen for the a-amine protection usually tert-butyl based protecting groups are acceptable. For instance, Boc can be used for lysine, tert-butyl ether for serine/ threonine and tyrosine, and tert-butyl ester for glutamic and aspartic acids. 30 Once the elongation and cyclization of the peptide is completed all of the protecting groups are removed. For the liquid phase synthesis the protecting groups are removed in the manner dictated by the choice of protecting groups. These procedures are well known to 35 those skilled in the art.

PCT /US94/03222 (0(0 Unusual amino acids used in this invention can be synthesized by standard methods familiar to those skilled in the art ("The Peptides: Analysis, Sythesis, Biology, Vol. 5, pp. 342-449/ Academic Press, New York 5 (1981)). N-Alkyl amino acids can be prepared using proceedures described in previously (Cheung et al., (19*77) Can. J. Chem. 55: 906; Freidinger et all, (1982) J. Org. Chem. 84: 77 (1982))/ which are incorporated here by reference.

The process of the present invention utilizes the general methods described above along with the novel methods described below to prepare the compounds of Formula (I) : NH hA 2 NH_ ^(CH2)n , \ R# O rj^A_ O r r«T V-r1^n o O H Formula (I) A protected form of Gin is. dehydrated to give the corresponding protected derivative of 2-amino-4-cyano-20 butyric acid, which then can be methylated exclusively at the 2-amino group. At a convenient point in the synthesis, the 4-cyano group is reduced to the corresponding aminomethyl group# giving a derivative of methy 1—ornithine • Guanylatxcn of this amine# for 25 instance as described in Z. Tian, R. W. Roeske, Int. Journal Pept. Prot. Res. 1991/ 37: 425—429 and G1 references therein, and which is hereby incorporated by reference, converts the N^methyl-ornithine into a derivative of N^-MeArg.

The process of the present invention begins with 5 the sequence of steps shown in Scheme I.

Schema Z PAKT A.

Part A.

Step 1 of the process begins with a commercially available compound (1) in which W is an amine protecting group, such as an alkyl-urethane, t-Boc, acyl, phthalyl, o-nitrophenylsulfenyl, Cbz, Fmoc, fluorenylphenyl, or 15 some other amine protecting group as described above. The preferred protecting group is Cbz.

The carboxamide group of formula (1) is dehydrated to the corresponding nitrile through the action of an appropriate dehydrating agent such as COC12/ acetic 20 anhydride, or a coupling agent as described in the references: Z. Grzonka, B. Liberek, Bull. Acad. Pol. Sci. Ser. Sci. Biol. (1969), 17: 219-22; T. Yoneta, S. Shibahara, S. Fukatsu, S. Seki, Bull. Chem. Soc. Jpn. (1978); M. Wilchek, S. Ariely, A. Patchornik, J, Org. 25 Chem. (1968), 33: 1258-9, which are hereby incorporated by reference. The preferred reagent is phosgene in toluene, THF, dioxane or methylene chloride or mixtures 68 of these solvents at temperatures ranging from 0° to 50°C.

The resulting aminonitrile compound (2) is then selectively alkylated at the a-amino group using an alkylating agent, such as an alkyl halide or dialkylsulfate, and a base, such as NaH or K-O-t-Bu, Na~ O-t-Bu, LDA, LiHMDS, NaHMDS, or KHMDS, to introduce a Ci to C8 straight or branched alkyl group, or benzyl to produce compound (3). The preferred method uses NaH or 10 K-O-t-Bu as bases and alkyliodide or dialicylsulfate as the alkylating agent in THF or dioxane at temperatures ranging from 0° to 50° C. Alternatively, .compound (2) can be alkylated using the approach of Freidinger et al., J. Org. Chem. (1983), 48: 77-81.

Part. B r3 oh a 4 o R3 O R5 5.

R3 O R5 & Part B. £9 PCT /US94/03222 In step 3, compound (3) is converted to the corresponding N-carboxyanhydride by reaction with an acid chloride, anhydride or a coupling agent as described in E. Fr6rot, J. Coste, J. Poncet, P. Jouin, 5 B. Castro, Tetrahedron Lett. (1PT2), 33: 2815-2816. In the preferred method, this is accomplished using PCI5 in THF, dioxane, methylene chloride, or toluene between 0° and 50 °C. The resulting N-carboxyanhydride (4) is then reacted with an amino acid or an amino acid derivative 10 in step 4. The amino acid can be used with, or without a carboxylate protecting group as described above. The . preferred method of Step 4 for the preparation of the compound of formula (5) where Y is t-butyl is via reaction with Gly-t-butyl ester, in solvents such as 15 DMF, methylene chloride, chloroform, acetontrile between -4 0° and 0 °C.

Compound (5) can alternatively be prepared from compound (3) using steps 3a and 4a above. Compound (3) is coupled to an amino acid or an amino acid ester using 20 well-known methods as described above giving rise to dipeptide (6). Selective deprotection of the alpha-amino protecting group gives rise to compound (5).

Part. C.

R^2 O N9 wV^OH NQ (CH2)m R9 O r2 R12 o (CH2)m R o VyvV' .rVSrVVV r3 O R5 step 5 R2 R3 O R5 a 1 Part C. J- In step 5 (above), the NB-alkyl dipeptide (5) is coupled with a a-amino-protected amino acid to give lo tripeptide (7) using well-known methods for peptide coupling as previously described. The preferred method to prepare (7) wherein W is Boc, Y is t-butyl, and is alkyl, is to couple the Boc-protected amino acid to (5) 5 using activating agents that include diphenylphosphinic chloride/ chloroformates/ TBTU, carbodiimides plus hydroxylamine derivatives. Bop, PyBOP, or PyBrOP as previously described at temperatures ranging from -30° to 70 °C in the presence of a tertiary amine such as 10 DIEA in solvents including DMF or methylene chloride.

Part D.

NH, I RI2 o (CH*). R9 0 w'V^S step 6 R2 R3 O R5 sl N-XX XX-NH-^ NH step 7 XX-N^NH-XX ( ?12 O (CH2)„ Rq 0 wSAN>VNYXcrY R2 R3 o Rs XL Part D.

Part D illustrates the method used to convert the substituted 2-amino-4-cyano-butyric acid moiety of (7) into the corresponding ornithine derivative in compound (8)/ and into an Arg derivative in compound (10). An WO 94/22911 PCT/US94/03222 7i advantage of the present invention is that this sequence of transformations can be carried out at any point that is convenient within the overall synthesis of a peptide.

Step 6 involves the reduction of the nitrile to the 5 corresponding aminomethyl function. This transformation can be carried out using reaction conditions well known in the literature for reducing cyano groups, as described in Tetrahedron Lett., 4393 (1975); Modern Synthetic Reactions, H.O. House (1972); or Harting et 10 al. J. Am. Chem. Soc., 50: 3370 (1928). The preferred method for preparing (8) from (7) involves reductive hydrogenation at elevated hydrogen pressure, with Pt02 in an alcohol solvent like ethanol between ambient temperature and about 60°C.

Step 7 involves reaction of the amine (B) released in step 6 with a guanylating agent (9) in which XX is H or an amine protecting group as listed above and Z is a leaving group such as S03~, S-alkyl, O-alkyl. Methods for synthesizing guanidines are known in the art and 20 described in "The Peptides" vol 2, 169-175; Garigipat et al, Tetrahedron Lett. 31: 1969 (1990); Kim et al, Tetrahedron Lett. 29: 3183 (1988); Miller and Bischoff, Synthesis 777,(1986), Delle Monache, EPO Application I330629A2 (published 1989); and Bernard et al, Can. J. 25 Chem. 36:1541 (1958) all of which are hereby incorporated by reference. In the preferred method XX is Cbz, and Z is S-ethyl or S-methyl, and this reagent is reacted with (8) in the presence of a tertiary amine such as DIEA in solvents such as water, methanol, 30 ethanol, dioxane or combination of these solvents at ambient temperature to reflux temperature of the solvent. ~73- Part E.

N-XX N-XX XX-NH-^ XX-NH-K NH NH I ( B12 O (CH;) n R, 0 . ft* 9 (ch2)n <? «V~«W*y — "AW R2 R3 O R5 R2 R3 O Rg XL •LL PartE.

In Step 8 (above), the free amino acid tripeptide (11) is prepared by the deprotection of compound (10) . For example# deprotection of (10) wherein Y is t-butyl alkyl and W is t-Boc may be accomplished using any of a variety of methods well known in the literature- for the 10 deprotection of t-butyl esters and t-Boc groups. Such methods include: hydrogen chloride in dioxane/ and trifluoroacetic acid neat or in methylene chloride. The preferred method, to prepare the free amino acid compound# (11)# by deprotection of compound (10) wherein 15 W is t-Boc and Y is t-butyl alkyl, utilizes trifluoroacetic acid in methylene chloride or hydrogen chloride in dioxane, at ambient temperature.

WO 94/22911 PCT/US94/03222 73 Part. F- N-XX xx-nh""NH R12 Q(CH«). R®0 HN-^hr\rNrfLOH R2 r3 o R5 11 XX-NH-*.

N-XX < NH step 9 C°0H R6 H 12.

N-XX xx-nh-^ O (C.H2) n p9 R12 N R3 0 r-o R° O R <VA5L. 12. >11 step 10 XX-NH-« N-XX NH R9 Stepi1 2 O (CH2)n ,n o V'mN'V^oh Jl h N-Riili R12N R3 o R5 OH rix^R6 rA H R® ^ >11 step 12 N-XX xx-nh^h O (QH2) n r9 r"1 *H° te« - •vVt° OH Part F. 7<f In Step 9, the fully elaborated protected linear peptide compound, (13), is prepared by coupling the carboxylic acid compound, (12), and the amino tripeptide compound, (11) . This step may be carried out using any 5 of the variety of methods well known in the literature for forming amide bonds, as previously described. The preferred coupling method for the preparation of the linear pentapeptide compound of formula (13) wherein G is t-Boc, involves preactivation of (12) to form an 10 active ester using a carbodiimide and hydroxysuccinimide or pentafluorophenol at 0 °C to ambient temperature, followed by addition of (11) dissolved in- DMF or acetonitrile at 0° to 100 °C.

In Step 10, the free amino acid pentapeptide 15 compound, (14), is prepared by the deprotection of compound (13) . For example, deprotection of (14) wherein G is t-Boc may be accomplished using any of a variety of methods well known in the literature for the deprotection of t-butyl esters and t-Boc groups. Such 20 methods include: hydrogen chloride in dioxane or ethyl acetate; and trifluoroacetic acid neat or in methylene chloride, chloroform, ether, or toluene. The preferred method to prepare the free amino acid compound (14), is deprotection of compound (13) wherein G is t-Boc, 25 utilizing trifluoroacetic acid in methylene chloride or hydrogen chloride in dioxane, at ambient temperature.

In Step 11, the cyclic compound, (15), is prepared by cyclization of the linear pentapeptide compound, (14). This step may be accomplished using any of the 30 variety of amide bond forming reactions well known in • the literature as described above, or under conditions known to promote macrocyclization as described is R. Schmidt, K. Neubert, Int. Jour. Peptide. Prot. Res. (1991), 37: 502-507 which is hereby incorporated by 35 reference. The preferred cyclization methods for the preparation of compounds of formula (15) from the linear 75 PCT /US94/03222 compound, (14), utilizes a tertiary amine as base, such as DIEA, and TBTU, BOP, PyBrOP, PyBOP, or a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or DCC in a solvent such as N,N-5 dimethylformamide or acetonitrile, at ambient temperature.

In Step 12 a compound of formula (I), wherein R4 is H, is formed: the {5-carboxylic acid, (16), is prepared from the corresponding compound of formula (15) wherein 10 r6 is CH2C02Bn by catalytic hydrogenation: the protecting groups on the guanidino function are . simultaneously removed if XX is Cbz or another protecting group which can be removed by hydrogenolysis. One may use any of the many hydrogenation methods well 15 known in the literature, such as described in: P. N.

Rylander, Hydrogenation Methods, Acedemic Press, (1985) . Such methods include: catalytic reduction with hydrogen over platinum oxide; catalytic reduction at elevated hydrogen pressure over palladium on charcoal; or phase 20 transfer hydrogenation with cyclohexene or ammonium formate, in an appropriate solvent such as methanol or ethanol. The preferred method for the preparation of compound (7) wherein R6 is CH2CO2Y and where Y is Cbz, involves hydrogenation of.compound (15) with 10% 25 palladium on charcoal in an alcohol solvent, at a temperature between ambient temperature and 70° C. Alternatively, the reaction may be carried out with 10% palladium on charcoal, at elevated hydrogen pressure, in an alcohol solvent. 1G Schfimn 2 n-xx n-xx xx-nh-\ xx-nh-4 nh nh I 9 <U>" R'l oh 1 " 11 ^ & R! R l R11 * oh W o r11 xx-nh-4 n-xx \ n- r11 isa- ,<S \ , XX-NH-^( n-xx nh Js. Z^R" <-nh-<( n-xx 15b HzUA nh 1 ,N~R11 4 Scharrw 2 l£a.

Scheme 2 illustrates a process for the synthesis of Formula I wherein R4 is other than H, e.g. an ester.

WO 94/22911 PCT/US94/03222 77 The synthesis proceeds similarly to scheme 1, but differs at Part F where here the protecting groups on the a-amino group and the |J-carboxylate are orthogonally removed. In the preferred method, G of (13) is Fmoc, 5 and R11 is CH2-C02~t-Bu.

In the first reaction of Scheme 2, the Fmoc is removed using a secondary or tertiary amine, such as piperidine, in a polar organic solvent, such as DMF. Alternatively, this deblocking reaction step can be 10 carried out in situ during the cyclization step if the cyclization reaction is carried out in the presence of DMAP or a similar base. Thus, in the pr&fered method, compound (13) wherein G is FMOC, is deprotected and cyclized by treating it with DMAP and TBTU in DMF. 15 In the third reaction in Scheme 2, the carboxylate protecting group is removed. In the preferred method in which R6 is CH2-C02~t-Bu, the deprotection is effected using the conditions described above to convert compound (10) to (11) .

The fourth reaction in Scheme 2 involves alkylation of the carboxylate that was liberated in the previous step. This is carried out using an alkyl halide or alkyl sulfonate ester, such as alkyl-tosylates, in DMF with a tertiary amine as base at temperatures ranging 25 from 0 °C to 50 °C.

PCT /US94/03222 76 Scheme 3 O HO^Rl^CN — HO^R/CHrNH2 OR 1L HO >Rl 11 12.

IS.

O Rn o o R„ ho/T'Nhg Jk {S>"2ln JOL Re HO R, NH J G ; Re 12. n = 0,1 Scheme 3 The preparation of intermediate compound (12) is shown in Scheme 3. The pseudodipeptide (12) is prepared by coupling the amino carboxylic acid compound of formula (18) or formula (18A), with the activated carboxylic acid of an appropriately substituted N-a protected amino acid of (19) wherein G is a protecting group such as Fmoc or t-Boc# using any of the amide bond forming reactions previously described. The preferred method for preparing the pseudodipeptide compound# (12) , wherein R1 is phenyl, is by reaction of the free amino 15 acid compound, (18) wherein R1 is phenyl, with a carboxylic acid, (19), activated with N,N'-carbonyldiimidazole, in the solvent N,N~ dimethylformamide, at ambient temperature.

Alternatively, the carboxylic acid can be activated as 20 the N-hyroxysuccinate ester in a solvent such as methylene chloride or N#N-dimethylformamide.

The amino carboxylic acid compound of formula (18) or formula (18A) can be purchased or can be prepared by reduction of the appropriately substituted cyano 14 carboxylic acid compound (17) by methods well known in the literature for reducing cyano groups, as described in Tett. Lett., 4393 (1975); Modern Synthetic Reactions, H.O. House (1972); or Harting et al. J. Am. Chem. Soc., 5 50: 3370 (1928). The preferred method for preparing the amino acid (IB), wherein R1 is phenyl from (17) involves reductive hydrogenation at elevated hydrogen pressure, with 10% palladium on charcoal in an alcohol solvent like ethanol between ambient temperature and 60°C. For 10 example, reduction of 3- or 4-cyanobenzoic acid, which is a compound of formula (17) wherein R* is phenyl, under these conditions affords the corresponding benzyl amine of formula (18) . (18A) may be prepared by any of a number of methods well known in the literature or as described in the following Schemes.

Other analogues of compounds of formula (18) and SchMift A O o BOC-NH OH ^1° < BOO CHjl DMF, 45* OMe O 1) NaOH/EtOH 2) deprotection 24L Scheme 4 The N-alkylated compound of formula (24) can be prepared according to standard procedures, for example, 80 Olsen, J. Org. Chem. (1970) 35: 1912). This compound may also be prepared as shown in Scheme A.

HO Schemes 5-B o „N o ■ M o NH2.HCI DBU/CHjI JL ^ J&N 10SM-C TT ^MeO-VY* YT ^ TW Hj/HCl/ElOH t HNBph ICHfih Ph Ph £-Ph O NH2 (1) 0,pn,uelt((n O N^Ph HOUR'S MeO^^Y^R^ Me0^Q) 2A Scheme 5 ? H2S04oq § 2 Q fS,Me3 1(0 R,sLi (11) VfeO/H (11) VfeO/HCI O NH2.HCI no^R^; Schema 6 2A 6\ □ 0 II || Q NH2HC1 ■•W.» NH<0AC/N.(CN)BH3 | HOA^JL.R,S CHjOH/hol. Slaves Boc-On/Acetone NH-BOC Scheme 7 1A o o NH2HC1 <0 NhfeOH.HCl/EtOH/Pyr.

IJ * ho (11) P«J-C/EtOH/HCJon,/H2 Ai0rv H0'^Oxl,fcR,s Scheme 0 Boc-On/Acatone NH-BOC Schemes 5-8 show a number of alternative routes to intermediate compounds of formula (24). Compound (24) falls within general formula (18) and is useful for the synthesis of compounds of formula (12). Scheme 5 10 details a method for the preparation of compounds of formula (24) wherein R15 is Ci-Cs alkyl, Ci-Cs cycloalkyl, or aryl. Scheme 8 shows a route for the preparation of compounds of formula (24) wherein R1^ is alkyl or phenyl. Schemes 9 and 10 show routes for the 15 preparation of compounds of formula (24) wherein R1^ is CH3, or phenyl.

S3- Schauta Q co2h EtOH ch3c HjSQI co2ei cr-~ coje! AJC13, Aoatyl CI EDO NaOH. ECH HjCT cojh NaOCI, NaOH HCL O hoc c02h MCI}, Nad hoc" NaOAe fJCQ^ssjXX) Hg/Pd-C M*OH/HCI W»OH H£Q, I n-oh ■j-CQ ao. H NH2 ■ HCI maoc 1 ,)TMSCN / Znl? in Btiztw 2.) POO 3 / Pyridine ; raflux m#oc 1.)H j/Pd-C MaOH/HCI 2.Saporufy „ m«oc chjnh2 Diosaiw 1.)H,/P« MsOH/HCI 3.) Saponify cn hoc ctCQ h ch2nh2 Scheme 9 Alternative carbocylic residues for R1 of the invention include aminoalkyl-naphthoic acid, Formula (29), and aminoalkyl-tetrahydronaphthoic acid, Formula (30) as depicted above in scheme 9.

Some other possible analogues for R* Formula (I) can be prepared according to a modification of standard 94/22911 S3 procedures previously reported in the literature such as described in Earnest, I.,et al., Tett. Lett., (1990) 31: 4011-4014.

An alternative process for the synthesis of compounds of Formula (I) is shown in Scheme 10 below.

Schfinm 10 Part A WI1 I - o «*»■ 1 9 f ? T °"H R2 R» * 8t#p6 R2 R9 L Formula (V) An alternative process from scheme 1 is as follows 15 and begins at compound (7) from scheme 1, part C above. The free amino acid tripeptide Formula (V) is prepared by the deprotection of compound (7) as in step 6 above. For example, deprotection of (7) wherein Y is benzyl and W is Cbz may be accomplished using any of a variety of 20 methods well known in the literature for the deprotection of benzyl esters and Cbz groups. However, the reaction must be carefully monitored to avoid reduction of the nitrile. One may use any of the many hydrogentation methods well known in the literature, 25 such as described in: P. N. Rylander, Hydrogenation Methods, Acedemic Press, (1985). Such methods include: catalytic reduction with hydrogen over platinum oxide; catalytic reduction at elevated hydrogen pressure over palladium on charcoal; or phase transfer hydrogenation 30 with cyclohexene or ammonium formate, in an appropriate WO 94/22911 PCT/US94/03222 8<r solvent such as methanol or ethanol. The preferred method for the preparation of Formula (V) involves hydrogenation of compound (7) with 10% palladium on charcoal in an alcohol solvent, at a temperature between 5 ambient temperature and 70° C. Alternatively# the reaction may be carried out with 10% palladium on charcoal, at elevated hydrogen pressure, in an alcohol solvent.

PCT /US94/03222 CN R18 q (OH2) m rf hn-vAI/N'V1OH r2 r3 o r5 . step 7 R11 O W nvH....-R,n nh cooh J2.

CN 9 O (CH2)myR fj) Br 0H si2 ' 3 O Ft •n r 21 nh ifVG r» r>11 o r steps /cn on o wrn r» jh ) rf " V R5 n \ " n step9_ . R12 ' ^^5 OH \ N-r" H-N 'VY* c\ 23. Nv " i_~1f ^ r3 O R5 rl h o r11 r6 22. step 10 X nh2 h2^nh n(ch2)n d® step 11 o (ch2) n r9 n r3 r O t r"N * 0 V°„ "" i"™ "W'-C . O OH Formula (I) Part B.

In Step 7, the fully elaborated protected linear peptide compound, (21), is prepared by coupling the carboxylic acid compound, (12), and the amino tripeptide compound, (20). This step may be carried out using any 5 of the variety of methods well known in the literature for forming amide bonds, as previously described. The preferred coupling method for the preparation of the linear pentapeptide compound of formula (21) wherein G is t-Boc, involves preactivation of (12) to form an 10 active ester using a carbodiimide and hydroxysuccinimide or pentafluorophenol at 0 °C to ambient temperature, ' followed by addition of (20) dissolved in'DMF or acetonitrile at 0° to 100 °C.

In Step 8, the free amino acid pentapeptide 15 compound, (22), is prepared by the deprotection of compound (21). For example, deprotection of (21) wherein G is t-Boc may be accomplished using any of a variety of methods well known in the literature for the deprotection of t-Boc groups. Such methods include: 20 hydrogen chloride in dioxane or ethyl acetate; and trifluoroacetic acid neat or in methylene chloride, chloroform, ether, or toluene. The preferred method to prepare the free amino acid compound (22), is deprotection of compound (21) wherein G is t-Boc, 25 utilizing trifluoroacetic acid in methylene chloride or hydrogen chloride in dioxane, at ambient temperature.

In Step 9, the cyclic compound, (23), is prepared by cyclization of the linear pentapeptide compound, (22). This step may be accomplished using any of the 30 variety of amide bond forming reactions w^ll known in the literature as described above, or under conditions known to promote macrocyclization as described is R. Schmidt, K. Neubert, Inc. Jour. Peptide. Prot. Res. (1991), 37: 502-507 which is hereby incorporated by 35 reference. The preferred cyclization methods for the preparation of compounds of formula (23) from the linear 87 compound, (22), utilizes a tertiary amine as base, such as DIEA, and TBTU, BOP, PyBrOP, PyBOP, or a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or DCC in a solvent such as N,N-5 dimethylformamide or aoetonitrile, at ambient temperature.

In Step 10, the aminc-B-carboxylic acid, (25), is prepared from the corresponding compound of formula (23) wherein R^ is CH2C02Bn by nitrile reduction using 10 catalytic hydrogenation with simultaneous benzyl hydrogenolysis. This transformation can -be carried out using reaction conditions well known in the literature for reducing cyano groups, as described in Tett. Lett., 4393 (1975); Modern Synthetic React ions, H.O. House 15 (1972); or Harting et al. J. Am. Chem. Soc., 50: 3370 (1928).

Step 11 involves reaction of the amine released in Step 10 with a guanylating agent (9) in which XX is H or an amine protecting group as listed above and Z is a 20 leaving group such as S03", S-alkyl, O-alkyl to form compounds of Formula (I). Methods for synthesizing guanidines are given in The Peptides" vol 2, 169-175; Garigipat et al, Tetrahedron Lett. 31: 1969 (1990); Kim et al, Tetrahedron Lett.. 29: 3183 (1988); Miller and 25 Bischoff, Synthesis 777, (1986) , Delle Monache, EPO Application #330629A2 (published 1989); and Bernard et al, Can. J. Chem. 36:1541 (1958) all of which are hereby incorporated by reference.

BXftMPLBS All chemicals and solvents (reagent grade) were used as supplied from the vendors cited without further 35 purification. t-Butyloxycarbonyl (Boc) amino acids and other starting amino acids may be obtained commercially from Bachem Inc., Bachem Biosciences Inc. (Philadelphia, PA), Advanced ChemTech (Louisville, KY), Peninsula Laboratories (Belmont, CA), or Sigma (St. Louis, MO). 2-(lH-Benzotriazol-l-yl)-1,1,3,3-tetramethyluronium 5 hexafluorophosphate (HBTU) and TBTU were purchased from Advanced ChemTech. N-methylmorpholine (NMM), /n-cresol, D-2-aminobutyric acid (Abu), trimethylacetylchloride, diisopropylethylamine (DIEA), 3-cyanobenzoic acid and [2- (tert-butyloxycarbonyloxylimino)-phenylacetonitrile] 10 (Boc-ON) were purchased from Aldrich Chemical Company. Dimethylformamide (DMF), ethyl acetate, chloroform (CHCI3), methanol (MeOH), pyridine and hydrochloric acid (HC1) were obtained from Baker. Acetonitrile, dichloromethane (DCM), acetic acid (HOAc), 15 trifluoroacetic acid (TFA), ethyl ether, triethylamine, acetone, and magnesium sulfate were purchased from EM Science. Palladium on carbon catalyst (10% Pd) was purchased from Aldrich Chemical Company or Fluka Chemical Company. Absolute ethanol was obtained from 20 Quantum Chemical Corporation. Thin layer chromatography (TLC) was performed on Silica Gel 60 F254 TLC plates (layer thickness 0.2 mm) which were purchased from EM Separations. TLC visualization was accomplished using UV light, iodine, and/or ninhydrin spray. Melting 25 points were determined using a Thomas Hoover or Electrothermal 9200 melting point apparatus and are uncorrected. NMR spectra were recorded on a 300 MHz General Electric QE-300, Varian 300, or Varian 400 spectrometer. Fast atom bombardment mass spectrometry 30 (FAB-MS) was performed on a VG Zab-E double-focusing mass spectrometer using a Xenon FAB gun as the ion source or a Finnigan MAT 8230.

The following examples represent (but are not intended to be limiting) the processes and intermediates 35 of the present invention. 87 Example 1: Wfl-benzvlQxvearbonvl-Wg-metihvl-4-evanQ-IJ-2-»minnhn<-vrle acid 5 Z-Gln (28.03 g, 100 mmol) was dissolved in 300 mL THF in a flask bottle protectected from moisture and to it was added 100 mL 1.93 M phosgene in toluene (193 mmol). The solution was stirred at room temperature for 2 h and concentrated at 30° C to 200 mL. Water (200 mL) 10 was added slowly with stirring. After stirring at room temperature for 2 h, the organic phase was seperated, and the water phase was extracted with ethyl acetate twice. The combined organic solution was washed with brine four times, dried (MgS04), and concentrated. The 15 oily product was dried over KOH overnight.

The dried oily product was taken up in 300 mL dry THF and 49.8 mL (800 mmol) methyl iodide in a flask bottle protected from moisture and the solution was cooled in an ice bath. To it was slowly added 10 g 20 sodium hydride (250 mmol, 60% dispersion in oil). The mixture was stirred in the ice bath for 1 h and then at room temperature for 22 h. Ethyl acetate (50 mL) was added, and after stirring for 10 min, 100 mL water was added slowly. The solution was acidified with a few 25 drops of 4 N HC1 to pH8-9 and then concentrated at 30° C to remove the organic solvents. Water (100 mL) was added followed by 10 mL 0.1 N sodium thiosulfate, and the solution was extracted with ether twice. The water layer was cooled in an ice bath and to it was slowly added 4 N 30 HC1 to pH 3 with stirring. The product , which crystallized during the acidification, was filtered, washed with water several times, and dried. Yield 26.0 g (94%). mp 81-83° C. 3-H-NMR (CDC13) : 5=2.15 (m, 1H) ; 2.38 (m, 1H); 2.42 <m, 2H); 2.96 & 2.98 (2s, cis & trans N-35 CH3); 4.62 (m, 1H); 4.90 (b, 1H); 5.19 (s, 2H); 7.35 (m, 5H) . °)0 Sxampla 2: Wfl-methvl-4-evano-L-?-aminnh^vrie acid-K-rarhoxvanhvririda To a solution of example 1 (11.05 g, 40 nunol) in 50 5 mL dry THF cooled in an ice bath was added phosphorus pentachloride (15 g, 72 nvxnol) and the mixture was stirred for 2 h and concentrated to dryness. The residue was triturated with petroleum ether to give a solid which was filtered, washed with petroleum ether and 10 dissolved in dry acetonitrile. Insoluble material was filtered off and the solution was concentrated. The solid was washed with cold ether and dried. Yield 5.86 g (87%). mp 90-92° C. ^-H-NMR (CDC13) : 5=2.18 (m, 1H) ; 2.39 (m, 1H); 2.60 (m, 2H); 3.02 (s, 3H); 4.28 (m, 1H).

Example 3 : H-Boe-D-2-«ninp»mfrvT'vl -Kfl-fflPt-hvl -4-evano-I,-2-aminobutvrvl-glveine fc-bufcvl gafccr To a solution of glycine t-butyl ester hydrochloride (3.68 g, 22 mmol) in 40 mL chloroform and 20 4.84 mL N-methylmorpholine cooled to -40° C was added a solution of example 2 (3.36 g, 20 mmol) in 20 mL dry acetonitrile, the solution was stirred at -20° C for 1 h, and the solvent was reduced to about 10 mL.

To a solution of N-Boc-D-2-aminobutyric acid 25 dicyclohexylamine salt (8.08 g, 21 mmol) in 30 mL chloroform cooled to -10° C was added diphenylphosphinic chloride (3.91 mL, 20.5 mmol) and the mixture was stirred at -5° to -10° C for 1 h. To it was added the above prepared solution (10 mL) followed by 2.42 mL N-30 methylmorpholine. The mixture was stirred at 0° to -5° C for 24 h, and then concentrated. Ethyl acetate was added and insoluble material was filtered off. The filtrate was washed with NaHC03 four times and with brine three times, dried over MgSOij, and concentrated to a small 35 amount at which time the product crystallized. Petroleum ether was added, and after cooling, the solid was PCT /US94/03222 filtered/ washed with petroleum ether, and dried. Yield 6.2 g (70%). mp 90-92° C. FAB-MS (MH+): Calculated 441.3; Found 441.3.

Example 4: It Bpc-D-Z-nainnhuf.yrYl-l^-mftthyl-N&^-Ha^-. abftnivlorvearhBiivl 1 -1.—aroinvl—olveina t-butvl astar Example 3 (4.63 g, 10.5 mmol) was dissolved in 70 mL methanol in a Parr bottle and to it was added a cold solution of 1.2 mL concentrated hydrochloric acid (38%) 10 in 10 mL methanol followed by 200 mg platinum(IV) oxide.

. The mixture was hydrogenated at 55 psi for 1 h, the catalyst was filtered off, and 2.09 mL (15 mmol) triethylamine was added. The solvent was removed under reduced pressure and the residue was taken up in 20 mL 15 THF. To it was added N, N'-bisbenzyloxycarbonyl-S- methylisothiourea (3.58 g, 10 mmol) followed by 2.09 mL (15 mmol) triethylamine. The mixture was stirred overnight during which time the bottle was evacuated several times to remove the byproduct methanethiol. 20 Ethyl acetate was added, and the solution was washed with 1% citric acid, brine, 5% NaHC03 and brine, dried (MgS04), and concentrated. Crystallization from ethyl ether-petroleum ether gave 7.2 g (95%) product. FAB-MS (MH+): Calculated 755.4; Found 755.4.

Exsrnpla 5: D-2-amlnobutvrvl-Hg-mefchvl-Wffl. KflH-fbl abanzvl OTvearhonvl 1 -T.-arolnvl-ttlvcine TFA aalt A solution of Example 4 (9 g, 11.9 mmol) in 90 mL 50% TFA in methylene chloride was stirred at room 30 temperature for 2 h and the solution was concentrated at 30° C. Cold ether was added, and after standing, the solid was filtered, washed with ether, and dried. Yield 8.4 g (99%). FAB-MS (MH+) : Calculated 599.3; Found 599.3.

PCT /US94/03222 SX Example 6: H-Boe-I-Mpartvl fbenzvll -3- (aminomethvll -hpntole acid 3-cyanobenzoic acid (3.38 g, 23 mmol) was dissolved in 30 mL THF by warming and stirring. Isopropanol (20 5 mL) was added and the solution was allowed to cool to' room temperature. To it was added 2.5 mL precooled concentrated HC1 (38%) followed by 160 mg platinum(IV) oxide. The mixture was hydrogenated at 55 psi overnight. The product precipitated during the hydrogenation. 10 Ether (100 mL) was added and the mixture was stirred and then cooled. The precipitate was filtered, washed with cold ether, and dissolved in 40 ml DMF. The catalyst was filtered off and rinsed with DMF. BocAsp(Bzl)OSu (8.4 g, 20 mmol) was added followed by 7.7 mL (44 mmol) 15 diisopropylethylamine. After stirring at room temperature for 5 h, the solution was added slowly to 200 mL 3% citric acid with stirring. After cooling, the precipitate was filtered, washed with water and cold ether, and dried. Yield 8.2 g (90%). mp 148-150° C. ^-H-20 NMR (DMSO-d6) : 6=1.38 (S, 9H); 2.62 (m, 1H) / 2.80 (m, 1H); 4.32 (d, 2H); 4.40 (m, 1H); 5.07 (s, 2H); 7.20 (d, 1H); 7.36 (s, 5H); 7.44 (m, 2H); 7.81 (m, 2H); 8.4 6 (t, 1H); 12.90 (s, 1H).

Example 7: M-Boe-t-aap^rtvlfbenzvll-3- f»Tnlnnmofrhvl>bgngovl-P-2-M^nobufcvrvl-lia-methvl-Ntt. Kffil-tbiabengvlo»vcarbonvH-L-*rcrlnvl-plvcin« To a solution of example 6 (2.29 g, 5 mmol) and pentafluorophenol (1.01 g, 5.5 mmol) in 15 mL THF was 30 added DCC (1.03 g, 5 mmol) and the mixture was stirred overnight. Dicyclohexylurea was filtered off and rinsed with THF, and the solvent was removed under reduced pressure. To the residue was added a solution of example 5 (3.56 g, 5 mmol) in 10 ml DMF followed by 2.1 mL (12 35 mmol) diisopropylethylamine. After stirring at room temperature for 6 h, 50 mL 5% citric acid was added S3 followed by 80 mL ethyl acetate. The organic phase was seperated, washed with 1% citric acid and brine, dried (MgSO^), and concentrated. The residue was triturated with ether-petroleum ether to give 4.8 g (92%) product. 5 FAB-MS (MH+) : Calculated 1037.5; Found 1037.3.

Example 8: l.-»apartvl fbenzvl ^ -3- faminnmof-hvl 9-ami nfttaufcvrvl-KP-mgfchvl-lia. HID' - fhtsbengvloxvearbonvll - Irarginyl-qlycinfl TFft aalfc A solution of example 7 (5.7 g, 5.5 mmol) in 50 mL 50% TFA in methylene chloride was stirred at room • temperature for 1 h and concentrated. The- residue was triturated with cold ether, and the solid was filtered, washed with ether, and dried. Yield 5.8 g (100%). FAB-MS 15 (MH+) : Calculated 937.4; Found 937.1.

Example 9: CvelorE-asoartvl feenzvn-3- /aminomftthvl^ bengevl-P—2-amlnobutivrvl—MC-methvl-Wfl). Nffl' -(bisbengvloxvearbonvH-L-arqlnvl-alvcvn 20 To a solution of TBTU (963 mg, 3 mmol) in 25 mL DMF was added slowly a solution of 3.15 g (3 mmol) example 8 in 25 mL DMF and 1 mL (9 mmol) N-methylmorpholine over a period of 1.5 h and stirring was continued for 2.5 h. The solution was added slowly to 200 mL 1% citric acid 25 cooled in an ice bath and the precipitate was filtered, washed with water and ether, and dried. Yield 2.5 g (90%). FAB-MS (MH+): Calculated 919.4; Found 919.0.

Example 10: Cvelori^aspartvl-3-t aminomefchvllbgngovl-P- A mixture containing example 9 (919 mg, 1 mmol), methanesulfonic acid (71 pL, 1.1 mmol) and 150 mg 10% palladium on carbon in 5 mL DMF was hydrogenated at atmospheric pressure for 4 h and the catalyst was 35 filtered off and rinsed with DMF. The solution was added to 50 mL acetonitrile with stirring and the precipitate was filtered and washed with ether to give 590 mg (90%) methanesulfonic acid salt of the title compound which is over 90% pure. The product was dissolved in water and the pH of the solution was adjusted to pH 7.4 by addition of ammonium hydroxide. Acetone was added to 5 give a precipitate. Crystallization from water gave pure zwitterion product. FAB-MS (MH+) : Calculated 561.3; Found 561.3.

ExamplA 11: acid hydrochloride 3-cyanobenzoic acid (5.88 g, 40 mmol) was suspended in 50 mL THF and the mixture was warmed up with stirring. After all solid went into solution, 50 mL isopropanol was added and the solution was allowed to cool to room temperature. To it was added 4.2 mL 15 precooled concentrated HC1 followed by 300 mg platinum(IV) oxide. The mixture was hydrogenated at 55 psi overnight. Ether (50 mL) was added, and the precipitate was filtered, washed with ether and dissolved in methanol. The catalyst was filtered off and 20 the solvent was removed under reduced pressure to give 6.2 g (82%) product. ^-H-NMR (DMSO-d6) : 5=4.08 (d, 2H) ; 7.53 (t, 1H); 7.80 (d, 1H); 7.94 (d, 1H); 8.10 (s, 1H); 8.65 (s, 3H).

Example 12: Pmee-^agpartvl ffr-bufcvll -3- faminnmpl-hvl 1 - feenagic acid To a solution of FmocAsp(But)OPfp (17.33 g, 30 mmol) and example 11 (6.19 g, 33 nunol) in 50 mL DMF cooled in an ice bath was added 11.5 mL (66 mmol) 30 diisopropylethylamine, and after stirring at room temperature for 5 h, 200 mL 5% citric acid was added and the solution was extracted with ethyl acetate twice. The combined extracts were washed with brine, dried (MgS04) , and concentrated to give a solid which was washed with 35 ether-petroleum ether and dried. Yield 16.3 g (100%). !h-NMR (DMSO-d6): 6=1.35 (s, 8h) ; 2.48 (dd, 1h) ; 2.70 (dd, 1H); 4.2-4.4 (m, 6H); 7.30 (t, 2H); 7.4-7.5 (m, 4H); 7.7-7.9 (m, 7H); 8.55 (t, 1H); 12.92 <s, 1H).

Example 13: rmoe-l->gpartvl I fr-bufcvl > -3-5 t»inlnranttfchvllfeftnzovl-.P-g-»tninofrmfrv™i-K*-mgthvl-Wffl. Nffll-fhi gbgngvloyvearbonvl1-I-argi nvl-glveina A mixture containing example 12 (10.89 g, 20 mmol), pentafluorophenol (4.05 g, 22 mmol) and DCC (4.13 g, 20 mmol) in 50 mL THF was stirred at room temperature 10 overnight. Dicyclohexylurea was filtered off, rinsed with THF, and the filtrate was concentrated. To it was added a solution of example 5 (14.25 g, 20 mmol) in 40 tuL DMF followed by 7.32 mL (42 mmol) diisopropylethylamine. The mixture was stirred at room 15 temperature for 4 h, insoluble material was filtered off, and the filtrate was added to 200 mL 3% citric acid with stirring. The solution was extracted with ethyl acetate twice and the combined extracts were washed with brine, dried (MgS04), and concentrated. The residue was 20 triturated with ether-petroleum ether to give 22 g (98%) product. FAB-MS (MH+) : Calculated 1125.5; Found 1125.7.

Example 14: cyclo rt-a aparty], (t-butyl) -3- faTnlnnmp^hvHbftngovl-fl-2-aTiilnQhiit'.vrvl-Wtll. 1-25 fblabengvleTvearbonvl \ -I^arginvl-crlvevl 1 A solution of example 13 (22.5 g, 20 mmol) and 4-dimethylaminopyridine (14.66 g, 120 mmol) in 100 mL DMF was stirred overnight at room temperature and added slowly to a solution of TBTU (6.42 g, 20 mmol) in 200 mL 30 DMF over 3 h and stirring was continued for 1 h. Ethyl acetate (1000 mL) was added and the solution was washed with 1% citric acid 2 times, brine 3 times and concentrated to dryness. The residue was taken up in THF and after filtration, the solvent was removed under 35 reduced pressure to give a solid which was washed with 94/22911 % ether and dried. Yield 16 g (90%). FAB-MS (MH+): Calculated 885.4; Found 885.2.

Zxaapla 15 : Cvelori,-aap*yl-vl-3- fMiinnmBthvUhPngovl-fl-5 2-«ninohutvrvl-Kffl. Nffli- fblahengvloxvMrbonvH -I-aroinvl- glycyll A solution of example 14 (16 g, 18 mmol) in 200 mL 50% TFA in methylene chloride was stirred at room temperature for 1.5 h and then concentrated. The residue 10 was triturated with ether to give 14.5 g (97%) product. FAB-MS (MH+) : Calculated 829.4; Found 829.1 .

Example 16: Cvelofl-iapartylfanAfcoxvniefchvl1-3-raminotnftthv] 1 bcnzovl-.D-2-amlnobufr.vrvl-.E-ai-rrinvl -olvryl 1 15 A mixture containing example 15 (1.42 g, 1.7 mmol), bromomethyl acetate (980 mL, 10 mmol) and triethylamine (976 mL, 7 mmol) in 10 mL DMF was stirred at room temperature overnight. Ethyl acetate was added and the solution was washed with brine 3 times, dried <MgS04), 20 concentrated, and dried. The residue was taken up in 8 mL DMF and to it was added 130 mL (2 mmol) methanesulfonic acid followed by 150 mg 10% palladium on carbon. The mixture was hydrogenated at atmospheric pressure for 2 h, the catalyst was filtered off, and the 25 solution was diluted with water. Purification using semipreparative HPLC gave 650 mg (51) pure product. FAB-MS (MH+): Calculated 633.3; Found 633.2.

Zxaapla 17: evclorx^agpartvl /plvalovloxymefchvll -3-30 (aminampfchvl >bpngovl—P—2-aminobufcvrvl-Ii—agginvl-glvrfyl 1 A mixture containing example 15 (4.14 g, 5 mmol), chloromethyl pivalate (4.3 mL, 30 mmol), triethylamine (2.8 mL, 20 mmol), Nal (4.5 g, 30 mmol) in 10 mL DMF was stirred at room temperature for 18 h. Ethyl acetate (100 35 mL) was added and the solution was washed with brine 3 times, dried (MgSO^) , and concentrated. The residue was

Claims (19)

WO 94/22911 PCT /US94/03222 V taken up in 15 mL ethyl acetate and passed through a silica gel column using ethyl acetate-THF (1:1) as eluent to give 1.5 g pure product. The product was dissolved in 10 mL DMF and hydrogenated at atmospheric 5 pressure using 10% palladium on carbon (130 mg) in the presence of methanesulfonic acid (100 mL) for 2 h. The catalyst was filtered off, rinsed with DMF, and the solution was diluted with water. Purification using semipreparative HPLC gave 1 g (26%) pure product. FAB-MS 10 (MH+) : Calculated €75.3; Found 675.3. Example 18: Cve1ar aapartvl-(i mooronvloxvcarbonvl-ottvmefchvll-3-aminomftfchvllfa«m«ftvl-P-2-aminpbT3fcvrvl-l.-arerinvl-glvevn 15 A mixture containing example 15 (4.14 g, 5 mmol), chloromethyl isopropyl carbonate (4.58 g, 30 mmol), triethylamine (2.8 mL, 20 mmol), Nal (4.5 g, 30 mmol) in 10 mL DMF at stirred at room temperature for 18 h. Ethyl . acetate (100 mL) was added and the solution was washed 20 with brine 3 times, dried (MgSC>4), and concentrated. The residue was taken up in 10 mL ethyl acetate-THF (1:1) and passed through a silica column using ethyl acetate-THF (1:1) as eluent to give 1.6 g product. The product was dissolved in 10 mL DMF and hydrogenated at 25 atmospheric pressure using 10% palladium on carbon (150 mg) in the presence of 130 mL for 2 h. The catalyst was filtered off, rinsed with DMF, and the solution was diluted with water. Purification using semipreparative HPLC gave lg (25%) pure product. FAB-MS (MH+) : 30 Calculated 667.3; Found 667.3. WO 94/22911 PCT/US94/03222 5 96 26 5 7 5 3 CLAIMS WHAT IS CLAIMED IS:

1. A process for the preparation of compounds of formula I: NH IT o - r ,.T }—CH-COjR4 Rta-N / 2 2 ^"'""8 0 Formula (I) 10 comprising the steps of: (a) alkylating the a-amino group of an aminonitrile of the formula: Nq (CHzJn, W„ JL^ O NH^f* 15 with an alkylating agent containing the group R (provided R is not H) to product a compound of the formula (IV): /CN (CHa)m fP V* OH Formula (IV) WO 94/22911 PCT/US94/03222 10 ^ 265 75 3 and coupling with amino acid derivatives to produce a nitrile tripeptide of the formula: CN I Rta _ (CHa) X o \T " t 9 V^O-Y W T, U O R« (b) reducing the nitrile group from the product of step (a) to form the compound of the formula: NHa o« Q W J* o -'VsN'V (c) reacting the amino group of the product of step (b) with a guanylating agent of the formula: N-XX XX-N-\ 15 Z / to produce the compound of the formula: N-XX XX-N-\ <9Ha>n ?12 O I f O O-Y 'Y*-i R4 Ij O R» (d) deprotecting the carboxyl and a-amino groups 20 of the product from step (c) to form the compound of the formula: WO 94/22911 PCT/US94/03222 loo 265 75 3 R I H-N N-XX XX-N-^ ^NH (CHj),, 0 l ?# ° t*~£ST and coupling the compound of the -above formula with a carboxylic acid derivative of formula: HO^r tr R11 t G 10 to produce a protected linear peptide of formula: N-XX 15 (e) removing the protecting group (G) of the product of Step (d) to produce a deprotected linear peptide of formula (III): WO 94/22911 PCT /US94/03222 26 5 7 5 3 Formula (III) (f) cyclizing the deprotected linear peptide of formula (III) to produce a cyclic peptide of formula (II): Formula (II) ; and 10 (g) then, provided XX is hot H when R® is CH^CC^H, converting; the cyclic peptide of the formula- (II) by a series' of deprotecting and/or alkylating steps to a compound of formula (I) O WO 94/22911 5 10 15 PCT/US94/03222 loz- 265 75 3 NH I O H Formula (I) wherein: ° /-CH>c<y R1 is w: ri. rk bit B,8; Wherein: p and p1 are 0 or 1; Rl9 is a C6'Ci4 saturated, partially saturated, or aromatic carbocyclic ring system or heterocyclic ring system composed of carbon atoms and 1-3 heteroatoms selected from N, 0/ S; these ring systems being optionally 7 substituted with 1 or 2 R ; R17 and R1S are independently selected from the group: hydrogen, C1-C4 alkyl, optionally substituted with halogen, C1-C2 alkoxy, and WO 94/22911 PCT/US94/03222 103 26 575 3 benzyl; R15 and R18 are independently selected from the group: 5 hydrogen, Ci-Cs alkyl substituted with 0-2 R8, C2-C8 alkenyl substituted with 0-2 R8, C2-C8 alkynyl substituted with 0-2 R8/ 10 C3-C8 cycloalkyl substituted with 0-2 R8/ C6-C10 bicycloalkyl substituted with 0-2 R8, C1~C4 alkoxy, 15 aryl substituted with 0-2 R*3, and a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms with the remaining 20 atoms being carbon, optionally substituted with 1 or 2 R13; or R15 and R17 can alternatively join to form a 5-7 membered carbocyclic ring 25 substituted with 0-2 R13; or R18 and R16 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R13; or 30 R7 is independently selected at each occurrence from the group: H/ phenyl, benzyl, phenethyl, phenoxy, 35 benzyloxy, halogen, hydroxy, nitro, cyano, Ci-C^. alkyl, C3-C6 cycloalkyl, PCT/US94/03222 l©^ 26 C.jj-C7 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2R20/ sulfonamide/ formyl, C3-C6 cycloalkoxy, -OC («0) R20, -C («0) R20/ -OC (»0) OR208/ -OR20/ -CH2OR20, and C1-C4 alkyl optionally substituted with -Nr20r21. R8 is independently selected at each occurrence from the group: =0/ F, CI, Br, I, -CF3, -CN, -C02R20, -C(=O)NR20R21, -CH2OR20, -OC(=0)R20, -CH2NR20R21, and -NR20R21; Rl3 is independently selected at each occurrence from the group: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C 4*C7 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2R20, sulfonamide, formyl, C3-C6 cycloalkoxy, -0C(«0)R20, -C(«O)R20,-OC(=O)OR20a, -OR20, -CH2OR20, and C1-C4 alkyl optionally substituted with -NR2®R2^; R20 is independently selected at each occurrence from the group: H, C1-C8 alkyl, aryl, -(Ci-Cg alkyl)aryl, and C3-C6 alkoxyalkyl; on R20a is as defined for R with the exception of H; R21 is independently selected at each occurrence from the group: V. WO 94/22911 PCT AJS94/03222 105 265 75 ^ H, C1-C4 alkyl, and benzyl; " R12 is H or C1-C8 alkyl; 5 R2 is H, C1-C8 alkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylmethyl, C5~C8 cycloalkylethyl, phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3, CH2SCH3, CH2CH2SCH3, (CH2)aNH2, (ch2)aNHC(-NH) (NH2), or (CH2) aNHR21, wherein s 10 is 3-5; or R12 and R2 can be taken together to -form -(ch2)t- > or -CH2SC (ch3) 2- , wherein t is 2-4; 15 R^ is H or Ci-Cs alkyl or C1-C4 alkylphenyl; R9 is H. or c]_~cg alkyl; R5 is H or C^-Cg alkyl; 20 R11 is H or Ci-Cs alkyl; R4 is selected from: 25 H;' Ci-Ca alkyl; C2-C8 alkenyl; C2-CB alkynyl; 30 c3-c8 cycloalkyl; Ci-Cs alkyl substituted with (i) aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-c5 alkyl, C1-c5 35 alkoxy, no2, -S (0) 0-2 (C1-c5 alkyl), OH, WO 94/22911 PCT/US94/03222 it*. 26 5 7 5 3 N(R22)2/ CO2R22, CON(R22)2 and -C F where v w v ■ 1 to 3 and w = 1 to (2v+l); (ii) c3-c8 cycloalkyl; or (ill) *-C (CHa) N' I rm aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl/ C1-C5 alkyl, C1-C5 alkoxy, NO2/ -S(O)0-2(C1-C5 10 alkyl)/ OH, N(R22)2/ CO2R22, CON (R22) 2 and -CVFW where v ■ 1 to 3 and w = 1 to (2v+l); C2-C8 alkyl, alkenyl or alkynyl; substituted with 1-2 substituents independently selected from C1-c4 alkyl, c3-c8 cycloalkyl, C1-c5 alkoxy, 15 phenoxy, benzyloxy, halogen, NO2, CN, CO2R22, CON (R22) 2> N(R24)C0R24, morpholino, 2-(l-morpholino)ethoxy, N(R22)2, N+(R22)3, 0C0CH3, cf3, and S(0)Q_2R22; -CH (R24) OR26; 20 -CH(R24)0C(=0)R25; ' -CH (R24)0C(«0)0R26; -CH (R24)0C(=0)N(R25)2; -CH (R24)N(R24)C(-0)R24; -CH (R24)C02R25; 25 -CH(R24)C0N(R22)2/ -CH (R24) N (R22) 2; R27. WO 94/22911 PCT/US94/03222 10*7 10 15 20 O A o o 265 753 .27 !XX> wherein r22 is selected independently at each occurrence from-; H, alkyl, C3-C10 cycloalkyl, C^-C^ alkylcycloalkyly aryl, ■ (C1-C10 alkyl) aryl, and C3-C10 alkoxyalkyl; or when two R22 groups are bpnded to a single N, said R22 groups may alternatively be taken together to form -(CH2)2~5~ or -(CH2)0(CH2)-; r24 is selected independently at each occurrence from: H., C^-Cg alkyl, C^-C^q cycloalkyl, phenyl, and benzyl; r25 is selected from: H; PCT/US94/03222 lo8 265 75 3 Ci-Cs alkyl or C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: (i) C1-c4 alkyl; (ii) C3-C8 cycloalkyl; (iii) C1-C5 alkoxy; and (iv) aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, no2, -S (C1-c5 alkyl), -S0(Ci-C5 alkyl), -SOS(Ci-C5 alkyl), -OH, -N(R22)2/ -C02R22, -C (»0)N(R22) 2/ and -C P where v = 1 v w to 3 and w ■ 1 to (2v+l),\ and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-C® alkyl, Cj.-C6 alkoxy, N02, -S (C1-C5 alkyl), -SO(Ci-C5 alkyl), -S02 (C1-C5 alfcyl), -OH, —N (R22) 2/ -CO2R22, -C(«0)N (R22)2/ and -CvFw where v = 1 to 3 and w ■ 1 to (2v+l); r26 is selected from: Ci-Ca alkyl or C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: (i) C1-c4 alkyl; (ii) C3-C8 cycloalkyl; (iii) C1-C5 alkoxy; and (iv) aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-Cs alkyl, C-.-C6 PCT/US94/03222 lcn 265 75 3 alkoxy, NO2, -S(C1-C5 alkyl), -SCXC1-C5 alkyl), —SO2(C1-C5 alkyl), -OH, -N(R22)2, -C02R22, -C (=0) N (R22) 2, and -C F where v = 1 v w to 3 arid w « 1 to (2v+l) ; and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-C$ alkyl, C1-C6 alkoxy, NO2, -S (C1-C5 alkyl) , -SCHC1-C5 alkyl), -S02(Ci-C5 alkyl), -OH, —N(R22)2/ -CO2R22, -C(=0)N(R22)2, and -CvFw where v « 1 to 3 &nd w = 1 to (2v+l)/ R27 is selected from: H; Ci-Ce alkyl or C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: (i) C1-C6 alkyl; (ii) C1-C6 alkoxy; and (iii) aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2/ -S(C3.-C5 alkyl), -SO (C1-C5 alkyl), -S02(Ci-Cs alkyl), -OH, -N(R22)2, -CO2R22, -C (*»0) N (R22) 2, and -C^F^ where v = 1 to 3 and w « 1 to (2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Cj.-C$ alkyl, C1-C6 alkoxy, N02/ -S(C1-C5 alkyl), -S0(Ci-C5 alkyl), -S02(C1-C5 alkyl), -OH, —N (R22) 2/ -C02R22, -C (=0) N (R22) 21 and WO 94/22911 PCT/US94/03222 Uo 265 75 3 -CVFW where v ■ 1 to 3 and w = 1 to (2v+l); and r28 is selected from: H, C3.-C5 alkyl, or 5 benzyl; and R6 is CH2CO2Y CH2C02R4; n is 1 to 4; m is 0 to 3; 10 W and G are amino protecting groups and are independently selected from the group 15 consisting of: formyl, trifluoroacetyl, phthalyl, p_ toluenesulfonyl/ benzyloxycarbonyl (Cbz) , substituted benzyloxycarbonyls, 1-(p-20 biphenyl)-1-methylethoxycarbonyl,9- fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), ethoxycarbonyl, di isopropylmethoxycarbony1, 25 allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, 30 phenylthiocarbonyl, dithiasuccinoylalkyl-urethane, O-nitrophenylsulfenyl (NPS) and O-nitropyridylsulfenyl (NPYS); 35 Y is • a suitable, carboxylate proctecting group and can be selected from the group PCT/US94/03222 265 75 3 Hi consisting of: to C3 alkyl, C5 to C3 cycloalkylalkyl, benzyl, substituted benzyl, triphenylmethyl, diphenylmethyl, CH2CH2CN, trialkylsilyl, phthalimidomethyl, anthrylmethyl, phenylfluorenyl, 4-picolyl and phenacyl; or any other group which can be cleaved by acidolysis, mild base treatment or mild reductive means. H or a suitable amino protecting group and is selected from the group consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, phenylthiocarbonyl, dithiasuccinoylalkyl -urethane, O-nitrophenylsulfenyl (NPS), nitropyridylsulfenyl (NPYS), 2,3,6-trimethyl-4 -methoxybenzenesulf onamide (Mtr-NR.2), 2,4,6- WO 94/22911 PCT /US94/03222 10 26 5 753 trimethoxybenzenesulfonamide (Mtb-NR2)t 2,6-dimethyl-4-methoxybenzenesulfonamide (Mds-NR2)/ pentamethylbenzenesulfonamide (Pme-NR2)/ 2,3/5,6-tetramethyl-4-methoxybenzene-sulfonamide (Mte-NR2)# 4-methoxybenzenesulf onamide (Mbs-NR2) / 2,4,6-trimethylbenzenesulfonamide (Mts-NR2)t 2,6-dimethoxy-4-methoxybenzenesulfonamide (iMds-NR2)/ and 2,2,5,1,8-pentamethylchroman-6-sulfonamide (Pmc-NR2i. and fluorenylphenyl; and 15 Z is SO^"/ S-alkyl, 0- alkyl or an O-substituted derivative of hydroxylamine.

2. A process of claim 1 wherein: n is 3; Rl9 is selected from: 20 and 25 R15 and R10 are independently selected from H, C1-C4 alkyl, phenyl, WO 94/22911 PCT/US94/03222 M3 265 7 5 benzyl, phenyl-(C2-C4)alkyl, and C^-C^ alkoxy; R17 and R16 are independently H or C1-c4 5 alkyl; R7 is H, Ci-Cs alkyl, phenyl, halogen, or C1-C4 alkoxy; 10 R11 is H or C1-C3 alkyl; R12 is H or CH3; R3 is H or C^-Cg alkyl; 15 R9 is H or" C^-C^ alkyl; R5 is H or C^-C^ alkyl; 20 R4 is selected from: H, Ci-Cs alkyl; C2-C8 alkenyl; C2-C8 alkynyl; 25 C3-C8 cycloalkyl; Ci-Ca alkyl substituted with (i) aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-C5 alkyl, C1-C5 30 alkoxy, NO2, -S (0) 0-2 (C1-C5 alkyl), OH, N(R22)2/ C02R22f CON(R22)2 -CVF^ where v » 1 to 3 and w « 1 to (2v+l); (ii) C3-CB cycloalkyl; or (iii) Sec O WO 94/22911 PCT/US94/03222 20 ACHz) o-i N I Rm aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, 5 C3.-C5 alkyl, C1-C5 alkoxy, NO2, -S (0) 0-2 (C1-C5 alkyl), OH, N(r22)2/ CO2R22, CON(r22)2 and -CvFw where v = 1 to 3 and w » 1 to (2v+l); C2-C8 alkyl, alkenyl or alkynyl; substituted with 1-2 substituents independently'selected from 10 C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy, phenoxy, benzyloxy, halogen, NO2, CN, CO2R22/ C0N(R22)2/ N(R24)C0R24, morpholino, 2-(l-morpholino)ethoxy, n(r22)2/ n+(r22)3, OCOCH3, CF3, and S(O)0_2R22; 15 -CH (R24) OR26; -CH (R24) OC (=0) R25; -CH (R24) OC (»0) OR26; -CH (R24) OC (=0) N (R25) 2; -ch(r24)c02r25; O cA R27 and -CH(R24)0—^ \ o—'' 22 24 25 26 27 70 and R , R r / r , R • and R are as defined in claim 1. 25 3. A process of claim 1 wherein: WO 94/22911 PCT/US94/03222 11 265 75 3 R2 is H or C1-C4 alkyl; r5, r9, rl6, r17 and r18 are h; 5 R11 and R12 are H or ch3; R15 is H, c1-c4 alkyl, phenyl, benzyl, or phenyl-(c2-c4)alkyl; and 10 R3 is H or C3.-C3 alkyl; R4 is selected from: H ? -CH(R24)0C(»0)R25; 15 -CH(R24)OC(=0)OR2®; -ch2oc(«0)n(r25)2; -ch2ch2n (r22)2; -ch(r24)c02r25; and O

A 'R27 20 . / wherein R24 is selected from: H, C^-Cg alkyl, phenyl, and benzyl; 25 R27 is selected from: C1-C5 alkyl, benzyl and phenyl, and 22 2 5 26 R , R and R are as defined in claim 1.

4. A process of claim 1 wherein: 30 n is 3; t yx ii" : ■ , A - r * •" 0 e WO 94/22911 PCT/US94/03222 10 15 Ufc 265 75 3 p is 0, p' is 1; r19 is phenyl; R5, R9, R11, and R12 are H; R2 is ethyl; R3 is methyl; and R* is selected from: H; -CH(R24)0C(®0)R25; -CH (R24) OC (=0) OR26; and o <A R27 ; wherein R24 is Cx~C4 linear alkyl or H; -artd 20 R27 is C1-c4 alkyl, benzyl, or phenyl, and 25 26 R and R are as defined in claim 1.

5. A process for the preparation of compounds of formula I: WO 94/22911 PCT/US94/03222 in nh 265 75 3 HjN'^NH^ ^(CHa)n ° 10 tfyV ° R» Formula (I) , comprising the steps of: (a) alkylating an aminonitrile of the formula: Nq <CH2)m NH with an alkylating agent containing the group ided ] formula (IV): 3 3 R (provided R is not H) to produce a compound of the CN / (CH2)m £ OH Formula (IV) converting formula (IV) above through a series ci deprotecting steps and coupling with amino acid derivatives to produce a protected nitrile tripeptide of the formula (V): 15 WO 94/22911 PCT/US94/03222 10 (q4m ,R" 265 75 3 CN R R3 Formula (V) (b) removing the protecting groups of the compound of formula (V) and coupling with a carboxylic acid derivative of the formula: 11 HO R1^ N«G NH O R11 wherein G is a suitable amine protecting group, to produce a protected linear peptide of formula: CN / P9 (CH2) rn J. 0 OH 7 i> O R8 A y- i1 i? / R" (c) removing the protecting group G of the product of Step (b) to produce a deprotected linear peptide 15 of formula: WO 94/22911 PCT/US94/03222 w / (CH2) CN r R R12-N O m • o / p3 O R5 V-Rj OH I u / 265 75 3 (d) cyclizing the deprotected linear peptide of the product of step (c) to produce a cyclic peptide of formula (VI): /CN (CH2)m ' x._ .R6 >/ I f- R11 R6 Formula (VI) 10 (e) reducing the nitrile from the product of step (d) to form the compound of formula: WO 94/22911 PCT/US94/03222 \ lo NH; / (CHa) "O H %/W I N-R" 265 75 3 10 (f) reacting the product of step (e) with a guanylating agent of the formula: N-XX XX-N-^ Z , leading directly to a compound of Formula I, or via a series of deprotecting and/or alkylating steps converting to a compound of formula (I): H,N NH A NH^ <9H2>n jny'* r-•*V° J~CH=C0=R4 Formula (I) 15 wherein: R1 is WO 94/22911 PCT/US94/03222 265 ,53 R1. R1. R17 Rn,f wherein: p and p* are 0 or 1; 5 R1' is a Cg-Ci4 saturated, partially saturated, or aromatic carbocyclic ring system or heterocyclic ring system composed of carbon atoms and 1-3 heteroatoms selected from N, 0, S; 10 these ring systems being optionally substituted with l or 2 R7; R17 and R16 are independently selected from the group: 15 hydrogen, C1-C4 alkyl, optionally substituted with halogen, c1-c2 alkoxy, and 20 benzyl; and r18 are independently selected from the group: 25 hydrogen, C1-C8 alkyl substituted with 0-2 R®, C2-C8 alkenyl substituted with 0-2 R®, C2-C8 alkynyl substituted with 0-2 R®, c3-c8 cycloalkyl substituted with 0-2 30 R8, C6~Ci0 bicycloalkyl substituted with 0-2 r8, ci~c4 aikoxy/ WO 94/22911 5 10 15 20 25 30 PCT/US94/03222 265753 1X2. aryl substituted with 0-2 R13, and a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms with the remaining atoms being carbon, optionally 13 substituted with 1 or 2 r ; or R15 and R17 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R13; or R18 and R16 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R13; or R7 is independently selected at each occurrence from the group: H, phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, Ci-Cg alkyl, C3-C6 cycloalkyl, Cj-Ctj cycloalkylmethyl, C7^Cio arylalkyl, C1-C4 alkoxy, -CO2R20, sulfonamide, formyl, C3-C6 cycloalkoxy, -OC (=0) R20 , -C <«0) R20, -OC <»0) OR20a, -OR20, -CH20R20, and C1-C4 alkyl optionally substituted with -Nr20r21. R8 is independently selected at each occurrence from the group: -0, F, CI, Br, I, -CF3, -CN, -CO2R20, -C(«O)NR20R21, -CH2OR20, -OC(=0)R20, -CH2NR20R21, and -NR20R21/ WO 94/22911 PCT/US94/03222 265 75 3 Rl3 is independently selected at each occurrence from the group: 5 phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, C4"C7 cycloalkylmethyl, C7-C10 arylalkyl, C1-C4 alkoxy, -CO2R20/ 10 sulfonamide, formyl, C3-C6 cycloalkoxy, -0C(=0)R20, -C (=O)R20,-OC(»O)OR20a, -OR20, -CH2OR20, and C1-c4 alkyl optionally substituted with -NR2®R21; 15 R20 is independently selected at each occurrence from the group: H, C1-C8 alkyl, aryl, -(C1-C6 alkyl)aryl, and C3-C6 alkoxyalkyl; p20a ig as definea for R ^ with the exception of H; 20 R21 is independently selected at each occurrence from the group: H, C1-C4 alkyl, and benzyl; 25 R12 is H or C1-C8 alkyl; R2 is H, Ci-Cs alkyl, C3-C6 cycloalkyl, cycloalkylmethyl, -Cg cycloalkylethyl, 30 phenyl, phenylmethy1, CH2OH, CH2SH, CH20CH3, ch2sch3/ CH2CH2SCH3, (ch2)9nh2/ (CH2)aNHC(-NH) (NH2) / or (CH2)8NHR2i, wherein s is 3-5; or 35 R12 and R2 can be taken together to form -(CH2)t~ / or -CH2SC(CH3)2~ > wherein t is 2-4; vi i O f 1 >- >1 i! l . o ^ ■- !/ WO 94/22911 PCT/US94/03222 26 5 7 5 3 ixH R3 is -H or Ci-Ca alkyl or c1-c4 alkylphenyl; R9 is H, or C^-Cg alkyl; 5 R5 is H( or C^-Cg alkyl; R11 is H or Ci-Ce alkyl; 10 R4 is selected from: h; Ci-Ce alkyl; 15 C2-C8 alkenyl; C2-C8 alkynyl; C3-C8 cycloalkyl; C3.-C8 alkyl substituted with (i) aryl, optionally substituted with 1-2 20 substituents independently selected from halogen, phenyl, C3.-C5 alkyl, C1-C5 alkoxy, NO2, -S (0) 0-2 (C1-C5 alkyl), OH, N(R22)2f C02R22, CON(R22)2 and _c F where V W v " 1 to 3 and w ■ 1 to (2v+l) ; 25 (ii) C3-C8 cycloalkyl; or (iii) *-c (CH2) N" R" aryl, optionally sxibstituted with 1-2 substituents 30 independently selected from halogen, phenyl, C1-C5 alkyl, C1-C5 alkoxy, no2, -S (0) 0-2 (C1-C5 alkyl), OH, N(R22)2, C02R22, C0N(r22) 2 and -CvFw where v = 1 to 3 and w = 1 to (2v+l); WO 94/22911 PCT/US94/Q3222 {vs 26 5 75 3 C2-C8 alkyl, alkenyl or alkynyl; substituted with 1-2 substituents independently selected from C1-c4 alkyl, C3-C8 cycloalkyl, C3.-c5 alkoxy, phenoxy, benzyloxy, halogen, no2, CN, co2r22, 5 CON(R22)2; N(R24)COR24, morpholino, 2- ti me rpholino)ethoxy, N(R22)2, N+(R22)3, OCOCH3, CF3, and S(O)0_2R22. -CH(R24)OR26; -CH(R24)0C(»0)R25; 10 -CH(R24)0C(«0)0R26; -CH (R24) OC <»0) N (R25) 2; -CH(R24)N(R24)C(«0)R24; -ch(r24)c02r25; -ch(r24)con(r22)2; 15 -CH(R24)N(R22)2; 20 A R27 . A 0 o o27 -CH(R24)0 ■o PCT/US94/03222 ixk 265 7 5 3 ' and ; wherein R22 is selected independently • at each occurrence from: H; alkyl, C3-C1Q cycloalkyl, C4-C^2 alkylcycloalkyl, aryl, (ci~exo and C3-C10 alkoxyalkyl; or when two R22 groups are bonded to a single N, said R22 groups may alternatively be taken together to form -(CH2)2-5~ or -<CH2)0(CH2)-; R24 is selected independently-at each occurrence > from: H, C^-Cg alkyl, C3-C10 cycloalkyl, phenyl, and benzyl; . r25 is selected from: «; Ci-Cb alkyl or C3-Ce cycloalkyl, said alkyl cr cycloalkyl being substituted with 1-2 groups independently selected from: (i) C1-c4 alkyl; (ii) C3-C8 cycloalkyl; (iii) C1-C5 alkoxy; and (iv) aryl substituted with 0-2 groups independently selected from: WO 94/22911 PCT/US94/03222 ^ 265 75 3 halogen, phenyl, C1-C6 alkyl, Ci-Ce alkoxy, NO2, -S (C1-C5 alkyl), —SO(C1—C5 alkyl), -SO2(C1-C5 alkyl), -OH, —N(R22)2/ -C02R22, 5 -C («*0) N (R22) 21 and -C^F where>v = 1 to 3 and w « 1 to (2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-Cg alkyl, Ci-C$ alkoxy, 10 N02, -S(Ci-C5 alkyl), -SO(C1-C5 alkyl), -SO2(C1-C5 alkyl), -OH, -N (R22) 2r -CO2R22, -C(=0')N(R22;2/ and -CvFw where v = 1 to 3 and w «= 1 to (2v+l); 15 r26 iS selected from: Ci-Cs alkyl or C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected 20 from: (i) C1-C4 alkyl; (ii) C3-C8 cycloalkyl; (iii) C1-C5 alkoxy; and (iv) aryl substituted with 0-2 groups 25 independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, -S(Ci-Cs alkyl), -SO(Ci-C5 alkyl), -S02 (C1-C5 alkyl), -OH, —N (R22) 21 -C02R22, 30 —C ("0) N (R22) 2, and -C F where v = 1 V w to 3 and » « 1 to (2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C3.-C6 alkyl, Ci-Cg alkoxy, 35 N02, -S(C1-C5 alkyl), -SO(Ci-C5 alkyl), -S02(C1-C5 alkyl), -OH, WO 94/22911 PCT/US94/03222 |a-® 265 75 3 -N(R22)2, -co2r22, -C(«0)N(R22)2/ and -CVFW where v « l to 3 and w » 1 to <2v+l); 10 15 20 25 R27 is selected from: H? Ci-Cb alkyl or c3-c8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: (i) C!-C6 alkyl; (ii) C1-C6 alkoxy; and (iii) aryl substituted with 0-2 groups independently selected from: halogen/ phenyl, Ci-Cg alkyl, C1-C6 alkoxy, NO2/ -S(C1-C5 alkyl), —SO(C1-C5 alkyl), -SO2 (Ci-Cs-alkyl)/ -OH/ —N (R22)2/ -C02R22/ -C («0) N (R22) 2/ an<^ -CvFw where v = 1 to 3 and w «= 1 to (2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Ci-C« alkyl, Ci-Cfi alkoxy, NO2/ -S(Ci-C5 alkyl), -SO(Ci-C5 alkyl), -SO2(C1-c5 alkyl), -OH, -N (R22) 2t -C02R22, -C(=0)N(R22)2/ and -CvFw where v « 1 to 3 and w » 1 to (2v+l) ; and 30 R28 is selected from: H, C3.-C5 alkyl, and benzyl; R6 is CH2CO2Y or CH2C02R4; 35 n is 1 to 4; WO 94/22911 PCT/US94/03222 laC| 26 5 7 5 3 m is 0 to 3; W and G are amino protecting groups and are independently selected from the group 5 consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz) , 1 substituted benzyloxycarbonyls, l-(p-10 biphenyl)-1-methylethoxycarbonyl, 9_ fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, 15 allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, .. triphenylmethyl, benzyl, triraethyIs ilane, 20 phenylthiocarbonyl, dithiasuccinoylalkyl-urethane, O-nitrophenylsulfenyl (NPS) and O-nitropyridylsulfenyl (NPYS); 25 Y is a suitable carboxylate protecting group and can be selected from the group consisting of: C- to r alkyl, ' * ■ ® C,.. .to Cg cycloalkylalkyl, . sxibstituted benzyl, triphenylmethyl, 30 diphenylmethyl,. CH?CH2CN, trialkylsilyl, phthalimidomethyl, anthrylmethyl, phenylfluorenyl, 4-picolyl and phenacyl, or any other group which can be cleaved by acidolysis, mild base treatment or mild 35 reductive means; 1 v I- PCTAJS94/03222 \SO 26 5 is H or a suitable amino protecting group and is selected from the group consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), substituted benzyloxycarbonyls., 1-(p-biphenyl)-1-methylethoxycarb'onyl, and 9-fluorenylmethyloxycarbonyl (Fmoc)., tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, phenylthiocarbonyl, dithiasuccinoylalkyl-urethane, O-nitrophenylsulfenyl (NPS) , nitropyridylsulfenyl (NPYS), 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr-nr2), 2,4,6-trimethoxybenzenesulfonamide (Mtb-nr2), .2,6-dimethyl-4-methoxybenzenesulfonamide (Mds-NR2), pentamethylbenzenesulfonamide (Pme-nr2), 2, 3,5, 6-tetramethyl-4-methoxyben2ene-sulfonamide (Mte-nr2), 4-methoxybenzene-sulfonamide <Mbs-nr2), 2,4,6-trimethylbenzenesulfonamide (Mts-nr2), 2,6-dimethoxy-4-methoxybenzenesulfonamide (iMds-nr2), and 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc-nr2); and WO 94/22911 PCT /US94/03222 131 265 7 Z is s°3~/" S-alkyl, O-alkyl or an O-substituted derivative of hydroxylamihe.

6. A process of claim 5 wherein: n is 3; 10 R« is selected from: 15 R15 and R18 are independently selected from H, c1-C4 alkyl, phenyl, benzyl, phenyl-(C2-C4)alkyl, and C1-C4 alkoxy; 20 R17 and R16 are independently H or C1-C4 alkyl; R7 is H, Ci-Cs alkyl, phenyl, halogen, or C1-C4 alkoxy; WO 94/22911 PCT/US94/03222 ^ 265 7 5 3 R1* is H or C3.-C3 alkyl; R12 is H or CH3; 5 R3 is H, or C^-Cg alkyl; R9 is H or ci~"c3 alkyl; R5 is H, or C^-C^ alkyl; 10 R4 is selected from: H; Ci-Ce alkyl; C2-C8 alkenyl; 15 C2-C8 alkynyl; C3-C8 cycloalkyl; Ci-Ce alkyl substituted with (i) aryl, optionally substituted with 1-2 substituents independently selected from 20 halogen, phenyl, C1-C5 alkyl, C1-C5 alkoxy, NO2, -S (0) 0-2(C1-C5 alkyl), OH, N(R22)2/ CO2R22, CON (R22) 2 and -C Fw where v «= 1 to 3 and w = 1 to (2v+l) ; (ii) C3-C8 cycloalkyl; or 25 (iii) .(CH2) <m N aryl, optionally sxibstituted with 1-2 sxibstituents independently selected from halogen, phenyl, 30 C1-C5 alkyl, C1-C5 alkoxy, NO2, -S (0) 0-2(C1-C5 alkyl), OH, N(R22)2/ C02R22, CON(R22)2 and -C F v w where v = 1 to 3 and w = 1 to (2v+l); PCT/US94/03222 265 7 5 3 C2-C8 alkyl, alkenyl or alkynyl; substituted with 1-2 substituents independently selected from C1-c4 alkyl, c3-c8 cycloalkyl, C1-c5 alkoxy, phenoxy, benzyloxy, halogen, N02> CN, co2r22# CON (R22) 2/ N(R24)COR24, morpholino, 2-<l-morpholino)ethoxy, N(R22)2, N+(R22>3, OCOCH3, CF3, and S(0)Q_2R22; -CH (R24) OR2®; -CH (R24)0C(«0)R25; -CH (R24) OC (-0) OR26; -CH (R24) OC (=0) N (R25) 2; -CH(R24)C02R25; <A R27 . and -CH(R24)0 -O 22 24 25 26 27 28 and R , R , R , R R and R are as defined in clain

A process of claim 5 wherein: R2 is H or C1-C4 alkyl; R?, R9# R16# R17 and R18 are JJ. R11 and R12 are H or CH3; R15 is H, C1-C4 alkyl, phenyl, benzyl, or phenyl-(C2-C4)alkyl; and R3 is H or C1-C3 alkyl; S? <c /V t WO 94/22911 PCT/US94/G3222 265 75 R4 is selected from: H? -ch(r24)0c(=0)r25; -ch(r24)0c(=0)0r26; -ch20c(=0)n(r25)2/ -ch2ch2n(r22)2; -CH(R24)C02R25; and A, R27 10 ; wherein R24 is selected from: H, C^Cg alkyl, phenyl, and benzyl; 15 R27 is selected from: C3.-C5 alkyl, benzyl and phenyl, and 22 25 2 6 R , R and R are. as defined in claim 5.

8. A process of claim 5 wherein: 20 n is 3; p is 0, p' is 1; R19 is phenyl; 25 R5, R9, R11, and R12 are H; r2 is ethyl; 30 R3 is methyl; and WO 94/22911 PCT /US94/03222 R4 is selected from: H; -CH(R24)0C(=0)R25; -CH (R24) OC (=0) OR26; and o ,Mr 26 5 A R24 is C1-C4 linear alkyl or H; 10 R27 is C1-C4 alkyl, benzyl, or phenyl, and 25 26 R and R are as defined in claim 5.

9. A process for the preparation of an intermediate compound of the formula (II): .NXX XXN^ 15 Formula (II) comprising the steps of cyclizing a compound of formula (III) : WO 94/22911 PCT/US94/03222 1 N-XX XX-N-\ NH / <CHa)„ o \ R" O n'N'"v^oh / R3 ° RS Ria-N V o T o^rs^tn-h ft R« Formula (111) wherein: 5 n is 1 to 4; R1 is W. R1« Ri« rit R1«/ wherein: 10 p and p1 are 0 or 1; Rl9 is a C6-C14 saturated, partially saturated, or aromatic carbocyclic ring system or heterocyclic ring system 15 composed of carbon atoms and 1-3 heteroatoms selected from N, 0/ S; these ring systems being optionally substituted with 1 or 2 r'; . 20 R17 and R16 are independently selected from the group: hydrogen. 2*5 753 WO 94/22911 PCT/US94/03222 1V7 ■ 265 7 5 C1-C4 alkyl, optionally substituted with halogen, C1-C2 alkoxy, and benzyl; 5 R1^ and R18 are independently selected from the group: 10 15 hydrogen, C1-C8 alkyl substituted with 0-2 R8, C2-C8 alkenyl substituted with 0-2 R8, C2-C8 alkynyl substituted with 0-2 R8, c3-c8 cycloalkyl sxibstituted with 0-2 R8, Cg-Cio bicycloalkyl substituted with 0-2 R8, alkoxy, aryl substituted with 0-2 R13, and 20 25 a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms with the remaining atoms being carbon, optionally 13 substituted with 1 or 2 R ; R15 and R17 can alternatively join to form a 5-7 membered carbocyclic ring sxibstituted with 0-2 R13; or 30 R18 and R16 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R13; or 35 R7 is independently selected at each occurrence from the group: WO 94/22911 PCT/US94/03222 136 265 75 3 H, phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, Ci-Cg alkyl, C3-C6 cycloalkyl, 5 C4~C6 cycloalkylmethyl, C7-C10 arylalkyl, c3.-C4 alkoxy, -co2r20/ sulfonamide, formyl, C3-C6 cycloalkoxy, -0C(=0)R20, -C(=O)R20,-OC(=O)OR20a, -OR20, -CH2OR20, and C1-C4 alkyl 10 optionally sxibstituted with -NR20R21; Re is independently selected at each occurrence from the group: 15 =0, F, CI, Br, I, -CF3, -CN, -C02R20/ —C <=0) Nr20R>-1 , _CH2OR20, —OC (=0) R20, -CH2NR2(3R21, and -NR20R21; Rl3 is independently selected at each 20 occurrence from the group: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C1-C5 alkyl, C3-C6 cycloalkyl, 25 C4~*^ cycloalkylmethyl, C7-C10 arylalkyl, C3.-C4 alkoxy, -CO2R20i sulfonamide, formyl, C3-C6 cycloalkoxy, -OC (=0) R20, -C (=0) R20, -OC (=0) OR20®, -OR20, -CH20R20, and C1-C4 alkyl 30 optionally substituted with -NR2^R21; R20 is independently selected at each occurrence from the group: H, C1-C8 alkyl, aryl, - (C3.-C6 35 alkyl)aryl, and C3-C6 alkoxyalkyl; R20a is as defined for with the exception of H ; WO 94/22911 PCT/US94/03222 13^ 265 75 r21 is independently selected at each occurrence from the group: 5 H, C1-C4 alkyl, and benzyl; R12 is H or C1-C8 alkyl; R2 is H, Ci-Ce alkyl, c3-c6 cycloalkyl, 10 cycloalkylmethyl, cycloalkylethyl, phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3, CH2SCH3, CH2CH2SCH3, (CH2)9NH2, (CH2) aNHC(=NH) (NH2) , or (CH2)SNHR21, wherein s is 3-5; or 15 R12 and R2 can be taken together to form -(ch2)t~ * or -ch2sc (ch3) 2~ / wherein t is 2-4; R3 is H or C1-C8 alkyl; 20 R9 is H or Cj-Cg alkyl; R5 is H or c^~cg alkyl; 25 R11 is H or C1-C0 alkyl; R6 is CH2CO2X or CH2C02R4; Y is a suitable carboxylate protecting group 30 and can be selected from the group consisting of:c^to Cq alkyl, c5 to C8 cycloalkylalkyl benzyl, sxibstituted benzyl, triphenylmethyl, diphenylmethy1, 35 WO 94/22911 PCT/US94/03222 ilo 265 75 3 CH2CH2CN' trialkylsilyl, phthalimidomethyl, anthrylmethyl, phenylf luorenyl, 4-picolyl and phenacyl; or any other group which can be cleaved by acidolysis, mild base treatment or mild reductive means; and XX is H or a suitable amino protecting group and is selected from the group consisting 10 of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, allyoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, phenylthiocarbonyl, dithiasuccinoylalkyl -urethane, O-nitrophenylsulfenyl (NPS), nitropyridylsulfenyl (NPYS), 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr-NR.2) , 2,4,6-trimethoxybenzenesulfonamide (Mtb-NR2)/ 2,6-dimethyl-4-methoxybenzenesulfonamide (Mds-NR.2) , pentamethylbenzenesulfonamide (Pme-NR2) 2,3,5,6-tetramethyl-4-methoxybenzenesulf onamide (Mte-NR.2) / 4-methoxybenzene-sulfonamide (Mbs-NR.2) / 2,4,6- 20 25 30 WO 94/22911 PCT/US94/03222 10 11+1 265 7 5 3 trimethylbenzenesulfonamide (Mts-NR2), 2,6-dimethoxy-4-methoxybenzenesulfonamide (iMds-NR2) / 2,2,5,7,8-p'entamethylchroraan*-6-sulfonamide (Pmc-NR2), and fluorenylphenyl.

10. A process of claim 9 wherein: n is 3; Rl9 is selected from: 15 R15 and R18 are independently selected from H, C1-C4 alkyl, phenyl, benzyl/ phenyl-(C2-C4)alkyl, C1-C4 alkoxy; 20 R17 and R16 are independently H or C1-C4 alkyl; R7 is H, Ci-Cg alkyl, phenyl/ halogen, or C1-C4 alkoxy; 25 r11 is h or c1-C3 alkyl; WO 94/22911 PCT/US94/03222 Wl- 26 5 7 5 3 R12 is H or ch3; 10 R9 is H.or C^-C3 alkyl; R5 is H.or alkyl; and XX is selected from the group consisting of: t-Boc, acyl, o-nitrophenylsulfenyl, Cbz, Fmoc, and fluorenylphenyl. 15 20

11. A process of claim 9 wherein: R2 is H or c1-c4 alkyl; R5, R9, R16, R17 and R18 are H; R11, and R^2 are H or ch3; or R2 and R12 together are -(ch2)3-; 25 R15 is H, C1-C4 alkyl, phenyl, benzyl, or phenyl-(C2-C4)alkyl; and R3 is H or C1-C3 alkyl. 30 35

12. A process of claim 9 wherein: p is 0, p' is 1; n is 3; Rl9 is phenyi; R5, R9, R11, and R12 are H; WO 94/22911 PCT/US94/03222 t+s 265 7 5 R2 is ethyl; R3 is methyl; 5 R^ is CH2~OBnf CH2-OtBu, or CH2-0-tBoc; and XX is Cbz or Boc.

13. A process according to claim 1 wherein the 10 intermediate compound of formula (IV): /CN (CHa)m £ w Formula (IV) is prepared by the steps of: 15 (a) dehydrating the carboxamide group of the formula: HzN (CHa) » w H OH 20 to the corresponding nitrile to produce the formula: NC% (CHaJm w-nhV° OH WO 94/22911 PCT/US94/03222 W4- 2*5 5 7 5 3 (b) then selectively alkylating the product of step (a) at the a-amino group using a suitable alkylating agent containing the group R3 (provided R3 is not H) to produce formula (IV) above, 5 wherein: R3 is H or Ci-Cs alkyl; 10 m is 0 to 3; and W is a suitable amino protecting group and is selected from the group consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, 15 benzyloxycarbonyl (Cbz), substituted benzyloxycarbonyls, 1-(p-biphenyl)-1 -methylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbony1, allyoxycarbonyl, 20 cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, phenylthiocarbonyl and dithiasuccinoylalkyl -urethane. 25 30

14. An intermediate compound selected formulae II, III, IV, V and VI: from the compounds of WO 94/22911 PCTAJS94/03222 \i-5" . NXX XXN-^ \ NH / (CH2)n ^ n! N o I Formula (II) 26 5 N-XX XX-N-^ NH / (CH*), O \ ?* o R'sA n>YnY^0H / R* ° "* \ H11 u • •rtN-H Formula (III) CN ■<£ OH Formula (IV) cn ^2) m iR „ o <c^"" v' o O-Y R2 R3 Formula (V) , and CN / (CHz) m 0 N O V ^R12 N-R" * Y i r6 'V^R1 A Formula (VI) WO 94/22911 PCT/US94/03222 1H4> wherein: 26575 3 R1 is VV Ria Ri« R17 R1^ wherein: 5 p and p' are 0 or 1; R*9 is a C6-C14 saturated, partially saturated, or aromatic carbocyclic ring 10 system or heterocyclic ring system composed of carbon atoms and 1-3 heteroatoms selected from N, 0, S; these ring systems being optionally substituted with 1 or 2 R ; 15 R17 and R16 are independently selected from the group: hydrogen, 20 C1-C4 alkyl, optionally substituted with halogen, C1-C2 alkoxy, and benzyl; 25 R1^ and R*8 are independently selected from the group: hydrogen, Ci-Cs alkyl substituted with 0-2 R8, 30 C2~C8 alkenyl substituted with 0-2 R8, C2-C8 alkynyl substituted with 0-2 R8, c3-c8 cycloalkyl substituted with 0-2 R8, WO 94/22911 PCT/US94/03222 m 265 75 3 C6~ClO bicycloalkyl substituted with 0-2 R8, C1~C4 alkoxY' aryl substituted with 0-2 R13, and 5 a heterocylic ring system composed of 5-10 atoms including 1-3 nitrogen, oxygen, or sulfur heteroatoms with the remaining atoms being carbon, optionally 13 10 sxibstituted with 1 or 2 R ; or R15 and R17 can alternatively join to form a 5-7 membered carbocyclic ring substituted with 0-2 R13; or 15 R10 and R1€ can alternatively join to form a 5-7 membered carbocyclic ring sxibstituted with 0-2 R13; 20 R7 is independently selected at each occurrence from the group: H, phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, 25 cyano, Ci-Cg alkyl, c3-c6 cycloalkyl, C^-C7 cycloalkylmethyl, c7-c10 arylalkyl, C1-C4. alkoxy, -CO2R20/ sulfonamide, formyl, C3-C6 cycloalkoxy, -OC <«0) R20, -C (=0) R20, -OC (=0) OR20*, 30 -OR20, -CH2OR20, and C1-C4 alkyl optionally substituted with -Nr20r21. 35 R8 is independently selected at each occurrence from the group: PCT/US94/03222 iMrB 26 5 7 5 3 =0, F, CI, Br, I, -CF3, -CN, -C02R20, -C<=O)NR20R21, -CH2OR20, -OC(=0)R20, -CH2NR20R21/ and -NR20R21; Rl3 is independently selected at each occurrence from the group: phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, c1-c5 alkyl, c3-c6 cycloalkyl, C4~C7 cycloalkylmethyl, c7-c10 arylalkyl, c1-c4 alkoxy, -co2r20, sulfonamide, formyl, c3-c6 cycloalkoxy, -OC (»0) R20, -C (=0) R20, -OC (=0) OR20a, -OR20, -CH2OR2°, and C1-c4 alkyl optionally substituted with -Nr20r21/ R20 is independently selected at each occurrence from the group: H, C1-C8 alkyl, aryl, -(c1-c6 alkyl)aryl, and c3-c6 alkoxyalkyl; R20a is as defined for R&P with the exception of H R21 is independently selected at each occurrence from the group: H, C1-C4 alkyl, and benzyl; is H or alkyl; is H, C1-C8 alkyl, c3-c6 cycloalkyl, c4-c7; cycloalkylmethyl, C5-C8 cycloalkylethyl, phenyl, phenylmethyl, CH2OH, CH2SH, CH2OCH3, CH2SCH3, CH2CH2SCH3, (CH2)aNH2, PCT/US94/03222 (CH2) sNHC (»NH) <NH2) / or (CH2)9NHR21/ wherein s is 3-5; or r*2 and R2 can be taken together to form -{CH2)t~ / or -CH2SC(CH3)2- , wherein t is 2-4; R3 is H or Ci-Cb alkyl; R9 is H, Ci-Ce alkyl; R5 is H, Ci-Cs alkyl; R11 is H or Ci-Ce alkyl; R6 is ch2co2y or ch2co2r4; R4 is selected from: h; Ci-Cs alkyl; C2-C8 alkenyl; C2-C8 alkynyl; C3-C8 cycloalkyl; Ci-Cs alkyl substituted with (i) aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-C5 alkyl, C1-C5 alkoxy, N02, -S(0) 0-2(C1-C5 alkyl), OH, N(R22) 2/ CO2R22, CON (R22) 2 and -C^ where v » 1 to 3 and w » 1 to (2v+l); (ii) C3-C6 cycloalkyl; or (iii) •I WO 94/22911 PCT/US94/03222 15b 265 75 3 aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-C5 alkyl, C1-C5 alkoxy, NO2, -S (O)0-2(C1-C5 alkyl) , OH, N(R22)2, C02R22, CON(R22)2 and -C F V w where v ■ 1 to 3 and w * 1 to (2v+l); C2-Cs alkyl, alkenyl or alkynyl; substituted with 1-2 substituents independently'selected from C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy, phenoxy, benzyloxy, halogen, NO2, CN, C02R22, CON (R22) 2t N(R24)COR24, morpholino, 2-<l-morpholino) ethoxy, N(R22)2» N+(R22)3, 0C0CH3, CF3, and S(0)0_2R22; -CH(R24) OR26; -CH (R24)OC(«0)R25; -CH (R24) OC (*0) OR2®; -CH (R24) OC <«0) N (R2^) 2; -CH (R24) N (R24) C (=0) R24; -CH(R24)C02R25; -CH (R24) CON (R22) 2; -CH (R24)N (R22) 2/ 25 PCT AJS94/03222 265 753 ' wherein R22 is selected independently at each occurrence from: H, C]_-C]_q alkyl, C3-C1Q cycloalkyl, C4-C12 alkylcycloalkyl, aryl, (Cx-Cio alkyl)aryl, or C3-C10 alkoxyalkyl; or when two R22 groups are bonded to a single N, said R22 groups may alternatively be taken together to form - <CH2)2-5-'or - (ch2)0(ch2)-; R24 is selected independently at each occurrence from: H, C^Ca alkyl, C3-CK) cycloalkyl, phenyl and benzyl; R25 is selected from: \5\ o X o o R37 CH(R24)0 o and XX) PCT/US94/03222 IS "2- 265 7 Ci-Ce alkyl or C3-C0 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: (i) C1-c4 alkyl; (ii) c3-c8 cycloalkyl; (iii) C1-C5 alkoxy; and (iv) aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2, -S (C1-C5 alkyl), -SO(C1-c5 alkyl), -S02(C1-c5 alkyl), -OH, -N(R22)2, -C02R22, -C("0)N(R22)2, and —C F where v = 1 v w to 3 and w ■ 1 to (2v+l); and aryl substituted with 0-2 groups independently selected from: halogen, phenyl, Cj-C6 alkyl, C1-C6 alkoxy, NO2, -S(C1-C5 alkyl), -SO(C1-C5 alkyl), -S02(Ci-C5 alkyl), -OH, —N (R22) 2/ -CO2R22, -C (»=0) N (R22) 2t or -CVFW where v « 1 to 3 and w = 1 to (2v+l) ; R26 is selected from: Ci-Cs alkyl or C3-C8 cycloalkyl, said alkyl or cycloalkyl being substituted with 1-2 groups independently selected from: (i) C1-C4 alkyl; (ii) C3-CB cycloalkyl; (iii) C1-C5 alkoxy; and (iv) aryl substituted with 0-2 groups independently selected from: halogen, phenyl, C1-C6 alkyl, C1-C6 WO 94/22911 PCT/US94/03222 ® H3 26 5 7 5 3 alkoxy, NO2, -S (Cx-Cs alkyl), -SO(Ci-C5 alkyl), -SO2(Cx-C5 alkyl), -OH, -N(R22)2, -C02R22, —C (»0) N (R22) 2, and -C F where v = 1 • v w 5 to 3 and w = 1 to (2v+l); and aryl sxibstituted with 0-2 groups independently selected from: halogen, phenyl, Cx-Cg alkyl, Cx-Cg alkoxy, NO2, -S(Cx-Cs alkyl), -SO(Ci-Cs 10 alkyl), -SO2 (C1-C5 alkyl), -OH, —N (R22) 2/ -C02R22, -C («0)N(R22)2, and -CVFW where v « 1 to 3 and w « 1 to (2v+l); 15 R27 is selected from: H ; Cx-Cfl alkyl or C3-C8 cycloalkyl, -said alkyl or cycloalkyl being substituted with 1-2 groups independently selected 20 from: <i) Cx-C6 alkyl; (ii) Ci-Ce alkoxy; and (iii) aryl substituted with 0-2 groups independently selected from: 25 halogen, phenyl, C1-C6 alkyl, C1-C6 alkoxy, NO2/ -S (C1-C5 alkyl), -SO(Cx-C5 alkyl), -S02(Ci-C5 alkyl), 0 -OH, —N (R22) 2, -CO2R22, -C (®0) N (R22) 2/ and where v = 1 30 to 3 and w « 1 to (2v+l); and aryl substituted with 0-2 groups ' independently selected from: halogen, phenyl, Cx-C6 alkyl, C1-C6 alkoxy, NO2, -S(Cx-Cs alkyl), -SO(Cx-Cs 35 alkyl), -SO2 (C1-C5 alkyl), -OH, —N (R22) 2, -c:02R22, -C(»0)N(R22)2/ and WO 94/22911 PCT/US94/03222 is4- 265 7 5 -CvFw where v = l to 3 and w = 1 to (2v+l); and r28 is selected from: H, C1-C5 alkyl, and 5 benzyl; n is 1 to 4; m is 0 to 3; 10 Y is a suitable carboxylate protecting group and can be selected from the group consisting of: to C3 alkyl, C5 to Cq cycloalkylalkyl, benzyl, substituted benzyl, 15 triphenylmethyl, diphenylmethyl, CH2CH2CN, trialkylsilyl, phthalimidomethyl, anthrylmethyl, phenylfluorenyl, 4-picolyl and phenacyl; or any other group which can be cleaved by acidolysis, mild base treatment or mild reductive means; 25 W is an amino protecting group and is selected from the group consisting of: formyl, 30 trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz), substituted benzyloxycarbonyls, 1-(p-biphenyl) -1-methylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), 35 tert-butyloxycarbonyl PCT/US94/03222 (Boc), ethoxycarbonyl, diisopropylmethoxycarbony1, allyloxycarbony1 cyclopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, phenylthiocarbonyl, dithiasuccinoylalkyl -urethane, O-nitrophenylsulfenyl (NPS) and nitropyridylsulfenyl (NPYS); and is h or a suitable amino protecting group and is selected from the group consisting of: formyl, trifluoroacetyl, phthalyl, p-toluenesulfonyl, benzyloxycarbonyl (Cbz) , sxibstituted benzyloxycarbonyls, 1- (p-biphenyl) -1-methylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, allyloxycarbonyl, eye lopentyloxycarbonyl, adamantyloxycarbonyl, triphenylmethyl, benzyl, trimethylsilane, phenylthiocarbonyl, dithiasuccinoylalkyl -urethane, O-nitrophenylsulfenyl (NPS), nitropyridylsulfenyl (NPYS), 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr-NR.2), 2,4,6-trimethoxybenzenesulfonamide (Mtb-NR.2) , 2,6-dimethyl-4-methoxybenzenesulfonamide (Mds-NR2) , pentamethylbenzenesulfonand.de (Pme-NR.2) PCT/US94/03222 \S6> 26 2/3,5/6-tetramethy1-4-methoxybenzenesulf onamide (Mte-NR2)/ 4-methoxybenzene— sulfonamide (Mbs-NR2), 2,4,6-trimethylbenzenesulfonamide (Mts-NR2)t 2,6-dimethoxy-4-methoxybenzenesulfonamide (iMds-. NR2) / and 2,2, 5/7, 8-:pentamethylchroman-6-sulfonamide (Pmc-NR2)• An intermediate compound of claim 14 wherein: W and XX are independently Cbz, or t-Boc; r!9 is selected from: R15 and R18 are independently selected from H, C1-C4 alkyl, phenyl, benzyl/, phenyl-(C2-C4)alkyl, C1-C4 alkoxy; R17 and R16 are independently H or C1-C4 alkyl; WO 94/22911 PCT/US94/03222 265 7 5 3 R7 is H, Ci-Ce alkyl, phenyl, halogen, or Ci~ C« alkoxy; R11 is H or C1-C3 alkyl; 5 R12 is H or CH3; R9 is H or alkyl; 10 R5 is H or alkyl; R4 is selected from: 15 H; Ci-Cs alkyl; C2-Ce alkenyl; C2-C8 alkynyl; C3-C8 cycloalkyl; 20 Ci-Cs alkyl sxibstituted with (i) aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-C5 alkyl, C3.-C5 alkoxy, no2, -S (0) 0-2 (C1-c5 alkyl), OH, 25 N(R22)2* CO2R22, C0N(R22)2 and -C F where v w v » 1 to 3 and w ■ 1 to (2v+l) ; (ii) C3-C8 cycloalkyl; or (iii) 30 (ch2) lM aryl, optionally substituted with 1-2 substituents independently selected from halogen, phenyl, C1-C5 alkyl, Ci~Cs alkoxy, NO2, -S (0) 0-2(C1-C5 WO 94/22911 PCT /US94/03222

15 25 ise 26 5 7 5 3 alkyl) , OH, N(R22)2# C02R22/ CON(R22)2 and -C F v w where v » 1 to 3 and w « 1 to (2v+l); C2-Ce alkyl, alkenyl or alkynyl; substituted with 1-2 substituents independently selected from 5 C1-C4 alkyl, C3-C8 cycloalkyl, C1-C5 alkoxy, • phenoxy, benzyloxy, halogen, NO2, CN,'CO2R22/ CON(R22)2, N<R24)C0R24, morpholino, 2-(l-morpholino)ethoxy, N(R22)2, N+(R22)3, 0C0CH3, CF3, and S(0)Q_2R22; 10 -CH(R24)OR26; -CH (R24) OC (=0) R25; -CH(R24)0C(=0)0R26; -CH (R24) OC 0) N (R25) 2/ -CH (R24) C02R25; O <A> -CH(R24)0 R27 • H / and -o and 22 „24 25 26 _,27 . „28 . .. . , R , R , R and R are as defined in claim 20 m is 2, and n is 3, and 22 24 25 26 27 A f X\ f I\ j •£> f

16. An intermediate compound of claim 14 wherein: R2 is C1-C4 alkyl; R5, R9, R16, R17 and R18 are H; R*1, and R-*-2, are H or CH3; WO 94/22911 PCT/US94/03222 265 75 3 R15 is H, c3.-c4 alkyl, phenyl, benzyl, or phenyl-(C2-C4)alkyl; R3 is H or C1-C3 alkyl; 5 R4 is selected independently at each occurrence from: H; -CH (R24) OC (»0) R25; 10 -CH(R24)0C(=0)0R26; -ch2oc{=o)N(r25)'2; -ch2ch2n(R22)z; -CH(R24)C02R25; and o 30

A r27 15 ; wherein R24 is selected independently from: H, Ci-Cs alkyl, phenyl, and benzyl; and 20 R27 is selected from: C1-C5 alkyl, benzyl and phenyl; m is 2, and n is 3, and R22, R2"' and R^ are as defined in claim 14. 25 17. An intermediate compound of claim 14 wherein: p is 0, p' is 1; r19 is phenyl i r5# r9, Rll, and/- R1,2 are H; WO 94/22911 PCT/US94/03222 ^ 265 75 3 R2 is ethyl; R3 is methyl; 5 n is 2/ n is 3; R6 is CH2-OBn, CH2~0tBu, CH2-0-tBoc or CH2C02R4/ 10 R4 is selected independently at each occurrence from: H; ~CH(R24)0C(=0)R25; -CH (R24) OC (=0) OR26; and 15 o <Ao R27 ; wherein R24 is C1-C4 linear alkyl or H; and 20 R27 is C1-C4 alkyl, benzyl, or phenyl; XX is Cbz or Boc , and 25 26 R and R are as defined in claim 14.

18. A process according to any one of claims 1 to 13 substantially as herein described with reference to the Examples.

19. An intermediate compound of any one of claims 14 to 17 as specifically set forth herein.