HAVING SPECIFICITY FOR THE GPIIbHI _a RECEPTOR

FIELD OFTHE INVENTION The present invention relates to nonpeptidyl inhibitors of integrin receptors.

Specifically, the invention is directed to antagonists of the final common pathway of platelet aggregation. These antagonists act as potent antithrombotics. The invention further relates to therapeutic applications of these nonpeptidyl inhibitors in diseases for which blocking platelet aggregation is indicated. BACKGROUND OF THE INVENTION

A. Platelets

Platelets are particles found in whole blood that initiate and provide the structural basis for the hemostatic plug necessary to stop bleeding. Platelets depend on adhesive interactions with extracellular proteins and other cells for proper function (see Hawiger, J. Atherosclerosis Reviexvs 21:165-186 (1990) and Roth J. R. Immunology Today 13(2):100-105 (1992)). The external platelet plasma membrane surface is covered with a variety of membrane bound glycoproteins, many of which have recognition and adhesive functions. Perhaps the most abundant platelet membrane adhesive proteins belong to the integrin superfamily which include the glycoproteins; GPIIblII _a , GPI _a iI _a , GPl _c Il _a , GPI lX, and the fibronectin and vitronectin receptors (Hynes, R. O., Cell, 48: 549 (1987). Each integrin receptor is an αβ heterodimer displaying characteristic affinity and specificity toward various protein ligands found in serum and /or the extracellular matrix including; von Willebrand factor (vWF), collagen, entactin, tenascin, fibronectin (Fn), vitronectin (Vn), and laminin, as well as fibrinogen (Fg) and thrombospondin (see Kieffer et al. , Ann. Rev. Cell Biol. 6:329-357(1990) and Ruoslahti, /. Clin. Invest., 87:1-5 (1991)). The most abundant integrin found on the surface of normal platelets is GPUtιlII _a comprising about 50,000 molecules per platelet and representing about 2% of the total platelet protein. GPlIt _> UI _a is a non-covalent, calcium ion dependent heterodimeric complex (Jennings, et al, J. Biol. Cliem. 257: 10458 (1982)) that is restricted in distribution to platelets and other cells of the megakaryocytic lineage (Kieffer et al., supra ). On activated platelets, GPllbUla promiscuously binds a number of protein ligands with varying affinities, including; fibrinogen, fibronectin, von Willebrand factor, vitronectin and thrombospondin (Plow et al. , Biochemistry of Platelets, Phillips and Shuman eds., p. 225-256, Orlando: Academic Press [1986]). Each of these protein ligands contain at least one tripeptide sequence Arg-Gly- Asp (RGD) which is commonly referred to as the "recognition sequence". It is believed the most important interactions mediating platelet aggregation involve GPIIbIII _a binding with the trinodular fibrinogen and, to a lesser extent, with the filamentous von Willebrand factor (Kieffer et al. , siψra and Albeda et al, The FASEB journal , 4:2868-2880 [1990]).

GPIIblll _a binding to its natural ligands can be inhibited to varying degrees by peptides and proteins containing the amino acid recognition sequences; Arg-Gly-Asp (Ruoslahti, supra and EPO 368 486, assigned to Merck & Co.), Lys-Gly-Asp (KGD), and the fibrinogen γ-chain

carboxy-terminal dodecapeptide HHLGGAKQAGDV and analogues thereof (Timmons et al., Biochemistr , 28:2919-2922 [1989]). B. The Hyperthrombotic State

Many common human disorders are characteristically associated with a hyperthrombotic state leading to intravascular thrombi and emboli. These are a major cause of medical morbidity, leading to infarction, stroke and phlebitis, and of mortality from stroke and pulmonary and cardiac emboli. Patients with atherosclerosis are predisposed to arterial thromboembolic phenomena for a variety of reasons. Atherosclerotic plaques form niduses or platelet plugs and thrombi that lead to vascular narrowing and occlusion, resulting in myocardial and cerebral ischemic disease. This may happen spontaneously or following procedures such as angioplasty or endarterectomy. Thrombi that break off and are released into the circulation cause infarction of different organs, especially the brain, extremities, heart and kidneys.

In addition to being involved in arterial thrombosis, platelets may also play a role in venous thrombosis. A large percentage of such patients have no antecedent risk factors and develop venous thrombophlebitis and subsequent pulmonary emboli without a known cause. Other patients who form venous thrombi have underlying diseases known to predispose them to these syndromes. Some of these patients may have genetic or acquired deficiencies of factors that normally prevent hypercoagulability, such as antithrombin-3. Others have mechanical obstructions to venous flow, such as tumor masses, that lead to low flow states and thrombosis. Patients with malignancy have a high incidence of rhrombotic phenomena for unclear reasons. Antithrombotϊc therapy in this situation with currently available agents is dangerous and often ineffective.

Patients whose blood flows over artificial surfaces, such as prosthetic synthetic cardiac valves or through extracorporeal perfusion devices, are also at risk for the development of platelet plugs, thrombi and emboli. It is standard practice that patients with artificial cardiac valves be treated chronically with anti-coagulants. However, in all instances, platelet activation and emboli formation may still occur despite adequate anticoagulation treatment.

Thus, a large category of patients, including those with atherosclerosis, coronary artery disease, artificial heart valves, cancer, and a history of stroke, phlebitis, or pulmonary emboli, are candidates for limited or chronic antithrombotic therapy. The number of available therapeutic agents is limited and these, for the most part, act by inhibiting or reducing levels of circulating clotting factors. These agents are frequently not effective against the patient's underlying hematologic problem, which often concerns an increased propensity for platelet aggregation and adhesion. They also cause the patient to be susceptible to abnormal bleeding. Available antiplatelet agents, such as aspirin, inhibit only part of the platelet activation process and are therefore often inadequate for therapy and also cause the patient to be susceptible to abnormal bleeding. An ideal anti-thrombotic drug would have many properties currently not available (see e.g. Sϊxma, et al Thrombosis Research 67: 305-311 [1992]).

C. Therapeutic Agents

An agent which effectively inhibits the final common pathway of platelet activation, namely fibrinogen binding to the GP IlbHIa receptor, should accordingly be useful in a large group of disorders characterized by a hyperthrombotic state as described above. Such agents include anri-thrombotic peptides and pseudopep ides capable of inhibiting platelet aggregation. Ruoslahti et al. (U.S. patent no. 4,578,079) suggest that tetrapeptides containing the RGD sequence may be used to inhibit platelet aggregation. Zimmerman et al. (U.S. patent no. 4,683,291) disclose that positively charged amino acid residues (e. g. Arg and Lys) and homologues located before or toward the amino terminus of the RGD sequence are superior for inhibiting fibrinogen-platelet binding. Adams et al. (U.S. patent no. 4,857,508) describe superior results for in vitro inhibition of human platelet aggregation in platelet-rich plasma for linear tetrapeptides containing O-methyl-Tyr-amide immediately following the RGD (or homo-RGD) sequence. Barker et al , WO 90/01331, disclose substantially rigid RGD cyclic peptides possessing high affinity for the GP IlbMa receptor. A particularly efficacious rigid RGD cyclic peptide described by Barker et al. is represented by the following structure:

Tjoeng et al (U.S. patent no. 4,879,313) describe peptide mimetic platelet aggregation inhibitors in which the first two residues of the RGD sequence are replaced by the pseudodipeptidyl 8- guanidino-octanoyl moiety. Other peptidomimetics in which the Arg of the RGD sequence has been altered include; WO89/07609 (homo-Arg[Har]), EP 341 915 (Har and alkyl-Arg), WO90/15620 (Har and amidino derivatives e. g. imidazolinyl, imidazolyl, and substituted imidazolyl), EP 422 937 (aryl-, arylalkyl-, and cycloalkyl-amines), WO91/07976 (alkylamidino and alkylamino derivatives), and WO91/04247 (alkylamino and alkylguanidino proline derivatives). See also EP 384362 (glycine derivatives) and EP 381 033.

Complete replacement of all residues in the RGD sequence has been described in EP

372 486, assigned to Hoffmann La Roche, where platelet aggregation inhibitors that are derivatives of benzoic and phenylacetic acid are presented. A benzoic acid derivative inhibitor having a particular low ICso in an ELISA measurement of fibrinogen GPII _D III _a binding has the following structure:

Fibrinogen receptor antagonists possessing similar structures can be found in EP 478362, EP 478363, and EP 478328, all assigned to Merck. A representative Merck compound has the following structure:

Also of interest are biphenyl derivatives described in EP 483 667 and EP 496378, the latter publication providing a representative compound having the structure;

Quϊnazoline-3-alkanoic acid derivatives are also reported to have an inhibitory effect on platelet aggregation(although possibly by a different mechanism) in EP 456835 Al. A generic formula representing these compounds is given by:

where n is 1 to 3 and R ² and R° may be interπlia hydrogen, lower alkyl, lower alkoxy, aralkyl groups that may be substituted with interalia -NR ⁴ R^, where R^ or R^ may be hydrogen, lower alkyl, or connected with each other to make five- or six-membered heterocycles which may contain another heteroatom, and A-R^ may be lower alkyl. D. Benzodiazepines

It is well established that benzodiazepines and related ligands interact with a specific site commonly referred to as the "benzodiazepine receptor" that is associated with a neuro-

inhibitory postsynaptic GABA receptor and a chloride ionophore channel (see eg. Watjen et al, ]. Med. Chem. 32:2282-2291[1989]). Binding of ligands to this receptor is known to produce a wide variety of neuro-physiological effects. Benzodiazepines have not been reported to have platelet aggregation inhibition activity. The preparation and therapeutic use of benzodiazepines is described in, for example; EP 0059390, EP 0059386, and EP 0394 101.

Benzodiazepinediones have been employed as intermediates in the synthesis of various anti-HlV-1 compounds. For example Kukla, M. J. et al, J. Med. Chem. 34:3187-3197 (1991) reduce the dilactam to either the corresponding "-one" or diamine in the preparation of various TIBO derivatives having anti-HIV activity. Pyridodiazepines are also described as useful for treatment of HIV infection in U.S. Patent No.5,087,625. E. Objects

It is an object of this invention to produce nonpeptidyl compounds having potent antithrombotic activity. It is another object of the invention to produce such compounds that are essentially free of amide bonds, substantially rigid, and stable to degradation. It is a further object to produce potent nonpeptidyl antithrombotics that specifically inhibit the GPIIbIIIa-Fg interaction but do not strongly inhibit other RGD sensitive integrin interactions including the Vn-VnR, Fn-FnR, and GPIIbHIa-vWF interactions. It is still a further object to produce potent nonpeptidyl platelet aggregation inhibitors that do not significantly increase cutaneous bleeding time or diminish other hemodynamic factors. It is also an object of this invention to produce nonpeptidyl compounds having a long half-life and a large therapeutic range.

It is still a further object to produce nonpeptidyl compounds that are capable of inhibiting other integrin interactions such as the Vn-VnR interaction.

These and other objects of this invention will be apparent from consideration of the invention as a whole. SUMMARY OF THE INVENTION

The objects of this invention are accomplished by providing a nonpeptidyl compound represented by structural formula I :

where the partial structure

represents;

where R* and R^ are one to three optional groups typically selected from; hydrogen, halo(F, Cl, Br, I), cyano, carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido, thioureido, thiocyanato, hydroxy, mercapto, sulfonamido, and an optionally substituted radical selected from; C1-C12 alkyl, C2-C12 alkenyl, C3- 2 alkynyl, C3- 2 cycloalkyl, C6- 4 aryl, Cό-Cio aryl-Cι-C8 alkyl, -C12 alkyloxy, C6-C14 aryloxy, C1-C12 acylamino, N,N-di(Cι- Ci2)acylamino, N-(Cι-Ci2)alkyl-N-(Ci-Ci2)-acylamino, C1-C12 alkylsulfonamido, N-(C - Ci2)-alkyl-N-(Cι-Ci2)aIkyl-suIfonyIamino, C1-C12 alkylthiocarbonyl, C1-C12 alkylthio, Ci- C12 alkylsulfinyl, C1-C12 alkylsulfonyl, Q-C12 alkylsulfonato, N-(Cι-Ci2)alkylsulfona ido, N,N-di-( -Ci2) sulfonamido, N-(Cι-Ci2) alkyl-N-thioformylamino, C1-C12 thioacylamino, N- (Cι-Ci2)aIkyl-N-(Cι-Cχ2) thioacylamino, C1-C12 alkylsulfinamido, N-(Cι-Ci2)alkyl-N-(Cι-

Ci2)alkylsulfinylamino, C1-C12 carbalkoxy, C1-C12 alkylcarbonyl, C1-C12 alkanoyloxy, N-(Cι- Ci2)alkylcarboxamido, N,N-di-(Cι-Ci2)carboxamido, N-(Cι-Ci2) alkylcarbamoyloxy, N,N-di- (Cι-Ci2)carbamoyloxy, and heterocycloalkyl or heteroaryl having from 1 to 3 rings, each ring having from 5 to 7 atoms with from 0-3 heteroatoms selected from N, O, and S, provided that at least one ring contains a heteroatom, where the substituents are typically selected from halo (F, Cl, Br, I), cyano, azido, nitro, hydroxy, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, Cι-C4alkyl, Cι-C4alkoxy, phenyl, and phenoxy. Optionally, R^ and R ² when bonded to adjacent carbon atoms may join to form an unsubstituted or substituted aryl ring, where the substituents are typically selected from halo (F, Cl, Br, I), cyano, azido, nitro, hydroxy, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, Cι-C4alkyl, Cχ-C4alkoxy, phenyl, and phenoxy.

Y ¹ , Y ² , Y ³ , γ4 and Y ⁵ are independently selected from CH, CR ¹ , CR ² , and N; X is O, S, =NCN, or =NO(Cι-C3)alkyl; and Z ¹ is selected from CH2, NH, S, and O; Cjl is a substituted or unsubstituted positively charged nitrogen-containing moiety.

Preferably Cjl is selected from: (A) an amino group including;

(1) -NH2,

(2) -NR H, (3) -NR R ⁴ , and

(4) -NR ³ R ⁴ R ⁵ , where R ³ , R ⁴ , and R^ are typically selected from; (i) an optionally substituted radical selected from (a) -NR ⁶ R ⁷ , (b) -C(=NR ⁸ )-NR ⁶ R ⁷ , (c) -N=CR ⁹ -NR ⁶ R ⁷ , (d) -NR ¹⁰ -CR ⁹ =NR ⁸ , and (e) -NR ¹⁰ -C(=NR ⁸ )-NR6R7 where each R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ is independently selected from hydrogen, C1-C4 alkoxy, C1-C4 alkyl, and halo(F, Cl, Br, I)-Cι-C4 alkyl, (ii) optionally substituted -C12 alkyl, (iii) optionally substituted C3-C7 alkenyl, (iv) optionally substituted C3-C7 alkynyl, (v) optionally substituted C3- 2 cycloalkyl, (vi) optionally substituted C5-C12 cycloalkenyl, (vii) optionally substituted C - 4 aryl, (viii) optionally substituted Ci-Cβ alkyl- C6-Ci4-aryl, (ix) optionally substituted C3-C6 alkenyl-Qj-Cio aryl, (x) optionally substituted heterocyclyl, (xi) optionally substituted Ci-C alkyl-heterocyclyl, (xii) optionally substituted Ci-Cfl alkoxy, (xiii) optionally substituted -Cfl thioalkoxy, (xiv) optionally substituted C3- C10 alkenoxy, and (xv) optionally substituted C6-C14 aryloxy, where the substituents are usually one to three R^, each R^ typically selected from (a) optionally substituted C6-C12 aryloxy, (b) optionally substituted C6-C12 arylamino, (c) optionally substituted C -C12 aroyl, (d) optionally substituted Cft-Ci2 arvlthio, where the substituents are usually one to three R^ , each R^ ² typically selected from nitro, amino, Ci-Cg alkylamino, di-( -C8) alkylamino, amidino, aminomethylenei ino, imino, imino-Cι-C4 alkyl, iminomethyleneamino, guanidino, Cg-Ci arylamino, Q-Cs acylamino, C1-C4 alkylsulfonamino, azido, cyano, hydroxy, hydroxy- -Cs-alkyl, Ci-C^-alkoxy, phenyloxy, Ci-Cs alkanoyloxy, -Q? alkanoyl, C5-C12 aroyl,

benzamido, phenyl, haIo(F, Cl, Br, I), halo-Ci-Cs-alkyl, and Cχ-C8-alkyl, (e) Cχ-C8 alkoxy (f) Ci-C8alkthio (g) halo(F, Cl, Br, I), (h) hydroxy, (i) mercapto, (j) _. -C8 alkylcarbonyl, (k) carbamoyl, (1) formyl, (m) formyloxy, (n) carboxy, (o) carb-Cχ-Cs alkyloxy, (p) Cχ-Cδ alkanoyloxy, (q) N-(Cι-C8)-alkylcarboxamido, (r) N-(Cι-Cs), N-(Cι-C8)-dialkylcarboxamido, (s) carbamoyloxy, (t) N-(Cι-Cs) alkylcarbamoyloxy, (u) N-(Cχ-C8)/ N-(Cχ- C8)dialkylcarbamoyloxy, (v) Cχ-Cs alkylsulfinyl, (w) Cχ-Cs alkylsulfonyl, (x) Cχ-Cs alkylsulfonato, (y) sulfo, (z) sulfonamido, (aa) N-(Cχ-Cs) alkylsulfonamido, (ab) N-(Cχ-C8), N- (Cχ-C8) dialkylsulfonamido, (ac) amino, (ad) Cχ-Cδ alkylamino, (ae) Cχ-Cδ dialkylamino, (af) Cχ-C8 acylamino, (ag) N-(Cχ-Cδ), N-(Cχ-C8)-diacylamino, (ah) N-(Cχ-Cs)-alkyl-N-(Cχ-C8)- acylamino, (ai) formylamino, (aj) ureido, (ak) isothioureido, (al) amino-C2-Cs alkylthio, (am) amino-C2-C8 alkloxy, (an) amidϊno,(ao) guanidino, (ap) aminomethyleneϊmino, (aq) imino, (ar) imino-Cχ-C4 alkyl, (as) iminomethyleneamino, (at) glycylamino, (au) glycyl,(av) phthalimido, (aw) succϊnimido, (ax) morpholino, (ay) Cχ-C8 alkylsulfonamido, (az) N-(Cχ-Cs)-alkyl-N-(Cχ- Cδ) alkyl sulfonoylamino, (ba) Cχ-Cs alkylsulfinamino, (bb) N-(Cχ-Cδ) alkyl-N-(Cχ-Cs) alkylsulfinamino, (be) Cχ-Cs alkoxyamino, (bd) Cχ-Cs alkoxyamino, (be) N-(Cχ-Cs) alkyl-N- (Cχ-C8) alkoxyamino, (bf) C3-C7 cycloalkyl, (bg) oxo, and (bh) heterocyclyl, optionally any one or two pairs of R -R^0 may independently be joined to form one or two optionally substituted heterocyclic rings, each ring optionally fused with one or two optionally substituted homocyclic or heterocyclic rings of from four to seven atoms where any heterocyclic ring contains from one to four heteroatoms selected from N, O, and S and where any ring may be substituted with from one to three R ² ,

(B) an amidino (aminoiminomethyl) group including;

(1) -C(=NH)-NH2,

(2) -C(=NH)-NHR ³ , (3) -C(=NR ⁴ )-NHR ³ ,

(4) -C(=NH)-NR R ⁴ ,and

(5) -C(=NR ⁵ )-NR ³ R ⁴ , where R ³ , R ⁴ , and R^ are defined above,

(C) an aminoalkyleneamino group including; (1) -N=CH-NH2,

(2) -N=CH-NHR ³ ,

(3) -N=CH-NR ³ R ⁴ ,and

(4) -N=CR ⁵ -NR ³ R ⁴ , where R ³ , R ⁴ , and R^ are defined above, (D) an iminoalkyleneamϊno group, including;

(1) -NH-CH=NH,

(2) -NH-CH=NR ³ , (3) -NH-CR ⁴ =NR ³ , and (4) -NR ⁵ -CR ⁴ =NR ³ ,

where R ³ , R ⁴ , and R^ are defined above,

(E) a guanidino (aminoiminomethyleneamino) group including;

(1) -NH-C(=NH)-NH2,

(2) -NH-C(=NH)-NR ³ H,

(3) -NH-C(=NH)-NR ³ R ⁴ ,

(4) -NH-C(=NR ⁵ )-NR ³ R ⁴ ,

(5) -NR ³ -C(=NR ³ )-NR ³ R ⁴ ,

(6) -NR ³ -C(=NH)-NR ³ R ⁴ ,

(7) -NR ³ -C(=NR ³ )-NH2,

(8) -NR ³ -C(=NH)-NH2,

(9) -NR ³ -C(=NR ³ )-NHR ⁴ , and

(10) -NR -C(=NH)-NHR ⁴ , where R ³ , R ⁴ , and R^ are defined above,

(F) an optionally substituted saturated heterocyclic group including;

where (1) n is 0, 1, 2, or 3, (2) R ¹³ is selected from; R ⁶ , -CR ⁹ =NR ⁸ , -CR ⁹ (=NR ⁸ )-NR ⁶ R ⁷ , -C(=NR ⁸ )-NR ⁶ R ⁷ , -N=CR ⁹ -NR ⁶ R ⁷ , -NR ¹⁰ -CR ⁹ =NR ⁸ , and -NR ¹⁰ -(C=NR ⁸ )-NR ⁶ R ⁷ where R^-RI are defined above, (3) Z ² is O, S, or NR* ³ , and (4) the substituents are independently one to three R ² , (G) an optionally substituted unsaturated (nonaromatic) heterocyclyl including;

where (1) m is 1, 2, or 3, (2) Z ² and R ¹³ are defined above, and (3) the substituents are typically one to three R* ,

(H) an optionally substituted unsaturated (aromatic) heterocyclyl including;

where (1) Z ³ , Z ⁴ , and 7 are typically selected from O, S, N, and NH, provided at least one Z ³ , Z ⁴ , or 7? is N or NH, (2) R^ ³ is defined above/and the substituents are independently one to three R ¹² , (I) an optionally substituted bicycloheterocyclic group including;

where the partial structure

represents

where Z ⁷ , Z ⁸ ,

-NR ¹³ -

provided that at least one Z ⁷ , Z ⁸ , or Z ⁹ is

where (1) o is 0, 1, or 2, (2) R ³ is defined above, and (3) the substituents are independently one to three R ² . Exemplary heterocyclic Q* groups include; isoindolinyl, quinuclidinyl, morpholinyl, and l,3-diazacyclohex-4-ene. Optionally, any of the nitrogen containing heterocycles described above may be substituted with amino, imino, amidino, aminomethyleneimino, iminomethyleneamino, guanidino, N^-aminoguanidino, alkylamino, dialkylamino, trialkylamino, or alkylideneamino groups.

L is a bivalent radical containing from 3 to 9 methylene groups where any methylene group or groups may be replaced with one or more alkene, alkyne, aryl, or functional groups containing the heteroatoms selected from the group N, O, and S. Preferably, l} is a saturated or unsaturated, linear, branched, or cyclic bivalent radical separating Q from the 7 carbon of the benzodiazepinedione nucleus. Typically, the heteroatoms (N, O, and S) will comprise from 0-5 of the atoms separating Q from the benzodiazepinedione nucleus. Preferably, L^ is typically an optionally substituted bivalent radical including; (A) C3-C7-alkylene, (B) C3-C7-cycloalkylene, (C) C3-C7-alkenylene, (D) C3-C7-alkadienylene, (E) C3-C7-alkynylene, (F) C4-C7- alkadiynylene, (G) C4-C7-alkenynylene, (H) C6-Cχ4-arylene, (1) C6-Cχ4-aryl-C2-C4-alkynylene, (J) Cχ-C3-alkyl-C6-Cχ4-aryl-C2-C4-alkynylene, (K) C6-Cχ4-aryl-C2-C4-alkenylene, (L) C1-C3- alkyl-C6-Cχ4-arylene, (M) Cχ-C3-alkyl-C6-Cχ4-aryl-C2-C4-alkenylene, (N) C6-Cχ4-aryl-Cχ-C3- alkylene, (O) C6-Cχ4-aryI-Cχ-C3-alkyloxyene, (P) Cχ-C2-aIkyl-C6-Cχ4-aryl-Cχ-C2-alkylene, (Q) Cχ-C3-alkyloxy-C6-Cχ4-aryIene, (R) C2-C6-aIkyloxyene, (S) Cχ-C5-alkyloxy-Cχ-C5-alkylene, (T) C6-Cχo-aryloxyene, (U) C6-Cχo-aryloxy-Cχ-C5-alkylene, (V) C2-C6-alkylthioene, (W) Cχ> C5-alkylthio-Cχ-C5-alkylene, (X) Qi-Cxo-arylthioene, (Y) C6-Cχo-arylthio-Cχ-C5-alkylene, (Z) Cχ-C5-alkylsulfoxide-Cχ-C5-alkylene, (AA) Cχ-C5-alkylsulfone-Cχ-C5-alkylene,

R ⁶ R ⁶

where (1) R ¹⁴ is selected from; (i) a chemical bond, (ii) Cι-05-alkyl, (iii) C3-C7-cycloalkyl, (iv) C2-C5-alkenyI, (v) C3-C5-alkynyI, (vi) Cg-Cxo-aryl, (vii) Cχ-C2-alkyl-C6-Cχo-aryl-Cχ-C2-alkyl, (viii) Cχ-C3-alkyl-C6-Cχ2-aryl, (ix) C6-Cχo-aryl-Cχ-C2-alkyl, (x) C6-Cχo-aryloxy-Cχ-C2-alkyl, and (xi) piperizinyl, (2) R ¹ ^ j _s selected from; (i) a chemical bond, (ii) Ci- -alkyl, (iii) C2-C4- alkenyl, (iv) C2-C4-alkynyl, (v) Cχ-C3-alkyI-C6-Cχ2-aryl, and (vi) C6-Cχo-aryl, (3) R ¹⁶ is selected from; (i) a chemical bond, (ii) Cχ-Cs-alkyI, (iii) C3-C7-cycloalkyl, (iv) C3-C5-alkenyl, (v) C3-C5-alkynyl, (vi) C6-Cχo-aryl, (\αi) Cχ-C3-alkyl-Cδ-Cχ2-aryl, (viii) C6-Cχo-aryl-Cχ-C2-alkyl, and (ix) piperizinyl, (4) R ¹⁷ is selected from; (i) Cs- -alkenyl, (ii) C3-C4-aIkynyl, (iii) C6-C o- aryl, and (iv) benzyl, (5) HET is a saturated or unsaturated heterocycle having from 5-14 atoms in the cycle(s) and from 1-3 heteroatoms selected from N, O, and S, where the substituents are selected from one to three R . L ² is typically an optionally substituted bivalent radical including but not limited to;

R ^e R ⁶

I I -(CH ₂ ) ₀ — — N , — (CH2) ₀ -N— C-

II

O o

R ⁶ R ⁶

I I

-CH ₂ — O— C— N- -CH ₂ — — c— ro¬

II ll 0 0

o (CH ₂ ) _P -C- — (CH ₂ ) _p S-

II o

— CH ₂ — O— C— O- (CH ₂ ) ₀ C (CH ₂ ) ₀ - ,

II

0 O J _o —

(CH ₂ ) ₀ C≡C ^■ (CH ₂ ) ₀ — CH=CH-

— O— (CH ₂ ) _p — , and ^■ HET- where; (1) p is 1, 2, 3 or 4, (2) R \ R ⁷ , o, and HET are defined above, and (3) the substituents are typically selected from one to three R* .

T-U-G is selected from;

10

where; (1) X is defined above, (2) R ¹⁸ , R ¹⁹ , R ²⁰ , R ²³ , are typically selected from (i) hydrogen, (ϊϊ) optionally substituted Cχ-Cχ2 alkyl, (iii) optionally substituted C3-C12 alkenyl, (iv) optionally substituted C3-C14 cycloalkyl, (v) optionally substituted Cχ-Cχ2 alkyl-Q;-Cχ4 aryl, (vi) optionally substituted C6-Cχ4 aryl, (vii) optionally substituted Cχ-C4 alkylphenyl, and (viii) optionally substituted Cχ-Cχ2 alkoxy, (3) R ² * and R ²² are typically selected from (i) Q ² - L ³ - where Q ² is selected from hydrogen and Q ¹ , and L ³ is either a chemical bond, * or , (ii) optionally substituted Cχ-Cχ2-alkyl, (iii) optionally substituted Q;-Cx4-aryl, (iv) optionally substituted C3-Cχ4-cycIoalkyl, (v) optionally substituted Cχ-Cχ2-alkyl-C6-Cχ4 aryl, and (vi) optionally substituted Cχ-Cχ2-alkyl-C3-Cχ4-cycloalkyl, where the substituents are usually (a) halo (F, Cl, Br, 1), (b) nitro, (c) hydroxy, (d) carboxy, (e) tetrazole, (f) hydroxamate, (g) sulfonamide, (h) trifluoroimide, (i) phosphonate, (j) Ci-Cg-alkyl, (k) C6-Cχ4-aryl, (1) benzyl, (m) C3-Cχ4-cycloalkyl, (n) COR ²⁴ where R ²⁴ is selected from Ci-Cβ-alkoxy, C3-Cχ2-alkenoxy, Cg- Cχ2-aryIoxy, dϊ-Cx-Cg-alkylamino-Cx-Cs-alkoxy, acylamino-Cχ-C8-alkoxy selected from acetylaminoethoxy, nicotinoylaminoethoxy, succinamidoethoxy, and pivaloyloxyethoxy, and C6-Cχ2-aryl-Cχ-C8-aIkoxy where the aryl group is unsubstituted or substituted with one to three of the groups nitro, halo (F, Cl, Br, I), Cχ-C4-alkoxy, amino, hydroxy, hydroxy-C2-Cs- alkoxy, and dϊhydroxy-C3-C8-alkoxy, and (o) CONR ² ^R ² ^ where R ^ and R ² ° are typically selected from hydrogen, Cχ-Cχn-alkyI, C3-C n-alkenyl, C6-Cχ4-aryl, Cχ-C6-alkyl-C6-Cχo-aryI. Optionally, R ² ^ and R ² " taken together may form trimethylene, tetramethylene, pentamethylene, and 3-oxopentamethylene. Also, optionally, R* and R ²² taken together may form an optionally substituted 5, 6, or 7 member saturated or unsaturated homocyclic or heterocyclic ring containing 0-3 heteroatoms selected from O, S, and N, where the substituents are selected from R ^.

D is typical!}' (A) R ^, or (B) -(C=0)-Xaa, where Xaa is one to three D or L α-amino acid residues.

W is -R^-w.

R ²⁷ is selected from (a) a covalent bond, (b) substituted or unsubstituted methylene, and (c) substituted or unsubstituted ethylene where the substituents are selected from (i) nitro,

(ii) halo(F, Cl, Br, I), (iii) C\-Cf, alkyl, (iv) halo(F, Cl, Br, 1)-Cχ-C6 alkyl, and (v) substituted or unsubstituted phenyl where the substituents are selected from (1) -C6 alkyl, (2) Cχ-C6 alkoxy, (3) halo(F, Cl, Br, I), and (4) CF ₃ .

"w" is selected from (a) -COR ²⁸ , (b) -SO3R ³¹ , (c) -NHS0 ₂ R ³² , (d) -PO(OR ³¹ ) ₂ , (e) -SO2NHR ³² , (f) -CONHOR ³¹ , (g) -C(OH)R ³³ PO(OR ³³ ) ₂ , (h) -CN, (i) -Sθ2NH-heteroaryl where the heteroaryl is a 5- or 6-member aromatic ring containing 1 to 3 heteroatoms selected from O, N, and S and where the heteroaryl is unsubstituted or substituted with one or two substituents selected from the group (i) -OH, (ii) -SH, (iii) -(Ci -C4alkyl), (iv) -Cχ-C4alkoxyl, (v) CF _3/ (vi) halo(F, Cl, Br, I), (vii) N0 ₂ , (viii) -COOH, (ix) -COO-(Cι-C alkyl), (x) -NH ₂ , (xi) -NH(Cι-C aIkyl), or (xii) -N(Cι-C ₄ alkyl) ₂ , (j) -CH2Sθ2NH-heteroaryl, (k) -SO2NHCOR ³³ , (1) -CH2SO2NHCOR ³² ' (m) -CONHSO2R ³³ , (n) -CH2CONHSO2R ³³ , (o) -NHCONHSO2R ³³ , (p) -NHSO2NHCOR ³³ , (q) -CONHNHSO2CF3, (r) CON(OH)R ³¹ , (s) -CONHCOCF3, (t) -CONHSO2R ²⁸ , (u) -CONHSO2R ²⁹ , (v) -CONHSO2R ³⁰ ,

R ² ° is selected from tine group consisting of (a) hydroxy, (b) Cχ-C8-alkoxy, (c) C3-C12- alkenoxy, (d) C6-Cχ2-aryloxy, (e) Cχ-C6-alkyl-C6-Cχ2-aryloxy, (f) di-Cχ-C8-alkylamino-Cχ-C8- alkoxy, (g) acylamino-Cχ-C8-alkoxy selected from the group (i) acetylaminoethoxy, (ii) nicotinoylaminoethoxy, and (iii) succinamidoethoxy, (h) Cχ-C8-alkoyloxy-Cχ-C8-alkoxy, (i) C6- Cχ2-aryl-Cχ-C8-alkoxy where the aryl group is unsubstituted or substituted with one to three of the groups (i) nitro, (ii) halo (F, Cl, Br, I), (iii) Cχ-C4-alkoxy, and (iv) amino, (j) hydroxy-C2- C8-alkoxy, (k) dihydroxy-Qj-Cs-alkoxy, and (1) NR ²⁹ R ³⁰ .

R ² " and R ³ ^' are independently selected from tine group consisting of (a) hydrogen, (b) Cχ-Cs-aIkyl, (c) C3-C8-alkenyI, (d) C6-Cχ2-aryl where the aryl group is unsubstituted or substituted with one to three of the groups (i) nitro, (ii) halo (F, Cl, Br, 1), (iii) Cχ-C4-alkoxy, and (iv) amino, and (e) C6-Cχ2-aryl-Cχ-C8-alkyl where the aryl group is unsubstituted or substituted with one to three of tine groups (i) nitro, (ii) halo (F, Cl, Br, I), and (iii) Cχ-C4-alkoxy. R ³¹ is selected from tine group consisting of (a) H, (b) Cχ-C6 alkyl, (c) halo(F, Cl, Br, 1)- C1-C6 alkyl, (d) phenyl, (e) benzyl, and (f) -CH2-O-COCH3.

R ³² is selected from the group consisting of (a) H, (b) benzyl and (c) -CH(R ³ ^)-0- C(0)R ³⁵ . R ³³ is selected from the group consisting of (a) aryl, (b) heteroaryl, (c) (C3-C7)- cycloalkyl, (d) (C]-C4)-al yl, unsubstituted or substituted with a substituent selected from the group consisting of (i) aryl, (ii) heteroaryl, (iii) -OH, (iv) -SH, (v) (C]-C4)-alkyl, (vi) (Cχ-C4)- alkoxy, (vii) (Cι-C4)-alkylthio, (viii) -CF , (ix) halo (F, Cl, Br, 1), (x) -NO2, (xi) -CO2H, (xii) CO2- (Cχ-C4)-alkyl, (xiii) -NH2, (xiv) -N[(Cι-C4)-alkyl]2, (xv) -NH[(Cχ-C )-aIkyl], (xvi) -PO3H or (xvii) PO(OH)(Cχ-C4)-alkoxy, or (e) (Cι- )-perfluoroalkyl.

R ³⁴ is selected from the group consisting of (a) -CN, (b) -NO2, (c) -COOR ³¹ , (d) Cχ-Cg- perfluoroalkyl, and (e) CF3.

R ³ ^ is independently selected from the group consisting of (a) H, (b) (Cχ-C6)-alkyI, (C2- C6)-alkenyl, (C2-C6)-alkynyl or (C3-C8)-cycloaIkyl, each of which is unsubstituted or substituted with: (i) OH, (ii) (Cχ-C4)-alkoxy, (iii) CO2R ³³ , (iv) OCOR ³³ , (v) CONHR ³³ , (vi) CON(R ³ )2, (vϋ) N(R ³³ )C(0)R ³³ , (viii) NH2, (ix) ( -Gi kylamino, (x) di[(Cχ-C4)- alkyl]amino, (xi) aryl, (xii) heteroaryl, (c) -C(0)-aryl, (d) -NO2, (e) halo(Cl, Br, I, F), (f) -OH, (g) -OR ³⁶ , (In) (C]-C4)-perfluoroalkyl, (i) -SH, (j) -S(0)j-2 (Cι )-alkyl, (k) CO2R ³³ , (1) -SO3H, (m) -NR ³³ R ³⁶ , (n) -NR ³³ C(0)R ³⁶ , (o) -NR ³³ COOR ³² , (p) -SO2NHR ³² , (q) -SQ2NR ³³ R ³³ , (r) -NHSChR ³² , (s) -C(0)NHS02R ³² , (t) aryl, (u) heteroaryl, (v) morpholin-4-yl, (w) CONH2, or (y) lH-tetrazol-5-yl.

R ³ ^ is selected from the group consisting of (a) H or (b) (Cχ-C4)-aIkyl unsubstituted or substituted with (i) NH2, (ii) NH[(Cχ-C4)-alkyl], (iii) N[(Cχ-C4)-alkyI] ₂ , (iv) CO ₂ H, (v) Cθ2(Cχ- C4)-alkyI, (vi) OH, (vii) SO3H, or (viii) SO2NH2.

R ³⁷ is selected from the group consisting of (a) H, (b) (Cχ-C6)-alkyl, (c) (C2-C6)- alkenyl, (d) (Cχ-C6)-alkoxyalkyl, (e) -CH2-O-COCH3, or (f) -CH ₂ -ρhenyI, where the phenyl is unsubstituted or substituted with a substituent selected from -NO2, -NH2, -OH, or -OCH3.

R ³⁸ , R ³⁹ , and R ⁴⁰ are each independently selected from H, Cl, CN, NO2, CF3, C2F5, C3F7, CHF2, CH2F, CO2CH3, CO2C2H5, SO2CH3, SO2CF3 and SO2C6F5, where Z is selected from O, S, NR ⁴¹ and CH2- R ⁴¹ is selected from hydrogen, CH3, and CH2C6H5 or a tautomer thereof.

The invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and/or pharmaceutically acceptable hydrates, solvates, and salts of I.

The invention provides a method for inhibiting platelet aggregation or reducing platelet aggregation in a mammal comprising administering a platelet aggregation inhibiting amount of the pharmaceutical composition of I. Optionally, the method includes administering the pharmaceutical composition in combination with a peptidyl antithrombotic and/or a thrombolytϊc agent and/or an anticoagulant.

DETAILED DESCRIPTION OF THE INVENTION

A. Definitions

Terms used in the claims and specification are defined as set forth below unless otherwise specified.

As used herein, the term "positively charged" when used to describe the moiety Q (either Ql or Q~) means at least 10% of the Q groups are positively charged at physiological pH. This will normally mean that the pK _D of the nitrogen containing moiety will be about 6.9 or higher. The phrase "positively charged Q moiety;" as used to define Q, is intended to embrace chemical groups which, when attached to the linking moiety L of Formula I, confers basic character to the compound of Formula I. "Basic character" means proton accepting or electron donating capability, that is, the capacity of tine compound of Formula I to be a proton acceptor in the presence of a proton donor, such as water. Optionally, Q will be a prodrug that is capable of being converted, in vivo _r into a positively charged basic moiety. An example of a basic group having "basic character" is the guanidino (H2N-C(=NH)-NH-) group. There are many examples of other equivalent basic groups other than the guanidino group that can be substituted into Q to produce biologically equivalent compounds of Formula I. Such other basic groups are collectively referred to as "bϊoisosteres of the guanidino group" or "basic bioisoteres". Representative examples of such "basic bioisoteres" are set forth above under Q (A) through (I).

T)

The term "alkyl" means a branched or unbranched, saturated aliphatic hydrocarbon radical, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2- methylpentyl, 2,2-dimethylbutyl, n-heptyl, 2-methyIhexyI, and the like. The terms "lower alkyl" "Cχ-C6 alkyl" and "alkyl of 1 to 6 carbon atoms" are synonymous and used interchangeably. A preferred "Cχ-C6 alkyl" group is methyl.

The term "substituted C _n -Cm alkyl" where m and n are integers identifying the range of carbon atoms contained in the alkyl group, denotes the above alkyl groups that are substituted by one, two or three halogen, hydroxy, protected hydroxy, amino, protected amino, C1-C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, methylsulfonylamino or Cχ-C4 alkoxy groups. The substituted alkyl groups may be substituted once , twice or three times with tine same or with different substituents.

Examples of the above substituted alkyl groups include but are not limited to; cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, alkyloxycarbonylmethyl, allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl),

2-amino(iso-propyl), 2-carbamoyloxyethyl and the like. A preferred group of examples within the above "Cχ-Cχ2 substituted alkyl" group includes the substituted methyl group, e.g. a methyl group substituted by the same substituents as the "substituted Cn-C _m alkyl" group.

Examples of the substituted methyl group include groups such as hydroxymethyl, protected hydroxymethyl (e.g. tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, bromomethyl and iodomethyl. The terms "Cχ-Cχ2 alkyloxy" or "Cχ-Cχ2 alkoxy" are used interchangeably herein and denote groups such as methoxy, etlnoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.

The terms "C]-Cχ2 acyloxy" or "Cχ-Cχ2 alkanoyloxy" are used interchangeably and denote herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, and the like.

The terms "Cχ-Cχ2 alkylcarbonyl", "Cχ-Cχ2 alkanoyl" and "Cχ-Cχ2 acyl" are used interchangeably herein encompass groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like.

Tine term "cycloalkyl" as used herein refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms.

The term "alkenyl" means a branched or unbranched hydrocarbon radical having the number of carbon atoms designated containing one or more carbon-carbon double bonds, each double bond being independently cis, trans, or a nongeometric isomer.

The term "alkynyl" means a branched or unbranched hydrocarbon radical having the number of carbon atoms designated containing one or more carbon-carbon triple bonds.

The terms "Cχ-Cχ2 alkylthio" and "Cχ-Cχ2 substituted alkylthio" denote Cχ-Cχ2 alkyl and Cχ-Cχ2 substituted alkyl groups, respectively, attached to a sulfur which is in turn the point of attachment for the alkylthio or substituted alkylthio group to the group or substituent designated.

The term "aryl" when used alone means a homocyclic aromatic radical whether or not fused having the number of carbon atoms designated. Preferred aryl groups include phenyl, napthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g. Lang's Handbook of Chemistry (Dean, J. A., ed) 13 ^th ed. Table 7-2 [1985]).

The term "substituted phenyl" or "substituted aryl" denotes a phenyl group or aryl group substituted with one, two or three substituents chosen from halogen(F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, Cχ-C6 alkyl, Cχ-C6 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl N-(methylsulfonylamino) or other groups specified.

Examples of the term "substituted phenyl" includes but is not limited to a mono- or dϊ(halo)phenyl group such as 4-chIorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro- 4-fIuorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4- hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4- dimethylphenyl, 2-methylphenyl, 4-(iso-propyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 2,6-di methoxy phenyl, 4- methoxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(t-butoxy)phenyI, 3-ethoxy-4- methoxyphenyl and the like; 3- or 4- trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyI group such 4-carboxyphenyl; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4- di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyI)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or dϊ(N-(methylsulfonylamino))phenyl such as 3-(N-methylsulfonylamino))phenyl. Also, the term "substituted phenyl" represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromoρhenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4- chlorophenyl and the like. Preferred substituted phenyl groups include the 2- and 3- trifluoromethylphenyl, the 4-hydroxyphenyl, the 2-aminomethylphenyl and the 3-(N- (methylsuIfonylamino))phenyl groups.

The term "arylalkyl" means one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl radical having the number of carbon atoms designated including but not limited to; benzyl, naptlnylmethyl, phenethyl, benzhydryl (diphenylmethyl), trityl, and the like. A preferred arylalkyl group is the benzyl group. The term "substituted C6-Cχoaryl-Cχ-C8alkyl" denotes a Cχ-Csalkyl group substituted at any carbon with a C6-Cχnaryl group bonded to the alkyl group through any aryl ring position and substituted on the Cχ-C8alkyl portion with one, two or three groups chosen from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, amino, protected amino, Cχ-C7acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbamoyloxy, cyano, Cχ-C6alkylthio, N- (methylsulfonylamino) or Cχ-C4alkoxy. Optionally the aryl group may besubstituted with one, two, or three groups chosen from halogen, hydroxy, protected hydroxy, nitro, Ci-Qjalkyl,

Cχ-C4alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, or an N-

(methylsulfonylamino) group. As before, when either the Cχ-C8alkyl portion or the aryl portion or both are disubstituted, tine substituents can be the same or different.

Examples of the term "substituted C6-Cχoaryl-Cχ-C8alkyl" include groups such as 2- phenyl-1-chloroetlnyl, 2-(4-metlnoxyphenyl)ethyl, 2,6-dihydroxy-4-phenyl(n-hexyl), 5-cyano-3- methoxy-2-phenyl(n-pentyl), 3-(2,6-dimethylphenyl)n-propyl, 4-chIoro-3-aminobenzyl, 6-(4- methoxyphenyl)-3-carboxy(n-lnexyl), 5-(4-aminomethyl phenyl)-3-(aminomethyl)(n-pentyl), and the like.

The term "carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyI, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl,4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, trimetlnylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2- trichloroethyl, β-(trimetlnylsilyl)ethyl, β-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4- nitrobenzylsulfonylethyl, allyl, cinnamyl, l-(trimethylsilylmethyl)prop-l-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the benzodiazepinedione molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject the carboxy-protected benzodiazepinedione molecule to strong nucleophilic bases or reductive conditions employing highly activated metal catalysts such as Raney nickel. (Such harsh removal conditions are also to be avoided when removing a mi no-protecting groups and hydroxy-protecting groups, discussed below.) Preferred carboxylic acid protecting groups are the allyl and p-nitrobenzyl groups. Similar carboxy-protecting groups used in the

cephalosporin, penicillin and peptide arts can also be used to protect a carboxy group substituents of the benzodiazepinedione. Further examples of these groups are found in E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981, Chapter 5. The term "protected carboxy" refers to a carboxy group substituted with one of the above carboxy-protecting groups.

As used herein the term "amide-protecting group" refers to any group typically used in the peptide art for protecting the peptide nitrogens from undesirable side reactions. Such groups include p-methoxyphenyl, 3,4-dimethoxybenzyl, benzyl, O-nitrobenzyl, di-(p- methoxyphenyl)methyl, triphenylmethyl, (p-methoxyphenyl)diphenylmethyl, diphenyl-4- pyridylmethyl, m-2-(picoIyl)-N'-oxide, 5-dibenzosuberyl, trϊmethylsilyl, t-butyl dimethylsϊlyl, and the like. Further descriptions of these protecting groups can be found in "Protective Groups in Organic Synthesis", by Theodora W. Greene, 1981, John Wiley and Sons, New York. Unless otherwise specified, the terms "heterocyclic group" or "heterocyclic" or "HET' or "heterocyclyl" are used interchangeably as used herein refer to any mono-, bi-, or tricyclic saturated, unsaturated, or aromatic ring having the number of atoms designated where at least one ring is a 5-, 6- or 7-membered ring containing from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur preferably at least one heteroatom is nitrogen (Lang's Handbook of Chemistry, supra). Typically, the 5-membered ring has 0 to 2 double bonds and the 6- or 7-membered ring has 0 to 3 double bonds and the nitrogen or sulfur heteroatoms may optionally be oxidized, and any nitrogen heteroatom may optionally be quaternized. Included in the definition are any bϊcyclic groups where any of the above heterocyclic rings are fused to a benzene ring. Heterocyclics in which nitrogen is the heteroatom are preferred.

The following ring systems are examples of the heterocyclic (whether substituted or unsubstituted) radicals denoted by the term "heterocylic": thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isotlniazolyl, oxazolyl, ϊsoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyrϊdyl, pyrimidyl, pyrazinyl, pyridazϊnyl, thϊazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazϊnyl, dioxazϊnyl, oxathiazinyl, tetrazinyl, thiatrϊazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazoIo[l,5-b]pyridazinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzthiazolyl, beπzimidazolyl and indolyl.

Heterocyclic 5-membered ring systems containing a sulfur or oxygen atom and one to three nitrogen atoms are also suitable for use in the instant invention. Examples of such preferred groups include thiazolyl, in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular l,3,4-thiadiazol-5-yl and l,2,4-thiadiazol-5-yl, oxazolyl, preferably oxazol-2-yl, and oxadiazolyl, such as l,3,4-oxadiazol-5-yl, and l,2,4-oxadiazol-5-yl. A group of further preferred examples of 5-membered ring systems with 2 to 4 nitrogen atoms include imidazolyl, preferably imidazol-2-yl; triazolyl, preferably l,3,4-triazol-5-yl; l,2,3-triazol-5-yl,

l,2,4-triazoI-5-yl, and tetrazolyl, preferably lH-tetrazol-5-yl. A preferred group of examples of benzo-fused derivatives are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.

Further suitable specific examples of the above heterocylic ring systems are 6- membered ring systems containing one to three nitrogen atoms. Such examples include pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, preferably pyrimid-2-yl and pyrimid-4-yl; triazinyl, preferably l,3,4-triazin-2-yl and l,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the l,3,4-triazin-2-yl radicals, are a preferred group. The substituents for the optionally substituted heterocyclic ring systems, and further examples of the 5- and 6-membered ring systems discussed above can be found in W. Druckheimer et al, U.S. Patent No. 4,278,793.

A particularly preferred group of "lneterocyclics" or "HET" include; l,3-thiazol-2-yl, 4- (carboxymethyl)-5-metinyI-l,3-thiazoI-2-yl, 4-(carboxymethyl)-5-methyl-l,3-thiazol-2-yl sodium salt, l,2,4-tlniadiazol-5-yl, 3-methyl-l,2,4-thiadiazol-5-yl, l,3,4-triazol-5-yl, 2-methyl-l,3,4- triazol-5-yl, 2-hydroxy-l,3,4-triazol-5-yl, 2-carboxy-4-rnethyl-l,3,4-triazol-5-yl sodium salt, 2- carboxy-4-methyI-l,3,4-triazol-5-yl, l,3-oxazol-2-yl, l,3,4-oxadiazol-5-yl, 2-methyl-l,3,4- oxadiazoI-5-yl, 2-(lnydroxymethyI)-l,3,4-oxadiazol-5-yl, l,2,4-oxadiazol-5-yl, l,3,4-thiadiazol-5- yl, 2-thiol-l,3,4-thiadiazol-5-yl, 2-(methylthio)-l,3,4-thiadiazol-5-yl, 2-amino-l,3,4-thiadiazol-5- yl, lH-tetrazoI-5-yl, l-methyl-lH-tetrazol-5-yl, l-(l-(dimethylamino)eth-2-yl)-lH-tetrazol-5-yl, l-(carboxymethyl)-l H-tetrazol-5-yl, l-(carboxymethyl)-lH-tetrazol-5-yl sodium salt, 1- (methylsulfonic acid)-lH-tetrazoI-5-yI, l-(metlnylsulfonic acid)-lH-tetrazol-5-yl sodium salt, 2- methyl-lH-tetrazol-5-yl, l,2,3-triazoI-5-yl, l-methyl-l,2,3-triazol-5-yl, 2-methyl-l,2,3-triazol-5- yl, 4-methyl-l,2,3-triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6- hydroxypyridaz-3-yl, l-methylpyrid-2-yl, l-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1,4,5,6- tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, l,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as- triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as- triazin-3-yl sodium salt, 2,5-dilnydro-5-oxo-6-hydroxy-2-methyl-astriazin-3-yl sodium salt, 2,5- dihydro-5-oxo-6-hydroxy-2-rnetlnyl-as-triazin-3-yl, 2,5-dilnydro-5-oxo-6-methoxy-2-methyl-as- triazin-3-yl, 2,5-dihydro-5-oxo-as-triazin-3-yI, 2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl, 2,5- dihydro-5-oxo-2,6-dimetlnyl-as-triazin-3-yl, tetrazolo[l,5-b]pyridazin-6-yl and 8- aminotetrazolo[l,5-b]-pyridazin-6-yl.

An alternative group of "lneterocyclics" includes; 4-(carboxymethyl)-5-methyl-l,3- thiazol-2-yl, 4-(carboxymethyl)-5-methyl-l 3-thiazol-2-yl sodium salt, l,3,4-triazol-5-yl, 2- methyl-l,3,4-triazol-5-yl, lH-tetrazol-5-yl, l-methyl-lH-tetrazol-5-yl, l-(l-(dimethylamino)eth- 2-yl)-lH-tetrazol-5-yl, l-(carboxymethyl)-1H-tetrazol-5-yl, l-(carboxymethyl)-lH-tetrazol-5-yl sodium salt, l-(methylsulfonic acid)-lH-tetrazol-5-yl, l-(methylsulfonic acid)-lH-tetrazol-5-yl sodium salt, l,2,3-triazol-5-yl, l,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4,5,6- tetrahydro-4-(2-formylrnethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dilnydro-5-oxo-6-hydroxy-2-

methyI-as-triazϊn-3-yI sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, tetrazolo[l,5-b]pyridazin-6-yl, and8-aminotetrazolo[l,5-b]pyridazin-6-yl.

Bivalent radicals L (either t , L ² , or L ³ ) whether branched or unbranched, derived from alkanes, alkenes, alkadienes, alkynes, alkadiynes, and arenes optionally containing O, N and /or S atoms, or homo- and heterocycles either aromatic or aliphatic, are designated by adding the suffix "ene" to the corresponding monovalent radical. Atoms bearing the free valences may include any C, O, N or S.

The phrase "negatively charged acidic moiety" as used to define the W moiety, is intended to embrace chemical groups which, when attached to the 7-member lactam ring of Formula I, confers acidic character to the compound of Formula I. "Acidic character" means proton-donor capability, that is, the capacity of the compound of Formula I to be a proton donorin the presence of a proton acceptor, such as water. Typically, the acidic group should be selected to have proton donor capability such that the compound of Formula I has a pK _a in a range from about one to about twelve. More typically, the Formula I compound would have a pK _a in a range from about two to about seven. Also typically, W will be a group that contains at least one acidic hydrogen. Optionally, W will be a prodrug that is capable of being converted, in vivo, into a negatively charged acidic moiety. An example of an acidic group containing at least one acidic hydrogen atom is the carboxyl group (-COOH). A preferred example of W in Formula 1 containing a carboxyl group is where R ²⁷ is -CH2- and "w" is -COOH. There are many examples of equivalent acidic groups other than carboxyl group, that can be substituted into W to produce biologically equivalent compounds of Formula I. Such other acidic groups are collectively referred to as "bioisosteres of the carboxylate" or "acidic bioisoteres". Representative examples of such "basic bioisoteres" are set forth above under "w" (a) through (ap). Other specific examples of such acidic bioisoteres may be independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2, NHSO2CF3, NHSO2C6F5, SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3, CONHOC2H5, CONHCF3, OH, CH2OH, C2H4OH, OPO3H2, OS 3H,

wherein each of R ³⁷ , R ³⁸ , R ³⁹ , and R ⁴⁰ is independently selected from H, Cl, CN, NQ2, CF3, C2F5, C3F7, CHF2, CH2F, CO2CH3, CO2C2H5, SO2CH3, SO2CF3 and SO2C6F5; wherein Z is selected from O, S, NR ⁴¹ and CH2; wherein R ⁴¹ is selected from hydrido, CH3 and CH2C6H5; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

"Pharmaceutically acceptable salts" include both acid and base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid,

sucdnϊc acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.

"Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethyIaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidihe, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.

The term "prodrug" as used herein means a derivative of a parent drug molecule that enhances pharmaceutically desirable characteristics or properties (e.g. transport, bioavailablity, pharmacodynamϊcs, etc.) and that requires bϊotransformation, either spontaneous or enzymatic, within the organism to release the active parent drug. B. Utility

The present invention is the result of the unexpected discovery that substituted fused 7- membered "lactam" ring compounds defined by formula I, especially including substituted 3,4- dihydro-lH-l,4-benzodiazepine-2,5-diones (referred to hereafter as substituted benzodiazepinedϊones) are capable of acting as fibrinogen receptor antagonists, that is inhibiting both platelet aggregation and binding of fibrinogen to the platelet receptor, GPlIbIII _a , at concentrations comparable to many of the more potent anti-aggregatory peptides of the prior art ( see e.g. AH et al EP 341 915). Thus, the instant fibrinogen receptor antagonists are particularly useful when they inhibit the binding of fibrinogen to the GPII HIa receptor with an IC50 in a Fg/GPIIbin _a ELISA as described herein of at least about 35nM and an IC50 in a platelet aggregation (PA) assay, also described herein, of at least about 3μM. Since there is some variability in the values obtained for ELISA and PA assays in different laboratories, preferred fibrinogen receptor antagonists represented by Formulae I-VI will have ICso's for Fg/GPIIbIII _a ELlSA's and PA assays equal to or greater than that of the prior art compound N- [3-(4-amidinobenzamϊdo)benzoyl]-3-aminoproprionoϊc acid,

This compound is used as an internal standard and has been found to have an Fg/GPIlblUa ELISA IC50 of about 25 nM and a PA inhibition assay IC50 of about 3μM when measured according to the assays described herein. Most preferred fibrinogen receptor antagonists represented by Formulae I-VI have IC50S in Fg/GPIIbIII _a ELISA of at least about 15 nM and in platelet aggregation inhibition assays of at least about lμM or three times more potent in a platelet aggregation inhibition assay than the reference compound N-[3-(4- amidinobenzamido)benzoyl]-3-aminoproprionoic acid. This reference compound is readily prepared by standard methods from commercially available precursors (e.g. β-alanine, m- aminobenzoic acid, and μ-amidinobenzoic acid) or may be synthesized according to the procedures set forth in EP 372486 A2.

The compounds described in the present invention may therefore inhibit the binding of fibrinogen to its receptor on platelets, GPlIbWa and thus prevent the aggregation of platelets and tine formation of platelet plugs, emboli and thrombi in the circulatory system in mammals. Thromboembolic disorders have been shown to be directly related to the susceptibility of blood platelets to aggregate. Mammals exposed to medical procedures such as angioplasty and thrombolytic therapy are particularly susceptible to thrombus formation. The compounds of the present invention can be used to inhibit thrombus formation following angioplasty. They may also be used in combination with antithrombolytic agents such as tissue plasminogen activator and its derivatives (US patents 4,752,603; 4,766,075; 4,777,043; EP 199 574; EP 238 304; EP 228 862; EP 297 860; PCT WO89/04368; PCT WO89/00197), streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial reocclusion following thrombolytic therapy. When used in combination with the above thrombolytic agents, the compounds of the present invention may be administered prior to, simultaneously with, or subsequent to the antithrombolytic agent. Mammals exposed to renal dialysis, blood oxygenation, cardiac catlneterization and similar medical procedures as well as mammals fitted with certain prosthetic devices are also susceptible to thromboembolic disorders. Physiologic conditions, with or without known cause may also lead to thromboembolic disorders. Thus, the compounds described herein may be useful in treating thromboembolic disorders in mammals. The compounds described herein may also be used as adjuncts to anticoagulant therapy, for example in combination with aspirin, heparin or warfarin and other anticoagulant agents. The application of the compounds described herein for these and related disorders will be apparent to those skilled in the art.

Compounds represented by Formula 1 are also capable of antagonizing the interaction between vitronectin(Vn) and the vitronectin receptor (VnR) and thus are useful in situations where such antagonism is indicated. Vn-VnR antagonism is particularly pronounced when substituent Cfl -l}- is bonded to position 8 or 9 of the substituted benzodiazapinedione, as represented by Formula Via below. Thus, it is contemplated the instant compounds are useful in treating bone disorders such as osteoporosis.

Compounds of this invention are also useful as intermediates generally, or as precursors of inhibitors to GPIIbHl _a or other integrin receptors and thus in addition to treating cardiovascular and bone disease, these compounds may be usefully employed in metastatic disease, or for any disease where antagonism of RGD binding integrin receptors is indicated.

C. Preferred Embodiments

1. Nonpeptidyl GPIIbIII _a Inhibitors

One embodiment of the invention comprises a compound represented by formula I capable of inhibiting binding of the platelet GPIIblUa receptor to its native in vivo ligands. Preferred nonpeptidyl inhibitors include compounds represented by structural formulae II-VI:

where R ¹ , R ² , R ^2U , R ²¹ , R ²² , R ²⁸ , R ²⁹ , Q ¹ , L ¹ and L ² are defined above.

Referring to formulae I-VI the following structural features of the instant nonpeptidyl antithrombotic inhibitors can be identified: a. The positively charged Q moiety; b. The linking moiety L; c. The flat (usually aromatic) ring A; d. The 7-member "lactam" ring containing TUG; e. Substituents of T U G especially R ²² ;

f. The amino acid linking moiety D; and g. The negatively charged acidic moiety W. a. Positively charged Q

Suitable groups Q (either Q ¹ or Q ² ) contain one or more nitrogen atoms and have a pK sufficiently high so that they are at least 10% positively charged at physiological pH. Q may be one or more primary, secondary, tertiary, or quartinary amines or imines either isolated or conjugated with other nitrogen atoms to form groups including but not limited to; aminomethyleneimino, amidϊno, and guanidino groups and multiples thereof. Alternatively, Q may be a saturated or unsaturated (including aromatic) heterocyclic group provided the group bears a positive charge at physiological pH. In one embodiment of the invention, Q is preferably selected from; amino (H2N-), imino (=NH), amidino (H2NC(=NH)-), aminomethyleneamino (H2N-CH=N-), iminomethylamino (HN=CH-NH-), guanidino (H2N- C(=NH)-NH-), N ^G -aminoguanidino (H2N-HN-C(=NH)-NH-), alkylamino (RΪNH-), dialkylamino (R-^ -), trialkylamino (RI3N-), alkylϊdeneamino (R^2C=N-), pyranyl, pyrrolyl, imadazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H- indolyl, ϊndolyl, IH-ϊndazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quϊnazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, b-carbolϊnyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, and 1,3- diazacyclohex-4-ene, where R- is selected from; hydrogen, Cχ-C6-alkyl, C6-Cχn-aryl, and C3- Cχo-cycloalkyl. Optionally, any of the nitrogen containing heterocycles described above may be substituted with amino, imino, amidino, aminomethyleneamino, iminomethylamino, guanidino, N^-amino-guanϊdϊno, alkylamino, dialkylamino, trialkylamino, or alkylideneamino groups.

Exemplary preferred Q ¹ groups include the following: (A) Amino and ammonio groups;

^■ NH ₂ , NHCH,

(B) Amidino groups;

NH NCH ₃

II II ^■ C— NH ₂ ^■ C— H ₂

NH

NCH ₃

II II C— NH-OCH ₃ ^• C — NHCH ₃

(C) Aminoalkyleneimino groups;

(D) Iminoalkyleneamino groups;

NH NH

II II NH-CH . ^■ NH-C— CH ₃

CH ₃ NH CH ₃ N — CH ₃

I II I II ^■ N— CH ^• N— CH

N — OCH ₃ CH ₃ 0 NH

If I II ^■ NH-CH N— C— CH ₃

(E) Guanidino groups;

NH N— CH ₃

II ^■ NH-C— NH ₂ II ^• NH-C— NH ₂

CH ₃ NH CH ₃ NH

I II I II ^■ N— C — NH ₂ ^■ N— C— N(CH ₃ ) ₂

CH ₃ N — CH ₃ CH ₃ 0 NH

I II I II N — C— H ₂ ^■ N — C — N(CH ₃ ) ₂

NH NH . .

II / \ II / \

^■ NH-C— N NH ^■ NH-C— N NCH ₃

\_/

(F) Saturated heterocyclic groups;

(G) Unsaturated (nonaromatic) heterocyclic groups;

25

(H) Unsaturated aromatic heterocyclic groups:

(I) Bicycloheterocyclic groups;

15 (]) Multiple amino, guanidino, and amidino groups;

NH NH NH CH ₃ NH

II II II I II NH-C — C— NH ₂ . ^■ C— N— C— NH ₂ ,

CH, NH NH CH ₃ NH H NH

I II II II I II

20 ^• N— C — C — NH ₂ N — C — N — C — NH ₂ ,

NH H NH NCH ₃ NH

II I II II II ^■ N — C — N — C — NH ₂ , ^■ C — NH-NH-C — NH ₂

N(CH ₃ ) ₂

25

NH

II

NH C— NH,

II ^■ N I ^• NH-C— NH-NH ₂ \

C — ^■ NH,

II NH

Most preferred Q groups are amino, amidino, and guanidino groups. b. The linking group L The length of the bivalent radical L appears to be important to biological activity. By length is meant the distance between the A ring and the first charge bearing N of substituent Q. For example, when the A moiety is a 5 or 6-member ring [e.g. the benzene moiety of the benzodiazepinedione nucleus (carbon 7 of Formula II)], suitable lengths for bivalent radical L ¹ range from about 3 to about 9 methylene equivalents. L ¹ is therefore a bivalent radical containing from 3 to 9 methylene groups connecting Q to the number 7 carbon of the benzodiazepinedione nucleus (or an equivalent position on other 5 or 6-member A rings) where any methylene group or groups may be replaced with one or more or a combination of; alkene, alkyne, aryl, heterocycle or a functional group or groups containing tine heteroatoms N, O, and S, so long as the overall length is equivalent to from 3 to 9 methylene groups. These functional groups include one or more of the following:

o o 1

and may be isolated within the linker ( e.g. forming ethers, thioetlners, ketones, sulfoxides and the like) or combined in any combination, provided only that the compounds so produced are stable in aqueous solution and do not exceed the above stated length requirements. For example, combining these functional groups produces esters, amides, ureidos, carbamates, carbonates, sulfonamides, sulfoxides, sulfones, and the like. Preferred lengths for i are from 4 to 6 while most preferred lengths are about 5 methylene equivalents. In counting atoms comprising \ , only those atoms sequentially linking Q with ring A are counted except when a homo- or heterocycle comprises L ¹ in which case the fewest number of atoms separating these moieties are counted. Furthermore, given that a bivalent radical is of appropriate length, it is preferred that it be somewhat rigid, that is, contain one or more sp ² or sp atoms.

In the description that follows, the free valence to the left of the page is bonded to Q, while the free valence to the right is bonded to carbon 7 of the compound of formula II (or an equivalent position on other 5 or 6-member A rings) Preferred L^-'s are selected from

substituted or unsubstituted; C3-C7-alkylene, C3-C7-cycloalkylene, C3-C7-alkenylene, C4-C7- cycloalkenylene, Cs-Cs-cycloalkadienylene, C3-C7-alkadienylene, C3-C7-alkynylene, C4-C7- alkenynylene, C6-Cχ4-arylene, C6-Cχ4-aryl-C2- -alkynylene, Cχ-C3-alkyl-C5-Cχ4-aryl-C2-C4- alkynylene, C6-Cχ4-aryl-C2-C4-alkenylene, Cχ-C3-alkyl-C6-Cχ4-arylene, Cχ-C3-alkyl-C6-Cχ4- aryl-C2-C4-alkenylene, C6-Cχ4-aryl-Cχ-C3-alkylene, C6-Cχ4-aryl-Cχ-C3-alkyloxyene, Q-C3- alkyl-C6-Cχ4-aryl-Cχ-C2-alkylene, Cχ-C3-alkyloxy-Gό-Cχ4-arylene, C2-C8-alkyloxyene, C1-C5- alkyloxy-Cχ-C5-alkylene, Q;-Cχo-aryloxyene, C6-Cχo-aryloxy-Cχ-C5-alkylene, C5-C10- arylthio-Cχ-C5-alkylene,

R ⁶

-R ¹⁴ — C — N — R ¹⁵ - , II 0

R ¹⁶ — N- ^■ C — R ¹⁵ -

II 0

0 R ⁶

}14. ^■ S ^N — N I— R 1 ¹ 5 ⁵ - ,

R ⁶ O -R 1 ¹ . ⁶ — N ' — S "- ^• R ¹⁵ -

II 0

R ⁴ -S— R ¹⁵ -

0 -R ¹⁴ — S— R ¹⁵ - .

O _ _R 14 _S _ _R 15_ , π

0

-R ¹⁶ — C — R ¹⁵ - <

II 0

R ⁶ -R ¹⁴ — N— R ¹⁵ - and

-R ¹⁴ _ o— R ¹⁵ - ,

where R ¹ ^ is selected from; a chemical bond, Cχ-C8-alkyl, C3-C7-cycloalkyl C2-Cs-alkenyl, C3- C5-alkynyl, C6-Cχo-aryl, Cχ-C3-alkyl-C6-Cχ2-aryl, Cχ-C2-alkyl-C6-Cχo-aryl-Cχ-C2-alkyl, C - Cχo-aryl-Cχ-C2-alkyI, and C6-Cχo-aryloxy-Cχ-C2-aIkyl. R ¹ ^ is selected from; a chemical bond, Cx- -alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C6-Cχo-aryl, and Cχ-C3-alkyl-C6-Cχ2-aryl. R ¹⁶ is selected from; a chemical bond, Cχ-C5-alkyI, C3-C7-cycloalkyl C3-Cs-alkenyl, C3-C5-alkynyl, C6-Cχn-aryl, Cχ-C3-alkyl-C6-Cχ2-aryl, and C6-Cχo-aryl-Cχ-C2-alkyl. The substituents are preferably selected from one to three R defined above.

More preferred bivalent radicals L ¹ are selected from the following groups:

Group 1

CH,— C-≡ C-

^• CH ₂ - CH ₂ -CH ₂ — C≡ C-

- CH ₂ - CH ₂ - CH ₂ - CH ₂ — C≡ C

Group 2

H

I

- CH ₂ C- N— CH ₂ -C≡ C-

O

CH, C- O— CH ₂ -C≡ C-

II 0

H

CH, — S — N— CH ₂ -C≡ C ,

II 0

H I CH,-CH ₂ — N— C— C≡ C-

CH,— C— C≡C- II O

10

•CH,-CH,— C— C≡C-

CH^' CH^' CH^"™ ^{- ■} C *— C ss C ^*

15

CH ¹ 2,-C ^Hπg,— O — C— C≡ C-

CH,— O-C— C≡C-

20 0

0 II

CH CHi ^■ S — C≡C- II O

O II

CH ₂ -CH ₂ -CH ₂ - ■S — C≡C-

II O

-

Group 3

CH ₂ -CH ₂ -CH ₂

CH ₂ -CH ₂ -CH ₂ -CH ₂ -

- CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ ,

CH ₂ - CH ₂ - CH ₂ - CH ₂ - CH ₂ CH ₂ ,

Group 4

Group 5

H

CH, ^■ C-N- II 0

H

CH ₂ -CH ₂ - -C- N- II 0

H

CH, 2-C ^H"2,-C ^H"2 ^■ C-N- II o

H I CH ₂ - CH ₂ - CH ₂ - CH ₂ C - N-

10

H

CH ₂ - CH,- CH: CH— C— N- II 0

H I CH ₂ - CH,— C≡ C— C— N- II O

20

-

Group 6

H

I

-CH,-CH ₂ — 0— C— N-

II O

H I CH,- CH,- CH ₂ — O — C— N-

H

— CH ₂ — C≡ C- O — C— N-

II 0

Group 7

H H I

H H

CH 12,- wCπHj,-CrHi2,— N— C— N-

H H I

— CH,— C≡C— N- C— N-

II

O

Group 8

H I

0

H

CH,-CH,-CH,— N— C— 0 ,

H

— CH,— C≡ C- N— C— O ,

Group 9

-CH ₂ — O-C O ,

II O

CH,- CH,— O - C — 0

II O

0

— CH,— C≡C-O-C — O ,

Group 10

H I CH ₂ -CH ₂ — N— C- II O

H

I

CH,- CH,- CH,- N— C ,

II 0

H

H I CH ₂ - CH= CH-CH ₂ — N— C-

0

H I CH ₂ — C≡ C-CH ₂ — N— C-

0

Group 11

CH ₂ -CH ₂ — O-C ,

II O

- CH,- CH ₂ -CH ₂ — O — C

CH ₂ - CH= CH-CH ₂ — O-C

0

- CH _o — C≡ C-CH ₂ — O - C ,

Group 12

CH,-CH ₂ -0-

CH ₂ - CH ₂ - CH ₂ - O ^■

Group 13

H 0

^■ N S-

10 H 0

- — CH, — CH, ^■ N-

15

H 0

— CH ₂ - CH ₂ - CH ₂ - CH ₂ N S

Group 14

Group 15

H

0 H

™~ CHo**— CHo ^■ N-

O H

^■ CH ₂ -CH ₂ -CH ₂ -CH ₂ I SI N I

Group 16

o

II

— CH ₂ - CH ₂ - CH ₂ S O ^■

— CH,- C wHn ₂ ,-— CH, ^{- ■} CH,

o II

Group 17

o

Group 18

Most preferred L ^ll s are selected from; (CH^q— R ¹⁵ - ,

(CHa)- — C≡C— R ¹⁵ - , (CH^. — CH-=CH-R ¹⁵ - ,

R ⁶ -R ¹⁶ — N I — C— R ⁵ -

II o

R ⁶ 0

-R ¹⁶ — N — S — R ¹⁵ -

II 0

>1 ^■ S — R ¹⁵ -

o

_R14 _S _ _R 15 _

_ _R 16 _ _C . ^• R 15.

II 0

R ⁶ -R ¹⁴ — N — R ¹⁵ - and

-R ¹⁴ — O— R ^{1 S} - ,

where p is 1, 2, 3, or 4; q is 3, 4, 5, 6 or 7; r is 1, 2, 3, 4, or 5; s is 2 or 3. R*4 is selected from; a chemical bond, Cχ-C5-alkyl, C3-C7-cycloalkyl, C2-C5-alkenyl, C3-Cs-alkynyl, C6-Cχo-aryl, Cχ~

C2-alkyl-C6-Cχ2-aryl, Cχ-C2-alkyl-C6-Cχo-aryl-Cχ-C2-alkyl, C6-Cχo-aryI-Cχ-C2-alkyl, C6-Cχø- aryloxy-Cχ-C2-alkyl, and piperizinyl. R^ is a chemical bond connecting L^ to position 7 of the benzodiazepinedione. R^ is selected from; Ci-Cs-alkyl, C3-C7-cycloalkyl, C3-Cs-alkenyl, C3-

C5-alkynyl, C -Cio-aryl, Cι-C3-aIkyl-Qi-Cχ2-ary], C6-Ci()-aryl-Cχ-C2-alkyl, and piperizinyl. For the foregoing most preferred L ^lτ s ^ and R'" bond L' to Q*.

Most preferred Q^-L ¹ - combinations are selected from;

H ₂ N — (CH ₂ ) ₃ -

H ₂ N — (CH ₂ ) ₄ -

H ₂ N— (CHa

H ₂ N— (CH ₂ ) ₆

NH H,N— C— HN— (CH ₂ ) ₃ -

10

NH H _o N— C— HN— (CH2) ₄

15

NH H,N— C— HN— (CHa

NH

II H ₂ N— C (CH ₂ ) ₃ -

20

NH

II

H,N- ^■ C - -(CH^

25

NH

II H ₂ N— C (CH ₂ ) ₅ -

NH

II H ₂ N— C (CH ₂ ) ₆ -

30

H ₂ N— (CH ₂ ) ₂ O ,

H ₂ N— (CH ₂ ) ₃ O ,

35

H ₂ N— (CH ₂ ) ₄ O ,

40

H ₂ N— (CH ₂ ) ₅ O ,

NH

II H ₂ N — C — HN — (CH _j a — O-

NH

H ₂ N — C — HN — (CH ₂ ) ₄ O

NH

H ₂ N — C— HN — (CH^g — O-

10

NH

II

H,N- ^• C— HN — (CH ₂ ) ₆ — O-

NH

II H ₂ N — C (CH ₂ ) ₂ O

15

NH

II

H,N- ^■ C - ^■ (CH ₂ ) ₃ — O

NH

II

20 H,N- ^• C- ^■ (CH ₂ ) ₄ — O

NH

II

H,N- ^■ C - ^■ (CH ₂ ) ₅ — 0

25

30

15

H,N- ■CH, — C≡C

H ₂ N (CH _g Ja— C≡C ,

25

H ₂ N (CH ₂ ) ₄ — C≡C ,

30

NH

II H ₂ N— C— HN CH ₂ — C≡C

NH H ₂ N— C— HN (CH ₂ ) ₂ — C≡C ,

35

NH

H ₂ N — C — HN (CH ₂ ) ₃ — C≡C

NH

II

H,N- ^■ C HN (CH ₂ ) ₄ — C≡C-

NH

NH

II

H,N- ^■ C — HN-(CHo3 ₂ ^• (CH ₂ ) ₂

10

30

10

NH H

II I

H ₂ N— C — CH ₂ C— N-

0

NH H

II I

H ₂ N— C - CH ₂ — CH ₂ — C— N

II O

15

NH H

II I

H ₂ N— C— CH ₂ - CH ₂ — CH ₂ — C— N"

II 0

NH H II

H ₂ N— C - NH — CH ₂ — C— N-

20 O

25

Very most preferred Q^-L ¹ - combinations are selected from;

The length of the bivalent radical L ² is also important to biological activity. Here, when the A moiety is a 10-member fused ring [e.g. the napthalene moiety of the napthadiazepinedione nucleus (carbon 8 of Formula III)], suitable lengths for bivalent radical

L ² range from about 1 to about 7 methylene equivalents. L ² is therefore a bivalent radical containing from 1 to 7 methylene groups connecting Q* to the number 8 carbon of the napthadiazepinedione nucleus (or an equivalent position on other 10-member A rings) where any methylene group or groups may be replaced with one or more alkene, alkyne, aryl, heterocycle or functional groups containing the heteroatoms N, O, and S, so long as the overall length is equivalent to 1 to 7 methylene groups. Here, the functional groups are the same as described above for L ¹ and may be combined in any combination provided again that the compounds produced are stable in aqueous solution and do not exceed the stated length requirements for L ² . Preferred lengths for L ² are from 2 to 4 while most preferred lengths are about 3 methylene equivalents.

Preferred L ² 's are optionally substituted bivalent radicals selected from;

R ⁶

I — (CH ₂ ) ₀ — C — N ,

0

^• (CH ₂ ) ₀ N — C

0

R ⁶ O

II

^• (CH ₂ ) ₀ N N-—SS —-

II

0

where o is 0, 1 or 2, p is 1, 2, 3 or 4, R^ is defined above, and where the substituents are selected from one to three R-^ groups defined above.

c. Ring A

Preferred A rings include; benzene, napthalene, tetrahydronapthalene, cyclohexane, thiophene, pyridine, pyrazine, pyrimidine, quinoline, isoquinoline, quinoxaline, quinazoline, pteridine, and naphthyridine. The most preferred A ring is benzene. Preferred substituents of rings A are R ¹ and R ² , where each ¹ and R ² , is independently selected from hydrogen, halogen(F, Cl, Br, I), cyano, nitro, carboxyl, mercaptocarbonyl, mercapto, pthalimϊdo and a substϊtuent having from 1 to 12 carbon atoms selected from: alkyl, hydroxyalkyl, formyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylhaloalkyl, cycloalkylcarbonyl, alkoxy, aralkyl, aralkylhaloalkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,

alkenyl, cycloalkenyl, alkylnyl, carboxylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, cycloalkylalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkvlthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, pthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, and cycloheteroalkylcarbonylalkyl where each heteroaryl- and cyclohetero-containing groups has one or more ring hetero atoms selected from oxygen, sulfur and nitrogen. Optionally, each R* and R ² also may be independently selected from sulfonyl, sulfonylamido, amino and amido radicals of the formula

where X is oxygen or sulfur, each "a" is a number independently selected from zero to six, inclusive, and where each of R ³ through R ⁵ is independently selected from the groups described above. Optionally, R ³ and R ⁴ taken together, R ⁴ and R ⁵ taken together and R ³ and R5 taken together may each form a heterocyclic having from five to seven ring members including the hetero atom of the sulfonyl, amino or amido radical and which heterocyclic may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen, and sulfur and which heterocyclic group may be saturated or partially saturated. R ²⁸ is selected from the groups defined below.

d. The 7-member "lactam" ring containing TUG;

Preferred seven member rings are those of formula I where T bears the substituent R ²² . Thus T is preferably s ^ carbon or nitrogen. Also preferably G is a methylene group. The most preferred "lactam ring" is a diazepinedione.

e. Substituents of T-U-G

R ¹⁹ and R ²⁰ are preferably hydrogen or halogen. R ¹⁸ and R ²¹ are preferably hydrogen or halogen or taken together form oxo. R ²² is preferably selected from; hydrogen, optionally substituted Cι-C6-alkyl, where the substituents are selected from amino, hydroxy, halo (F, Cl, Br, I), carboxy, and Cι-C4-alkoxycarbonyl, optionally substituted C6-Cio-aryl, and optionally substituted C6-Ci2-aryl-Cι-C4-aIkyl, where the substituents on any aryl group are selected from amino, nitro, halo (F, Cl, Br, I), halo(F, Cl, Br, I)-Cι-C6-aIkyl, -Cό-alkoxy, Cg- Cio-aryloxy, amino-Ci-Cή-acylamino, amϊno-Ci-Cβ-acyl, and guanidino Qj-Cin-aroylamino. f. The amino acid linking moiety D D is preferably hydrogen, phenyl, or lower alkyl. Optionally, D is -(C=O)-Xaa, where

Xaa is one to three natural, unnatural, or modified α-amino acid residues, preferably one or two naturally occurring amino acid residues, and most preferably a naturally occurring hydrophobic amino acid residue. Optionally, when Xaa is two amino acid residues, the terminal residue is Arg or Lys amide. Common naturally occurring a-amino acids are described by the standard three letter amino acid code when referring to amino acids or residues. When tine three-letter code begins with a lower-case letter, it is understood the amino acid is the unnatural or D-ϊsomeric form. Standard abbreviations are listed in The Merck Index, 10th Edition, pp Misc-2 - Misc-3. Modified or unusual α-amino acids such as norleucine (Nle) and ornithine (Orn) are designated as described in U.S. Patent and Trademark Office Official Gazette 1114TMOG, May 15, 1990. g. The negatively charged acidic W moiety W is-R ²⁷ -w.

R ² ^ is preferably selected from (a) a covalent bond, (b) substituted or unsubstituted methylene, and (c) substituted or unsubstituted ethylene, where the substituents are independently selected from one or more of the groups (i) nitro, (ii) halo(F, Cl, Br, I), (iii) Q- Cβalkyl, (iv) halo(F, Cl, Br, IJ-Ci-Cβalkyl, and (v) substituted or unsubstituted phenyl where the substituents are selected from (1) -C6alkyl, (2) -C6alkoxy, (3) halo(F, Cl, Br, I), and (4) CF ₃ .

"w" is selected from (a) -COR ²⁸ , (b) -SQ3R ³¹ , (c) -NHSO2R ³² (d) -PO(OR ³¹ ) , (e) -SO2NHR ³² , (f) -CONHOR ³¹ , (g) -C(OH)R ³³ PO(OR ³³ )2, (h) -CN, (i) -SO ₂ NH-heterocycle where the heterocycle is a 5- or 6-member aromatic ring containing 1 to 3 heteroatoms selected from O, N, and S and where the heterocycle is unsubstituted or substituted with one or two substituents selected from the group (i) -OH, (ii) -SH, (iii) -( -C4alkyl), (iv) -( ^alkoxyl), (v) CF3, (vi) halo(F, Cl, Br, I), (vii) NO ₂ , (viii) -COOH, (ix) -COO-(Cι-C alkyl), (x) -NH ₂ , (xi) -NH(Cι-C alkyl), or (xii) -N(Cι-C4aIkyl) , (j) -CH2SO2NH-heterocycle, (k) -SO2NHCOR ³³ , (1) -CH2SO2NHCOR ³² ' (m) -CONHSO ₂ R ³³ , (n) -CH2CONHSO2R ³³ , (o) -NHCONHSCbR ³³ , (p) -NHSO2NHCOR ³³ , (q) -CONHNHSO2CF3, (r) CON(OH)R ³¹ , (s) -CONHCOCF3, (t) -CONHSO ₂ R ²⁸ , (u) -CONHSO ₂ R ²⁹ , (v) -CONHSO?R ³⁰ ,

H

15

R28 is selected from the group consisting of (a) hydroxy, (b) -Cs-alkoxy, (c) C3-C12- alkenoxy, (d) Cβ-Qtø-aryloxy, (e) Cι-C6-alkyl-QrCi2-aryloxy, (f) di- -Cg-alkylamino-Ci-Cs- alkoxy, (g) acylamino-Ci-Cg-alkoxy selected from the group (i) acetylaminoethoxy, (ii) nϊcotinoylaminoethoxy, and (iii) succinamidoethoxy, (h) Ci-Cg-alkoyloxy-Ci-Cs-alkoxy, (ϊ) Cβ- Ci2-aryI-Cι-C8-alkoxy where the aryl group is unsubstituted or substituted with one to three of the groups (i) nitro, (ii) halo (F, Cl, Br, 1), (iii) Cχ-C4-alkoxy, and (iv) amino, (j) hydroxy-C2- Cs-alkoxy, (k) dihydroxy-C3-C8-aIkoxy, and (1) NR ²⁹ R ^t 29 and R ³ ^ are independently selected from the group (a) hydrogen, (b) -Cs-alkyl,

(c) C3-C8-alkenyl, (d) C6-Cχ2-aryl where the aryl group is unsubstituted or substituted with one to three of the groups (i) nitro, (ii) halo (F, Cl, Br, 1), (iii) C -C4-alkoxy, and (iv) amino, and (e) C6-Ci2-aryl-C]-C8-alkyl where the aryl group is unsubstituted or substituted with one to three of the groups (i) nitro, (ii) halo (F, Cl, Br, 1), and (iii) -Cφ-aikoxy.

R ³ 1 is selected from the group consisting of (a) H, (b) -C6 alkyl, (c) halo(F, Cl, Br, I)- C1-Q5 alkyl, (d) phenyl, (e) benzyl, and (f) -CH2-O-COCH3.

R ³² is selected from the group consisting of (a) H, (b) benzyl, and (c) -CH(R ³ ^)-0- C(O)R ³⁵ .

R33 i _s selected from the group consisting of (a) aryl, (b) heterocycle, (c) (C3-C7)- cycloalkyl, (d) (Cι-C4)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of (i) aryl, (ii) heterocycle, (iii) -OH, (iv) -SH, (v) (Cι-C4)-alkyl, (vi) ( -C4)- alkoxy, (vii) (Cι-C4)-aIkylthio, (viii) -CF^ (ix) halo (F, Cl, Br, 1), (x) -NO2, (xi) -CO2H, (xii) CO2- (Cι-C4)-alkyl, (xiii) -NH2, (xiv) -N[(Cι-C4)-alkyl] ₂ , (xv) -NH[(Cι-C ₄ )-alkyl], (xvi) -PO3H, or (xvii) PO(OH)(Cι-C4)-alkoxy, or (e) (Ci- j-perfluoroalkyl.

R ³⁴ is selected from the group consisting of (a) -CN, (b) -NO ₂ , (c) -COOR ³¹ , (d) -Co- perfluoroalkyl, and (e) CF3.

R ³⁵ is independently selected from the group consisting of (a) H, (b) (Ci- -alkyl, (C ₂ - C6)-aIkenyl, (C ₂ -C6)-alkynyl or (C3-C8)-cycloalkyl, each of which is unsubstituted or substituted with: (i) OH, (ii) (Cι-C ₄ )-alkoxy, (iii) CO ₂ R ³³ , (iv) OCOR ³³ , (v) CONHR ³³ , (vi) CON(R ³³ )2, (vii) N(R ³³ )C(O)R ³³ , (viii) NH2, (ix) (Cι-C )-alkylamino, (x) di[(C C ₄ )- alkyl]amino, (xi) aryl, (xii) heteroaryl, (c) -C(0)-aryl, (d) -N0 ₂ , (e) halo(Cl, Br, I, F), (f) -OH, (g) -OR ³⁶ , (h) (Cι-C4)-perfluoroalkyl, (i) -SH, (j) -S(0)ϊ_2 (Cι-C4)-aIkyl, (k) CO2R ³³ , (1) -SO3H, (m) -NR ³ R ³⁶ , (n) -NR ³³ C(O)R ³⁶ , (o) -NR ³ COOR ³² , (p) -SO2NHR ³² , (q) -Sθ2NR ³³ R ³³ , (r) -NHSO2R ³² , (s) -C(0)NHS0 ₂ R ³² , (t) aryl, (u) heteroaryl, (v) morphoIin-4-yl, (w) CONH ₂ , or (y) lH-tetrazol-5-yl. R ³ " is selected from the group (a) H; or (b) (Cι-C4)-alkyl unsubstituted or substituted with (i) NH , (ii) NH[(Cι-C ₄ )-alkyl], (iii) N[(Cι-C4)-alkyl] ₂ , (iv) CO ₂ H, (v) CO2(Ci-C4)-alkyl, (vi) OH, (vii) SO3H, or (viii) SO2NH2.

R ³ ? is selected from the group consisting of (a) H, (b) (Cι-C6)-alkyl, (c) (C2-C6)- alkenyl, (d) (C -C6)-alkoxyalkyl, (e) -CH ₂ -0-COCH3 _/ or (f) -CH ₂ -phenyI, where the phenyl is unsubstituted or substituted with a substituent selected from -N0 , -NH ₂ , -OH, or -OCH3.

R ³⁸ , R ³⁹ , and R ⁴⁰ are each independently selected from H, Cl, CN, NO2, CF3, C2F5, C3F7, CHF2, CH2F, CO2CH3, CO2C2H5, SO2CH3, SO2CF3 and SO2C6F5; wherein Z is selected from O, S, NR ⁴¹ and CH2.

R 1 is selected from hydrogen, CH3, and CH2C6H5 or a tautomer or pharmaceutically acceptable salt thereof.

Preferred "w'"s are selected from; -COR ²⁸ . -NHS0 ₂ CF3,

Most preferred W ^r s are either a tetrazole or a carboxylate. Preferably these groups are represented by;

o

II

CH,— C— R ²⁸ .

where R ² ^ is methylene, and R ²⁸ and R ³ * are hydroxy and hydrogen respectively. Optionally,

R ²⁸ and R ³ * are substituents that transform compounds represented by structural formulae I- VI into prodrugs. When W contains a carboxylate, for example, preferred prodrug forms include simple esters, α-acyloxyalkyl esters, and amides. Preferred esters include compounds where R ²⁸ is selected from;

O— CH -CH ₂ -CH ₂ -CH ₃ ,

0

II O— CH ₂ -0— C— CH,

0

0

II O— CH ₂ -0— C— CH ₂ -CH ₂ -CH ₃ ,

0 C , II

^■ CH ₂ -0— C— C- ^• CH _a

I H

0 CH ₃

II I

^■ 0 — CH,-0- ^■ C— C— CH ₃

I

CH ₃

The most preferred compounds of this invention are represented by structural formula II and are selected from the following: l-(4-chlorophenyl)methyl-4-(2-carboxyethyl)-7-(4-(l-piperizi n)-phenyl)-3,4-dihydro-lH-l,4- benzod iazapine-2,5-dione. l-(diphenyl)methyI-4-(2-carboxyethyl)-7-(4-(l-piperizin)-phe nyl)-3,4-dihydro-lH-l,4- benzodiazaρine-2,5-dione.

l-( -trifluromethyl)phenyi-4-(2-carboxyethyl)-7-(4-(l-piperizin) -phenyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-methyl-4-(2-carboxyethyl)-7-(4-(l-piperϊzin)-phenyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5- dione. l-(l-methyl)ethyl-4-(2-carboxyethyl)-7-(4-(l-piperizin)-phen yl)-3,4-dihydro-lH-l _/ 4- benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-(2-carboxyethyl)-7-(4-(l-pϊperizin)-ph enyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-(2-carboxyethyI)-7-(4-(2-aminoeth oxy)-phenyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-(2-carboxyethyl)-7-(4-(2-aminoethoxy)-p henyl)-3,4-dihydro-lH-l,4- benzodϊazapine-2,5-dione. l-(m-trifIuromethyl)phenyl-4-(2-carboxyethyI)-7-(4-(2-aminoe thoxy)-phenyl)-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-methyl-4-(2-carboxyethyI)-7-(4-(2-aminoethoxy)-phenyl)-3,4 -dihydro-lH-l,4-benzodiazapine- 2,5-dione. l-(l-methyl)ethyl-4-(2-carboxyethyl)-7-(4-(2-aminoethoxy)-ph enyl)-3,4-dihydro-lH-l,4- benzodiazapϊne-2,5-dione. l-(2-methyl)propyI-4-(2-carboxyethyl)-7-(4-(2-aminoethoxy)-p henyl)-3,4-dihydro-lH-l,4- benzodiazapϊne-2,5-dione. l-(diphenyI)methyI-4-(2-carboxyethyI)-7-(6-aminohexyl)-3,4-d ihydro-lH-l,4-benzodiazapine- 2,5-dione. l-(diphenyl)methyl-4-(2-carboxyethyl)-7-(6-aminohex-l-ynyl)- 3,4-dihydro-lH-l,4- benzodiazapine-2,5-dϊone. l-(diphenyl)methyl-4-(2-carboxyethyl)-7-(5-aminopentoxy)-3,4 -dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyI-4-(2-carboxyethyl)-7-(5-guanidinopentyl)- 3,4-dihydro-lH-l,4- benzodϊazapine-2,5-dione. l-(diphenyl)methyl-4-(2-carboxyethyl)-7-(4-guanϊdinobutoxy) -3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-(2-carboxyethyl)-7-(5-aminopent-l-ynyl) -3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyI)methyl-4-(2-carboxyethyl)-7-(5-guanidinopent-l-y nyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-(2-carboxyethyl)-7-(4-amidino)benzamido -3,4-dihydro-lH-l,4- benzodiazapϊne-2,5-dione. l-(diphenyl)methyI-4-(2-carboxyethyl)-7-(4-amidino)benzyloxy -3,4-dihydro-lH-l,4- benzodiazapϊne-2,5-dione.

- p eny me y - - -car oxye ny - - - -am nop e - , - - - , - benzod iaza pine-2,5-d ione. l-(diphenyl)methyl-4-(2-carboxyethyl)-7-[2-(4-amidinophenyl) ]ethynyl-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-(2<arboxyethyl)-7-(6-aminohexy l)-3,4-dihydro-lH-l,4- benzod iazapine-2,5-dione. l-(4-chlorophenyI)methyl-4-(2-carboxyethyl)-7-(5-aminopentox y)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-(2-carboxyethyl)-7-(4-amidino)ben zamido-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-(2-carboxyethyl)-7-(4-amidino)ben zyloxy-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-(2-carboxyethyl)-7-[2-(4-amidinop henyl)]ethenyl-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyI-4-(2-carb()xyethyl)-7-[2-(4-amidino phenyl)]ethynyl-3,4-dihydro-lH-

1,4-benzod iazapine-2,5-d ione. l-methyl-4-(2-carboxyethyl)-7-(4-amidino)benzamido-3,4-dihyd ro-lH-l,4-benzodiazapine-2^- dione. l-methyl-4-(2-carboxyethyl)-7-(4-amidino)benzyloxy-3,4-dihyd ro-lH-l,4-benzodiazapine-2,5- dione. l-methyI-4-(2-carboxyethyl)-7-[2-(4-amidinophenyl)]ethenyl-3 ,4-dihydro-lH-l,4- benzod iazapine-2,5-d ione. l-methyl-4-(2-carboxyetlny])-7-[2-(4-amidinophenyl)]ethynyl- 3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(l-methyl)ethyl-4-(2-carboxyethy])-7-(4-amidino)benzamido- 3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(l-methyl)ethyl-4-(2-carboxyethyl)-7-(4-amidino)benzyloxy- 3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(l-methyl)ethyl-4-(2-carboxyethyl)-7-[2-(4-amidinophenyl)] etlnenyl-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyl)ethyI-4-(2-carboxyetlnyl)-7-[2-(4-amidinophenyl) ]ethynyl-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-(2-carboxyethyI)-7-(4-amidino)benzamido -3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-(2-carboxyetlnyl)-7-(4-amidino)benzylox y-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-(2-carboxyethyI)-7-t2-(4-amidinophenyl) ]ethenyl-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione.

l-(2-methyl)propyl-4-(2-carboxyethyl)-7-t2-(4-amidinophenyl) ]ethynyl-3,4-dihydro-lH-l,4- benzodiazapϊne-2,5-dione- l-(2,4-diflurophenyl)methyl-4-(2-carboxyethyl)-7-(4-(l-piper izin)-phenyl)-3,4-dihydro-lH-l _/ 4- benzodiazapine-2,5-dione. l-(2,4-dϊflurophenyl)me yl-4-(2-carboxyethyl)-7-(4-(2-aminoethoxy)-phenyl)-3,4-dihyd ro-lH- l,4-benzodiazapine-2 -dione. l-(2,4-diflurophenyl)methyl-4-(2-carboxyethyl)-7-(6-aminohex yl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2,4-diflurophenyl)methyl-4-(2-carboxyethyI)-7-(5-aminopen toxy)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2,4-diflurophenyl)methyl-4-(2-carboxyethyl)-7-(4-amidino) benzamido-3,4-dihydro-lH-l,4- benzodiazapine-2^-dione- l-(2,4-diflurophenyI)methyl-4-(2-carboxyethyl)-7-(4-amidino) benzyloxy-3,4-dihydro-lH-l,4- benzodϊazapine-2,5-dione. l-(2,4-dϊflurophenyl)memyl-4-(2-carboxyethyl)-7-[2-(4-amidi nophenyl)]ethenyl-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione. l-(2,4-diflurophenyl)memyl-4-(2-carboxyethyI)-7-[2-(4-amidin ophenyl)]ethynyl-3,4-dihydro- lH-l,4-benzodϊazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-(2-carboxyethyl)-7-[2-(4-piperid� �nyl)ethyIoxy]-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-(2-carboxyethyI)-7-[2-(4-piperidinyl)et hyloxy]3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(j«-trifluromethyl)phenyI-4-(2-carboxyethyl)-7-[2-(4-pipe ridinyl)ethyloxy]-3,4-dihydro-lH- l,4-benzodiazapϊne-2,5-dϊone. l-methyl-4-(2-carboxyethyl)-7-[2-(4-piperidinyl)ethyloxy]-3, 4-dihydro-lH-l,4-benzodiazapine- 2,5-dione. l-(l-methyI)ethyl-4-(2-carboxyethyI)-7-[2-(4-piperidinyl)eth yloxy]-3,4-dihydro-lH-l,4- benzodiazapϊne-2,5-dione. l-(2-methyI)propyl-4-(2-carboxyethyI)-7-[2-(4-piperidinyl)et hyIoxy]-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2,4-diflurophenyl)methyl-4-(2-carboxyethyl)-7-[2-(4-piper idinyl)ethyloxy]-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(4-chlorophenyI)methyl-4-(3-butanoyl)-7-(4-(l-piperizin)-p henyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(dϊphenyl)methyl-4-(3-butanoyl)-7-(4-(l-piperizin)-phenyl )-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dϊone. l-( -trifluromethyl)phenyl-4-(3-butanoyl)-7-(4-(l-piperizin)-phe nyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione.

l-methyl-4-(3-butanoyl)-7-(4-(l-piperizin)-phenyl)-3,4-dihyd ro-lH-l,4-benzodiazapine-2^- dione. l-(l-methyl)ethyl-4-(3-butanoyl)-7-(4-(l-piperizin)-phenyl)- 3,4-dihydro-lH-l,4-benzodiazapine-

2,5-dione. l-(2-methyl)propyl-4-(3-butanoyl)-7-(4-(l-piperizin)-phenyl) -3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-(3-butanoyl)-7-(4-(2-aminoethoxy) -phenyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-(3-butanoyl)-7-(4-(2-aminoethoxy)-pheny l)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-( -trifluromethyl)phenyl-4-(3-butanoyl)-7-(4-(2-aminoethoxy)-p henyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-methyl-4-(3-butanoyl)-7-(4-(2-aminoethoxy)-phenyl)-3,4-dih ydro-lH-l,4-benzodiazapine-2^- dione. l-(l-methyl)ethyl-4-(3-butanoyl)-7-(4-(2-aminoethoxy)-phenyl )-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-(3-bu tanoyl )-7-(4-(2-aminoethoxy)-phenyl )-3,4-d ihyd ro-1 H-1,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-(3-butanoyl)-7-(6-aminohexyl)-3,4-dihyd ro-lH-l,4-benzodiazapine-2,5- dione. l-(diphenyl)methyl-4-(3-butanoyl)-7-(6-aminohex-l-ynyl)-3,4- dihydro-lH-l,4-benzodiazapine-

2,5-dione. l-(diphenyl)methyl-4-(3-butanoyl)-7-(5-aminopentoxy)-3,4-dih ydro-lH-l,4-benzodiazapine-2,5- dione. l-(diphenyl)methyl-4-(3-butanoyI)-7-(5-guanidinopentyl)-3,4- dihydro-lH-l,4-benzodiazapine-

2,5-dione. l-(diphenyl)methyl-4-(3-butanoyl)-7-(4-guanidinobutoxy)-3,4- dihydro-lH-l,4-benzodiazapine-

2,5-dione. l-(diphenyl)methyl-4-(3-butanoyI)-7-(5-aminopent-l-ynyl)-3,4 -dihydro-lH-l,4-benzodiazapine- 2,5-dione. l-(diphenyl)methyl-4-(3-butanoyl)-7-(5-guanidinopent-l-ynyl) -3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-(3-butanoyl)-7-(4-amidino)benzamido-3,4 -dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-(3-butanoyl)-7-(4-amidino)benzyloxy-3,4 -dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-(3-butanoyI)-7-[2-(4-amidinophenyl)]eth enyl-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione.

l-(diphenyl)methyl-4-(3-butanoyl)-7-[2-(4-amidinophenyl)leth ynyl-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-(3-butanoyl)-7-(6-aminohexyl)-3,4 -dihydro-lH-l,4-benzodiazapine- 2,5-dione. l-(4-chlorophenyl)methyl-4-(3-butanoyl)-7-(5-aminopentoxy)-3 ,4-dihydro-lH-l,4- benzodiazapine-2,5-dϊone. l-(4-chlorophenyl)methyI-4-(3-butanoyI)-7-(4-amidino)benzami do-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyI-4-(3-butanoyl)-7-(4-amidino)benzylo xy-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dϊone. l-(4-chlorophenyl)methyl-4-(3-butanoyl)-7-[2-(4-amidϊnophen yl)]ethenyI-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-(3-butanoyl)-7-[2-(4-amidinopheny l)]ethynyl-3,4-dihydro-lH-l,4- benzodiazapϊne-2,5-dione. l-methyl-4-(3-butanoyl)-7-(4-amidino)benzamido-3,4-dihydro-l H-l,4-benzodiazapine-2,5- dione. l-methyI-4-(3-butanoyl)-7-(4-amidino)benzyloxy-3,4-dihydro-l H-l,4-benzodiazapine-2^-dione. l-methyl-4-(3-butanoyl)-7-[2-(4-amidinophenyl)]ethenyl-3,4-d ihydro-lH-l,4-benzodiazapine- 2,5-dϊone. l-methyI-4-(3-butanoyl)-7-[2-(4-amidinophenyl)]ethynyl-3,4-d ihydro-lH-l,4-benzodiazapine- 2,5-dione. l-(l-methyl)etlnyl-4-(3-butanoyl)-7-(4-amidino)benzamido-3,4 -dihydro-lH-l,4-benzodiazapine- 2,5-dϊone. l-(l-methyl)ethyl-4-(3-butanoyl)-7-(4-amidino)benzyloxy-3,4- dihydro-lH-l,4-benzodiazapine- 2,5-dione. l-(l-methyl)ethyl-4-(3-butanoyl)-7-[2-(4-amϊdϊnophenyl)]et henyl-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyl)etlnyl-4-(3-butanoyl)-7-[2-(4-amidinop.henyl)]et hynyl-3,4-dϊhydro-lH-l,4- benzodϊazapine-2,5-dϊone. l-(2-methyl)propyI-4-(3-butanoyI)-7-(4-amid ino)benzamϊdo-3,4-d ihydro-lH-1,4- benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-(3-butanoyl)-7-(4-amϊdino)benzyloxy-3, 4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyI)propyl-4-(3-butanoyl)-7-f2-(4-amidinophenyl)]etl nenyl-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-(3-butanoyl)-7-t2-(4-amϊdinophenyl)]et hynyl-3,4-dihydro-lH-l,4- benzodiazapϊne-2,5-dione. l-(2,4-difluroplnenyl)methyl-4-(3-butanoyl)-7-(4-(l-piperizi n)-plnenyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione-

l-(2,4-diflurophenyl)methyl-4-(3-butanoyl)-7-(4-(2-aminoetho xy)-phenyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2,4-difluropheny])methyl-4-(3-butanoyl)-7-(6-aminohexyl)- 3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2 _/ 4-diflurophenyl)methyl-4-(3-butanoyl)-7-(5-aminopentox y)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2,4-diflurophenyl)methyl-4-(3-butanoyl)-7-(4-amidino)benz amido-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2,4-diflurophenyl)methyl-4-(3-butanoyl)-7-(4-amidino)benz yloxy-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2,4-diflurophenyl)methyl-4-(3-butanoyl)-7-[2-(4-amidinoph enyl)]ethenyl-3,4-dihydro-lH-l,4- benzod iaza pine-2,5-d ione. l-(2,4-diflurophenyl)metlnyl-4-(3-butanoyl)-7-[2-(4-amidinop henyl)]ethynyl-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-(3-butanoyl)-7-[2-(4-piperidinyl) ethyloxy]-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-(3-butanoyl)-7-[2-(4-piperidinyl)ethylo xy]3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-( -trifluromethyl)plnenyl-4-(3-butanoyI)-7-[2-(4-piρeridinyl) ethyloxy]-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-methyl-4-(3-butanoyl)-7-[2-(4-piperidinyl)ethyloxy]-3,4-di hydro-lH-l,4-benzodiazapine-2^- dione. l-(l-methyl)etlnyl-4-(3-butanoyl)-7-[2-(4-piperidinyl)etlnyl oxy]-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-(3-butanoyl)-7-[2-(4-piperidinyl)ethylo xy]-3,4-dihydro-lH-l,4- benzod iazapine-2,5-d ione. l-(2,4-difluroplnenyl)methyl-4-(3-butanoyl)-7-[2-(4-piperidi nyI)ethyloxy]-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chloroplnenyl)metlny]-4-[(2-methyl)carboxyethyl]-7-(4-( l-piperizin)-phenyl)-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-[(2-methyl)carboxyethyI]-7-(4-(l-piperi zin)-phenyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(w-trifluromethyl)phenyl-4-[(2-methyl)carboxyethyl]-7-(4-( l-piperizin)-phenyl)-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione. l-methyl-4-[(2-methyl)carboxyethyl]-7-(4-(l-piperizin)-pheny l)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(l-metlnyl)ethyI-4-[(2-methyl)carboxyetlnyl]-7-(4-(l-piper izin)-phenyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione.

l-(2-methyl)propyI-4-[(2-methyl)carboxyethyl]-7-(4-(l-piperi zin)-phenyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chIorophenyI)methyI-4-t(2-methyl)carboxyethyl]-7-(4-(2- aminoethoxy)-phenyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione- l-(diphenyl)methyl-4-[(2-methyl)carboxyethyl]-7-(4-(2-aminoe thoxy)-phenyl)-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(7n-tiifluromethyl)phenyl-4-[(2-methyl)carboxyethyl]-7-(4- (2-aminoethoxy)-phenyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione. l-methyl-4-[(2-methyl)carboxyethyl]-7-(4-(2-aminoethoxy)-phe nyl)-3,4-dihydro-lH-l,4- benzodiazapϊne-2,5-dϊone. l-(l-me yl)emyI-4-[(2-methyl)carboxyetlnyl]-7-(4-(2-aminoethoxy)-phe nyI)-3,4-dihydro-lH-l,4- benzodiazapϊne-2,5-dione. l-(2-methyl)propyl-4-[(2-methyI)carboxyethyl]-7-(4-(2-amϊno etlnoxy)-phenyl)-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(diphenyI)methyl-4-[(2-methyl)carboxyetlnyl]-7-(6-aminohex yl)-3,4-dihydro-lH-l,4- benzodϊazapine-2,5-dϊone. l-(diphenyl)methyI-4-[(2-methyl)carboxyethyl]-7-(6-aminohex- l-ynyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-[(2-methyl)carboxyethyl]-7-(5-aminopent oxy)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-[(2-methyl)carboxyethyI]-7-(5-guanϊdin opentyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(dϊphenyI)methyl-4-[(2-methyl)carboxyethyl]-7-(4-guanidin obutoxy)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dϊone. l-(dϊphenyI)methyl-4-[(2-methyl)carboxyethyl]-7-(5-aminopen t-l-ynyl)-3,4-dϊhydro-lH-l,4- benzodiazapϊne-2,5-dione. l-(diphenyI)methyl-4-[(2-methyl)carboxyethyI]-7-(5-guanidino pent-l-ynyI)-3,4-dihydro-lH-l,4- benzodϊazapine-2,5-dione. l-(diphenyl)methyl-4-[(2-methyl)carboxyethyl]-7-(4-amidino)b enzamϊdo-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dϊone. l-(diphenyl)methyl-4-[(2-methyl)carboxyethyl]-7-(4-amidϊno) benzyloxy-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(diphenyl)methyl-4-[(2-methyl)carboxyethyl]-7-[2-(4-amidin ophenyl)]ethenyl-3,4-dihydro- lH-l,4-benzodϊazapϊne-2,5-dione. l-(diphenyI)methyl-4-[(2-methyI)carboxyethyl]-7-[2-(4-amidin ophenyl)]ethynyl-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-[(2-methyl)carboxyetlnyl]-7-(6-am ϊnohexyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dϊone.

l-(4-chlorophenyl)methyl-4-[(2-methy])carboxyethyl]-7-(5-ami nopentoxy)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-[(2-methyl)carboxyethyl]-7-(4-ami dino)benzamido-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-[(2-methyl)carboxyethyI]-7-(4-ami dino)benzyloxy-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-[(2-methyl)carboxyethyl]-7-[2-(4- amidinophenyl)]ethenyl-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione. l-(4-chlorophenyl)methyl-4-[(2-methyl)carboxyethyl]-7-[2-(4- amidinophenyl)]ethynyl-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione. l-methyl-4-[(2-methyl)carboxyethyI]-7-(4-amidino)benzamido-3 ,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-methyl-4-[(2-methyl)carboxyethyl]-7-(4-amidino)benzyloxy-3 ,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-methyl-4-f(2-methyl)carboxyetlnyl]-7-[2-(4-amidinophenyl)] etheny]-3,4-dilnydro-lH-l,4- benzodiazapine-2,5-dione. l-methyl-4-[(2-methyl)carboxyethyI]-7-[2-(4-amidinophenyI)]e thynyl-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(l-methyl)etInyl-4-[(2-methyl)carboxyethyl]-7-(4-amidino)b enzamido-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(l-methyl)ethyl-4-[(2-methyl)carboxyetlnyl]-7-(4-amidino)b enzyloxy-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(l-methyl)ethyl-4-t(2-methyl)carboxyethyl]-7-[2-(4-amidino phenyl)]ethenyl-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(2-metlnyl)ethyl-4-[(2-methyl)carboxyethy]]-7-[2-(4-amidin ophenyl)]ethynyl-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-[(2-metlnyl)carboxyethyl]-7-(4-amidino) benzamido-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-[(2-methyl)carboxyethyl]-7-(4-amidino)b enzyloxy-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-[(2-methyl)carboxyethyl]-7-[2-(4-amidin oplnenyl)]ethenyl-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione. l-(2-methyl)propyl-4-[(2-methyl)carboxyetlnyI]-7-[2-(4-amidi nophenyl)]ethynyl-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione. l-(2,4-diflurophenyl)metlnyl-4-[(2-methyI)carboxyethyI]-7-(4 -(l-piperizin)-phenyl)-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione. l-(2,4-diflurophenyl)metlnyl-4-[(2-metlnyl)carboxyethyl]-7-( 4-(2-aminoethoxy)-phenyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione.

l-(2,4-diflurophenyl)memyl-4-t(2-methyl)carboxyethyl]-7-(6-a minohexyl)-3,4-dihydro-lH-l,4- benzodϊazapine-2,5-dione. l-(2,4-diflurophenyl)memyl-4-[(2-methyl)carboxyethyl]-7-(5-a minopentoxy)-3,4-dihydro-lH- l,4-benzodiazapme-2,5-dione. l-(2,4-diflurophenyl)me yl-4-[(2-methyI)carboxyethyl]-7-(4-amidino)benzamido-3,4-dih ydro- lH-l,4-benzodϊazapine-2,5-dione. l-(2,4-dϊflurophenyl)memyl-4-[(2-methyl)carboxyethyl]-7-(4- amidino)benzyloxy-3,4-dihydro- lH-l,4-benzodϊazapine-2,5-dione. l-(2,4-diflurophenyl)memyl-4-[(2-methyl)carboxyethyl]-7-[2-( 4-amidinophenyl)]ethenyl-3,4- dihydro-lH-l,4-benzodϊazapine-2,5-dione. l-(2,4-diflurophenyl)memyl-4-[(2-methyl)carboxye-hyl]-7-[2-( 4-amidinophenyl)]ethynyl-34- dihydrp-lH-l,4-benzodiazapϊne-2,5-dione. l-(4-chIorophenyl)methyl-4-[(2-methyl)carboxyethyl]-7-[2-(4- piperidinyI)ethyloxy]-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione. l-(dϊphenyl)methyl-4-[(2-methyl)carboxyethyl]-7-[2-(4-piper ϊdinyl)ethyloxy]3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(;n-trifluromethyl)phenyl-4-[(2-methyI)carboxyethyl]-7-[2- (4-piperidinyl)ethyloxy]-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dϊone. l-methyI-4-[(2-methyl)carboxyethyI]-7-[2-(4-piperidinyl)etln yloxy]-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(l-methyl)ethyl-4-[(2-methyI)carboxyetlnyl]-7-[2-(4-piperi dinyl)ethyloxy]-3,4-dihydro-lH-l,4- benzodϊazapine-2,5-dione. l-(2-methyl)propyl-4-[(2-methyl)carboxyethyl]-7-[2-(4-piperi dinyl)ethyloxy]-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(2,4-dϊflurophenyl)methyl-4-[(2-methyl)carboxyetlnyl]-7-[ 2-(4-piperidinyl)ethyloxy]-3,4- dihydro-lH-l,4-benzodiazapϊne-2,5-dione. l-(3-(butyryI)aminophenyl)methyl-4-(2-carboxyethyI)-7-(6-am� �nohexyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(3-(butyryl)aminophenyl)methyl-4-(2-carboxyethyl)-7-(5-gua nidinopentyI)-3,4-dihydro-lH- l,4-benzodϊazapine-2,5-dione. l-(3-(4-amϊnobutyryl)aminophenyl)methyl-4-(2-carboxyethyl)- 7-(6-aminohexyl)-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dϊone. l-(3-(4-guanidinobutyryl)aminophenyl)methyl-4-(2-carboxyethy I)-7-(5-guanidinopentyI)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dϊone. l-(3-(6-amϊnohexoyl)aminophenyl)methyl-4-(2-carboxyetlnyl)- 7-(6-aminohexyl)-3,4-dihydro- lH-l,4-benzodϊazapine-2,5-dϊone. l-(3-(6-guanϊdinohexoyl)aminophenyl)methyI-4-(2-carboxyethy l)-7-(5-guanidinopentyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione.

l-(3-(6-aminopentoyl)aminophenyl)methyl-4-(2-carboxyet y -7-(6-amino exy - , - y ro- lH-l,4-benzodiazapine-2,5-dione. l-(3-(6-guanidinopentoyl)aminophenyl)methyl-4-(2-carboxyethy l)-7-(5-guanidinopentyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione. l-(3-(6-aminopropionyl)aminophenyl)methyl-4-(2-carboxyethyl) -7-(6-aminohexyl)-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione. l-(3-(6-guanidinopropionyl)aminophenyl)methyl-4-(2-carboxyet lnyI)-7-(5-guanidinopentyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione. l-(3-(6-aminoacetyl)aminophenyl)methyl-4-(2-carboxyethyI)-7- (6-aminohexyl)-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione. l-(3-(6-guanidinoacetyl)aminophenyl)methyl-4-(2-carboxyethyl )-7-(5-guanidinopentyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione. l-(3-(4-guanidinobenzoyl)aminophenyl)methyl-4-(2-carboxyethy l)-7-(6-aminohexyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione. l-(4-(6-aminopropionyI)aminoρhenyl)methyl-4-(2-carboxyethyl )-7-(6-aminohexyl)-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione. l-(3-(4-aminobutyl)phenyl)metlnyl-4-(2-carboxyethyl)-7-(6-am inohexyl)-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione. l-(4-carboxyphenyl)methyl-4-(2-carboxyethyl)-7-(6-aminohexyl )-3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione.

2. Nonpeptidyl α _v β3 inhibitors

An alternative embodiment of the invention comprises a compound represented by formula VII capable of inhibiting binding of the osteoclast α _v β3 receptor to its native in vivo ligands.

where R ¹ , R ² , R ²⁰ , R ²² , R ²⁸ , Q ¹ , and L ¹ are defined above. Compounds represented by formula VII are potent inhibitors of the vitronectin- vitronectin receptor (Vn-VnR) interaction, typically yielding ICso's in a Vn-VnR ELISA of

between 150 and 200 nM. These compounds show roughly a 20-fold selectivity when compared with the GPII _b III _a -Fg inhibition. - - „-_ ^* " ...

D. Methods of Making

Compounds of the present invention can be prepared by many methods, employiqc standard chemical methodologies described and referenced in standard textbooks (e.g. March, J. "Advanced Organic Chemistry" McGraw-Hill, New York, 1977; Collman, J.P., Hegedus, L.S., Norton, J.R., Finke, R.G. "Principles and Applications of Organotransition Metal Chemistry" University Science, Mill Valley, 1987; Larock, R.C. "Comprehensive Organic Transformations" Verlag, New York, 1989). In the description that follows standard abbreviations as recommended by the Journal of Organic Chemistry (see "Guidelines for Authors" in any volume) are employed unless otherwise specified. 1. The Q Group The nitrogen containing substituents Q or a precursor thereof may added to the linker

L and the combination Q-L-, usually in protected form, may be bonded to ring A. Alternatively, Q or Q plus a portion of L may be added to L or a portion thereof after ring A and the rest of the molecule have been formed. Q itself may be prepared and bonded to ring A by standard methods published in both the scientific and patent literature (see e.g. US patents; 4,992,542, ,997,936, 4,194,047, 5,003,076, 5,063,207, 5,063,208, and 5,079,357, and references cited therein).

In the description immediately following, addition of Q-L- to the benzene moiety of 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone is specified. It will be understood that these same procedures may be applied to other ring systems encompassed by formula I. 2. The benzodiazepinedione

The key intermediate is tine substituted 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione 1.

The benzodiazepinedione 1 (R≠H) may be prepared using a triply convergent approach from the isatoic anhydride 2, the b-alanine ester 3, and the a-haloacetyl halide 4 (Scheme 1). The benzodiazepinedione 1 (R=H) may be prepared using a doubly convergent approach from the isatoic anhydride 2 (R=H) and the substituted N-carboxymethyl b-alanine ester 5 (Scheme 2).

Methods for preparation of the isatoic anhydrides 2, b-alanine esters 3, and a-halo acetyl halides 4 (Scheme 1), are known in the art and a number of them are available from commercial sources such as Aldrich Chemical Co. A reaction sequence, similar to that shown in Scheme 1 to prepare 3,4-dihydro-lH-l,4-benzodiazepine-2,5-diones has been previously described (Lee, CM. /. Heterocyclic Chem. 1: 235 (1964). Briefly, the isatoic anhydrides are converted to N-(2-amϊnobenzoyl)-b-alanine esters 6 by allowing 2 to react with 3, or its salt, in the presence an organic base. The isatoic anhydride 2 may be substituted or unsubstituted, but the 5-iodo isatoic anhydride is preferred (2, R ^a =I). The b-alanine ester 3 may also be substituted or unsubstituted as the free amine or, more conveniently, as its salt (e.g. HCl). For

example, the reaction may be carried out with b-alanine ethyl ester hydrochloride, ethyl 3- phenyl-3-aminopropionate p-tosylate, aspartyl-valine dibenzyl ester hydrochloride, or the like. Generally, tine reaction is conducted in a dry polar aprotic solvent, such as dimethylformamide or the like, in the presence of an equimolar amount, or up to 30% excess, of a tertiary amine as the organic base, e.g. triethylamine. Alternatively, the reaction may be catalysed by dimethylaminopyridine (Venuti, M.C. Synthesis 266 (1982)). The reaction requires between about 0.5 to 4 hours at temperatures between about room temperature and 100°C . Preferably, the reaction is conducted at 50°C for about 2 hours in dimethylformamide as the solvent.

The products are isolated and purified by conventional methods, typically by solvent extraction into a compatible solvent. The product may be further purified by column chromatography or other appropriate methods.

If the anilino nitrogen in N-(2-aminobenzoyl)-b-alanine esters 6a is unsubstituted such that R=H, this position can be alkylated by allowing 6b (R=H) to react with a molar amount, but up to 50% excess, of an alkyl halide to produce 6 (R≠H). Generally, the reaction can be accomplished in a polar aprotic solvent, in the presence of a molar amount, or up to 50% excess, of an organic base. Preferably, the reaction will be conducted in dimethylformamide as solvent and 2,6-lutidine as the organic base. The reaction is allowed to proceed at temperatures between about room temperature to 200°C for about 0.5 hours to 2 days. Preferably, the reaction will be run at 80°C for 16 hours. The products are isolated and purified by conventional methods, typically by solvent extraction into a compatible solvent. The product may be further purified by column chromatography or other appropriate methods.

Alternatively, 6 (R≠H) may be prepared by allowing 6a to react with an aldehyde or ketone, under dehydrating conditions, in the presence of a catalytic amount of acid followed by reduction with a trialkylsilane and a strong acid. Generally, the first of these reactions can be accomplished in a non-polar aprotic solvent, such as toluene, and an organic acid, such as p- toluenesulphonic acid at temperatures between 80-160°C for times between 1 to 60 mins. Preferably, the reaction will be conducted at reflux for 10 mins. The product may be isolated by crystallization or carried on to reduction without further purification. Reduction can be achieved by tine addition of an excess of trialkylsilane, such as triethylsilane, in the presence of an excess of a strong acid, such as trifluoroacetic acid, at temperatures between -30 to 30°C for times between 0.5 to 48 hours with a non-reactive organic solvent, such as dichloromethane. Preferably, reduction is run at 0°C for 2 hours with dichloromethane as a co-solvent. The products are isolated and purified by conventional methods, typically by crystallization from suitable solvents. The product may be otherwise purified by solvent extraction into a compatible solvent followed by column chromatography or other appropriate methods.

Conversion of N-(2-aminobenzoyl)-b-alanine esters 6 to the benzodiazepinedione 1 (R≠H) involves first the acylation of the anilino nitrogen, followed by a base promoted ring formation. The acylation reaction can be achieved by either reaction of 6 with an a-haloacyl halide in tine presence of an equimolar amount, or up to 30% excess, of an organic base, such as

triethylamine, or with an a-haloacϊd in the presence of an amide coupling reagent, such as dicyclohexylcarbodiϊmide. Acylation of 6 with an a-haloacyl halide may also be conducted in the absence of an organic base and can be run with water in a biphasic reaction system. Generally, these reactions are conducted in a pre-dried, non-reactive organic solvent, such as methylene chloride, diethyl ether, or tetrahydrofuran under a dry,- inert atmosphere, such as nitrogen. Preferably, acylation with an a-halo acylhalide will be run in methylene chloride, whereas acylation with an a-halo-acid will be run in tetrahydrofuran. The reactions are allowed to run at temperatures between about 0°C to room temperature for times between about 0.5 to 24 hours. Preferably, the reactions will be allowed to run for 2 hours at room temperature. The products are isolated and purified by conventional methods, typically by solvent extraction into a compatible solvent. Generally, further purification of the acylated products 7 is not required.

Cyclization of the acylated N-(2-acylaminobenzoyl)-b-alanine esters 7 may be achieved by reaction with a base such as an alkali metal alkoxide, hydride, or carbonate in a polar solvent at temperatures between about 0 and 100°C for about 0.5 to 2 hours. For example, a solution of the N-(2-aminobenzoyI)-b-aIanine ester 7 is commonly added over a period of approximately 15 to 60 minutes to a slurry of an alkali metal hydride in an appropriate solvent, cooled to 0"C SCHEME 1

It is preferable that the solvent will be a polar aprotic solvent such as dimethylfomamide and the alkali metal hydride be sodium hydride or calcium carbonate. Once the addition is complete, the reaction mixture is generally allowed to warm to room temperature and run for an additional 60 to 105 minutes after which the reaction is neutralized by the addition of a solution of an acid, such as 10% citric acid or the like, and the solvent evaporated. The product is then isolated by solvent extraction and further purified by column chromatography.

In Scheme 2, the substituted N-carboxymethyl b-alanine esters 5 are also known in the art and may be prepared in two steps by first reaction of an acrylate ester and a-amino acid ester to give 8, followed by selective conversion of tine glycine ester group to its corresponding acid. For example, allowing glycine benzyl ester to react with ethyl acrylate in an alcoholic solvent such as methanol for about 1 day yields N-(carboxymethyl benzyl ester)-b-alanine ethyl ester. Removal of the benzyl ester by hydrogenation in the presence of a catalytic amount 10% palladium on carbon provides N-carboxymethyl-b-alanine ester 5 (M'=H, R' ³ =ethyl).

Preparation of the benzodiazepinedione 1 (R=H) may be accomplished by allowing 5 to react with 2 (R=H). The reaction can be conducted in either a SCHEME 2

polar aprotic solvent, such as dimethyl sulfoxide, or weak organic base, such as pyridine, at temperatures of 100-200"C for about 2-86 hours. Preferably, the reaction will be run in pyridine at refluxing temperature for about 24 hours. The product is then isolated by dilution with an appropriate organic solvent, such as ethyl acetate, and washed with aqueous acid, such as 10% citric acid, and aqueous base, such as saturated sodium bicarbonate. The products can be further purified by column chromatography or crystallization from an appropriate organic solvent to provide the compounds 1 (R=H).

Reaction Scheme 3 outlines the preparation of tine compounds of the present invention from compound 9 [1 (R ^a =I)].

Conversion of the compounds having the structural formula 9 to compounds having the structural formula 10, provides those compounds classified in Groups 1 and 2. This may be accomplished by allowing 9 to react with an alkyne 11 in the presence of a palladium (II) salt, a copper (I) salt, and an organic base. Preferably, the alkyne 11 is substituted in a way such that the Y group can be synthetically converted to the positively charged Q group of structural Formula I. More preferably, the Y group is a protected form of the positively charged Q group of structural Formula I. For example, the alkyne may be a N-Boc-amino alkyne, a benzo or alkylnitrile alkyne, a nitrobenzo alkyne, or the like. L' is L less the functional groups shown below in scheme 3.

Generally, the reaction is allowed to run in a dry organic polar aprotic solvent, such as ethyl acetate or the like, to the exclusion of oxygen at temperatures between about SCHEME 3

10

room temperature and 180°C for times between about 2 and 48 hours. Preferably, the reaction will run with a catalytic amount of palladium(II) salt at 10 molar percent and cupric(I) salt at 5 molar percent. A 2 fold excess of the alkyne 11 and a 5 fold excess of a tertiary amine as the organic base, such as triethylamine or the like, is preferred. For example, a mixture of the iodo arene 9, a 2 fold excess of the alkyne 11, 10 molar percent of bϊs(triphenylphosphine)palladϊum dichlorϊde, 5 molar percent cupric iodide, 5 fold excess of triethylamine, and ethyl acetate under a dry, inert atmosphere, such as nitrogen, is allowed run for about 2 hours. The product can be isolated by solvent extraction in to a suitable organic solvent, such as ethyl acetate, and washed with a solution of 10% ethylenediaminetetraacetic acid and the solvent evaporated. The products may be further purified by column chromatography.

Preparation of the compounds classified in Groups 3 and 4 may be achieved by reduction of the alkyne moiety in compounds of the general formula 10 to yield the saturated compounds 12 by allowing the alkyne to stir under an atmosphere of hydrogen in the presence

o a sma amount o pa a um on car on. yp ca y, t e react on s run n an nert so vent, such as ethyl acetate, with a 5-10 molar percent by weight of 10% palladium on carbon at temperatures between about room temperature and 50°C for times between about 15 - 240 minutes. Preferably, the reaction is carried out at room temperature for 1 hour. The products are isolated by filtration of the mixture through a filter agent, such as Celite®, and evaporation of solvent.

SCHEME 3, cont.

1 0

Conversion of the compounds of the general formula 10 or 12 in which Y is a N-(tert- butoxycarbonyl) amino protected moiety (N-BOC) to the amino esters 13 can be accomplished

by allowing the material to react with a strong acid. Generally, the reaction is carried out by mixing the N-BOC amino ester with a large excess of concentrated solution of a strong acid, such as hydrogen chloride, dissolved in an appropriate inert solvent, such as ethyl acetate. The reaction can be conducted at a temperature between about minus 30°C and room temperature for about 0.5 to 24 hours. The reaction can be run in the presence of a molar amount of trialkylsilane, such as triethylsilane or the like. Preferably, the reaction will be carried out at room temperature for 2 hours with a molar equivalent of triethylsilane in ethyl acetate. The solvent is evaporated and the products can be further purified by high-pressure liquid chromatography using a reverse phase column. Conversion of the compounds of the general formula 10 or 12 in which the Y functional group is an arylnitrile to the amino esters 13 can be achieved by allowing the arylnitriles 10 or 12 to react with dicobalt octacarbonyl in the presence of trimethylsilane. The reduction of a benzonitrile to a benzylamine is a known reaction (Murai, T.; Sakane, T.; Kato, S. Tetrahedron Lett. 26: 5145-5148[1985]) and is generally carried out in an inert solvent, such as toluene or the like, at 60 ^* C for 20 hours with an 8 molar percent of dicobalt octacarbonyl and a 10 fold excess of trimethylsilane. The solvent is evaporated and the resulting material diluted with methanol and allowed to react with a 5 fold excess of potassium fluoride. The products are then isolated by solvent extraction and further purified high-pressure liquid chromatography using a reverse phase column. Conversion of the compounds of the general formula 10 or 12 in which the Y functional group is a nitroarene, to tine amino ester 13 can be executed by a selective reduction (Bellamy, F.D.; Ou, K. Tetrahedron Lett. 25: 839-842[1984]). The reaction is generally run with a five molar excess of stannous chloride dihydrate in either ethyl acetate or ethanol as the solvent at temperatures between about 50 and 100°C for times between about 15-120 minutes under an inert atmosphere, such as nitrogen. Preferably, the reaction is carried out at 70°C in ethanol for approximately 30 minutes. The products are then isolated by solvent extraction and further purified by high-pressure liquid chromatography using a reverse phase column.

Conversion of the amino esters to t eir corresponding amino acids of the structural formula I involves saponification using well known conditions and reagents. For example, an aqueous solution of a strong alkali metal base, such as sodium hydroxide, lithium hydroxide or the like, is added to an alcoholic solution of the ester. Alcohols which may be used as the solvent for this reaction may include, for example, methanol, ethanol, and isopropanol, but, methanol is preferred. The preferred base is sodium hydroxide at a concentration between about 1 to 6N, though 2N Is preferred. The reaction may be conducted at a temperature between about 0 to 50°C for times between about 10 to 60 minutes. Preferably, the reaction is carried out at room temperature for 30 minutes after which the reaction is neutralized with a concentrated solution of a strong acid, such as hydrochloric acid or the like, and the solvent evaporated. The products are isolated by high-pressure liquid chromatography using a reverse phase column.

The conversion of the amino acids to their corresponding guanidino acids of the structural formula I is a known reaction (Kim, K. Lin, Y.-L.; Mosher, H.S. Tetrahedron Lett.3183- 3186 [1988]). The reaction can be accomplished by allowing the amino acid to react with aminoiminomethanesulfonic acid. Generally, the reaction can be conducted with a equimolar to a 10 fold molar excess of aminoiminomethanesulfonic acid at temperatures between 0 to 50"C for times between about 15 to 120 minutes in a polar protic solvent, such as methanol, water or the like. The solution, prior to the addition of aminoiminomethanesulfonic acid, may be made neutral or basic by the addition of weak base, such as an alkali metal carbonate. Preferably, for alkyl amines the amino acid will be allowed to react with a 5 fold excess aminoiminomethanesulfonic acid at room temperature for 30 minutes with 5% potassium bicarbonate in water as the reaction medium, whereas for aryl amines the amino acid will be allowed to react with an equimolar amount of aminoiminomethanesulfonic acid at room temperature for 1 hour in methanol. Generally, the reaction mixture will be made acidic by the addition of a dilute solution of an acid, such as acetic acid and the solvent evaporated. The products are isolated by high-pressure liquid chromatography using a reverse phase column. Preparation of tine compounds classified as Groups 4-11 may also be prepared from the key intermediate 9. Conversion of the iodoarene 9 to a synthetic precursors of those compounds found in Groups 5-11 namely compounds 15-18, may be accomplished by a multistep reaction sequence (Scheme 4). First, the iodoarene is carbonylated in an alcoholic solvent (R'OH) under a carbon monoxide atmosphere utilizing a palladium (0) catalyst. The alcoholic solvent (R'OH) must be chosen so as to allow for the selective removal of the R' group of the diester 14. For example, when R' = CH3 and R^= tcrf-butyl, the alcoholic solvent is methanol, and this methyl ester functionality in 14 can be removed by mild basic hydrolysis to afford acid 15. The treatment of 15 with a molar equivalent of diphenylphosphoryl azide and a molar equivalent of a tertiary amine such as triethylamine at room temperature in a non-protic solvent such as dichloromethane affords the isocyanate 16. This may be hydrolyzed to the amine 17 by the addition of water to a solution of 16 in tetrahydrofuran at room temperature. Finally, conversion of the aniline 17 to its corresponding diazonium salt by treatment with nitrous acid and subsequent heating of the diazonium salt in the presence of water produces the phenol 18.

SCHEME 4

Schemes 5 and 6 depict methods that may be used to introduce the linking groups of compounds classified as Groups 4-11 onto the benzodiazepinedione nucleus. For example, preparation of the biaryl adducts 19, precursors of Group 5 type compounds, may be accomplished by allowing 9 to react with substituted aryl molecules 20, where Y and L' are defined as above, in the presence of palladium(O). Allowing the carboxylic acid 15 to react with an amine 21 or alcohol 22 in the presence of a dehydrating reagent, such as dicyclohexylcarbodiimide (DCC) or the like, will yield the amide 23 and ester 24, forerunners of Group 10 and 11 type compounds, respectively. Similarly, 25 can be prepared from the aniline

17 by reaction with a carboxylic acid 26 in tine presence of a coupling reagent, such as DCC or the like. Compounds of the general formula 25 are precursors of Group 5 type compounds. SCHEME 5

Conversion of aniline 17 into its corresponding urea 27 or carbamate 28 (Scheme 6) may be accomplished by reaction of the isocyanate 16 in the presence of an amine 21 or alcohol 22, respectively. Treatment of the phenol 18 with phosgene and an amine 21 or alcohol 22 yields the carbamate 29 and carbonate 30, respectively. Reaction of a sulfonvlhalide 32 with either the aniline 17 or phenol 18 would produce the corresponding sulfonamide 33 and sufinyl ester 34, respectively. Allowing the phenol 18 to react with an alcohol 22 in the presence of diethylazodicarboxylate and triphenylμnhophine will furnish 31, a precursor to Group 12 type compounds. The product 27 is a synthetic precursor to those compounds classified as Group 7, product 28 is a forerunner to Group 6 type compounds, product 29 will give rise to Group 8

type compounds, whereas, product 30 is a precursor to Group 9 type compounds. Products 33 and 34 are precursors to Group 15 and 16, respectively. SCHEME 6

17 J=NH ₂ 33 J=NH 1 8 J=OH 34 J=0

Scheme 7 depict methods that may be used in the preparation of the compounds classified as Groups 13, 14, 17 and 18. Diazotization of the aniline 17, by the reaction of 17 with nitrous acid, followed by treatment with sulfur dioxide in the presence of cupric chloride (Gilbert, Synthesis, 1969, 1-10) yields the sulfonyl chloride 35. Reaction of 35 with either the amine 21 or the alcohol 22 will provide the synthetic precursor to Groups 13 and 14, respectively, namely, the suphonamide 36 and sulfinyl ester 37. The diazonium salt prepared by diazotization of 17 when allowed to react with oximes in the presence of copper sulphate and sodium sufite will give tine corresponding oxime 38, which can be readily hydrolyzed to yield the aryl ketone 39 (Beech, /. Chem. Soc, 1954, 1297). Clemmensen reduction of the ketone 39 using zinc amalgam and aqueous hydrogen chloride gives rise to the benzyl adduct 40 (Vedejs, Org. React. 1975, 22, 401). The products 39 and 40 are precursors to the compounds classified as Groups 17 and 18, respectively. SCHEME 7

Each of the protected precursors 19, 23, 24, 25, 27, 28, 29, 30, 31, 33, 34, 36.37, 39, and 40 may be treated in a similar way as described above for compounds 10 and 12 (Scheme 3) to prepare the compounds encompassed by this invention.

3. Other "6-7" Fused Ring Systems

Other "6-7" fused ring systems where each T, U, or G of formula I is independently selected from NH, N, NR, C=X, CR2, CHR, CH2, CR, CH, O, S, SO, or SO2 can be prepared by methods known in the art. To provide guidance, however, specific representative synthetic routes are provided in scheme 8. It will be understood that other synthetic routes may be preferred when specific substituents or T-U-G are targeted. SCHEME 8

(IA)

8) H ₂ , Pd/C

3) H ₂ CO, Δ

(54, where R ³ =H)

1) TsCI, pyridine

4) H ₂ CO, Δ

Starting reagents employed in scheme 8 are either commercially available or readily synthesized by known procedures.

4. Isomeric Products

In products of Formula I carbon atoms bonded to four nonidentϊcal substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof. Tine syntheses described above may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods. Likewise, enantϊomeric product mixtures may be separated using the same techniques or by other methods known in the art. Each of the asymmetric carbon atoms, when present in compounds of Formula I, may be in one of two configurations (R or S) and both are within the scope of the present invention. E. Pharmaceutical Compositions

The compounds described in this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this invention. Examples of such salts include ammonium, metal salts like sodium, potassium, calcium and magnesium; salts with organic bases like dicyclohexylamine, N- methyl-D-glucamfne and the like; and salts with amino acids like arginϊne or lysϊne. Salts with

inorganic and organic acids may be likewise prepared, for example, using hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, methanesulfonic, malic, maleic, fumaric and the like. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification. 5 A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, reaction of the free acid or free base form of a compound of Formula I with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble; or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid 10 or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process.

In the management of thromboembolic disorders the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions or suspensions for injectable

15 administration, and tine like. Animals in need of treatment using compounds of this invention can be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from animal to animal and be dependent upon such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

20 Dosage formulations of the nonpeptidyl inhibitors of the present invention are prepared for storage or administration by mixing the inhibitor having the desired degree of purity with physiologically acceptable carriers, excipients, or stabilizers. Such materials are non-toxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts; antioxidants such as ascorbic

25 acid; low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidinone; amino acids such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, or dextrins; chela ting agents such as EDTA; sugar alcohols such as mannitol

30 or sorbitol; counterions such as sodium and /or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol.

Dosage formulations of tine nonpeptidyl inhibitors of the present invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes such as 0.2 micron membranes. Nonpeptidyl inhibitor 35 formulations ordinarily will be stored in lyophilized form or as an aqueous solution. The pH of

♦ _* the cyclic inhibitor preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by hypodermic injection needle, other methods of

administration are also anticipated such as suppositories, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches.

Therapeutic nonpeptidyl inhibitor formulations generally are paced into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pϊerceable by hypodermic injection needle.

Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular nonpeptidyl inhibitor of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will naturally be influenced by the route of administration. For injection by hypodermic needle it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absorption efficiency must be individually determined for each inhibitor by methods well known in pharmacology.

The range of therapeutic dosages is from about 0.001 nM to 1.0 mM, more preferably from 0.1 nM to 100 mM, and most preferably from 1.0 nM to 50 mM. Typical formulation of compounds of Formula I as pharmaceutical compositions are discussed below.

About 0.5 to 500 mg of a compound or mixture of compounds of Formula I, as the free acid or base form or as a pharmaceutically acceptable salt, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., as called for by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained.

Typical adjuvants which may be incorporated into tablets, capsules and the like are a binder such as acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent like corn starch or alginic acid; a lubricant such as magnesium stearate; a sweetening agent such as sucrose or lactose; a flavoring agent such as peppermint, wintergreen or cherry- When the dosage form is a capsule, in addition to the above materials it may also contain a liquid carrier such as a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. A syrup or elixir may contain the active compound, a sweetener such as sucrose, preservatives like propyl paraben, a coloring agent and a flavoring agent such as cherry. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. Buffers, preservatives, antioxidants and tine like can be incorporated according to accepted pharmaceutical practice.

F. Platelet Inhibition Assays

Evaluation of the Formula I inhibitors of the fibrinogen-platelet interaction is guided by in vitro receptor binding assays and in vitro platelet aggregation inhibition assays.

In-vitro biological activity of the compounds of Formula I are monitored using a modified fibrinogen-GPIIbllla ELISA based on the method of Nachman and Leung (/. Clin. Invest. 69:263-269 (1982)) which measures the inhibition of fibrinogen binding to purified human platelet GPIIblUa receptor. Human fibrinogen is prepared by the method of Lipinska, et al. (/. Lab. Clin. Med. 84:509-516 (1974)). Platelet GPIIblUa is prepared by the method of Fitzgerald, et al, Anal. Biochem.,151:l69-177 (1985).

Briefly, microtiter plates are coated with fibrinogen (10 mg/ml) and then blocked with TACTS buffer containing 0.5% bovine serum albumin (BSA). (TACTS buffer contains 20mM Tris.HCl, pH 7.5, 0.02% sodium azide, 2 mM calcium chloride, 0.05% Tween 20, 150 mM sodium chloride.) The plate is washed with phosphate buffered saline (PBS) containing 0.01% Tween 20 and the sample to be determined added, followed by addition of solubilized GP Ilbllla. receptor (40 mg/ml) in TACTS, 0.5% BSA. After incubation, the plate is washed and 1 mg/ml of murine anti-platelet monoclonal antibody AP3 ( Newman et al, Blood 65:227-232 (1985)) is added. After another wash a goat anti-mouse IgG conjugated to horseradish peroxidase is added. A final wash is performed and developing reagent buffer (10 mg o- phenylenediamine dihydrochloride, 0.0212% hydrogen peroxide, 0.22 mM citrate, 50 mM phosphate, pH 5.0) is added and then incubated until color develops. The reaction is stopped with IN sulfuric acid and the absorbance at 492 nm is recorded.

In addition to the GPIIbHI _a ELISA assay, platelet aggregation assays may be performed in human platelet rich plasma (PRP). Fifty milliliters of whole human blood (9 parts) is drawn on 3.6% sodium citrate (1 part) from a donor who has not taken aspirin or related medications for at least two weeks. Tine blood is centrifuged at 160 x g for 10 min at 22° C and then allowed to stand for 5 min after which the PRP is decanted. Platelet poor plasma (PPP) is isolated from the remaining blood after centrifugation at 2000 x g for 25 min. The platelet count of the PRP is adjusted to ca. 300,000 per microliter with PPP.

A 225 mL aliquot of PRP plus 25 mL of either a dilution of tine test sample or a control (PBS) is incubated for 5 min in a Chrono-log Whole Blood Aggregometer at 25 C. An aggregating agent (collagen, 1 mg/ml; U46619, 100 ng/ml; or ADP, 8 mM) is added and the platelet aggregation recorded. Without further description, it is believed that one of ordinary skill in tine art can, using the preceding description and illustrative examples, make and utilize the present example to the fullest extent. The following working examples therefore, specifically point out preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

EXAMPLES

l-methyl- -(2-carboxyethyl)-7-(5-amino-l-pentynyl)-3,4-dihydro-lH-l,4- benzodiazepine-

2,5-dione trifluoracetate. a) To a mechanically stirred solution of 26.3 grams of 5-iodo-2-amino benzoic acid (0.1 mol), 10.6 grams of sodium carbonate (0.1 mol), and 250 mL water, cooled to 0°C, was slowly added, via an addition funnel, 80mL of a 1.93M solution of phosgene in toluene. After 2 hours, the precipitated product was isolated by filtration. The solids were washed with 200mL water, 300mL of a 1:1 mixture ethanol and ether, 200mL of ether, and dried under vacuum to yield 24.3 grams (84%) of 5-iodoisatoic anhydride (264-268'C, decomposition).

b) A magnetically stirred solution of 5 grams of 5-iodoisatoic anhydride (0.0173 mol), 5.85 grams of b-alanine benzyl ester tosylate (0.0173 mol), 35mL pyridine, and 0.5 of dimethylaminopyridϊne (0.0041 mol) was heated to 80°C for 2 hrs. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was dissolved in lOOmL ethyl acetate and washed 2X50mL of 10% cupric sulfate, lX50mL sat. sodium bicarbonate, IX 50mL brine, dried over sodium sulfate, filtered and concentrated in vacuo. The product was further purified by column chromatography, using silica gel, eluting with a 1:1 mixture of ethyl acetate and hexane (TLC, Siθ2, 1:1 EtOAc/hexane, Rf=0.65, un positive) to yield 1.85 grams (25%) of N-(2-amino-5-ϊodobenzoyl)-b-alanine benzyl ester. H NMR (CDCI3 , dTMS) 7.54 (IH, d, JHH = 2Hz, Ar-H o-CON), 7.42 (IH, dd, ³ JHH=9Hz, CONH), 6.46 (IH, d, ³ JHH=9Hz, Ar-H m-CON), 5.16 (2H, s, OCH2), 3.68 (2H, q, ³ jHH=6Hz, NCH2), 2.69 (2H, t, ³ JHH=6Hz, CH2CO2). ¹³ C NMR (CDCl3,dTMS) 172.4, 167.8, 148.2, 140.6, 135.6, 135.5, 128.7, 128.4, 128.3, 119.3, 118.1, 76.3, 66.7, 35.2, 34.0.

Using the above procedure, but substituting the appropriate 3-aminoproprionate alkyl ester for b-alanine ethyl ester and N-substϊtuted-5-iodo-isatoic anhydride for 5- iodoisatoic anhydride there may be prepared, for example, the following compounds: ethyl N-(2-amino-5-iodobenzoyl)-3-amϊno-3-methylpropanoate, ethyl N-(2-amino-5-iodobenzoyl)-3-amino-3-phenylpropanoate,

ethyl N-(2-amino-5-iodobenzoyl)-3-amino-3-(3-(methoxycarbonyl)phen yl)propanoate, r-butyl N-[N-(2-amino-5-iodobenzoyl)-L-(b-benzyl)-aspartinate, ethyl N-[N-(2-amino-5-iodobenzoyl)-L-aspartyl-(b-benzyl ester )]-glycinate, ethyl N-[N-(2-amino-5-iodobenzoyl )-L-aspartyl-(b-benzyl ester)]-valinate, ethyl N-[N-(2-amino-5-iodobenzoyl)-L-aspartyl-(b-benzyl ester)]-phenylalaninate, ethyl N-(2-(N-methyl)-amino-5-iodobenzoyl)-3-amino-3-methylpropano ate, ethyl N-(2-(N-methyl)-amino-5-iodobenzoyl)-3-amino-3-phenylpropano ate, ethyl N-(2-(N-methyl)-amino-5-iodobenzoyl)-3-amino-3-(3-

(methoxycarbonyl)phenyl)propanoate, t-butyl N-[N-[2-(N-methyl)-amino-5-iodobenzoyl]-(±)-(b-benzyl)-aspa rtinate, ethyl N-[N-(2-(N-methyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b-ben zyl ester)]-glycinate, ethyl N-[N-(2-(N-methyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b-ben zyl ester )]-valinate, ethyl N-[N-(2-(N-methyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b-ben zyl ester)]- phenylalaninate, ethyl N-(2-(N-phenyl)-amino-5-iodobenzoyl)-3-amino-3-methylpropano ate, ethyl N-(2-(N-phenyl)-amino-5-iodobenzoyl)-3-amino-3-phenyIpropano ate, ethyl N-(2-(N-phenyl)-amino-5-iodobenzoy])-3-amino-3-[3-

(methoxycarbonyl)phenyl]propanoate, f-butyl N-[N-[2-(N-phenyl)-amino-5-iodobenzoyl]-(±)-(b-benzyl)-aspa rtinate, ethyl N-[N-(2-(N-phenyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b-ben zyl ester)]-glycinate, ethyl N-[N-(2-(N-phenyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b-ben zyl ester )]-valinate, ethyl N-[N-(2-(N-phenyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b-ben zyl ester)]- phenylalaninate, ethyl N-(2-(N-benzyl)-amino-5-iodobenzoyl)-3-amino-3-methylpropano ate, ethyl N-(2-(N-benzyl)-amino-5-iodobenzoyl)-3-amino-3-phenylpropano ate, ethyl N-(2-(N-benzyl)-amino-5-iodobenzoyl )-3-amino-3-(3-

(methoxycarbonyl)phenyl)propanoate, f-butyl N-[N-[2-(N-benzyI)-amino-5-iodobenzoyl]-(±)-(b-benzyl)-aspa rtinate, ethyl N-[N-(2-(N-benzyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b-ben zyl ester)]-glycinate, ethyl N-[N-(2-(N-benzyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b-ben zyl ester)]-valinate, ethyl N-[N-(2-(N-benzyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b-ben zyl ester)]- phenylalaninate, ethyl N-(2-(N-isopropyl)-amino-5-iodobenzoyl)-3-amino-3-methylprop anoate, ethyl N-(2-(N-isopropyl)-amino-5-iodobenzoyl)-3-amino-3-phenylprop anoate, ethyl N-(2-(N-isopropyl)-amino-5-iodobenzoyl)-3-amino-3-(3-(methox ycarbonyl)phenyl) propanoate, t-butyl N-[N-[2-(N-isopropyl)-amino-5-iodobenzoyl]-(±)-(b-benzyl)-a spartinate, ethyl N-[N-(2-(N-isopropyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b- benzyl ester)]- glycinate,

ethyl N-[N-(2-(N-isopropyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b- benzyl ester)]- valϊnate, ethyl N-[N-(2-(N-isopropyl)-amino-5-iodobenzoyl)-(±)-aspartyl-(b- benzyI ester)]- phenylalaninate,

c) A magnetically stirred solution of 0.848gram of N-(2-amino-5-iodobenzoyl)-b- alanine ethyl ester (2.0 mmol), 0.35mL 2,6-lutidine (3,0 mmol), 0.19mL methyl iodide (3.0 mmol), and 15mL dimethylformamide was heated to 50'C for 15 hours. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was dissolved in 75mL ethyl acetate and washed lX50mL 10% citric acid, lX50mL sat. sodium bicarbonate, lX50mL brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 35/65 ethyl acetate/hexane to 65/35 ethyl acetate/hexane (TLC, Siθ2, 1:1 EtOAc/hexane, Rf=0.84, un positive) to yield 305 mgs (35%) of N-(2-methylamino- 5-iodobenzoyI)-b-alanine benzyl ester . ^λ NMR (CDCI3 , dTMS) 7.56 (2H, m, Ar-H o,p-

CON), 7.43 (IH, bq, NHMe), 7.38-7.32 (5H, s, ArH Ph), 6.62 (1H bt, ³ JHH=6HZ, CONH), 6.42 (IH, d, ³ JHH=9HZ, Ar-H -CON), 5.16 (2H, s, OCH2), 3.64 (2H, q, ³ jHH=6Hz, NCH2), 2.81 (3H, d, NCH3), 2.64 (2H, t, ³ JHH=6Hz, CH2CO2). ¹³ C NMR (CDCI3, dTMS) 172.4, 168.4, 148.8, 141.0, 135.5, 128.7, 128.4, 128.3, 117.3, 113.4, 74.1, 66.7, 35.2, 34.0, 29.6.

d) To a magnetically stirred solution of 0.305 grms of N-(2-methylamino-5- iodobenzoyl)-b-alanϊne benzyl ester (0.69 mmol), 3 mL methylene chloride, and 0.144mL triethylamine (1.04 mmol), cooled to -30°C under an atmosphere of nitrogen was slowly added 0.09 mL of a-bromoacetylbromϊde (1.04 mmol) as a solution in 2mL methylene chloride. The reaction mixture was allowed to warm to room temperature and stir for 2 hours. The mixture was diluted with 40mL methylene chloride and washed with 1X50 10% citric acid, 1X50 sat. sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was dissolved in 3mL dimethylformamide and added, via an addition funnel, to a slurry of 25 mgs sodium hydride (1.04 mmol) in 2mL dimethylformamide that was cooled to 0"C. After 2 hours, the mixture was poured over 50mL of an ice cooled solution of 10% citric acid and extracted with 3X40mL ethyl acetate. The combined organic layers were washed with lX50mL sat. sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 40:60 ethyl acetate/hexane to 70:30 ethyl acetate/hexane to yield 0.16 gms (49%) of l-methyl-4-(2-carboxyethyl)-7-iodo-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione benzyl ester (TLC, SΪO2, 1:1 ethyl acetate/ hexane, Ar-H o-CON), 7.78 (IH, dd, ⁴ jHH=2Hz, ³ JHH=9HZ, Ar-H p-CON), 6.90 (IH, d, ³ J _H H=9Hz, Ar-H m-CON), 5.1

(2H, s, OCH2), 3.92 (IH, d, ² JHH=14HZ, COCHHN), 3.90 (2H, t, ³ J _H H=8Hz, NCH2),3.82 (IH, d,

CHHCO2), 2.68 (IH, dt, CHHCO ₂ ).

Using the above procedure, but substituting the appropriate N-(2-amino-5- iodobenzoyl)-b-alanine alkyl ester for N-(2-methylamino-5-iodobenzoyl)-b-alanine benzyl ester and a-substituted-a-halo acetyl halide for a-bromo acetyl bromide there may be prepared, for example, the following compounds: l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-iodo-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-iodo-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-rhethyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7- iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s ucciny])]-7-iodo-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-iodo-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-iodo-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-r-butoxy-4-benzyloxy)succinyI)]-7-i odo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-iodo-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-iodo-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-proρyI)-7-iodo-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-i odo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyvalinyI-4-benzyloxy)succinyl) ]-7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-iodo-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-iodo-3,4- dihydro-lH-l,4- benzodiazepine-2,5-dione, l-isopropyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-iodo-3,4- dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-isopropyI-4-[2-(l-f-butoxy-4-benzyIoxy)succinyl)]- 7-iodo-3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxygIycinyl-4-benzyloxy)su ccinyl)]-7-iodo-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)suc cinyl)]-7-iodo-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione, (±)-l-ϊsopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-iodo-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione, l-methyI-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-iod o-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, l-methyl-3-phenyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-iod o-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dϊone,

(±)-l-methyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succ� �nyl)]-7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyIoxyglycinyl-4-benzyl oxy)sucάnyl)J-7-iodo-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyI-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succϊnyl)]-7-iodo-3,4- dihydro-3-phenyl-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylaIanyI-4-be nzyloxy)succinyI)]-7-iodo-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione, l,3-dϊphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-iodo-3, 4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione, l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-iodo-3,4 -dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)] -7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succ inyl)]-7-iodo-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione,

(±)-l,3-dϊphenyl-4-[2-(l-benzyloxyvalϊnyl-4-benzyloxy) succinyl)]-7-iodo-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-iodo-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-iod o-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-iod o-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-iodo-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-iodo-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyIoxyphenylalanyl-4-be nzyloxy)succinyl)]-7-iodo-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7- iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7- iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-r-butoxy-4-benzyloxy)su ccinyl)]-7-iodo-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyI-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-ben zyloxy)succinyl)]-7-iodo-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benz yloxy)succinyl)]-7-iodo-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-iodo-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

e) To a magnetically stirred solution of 9.13 grams hex-5-ynoic acid (0.081 mol), 7.12mL triethylamine (0.051 mol), 30mL terf-butanol, was added 17.7mL diphenylphosphoryl azide (0.082 mol) and the mixture heated to reflux for 3 hours. The reaction mixture was allowed to cool to room temperature and poured over a biphasic mixture of 200mL water and 200mL ether. The layers were separated and the organic layer was washed lX50mL 5% ethylene- diaminetetraacetic acid disodium salt, lX50mL 10% sodium bicarbonate, lX50mL brine, dried over magnesium sulfate and activated carbon, filtered and concentrated in vacuo. The resulting residue was further purified by column chromatography, using silica gel, eluting with 1:1 ether/hexane (TLC, SiQ2, 1:3 ethyl acetate/hexane, Rf=0.18, ninhydrin char) to yield 3.8 grams (25%) N-boc-5-amino-l-pentyne. ^! H NMR (CDCI3 , dTMS) 4.65 (IH, bs, NH), 3.22 (2H, q, J _HH =6Hz, NCH2), 2.23 (2H, dt, ³ J _H H=6Hz, ⁴ JHH=3Hz, CH2CJC), 1.98 (IH, t, 4j _HH =3Hz, CJ ^' CH), 1.73 (2H, p, ³ J _H H=6Hz, CH ₂ ), 1.42 (9H, s, f-Bu)

f) To a magnetically stirred solution of 160mgs l-methyl-2-(carboxyethyl)-7-iodo-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione benzyl ester (0.335mmol) in 5mL ethyl acetate, degassed of oxygen, under an atmosphere of nitrogen was added 123mgs N-boc-5-amino-l- pentyne (0.67mmol), lOmgs bis-tripheήylphosphine palladium dichloride (0.014mmol), 5mgs cuprous iodide (0.026mmol) and 0.233mL triethylamine (1.675mmol). After 2 hours, the reaction mixture was diluted with 50mL ethyl acetate and washed 2X50mL 10% citric acid, 2X50mL sat. sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 50:50 ethyl acetate/hexane to 75:25 ethyl acetate/hexane (TLC, Siθ2, 1:1 ethyl acetate/ hexane, Rf=0.39, un positive) to yield 90mgs (50%) 1-methyl- 4-(2-carboxyethyl)-7-(N-boc-5-amino-l-pentynyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5- dione ethyl ester. *H NMR (CDCI3 , dTMS) 7.85 (IH, d, ⁴ J _HH =2Hz, Ar-H o-CON), 7.48 (IH, dd, ⁴ JHH=2Hz, ³ jHH=8Hz, Ar-H p-CON), 7.32 (5H, s, Ph), 7.06 (IH, d, ³ jHH=8Hz, Ar-H 7H-CON), 5.10 (2H, s, OCH ₂ ), 4.67 (IH, bs, NH), 3.95 (IH, d, ² J _HH =l5Hz, NCHHCO), 3.91 (2H, t, ³ JHH=7Hz, NCH2), 3.81 (IH, d, ² J _HH =l5Hz, NCHHCO), 3.29 (3H, s, NCH3), 3.26 (2H, q, ³ jHH=7Hz, B0CNHCH2), 2.82 (IH, dt, CHHCO2), 2.69 (IH, dt, CHHCO2), 2.46 (2H, t, ³ JHH=7HZ, CJCCH2), 1.78 (2H, p, ³ JHH=7Hz, CH2CH2CH2). Using the above procedure, but substituting the appropriate 7-iodo-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dϊone for l-methyl-2-(carboxyethyl)-7-iodo-3,4-dihydro-lH-l,4- benzodϊazepme-2,5-dϊone benzyl ester and alkyne for N-boc-5-amino-l-pentyne there may be prepared, for example, the following compounds: l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-(N-Boc)-a mino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-(N-Boc)-a mino-l-pentyne]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-methyI-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 5-(N-Boc)-amino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyI-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone,

(±)-l-methyI-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone, l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-(N-Boc)-a mino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[5-(N-Boc)-a mino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[5-( N-Boc)-amino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-(N-Boc)-a mino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-(N-Boc)-a mino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[ 5-(N-Boc)-amino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-(N-Boc )-amino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-(N-Boc )-amino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 5-(N-Boc)-amino-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazeρine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)su ccinyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)suc cinyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzylox y)succinyl)]-7-[5-(N-Boc)-amino- l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-cyano-l-p entyne]-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[5-cyano-l-p entyne]-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-f-butoxy-4-benzyloxy)sιιccinyl)]- 7-[5-cyano-l-pentyne]-3,4-dihydro- lH-l,4-benzodiazeρine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyI )]-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy)succinyl) ]-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyphenylalanyI-4-benzyloxy)succ inyl)]-7-[5-cyano-l-pentyne]-

3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione, l-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)-7-t5-cyano-l-p enryne]-3,4-dihydro-lH- l,4-benzodϊazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-ρhenyl-3-oxo-l-propyl)-7-t5-cyano-l- pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dϊone,

(±)-l-phenyl-4-t2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[ 5-cyano-l-pentyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-t2-(l-benzyIoxyglycinyI-4-benzyloxy)succi nyl)]-7-[5-cyano-l-penryne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-t2-(l-benzyIoxypheny!alanyl-4-benzyloxy)s uccinyl)]-7-[5-cyano-l-pentyneI- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyI-3-oxo-l-proρyl)-7-[5-cyano-l- pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dϊone, l-benzyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)-7-[5-cyano-l-p entyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succϊnyl)]-7- [5-cyano-l-pentyne]-3,4-dihydro-lH- l,4-benzodiazepϊne-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyglycϊnyl-4-benzyIoxy)succϊn yl)]-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyI-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy)succin yI)]-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyIoxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[5-cyano-l-pentyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyI-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-cyano- l-pentyne]-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-cyano- l-pentyne]-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione, (±)-l-isopropyI-4-[2-(l-f-butoxy-4-benzyIoxy)succinyl)]-7-[ 5-cyano-l-pentyne]-3,4-dihydro- lH-l,4-benzodiazepϊne-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxygIycinyl-4-benzyloxy)su ccinyl)l-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzylox y)succinyl)]-7-[5-cyano-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[2-(3-cyanop henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(3-cyanop henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 2-(3-cyanophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methy]-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy!oxy)succ inyl)]-7-[2-(3-cyanophenyl)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-etlnoxy-l-metlnyl-3-oxo-l-propyl)-7-[2-(3-cyan ophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(3-cyanop henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 2-(3-cyanophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyglycinyI-4-benzyloxy)succi nyl)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[2-(3-cyanophenyl)- l-ethyne]-3,4-d ihydro-1 H-l ,4-benzod iazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(3-cyanop henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5- ione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(3-cyanop henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 2-(3-cyanophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yI)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyIoxyphenyIaIanyl-4-benzyIoxy)succ inyl)]-7-[2-(3-cyanophenyl)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyI-4-(3-ethoxy-l-methyI-3-oxo-l-propyI)-7-[2-(3-cya nophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(3-cya nophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]- 7-[2-(3-cyanophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)su ccinyl)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyI-4-[2-(l-benzyIoxyvalinyl-4-benzyloxy)suc cinyl)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyphenyIalanyI-4-benzylox y)succinyl)]-7-[2-(3- cyanophenyl)-l-etInyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2 ,5-dione, l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(4-nitrop henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone, l-methyl-4-(3-ethoxy-I-phenyl-3-oxo-l-propyl)-7-[2-(4-nitrop henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-t-butoxy-4-benzyloxy)succϊnyl)]-7- [2-(4-nitrophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyvalinyI-4-benzyloxy)succin yI)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyIoxyphenylaIanyl-4-benzyIoxy)succ inyl)]-7-[2-(4-nitrophenyl)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyI-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[2-(4-nitrop henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)-7-[2-(4-nitrop henyI)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-dϊone,

(±)-l-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 2-(4-nitrophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyI-4-[2-(l-benzyIoxyglycinyl-4-benzyloxy)succi nyl)]-7-t2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyphenylaIanyl-4-benzyloxy)s uccϊnyl)]-7-[2-(4-nirrophenyl)- 1 -ethyne]-3,4-d ihyd ro-1 H-l ,4-benzod iazep ϊne-2,5-dione,

l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(4-nitrop henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(4-nitrop henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[2-( 4-nitrophenyl)-l-ethyne]-3,4- dihyd ro-lH-l,4-benzodiazepine-2,5-d ione,

(±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazeρine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-d ihyd ro-1 H-l ,4-benzod i azepine-2,5-d ione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[2-(4-nit rophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(4-nit rophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-r-butoxy-4-benzyloxy)succinyl)]- 7-[2-(4-nitrophenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)su ccinyl)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyI-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)suc cinyl)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihyd ro-1 H- 1 ,4-benzod i azepine-2,5-d ione,

(±)-l-isopropyl-4-[2-(l-benzyloxyphenylaIanyl-4-benzylox y)succinyl)]-7-[2-(4- nitrophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[N-[2-(N-Boc )-aminoethane]-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-pheny]-3-oxo-l-propyl)-7-[N-[2-(N-Boc )-aminoethane]-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ N-[2-(N-Boc)-aminoethane]-3- keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione,

(±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-ρropyn-3-amine]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[N-[2-(N-Boc )-aminoethane]-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[N-[2-(N-Boc )-aminoethane]-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyI-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ N-[2-(N-Boc)-aminoethane]-3- keto-l-propyn-3-amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2, 5-dione, (±)-l-phenyl-4-[2-(l-benzyIoxyglycinyl-4-benzyloxy)succinyl )]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyΛ'aIϊnyl-4-benzyloxy)succin yl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyI-4-benzyloxy)succ inyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[N-[2-(N-Boc )-aminoethane]-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[N-[2-(N-Boc )-aminoethane]-3-keto-l- propyn-3-amϊne]-3,4-dϊhydro-lH-l,4-benzodiazepϊne-2,5-dio ne, (±)-l-benzyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyI)]-7-tN-[ 2-(N-Boc)-aminoethane]-3-keto- l-propyn-3-amine]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dio ne, (±)-l-benzyl-4-[2-(l-benzyIoxyglycinyl-4-benzyloxy)succinyl )]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyI-4-[2-(l-benzyloxyvaIinyl-4-benzyIoxy)succinyl) ]-7-[N-[2-(N-Boc)- aminoethaneJ-3-keto-l-propyn-3-amϊne]-3,4-dihydro-lH-l,4-be nzodϊazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[N-[2-(N- Boc)-amϊnoethane]-3-keto- l-propyn-3-amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dio ne, l-isopropyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)-7-[N-[2-(N- Boc)-aminoethane]-3-keto- l-propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e,

(±)-l-isopropyl-4-[2-(l-t-butoxy-4-benzyIoxy)succinyl)]- 7-[N-[2-(N-Boc)-aminoethane]-3- keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-isopropyI-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[N-[2-(N-Boc)- aminoethanej-S-keto-l-propyn-S-aminej-S^-dihydro-lH-l^-benzo dϊazepϊne^S-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy)succin yl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyIoxyphenylalanyl-4-benzyloxy)s uccinyI)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-proρyιn-3-amine]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[3-keto-l-pr opyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[3-keto-l-pr opyn-3*[4-(N-Boc)-l- piperizine]l-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[3-k eto-l-propyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one, (±)-l-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[3-keto-l-propyn-3- [4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[3-keto-l-pr opyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[3-keto-l-pr opyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[ 3-keto-l-propyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[3-keto-l-propyn-3- [4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[3-keto-l-pr opyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-etlnoxy-l-phenyl-3-oxo-l-propyl)-7-[3-keto-l-p ropyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[3-k eto-l-propyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l-benzyI-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[3-keto-l-propyn-3- [4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, l-isopropyl-4-(3-ethoxy-l-metlnyl-3-oxo-l-propyl)-7-[3-keto- l-propyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-plnenyl-3-oxo-l-propyl)-7-[3-keto- l-propyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dilnydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]- 7-[3-keto-l-propyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyI-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[3-keto-l-propyn-3-[4- (N-Boc)-l-piperizϊne]]-3,4-dihydro-lH-l,4-benzodiazepine-2, 5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxy'alϊnyl-4-benzyIoxy)succi nyI)]-7-[3-keto-l-propyn-3-[4- (N-Boc)-l-pϊperizϊne]]-3,4-dϊhydro-lH-l,4-benzodϊazepine -2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyIoxyphenylalanyl-4-benzyIoxy)s uccinyl)]-7-[3-keto-l-propyn- 3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepin e-2^-dione, l-methyI-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-[2-(N-Boc )aminoethanethioI]-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-[2-(N-Boc )aminoethanethiol]-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyI)J-7-[ 2-t2-(N-Boc)aminoethanethioI]-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyglycinyI-4-benzyIoxy)succinyI )]-7-[2-[2-(N- Boc)aminoethanethϊol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodia zepϊne-2,5-dione, (±)-l-methyI-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[2-[2-(N-

Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyIoxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, l-phenyI-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-t2-(N-Boc )aminoethanethiol]-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)-7-[2-[2-(N-Boc )aminoethanethiol]-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyI-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[ 2-[2-(N-Boc)aminoethanethiol]-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyI-4-[2-(l-benzyloxyglycinyl-4-benzyIoxy)succinyI )]-7-[2-[2-(N-

Boc)aminoethanethiol]-l-ethyne]-3,4-dϊhydro-lH-l,4-benzo diazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzy!oxyvalinyl-4-benzyIoxy)succinyI) ]-7-[2-[2-(N- Boc)aminoethanethϊol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodia zepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyI-4-benzyloxy)succ inyl)]-7-[2-[2-(N- Boc)aminoethanethϊol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodia zepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[2-[2-(N-Boc )aminoethanethiol]-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-[2-(N-Boc )aminoethanethiol]-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione, (±)-l-benzyl-4-[2-(l-t-butoxy-4-benzyloxy)succϊnyl)]-7-[2- [2-(N-Boc)aminoethanethiol]-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyIoxy)succinyl )]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-[2-(N- Boc)aminoethanethiol]-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-[2-(N- Boc)aminoethanethiol]-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]- 7-[2-[2-(N-Boc)aminoethanethiol]- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)su ccinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(4-cyanot hiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(4-cyanot hiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(+)-l-methyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[2 -(4-cyanothiophenol)-l-ethyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[2-(4-cyanothiophenol)-l- ethyne]-3,4-d ihydro-1 H-l ,4-benzodiazepine-2,5-d ione, (±)-l-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazeρine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4 dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(4-cyanot hiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(4-cyanot hiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 2-(4-cyanothiophenol)-l-ethyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione,

(±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(4-cyanot hiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(4-cyanot hiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-t 2-(4-cyanothiophenol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone, (±)-l-benzyl-4-[2-(l-benzy!oxyphenylalanyI-4-benzyloxy)succ inyI)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dione, l-ϊsopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[2-(4-cy anothiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(4-cya nothiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-dione,

(±)-l-isopropyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]- 7-[2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)su ccinyl)]-7-[2-(4-cyanothiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyvalinyI-4-benzyloxy)suc cinyl)]-7-[2-(4-cyanothiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione, (±)-l-ϊsopropyl-4-[2-(l-benzyloxyphenylaianyl-4-benzyloxy) succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dϊone, l-methyI-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)-7-[4-[2-(N-Boc )amϊno-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[4-[2-(N-Boc )amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-methyI-4-[2-(l-f-butoxy-4-benzyloxy)succinyI)]-7-[4-[ 2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2^-dione, (±)-l-methyl-4-[2-(l-benzyloxyglycϊnyl-4-benzyloxy)succiny l)]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-methyI-4-[2-(l-benzyloxyvaIinyl-4-benzyIoxy)succinyl) ]-7-[4-[2-(N-Boc)amino-6- methylpyrϊmidine-4-yl]-4-oxa-l-butynel-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[4-[2-(N-Boc)amino- 6-methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[4-[2-(N-Boc )amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[4-[2-(N-Boc )amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-r-butoxy-4-benzyloxy)succinyl)]-7-[4-[ 2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[4-[2-(N-Boc)amino- 6-methylpyrimidine-4-yI]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[4-[2-(N-Boc )amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[4-[2-(N-Boc )amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[4-[ 2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[4-[2-(N-Boc)amino- 6-methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[4-[2-(N- Boc)amino-6- methyIpyrimidine-4-yI]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[4-[2-(N- Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-c-butoxy-4-benzyloxy)succinyl)]-7-[ 4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[4-[2-(N-

Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-di hydro-lH-l,4-benzodiazepine- 2,5-dione, l-methyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyI)-7-[5-[2-(N-Boc )aminopyridine-3-yI]-5- oxa-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-[2-(N-Boc )aminopyridine-3-yl]-5- oxa-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 5-[2-(N-Boc)aminopyridine-3-yl]- 5-oxa-l-penryne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione , (±)-l-methyl-4-[2-(l-benzyIoxyglycinyl-4-benzyloxy)succinyl )]-7-[5-[2-(N-

Boc)arnmopyridme-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5-dione, (±)-l-methyI-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[5-[2-(N- Boc)aminopyτidϊne-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5-dione, (±)-l-methyI-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[5-[2-(N- Boc)arninopyridϊne-3-yl]-5-oxa-l-penryne]-3,4-dihydro-lH-l, 4-benzodϊazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-[2-(N-Boc )aminopyridine-3-yl]-5- oxa-l-pentvne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-[2-(N-Boc )aminopyridine-3-yl]-5-oxa- l-penryne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-f-butoxy-4-benzyIoxy)succinyl)]-7-[5-t 2-(N-Boc)aminopyridine-3-yl]-5- oxa-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[5-[2-(N- Boc)amϊnopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4 -benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyIoxyvalinyl-4-benzyloxy)succinyl) ]-7-[5-[2-(N- Boc)amϊnopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4 -benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[5-[2-(N- Boc)aminopyτidine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4 -benzodiazepine-2,5-dione, l-benzyI-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-[2-(N-Boc )aminopyridine-3-yl]-5-oxa- l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)-7-[5-[2-(N-Boc )aminopyridine-3-yl]-5-oxa- l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyI)]-7-[ 5-[2-(N-Boc)aminopyridine-3-yI]-5- oxa-l-pentyne]-3,4-dihyd ro-IH-l,4-benzod iazepine-2,5-d ione, (±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyIoxy)succϊny l)]-7-[5-[2-(N- Boc)amϊnopyrϊdine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[5-[2-(N- Boc)aminopyridine-3-yI]-5-oxa~l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyI-4-benzy!oxy)succ inyl)]-7-[5-[2-(N- Boc)aminopyridϊne-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4 -benzodiazepine-2,5-dione, l-ϊsopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[5-[2-(N -Boc)aminopyridine-3-yl]-5- oxa-l-pentyne}-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, l-ϊsopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-[2-(N -Boc)aminopyridine-3-yl]-5- oxa-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 5-[2-(N-Boc aminopyridine-3- yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione, (±)-l-isopropyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[5-I2-(N- Boc)aminopyridine-3-yI]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy)succin yl)]-7-[5-[2-(N-

Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione, (±)-l-isoρropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy I)-7-[5-(N-Boc)-amino-l- pentyne]-3,4-d ihyd ro-1 H-l ,4-benzod iazepi ne-2,5-d ione,

(±)-l-methyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[5-(N-Boc)- amino-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyI)]-7-[5-(N-Boc)- amino-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[5-(N- Boc)-amino-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione,

(±)-l,3-diphenyl-4-(3-ethoxy-l-methy]-3-oxo-l-propyl)-7- [5-(N-Boc)-amino-l-pentyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5- (N-Boc)-amino-l-pentyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7- [5-(N-Boc)-amino-l-pentyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)s uccinyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxvvalinyl-4-benzyloxy)su ccinyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzylo xy)succinyl)]-7-[5-(N-Boc)- amino-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy I)-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succϊnyI)]-7-[5-(N-Boc)- amino-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione , (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[5-(N-Boc)- amϊno-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenyIalanyl-4-benzy loxy)succinyl)]-7-[5-(N-Boc)- amino-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-pr opyl)-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione,

(±)-l-isopropyl-3-phenyI-4-(3-ethoxy-l-phenyl-3-oxo-l-pr opyl)-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)su ccinyl)]-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-ben zyloxy)succinyl)]-7-[5-(N-Boc)- amino-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione , (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyI-4-benzyIo xy)succϊnyl)]-7-[5-(N-Boc)- amino-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ,

(±)-l-isopropyI-3-phenyl-4-[2-(l-benzyloxyphenylalanyI-4 -benzyloxy)succinyl)]-7-[5-(N- Boc)-amlno-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5 -dione, (±)-I-methyl-3-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)- 7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyIoxy)succi nyl)]-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyI-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[5-cyano-l- pentyne]-3,4-dϊhydro-lH-l,4-benzodϊazepϊne-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvaIinyl-4-benzyIo xy)succinyl)]-7-[5-cyano-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyI-4-[2-(l-benzyloxyphenylalanyl-4-be nzyIoxy)succϊnyl)]-7-[5-cyano- l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-dϊphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7 -[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone,

(±)-l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7- [5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-r-butoxy-4-benzyIoxy)succinyl)]-7- [5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone,

(±)-l,3-dϊphenyl-4-[2-(l-benzyIoxyglycϊnyl-4-benzyloxy )succinyI)]-7-[5-cyano-l -pentyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succi nyl)]-7-[5-cyano-l-pentyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-[5-cyano-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[5-cyano-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[5-cyano-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-ρhenyl-4-[2-(l-benzyloxyphenylalanyl-4-benz yloxy)succinyl)]-7-[5-cyano-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-pr opyl)-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-pr opyl)-7-[5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)su ccinyl)]-7-t5-cyano-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyI-4-[2-(l-benzyloxyglycinyl-4-ben zyloxy)succinyl)]-7-[5-cyano-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[5-cyano-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyphenylalany]-4 -benzyloxy)succinyl)]-7-[5- cyano-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propy l)-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihyd ro-1 H-l ,4-benzod iazepine-2,5-d ione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succi nyl)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyI-4-benzyloxy )succinyl)]-7-[2-(3- cyanophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy Ioxy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[2- (3-cyanophenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-dϊphenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)-7-[2 -(3-cyanophenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l^-dϊphenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)] -7-[2-(3-cyanophenyI)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l,3-dϊphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy) succinyl)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyvalinyl-4-benzyIoxy)su ccinyl)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyphenyIalanyl-4-benzy!o xy)succinyl)]-7-[2-(3- cyanophenyI)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propy I)-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyI-4-[2-(l-benzyIoxygIycϊnyl-4-benzy loxy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[2-(3- cyanophenyl)-l-efhyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenyla!anyl-4-benzy loxy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2, 5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy I)-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-pr opyl)-7-[2-(3-cyanophenyl)-l- ethynej-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyI-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)su ccinyl)]-7-[2-(3-cyanophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-ben zyloxy)succϊnyl)]-7-[2-(3- cyanophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dϊone, (±)-l-isopropyI-3-phenyl-4-[2-(l-benzyIoxyvalinyl-4-benzylo xy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-isopropyl-3-phenyI-4-[2-(l-benzyloxyphenyIalanyl-4-be nzyloxy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyI-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl )]-7-[2-(4-nitrophenyl)-l- erhyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[2-(4- nitrophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[2-(4- nitrophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione,

(±)-l-methyI-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[2-(4- nitrophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2- (4-nitrophenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2- (4-nitrophenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)] -7-[2-(4-nitrophenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)s uccinyl)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)su ccinyl)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyplnenylalanyl-4-benzyI oxy)succinyl)]-7-[2-(4- nitrophenyl)-l-ethyne]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)- 7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[2-(4- nitrophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[2-(4- nitrophenyl)-l-ethyne]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylalany]-4-benzy loxy)succinyl)]-7-[2-(4- nitrophenyl)-l-etlnyne]-3,4-dihydro-lH-l,4-benzodiazepine-2, 5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propy l)-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)su ccinyI)]-7-[2-(4-nitrophenyl)-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyI oxy)succinyl)]-7-[2-(4- nitrophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dϊone, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[2-(4- nitrophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-isopropyI-3-phenyl-4-[2-(l-benzyloxyphenyIalanyl-4-be nzyloxy)succinyl)]-7-[2-(4- nitrophenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propy I)-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amϊne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-methyI-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-methyI-3-phenyl-4-[2-(l-t-butoxy-4-benzyIoxy)succϊny l)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-methyI-3-phenyl-4-[2-(l-benzyIoxygIycϊnyl-4-benzyIox y)succinyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy) succinyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione,

(±)-l-methyI-3-phenyl-4-[2-(l-benzyIoxyphenylalanyl-4-be nzyloxy)succϊnyl)]-7-[N-[2-(N- Boc)-aminoethane]-3-keto-l-propyn-3-amϊne]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5- dione,

(±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7- [N-[2-(N-Boc)-aminoethane]-3- keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione,

(±)-l,3-dϊphenyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7 -[N-t2-(N-Boc)-amϊnoethane]-3- keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepϊne-2, 5-dione, (±)-l,3-diphenyl-4-[2-(l-f-butoxy-4-benzyloxy)succϊnyI)]-7 -[N-[2-(N-Boc)-aminoethane]-3- keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l,3-diphenyl-4-[2-(l-benzyIoxyglycinyl-4-benzyloxy)succ inyl)]-7-[N-[2-(N-Boc)- amϊnoethane]-3-keto-l-propyn-3-amϊne]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy)succi nyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dϊone, (±)-l,3-dϊphenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy )succinyl)]-7-[N-t2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dϊhydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-benzyI-3-phenyI-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)- 7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl )]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succinyl)]-7-[N-[2-(N- Boc)-aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5- dione, (±)-l-isopropyl-3-phenyI-4-(3-ethoxy-l-methy]-3-oxo-l-propy l)-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l^isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l -propyn-3-amine]-3,4-d ihyd ro-1 H-l ,4-benzodiazepine-2,5-dione, (±)-l-isopropyI-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[N-[2-(N- Boc)-aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5- dione, (+)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvaIinyl-4-benzylox y)succinyl)]-7-[N-[2-(N- Boc)-aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5- dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyplnenylalanyl- 4-benzyloxy)succinyl)]-7-[N-[2- (N-Boc)-aminoethane]-3-keto-l-propyn-3-amine]-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-(3-etlnoxy-l-phenyl-3-oxo-l-prop yl)-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one, (±)-l-methyl-3-ρhenyl-4-[2-(l-f-butoxy-4-benzyloxy)succiny l)]-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[3-keto-l- propyn-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[3-keto-l- propyn-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succinyl)]-7-[3-keto-l- propyn-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[3- keto-l-propyn-3-[4-(N-Boc)- l-piperizine]]-3,4-dihydro-lH-l,4-benzodia ^' zepine-2,5-dione,

(±)-l,3-diphenyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[3- keto-l-propyn-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)] -7-[3-keto-l-propyn-3-[4-(N-Boc)- l-pϊperizine]]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione , (±)-l,3-diphenyI-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succ inyl)]-7-[3-keto-l-propyn-3-[4- (N-Boc)-l-pϊperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2, 5-dione, (±)-l^-diphenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[3-keto-l-propyn-3-[4- (N-Boc)-l-piperizine]l-3,4-dihydro-lH-l,4-benzodiazepϊne-2, 5-dione, (±)-l,3-diphenyI-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-[3-keto-l- propyn-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperϊzine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperϊzine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione, (±)-l-benzyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl )]-7-[3-keto-l-propyn-3-[4-(N- Boc)-l-piperizϊne]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyI-4-benzyIoxy )succinyI)]-7-[3-keto-l- propyn-3-[4-(N-Boc)-l-piperϊzine]]-3,4-dϊhydro-lH-l,4-benz odiazepine-2,5-dione, (±)-l-benzyI-3-phenyI-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyI)]-7-[3-keto-l-propyn- 3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepϊ ne-2,5-dione,

(±)-l-benzyI-3-phenyl-4-[2-(l-benzyloxypheny!alanyl-4-be nzyloxy)succinyl)]-7-[3-keto-l- propyn-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-isopropyl-3-phenyI-4-(3-ethoxy-l-methyl-3-oxo-l-propy I)-7-[3-keto-l-propyn-3-[4- (N-Boc)-l-piperizme]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[3-keto-l-propyn-3-[4- (N-Boc)-I-ptperizinel]-3,4-dihydro-lH-l,4-benzodϊazepine-2, 5-dione, (±)-l-isopropyl-3-phenyI-4-f2-(l-t-butoxy-4-benzyIoxy)succi nyl)]-7-[3-keto-l-propyn-3-[4- (N-Boc)-l-piperizϊne]]-3,4-dihydro-lH-l,4-benzodiazepine-2, 5-dϊone, (±)-l-isopropyl-3-phenyl-4-t2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[3-keto-l- propyn-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyIoxyvalinyl-4-benz yloxy)succinyI)]-7-[3-keto-l- propyn-3-[4-(N-Boc)-l-pϊperizine]]-3,4-dihydro-lH-l,4-benzo diazepine-2,5-dione, (±)-l-isopropyI-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[3-keto- l-propyn-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benz odiazepine-2,5-dione, (±)-l-methyl-3-phenyI-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[2-[2-(N-

Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[2-[2-(N-

Boc)amϊnoethanethϊolH-ethyne]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl )]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy) succinyI)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2- [2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione,

(±)-l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7- [2-[2-(N-Boc)aminoethanethiol]- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7- [2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succ inyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy)succi nyl)]-7-[2-[2-(N- Boc)aminoethanethioI]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl )]-7-[2-[2-(N-

Boc)aminoethanethioI]-l-ethyne]-3,4-dilnydro-l H-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyk)xy )succinyl)]-7-[2-[2-(N- Boc)aminoetlnanethio]]-l-ethyne]-3,4-dihydro-lH-l,4-benzodia zepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyI-4-benzyloxy) succinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione,

(+)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-ben zyloxy)succinyl)]-7-[2-[2-(N- Boc)aminoetlnanetlniol]-l-ethyne]-3,4-dilnydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-plnenyl-3-oxo-l-prop yl)-7-[2-[2-(N-

Boc)aminoethanethiol]-l-etlnyne]-3,4-dihydro-lH-l,4-benzo diazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)su ccinyl)]-7-[2-[2-(N-

Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[2-[2-(N- BocJamϊnoethanethiolj-l-ethynel-S^-dihydro-lH-l^-benzodiaze pine^S-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-isopropyI-3-phenyl-4-[2-(l-benzyIoxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[2-[2- (N-Boc)aminoethanethiol]-l-ethyne]-3,4-dihydro-lH-l,4-benzod iazepine-2^-dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-t2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyI-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[2-(4-cyanothiophenoI)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyI-3-phenyl-4-[2-(l-benzyloxyglycϊnyl-4-benzy loxy)succinyl)]-7-[2-(4- cyanothioplnenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepin e-2,5-dione, (±)-l-methyl-3-phenyI-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyI)]-7-[2-(4- cyanothϊophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepin e-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succϊnyl)]-7-[2-(4- cyanothϊophenoI)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepin e-2,5-dϊone, (±)-l,3-diphenyI-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)-7-[2- (4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7- [2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-t-butoxy-4-benzyIoxy)succinyl)] -7-[2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione, (±)-l,3-dϊphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)suc cϊnyl)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dione, (±)-l,3-dϊphenyl-4-[2-(l-benzyloxyvaIϊnyl-4-benzyloxy)suc cinyl)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodtazepine -2,5-dione, (±)-l,3-dϊphenyI-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy )succinyl)]-7-[2-(4- cyanothϊoplnenoI)-l-etInyne]-3,4-dihydro-lH-l,4-benzodiazep ine-2,5-dione,

(±)-l-benzyI-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy I)-7-[2-(4-cyanothiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[2-(4-cyanothiophenoI)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-t-butoxy-4-benzylυxy)succiny l)]-7-[2-(4-cyanothiophenol)-l- ethyne] -3,4-d ihyd ro-1 H-l,4-benzod i azep ine-2,5-d ione,

(±)-l-benzyl-3-phenyl-4-[2-(I-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[2-(4- cyanothϊophenol)-l-ethyne]-3,4-dihydro-IH-l,4-benzodiazepin e-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[2-(4-cyanothiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-pr opyl)-7-[2-(4-cyanothiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)su ccinyl)]-7-[2-(4-cyanothiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-ben zyloxy)succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-bιιtyne]-3,4-dihydro-lH-l,4 -benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l -f-butoxy-4-benzyl xy)succinyl)]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-t2-(l-benzyloxyglycinyI-4-benzyloxy )succinyl)]-7-[4-[2-(N- Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihyd ro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-methyI-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[4-[2-(N- Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butvne]-3,4-dihyd ro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[4-[2-(N- Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihyd ro-lH-l,4-benzodiazepine- 2,5-dione, l(±)-,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[4- [2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-()xo-l-propy])-7-[4 -[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dilnydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7- [4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxn-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzvloxyglycinvl-4-benzyloxy)succ inyl)]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-t2-(l-benzyloxyvalinyl-4-benzyloxy)succi nyl)]-7-[4-[2-(N-Boc)amino-6- methyIpyrimidine-4-ylI-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-[4-[2-(N- Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihyd ro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[4-[2-(N-Boc)amino-6- methyIpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[4-[2-(N-Boc)amino-6- methyIpyrimidine-4-yI]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyIoxy)succinyl )]-7-[4-[2-(N-Boc)amino-6- methyIpyrimidine-4-yI]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyI-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succϊnyl)]-7-t4-[2-(N- Boc)amϊno-6-methylpyrimϊdine-4-yl]-4-oxa-l-butyne]-3,4-dih ydro-lH-l,4-benzodiazepine- 2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvaIinyl-4-benzyIoxy) succinyl)]-7-[4-t2-(N-

Boc)amϊno-6-methyIpyrϊmϊdϊne-4-yl]-4-oxa-l-butyne]-3, 4-dϊhydro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylaIanyl-4-be nzyloxy)succinyl)]-7-[4-[2-(N- Boc)amino-6-methylpyrimidϊne-4-yl]-4-oxa-l-butyne]-3,4-dϊh ydro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-isαpropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-p ropyI)-7-[4-[2-(N-Boc)amino-6- methylpyrϊmidine-4-yI]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-b enzodiazepϊne-2,5-dione, (±)-l-isopropyI-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[4-[2-(N-Boc)amino-6- methylpyrimidϊne-4-yll-4-oxa-l-butyne]-3,4-dϊhydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyIoxy)succi nyI)]-7-[4-t2-(N-Boc)amino-6- methylpyrimidϊne-4-yl]-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-isoproρyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzy loxy)succinyl)]-7-[4-[2-(N- Boc)amino-6-methylpyrϊmidine-4-yl]-4-oxa-l-butyne]-3,4-dihy dro-lH-l,4-benzodϊazepine- 2,5-dϊone, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyIoxyvalinyl-4-benzylo xy)succinyl)]-7-[4-[2-(N-

Boc)amino-6-methyIpyrimidϊne-4-yl]-4-oxa-l-butyne]-3,4-d ihydro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-ϊsopropyl-3-ρhenyl-4-[2-(l-benzyloxypheny!alanyI -4-benzyloxy)succinyI)]-7-[4-[2- (N-Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyne]-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyI-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl )]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyI)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[5-[2-(N-

Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5- [2-(N-Boc)aminopyridine-3- yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione,

(±)-l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7- [5-[2-(N-Boc)aminopyridine-3- yI]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione, (±)-l,3-diphenyl-4-[2-(l-i-butoxy-4-benzyloxy)succinyl)]-7- [5-[2-(N-Boc)aminopyridine-3- yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succ inyl)]-7-[5-[2-(N-

Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succi nyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyphenyla!anyl-4-benzyloxy) succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yI]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[5-[2-(N- Boc)aminopyridine-3-yI]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-benzyl-3-plnenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl) -7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succiny] )]-7-[5-[2-(N-

Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-benzyl-3-plnenyl-4-[2-(l-benzyloxyplnenylalanyl-4-ben zyloxy)succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[5-[2-(N-

Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)su ccinyI)]-7-[5-[2-(N-

Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione,

(±)-l-ϊsopropyI-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzy !oxy)succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[5-[2-(N- Boc)arrvinopyridϊne-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[5-[2- (N-Boc)aminopyridϊne-3-yl]-5-oxa-l-pentyne]-3,4-dihydro-lH- l,4-benzodiazepine-2,5- dione,

g) To a solution of 22mgs l-methyl-4-(2-carboxyethyl)-7-(N-boc-5-amino-l-pentynyl)- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione benzyl ester (0.0412mmol) in 0.5mL ethyl acetate was added 3mL sat. HCl in ethyl acetate. After 1 hour, the mixture was concentrated in vacuo and diluted with 2mL methanol. To the methanolic solution was added 0.5mL 2N sodium hydroxide. After 1 hour, the reaction was quenched with 3mL acetic acid, concentrated in vacuo, diluted with 3mL water and purified by high pressure liquid chromatography, using a 1 /2" C-18 reverse-phase column, eluting with a solvent gradient of 10:90 methanol(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to 50:50 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow = lOml/min (Rt=33.1 min, un detection 254nm) to yield 13mgs (92%) l-methyl-4- (2~carboxyethyl)-7-(5-amino-l-pentynyI)-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione trifluoracetate. HRMS (FAB) molecular ion m/z=344.1626 ( cald. C18H22 3O4, 344.1610). 1H NMR (D2O) 7.63 (IH, d, ⁴ ]HH, Ar-H o-CON), 7.54 (IH, dd, ⁴ JHH=2HZ, ³ JHH=8HZ, Ar- H -CON), 7.20 (IH, d, ³ J _H H=8Hz, Ar-H w-CON), 4.05 (IH, d, ² j _HH =i4Hz, NCHHCO), 4.0 (IH, m, NCHHCH2), 3.74 (IH, d, ² J _HH =l4Hz, NCHHCO), 3.59 (IH, m, NCHHCH2), 3.20 (3H, s, NCH3), 3.03 (2H, t, ³ J _H H=7Hz, NCH2), 2.59 (2H, , CH2CO2), 2.42 (2H, t, CH2CH2CH2).

Using the above procedure, but substituting the appropriate 3,4-dϊhydro-lH-l,4- benzodiazepϊne-2,5-dϊone for l-methyI-4-(2-carboxyethyl)-7-(N-boc-5-amino-l-pentynyl)- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione benzyl ester there may be prepared, for example, the following compounds: l-methyl-4-(2-carboxy-l-methylethyI)-7-(5-amino-l-pentyne)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyl)-7-(5-amϊno-l-pentyne)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succϊn-2-yl-(l-f-butoxy)J-7-(5-amino-l- pentyne)-3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-(5-amino-l-pe ntyne)-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(I-valine)]-7-(5-amino-l-pen tyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenylaianine)]-7-(5-amino-l -pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-(5-amino-l-pentyne)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyl)-7-(5-amino-l-pentyne)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5-amino-l-p entyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-gIycine)]-7-(5-amino-l-pe ntyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-(5-amino-l-pen tyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-(5-amin o-l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-d ione tri f I uoraceta te, l-benzyl-4-(2-carboxy-l-methylethyl)-7-(5-amino-l-pentyne)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyI)-7-(5-amino-l-pentyne)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5-amino-l-p entyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-(5-amino-l-pe ntyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-(5-amino-l-pen tyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-fsuccin-2-yl-(l-phenylalanine)]-7-(5-amino-l -pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-(5-amino-l-pentyne )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-(5-amino-l-pentyne )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5-amino- l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-(5-amino-l -pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyI-4-[succin-2-yl-(l-vaIine)]-7-(5-amino-l-pen tyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-(5-a mino-l-pentyne)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

l-methyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-amϊnoethane)-3 -keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-aminoethane)-3- keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-t-butoxy)]-7-[N-(2-aminoetha ne)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succϊn-2-yl-(l-glycine)]-7-[N-(2-aminoe thane)-3-keto-l-propyn-3-amine]- 3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-methyl-4-[sucdn-2-yl-(l-valine)]-7-[N-(2-aminoetha ne)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yI-(l-phenylalanine)]-7-[N-(2-a minoethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-amϊnoethane)-3 -keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyI-4-(2-carboxy-l-phenylethyl)-7-[N-(2-aminoethane)-3- keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodϊazepϊne-2,5-dϊone trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N-(2-aminoe thane)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyI-4-[succin-2-yI-(l-glycϊne)]-7-[N-(2-aminoe thane)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyI-4-[succin-2-yl-(l-valine)]-7-[N-(2-amϊnoet hane)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-fsuccin-2-yI-(l-phenylalanine)]-7-[N-(2-a minoethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methyIethyl)-7-[N-(2-aminoethane)-3- keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyI-4-(2-carboxy-l-phenyIethyl)-7-[N-(2-aminoethane)-3- keto-l-proρyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-4-[succin-2-yl-(l-f-butoxy)]-7-[N-(2-aminoe thane)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-4-[succin-2-yI-(l-glycϊne)]-7-[N-(2-aminoe thane)-3-keto-l-propyn-3-amine]- 3,4-dihydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-vaIine)]-7-[N-(2-amϊnoet hane)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-benzyI-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2-amin oethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-aminoethane) -3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-aminoethane) -3-keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-t-butoxy)]-7-[N-(2-ami noethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-aminoet hane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-amino ethane)-3-keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-( 2-aminoethane)-3-keto-l-propyn- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyn-3-(l -piρerizine)]-3,4-dihydro- lH-l;4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l-propyn-3-(l -piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-t-butoxy)]-7-[3-keto-l-propy n-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yI-(l-glycine)]-7-[3-keto-l-pro pyn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyI-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-prop yn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenyIalanine)]-7-[3-keto -l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyn-3-(l -piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyI-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l -proρyn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3-keto-l-pr opyn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l-pro pyn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-prop yn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[3-keto -l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyn-3-(l -piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l-propyn-3-(l -piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yI-(l-t-butoxy)]-7-[3-keto-l-propy n-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l-pro pyn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-propyn- 3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-phenyla!anine)]-7-[3-keto -l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyn-3 -(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l-propyn-3 -(l-piperizine)j-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-isopropyI-4-[succin-2-yI-(l-f-butoxy)]-7-[3-keto-l -propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyI-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l-pro pyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-vaIine)]-7-[3-keto-l-p ropyn-3-(l-piperϊzine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isoρropyl-4-[succin-2-yI-(l-phenylalanϊne)]-7-[3 -keto-l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyI)-7-[2-(2-aminoethanethϊ ol)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyI)-7-[2-(2-aminoethanethio l)-l-ethyne]-3,4-dihydro- lH-l,4-benzodϊazepϊne-2,5-dϊone trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-t-butoxy)]-7-[2-(2-aminoetha nethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-aminoet hanethioI)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yI-(l-valine)]-7-[2-(2-amϊnoet hanethiol)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2-a minoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-aminoethanethio l)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-amϊnoethanethi oI)-l-ethynel-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yI-(l-f-butoxy)]-7-[2-(2-aminoe thanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate.

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-aminoethan ethiol)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-aminoeth anethiol)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2-amin oethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-aminoethanethio l)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-aminoethanethio l)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-t-butoxy)]-7-[2-(2-aminoe thanethiol)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-aminoet hanethiol)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-aminoethane thiol)-l-ethyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2-a minoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-aminoethanet hiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-aminoethanet hiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-ami noethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-aminoet hanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-amino ethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-( 2-aminoethanethiol)-l-ethyne]-3,4- dihyd ro-1 H-l ,4-benzod iazepine-2,5-d ione tri f I uoraceta te, l-methyl-4-(2-carboxy-l-methylethyl)-7-[4-(2-amino-6-methylp yrimidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenyletInyl)-7-[4-(2-amino-6-methyl pyrimidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-[4-(2-amino-6-m ethylpyrimidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5- ione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[4-(2-amino-6-me thylpyrimidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-l H-l ,4-benzodiazepine-2,5- ione trifluoracetate,

(±)-l-methyl-4-[succin-2-yI-(l-valϊne)]-7-[4-(2-amino-6-me thylpyrimidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-[4-(2-a mϊno-6-methylpyrimidine-4-yl)-4- oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[4-(2-amino-6-methylp yrimidine-4-yI)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyl)-7-[4-(2-amϊno-6-methyl pyrimidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yI-(l-t-butoxy)]-7-[4-(2-amino-6-m ethylpyrimidine-4-yI)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[4-(2-amϊno- 6-methylpyrϊmidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone trifluoracetate, (±)-l-phenyI-4-[succin-2-yl-(l-valϊne)]-7-[4-(2-amino-6-me thylpyrimidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[4-(2-amin o-6-methylpyrimidine-4-yl)-4- oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, . l-benzyl-4-(2-carboxy-l-methylethyl)-7-[4-(2-amino-6-methylp yrimidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyI)-7-[4-(2-amino-6-methylp yrimidine-4-yl)-4-oxa-l- butyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yI-(l-t-butoxy)]-7-[4-(2-amϊno -6-methylpyrimidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yI-(l-glycϊne)]-7-[4-(2-amino-6-m ethylpyrimidine-4-yl)-4-oxa-l- butyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyI-4-[succin-2-yl-(l-valine)]-7-[4-(2-amϊno-6-me thylpyrimidine-4-yl)-4-oxa-l- butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyI-4-[succϊn-2-yl-(I-phenylalanine)]-7-[4-(2-am� �no-6-methylpyrimidine-4-yl)-4- oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[4-(2-amino-6-meth ylpyrimidine-4-yl)-4-oxa- l-butyne]-3,4-dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[4-(2-amϊno-6-met hylpyrimidine-4-yl)-4-oxa- l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-ϊsopropyl-4-[succin-2-yI-(l-t-butoxy)]-7-[4-(2-amino -6-methylpyrimidine-4-yl)-4-oxa- l-butyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-glycϊne)]-7-[4-(2-amino- 6-methylpyrimidine-4-yI)]-4-oxa- l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(I-valϊne)]-7-[4-(2-amϊno- 6-methylpyrimϊdine-4-yl)-4-oxa- l-butyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate.

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[4-(2-a mino-6-methylpyrimidine-4- yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[5-(2-aminopyridine-3 -yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyl)-7-[5-(2-aminopyridine-3 -yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-t-butoxy)]-7-[5-(2-aminop yridine-3-yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[5-(2-aminopy ridine-3-yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-valine)]-7-[5-(2-aminopyr idine-3-yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyI)-7-[5-(2-aminopyridine-3 -yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyl)-7-[5-(2-aminopyridine-3 -yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-i-butoxy)]-7-[5-(2-aminop yridine-3-y])-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[5-(2-aminopy ridine-3-yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-[5-(2-aminopyr idine-3-yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[5-(2-amin opyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-[5-(2-aminopyridine-3 -yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[5-(2-aminopyridine-3 -yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-f-butoxy)]-7-[5-(2-aminop yridine-3-yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[5-(2-aminopy ridine-3-yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[5-(2-aminopyridi ne-3-yl)-5-oxa-l-pentyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-phenylalanine)]-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate,

l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[5-(2-aminopyridin e-3-yl)-5-oxa-l-pentyne]- 3,4-d ihydro-1 H-l ,4-benzod iazepine-2,5-d ione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[5-(2-aminopyridϊ ne-3-yl)-5-oxa-l-pentyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-ϊsopropyl-4-[succϊn-2-yl-(l-t-butoxy)]-7-[5-(2-amin opyridine-3-yl)-5-oxa-l-pentyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-ϊsopropyl-4-[succin-2-yl-(l-glycine)]-7-[5-(2-ami nopyridine-3-yl)-5-oxa-l-pentyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-ϊsopropyl-4-[succin-2-yl-(l-vaIine)]-7-[5-(2-amϊ nopyridine-3-yl)-5-oxa-l-pentyne]- 3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succϊn-2-yI-(l-phenyIalanine)]-7-[5- (2-aminopyridϊne-3-yl)-5-oxa-l- pentyne]-3,4-dϊhydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-(5-amin o-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-(5-amϊ no-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-t-butoxy)]-7-(5- amino-l-pentyne)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yI-(l-glycϊne)]-7-(5- amino-l-pentyne)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succϊn-2-yl-(l-valine)]-7-(5-a mino-l-pentyne)-3,4-dihydro-lH- l,4-benzodϊazepine-2,5-dϊone trifluoracetate,

(±)-l-methyl-3-phenyI-4-[succin-2-yl-(l-phenylalanine)]- 7-(5-amino-l-pentyne)-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyI-4-(2-carboxy-l-methylethyl)-7-(5-amino-l-p entyne)-3,4-dihydro-lH-l,4- benzodϊazepϊne-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyI)-7-(5-amino- l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyI-4-[succin-2-yI-(l-t-butoxy)]-7-(5-amino -l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-(5-amino- l-pentyne)-3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-(5-amino-l -pentyne)-3,4-dϊhydro-lH-l,4- benzodiazepine-2^-dϊone trifluoracetate, (±)-l,3-diphenyI-4-[succin-2-yl-(l-phenylalanine)]-7-(5-ami no-l-pentyne)-3,4-dihydro-lH- l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyI)-7-(5-a mino-l-pentyne)-3,4-dihydro- lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate.

- - enzy - -p eny - - -car oxy- -p eny et y - - -am no- -pentyne - , - y ro- 1H-1 ,4-benzodiazepine-2,5-d ione tri fl uoraceta te,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5- amino-l-pentyne)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-(5-amin o-l-pentyne)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-(5-am ino-l-pentyne)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-(5-amino-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-( 5-amino-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-( 5-amino-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5- amino-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-( 5-amino-l-pentyne)-3,4-dihydro- 1H-1 ,4-benzodiazepine-2,5-d ione tri fl uoraceta te,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yI-(l-valine)]-7-(5 -amino-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine )]-7-(5-amino-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[N-( 2-aminoethane)-3-keto-l- proρyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-a minoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-r-butoxy)]-7-[N-(2- aminoethane)-3-keto-l-propyn- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-a minoethane)-3-keto-l-propyn- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyI-4-[succin-2-yl-(l-valine)]-7-[N-(2 -aminoethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyI-3-ρhenyl-4-[succin-2-yl-(l-phenylalanine)]-7- [N-(2-aminoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-methylethyI)-7-[N-(2-aminoe thane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-aminoe thane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-t-butoxy)]-7-[N-(2-amino ethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l^-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-aminoet hane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-aminoet hane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2- aminoethane)-3-keto-l-propyn- 3-amine]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-I-benzyl-3-phenyI-4-(2-carboxy-l-methyIethyl)-7-[N-(2-a minoethane)-3-keto-l- propyn-3-amιne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[N-( 2-aminoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yI-(l-f-butoxy)]-7-[N-(2- aminoethane)-3-keto-l-propyn- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-a minoethane)-3-keto-l-propyn-3- amunej-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-vaIine)]-7-[N-(2-am inoethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ N-(2-aminoethane)-3-keto-l- propyn-3-amine]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dϊon e trifluoracetate,

(±)-l-isopropyI-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[ N-(2-aminoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenyIethyl)-7-[N-( 2-aminoethane)-3-keto-l- prop)τn-3-amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dio ne trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yI-(l-r-butoxy)]-7-[N- (2-aminoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-I-isopropyI-3-phenyl-4-[succϊn-2-yl-(l-glycine)]-7-[N- (2-amϊnoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyI-3-phenyl-4-[sucdn-2-yl-(l-valϊne)]-7-tN-(2 -aminoethane)-3-keto-l- propyn-3-amine]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dion e trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yI-(l-phenylalanine )]-7-[N-(2-aminoethane)-3-keto- l-propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[3-keto -l-propyn-3-(l-piperizine)]- 3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyI-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto -l-propyn-3-(l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yI-(l-r-butoxy)]-7-[3- keto-l-propyn-3-(l-piperizine)]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dϊone trifluoracetate.

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto -l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[3-ke to-l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 3-keto-l-propyn-3-(l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-methyletlnyI)-7-[3-keto- l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l -propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3-keto- l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l -propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-pro pyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[3- keto-l-propyn-3-(l-piperizine)]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[3-k eto-l-propyn-3-(l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[3-k eto-l-propyn-3-(l-piperizine)]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3- keto-l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (+)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto- l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[3-ke to-l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-plnenylalanine)] -7-[3-keto-l-propyn-3-(l- piρerizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methyletlnyl)-7- [3-keto-l-propyn-3-(l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[ 3-keto-l-propyn-3-(l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyi-4-[succin-2-yl-Cl-i-butoxy)]-7-[3- keto-l-propyn-3-(l-piperizine)]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yI-(l-glycine)]-7-[ 3-keto-l-propyn-3-(l-piperizine)]-

3,4-dihydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[3-ke to-l-propyn-3-(l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyI-4-[succin-2-yl-(l-phenylalanine )]-7-[3-keto-l-propyn-3-(l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-a minoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-( 2-aminoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yI-(l-t-butoxy)]-7-[2- (2-aminoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyI-3-phenyI-4-[succin-2-yl-(l-glycine)]-7-[2-( 2-aminoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succϊn-2-yl-(l-valine)]-7-[2-( 2-aminoethanethioI)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 2-(2-aminoethanethiol)-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-methyiethyl)-7-[2-(2-aminoe thanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-ami noethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-am inoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-gIycine)]-7-[2-(2-ami noethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-dϊphenyI-4-[succin-2-yl-(l-valine)]-7-[2-(2-aminoe thanethiol)-l-ethyne]-3,4- dihydro-lH-I,4-benzodiazepine-2,5-dioιne trifluoracetate,

(±)-l,3-diphenyl-4-[succϊn-2-yl-(l-phenylalanϊne)]-7-[ 2-(2-aminoethanethiol)-l-ethynel- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methyIethyl)-7-[2-( 2-aminoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenyIethyl)-7-[2-( 2-aminoethanethiol)-l-ethyne]- 3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyI-4-[succin-2-yl-(l-f-butoxy)]-7-[2- (2-aminoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyI-4-[succin-2-yl-(l-glycine)]-7-[2-(2-a minoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yI-(l-valϊne)]-7-[2-( 2-aminoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 2-(2-aminoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-( 2-aminoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-( 2-aminoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-t-butoxy)]-7-[2- (2-aminoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[ 2-(2-aminoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2 -(2-aminoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-plnenylalanin e)]-7-[2-(2-aminoethanethiol)-l- ethyne]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5- ione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methyIethyl)-7-[4-(2-a mino-6-methylpyrimidine-4- yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazep)ine-2,5-d ione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenyIetlny!)-7-[4-(2- amino-6-methylpyrimidine-4- yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one trifluoracetate, (±)-l-methyI-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[4-(2- amino-6-methylpyrimidine-4- yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[4-( 2-amino-6-methylpyrimidine-4- yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[4-(2-am ino-6-methylpyrimidine-4-yl)- 4-oxa-l-butyne]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyI-4-[succin-2-yl-(l-phenylalanine)]-7-[ 4-(2-amino-6- methylpyrimidine-4-yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-[4-(2-ami no-6-methylpyrimidine-4-yl)-4- oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[4-(2-amino- 6-methylpyrimidine-4-yl)-4- oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[4-(2-amino -6-methylpyrimidine-4-yl)-4- oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyI-4-[succin-2-yl-(l-glycine)]-7-[4-(2-amino- 6-methylpyrimidine-4-yl)-4- oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[4-(2-amin o-6-methylpyrimidine-4-yl)-4-oxa- l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yI-(l-phenylalanine)]-7-[4-(2- amino-6-methylpyrimidine-4- yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[4-(2-a mino-6-methylpyrimidine-4- yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one trifluoracetate, (±)-l-benzyI-3-phenyI-4-(2-carboxy-l-phenylethyl)-7-[4-(2-a mino-6-methylpyrimidine-4- yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[4-(2- amino-6-methyIpyrimidine-4- yI)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one trifluoracetate, (±)-l-benzyl-3-phenyI-4-[succin-2-yl-(l-gIycine)]-7-[4-(2-a mino-6-methylpyrimidine-4-yl)- 4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[4-(2-am ino-6-methylpyrimidine-4-yl)- 4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 4-(2-amino-6- methylpyrimϊdϊne-4-yl)-4-oxa-l-butyne]-3,4-dϊhydro-lH-l,4 -benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyI-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[ 4-(2-amino-6- methyipyrimϊdine-4-yl)-4-oxa-l-butyne]-3,4-dϊhydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[ 4-(2-amino-6-methylpyrimidine- 4-yl)-4-oxa-l-butyne]-3,4-dϊhydro-lH-l,4-benzodiazepϊne-2, 5-dione trifluoracetate, (±)-l-isopropyI-3-phenyl-4-[succin-2-yl-(l-t-butoxy)]-7-[4- (2-amino-6-methyIpyrimidϊne-4- yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyI-3-phenyI-4-[succin-2-yl-(l-gIycϊne)]-7- [4-(2-amino-6-methylpyrimidine-4- yl)]-4-oxa-l-butynel-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-isopropyl-3-phenyI-4-[succϊn-2-yI-(l-valine)]-7-[4-( 2-amino-6-methyIpyrimidine-4- yl)-4-oxa-l-butyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one trifluoracetate, (±)-l-isopropyl-3-phenyI-4-[succin-2-yI-(l-phenylalanine)]- 7-[4-(2-amϊno-6- methylpyrϊmϊdine-4-yl)-4-oxa-l-butyne]-3,4-dilnydro-lH-l,4 -benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyI-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[5-( 2-aminopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succϊn-2-yl-(l-t-butoxy)]-7-[5-(2 -aminopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valϊne)]-7-[5-( 2-aminopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 5-(2-aminopyridine-3-yl)-5- oxa-l-pentyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-[5-(2-aminop yridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[5-(2-aminop yridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[5-(2-amino pyridine-3-yl)-5-oxa-l-pentyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[5-(2-ami nopyridine-3-yl)-5-oxa-l-pentyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[5-(2-amin opyridine-3-yl)-5-oxa-l-pentyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[5- (2-aminopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihyd ro-1 H-l ,4-benzod iazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyI)-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[5-(2- aminopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[5-(2 -aminopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 5-(2-aminopyridine-3-yl)-5- oxa-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l -methylethyl)-7-[5-(2-aminopyridine-3-yl)-5-oxa- l-pentyne]-3,4-dilnydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[5-( 2-aminopyridine-3-yI)-5-oxa- l-pentyne]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[5- (2-aminopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[ 5-(2-aminopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-plnenyl-4-[succin-2-yl-(l-valine)]-7-[5-( 2-aminopyridine-3-yl)-5-oxa-l- pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-[5-(2-aminopyridine-3-yl)-5- oxa-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate.

Example 2

l-methyl-4-(2-carboxyethyl)-7-(5-gιιamdino-l-pcntynyl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoraceta te. To a magnetically stirred solution of 6mgs of l-methyl-4-(2-carboxyethyI)-7-(5- amino-l-pentynyI)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e trifluoracetate (0.017mmol) in l.OmL 10% potassium bicarbonate was added 31.0mgs of formamidine sulfonic acid (0.25 mmol)- After 30 minutes, the reaction mixture was quenched with 0.5mL acetic acid and concentrated in vacuo. The resulting residue was diluted with 2mL water and purified by high pressure liquid chromatography, using a 1 /2" C-18 reverse-phase column, eluting with a solvent gradient of 10:90 methanol(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to 50:50 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, f low=1 ml /min (Rt=36.8 min, un detection 254nm) to yield 4.5mgs (67%) l-methyI-4-(2-carboxyethyl)-7-(5-guanidino-l-pentynyl)-3,4-d ihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate. HRMS (FAB) molecular ion m/z=386.1823 ( cald. C19H24N5O4, 386.1829). !H NMR (D2O) 7.60 (IH, d, ⁴ JHH, Ar-H o-CON), 7.51 (IH, dd, Ar-H p-CON), 7.20 (IH, d, Ar-H m-CON), 4.05 (IH, d, 2j _HH=1 H _2/ NCHHCO), 3.92 (IH, m, NCHHCH2), 3.72 (IH, d, ² J _HH =l4Hz, NCHHCO), 3.40 (IH, m, NCHHCH2), 323-3.15 (5H, NCH3, H2NC(=NH2)NHCH2), 2.58 (2H, m, CH2CO2), 2.38 (2H, t, CJCCH2), 1.76 (2H, p, CH2CH2CH2).

Using the above procedure, but substituting the appropriate amino acid for 1-methyl- 4-(2-carboxyethyl)-7-(5-amino-l-pentynyI)-3,4-dihydro-lH-l,4 -benzodiazepine-2,5-dione trifluoracetate there may be prepared, for example, the following compounds: l-methyl-4-(2-carboxy-l-methylethyl)-7-(5-guanidϊno-l-penty ne)-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoracetate, l-methyI-4-(2-carboxy-l-phenyIethyI)-7-(5-guanidino-l-pentyn e)-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-methyI-4-[succϊn-2-yl-(l-f-butoxy)]-7-(5-guanidino-l -pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-(5-guanidino-l-p entyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-valine)]-7-(5-guanidino-l -pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-(5-guanidi no-l-pentyne)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-(5-guanidino-l-pentyn e)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyl)-7-(5-guanidino-l-pentyn e)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5-guanidino -l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yI-(l-glycine)]-7-(5-guanidino- l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-(5-guanidino-l-pe ntyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-pheny]-4-[succin-2-yl-(l-phenylalanine)]-7-(5-guan idino-l-pentyne)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-(5-guanidino-l-pentyn e)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-(5-guanidino-l-pentyn e)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-4-[succin-2-yl-(l-f-butoxy)]-7-(5-guanidino -l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-(5-guanidino-l-p entyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-(5-guanidino-l -pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-plnenylalanine)]-7-(5-gua nidino-l-pentyne)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyI-4-(2-carboxy-l-methylethyl)-7-(5-guanidino-l-pen tyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-(5-guanidino-l-pen tyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-r-butoxy)]-7-(5-guanidino -l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5- ione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-(5-guanidi no-l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyI-4-[succin-2-yI-(l-valine)]-7-(5-guanidϊno- l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-(5-g uanidino-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-guanidinoethane )-3-keto-l-propyn-3- amϊne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-guanidinoethane )-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N-(2-guanidino ethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-gIycine)]-7-[N-(2-guanidi noethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succϊn-2-yl-(l-valϊne)]-7-[N-(2-guanidino ethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-phenyIalanine)]-7-[N-(2-guan idinoethane)-3-keto-l-propyn- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyI-4-(2-carboxy-l-methylethyl)-7-[N-(2-guanidinoethane )-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-I,4-benzodiazepine-2,5-dϊone trifluoracetate, l-phenyl-4-(2-carboxy-l-pheny!ethyl)-7-[N-(2-guanidinoethane )-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-r-butoxy)]-7-[N-(2-guanϊ dinoethane)-3-keto-l-propyn-3- amine]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-fsuccin-2-yl-(l-glycine)]-7-[N-(2-guanidinoe thane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-I,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l-phenyI-4-[succin-2-yl-(l-valϊne)]-7-[N-(2-guanidinoe thane)-3-keto-l-propyn-3- amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l-phenyl-4-[succin-2-yI-(l-phenylalanine)]-7-[N-(2-guan idinoethane)-3-keto-l-propyn- 3-amine]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyI)-7-[N-(2-guanidinoethane )-3-keto-l-propyn-3- amine]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-guanidinoethane )-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N-(2-guanϊdin oethane)-3-keto-l-propyn-3- amϊne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l -benzyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-guanid inoethane)-3-keto-l-propyn-3- amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-guanidinoet hane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2-guan idinoethane)-3-keto-l-propyn- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-guanidinoeth ane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyI)-7-[N-(2-guanidinoeth ane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N-(2-guanid inoethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-guanidi noethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-guani dinoethane)-3-keto-l-propyn-3- aminej-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2-g uanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyn-3-(4 -amidino-l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l-propyn-3-(4 -amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-t-butoxy)]-7-[3-keto-l-pr opyn-3-(4-amidino-l-piperizine)J- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l-pro pyn-3-(4-amidino-l-piperizine)]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-prop yn-3-(4-amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-plnenylalanine)]-7-[3-keto-l -propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyn-3-(4 -amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l-propyn-3-(4 -amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3-keto-l-pr opyn-3-(4-amidino-l-piperizine)]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l-pro pyn-3-(4-amidino-l-piperizine)]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyI-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-propyn- 3-(4-amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[3-keto -l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

l-benzyI-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyn-3-(4 -amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l-propyn-3-(4 -amϊdino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yi-(l-f-butoxy)]-7-[3-keto-l-propy n-3-(4-amidino-l-piperϊzine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l-ρr opyn-3-(4-amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succϊn-2-yI-(l-valine)]-7-[3-keto-l-pro pyn-3-(4-amϊdino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-benzyI-4-[succin-2-yl-(l-phenylalanine)]-7-[3-keto -l-propyn-3-(4-amidino-l- pϊperizine)]-3,4-dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate, l-isopropyI-4-(2-carboxy-l-methylethyI)-7-[3-keto-l-propyn-3 -(4-amidino-l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-ϊsopropyI-4-(2-carboxy-l-phenyletfnyl)-7-[3-keto-l-propyn -3-(4-amidino-l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-t-butoxy)]-7-[3-keto-l-pr opyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dϊone trifluoracetate, (±)-l-isopropyI-4-[succin-2-yl-(l-gIycine)]-7-[3-keto-l-pro pyn-3-(4-amidϊno-l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-p ropyn-3-(4-amidino-l-piperizine)]- 3,4-dihydro-lH-I,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenyIalanϊne)]-7-[3- keto-l-propyn-3-(4-amϊdino-l- piperizϊne)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-guanidinoethane thiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, l-methyl-4-(2-carboxy-l-phenyIethyl)-7-[2-(2-guanidinoethane thϊol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-guanϊ dϊnoethanethioI)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-dϊone trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-guanidi noethanethioI)-l-ethyne]-3,4- dihydro-IH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyI-4-[succin-2-yI-(l-valϊne)]-7-[2-(2-guanidi noethanethioI)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yI-(l-phenylalanine)]-7-[2-(2-guan idϊnoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methyIethyI)-7-[2-(2-guanϊdinoethan ethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

-p eny -4- -car oxy-l-p eny et y - - - -guan noet anet o - -et yne - , - dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-guanid inoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-guanidinoe thanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-guanidin oethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2-g uanidinoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-guanidinoethane thiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-guanidinoethane thiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-guanidino ethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-guanidi noethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-guanidin oethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2-g uanidinoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-metlnylethyl)-7-[2-(2-guanidinoet hanethioI)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-guanidinoeth anethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-gua nidinoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-guan idinoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-vaIine)]-7-[2-(2-guani dinoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-( 2-guanidinoethanethiol)-l-ethyne]- 3,4-dihydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-methyI-3-phenyl-4-(2-carboxy-l-methyIethyl)-7-(5-guan idino-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenyletlnyl)-7-(5- guanidino-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5-gua nidϊno-l-pentyne)-3,4-dihydro- lH-l,4-benzodϊazepine-2,5-d ione trifluoracetate,

(±)-l-methyl-3-phenyI-4-[succin-2-yl-(l-gIycine)]-7-(5-g uanidino-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyI-4-[succin-2-yl-(l-valine)]-7-(5-guani dino-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylalanϊne)] -7-(5-guanidino-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyI-4-(2-carboxy-l-methylethyl)-7-(5-guanid ino-l-pentyne)-3,4-dihydro-lH- l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l^-diphenyI-4-(2-carboxy-l-phenylethyl)-7-(5-guanidi no-l-pentyne)-3,4-dihydro-lH- 1,4-benzod iazepine-2,5-d ione tr if 1 uoraceta te,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-t-butoxy)]-7-(5-guani dino-l-pentyne)-3,4-dihydro-lH- I,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-tsuccin-2-yl-(l-glycϊne)]-7-(5-guanidin o-l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyI-4-[succin-2-yl-(l-vaIine)]-7-(5-guanidi no-l-pentyne)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l,3-diphenyI-4-[succϊn-2-yl-(l-phenylalanine)]-7-(5 -guanidino-l-pentyne)-3,4-dihydro- lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyI-4-(2-carboxy-l-methylethyl)-7-(5-g uanidino-l-pentyne)-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyI)-7-(5-g uanidϊno-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyI-4-[succin-2-yl-(l-f-butoxy)I-7-(5-gua nidino-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succϊn-2-yl-(l-glycine)]-7-(5- guanidino-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-(5-gu anidino-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-ρhenyl-4-[succin-2-yi-(l-phenylalanϊne) ]-7-(5-guanidino-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-ϊsopropyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7- (5-guanidino-l-pentyne)-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-(5-g uanidino-l-pentyne)-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succϊn-2-yl-(l-f-butoxy)]-7 -(5-guanidino-l-pentyne)-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate.

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-(5-g uanidino-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-(5 -guanidino-l-pentyne)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyI-4-[succin-2-yl-(l-phenylalanine)]- 7-(5-guanidino-l-pentyne)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[N-( 2-guanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-g uanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N- (2-guanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-g uanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazeμ>ine-2,5-d ione trifluoracetate, (±)-l-methyl-3-phenyl-4-tsuccin-2-yl-(l-valine)]-7-[N-(2-gu anidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ N-(2-guanidinoethane)-3- keto-l-propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-guanid inoethane)-3-keto-l-propyn- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethy])-7-[N-(2-gua nidinoethane)-3-keto-l-propyn- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N-(2-guani dinoethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diplnenyl-4-[succin-2-yl-(l-glyciιne)]-7-[N-(2-gua nidinoethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-guanidi noethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2- guanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[N-( 2-guanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-plnenylethyl)-7-[N-(2- gιιanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N-(2- guanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-g uanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-benzyl-3-phenyI-4-[succin-2-yl-(l-valine)]-7-[N-(2-gu anidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ N-(2-guanidinoethane)-3-keto- l-propyn-3-amine]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dio ne trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[N-( 2-guanidinoethane)-3-keto- l-propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e trifluoracetate, (±)-l-isopropyl-3-phenyI-4-(2-carboxy-l-phenylethyl)-7-[N-( 2-guanidinoethane)-3-keto-l- propyn-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-t-butoxy)]-7-[N- (2-guanidinoethane)-3-keto-l- propyn-3-amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-fsuccϊn-2-yl-(l-gIycine)]-7- [N-(2-guanidinoethane)-3-keto-l- propyn-3-amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-ϊsopropyI-3-phenyl-4-[succϊn-2-yl-(l-vaIine)]-7-[N- (2-guanidinoethane)-3-keto-l- propyn-3-amine] -3,4-d ihydro-1 H-l ,4-benzodiazep i ne-2,5-d ione tri f 1 uoraceta te, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-phenylaIanine)]- 7-[N-(2-guanidinoethane)-3- keto-l-propyn-3-amineJ-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[3-keto -l-propyn-3-(4-amidino-l- piperizϊne)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyI-3-phenyl-4-(2-carboxy-l-phenyIethyl)-7-[3-keto -l-propyn-3-(4-amidino-l- piperizϊne)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3- keto-l-propyn-3-(4-amidino-l- piperizine)]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyI-3-phenyl-4-[succin-2-yI-(l-glycϊne)]-7-[3-ket o-l-propyn-3-(4-amidino-l- piperizϊne)]-3,4-dihydro-lH-l,4-benzodiazeprne-2,5-dione trifluoracetate, (±)-l-methyl-3-ρhenyl-4-[succin-2-yl-(l-valine)]-7-[3-keto -l-propyn-3-(4-amidino-l- pϊperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyI-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 3-keto-l-propyn-3-(4-amidino- l-piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-pr opyn-3-(4-amidino-l- piperizϊne)]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyI-4-(2-carboxy-l-phenyIethyI)-7-[3-keto-l -propyn-3-(4-amidϊno-l- piperizine)]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3-keto-l-p ropyn-3-(4-amidino-l- piperizϊne)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l-pr opyn-3-(4-amidino-l- piperϊzine)]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-vaIine)]-7-[3-keto-l-pro pyn-3-(4-amidino-l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[3-ket o-l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[3-keto -l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyI)-7-[3-keto -l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-r-butoxy)]-7-[3-ket o-l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-g!ycine)]-7-[3-keto -l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[3-ke to-l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 3-keto-l-propyn-3-(4-amidino- l-piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[3-k eto-l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyI)-7-[3-k eto-l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate, (+)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-i-butoxy)]-7-[3-k eto-l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[ 3-keto-l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[3-ke to-l-propyn-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-[3-keto-l-propyn-3-(4- amidino-l-piperizine)]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methyletlnyl)-7-[2-(2- guanidinoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5.-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyI)-7-[2-(2-g uanidinoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2- (2-guanidinoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glvcine)]-7-[2-(2-g uanidinoethanethiol)-l- ethyne]-3,4-dihydro-1 H-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-gu anidinoethanethiol)-l-ethyne]- 3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-methyl-3-phenyI-4-[succin-2-yI-(l-plnenylalanine)] -7-[2-(2-guanidinoethanethiol)-l- ethyne]-3,4-dilnydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-dϊphenyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-guani dinoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-dϊphenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-gu anidinoethanethioI)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succϊn-2-yl-(l-f-butoxy)]-7-[2-(2-guan idinoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyI-4-[succin-2-yl-(l-glycine)]-7-[2-(2-gua nidinoethanethϊol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-tsuccin-2-yl-(l-valine)]-7-[2-(2-guan idinoethanethiol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyI-4-[succin-2-yl-(l-phenylalanine)]-7-[2- (2-guanidinoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-g uanidinoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyI-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-g uanidinoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyI-4-[succin-2-yl-(l-t-butoxy)]-7-[2-(2- guanldinoethanethioI)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succϊn-2-yl-(l-glycine)]-7-[2-(2- guanidinoethanethiol)-l-ethyne]- 3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succϊn-2-yl-(l-vaIine)]-7-[2-( 2-guanidinoethanethiol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yI-(l-phenylaIanine)]- 7-[2-(2-guanidinoethanethϊol)-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methyIethyI)-7-[2-( 2-guanidinoethanethϊol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyI-3-phenyI-4-(2-carboxy-l-phenylethyI)-7-[2-( 2-guanidinoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2- (2-guanidinoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yI-(l-glycine)]-7-[ 2-(2-guanidinoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succϊn-2-yl-(l-vaIine)]-7-[2-( 2-guanidinoethanethiol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yI-(l-phenylalanine)]- 7-[2-(2-guanidinoethanethiol)- l-ethyne]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate.

l-methyl-4-(2-c rboxyethyl)-7-(5-guanidino-1-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate. a) A magnetically stirred slurry of 45mgs l-methyI-4-(2-carboxyethyl)-7-(N-boc-5- amino _: l-pentynyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e benzyl ester (0.0924mmol) in 2.0mL ethyl acetate and lOmgs of 10% palladium on carbon was stirred under an atmosphere of hydrogen for 3 hours. The mixture was filtered, washing the solids with ethyl acetate, and concentrated in vacuo to yield 45mgs (99%) l-methyl-4-(2-carboxyethyl)-7-(N- boc-5-amino-l-pentyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione benzyl. ester. H NMR (CDCI3 , dTMS) 7.63 (IH, d, ⁴ JHH=2HZ, Ar-H o-CON), 7.35-7.27 (6H, Ph, p-CON), 7.06 (IH, d, NCHHCO), 3.94 (2H, q, ] _H H=7Hz, NCH2), 3.80 (IH, d, ² J _HH =i5Hz, NCHHCO), 3.35 (3H, s, NCH3), 3.08 (2H, q, BocNHCH ₂ ), 2.88-2.67 (2H, m, CH2CO2), 2.62 (2H, t, 1.42 (9H, s, f-Bu), 1.35 (2H, p, ¹ C NMR (CDCl3,dT S) 171.2, 168.9, 167.3, 140.1, 138.8, 135.6, 132.2, 130.2, 128.5, 128.4, 128.3, 120.9, 66.6, 52.3, 45.1, 40.4, 34.9, 34.8, 32.9, 30.7, 29.9, 28.4, 26.4. Using the above procedure, but substituting the appropriate 7-alkynyl-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione for l-metlnyl-4-(2-carboxyethyI)-7-(N-boc-5-amino-l- pentynyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione benzyl ester there may be prepared, for example, the following compounds: l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-prt)pyl)-7-[5-(N-Boc)- amino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-(N-Boc)-a mino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[ 5-(N-Boc)-amino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-metlnyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succiny l)]-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-1,4-benzodiazepine-2,5-dione,

(±)-l-metlnyl-4-[2-(l-benzyli)xyvalinyl-4-benzyloxy)succ inyl)]-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dilnydro-l H-l,4-benzodiazeρine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[5-(N-Boc)-amino-l- pentyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-(N-Boc)-a mino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-(N-Boc)-a mino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-t-butoxy-4-benzyIoxy)succinyl)]-7-[5-( N-Boc)-amino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyIoxyglycinyI-4-benzyloxy)succi nyl)]-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy)succin yl)]-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyIoxyphenylaIanyI-4-benzyloxy)s uccinyI)]~7-[5-(N-Boc)-amino-l- pentyl]-3,4-d ihyd ro-1 H-l ,4-benzod iazepi ne-2,5-d i one, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-ρropyI)-7-[5-(N-Boc)- amino-l-pentyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-(N-Boc)-a mino-l-pentyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyI-4-[2-(l-t-butoxy-4-benzyloxy)succinyI)]-7-[ 5-(N-Boc)-amino-l-pentyl]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-benzyI-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[5-(N-Boc)-amino-l- penrv'l]-3,4-dihydro-lH-l,4-benzodϊazepϊne-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyIoxyvalinyI-4-benzyIoxy)succin yl)]-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyphenyIalanyl-4-benzyloxy)s uccinyl)]-7-[5-(N-Boc)-amino-l- pentyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-(N-Boc )-amino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione, l-isopropyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-f5-(N-Boc )-amino-l-pentyl]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-isopropyI-4-[2-(l-f-butoxy-4-benzyIoxy)succinyI)]- 7-[5-(N-Boc)-amino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-t2-(l-benzyIoxyglycinyl-4-benzyloxy)su ccinyl)]-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyI-4-[2-(l-benzyloxyvalinyl-4-benzyIoxy)suc cinyI)]-7-t5-(N-Boc)-amino-l- pentyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyρhenylalanyl-4-benzyIoxy) succinyl)]-7-[5-(N-Boc)-amino- 1-pen tyl]-3,4-d ihyd ro-lH-1 ,4-benzod iazepine-2,5-d ione, l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-cyano-l-p entyl]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione.

l-methyl-4-(3-ethoxy-l-pheny 1-3-oxo-l -propyI)-7-[5-cyano-l-pentyl]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 5-cyano-l-pentyl]-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[5-cyano-l-pentyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-cyano-l-p entyl]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-cyano-l-p entyl]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-t-bu )xy-4-benzyloxy)succinyI)]-7-[5-cyano-l-pentyl]-3,4-dihydro- lH- l,4-benzodiazef>ine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-pheny]-4-[2-(l-benzyloxyvalinyI-4-benzyloxy)succin yI)]-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[5-cyano-l-pentyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-ρropyl)-7-[5-cyano-l- pentyl]-3,4-dihydro-lH-l,4- benzod iazepi ne-2,5-d ione, l-benzyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-cyano-l-p entyl-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-t 5-cyano-l-pentyl]-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazeρine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyI-4-benzyloxy)s uccinyI)]-7-[5-cyano-l-pentyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-proρyl)-7-[5-cyano -l-pentyl]-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-cyano- l-pentyl]-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione,

(±)-l-ϊsopropyI-4-[2-(l-f-butoxy-4-benzyIoxy)succinyl)]-7- [5-cyano-l-pentyI]-3,4-dihydro- lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-isopropyI-4-[2-(l-benzyloxygIycinyl-4-benzyloxy)su ccinyl)]-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-ϊsopropyl-4-[2-(l-benzyloxyΛ ^r alinyl-4-benzyloxy)succinyl)]-7-[5-cyano-l-pentyl]-3,4 - dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzylox y)succinyl)]-7-[5-cyano-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(3-cyanop henyl)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[2-(3-cyanop henyl)-l-ethyl]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 2-(3-cyanophenyl)-l-ethyI]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone, (±)-l-methyl-4-[2-(l-benzyloxyglycinyI-4-benzyloxy)succinyl )]-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-t2-(3-cyanophenyl)- l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione, l-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)-7-[2-(3-cyanop henyI)-l-ethyl]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dϊone, l-phenyI-4-(3-ethoxy-l-phenyI-3-oxo-l-propyI)-7-[2-(3-cyanop henyl)-l-ethyl]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dϊone, (±)-l-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[2-( 3-cyanophenyl)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxygIycϊnyl-4-benzyIoxy)succ inyI)]-7-[2-(3-cyanophenyI)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-(3-cyanophenyl)-l- ethyI]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-phenyl-4-[2-(I-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[2-(3-cyanophenyl)- l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(3-cyanop henyl)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(3-cyanop henyl)-l-ethyI]-3,4- dϊhydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyI-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 2-(3-cyanophenyl)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, 5 (±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[2-(3-cyanophenyl)- l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[2-(3-cya nophenyl)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(3-cya nophenyl)-l-ethyl]-3,4-

10 dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]- 7-[2-(3-cyanophenyl)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazeρine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)su ccinyl)]-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dilnydro-l H-l, 4-benzodiazepine-2,5-d ione,

15 (±)-l-isopropyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(+)-l-isopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy )succinyl)]-7-[2-(3- cyanophenyl)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione, l-methyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)-7-[N-[2-(N-Boc )-aminoethane]-3-keto-l-

20 propyl-3-amine]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione, l-methyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[N-[2-(N-Boc )-aminoethane]-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-Nbutoxy-4-benzyloxy)succinyl)]-7-[N -[2-(N-Boc)-aminoethane]-3- keto-l-propyl-3-amine]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione,

25 (±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dilnydro-lH-l,4-be nzodiazepine-2,5-dione, (+)-l-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl)] -7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[N-[2-(N-Boc)-

30 aminoethane]-3-keto-l-propyl-3-amine]-3,4-dilnydro-lH-l,4-be nzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-metlnyl-3-oxo-l-propyl)-7-[N-[2-(N-Bo c)-aminoethane]-3-keto-l- propyl-3-amine]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-plnenyl-3-oxo-l-propyI)-7-tN-[2-(N-Bo c)-aminoethane]-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, 35 (±)-l-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[N-[ 2-(N-Boc)-aminoethane]-3-

"ϋ- _* keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione,

(±)-l-phenyl-4-[2-(l-benzyk>xyglycinyl-4-benzyloxy)su ccinyl)]-7-tN-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyIoxyvaIinyl-4-benzyloxy)succinyl) ]-7-[N-[2-(N-Boc)- amϊnoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyphenyIalanyl-4-benzyloxy)succ inyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[N-[2-(N-Boc )-aminoethane]-3-keto-l- propyI-3-amine]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione , l-benzyl-4-(3-ethoxy-I-phenyl-3-oxo-l-propyI)-7-[N-[2-(N-Boc )-aminoethane]-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyI-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ N-[2-(N-Boc)-aminoethane]-3-keto- l-propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e,

(±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(I-benzyIoxyvaIinyl-4-benzyloxy)succinyI) ]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyIoxyphenylaIanyl-4-benzyloxy)succ inyl)l-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, l-isopropyI-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[N-[2-(N- Boc)-aminoethane]-3-keto- l-propyl-3-aminel-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e, l-isopropyI-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)-7-[N-[2-(N- Boc)-aminoethane]-3-keto- l-propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e,

(±)-l-ϊsopropyl-4-[2-(l-t-butoxy-4-benzyIoxy)succinyl)] -7-[N-t2-(N-Boc)-aminoethane]-3- keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-isopropyI-4-[2-(l-benzyloxyglycϊnyl-4-benzyloxy)succ inyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[N-[2-(N-Boc)- amϊnoethane]-3-keto-l-propyl-3-amiιne]-3,4-drhydro-lH-l,4- benzodiazepine-2,5-dione, l-methyl-4-(3-etlnoxy-l-methyl-3-oxo-l-propyl)-7-[3-keto-l-p ropyl-3-[4-(N-Boc)-l- piperϊzine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[3-keto-l-pr opyl-3-[4-(N-Boc)-l- piperizϊne]]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione,

(±)-l-methyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyI)]-7-[ 3-keto-l-propyl-3-[4-(N-Boc)-l- piperizϊne]]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dione, (±)-l-methyI-4-[2-(l-benzyloxygIycinyl-4-benzyIoxy)succϊny l)]-7-[3-keto-l-propyl-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-d ione,

(±)-l-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yI)]-7-[3-keto-l-propyl-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[3-keto-l-propyl-3- [4-(N-Boc)-l -piperizine]]-3,4-d ihyd ro-1 H-l ,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[3-keto-l-pr opyl-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, 5 l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[3-keto-l-pr opyl-3-[4-(N-Boc)-l- * piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 3-keto-l-propyl-3-[4-(N-Boc)-l- γ piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[3-keto-l-propyl-3-[4-(N-

10 Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[3-keto-l-propyl-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[3-keto-l-propyl-3- [4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione,

15 l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[3-keto-l-pr opyl-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[3-keto-l-pr opyl-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[3-k eto-l-propyl-3-t4-(N-Boc)-l-

20 piperizine]]-3,4-dihydro-l H-l,4-benzodiazeρine-2,5-dione,

(±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[3-keto-l-propyl-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[3-keto-l-propyl-3-[4-(N- Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

25 (±)-l-benzyl-4-[2-(l-benzyloxyplnenylalanyI-4-benzyloxy)suc cinyI)]-7-[3-keto-l-propyl-3- t4-(N-Boc)-l-piperizine]]-3,4-dihydro-l H-l,4-benzodiazeρine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)-7-[3-keto-l -propyl-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[3-keto-l -propyl-3-[4-(N-Boc)-l-

30 piperizine]]-3,4-dihydro-lH-l,4-benzodiazeρine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]- 7-[3-keto-l-propyl-3-[4-(N-Boc)-l- piperizine]]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxygIycinyl-4-benzyloxy)su ccinyI)]-7-[3-keto-l-propyl-3-[4- (N-Boc)-l-piperizine]]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione,

35 (±)-l-isopropyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[3-keto-l-propyl-3-[4- (N-Boc)-l-piperizine]]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione, (±)-l-isoproρyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyI)]-7-[3-keto-l-propyl- 3-[4-(N-Boc)-l-piperizine]]-3,4-dilnydro-lH-l,4-benzodiazepi ne-2,5-dione,

l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-[2-(N-Boc )aminoethanethiol]-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-[2-(N-Boc )aminoethanethiol]-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone, (±)-l-methyI-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[2-[ 2-(N-Boc)aminoerhanethiol]-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyI )]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-I-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyphenylaIanyl-4-benzyIoxy)succ inyl)]-7-[2-[2-(N- Boc)aminoethanethϊol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, l-phenyI-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[2-[2-(N-Boc )aminoethanethiol]-l- ethyl]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-[2-(N-Boc )aminoethanethϊol]-l- ethyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-I-phenyl-4-[2-(l-f-butoxy-4-benzyIoxy)succinyl)]-7-[ 2-[2-(N-Boc)aminoethanethiol]-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyIoxygIycϊnyl-4-benzyloxy)succiny l)]-7-[2-[2-(N- Boc)aminoethanethioI]-l-ethyl]-3,4-dϊhydro-lH-l,4-benzodϊa zepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyI) ]-7-[2-[2-(N- Boc)aminoethanethϊol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyI-4-benzyIoxy)succ inyl)]-7-[2-[2-(N- Boc)aminoethanethϊol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)-7-[2-[2-(N-Boc )aminoethanethiol]-l- ethyl]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-[2-(N-Boc )aminoethanethϊol]-l- ethyl]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 2-[2-(N-Boc)aminoethanethiol]-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyI-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyI)]-7-[2-[2-(N- Boc)aminoethanethiol]-I-ethyl]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyIoxyvalϊnyl-4-benzyIoxy)succinyl )]-7-[2-[2-(N- Boc)aminoethanetIniol]-l-etlnyl]-3,4-dihydro-lH-l,4-benzodia zepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaze pϊne-2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-[2-(N- Boc)aminoethanethiol]-l- ethyl]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione,

l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-[2-(N- Boc)aminoethanethiol]-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]- 7-[2-[2-(N-Boc)aminoethanethiol]- l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[2-[2-(N-

Boc)aminoethanethioI]-l-ethyl]-3,4-dihydro-lH-l,4-benzodi azepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)suc cinyl)]-7-[2-[2-(N-

Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodi azepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzylox y)succinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(4-cyanot hiophenol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(4-cyanot hiophenol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyI-4-[2-(l- butoxy-4-benzyloxy)succinyI)]-7-[2-(4-cyanothiophenol)-l-eth yl]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[2-(4-cyanothiophenol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- ione,

(±)-l-methyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-(4-cyanothiophenol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(4-cyanot hiophenol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenvl-3-oxo-l-propyl)-7-[2-(4-cvanot hiophenol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 2-(4-cyanothiophenol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyI-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[2-(4-cyanothiophenol)-l- ethyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[2-(4-cyanothiophenol)-l- ethyl]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyphenylaianyl-4-benzyloxy)s uccinyl)]-7-[2-(4- cyanothiophenol)-l-etlnyl]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dione, l-benzyl-4-(3-ethoxy-l-metlnyl-3-oxo-l-propyl)-7-[2-(4-cyano thiophenoI)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2-(4-cyanot hiophenol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyI)]-7-t2-( 4-cyanothiophenol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-benzyI-4-[2-(l-benzyloxyglycinyI-4-benzyloxy)succi nyl)]-7-[2-(4-cyanothiophenol)-l- ethyI]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dϊone, (±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[2-(4-cyanothiophenol)-l- ethyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone, (±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2-(4-cya nothiophenoI)-l-ethyl]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione, l-isopropyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[2-(4-cya nothiophenol)-l-ethyl]-3,4- dihyd.ro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-f-butoxy-4-benzyIoxy)succinyl)]- 7-[2-(4-cyanothiophenol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-I-isopropyl-4-[2-(l-benzyloxyglycϊnyl-4-benzyloxy)succ inyl)]-7-[2-(4-cyanothiophenol)- l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyvaIϊnyl-4-benzyloxy)su ccinyl)]-7-[2-(4-cyanothiophenol)- l-ethyl]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(I-benzyloxyphenyfalanyl-4-benzylox y)succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodϊazepine -2,5-dione, l-methyI-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[4-[2-(N-Boc )amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, l-methyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[4-[2-(N-Boc )amino-6- methylpyrimϊdine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-methyI-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[4-[ 2-(N-Boc)amϊno-6- methylpyrimϊdϊne-4-ylI-4-oxa-l-butyl]-3,4-dilnydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyIoxyglycinyl-4-benzyloxy)succinyl )]-7-[4-[2-(N-Boc)amϊno-6- methylpyrimϊdine-4-yI]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-methyl-4-[2-(l-benzyloxyvalinyI-4-benzyloxy)succinyl) ]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dϊhydro-lH-l,4-be nzodiazepine-2^-dione,

(±)-l-methyI-4-[2-(l-benzyIoxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[4-[2-(N-Boc)amino- 6-methylpyrimidine-4-yI]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, l-phenyI-4-(3-ethoxy-l-methyI-3-oxo-l-ρropyI)-7-[4-[2-(N-Bo c)amino-6- methylpyrimϊdine-4-yl]-4-oxa-l-butyl]-3,4-dilnydro-lH-l,4-b enzodiazepine-2,5-dione, l-phenyI-4-(3-ethoxy-l-phenyI-3-oxo-l-propyI)-7-[4-[2-(N-Boc )amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dilnydro-lH-l,4-be nzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[ 4-[2-(N-Boc)amino-6- methylpyrimϊdine-4-yl]-4-oxa-l-butyI]-3,4-dihydro-lH-l,4-be nzodϊazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyI )]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyk)xy)succinyl) ]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, 5 (±)-l-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[4-[2-(N-Boc)amino- i 6-methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione,

If l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[4-[2-(N-Boc )amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[4-[2-(N-Boc )amino-6- 10 methylpyrimidine-4-yl]-4-oxa-l-butyI]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[4-[ 2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyl )]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyI]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, 15 (±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)succ inyI)]-7-[4-[2-(N-Boc)amino- 6-methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l -methyl-3-oxo-l -propyl )-7-[4-[2-(N-Boc)amino-6- 20 methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[4-[2-(N- Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyI]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione, 25 (±)-l-isopropyI-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succi nyl)]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succin yl)]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-isopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[4-[2-(N- 30 Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione, l-methyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-[2-(N-Boc )aminopyridine-3-yl]-5- oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyl-4-(3-ethoxy-l-plnenyl-3-oxo-l-propyl)-7-[5-[2-(N-Bo c)aminopyridine-3-yl]-5- 35 oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-4-[2-(l-i-butoxy-4-benzyloxy)succinyl)]-7-[ 5-[2-(N-Boc)aminopyridine-3-yl]- 5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyI-4-[2-(l-benzyloxygIycinyl-4-benzyloxy)succinyl )]-7-[5-[2-(N- Boc)aminopyridine-3-yI]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione,

(±)-l-methyI-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl) ]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-mefhyl-4-[2-(l-benzyioxyphenylalanyl-4-benzyloxy)succ inyl)]-7-[5-[2-(N- Boc)aminopyrϊdine-3-yl]-5-oxa-l-pentylI-3,4-dihydro-lH-l,4- benzodiazepine-2^-dione, l-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[5-[2-(N-Boc )aminopyridine-3-yl]-5- oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-t5-[2-(N-Boc )aminopyridine-3-yl]-5-oxa- l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7-[ 5-[2-(N-Boc)aminopyridine-3-yI]-5- oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-phenyl-4-[2-(l-benzyloxygIycinyl-4-benzyloxy)succi nyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-phenyl-4-[2-(l-benzyloxyvaIϊnyI-4-benzyloxy)succinyl )]-7-[5-[2-(N- Boc)amϊnopyridine-3-yl]-5-oxa-l-pentyI]-3,4-dϊhydro-lH-l,4 -benzodiazepine-2,5-dϊone, (±)-l-phenyl-4-[2-(l-benzyloxyphenylaIanyl-4-benzyloxy)succ inyl)]-7-[5-[2-(N-

Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-[2-(N-Boc )aminopyridine-3-yl]-5-oxa- l-pentyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[5-[2-(N-Boc )aminopyridine-3-yl]-5-oxa- l-pentyl]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]-7-[ 5-[2-(N-Boc)aminopyridine-3-yl]-5- oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succinyI )]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succϊnyl )]-7-[5-[2-(N-

Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5-dione, (±)-l-benzyl-4-[2-(l-benzyloxyphenylalanyI-4-benzyloxy)succ inyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yI]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5-[2-(N- Boc)amϊnopyridine-3-yl]-5- oxa-l-pentyl]-3,4-dihydro-IH-l,4-benzodiazepine-2,5-dione, l-isopropyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5- oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)]- 7-[5-[2-(N-Boc)aminopyridine-3- yll-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one, (±)-l-isopropyl-4-[2-(l-benzy!oxyglycinyl-4-benzyloxy)succi nyl)]-7-[5-[2-(N-

Boc)aminopyridϊne-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyvalϊnyl-4-benzyloxy)su ccinyl)]-7-[5-[2-(N-

Boc)aminopyridine-3-yI]-5-oxa-l-pentyl]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy)s uccinyl)]-7-[5-[2-(N-

Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[5-(N-Boc)- amino-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[5-(N-Boc)- amino-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[5-(N-

Boc)-amino-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2, 5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)-7-[5- (N-Boc)-amino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(+)-l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)-7-[ 5-(N-Boc)-amino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-r-butoxy-4-benzyloxy)succinyl)] -7-[5-(N-Boc)-amino-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)s uccinyl)]-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)su ccinyI)]-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazeρine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-[5-(N-Boc)- amino-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[5-(N-Boc)-amino-l- penryl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[5-(N-Boc)-amino-l- penry]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[5-(N-Boc)- amino-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[5-(N-Boc)- amino-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyIoxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[5-(N-Boc)- amino-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyI-3-phenyI-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-pr opyl)-7-[5-(N-Boc)-amino-l- penryl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone, (±)-l-isopropyl-3-phenyl-4-t2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[5-(N-Boc)-amino-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzy!oxyglycinyl-4-ben zyloxy)succinyl)]-7-[5-(N-Boc)- amino-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyI-3-phenyl-4-[2-(l-benzyloxyvalinyI-4-benz yloxy)succinyl)]-7-[5-(N-Boc)- amino-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyphenylaIanyl-4 -benzyIoxy)succinyl)]-7-[5-(N- Boc)-amino-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone, (±)-l-methyl-3-phenyI-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succi nyl)]-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyioxyglycinyI-4-benzyI oxy)succinyl)]-7-[5-cyano-l- pentyl]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione,

(±)-l-methyI-3-phenyI-4-[2-(l-benzyloxyvalinyI-4-benzylo xy)succinyl)]-7-[5-cyano-l- pentylJ-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyI-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[5-cyano- l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-ox()-l-propyl)-7-t5 -cyano-l-pentyl]-3,4-dihydro- lH-l,4-benzodϊazepine-2,5-dϊone,

(±)-l,3-dϊphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7 -[5-cyano-l-pentyl]-3,4-dihydro- lH-l,4-benzodϊazepine-2,5-dione,

(±)-l,3-diphenyI-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)] -7-[5-cyano-l-pentyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-dϊphenyI-4-[2-(l-benzyloxyglycinyl-4-benzyloxy) succinyl)]-7-[5-cyano-l-pentyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone,

(±)-l,3-dϊphenyl-4-[2-(l-benzyIoxyvalϊnyl-4-benzyloxy) succinyl)]-7-t5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyIoxyphenylalanyl-4-benzyloxy) succinyl)]-7-[5-cyano-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, •

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[5-cyano-l-pentyl-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-r-butoxy-4-benzyloxy)succi nyI)]-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[5-cyano-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[5-cyano-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyI-4-be nzyloxy)succinyl)]-7-[5-cyano-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-pr opyl)-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-pr opyl)-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succi nyl)]-7-[5-cyano-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-ben zyloxy)succinyl)]-7-[5-cyano-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benz yloxy)succinyl)]-7-[5-cyano-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyI-4-[2-(l-benzyloxyρhenylalanyl- 4-benzyloxy)succinyI)]-7-[5- cyano-l-pentyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)- 7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-/-butoxy-4-benzyloxy)succi nyl)]-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione,

(±)-l-methyI-3-phenyl-4-[2-(l-benzyloxyvaIinyl-4-benzylo xy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyl]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyplnenylalanyl-4-b enzyloxy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2- (3-cyanophenyl)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7- [2-(3-cyanophenyl)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-t-butoxy-4-benzyloxy)succϊnyI)]-7 -[2-(3-cyanophenyl)-l-ethyI]- 3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyI-4-benzyloxy)s uccinyl)]-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-1 -diphenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succinyl)]-7- t2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione,

(±)-l,3-diphenyI-4-[2-(l-benzyloxyphenylalanyl-4-benzyIo xy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione, (±)-l-benzyl-3-phenyI-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyI-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[2-(3-cyanophenyl)-l- ethyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succi nyl)]-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[2-(3- cyanophenyI)-l-ethyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione, (±)-l-benzyl-3-phenyI-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy) succinyl)]-7-[2-(3- cyanophenyl)-l-ethyl]-3,4-dthydro-lH-l,4-benzodiazepine-2,5- dione, (±)-l-benzyI-3-phenyl-4-[2-(l-benzyloxyphenyIalanyl-4 ¹ benzyloxy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione,

(±)-l-isopropyI-3-phenyl-4-(3-ethoxy-l-metlnyl-3-oxo-l-p ropyl)-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-pr opyl)-7-[2-(3-cyanophenyl)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-isopropyI-3-phenyl-4-[2-(l-r-butoxy-4-benzyloxy)succi nyl)]-7-[2-(3-cyanophenyl)-l- ethyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-ben zy!oxy)succinyl)]-7-[2-(3- cy anophenyl)-l -ethyll-3,4-d ihyd ro-1 H-l,4-benzod iazepϊne-2,5-d ione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvaIinyl-4-benzylo xy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4 -benzyloxy)succinyl)]-7-[2-(3- cyanophenyl)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione, (±)-l-methyl-3-phenyI-4-(3-ethoxy-l-methyl-3-oxo-I-propyl)- 7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[N-[2-(N-Boc)- amϊnoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvalinyI-4-benzyloxy) succinyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, 5 (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succinyl)]-7-[N-[2-(N-

4 Boc)-aminoethane]-3-keto-l-propyI-3-amine]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5- ^' λ dione,

(±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7- [N-[2-(N-Boc)-aminoethane]-3- keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, 10 (±)-l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[N- [2-(N-Boc)-aminoethane]-3- keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l,3-diphenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7- [N-[2-(N-Boc)-aminoethane]-3- keto-l-propyI-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succ inyl)]-7-[N-[2-(N-Boc)- 15 aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succi nyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyphenylalanyI-4-benzyloxy) succinyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, 20 (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)- 7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl )]-7-[N-[2-(N-Boc)- 25 aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyI-4-benzyloxy) succinyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyI-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, 30 (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succinyl)]-7-[N-[2-(N- Boc)-aminoethane]-3-keto-l-propyI-3-amine]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5- dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-metlnyl-3-oxo-l-p ropyl)-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dilnydro-lH-l,4-be nzodiazepine-2,5-dione, 35 (+)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl )-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyI-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione,

(±)-l-isopropyl-3-ρhenyl-4-[2-(l-t-butoxy-4-benzyloxy)s uccinyl)]-7-[N-[2-(N-Boc)- aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[N-[2-(N- Boc)-aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l, 4-benzodiazeρine-2,5- dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyIoxyvalinyl-4-benz yloxy)succinyl)]-7-[N-[2-(N- Boc)-aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5- dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyphenyIalanyl-4 -benzyloxy)succinyl)]-7-[N-[2- (N-Boc)-aminoethane]-3-keto-l-propyl-3-amine]-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[3-keto-l-propyl-3-[4-(N- Boc)-l-piperizϊne]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-proρ yl)-7-[3-keto-l-propyl-3-[4-(N- Boc)-l-piperϊzine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione,

(±)-l-methyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[3-keto-l-propyl-3-[4-(N- Boc)-l-piperizine]]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-d ione,

(±)-l-methyI-3-phenyl-4-[2-(l-benzyIoxyglycϊnyl-4-benzy Ioxy)succinyI)]-7-[3-keto-l- propyl-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-methyi-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyIoxy) succϊnyl)]-7-[3-keto-l- propyl-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succinyl)]-7-[3-keto-l- propyl-3-[4-(N-Boc)-l-piperϊzϊne]]-3,4-dihydro-lH-l,4-benz odϊazepine-2,5-dione, (±)-l,3-diphenyl-4-(3-etlnoxy-l-methyl-3-oxo-l-propyl)-7-[3 -keto-l-propyl-3-[4-(N-Boc)-l- piperϊzine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)-7- [3-keto-l-propyl-3-[4-(N-Boc)-l- piperizϊnej]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)] -7-[3-keto-l-propyl-3-[4-(N-Boc)- l-pϊperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyIoxyglycinyl-4-benzyIoxy)s uccinyI)]-7-[3-keto-l-propyl-3-{4- (N-Boc)-l-piperizϊne]]-3,4-dihydro-lH-l,4-benzodiazepine-2, 5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyIoxyvalϊnyl-4-benzyloxy)succ inyl)]-7-[3-keto-l-propyl-3-[4- (N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-[3-keto-l- propyI-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyI)- 7-[3-keto-l-propyl-3-[4-(N- Boc)-l-piperizϊne]]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5- dione,

(±)-l-benzyI-3-phenyl-4-(3-ethoxy-I-phenyl-3-oxo-l-propy l)-7-[3-keto-l-propyl-3-[4-(N- Boc)-l-piperizϊne]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione,

(±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succi nyl)]-7-[3-keto-l-propyl-3-[4-(N- Boc)-l-pϊperizine]]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5- dione,

(±)-l-benzyl-3-pheny]-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[3-keto-l- propyl-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[3-keto-l-propyl- 3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepin e-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succinyl)]-7-[3-keto-l- propyl-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[3-keto-l-propyl-3-[4- (N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[3-keto-l-propyl-3-[4- (N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)su ccinyl)]-7-[3-keto-l-propyl-3-[4- (N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[3-keto-l- propyl-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzy!oxyvalinyl-4-benzylo xy)succinyl)]-7-[3-keto-l- propyl-3-[4-(N-Boc)-l-piperizine]]-3,4-dilnydro-lH-l,4-benzo diazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyphenylalany]-4-be nzyloxy)succinyl)]-7-[3-keto- l-propyl-3-[4-(N-Boc)-l-piperizine]]-3,4-dihydro-lH-l,4-benz odiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)- 7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)- 7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl )]-7-[2-[2-(N- Boc)aminoethanethioI]-l-ethyI]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l-methyI-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[2-[2-(N- Boc)aminoethanethioI]-l-ethyl]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyplnenylalanyI-4-benz yloxy)succinyl)]-7-[2-[2-(N- Boc)aminoethanethioI]-l-ethyI]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2- [2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)-7-[2- [2-(N-Boc)aminoethanethiol]- l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyI-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7- [2-[2-(N-

Boc)aminoethanethioI]-l-ethyl]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)s uccinyl)]-7-[2-[2-(N-

Boc)aminoethanethiol]-l-etlnyl]-3,4-dilnydro-l H-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succi nyl)]-7-I2-[2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyIoxyphenylaIanyl-4-benzyloxy) succinyl)]-7-[2-[2-(N- Boc)amϊnoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[2-[2-(N-

Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodi azepine-2,5-dione, (±)-I-benzyl-3-phenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)- 7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyI]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l-benzyI-3-phenyI-4-[2-(l-f-butoxy-4-benzyIoxy)succinyI )l-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyI]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxygIycinyl-4-benzyl oxy)succinyl)]-7-[2-[2-(N- Boc)aminoethanethϊol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalϊnyl-4-benzyloxy )succinyl)]-7-[2-[2-(N- Boc)aminoethanethϊol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyI-4-benzy loxy)succinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyI]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[2-[2-(N- Boc)aminoethanetIniol]-l-etlnyI]-3,4-dϊlnydro-lH-l,4-benzod ϊazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy I)-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaze pine-2,5-dione, (±)-l-isopropyl-3-phenyI-4-[2-(l-f-butoxy-4-benzyIoxy)succi nyl)]-7-[2-[2-(N- Boc)aminoethanethϊol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyIoxyglycinyl-4-benzyI oxy)succinyl)]-7-[2-[2-(N- Boc)aminoethanethiol]-l-ethyl]-3,4-dϊhydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-isopropyI-3-phenyl-4-[2-(l-benzyioxyvalinyl-4-benzylo xy)succinyl)J-7-[2-[2-(N- Boc)aminoethanethϊol]-l-ethyl]-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione, (±)-l-ϊsopropyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-b enzyloxy)succinyl)]-7-[2-[2- (N-Boc)aminoethanethiol]-l-ethyI]-3,4-dϊhydro-lH-l,4-benzod iazepϊne-2,5-dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyl)- 7-[2-(4-cyanothiophenol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyI-4-(3-ethoxy-I-phenyl-3-oxo-l-propy l)-7-[2-(4-cyanothiophenol)-l- ethyI]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succi nyl)]-7-[2-(4-cyanothiophenol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxygIycinyl-4-benzyloxy )succinyl)]-7-[2-(4- cyanothiophenoI)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepϊne -2,5-dione, (±)-l-methyl-3-phenyl-4-t2-(l-benzyIoxyvalinyI-4-benzyloxy) succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenyIalanyI-4-benzy loxy)succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[2- (4-cyanothiophenol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[2- (4-cyanothiophenol)-l- ethyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l,3-diphenyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl)] -7-[2-(4-cyanothiophenol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succ inyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyvalinyI-4-benzyloxy)succi nyl)]-7-[2-(4- cyanothiophenol )-l -ethyl]-3,4-d ihyd ro-1 H-l,4-benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, (±)-l-benzyI-3-phenyl-4-(3-etlnoxy-l-methyl-3-oxo-l-propyl) -7-[2-(4-cyanothiophenol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[2-(4-cyanothiophenoI)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l- butoxy-4-benzyloxy)succinyl)]-7-[2-(4-cyanothiophenol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyI-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[2-(4- cyanotlniophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine -2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyl xyphenyIalanyl-4-benzyloxy)succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, (±)-l-isopropyl-3-phenyI-4-(3-ethoxy-l-methyl-3-oxo-l-propy l)-7-[2-(4-cyanothiophenol)- l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[2-(4-cyanothiophenol)- l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyI-3-phenyI-4-[2-(l-f-butoxy-4-benzyloxy)su ccinyl)]-7-[2-(4-cyanothiophenol)- l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-ben zyloxy)succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[2-(4- cyanothiophenol)-l-ethyl]-3,4-dihydro-lH-l,4-benzodiazepine- 2,5-dione, (+)-l-isoproμ>yI-3-phenyl-4-[2-(l-benzyloxyphenylalanyl- 4-benzyloxy)succinyl)]-7-[2-(4- cyanothioρlnenol)-l-ethyl]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[4-[2-(N-Boc)amino-6- methylpyrimϊdine-4-yl]-4-oxa-l-butyI]-3,4-dihydro-lH-l,4-be nzodiazepine-2,5-dione, (±)-l-methyl-3-phenyI-4-(3-ethoxy-l-phenyI-3-oxo-l-propyl)- 7-[4-[2-(N-Boc)amino-6- methyIpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl )]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2^-dione, (±)-l-methyl-3-phenyI-4-[2-(l-benzyloxygIycinyl-4-benzyloxy )succinyl)]-7-[4-[2-(N- Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy) succinyl)]-7-[4-[2-(N-

Boc)amino-6-methylpyrϊmϊdine-4-yl]-4-oxa-l-buryl]-3,4-d ihydro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylaIanyl-4-be nzyloxy)succinyl)]-7-[4-[2-(N- Boc)amino-6-methylpyrimϊdine-4-yl]-4-oxa-l-butyl]-3,4-dihyd ro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l,3-diphenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propyI)-7- [4-[2-(N-Boc)amino-6- methyIpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)~l,3-diphenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)-7-[4- [2-(N-Boc)amino-6- methylpyrϊmidϊne-4-yI]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l,3-diphenyI-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)]-7- [4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-buryl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succ inyl)]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yll-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2^-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyvaIinyl-4-benzyloxy)succi nyl)]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyI)]-7-[4-[2-(N- Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyI]-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propy l)-7-[4-[2-(N-Boc)amino-6- methyIpyrimϊdϊne-4-yI]-4-oxa-l-butyI]-3,4-dϊhydro-lH-l,4- benzodiazepine-2^-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyI)- 7-[4-[2-(N-Boc)amino-6- methyIpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl )]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-benzyI-3-phenyl-4-[2-(l-benzy!oxyglycinyl-4-benzyloxy )succinyl)]-7-[4-[2-(N-

Boc)amιno-6-methyIpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-di hydro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[4-[2-(N- Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[4-[2-(N- Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-pr opyl)-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propy l)-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)su ccinyI)]-7-[4-[2-(N-Boc)amino-6- methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyIoxyglycinyl-4-benzyl oxy)succinyl)]-7-[4-[2-(N- Boc)amino-6-metlnylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihyd ro-lH-l,4-benzodiazepine- 2,5-dione,

(±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benz yloxy)succinyl)]-7-t4-[2-(N- Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[4-[2- (N-Boc)amino-6-methylpyrimidine-4-yl]-4-oxa-l-butyl]-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione,

(±)-l-methyl-3-phenyl-4-(3-ethoxy-l-methyI-3-oxo-l-propy l)-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[5-[2-(N- Boc)aminopyridine-3-yI]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl )]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy) succinyl)]-7-[5-[2-(N-

Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l, 4-benzodiazepine-2,5-dione, (±)-l-methyl-3-phenyl-4-[2-(l-benzyloxyphenylalanyl-4-benzy loxy)succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyI]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)-7-[5- [2-(N-Boc)aminopyridine-3- yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l,3-diphenyl-4-(3-etlnoxy-l-phenyl-3-oxo-l-propyl)-7 -[5-[2-(N-Boc)aminopyridine-3- yl]-5-oxa-l-pentyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l,3-diphenyl-4-[2-(l-f-butoxy-4-benzyloxy)succinyl)] -7-[5-[2-(N-Boc)aminopyridine-3- yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one,

(±)-l,3-diphenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy)succ inyl)]-7-[5-[2-(N- Boc)aminopyrϊdine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l,3-diphenyl-4-[2-(l-benzyloxyvalinyl-4-benzyloxy)succi nyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l,3-diphenyj-4-[2-(l-benzyloxyphenylalanyl-4-benzyloxy) succinyl)]-7-[5-[2-(N-

Boc)aminopyridϊne-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione ₇ (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-propyl)- 7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-(3-ethoxy-l-phenyl-3-oxo-l-propyl)- 7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyI]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-benzyI-3-phenyl-4-[2-(l-t-butoxy-4-benzyloxy)succinyl )]-7-[5-[2-(N- Boc)amϊnopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyloxy )succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yI]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyvalϊnyI-4-benzyIoxy )succinyl)]-7-[5-[2-(N-

Boc)amϊnopyridine-3-yI]-5-oxa-l-pentyl]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dϊone, (±)-l-benzyl-3-phenyl-4-[2-(l-benzyloxyphenylaIanyI-4-benzy loxy)succinyl)]-7-[5-[2-(N- Boc)aminopyridϊne-3-yl]-5-oxa-l-pentyl]-3,4-dϊhydro-lH-l,4 -benzodiazepine-2,5-dione, (±)-l-ϊsopropyl-3-phenyl-4-(3-ethoxy-l-methyl-3-oxo-l-prop yl)-7-[5-[2-(N- Boc)aminopyrϊdine-3-yI]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-ϊsopropyl-3-phenyl-4-(3-ethoxy-l-phenyI-3-oxo-l-prop yl)-7-[5-[2-(N- Boc)aminopyridine-3-yI]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-I-isopropyl-3-phenyl-4-[2-(l-f-butoxy-4-benzyloxy)succ� �nyl)]-7-[5-[2-(N- Boc)aminopyrϊdine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyglycinyl-4-benzyl oxy)succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yI]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyl-4-[2-(l-benzyloxyvalinyl-4-benzylo xy)succinyl)]-7-[5-[2-(N- Boc)aminopyridine-3-yl]-5-oxa-l-pentyl]-3,4-dihydro-lH-l,4-b enzodiazepine-2,5-dione, (±)-l-isopropyl-3-phenyI-4-[2-(l-benzyloxyphenylalanyl-4-be nzyloxy)succinyl)]-7-[5-[2- (N-Boc)aminopyridϊne-3-yI]-5-t)xa-l-pentylI-3,4-dihydro-lH- l,4-benzodiazepine-2,5- dione,

b) l-methyl-4-(2-carboxyethyl)-7-(5-amino-l-pentyl)-3,4-dihydro -lH-l,4- benzodiazepine-2,5-dione trifluoracetate was prepared using the method described in part (g) of example 1. Thus, 45mgs l-methyI-4-(2-carboxyethyl)-7-(N-boc-5-amino-l-pentyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione benzyl ester yielded 36mgs (93%) l-methyl-4-(2- carboxyethyl)-7-(5-amϊno-l-pentyl)-3,4-dihydro-lH-l,4-benzo diazepϊne-2,5-dione trifluoracetate (l/2' ^r C-18 reverse-phase column, eluting with a solvent gradient of 10:90 acetonϊtrile(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to

50:50 acetonitrile(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10ml/min, R _t =30.3 min, un detection 254nm). HRMS (FAB) molecular ion m/z=348.1931 ( cald. C18H25N3O4, 348.1923) 1H NMR (CDCI3 , dTMS) 7.39 (IH, bs, Ar-H 0-

CON), 7.34 (IH, d, p-CON), 7.16 (IH, d, m-CON), 4.00-3.90 (2H, m, NCHHCO, NCHHCH2), 3.67 (IH, d, ² J _HH =l6Hz, NCHHCO), 3.56 (IH, dt, ² J _HH =i4Hz, H3NCH2), 2.67-2.47

(4H, m, CH2CO2, ArCH2), 1.57-1.42 (4H, bs), 1.16 (2H, p,

Using the above procedure, but substituting the appropriate 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione for l-methyl-4-(2-carboxyethyl)-7-(N-boc-5-amino-l-pentyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione benzyl ester there could be prepared, for example, the following compounds: l-methyl-4-(2-carboxy-l-methylethyl)-7-(5-amino-l-pentyl)-3, 4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyl)-7-(5-amino-l-pentyl)-3, 4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5-amino-l-p entyl)-3,4-dihydro-lH-l,4- benzodiazeμnine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-(5-amino-l-pe ntyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-valine)]-7-(5-amino-l-pentyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-(5-amin o-l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-phenyI-4-(2-carboxy-l-methylethyl)-7-(5-amino-l-pentyl)-3, 4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenyletlnyl)-7-(5-amino-l-pentyl)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-plnenyl-4-[succin-2-yl-(l-Nbutoxy)]-7-(5-amino-l-p entyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-(5-amino-l-penty l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yI-(l-valine)]-7-(5-amino-l-pen tyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l -phenylalanine)]-7-(5-amino-l-ρentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-(5-amino-l-pentyl)-3, 4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-(5-amino-l-pentyl)-3, 4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-4-[succin-2-yl-(l-f-butoxy)]-7-(5-amino-l-pent yl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[sucdn-2-yl-(l-gIycine)]-7-(5-amino-l-pentyI )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-(5-amino-l-pentyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-phenylalanϊne)]-7-(5-amino- l-pentyl)-3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dione trifluoracetate, l-isoρropyl-4-(2-carboxy-l-methyIethyl)-7-(5-amϊno-l-penty l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-(5-amino-l-pentyl) -3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succϊn-2-yl-(l-t-butoxy)]-7-(5-amino -l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-I-isopropyl-4-[succin-2-yl-(l-glycine)]-7-(5-amino-l-pe ntyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succϊn-2-yl-(l-valϊne)l-7-(5-amino- l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanϊne)]-7-(5- amino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-tN-(2-aminoethane)-3- keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenyIethyl)-7-[N-(2-aminoethane)-3- keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succϊn-2-yl-(l-f-butoxy)]-7-[N-(2-amϊnoet hane)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-aminoet hane)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succϊn-2-yI-(l-valine)]-7-[N-(2-aminoet hane)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenyIalanϊne)]-7-[N-(2- aminoethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methyletlnyl)-7-[N-(2-amϊnoethane)- 3-keto-l-propyn-3-amine]- ,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-aminoethane)-3- keto-l-propyn-3-amine]-

3,4-dihydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l -phenyl -4-[succin-2-yl-(l-t-butoxy)]-7-[N-(2-aminoethane)-3-keto-l- propyn-3-amine]- 3,4-dihydro-lH-l ,4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-aminoethan e)-3-keto-l-propyn-3-amine]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-aminoethane )-3-keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 5 (±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2-amin oethane)-3-keto-l-propyn-3-

Λ amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, ^ l-benzyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-aminoethane)-3- keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-aminoethane)-3- keto-l-propyn-3-amine]- 10 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N-(2-aminoe thane)-3-keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-aminoet hane)-3-keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 15 (±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-aminoethane )-3-keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yI-(l-phenylalanine)]-7-[N-(2-a minoethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-aminoethane) -3-keto-l-propyn-3-amine]- 20 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-aminoethane) -3-keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isoprof>yI-4-[succin-2-yI-(l-t-butoxy)]-7-[N-(2 -aminoethane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 25 (±)-l-isopropy]-4-[succin-2-yl-(l-glycine)]-7-[N-(2-aminoet hane)-3-keto-l-propyn-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-amino ethane)-3-keto-l-propyn-3-amine]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-( 2-aminoethane)-3-keto-l-propyn- 30 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyn-3-(l -piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l-propyn-3-(l -piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5- ione trifluoracetate, 35 (±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3-keto-l-propy n-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzod iazepine-2,5-d ione tri f I uoraceta te,

(±)-l-methyl-4-[succin-2-yl-(l-glyciιne)]-7-[3-keto-l-p ropyn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyI-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-propyn- 3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-tsuccin-2-yl-(l-phenyIaIanine)]-7-[3-keto -l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyI)-7-[3-keto-l-propyn-3-(l -piperizine)]-3,4-dihydro- lH-l,4-benzodϊazepine-2,5-dϊone trifluoracetate, l-phenyI-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l-propyn-3-(l -piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-pbenyl-4-[sucdn-2-yl-(l-f-butoxy)]-7-[3-keto-l-pro pyn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-phenyl-4-[succin-2-yI-(l-glycine)]-7-[3-keto-l-pro pyn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-tsuccϊn-2-yl-(l-valine)]-7-[3-keto-l-pro pyn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepϊne-2,5-d ione tri fl uoraceta te, (±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[3-keto-l- propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyn-3-(l -piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenyletlnyl)-7-[3-keto-l-propyn-3-( l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-t-butoxy)]-7-[3-keto-l-pr opyn-3-(l-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trif luoraceta te,

(±)-l-benzyI-4-[succin-2-yl-(l-glycϊne)]-7-[3-keto-l-pr opyn-3-(I-piperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l-benzyI-4-[succϊn-2-yI-(l-vaIine)]-7-[3-keto-l-propyn -3-(l-pϊperizine)]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-benzyl-4-[sucdn-2-yl-(l-phenylalanϊne)]-7-[3-keto -l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-ϊsopropyl-4-(2-carboxy-l-methyIethyl)-7-[3-keto-l-propyn- 3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, l-ϊsopropyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l-propyn- 3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3-keto-l -propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-isopropyI-4-[succin-2-yl-(l-glycϊne)]-7-[3-keto-l-pr opyn-3-(l-piperϊzine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-vaIine)]-7-[3-keto-l-p ropyn-3-(l-piperizine)]-3,4- dihyd ro-lH-1 ,4-benzodiazepine-2,5-d ione tri f 1 uoraceta te,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[3-keto -l-propyn-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-aminoethanethio l)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 5 l-methyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-aminoethanethio l)-l-ethyl]-3,4-dihydro-

*> lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-i-butoxy)]-7-[2-(2-aminoe thanethiol)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-aminoet hanethiol)-l-ethyl]-3,4-dihydro- 10 lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-aminoeth anethiol)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2-a minoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 15 l-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-aminoethanethio l)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-] -phenylethyI)-7-[2-(2-aminoethanethiol)-l-ethyl]-3,4-dihydro - lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-bιιtoxy)]-7-[2-(2-ami noethanethiol)-l-ethyl]-3,4-dihydro- 20 lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-aminoet hanethiol)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyI-4-[succin-2-yl-(l-valine)]-7-[2-(2-aminoeth anethiol)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5- ione trifluoracetate, 25 (±)-l-plnenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2-ami noethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-aminoethanethio l)-l-ethyI]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-pheιnylethyl)-7-[2-(2-aminoethaneth iol)-l-ethyl]-3,4-dihydro- 30 lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-aminoe tlnanethiol)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-aminoet hanethiol)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 35 (±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-aminoethane thiol)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzy]-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2-a minoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-aminoethanet hiol)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-aminoetlnane thiol)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-aminoe thanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-amin oethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yI-(l-valine)]-7-[2-(2-amino ethanethiol)-l-ethyl]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-( 2-aminoethanethiol)-l-ethyI]-3,4- dihyd o-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l -methy lethyl )-7-[4-(2-a mi no-6-methyl py rimid ine-4-yI)-4-oxa-l- butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenyIethyl)-7-[4-(2-amino-6-methylp yrimidine-4-yl)-4-oxa-l- butyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-[4-(2-amino- 6-methylpyrimidine-4-yl)-4-oxa-l- butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yI-(l-glycine)]-7-[4-(2-amϊno- 6-methylpyrimidine-4-yl)-4-oxa-l- butylJ-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-methyI-4-[succin-2-yl-(l-valine)]-7-[4-(2-amino-6- methylpyrimidine-4-yI)-4-oxa-l- butyI]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenyIalanine)]-7-[4-(2-a mino-6-methyIpyrimϊdine-4-yl)-4- oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[4-(2-amino-6-methylp yrimidϊne-4-yl)-4-oxa-l- butyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyl)-7-[4-(2-amino-6-methylp yrimidine-4-yl)-4-oxa-l- butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[4-(2-amino- 6-methylpyrimidine-4-yl)-4-oxa-l- butyl]-3,4-dihydro-lH-I,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycϊne)]-7-[4-(2-amino- 6-methyIpyrimidine-4-yl)-4-oxa-l- butyl]-3,4-dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate, (±)-l-phenyI-4-[succin-2-yl-(l-valine)]-7-[4-(2-amino-6-met hylpyrϊmidine-4-yl)-4-oxa-l- buryl]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[4-(2-amin o-6-methylpyrimidine-4-yl)-4- oxa-l-butyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-metInylethyl)-7-[4-(2-amino-6-methyl pyrimidine-4-yl)-4-oxa-l- butyI]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[4-(2-amino-6-methylp yrimidine-4-yl)-4-oxa-l- butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyI-4-[succin-2-yl-(l-t-butoxy)]-7-[4-(2-amino-6-m ethylpyrimidine-4-yl)-4-oxa-l- butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[4-(2-amino-6-me thylpyrimidine-4-yl)-4-oxa-l- butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yI-(l-valine)]-7-[4-(2-amino-6-met hylpyrimidine-4-yl)-4-oxa-l- butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-phenylalanine)]-7-[4-(2-amin o-6-methylpyrimidine-4-yl)-4- oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyI)-7-[4-(2-amino-6-meth ylpyrimidine-4-yl)-4-oxa- l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l -phenylethyI)-7-[4-(2-amino-6-methylpyrimidine-4-yl)-4-oxa- l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-f-butoxy)]-7-[4-(2-amino- 6-methylpyrimidine-4-yl)-4-oxa- l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-f4-(2-amino-6 -methylpyrimidine-4-yl)]-4-oxa- l-butyl]-3,4-dihydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-isopropy]-4-[succin-2-yI-(l-valine)]-7-[4-(2-amino-6- methylpyrimidine-4-yl)-4-oxa- l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[4-( 2-amino-6-methylpyrimidine-4- yl)-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dio ne trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[5-(2-aminopyridine-3 -yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyl)-7-[5-(2-aminopyridine-3 -yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-[5-(2-aminop yridine-3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[5-(2-aminopyrid ine-3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyI-4-[succin-2-yl-(l-valine)]-7-[5-(2-aminopyr idine-3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yI-(l-ρhenylalanine)]-7-[5-(2- aminopyridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[5-(2-aminopyridine-3 -yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-ρhenylethyl)-7-[5-(2-aminopyridine- 3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyI-4-[succϊn-2-yl-(l-f-butoxy)]-7-[5-(2-aminopyr idine-3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycϊne)]-7-[5-(2-aminop yridine-3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yI-(l-valine)]-7-[5-(2-aminopyridi ne-3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-phenylaIanine)]-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- penryl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyI-4-(2-carboxy-l-methylethyl)-7-[5-(2-aminopyrϊdine- 3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-benzyI-4-(2-carboxy-l-phenyIethyl)-7-[5-(2-aminopyridine-3 -yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-f-butoxy)]-7-[5-(2-aminop yrϊdine-3-yl)-5-oxa-l-pentyl]-3,4- dϊhydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[5-(2-aminopyrid ine-3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[5-(2-aminopyr idine-3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[sucdn-2-yl-(l-phenylalanine)]-7-[5-(2-am inopyridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyI-4-(2-carboxy-l-methylethyl)-7-[5-(2-aminopyrϊdi ne-3-yl)-5-oxa-l-pentyl]-3,4- dihyd ro-1 H-l,4-benzod iazepine-2,5-d ione tri f 1 uoraceta te, l-isopropyl-4-(2-carboxy-l-phenylethyI)-7-[5-(2-amϊnopyridi ne-3-yI)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate, (±)-l-isopropyI-4-[sucdn~2-yl-(l-t-butoxy)]-7-[5-(2-aminopy ridine-3-yl)-5-oxa-l-pentyI]- 3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-glydne)]-7-[5-(2-amino pyridine-3-yl)-5-oxa-l-pentyl]-3,4- dihydro-IH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-valine)]-7-[5-(2-amino pyridine-3-yl)-5-oxa-l-pentyl]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dϊone trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[5-( 2-aminopyrϊdine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyI-4-(2-carboxy-l-methylethyI)-7-(5-amin o-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepϊne-2,5-dϊone trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenyIethyl)-7-(5-amin o-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succϊn-2-yl-(l-t-butoxy)]-7-(5 -amϊno-l-pentyI)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dϊone trifluoracetate,

± - -met y - -p eny - - succ n- -y - -g yc ne - - -am no- -pen y - , - y ro- - l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-(5-am ino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylaIanine)]-7-( 5-amino-l-pentyl)-3,4- dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-(5-amino-l-p entyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-d ione tri f 1 u o raceta te,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-(5-amino- l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l^-diphenyl-4-[succin-2-yl-(l-i-butoxy)]-7-(5-amino- l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-(5-amino- l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yI-(l-valine)]-7-(5-amino-l-pe ntyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-(5- amino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methyiethyI)-7-(5-a mino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyI-4-(2-carboxy-l-phenylethyl)-7-(5-a mino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5- amino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzy!-3-ρhenyI-4-[succin-2-yl-(l-gIycine)]-7-(5-ami no-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-(5-am ino-l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-(5-amino-l-pentyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-( 5-amino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyI-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-( 5-amino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5- amino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-( 5-amino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-(5-am ino-l pentyl)-3,4-dihydro-l l,4-benzodiazepϊne-2,5-dϊone trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine )]-7-(5-amϊno-l-pentyl)-3,4- dihydro-!H-l,4-benzodiazepine-2,5-dione trifluoracetate, (+)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-am inoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-a minoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-t-butoxy)]-7-[N- (2-aminoethane)-3-keto-l-propy 3-amine]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yI-(l-glycine)]-7-[N-( 2-aminoethane)-3-keto-l-propyl 3-amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyI-4-[succin-2-yl-(l-valine)]-7-[N-(2-am inoethane)-3-keto-l-propyl- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)l-7-[ N-(2-aminoethane)-3-keto-l- propyI-3-amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-dipInenyl-4-(2-carboxy-l-metInylethyI)-7-[N-(2-amin oethane)-3-keto-l-propyl-3- amine]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-amϊno ethane)-3-keto-l-propyl-3- amine]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-t-butoxy)]-7-[N-(2-am inoethane)-3-keto-l-propyl-3- amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-dϊphenyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-amino ethane)-3-keto-l-propyl-3- amine]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l,3-dϊphenyl-4-[succin-2-yl-(l-valϊne)]-7-[N-(2-amino ethane)-3-keto-l-propyl-3- amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-dϊphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2 -aminoethane)-3-keto-l-propyl 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-a minoethane)-3-keto-l- propyl-3-amine]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dϊon e trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[N-( 2-aminoethane)-3-keto-l- propyl-3-amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[sucdn-2-yl-(l-f-butoxy)]-7-[N-(2-a minoethane)-3-keto-l-propyI- 3-amϊne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-a mϊnoethane)-3-keto-l-propyI-3- amϊne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-vatine)]-7-[N-(2 -aminoethane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate.

propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[N-( 2-aminoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[N-( 2-aminoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N- (2-aminoethane)-3-keto-l- propyl-3-amine]-3,4-dihyd ro-1 H-l ,4-benzod iazepine-2,5-d ione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[N-( 2-aminoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[N -(2-aminoethane)-3-keto-l-propyl- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yI-(l-phenylalanine)]- 7-[N-(2-aminoethane)-3-keto- l-propyl-3-amine]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l -methylethyl)-7-[3-keto-l-propyl-3-(l-piperizine)]-

3,4-dihydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-methyI-3-phenyl-4-(2-carboxy-l-phenyiethyl)-7-[3-keto -l-propyl-3-(l-piperizine)]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3- keto-l-propyl-3-(l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[3-k eto-l-propyl-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yI-(l-valine)]-7-[3-ke to-l-propyl-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yI-(l -plnenylalanine)]-7-[3-keto-l-propyl-3-(l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-metlnylethyl)-7-[3-keto- l-propyl-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l -propyl-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l- butoxy)]-7-[3-keto-l-propyI-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l -propyl-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diplnenyl-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-pr opyl-3-(l-piperizine)]-3,4- d ihyd ro-1 H-l ,4-benzod iazep i ne-2,5-d ione tri fl uoraceta te,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[3- keto-l-ρropyl-3-(l-piperizine)]-

3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-benzyI-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[3-keto -l-propyl-3-(l-piperizine)]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyI)-7-[3-k eto-l-propyl-3-(l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyI-4-[succin-2-yI-(l-t-butoxy)]-7-[3-ket o-l-propyl-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[sucdn-2-yI-(l-glycine)]-7-[3-ke to-l-propyl-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[3-ke to-l-propyl-3-(l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-[3-keto-l-propyl-3-(l- pϊperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-ϊsopropyl-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[3- keto-l-propyl-3-(l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyI-4-(2-carboxy-l-phenylethyl)-7-[3-k eto-l-propyl-3-(l- piperizine)]-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione trifluoracetate, . (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3- keto-l-propyl-3-(l-piperizine)]- 3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-tsuccϊn-2-yl-(l-glycine)]-7- [3-keto-l-propyl-3-(l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-t3 -keto-l-propyl-3-(l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succϊn-2-yl-(l-phenylalanine)] -7-[3-keto-l-propyl-3-(l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-t2-(2-a minoethanethiol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-( 2-aminoethanethiol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2- (2-aminoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-( 2-aminoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyI-4-[succin-2-yl-(l-valϊne)]-7-[2-( 2-aminoethanethioI)-l-ethyl]-3,4- dihyd ro-1 H-l ,4-benzod iazep i ne-2,5-d ione tri f 1 uoraceta te, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenyIalanine)]-7-[ 2-(2-aminoethanethiol)-l- • ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyI-4-(2-carboxy-l-methyIethyl)-7-[2-(2-aminoe thanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-aminoe thanet io - -et y - , - dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-am inoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-aminoe thanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-amin oethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2- aminoethanethiol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[2-( 2-aminoethanethiol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-3-phenyl-4-(2-carboxy-l-plnenylethyl)-7-[2- (2-aminoethanethiol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyI-3-pheny]-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2- aminoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-( 2-aminoethanethiol)-l-ethyl]-3,4- dihydro-1 H-l ,4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-benzyI-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-am inoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yI-(l-phenylalanine)]- 7-[2-(2-aminoethanethiol)-l- ethyI]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-isopropyI-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[2-( 2-aminoethanethiol)-l- ethyl]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenyletlnyl)-7-[2- (2-aminoethanethiol)-l- ethyl]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7- [2-(2-aminoethanethiol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-( 2-aminoethanethiol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate,

(±)-l-isoproρyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[ 2-(2-aminoethanethiol)-l-ethyl]- 3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l -plnenylalanine)]-7-t2-(2-aminoethanethiol)-l- ethyl]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[4-(2-a mino-6-methylpyrimidine-4- yl)-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dio ne trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[4-(2-a mino-6-methylpyrimidine-4- yl)-4-oxa-l-butyl]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[4-(2- amino-6-methylpyrimidine-4- yl)-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-di one trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[4-(2-a mino-6-methylpyrϊmidine-4- yl)-4-oxa-l-butyl]-3,4-dihydro-IH-l,4-benzodiazepine-2,5-dio ne trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-vaIine)]-7-[4-(2-am ino-6-methyIpyrimidine-4-yl)- 4-oxa-l-butyIj-3,4-dihydro-lH-l,4-benzodiazepϊne~2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 4-(2-amino-6- methylpyrimidine-4-yl)-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-methyIethyl)-7-[4-(2-amino- 6-methylpyrimidine-4-yl)-4- oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3- ^s diphenyI-4-(2-carboxy-l-phenylethyl)-7-[4-(2-amϊno-6- methylpyrimidine-4-yl)-4- oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l,3-dϊphenyl-4-[sucdn-2-yl-(l-f-butoxy)]-7-[4-(2-amino -6-methylpyrimidine-4-yl)-4- oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-dIphenyl-4-[succϊn-2-yl-(l-glycine)]-7-[4-(2-am ϊno-6-methyIpyrimidine-4-yl)-4- oxa-l-butyl]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (+)-l,3-dϊphenyI-4-[succϊn-2-yI-(l-valine)]-7-[4-(2-amino- 6-methylpyrimidine-4-yI)-4-oxa- l-butyl]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l,3-diphenyI-4-[succϊn-2-yI-(l-phenylalanϊne)]-7-[4-( 2-amino-6-methylpyrimidine-4- yl)-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dio ne trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[4-(2-a mino-6-methylpyrimidine-4- yl)-4-oxa-l-butyI]-3,4-dihydro-IH-l,4-benzodiazepine-2,5-dio ne trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyI)-7-[4-(2-a mino-6-methylpyrimidine-4- yl)-4-oxa-l-butyl]-3,4-d ihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-t-butoxy)]-7-[4- (2-amino-6-methylpyrimidine-4- yl)-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-di one trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[4-(2-a mino-6-methylpyrϊmidine-4-yl)- 4-oxa-l-butyl]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[4-(2-am ino-6-methylpyrimidine-4-yl)- 4-oxa-l-butyl]-3,4-dϊhydro-lH-l,4-benzodϊazepϊne-2,5-dion e trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succϊn-2-yl-(l-phenylalanine)]-7- [4-(2-amino-6- methylpyrimidine-4-yl)-4-oxa-l-buty ^] ]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyI-3-phenyl-4-(2-carbc)xy-l-methylethyl)-7-t4- (2-amino-6- methylpyrimidine-4-yl)-4-oxa-l-butyl]-3,4-dϊhydro-lH-l,4-be nzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[ 4-(2-amino-6-methylpyrimidine- 4-yl)-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-isopropyI-3-pheny]-4-tsuccin-2-yl-(l-f-butoxy)]-7-[4- (2-amino-6-methylpyrimidine-4- yl)-4-oxa-l-buityl]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropy2-3-ρhenyl-4-[succin-2-yl-(l-glycine)]-7-[4- (2-amino-6-methylpyrimidine-4- yl)]-4-oxa-l-buryι]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[4-(2 -amino-6-methylpyrimidine-4- yl)-4-oxa-l-butyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dio ne trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine )]-7-[4-(2-amino-6- methylpyrimidine-4-yI)-4-oxa-l-butyl]-3,4-dihydro-lH-l,4-ben zodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyl]-3,4-d-ihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[5-(2- aminopyridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[5-( 2-aminopyridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyI-4-[succin-2-yl-(l-valine)]-7-[5-(2-am inopyridine-3-yI)-5-oxa-l- pentyI]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methy3-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 5-(2-aminopyridine-3-yl)-5- oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-[5-(2-aminop yridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-plnenylethyl)-7-[5-(2-amino pyridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diρlnenyl-4-[succin-2-yl-(l-Nbutoxy)]-7-[5-(2-a minopyridine-3-yl)-5-oxa-l-pentyl]- 3,4-dihydro-l H- ,4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[5-(2-ami nopyridine-3-yl)-5-oxa-l-pentyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[5-(2-aminopy ridine-3-yl)-5-oxa-l-pentyl]- 3,4-dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[5- (2-aminopyridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenvlethyI)-7-[5-( 2-aminopyridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[5-(2- aminopyridine-3-yl)-5-oxa-l- pentyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yI-(l-glycine)]-7-[5-(2-a minopyridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone trifluoracetate, (±)-l-benzyI-3-phenyI-4-[succin-2-yI-(l-vaIine)]-7-t5-(2-am inopyridine-3-yl)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 5-(2-aminopyridine-3-yl)-5- oxa-l-pentyl]-3,4-dihydro-IH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-ϊsopropyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[5- (2-aminopyridine-3-yl)-5-oxa- l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[5-( 2-aminopyridine-3-yl)-5-oxa- l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-ϊsopropyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7 -[5-(2-aminopyridine-3-yl)-5-oxa-l- pentyl].-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succϊn-2-yl-(l-glycine)l-7-[5- (2-aminopyrϊdine-3-yl)-5-oxa-l- pentyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-ϊsopropyI-3-phenyI-4-[succin-2-yl-(l-valine)]-7-[5-( 2-aminopyridine-3-yI)-5-oxa-l- pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyI-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-[5-(2-aminopyrϊdine-3-yl)-5- oxa-l-pentyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

c) l-methyI-4-(2-carboxyethyl)-7-(5-guanidϊno-l-pentyl)-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dione was prepared by the method described in Example 2. Thus, 18mgs l-methyl-4-(2-carboxyethyl)-7-(5-amino-l-pentyI)-3,4-dihydro -lH-l,4- benzodϊazepine-2,5-dione yielded 17mgs (87%) l-methyl-4-(2-carboxyethyl)-7-(5- guanidϊno-l-pentyl)-3,4-dihydro-IH-l,4-benzodiazepine-2,5-d ione trifluoracetate (1/2" C- 18 reverse-phase column, eluting with a solvent gradient of 10:90 methanol(0.1% trifluoracetic add)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to 50:50 methanol (0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10ml/min, R _t =38.5 min, un detection 254nm). HRMS (FAB) molecular ion m/z=390.2132 ( cald. C19H27N5O4, 390.2182) Using the above procedure, but substituting the appropriate amino acid for 1-methyl-

4-(2-carboxyethyl)-7-(5-amino-l-pentyI)-3,4-dihydro-lH-l, 4-benzodiazepine-2,5-dione there may be prepared, for example, the following compounds: l-methyl-4-(2-carboxy-l-methylethyI)-7-(5-guanidino-l-pentyI )-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoracetate, l-methyl-4-(2-carbc)xy-l-phenylethyl)-7-(5-guanidino-l-penty l)-3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-methyI-4-[succin-2-yl-(l-f-butoxy)]-7-(5-guanidino -l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate.

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-(5-guanidino-l-p entyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-valine)]-7-(5-guanidino-l -pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-(5-guanidi no-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyI)-7-(5-guanidino-l-pentyl )-3,4-dihydro-lH-l,4- benzodiazeρine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyl)-7-(5-guanidino-l-pentyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5-guanidino -l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-(5-guanidino- l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-(5-guanidino-l-pe ntyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-(5-guan idino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyI-4-(2-carboxy-l-methyletlnyl)-7-(5-guanidino-l-penty l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-(5-guanidino-l-pentyI )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l- butoxy)]-7-(5-guanidino-l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-(5-guanidino-l-p entyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-(5-guanidin()- l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-phenylalanine)]-7-(5-guan idino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-metlnylethyl)-7-(5-guanidino-l-pe ntyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-(5-guanidino-l-pen tyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-f-butoxy)]-7-(5-guanidino -l-pentyI)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-(5-guanidi no-l-pentyI)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-ϊsopropyl-4-[succin-2-yI-(l-valine)]-7-(5-guanidino- l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyI-4-[succin-2-yl-(l-phenylalanine)]-7-(5-g uanidino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-guanidinoethane )-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione trifluoracetate, l-methyI-4-(2-carboxy-l-phenylethyl)-7-[N-(2-guanidinoethane )-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N-(2-guanidino ethane)-3-keto-l-propyI-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-guanϊd inoethane)-3-keto-l-propyl-3- amϊne]τ3,4-dϊhydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-guanϊdinoe thane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2-guan idinoethane)-3-keto-l-propyl- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-guanidinoethane )-3-keto-l-propyI-3- amine]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-guanϊdinoethan e)-3-keto-l-propyl-3- amine]-3,4-dihydrυ-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yI-(l-f-butoxy)]-7-[N-(2-guanid inoethane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-guanidinoe thane)-3-keto-l-propyI-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyI-4-[succin-2-yl-(l-valine)]-7-[N-(2-guanidinoet hane)-3-keto-l-propyI-3- amine]-3,4-dϊhyd ro-1 H-l,4-benzod iazepine-2,5-d ione tri f luoraceta te, (±)-l-phenyl-4-[succϊn-2-yl-(l-phenylalanine)]-7-[N-(2-gua nidinoethane)-3-keto-l-propyl- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-[N-(2-guanidinoethane )-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyI-4-(2-carboxy-l-phenylethyI)-7-[N-(2-guanidinoethane )-3-keto-l-propyl-3- ammej-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-t-butoxy)]-7-[N-(2-guanidino ethane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-guanidinoe thane)-3-keto-l-propyl-3- amine]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l-benzyl-4-[succin-2-yI-(l-valine)]-7-[N-(2-guanϊdinoe thane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2-guan idinoethane)-3-keto-l-propyl- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyI)-7-[N-(2-guanidinoeth ane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-guanidinoeth ane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-r-butoxy)]-7-[N-(2-guanid inoethane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-guanidi noethane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-guani dinoethane)-3-keto-l-propyl-3- amine] ^: 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2-g uanidinoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyl-3-(4 -amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenyletlnyl)-7-[3-keto-l-propyl-3-( 4-amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3-keto-l-pr opyl-3-(4-amidino-l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l-pro pyl-3-(4-amidino-l-piperizine)]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yI-(l-valine)]-7-[3-keto-l-prop yl-3-(4-amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-[3-keto-l- proρyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyl-3-(4 -amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, ^• l-phenyl-4-(2-carboxy-l-phenyletlnyl)-7-[3-keto-l-propyl-3-( 4-amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3-keto-l-pr opyl-3-(4-amidino-l-piperizine)]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l-pro pyl-3-(4-amidino-l-piperizine)]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyI-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-propyl- 3-(4-amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[3-keto -l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-l H-l, 4-benzodiazepiιne-2,5-d ione trifluoracetate,

l-benzyl-4-(2-carboxy-l-methylethyI)-7-[3-keto-l-propyl-3-(4 -amidϊno-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l-propyI-3-(4 -amidino-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-t-butoxy)]-7-[3-keto-l-propy l-3-(4-amidino-l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-benzyl-4-[succϊn-2-yl-(l-glycine)]-7-[3-keto-l-pr opyl-3-(4-amidino-l-pϊperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-prop yl-3-(4-amϊdirio-l-piperizine)]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-phenyIalanϊne)]-7-[3-ket o-l-propyI-3-(4-amidino-l- pϊperizine)]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-propyl-3 -(4-amidino-l-piperizine)]- 3,4-dihydro-IH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyI-4-(2-carboxy-l-phenyIethyl)-7-[3-keto-l-propyl-3 -(4-amidino-l-piperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-diυne trifluoracetate,

(±)-l-ϊsopropyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3-keto- l-propyI-3-(4-amidino-l-piperϊzine)]- 3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-fsuccin-2-yl-(l-glycine)]-7-[3-keto-l- propyl-3-(4-amidino-l-piperizine)]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dϊone trifluoracetate,

(±)-l-isopropyI-4-[succϊn-2-yl-(l-valine)]-7-[3-keto-l- propyl-3-(4-amidino-l-pϊperizine)]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succϊn-2-yl-(l-phenyialanine)]-7-[3- keto-l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyI)-7-[2-(2-guanidinoethane thiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-guanidinoethane thiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-tsuccin-2-yl-(l-f-butoxy)]-7-[2-(2-guanid ϊnoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-t2-(2-guanidi noethanethiol)-l-ethyl]-3,4- dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yI-(l-valine)]-7-[2-(2-guanidin oethanethioI)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l-methyl-4-[succin-2-yI-(l-phenylaIanine)]-7-[2-(2-guan idinoethanethiol)-l-ethyl]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-guanidinoethane thiol)-l-ethyl]-3,4- dihydro-lH-I,4-benzod?azepine-2,5-dϊone trifluoracetate,

l-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-guanidinoethane thiol)-l-ethyl]-3,4- dihydro-1 H-l ,4-benzodiazepine-2,5-d ione tri f 1 uoraceta te,

(±)-l-pheny]-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-guanid inoethanethiol)-l-ethyI]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-guanidinoe thanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-guanidin oethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2-g uanidinoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-guanidinoethane thiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-guanidinoethane thiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-guanidino ethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-guanidi noethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-guanidin oethanethiol)-l-ethyI]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(2-g uanidinoethanethiol)-l-ethyl]-3,4- dihyd ro-1 H-l ,4-benzodiazepine-2,5-d ione tri f 1 uoraceta te, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-guanidinoeth anethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyI)-7-[2-(2-guanidinoeth anethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-r-butoxy)]-7-[2-(2-gua nidinoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-[2-(2-guan idinoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-guani dinoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-( 2-guanidinoethanethiol)-l-ethyl]-

3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l -methylethyl)-7-(5-guanidino-l-pentyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methy]-3-phenyl-4-(2-carboxy-l-plnenylethyl)-7-(5- guanidino-l-pentyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-t-butoxy)]-7-(5-gua nidino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycϊne)]-7-(5- guanidino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yI-(l-valine)]-7-(5-guani dino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-(5-guanidino-l-pentyl)-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-(5-guanid ino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyI)-7-(5-guanid ino-l-pentyI)-3,4-dihydro-lH- l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succϊn-2-yl-(l-t-butoxy)]-7-(5-guan idino-l-pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-dtphenyl-4-[succin-2-yl-(l-glycine)]-7-(5-guanidino -l-pentyI)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l,3-dϊphenyl-4-[sucdn-2-yl-(l-valϊne)]-7-(5-guanid ino-l-pentyl)-3,4-dihydro-lH-l,4- benzodϊazepϊne-2,5-dione trifluoracetate,

(±)-l,3-diphenyI-4-[succin-2-yl-(l-phenylalanϊne)]-7-(5 -guanidino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyI)-7-(5-g uanidino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepϊne-2,5-dϊone trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-(5-g uanidino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yI-(l-f-butoxy)]-7-(5-gua nidino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yI-(l-glycine)]-7-(5-g uanidino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-3-phenyl-4-[succin-2-yl-(l-valine)]-7-(5-gu anϊdino-l-pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-(5-guanidino-l-pentyl)-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methyIethyl)-7-( 5-guanidino-l-pentyl)-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-(5-g uanidino-l-pentyl)-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone trifluoracetate,

(±)-l-isopropyl-3-phenyI-4-[succin-2-yl-(l-t-butoxy)]-7- (5-guanidino-l-pentyl)-3,4- dihydro-lH-l,4-benzodϊazeρine-2,5-dione trifluoracetate,

9T>

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-(5-g uanidino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-(5 -guanidino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 5 (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-ρhenyIalanine)] -7-(5-guanidino-l-pentyI)-3,4- ' dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[N-( 2-guanidinoethane)-3-keto-l- _> propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyI)-7-[N-( 2-guanidinoethane)-3-keto-l- 10 propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N- (2-guanidinoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yI-(l-glycine)]-7-[N-(2-g uanidinoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 15 (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-gu anidinoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenyIalanine)]-7-f N-(2-guanidinoethane)-3- keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione trifluoracetate, (±)-l,3-diphenyI-4-(2-carboxy-l-methyIetlnyI)-7-[N-(2-guani dinoethane)-3-keto-l-propyl- 20 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2-gua nidinoethane)-3-keto-l-propyl- 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[N-(2-guani dinoethane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 25 (±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[N-(2-guanid inoethane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[N-(2-guanidi noethane)-3-keto-l-propyl-3- amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[N-(2- guanidinoethane)-3-keto-l- 30 propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-ρhenyl-4-(2-carboxy-l-methylethyl)-7-[N- (2-guanidinoethane)-3-keto-l- propyl-3-amine]-3,4-dilnydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-benzyl-3-plnenyl-4-(2-carboxy-l-phenylethyl)-7-[N-(2- guanidinoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 35 (±)-l-benzyl-3-plnenyl-4-[succin-2-yl-(l- -butoxy)]-7-[N-(2-guanidinoethane)-3-keto-l- * ^" propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[N-( 2-guanidinoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-benzyI-3-phenyl-4-[succϊn-2-yI-(l-valine)]-7-[N-(2-g uanϊdinoethane)-3-keto-l- propyI-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ N-(2-guanidinoethane)-3-keto- l-propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e trifluoracetate, (±)-l-ϊsopropyI-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[N- (2-guanidϊnoethane)-3-keto- l-propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e trifluoracetate, (±)-l-isopropyl-3-phenyI-4-(2-carboxy-l-phenylethyl)-7-[N-( 2-guanϊdinoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyI-3-phenyl-4-[succϊn-2-yl-(l-f-butoxy)]-7-[N -(2-guanidinoethane)-3-keto-l- propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glydne)]-7-[N -(2-guanidinoethane)-3-keto-l- propyl ⁱ 3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-ϊsopropyI-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[N-( 2-guanidinoethane)-3-keto-l- propyl-3-amine]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-[N-(2-gύanidinoethane)-3- keto-l-propyl-3-amine]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione trifluoracetate, (±)-l-methyI-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[3-keto -l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-methyI-3-phenyl-4-(2-carboxy-l-phenylethyI)-7-[3-keto -l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3- keto-l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-gIycine)]-7-t3-keto -l-propyl-3-(4-amidino-l- pϊperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succϊn-2-yl-(l-valine)]-7-[3-keto -l-propyl-3-(4-amϊdino-l- pϊperizine)]-3,4-dihydro-lH-I,4-benzodiazepine-2,5-dione trifluoracetate, (±)-I-methyI-3-phenyl-4-[succϊn-2-yl-(l-plneιnylalanine)] -7-[3-keto-l-propyl-3-(4-amidino- l-piperizine)]-3,4-dihydro-lH-I,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-[3-keto-l-pr opyl-3-(4-amidϊno-l- piperizine)]-3,4-dilnydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto-l -propyI-3-(4-amidϊno-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3-keto-l-p ropyI-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-I,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto-l-pr opyl-3-(4-amidino-l- piperizϊne)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[3-keto-l-pro pyl-3-(4-amidino-l-piperizine)]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[3-ket o-l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[3-keto -l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[3-keto -l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-t-butoxy)]-7-[3-ket o-l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[3-keto -l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[3-ke to-l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyI-4-[succin-2-yl-(l-phenylalanine)]-7-[ 3-keto-l-propyl-3-(4-amidino- l-piperizine)]-3,4-d ihyd ro-1 H-l, 4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[3-k eto-l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate/ (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[3-k eto-l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyI-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[3- keto-l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[ 3-keto-l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-isoproρyl-3-phenyI-4-[succin-2-yI-(l-valine)]-7-[3-k eto-l-propyl-3-(4-amidino-l- piperizine)]-3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-isopropyI-3-plnenyl-4-[succin-2-yl-(l-phenylalanine)] -7-[3-keto-l-propyl-3-(4- amidino-l-piperizine)]-3,4-dihydro-lH-l,4-benzodiazepine-2,5 -dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-(2-g uanidinoethanethiol)-l- ethyl]-3,4-dilnydro-l H-l, 4-benzodiazepine-2,5- ione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(2-g uanidinoethanethiol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yI-(l-f-butoxy)]-7-[2- (2-guanidinoethanethiol)-l-ethyl]- 3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l -glycine)] -7-[2-(2-guanidinoethanethiol)-l-ethyl]- 3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(2-gu anidinoethanethiol)-l-ethyl]- 3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-methyl-3-plnenyI-4-[succin-2-yl-(l-phenylalanine)] -7-[2-(2-guanidinoethanethioI)-l- ethyl]-3,4-d ihy ro-1 H-l, 4-benzodiazepine-2,5-d ione trifluoracetate.

(±)-l,3-diphenyI-4-(2-carboxy-l-methylethyl)-7-[2-(2-guanid inoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenyIethyl)-7-[2-(2-gua nidinoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(2-guani dinoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyI-4-[succin-2-yI-(l-glycine)]-7-[2-(2-gua nidinoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyI-4-[succin-2-yI-(l-va!ine)]-7-[2-(2-guan idinoethanethiol)-l-ethyl]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2- (2-guanidinoethanethiol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-( 2-guanIdinoethanethiol)-l- ethyI]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenyIethyl)-7-[2-(2-g uanidinoethanethiol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-benzyl-3-plnenyl-4-[succϊn-2-yl-(l-t-butoxy)]-7-[ 2-(2-guanidinoethanethiol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-3-phenyl-4-[succin-2-yl-(l-gIycine)]-7-[2-( 2-guanidinoethanethiol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(2 -guanidinoethanethiol)-l-ethyl]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyI-4-[succin-2-yl-(l-phenylalanine)]- 7-[2-(2-guanidinoethanethiol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-isopropyI-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[2-( 2-guanidinoethanethϊoI)-l- ethyl]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyI-4-(2-carboxy-l-phenyIethyI)-7-t2-( 2-guanidinoethanethiol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yI-(l-t-butoxy)]-7-[2- (2-guanidinoethanethiol)-l- ethyl]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycϊne)]-7- t2-(2-guanidinoethanethiol)-l- ethyI]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyI-4-[succin-2-yl-(l-valine)]-7-[2-(2 -guanidinoethanethiol)-l- ethyl]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-isopropyI-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-[2-(2-guanidinoethanethiol)- l-ethyI]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate.

l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-(5-amino-l-pentyny l)-3 _r 4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate. a ) N-(2-amino-5-iodobenzoyl)-b-alanine ethyl ester was prepared using the method described in part (b) of Example 1. Thus, from 21.0 grams of 6-iodoisatoic anhydride (0.73 mol) and 11.3 grams of b-alanine ethyl ester hydrogenchloride (0.73 mol) was prepared 9.1 grams (35%) N-(2-amino-5-iodobenzoyl)-b-alanine ethyl ester (mp=83-85°C, TLC, Siθ2, 1:1 EtOAc/hexane, Rf=0.46, un positive). 1H NMR (CDCI3 , dTMS) 7.57 (IH, d, ⁴ J _H H = 2Hz, Ar-H o-CON), 7.42 (IH, dd, Ar-H p-CON), 6.63 (IH, bs, CONH), 6.44 (IH, d, J _HH =9Hz, Ar-H w-CON), 5.57 (2H, bs, NH2), 4.10 (2H, q, ³ JHH=7Hz, OCH2), 3.63 (2H, q, J _H H=6Hz, NCH ₂ ), 2.63 (2H, t, J _H H=6Hz, CH ₂ CO ₂ ), 1.14 (3H, t, ³ J _H H=7Hz, CH3).

b) A magnetically stirred solution of 1.2 grams N-(2-amino-5-iodobenzoyl)-b-alanine ethyl ester (3.35 mmol), 0.43mL 2,6-lutidine (3.7 mmol), 0.713 grams 3-nitrobenyl bromide (3.3 mmol), and 20mL dimethylformamide, under an atmosphere of nitrogen, was heated to 50°C for 24 hours. The reaction mixture was allowed to cool to room temperature, poured over lOOmL 10% citric acid, and extracted 3X75mL ether. The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography, using silica gel, eluting with a solvent gradient of 1:4 ethyl acetate/hexane to 1 :1 ethyl acetate/hexane isolating the yellow band (TLC, Siθ2, 1:1 ethyl acetate/hexane, Rf=0.66, un positive) characterized as N-[2-(3-nitrobenzyl)-5-iodobenzoyl]- b-alanine ethyl ester (1.1 grams, 66%,mp=104-105°C).

c) To a magnetically stirred solution of 1.0 grams N-[2-(3-nitrobenzyl)-5-iodobenzoyl]- b-alanine ethyl ester (2.0 mmol), 5mL methylene chloride, 0.56mL triethylamine (4.0 mmol) at -30°C under an atmosphere of nitrogen was slowly added, via an addition funnel, 0.26mL a-bromoacetylbromide (3.0 mmol) as a solution in 4mL methylene chloride. After 2 hours, the mixture was diluted with 35mL methylene chloride and washed 2X75mL 10% citric acid,

2X75mL sat. sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was dissolved in 5mL dimethylformamide and added, via an addition funnel, to a slurry of 72mgs sodium hydride (3.0 mmol) in l.OmL dimethylformamide cooled to 0°C. The reaction was allowed to warm to room temperature, After 2 hours, the 5 mixture was poured over lOOmL of an ice cooled solution of 10% citric acid and extracted 3X75mL ethyl acetate. The combined organics were washed with lX50mL sat. sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 40:60 ethyl acetate/hexane to 70:30 ethyl acetate/hexane to yield 0.45 grams

10 (55%) l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-U -l,4-benzpdiazepine-2,5- dione ethyl ester (TLC, Siθ2, 1:1 ethyl acetate/hexane, Rf=0.39, un positive) and 0.18 grams of recovered N-[2-(3-nitrobenzyl)-5-iodobenzoyl]-b-alanine ethyl ester. 1H NMR (CDCI3 , dTMS) 8.09 (IH, d, o-CON), 8.06 [IH, dt, NCH2(C4-Ar- H)], 8.00 [IH, bs, NCH2(C2-Ar-H)], 7.73 (IH, dd, J _HH =9Hz, ⁴ J _HH =2Hz, Ar-H p-CON), 7.5-

15 7.4 [2H, m, NCH2(C5,C6-Ar-H)], 6.88 (IH, d, Ar-H m-CON), 5.20 (IH, d, 2j _HH= i6Hz, NCHHAr), 5.03 (IH, d, ² J _HH =i6Hz, NCHHAr), 4.15 (IH, d, ² JHH=15HZ, NCHHCO), 4.10 (2H, q, ³ JHH=7Hz, OCH2), 3.96 (IH, d, ² J _HH =l5Hz, NCHHCO), 3.98-3.92 (2H, m, NCH CH2), 2.71 (IH, dt, ² J _HH =16Hz, J _H H=8Hz, CHHCO2), 2.63 (IH, dt, CH3). ¹³ C NMR (CDCI3 , 20 dTMS) 171.2, 168.3, 165.3, 14S.4, 141.0, 139.7, 139.0, 138.5, 132.8, 131.1, 129.9, 122.9, 122.8, 121.9, 90.5, 0.8, 52.1, 50.3, 45.2, 32.7, 14.1.

d) l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-(N-boc-5-amino-l-pent ynyl)-3,4-dihydro- lH-l,4-benzodϊazepine-2,5-dione ethyl ester was prepared using the method described in

25 part (f) of Example 1. Thus, from 0.205 grams of l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-iodo- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone ethyl ester was prepared 168.2mgs (57%) l-(3- nitrobenzyl)-4-(2-carboxyethyl)-7-(N-boc-5-amino-l-pentynyl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester (TLC, Siθ2, 1:1 ethyl acetate/hexane, Rf=0!36, un positive). *H NMR (CDC13 , dTMS) 8.09 [IH, dt, NCH2(C4-Ar-H)],

30 8.02 [IH, bs, NCH2(C2-Ar-H)], 7.81 (IH, d, 7.50-7.35 [3H, m,

NCH2(C5,C6-Ar-H), Ar-H p-CON], 7.04 (IH, d, J _H H=9Hz, Ar-H m-CON), 5.22 (IH, d, ² JHH=16Hz, NCHHAr), 5.04 (IH, d, ² j _HH =i6Hz, NCHHAr), 4.70 (IH, bs, BocNH), 4.40 (IH, d, NCHHCO), 4.0-3.8 (2H, m, NCH2CH2), 3.23 (2H, q, ³ JHH= 6HZ, B0CNHCH2), 2.72 (IH, dt, S5 CHHCO2), 2.41 (2H, t, ³ j _HH =7Hz, CJ ^' CCH ₂ ), 1.74 (2H, p, ³ J _H H=7Hz, CH ₂ CH2CH ₂ ), 1.40 (9H, s, t-Bu), 1.24 (3H, t, ³ JHH=7HZ, CH3). ¹³ C NMR (CDCI3 , dTMS) 171.2, 168.4, 166.2, 155.9, 148.4, 138.6, 138.2, 134.9, 134.2, 132.8, 129.9, 129.5, 122.7, 122.4, 122.0, 121.2, 91.4, 79.2, 60.8, 52.2, 50.4, 45.2, 39.8, 32.7, 28.7, 28.4, 16.8, 14.1.

e) l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-(5-amino-l-pentynyl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate was prepared using the method described in part (g) of example 1. Thus, 84 mgs l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-(N-boc-5-amino-l- pentynyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester (0.142 mmol) yielded 75mgs (91%) l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-(5-amino-l-pentynyl)- 3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate (1/2" C-18 reverse-phase column, eluting with a solvent gradient of 10:90 methanol(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to 50:50 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10ml/min, Rf=45.1 min, un detection 254nm). HRMS (FAB) molecular ion m/z=465.1744 ( cald. C24H25N4O6, 465.1774) 1H NMR (CD3 CN, dTMS) 8.07 [IH, dt, 4j _HH= 2Hz, ³ J _HH =7Hz, NCH2(C4-Ar-H)], 8.02 [IH, bs, NCH2(C2-Ar-H)], 7.73 (IH, d, 4j _HH= 2Hz,o-CON), 7.60-7.50 [3H, m, NCH2(C5,C6-Ar-H), Ar-H p-CON], 7.25 (IH, d, NCHHAr), 4.13 (IH, d, NCHHCO), 4.0-3.6 (3H, m, NCHHCO, NCH2CH2), 3.1 (2H, bs, NH3CH2), 2.65 (2H, t, j _HH --7Hz, CH2CO2), 2.41 (2H, t, ³ JHH=7Hz, CJCCH2), 1.9 (2H, p, jHH=7Hz, CH ₂ CH ₂ CH ₂ ).

l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-(5-guanidiιw-l-pe ntyιιyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate. l-(3-nitrobenzyl)-4-(2-carboxyetlnyl)-7-(5-guanidino-l-penty nyl)-3,4-dihydro-lH-l _/ 4- benzodiazepine-2,5-dione trifluoracetate was prepared using the method described in Example 2. Thus, 30mgs of l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-(5-amino-l-pentynyl)- 3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate yielded 14mgs (44%) of l-(3- nitrobenzyl)-4-(2-carboxyethyl)-7-(5-guanidino-l-pentynyI)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate (1 /2" C-18 reverse-phase column, eluting with a solvent gradient of 20:80 methanol(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic

acid), time 0 to 10 min, to 70:30 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10ml/mϊn, Rt=33.8 min, un detection 254nm). HRMS (FAB) molecular ion m/z=507.2007 ( cald. C25H27N6O6 _Λ 507.1992) ^X H NMR (CD3 CN/CD3OD, dTMS) 8.04 [IH, d, ³ jHH=7Hz, NCH2(C4-Ar-H)], 7.98 [IH, bs, NCH2(C2-Ar-H)], 7.68 (IH, d, JHH=2Hz,o-CON), 7.60-7.40 [3H, m, NCH (C5,C6-Ar-H), Ar-H p-CON], 7.25 (IH, d,

3j _HH =9Hz, Ar-H m-CON), 5.37(1H, d, ² J _HH =i5Hz, NCHHAr), 5.00 (IH, d, ² J _HH =i5Hz,

NCHHAr), 4.13 (IH, d, ² j _HH =i2Hz, NCHHCO), 4.0-3.6 (3H, m, NCHHCO, NCH2CH2),

3.24 (2H, bs, H2N(H2N=)NHCH2), 2.65 (2H, t, CH2CO2), 2.41 (2H, t, C/CCH2), 1.9 (2H, p,

³ JHH=7Hz, CH ₂ CH ₂ CH ₂ ).

H ₂ N

l-(vιethyl)-4-(2-carboxycthyl)-7-(6-guanidino-l-hexynyl) -3 _r 4-dihydro-lH-l,4- bettzodiazepine-2,5-dione trifluoracetate. a) N-(2-methyIamino-5-iodobenzoyl)-b-alanine ethyl ester was prepared using the method described in part (c) of Example 1. Thus, 0.5grams N-(2-amino-5-iodobenzoyl)-b- alanine ethyl ester yielded 204.5 mgs (39%) of N-(2-methylamino-5-iodobenzoyl)-b-aIanine ethyl ester (TLC, Siθ2, 1:1 ethyl acetate/hexane Rf=0.67) and 253.2mgs of a 7:1 mixture of N- (2-aminυ-5-ϊodobenzoyl)-b-aIanϊne ethyl ester and N-(2-dimethyIamino-5-iodobenzoyl)-b- alanine ethyl ester (TLC, S1O2, 1:1 ethyl acetate/hexane Rf=0.46, un positive). 1H NMR

(CDCI3 , dTMS) 7.6-7.5 (2H, m, Ar-H o,p-CON), 7.43 (IH, bs, NHMe), 6.62 (IH, bt, CONH), (2H, q, CH2CO2), 1.28 (3H, t, ³ J _H H=7Hz, CH ₃ ).

b) l-methyl-4-(2-carboxyethyI)-7-iodo-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione ethyl ester was prepared using the method described in part (d) of Example 1. Thus, 1.9 grams of N-(2-methyIamino-5-iodobenzoyl)-b-alanine ethyl ester yielded 0.91 grams (43%) of 1- methyl-4-(2-carboxyethyl)-7-ϊodo-3,4-dihydro-lH-l,4-benzod� �azepine-2,5-dione ethyl ester (TLC, Siθ2, 1:1 ethyl acetate/hexane Rf=0.36, un positive). 1H NMR (CDCI3 , dTMS)

8.14 (IH, d, JHH=2Hz, Ar-H o-CON), 7.79 (IH, dd, J _H H=2Hz, JHH=9HZ, Ar-H p-CON), 6.92 (IH, d, OCH2), 4.01 (IH, d, NCH2), 3.87 (IH, d, ³ JHH=7HZ, CHHCO2), 2.63 (IH, dt, ² J _HH =17Hz, ³ J _H H=7Hz, CHHCO2), 1.24 (3H, t, ³ JHH=7HZ, CH3).

c) To a magnetically stirred slurry of 2.94 grams lithium aluminum hydride (0.077 mol) in 150mL ether cooled to 0°C was slowly added, via an addition funnel, 6 grams of 5-cyano-l- pentyne (0.065 mol) in 15mL ether. The reaction mixture was allowed to warm to room temperature. After 1 hour, the reaction was cooled to 0°C and quenched with 3.1 mL water, 2.33 mL 20% sodium hydroxide, 10.83mL water added in succession. After an additional 30 minutes, the slurry was filtered, washing the salts with 40mL ether. The ether was distilled at atmospheric pressure to leave an oil, which was further purified by Kugelrohr distillation (oven temp-Crt. 145°C) to yield 3.99 grams 6-amino-l-hexyne (64%).

d) To a magnetically stirred solution of 3.99 grams of 6-amino-l-hexyne (0.0413 mol) in 50mL tetrhydrofuran was added 9.1 grams of di- 'rr-butyl dicarbonate (0.042 mol). After 2 hours, the reaction mixture was concentrated in vacuo and the resulting residue chromatographed, using silica gel, eluting with 1:1 ether/hexane to yield 3.4 grams (42%) N- boc-6-amino-l-lnexyne (TLC, Siθ2, 1:1 ether/hexane, Rf=0.5, ninhydrin char). 1H NMR (CDCI3 , dTMS) 4.55 (IH, bs, BocNH), 3.13 (2H, bq, ³ J HH=5HZ, B0CNHCH2), 2.21 (2H, dt, CJCH), 1.6 (4H, m, CH2CH2CH2CH2), 1.42 (9H, s, r-Bu).

e) l-(methyl)-4-(2-carboxyethyl)-7-(N-boc-6-amino-l-hexynyl)-3, 4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester was prepared using the method described in part (f) of Example 1. Thus, 0.126 grams of l-methyl-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester and 0.119 grams of N-boc-6-amino-l-hexyne yielded 0.124 grams (84%) l-(methyl)-4-(2-carboxyethyI)-7-(N-boc-6-amino-l-hexynyl)-3, 4- dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester (TLC, Siθ2, 1:1 ethyl acetate/hexane, Rf=0.36, un positive). ^J H NMR (CDCI3 , dTMS) 7.84 (IH, d, ⁴ J _HH =2Hz, Ar-H o-CON), 7.47 (IH, dd, Ar-H p-CON), 7.07 (IH, d, Ar-H JM-CON), 4.60 (IH, bs, NH), 4.12 (2H, q, J _H H=7Hz, OCH2), 4.0 (IH, d, ² J _HH --15Hz, NCHHCO), 3.90 (2H, t, ³ J _HH =7Hz, NCH2), 3.84 (IH, d, ² J _HH =15Hz, NCHHCO), 3.26 (3H, s, NCH3), 3.15 (2H, q, CHHCO2), 2.63 (IH, dt, CJCCH2), 1.62 (4H, m, CH2CH2CH2CH2), 1.24 (3H, t, ³ JHH=7Hz, CH3).

f) l-(methyl)-4-(2-carboxyethyl)-7-(6-amino-l-hexynyl)-3,4-dihy dro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate was prepared using the method described in part (g) of Example 1. Thus, 62mgs of l-(methyl)-4-(2-carboxyethyI)-7-(N-boc-6-amino-l- hexynyl)-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester yielded 50mgs (83%) 1- (methyl)-4-(2-carboxyethyI)-7-(6-amino-l-hexynyl)-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione trifluoracetate (1/2" C-18 reverse-phase column, eluting with a solvent gradient of 20:80 methanol(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to 70:30 methanol(0.1% trifluoracetic add)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10ml/min, Rt=26.2 min, un detection 254nm). HRMS (FAB) molecular ion m/z=358.1761 ( cald. C19H24N3O4, 358.1767). ^l H NMR (D2O,) 7.47 (IH, d, ⁴ JHH=2HZ, Ar- H o-CON), 7.37 (IH, dd, Ar-H p-CON), 7.12 (IH, d, ³ JHH=9Hz, Ar- H m-C N), 3.95-3.8 (2H, m, NCHHCO, NCHHCH2), 3.63 (IH, d, ² J _HH =l5Hz, NCHHCO), 3.52 (IH, dt, NCHHCO2), 3.16 (3H, s, NCH3), 2.85 (2H, t, CJCCH2), 1.62 & 1.47 (each 2H, p, ³ J _H H=6Hz, CH2CH2CH2CH2).

g) l-(methyI)-4-(2-carboxyethyI)-7-(6-guanidino-l-hexynyl)-3,4- dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate was prepared by the method described in Example 2. Thus, from 25mgs l-(methyl)-4-(2-carboxyethyl)-7-(6-amino-l-hexynyl)-3,4-dihy dro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate was prepared 22mgs (71%) of l-(methyl)-4-(2- carboxyethyl)-7-(6-guanϊdino-l-hexynyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate (1/2" C-18 reverse-phase column, eluting with a solvent gradient of 20:80 methanol(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to 70:30 methanoI(0Λ% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10ml/mϊn, Rt=28.6 min, un detection 254nm). HRMS (FAB) molecular ion m/z=400.1956 ( cald. C20H26N5O4, 400.1985). 1H NMR (D2O,) 7.58 (IH, d, Ar- H o-CON), 7.43 (IH, dd, ⁴ j _HH= 2Hz, ³ J _H H=9Hz, Ar-H p-CON), 7.20 (IH, d, ³ JHH=9Hz, Ar- H -CON), 4.05-3.95 (2H, m, NCHHCO2, NCHHCH2), 3.71 (IH, d, ² J _HH =15Hz, NCHHCO), 3.56 (IH, dt, 2j _HH =15Hz, ³ J _H H=5Hz, NCHHCO2), 3.19 (3H, s, NCH3), 3.06 (2H, t, 2.7-2.5 (2H, m, CH2CO2), 2.32 (2H, t, ³ JHH=6Hz, CJCCH2), 1-60 & 1.49 (each 2H, p, ³ J _H H=6Hz, CH2CH2CH2CH2).

Example 7

l-(3-mtrobenzyl)-4-(2-carboxyethyl)-7-(6-amino-l-hcxynyl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dioιιe trifuroacetate. a) l-(3-nitrobenzyl)-4-(2-carboxyethyI)-7-(N-boc-6-amino-l-hexy nyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione ethyl ester was prepared using the method described in part (f) of Example 1. Thus, from 0.26 grams of l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-iodo- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester and 0.19 grams of N-boc-6-amino- 1-hexyne was prepared 226.3mgs (78%) l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-(N-boc-6- amino-l-hexynyi)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester (TLC, S1O2, 1:1 ethyl acetate/hexane, Rf=0.34, un positive). ^! H NMR (CDCI3 , dTMS) 8.09 [IH, dt, 3j _HH= 7Hz, ⁴ JHH=2Hz, NCH2(C4-Ar-H)], 8.02 [IH, bs, NCH2(C2-Ar-H)], 7.83 (IH, d, ⁴ JHH=2HZ,O-CON), 7.50-7.35 [3H, m, NCH2(C5,C6-Ar-H), Ar-H p-CON], 7.05 (IH, d,

3j _HH= 8Hz, Ar-H m-CON), 5.22 (IH, d, ² J _HH =i6Hz, NCHHAr), 5.02 (IH, d, ² J _HH --l6Hz, NCHHAr), 4.60 (IH, bs, BocNH), 4.20-4.08 (3H, m, NCHHCO, OCH2), 4.0-3.8 (3H, m, NCH2CH2, NCHHCO ), 3.16 (2H, q, JHH= 6Hz, BocNHCH ), 2.72 (IH, dt, ² J _H H=16Hz, 3j _HH= 8Hz, CHHCO2), 2.62 (IH, dt, 2j _HH =i6Hz, J _H H=8Hz, CHHCO2), 2.39 (2H, t, ³ J _H H=6Hz, CJCCH2), 1.60 (4H, bs, CH2CH2CH2CH2), 1.41 (9H, s, f-Bu), 1.24 (3H, t, ³ JHH=7Hz, CH3).

b) l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-(6-amino-l-hexynyl)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate was prepared using the method described in part (g) of Example 1. Thus, from 0.11 grams of l-(3-nitrobenzyI)-4-(2-carboxyethyl)-7-(N-boc-6- amino-l-hexynyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester was prepared 90mgs (79%) of l-(3-nitrobenzyl)-4-(2-carboxyethyI)-7-(6-amino-l-hexynyl)-3 ,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate (1/2" C-18 reverse-phase column, eluting with a solvent gradient of 20:80 methanol(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to 70:30 methanol(0.1% trifluoracetic acid)/water (0.1%

trifluoracetic acid), time 10 min to 40 min, flow=10ml/mϊn, Rt=39.2 min, un detection 254nm). HRMS (FAB) molecular ion m/z=479.1911 ( cald. C25H27N4O6, 479.1931). ^X H NMR (D2O) 7.7 [IH, bd, ³ jHH=8Hz, NCH2(C4-Ar-H)], 7.58 [IH, bs, NCH ₂ (C2-Ar-H)], 7.41 (IH, d, ⁴ JHH=2Hz,o-CON), 725-7.05 [3H, m, NCH2(C5,C6-Ar-H), Ar-H p-CON], 7.01 (IH, d, ³ J _HH =9Hz, Ar-H m-CON), 5.09 (IH, d, ² J _HH .=l6Hz, NCHHAr), 4.8 (IH, d, NCHHAr, overlapping with HOD), 4.00 (IH, d, ² j _HH =i4Hz, NCHHCO), 3.9-3.65 (2H, , NCHHCO, NCHHCH2), 3.6-3.5 (IH, m, NCHHCH2), 2.83 (2H, t, ³ jHH=7Hz, NH3CH2), 2.51 (2H, t, ³ JHH=7Hz, CH2CO2), 2.17 (2H, t, ³ J _H H=7Hz, CJCCH2), 1.57 & 1.40 (each 2H, p, ³ JHH=7Hz, CH2CH2CH2CH2). Example 8

l-(3-nitrobenzyl)-4-(2-carboxyethyl)-7-(6-guanidwo-l-hexy nyl)-3,4-dihydro-lH-l,4- benzodiazepinc-2,5-dione trifluoracetate. l-(3-nitrobenzyI)-4-(2-carboxyethyl)-7-(6-guanidino-l-hexyny I)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate was prepared using the method described in Example 2. Thus, 45mgs of l-(3-nitrobenzyl)-4-(2-carboxyethyI)-7-(6-amino-l-hexynyl)-3 ,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate yielded 25mgs (52%) of l-(3- nitrobenzyl)-4-(2-carboxyethyl)-7-(6-guanidino-l-hexynyl)-3, 4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate (1/2" C-18 reverse-phase column, eluting with a solvent gradient of 20:80 methanol(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to 70:30 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10ml/min, Rt=41.3 min, un detection 254nm). HRMS (FAB) molecular ion m/z=521.2161 ( cald. C26H28 6O6, 521.2148). 1H NMR (D2O) 7.86 [IH, dt, ⁴ JHH= ³ Hz, ³ JHH=6HZ, NCH2(C4-Ar-H)], 7.64 [IH, bs, NCH2(C2-Ar-H)], 7.46 (IH, d, ⁴ j _HH =2Hz,o-CON), 7.30-7.23 [3H, m, NCH2(C5,C6-Ar-H), Ar-H p-CON], 7.18 (IH, d, 3j _HH= 8Hz, Ar-H m-CON), 5.30 (IH, d, ² J _HH =i6Hz, NCHHAr), 4.7 (IH, NCHHAr, overlapping with HOD), 4.03 (IH, d, ² j _HH =i4Hz, NCHHCO), 3.85 (IH, dt, ² J _HH =l4Hz,

J _HH =7Hz, NCHHCH2), 3.74 (IH, d, j _HH =14Hz, NCHHCO), 3.55 (IH, dt, 2.49 (2H, t, CjCCH ₂ ), 1.48 & 1.38 (each 2H, p, 3j _HH= 7Hz, CH2CH2CH2CH2).

l~(methyl)-4-(2-carboxyethyl)-7-[4-(aιninoιnethyl)pheny l]ethynyl-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate. a) l-(methyl)-4-(2-carboxyethyI)-7-(4-cyanophenyl)ethynyl-3,4-d ihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester was prepared using the method employed in part (f) of Example 1. Thus, from 0.41 grams of l-methyl-2-(carboxyethyI)-7-iodo-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester and 0.127 grams of (4-cyanophenyl)ethyne (Gilbert, J.C.; Weerasooriya, U. J.Org.Chem. 1979, 44, 4997-98) was prepared 0.205 grams of 1- (methyl)-4-(2-carboxyethyl)-7-(4-cyanophenyl)ethynyl-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester (mp=l 60-161 °C, TLC, SiO2, 1:1 ethyl acetate/hexane, Rf=0.30, un positive). ^] H NMR (CDCI3, dTMS) 7.98 (IH, d, ⁴ JHH= 2HZ, Ar-Ho-CON), 7.65- 7.50 (5H, m, Ar-H p-CON, Ar-H o,p-CN), 7.17 (IH, d, ³ JHH= 9HZ, m-CON), 4.09 (2H, q, ³ JHH=7Hz, OCH2), 4.02 (IH, d, ² JHH=15Hz, NCHHCO), 3.89 (2H, t, ³ JHH=7Hz, NCH2CH2), 3.86 (IH, d, ² jHH=15Hz, NCHHCO), 3.34 (3H, s, NCH3), 2.72 (IH, dt, CHHCO2), 1.20 (3H, t, 3]HH=7Hz, CH3). ¹³ C NMR (CDCI3, dTMS) 171.2, 168.6, 166.2, 141.0, 134.8, 134.4, 132.0, 128.8, 127.5, 121.1, 119.7, 118.3, 111.8, 91.7, 88.9, 60.3; 52.1, 45.1, 32.7, 31.5, 14.1.

b) A magnetically stirred solution of 3mL toluene, 6.8mgs dicobalt octacarbonyl (0.02 mmol) cooled to -20°C was saturated with triethylsilane via a gas bubbler. 0.1 grams of l-(methyl)- 4-(2-carboxyethyI)-7-(4-cyanophenyl)ethynyI-3,4-dihydro-lH-l ,4-benzodiazepine-2,5- dione ethyl ester (0.24 mmol) was added as a solution in 0.5mL toluene and the reaction mixture heated to 60°C for 20 hours (Murai, T. et al, Tetrahedron Lett. 1985, 26, 5145-48). The mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was diluted with methanol and 2mL of 2N sodium hydroxide was added. After 30 minutes, the mixture was neutralized with 2mL acetic acid, concentrated in vacuo, diluted

with 2mL of a 1:1 methanol /water solution and purified by high-pressure liquid chromatography (1/2" C-18 reverse-phase column, eluting with a solvent gradient of 20:80 methanol(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to 70:30 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10ml/min, Rt=36.8 min, un detection 254nm) to yield 30.0 mgs (25%) of l-(methyl)- 4-(2-carboxyethyl)-7-[4-(amϊnomethyl)phenyl]ethynyl-3,4-dih ydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoracetate. ^X H NMR (CD3OD) 7.68 (IH, d, ⁴ jHH= 2Hz, Ar- Ho-CON), 7.48 (IH, dd, Ar-H p-CON) 7.4-7.3 (4H, m, Ar-H o,p~ CN), 7.17 (IH, d, m-CON), 4.02 (2H, s, ArCH2 ), 4.0-3.7 (4H, m, NCH2CO, NCH2CH2), 3.0 (3H, s, NCH3) 2.6 (2H, m, CH2CO2).

Using the above procedure, but substituting the appropriate 3,4-dihydro-lK-l,4- benzodiazepine-2,5-dione nitrile for l-(methyI)-4-(2-carboxyethyl)-7-(4- cyanophenyl)ethynyl-3,4-dihydro-lH-l,4-benzodiazepine-2,5-di one ethyl ester there may be prepared, for example, tine following compounds: l-methyl-4-(2-carboxy-l-methylethyl)-7-[2-(3-aminomethylphen yl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepϊne-2,5-d ione, l-methyl-4-(2-carboxy-l-phenylethyl)-7-[2-(3-aminomethyIphen yl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(3-aminom ethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dϊone trifluoracetate,

(±)-l-methyl-4-[succϊn-2-yl-(l-gIycine)]-7-[2-(3-aminom ethylphenyl)-l-ethyne]-3,4- dihyd ro-1 H-l ,4-benzod ϊazep ϊne-2,5-d ione trif 1 uoraceta te,

(±)-l-methyl-4-[succin-2-yI-(l-valine)]-7-[2-(3-aminomet hylphenyl)-l-ethyne]-3,4- dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyI-4-[succϊn-2-yl-(l-phenylalanϊne)]-7-[2-(3-am inomethylphenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-(3-aminomethyIphen yl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyI)-7-[2-(3-aminomethylphen yl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succϊn-2-yl-(l-f-butoxy)]-7-[2-(3-amino methylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(3-aminome thyIphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(3-aminomethyI phenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyI-4-[succϊn-2-yl-(l-plnenylaIanine)]-7-[2-(3 -aminomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate.

l-benzyl-4-(2-carboxy-l-methylethyI)-7-[2-(3-aminomethylphen yl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[2-(3-aminomethylphen yl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-r-butoxy)]-7-[2-(3-aminometh ylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-gIycine)]-7-[2-(3-aminome thylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[2-(3-aminomet hylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(3-a minomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyI)-7-[2-(3-aminomethylp henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[2-(3-aminomethylp henyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-t-butoxy)]-7-[2-(3-ami nomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-[2-(3-amin omethylphenyl)-l-ethyne]-3,4- dihyd ro-1 H-l ,4-benzod iazepine-2,5-d ione tri f I uoraceta te,

(±)-l-isopropyl-4-[succin-2-yl-(l-valine)]-7-[2-(3-amino methylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-( 3-aminomethylphenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-methylethyl)-7-[2-(4-aminomethylthio phenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-phenylethy])-7-[2-(4-aminomethylthio phenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate,

(±)-l-methy]-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(4-aminom ethylthiophenol)-l-ethyne]-3,4- dihyd ro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[2-(4-aminome thylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-valine)]-7-[2-(4-aminomet hylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(4-amin omethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-metlnylethyl)-7-[2-(4-aminomethylthi ophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

l-phenyl-4-(2-carboxy-l-phenylethyI)-7-[2-(4-aminomethylthio phenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyI-4-[succϊn-2-yI-(l-t-butoxy)]-7-[2-(4-amino methylthiophenoI)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[succin-2-yI-(l-glycine)]-7-[2-(4-aminomethy lthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(4-aminomet hylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-phenylaIanine)]-7-[2-(4-a minomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate, l-benzyI-4-(2-carboxy-l-methyIethyI)-7-[2-(4-aminomethylthio phenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenyIethyI)-7-[2-(4-aminomethylthϊ ophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yl-(l-t-butoxy)]-7-[2-(4-aminometh ylthiophenoI)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[2-(4-aminome thylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-4-[succin-2-yl-(l-valine)]-7-[2-(4-aminomet hylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-4-[succin-2-yl-(I-phenylaIanine)]-7-[2-(4-a minomethylthiophenoI)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[2-(4-aminomethylt hiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyI-4-(2-carboxy-l-phenyIethyI)-7-[2-(4-aminomethylt hiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(4-ami nomethylthiophenoI)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyI-4-[succin-2-yl-(l-gIycine)]-7-[2-(4-amin omethylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yI-(l-valine)]-7-[2-(4-amino methylthϊophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyI-4-[succin-2-yI-(l-phenyIaIanine)]-7-[2-( 4-aminomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-(3-a minomethylphenyI)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyI-3-phenyI-4-(2-carboxy-l-phenylethyl)-7-[2-(3-a mϊnomethyIphenyI)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-i-butoxy)]-7-[2-(3- aminomethylphenyl)-l-ethyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-( 3-aminomethylphenyl)-l-ethyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(3-am inomethylphenyl)-l-ethyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-[2-(3-aminomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-[2-(3-ami nomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(3-ami nomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-dipheny]-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(3-am inomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyI-4-[succin-2-yl-(l-glycine)]-7-[2-(3-aminom ethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[2-(3-amin omethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-dipheny]-4-[succin-2-yl-(l-phenylalanine)]-7-[2- (3-aminomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-( 3-aminomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyI-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-( 3-aminomethylphenyl)-l- etlnyne]-3,4-dilnydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(3- aminomethylphenyl)-l-ethyne]-

3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-( 3-aminomethylphenyl)-l-ethyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(3 -aminomethylphenyl)-l-ethyne]- 3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-plnenylalanine)] -7-[2-(3-aminomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[ 2-(3-aminomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-( 3-aminomethylphenyl)-l- ethyne]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-plnenyl-4-[succin-2-yl-(l-f-butoxy)]-7 -[2-(3-aminomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

ethyne]-3,4-dilnydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(4-am inomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 2-(4- aminomethylthiopheno -I-ethyneJ-S^-dihydro-lH-l^-benzodiazepine^S-dione trifluoracetate, (±)-l,3-dϊphenyl-4-(2-carboxy-l-methylethyI)-7-[2-(4-amino methylthϊophenol)-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-phenyIethyI)-7-[2-(4-amϊno methylthϊophenol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l,3-dϊphenyI-4-[succin-2-yl-(l-t-butoxy)]-7-[2-(4-a minomethyIthiophenol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(4-ami nomethylthiophenol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodrazepϊne-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[2-(4-amϊ nomethylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-dϊphenyl-4-[succin-2-yl-(l-pfnenylalanine)]-7-[2-( 4-aminomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzυdiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methyIethyl)-7-[2-(4-a minomethylthiophenol)-l- ethyne]-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dιone trifl uoraceta te, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(4-a minomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodϊazepιne-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyI-4-[succin-2-yl-(l-f-butoxy)]-7-[2- (4-aminomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(4-a minomethylthiophenol)-l- ethyne]-3,4-dihydro-!H-l,4-benzodiazepine-2,5-dione trifluoracetate.

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(4-am inomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[ 2-(4-aminomethylthiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyI-4-(2-carboxy-l-methylethyl)-7-[2-( 4-aminomethylthiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-( 4-aminomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2- (4-aminomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[ 2-(4-aminomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(4 -aminomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-[2-(4- aminomethylthiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benzodia zepine-2>5-dione trifluoracetate.

Example 10

l-(ιnethyl)-4-(2-carboxyetlιyl)-7-[4-(guanidinoιιιet ]ιyl)μhenyl]ethynyl-3,4-dihydro-lH- l,4-bcnzodiazcμine-2,5-dione trifluoracetate. l-(methyl)-4-(2-carboxyethyI)-7-[4-(guanidinomethyl)phenyI]e thynyl-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoracetate was prepared using the method described in example 2. Thus, from 15 mgs of l-(methyl)-4-(2-carboxyethyl)-7-[4- (aminomethyl)ρhenyl]ethynyl-3,4-dihydro-lH-l,4-benzodiazepi ne-2,5-dione trifluoracetate was prepared 7mgs (37%) of l-(methyl)-4-(2-carboxyethyl)-7-[4- (guanidinomethyl)phenyl]ethynyl-3,4-dihydro-lH-l,4-benzodiaz epine-2,5-dione trifluoracetate (1 IT C-18 reverse-phase column, eluting with a solvent gradient of 20:80 methanol(0.1% trifluoracetic acid)/ water (0.1% trifluoracetic acid), time 0 to 10 min, to

70:30 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10mi/mϊn, R _t =39.6 min, un detection 254nm). ^X H NMR (CD3OD, D2O) 7.50 (IH, d, Ar-H p-CON) 7.20 (IH, d, m-CON), 7.15-7.0 (4H, m, Ar-H o,p-CN), 4.23 (2H, s, ArCH2NHC(=NH2)NH2), 3.9-3.8 (2H, m, NCHHCO, NCHHCH2), 3.72 (IH, d, 2JHH=16Hz, NCHHCO), 3.58 (IH, m, NCHHCH2),

3.12 (3H, s, NCH3) 2.53 (2H, m, CH2CO2).

Using the above procedure, but substituting the appropriate amino acid for 1- (methyl)-4-(2-carboxyethyl)-7-[4-(aminomethyl)phenyl]ethynyl -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate there may be prepared, for example, the following compounds: l-methyI-4-(2-carboxy-l-methyIethyl)-7-[2-(3-guanidinomethyl phenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione, l-methyI-4-(2-carboxy-l-phenyIethyl)-7-[2-(3-guanidinomethyl phenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodrazepine-2,5-dione trifluoracetate, (±)-l-methyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(3-guanidino methylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycϊne)]-7-[2-(3-guanid inomethyIphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-Λ'aIine)]-7-[2-(3-guanϊ dinomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenylaIanine)]-7-[2-(3-g uanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodϊazepϊne-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-(3-guanidinomethyl phenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-phenylethyI)-7-[2-(3-guanidinomethyl phenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyI-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(3-guanid inomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-gIycine)]-7-[2-(3-guanϊd inomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-vaIϊne)]-7-[2-(3-guanidi nomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyI-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(3-g uanϊdinomethylphenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-[2-(3-guanidinomefhyI phenyI)-l-ethyne]-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenyIethyl)-7-[2-(3-guanidinomethyl phenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(3-guanidino methylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[2-(3-guanidi nomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 5 (±)-l-benzyl-4-[succin-2-yl-(l-valine)]-7-[2-(3-guanidinome thylphenyl)-l-ethyne]-3,4- * dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

*

(±)-l-benzyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(3-g uanidinomethylphenyl)-l-ethyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[2-(3-guanidinomet hylphenyl)-l-ethyne]-3,4- 10 dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenylethyl)-7-[2-(3-guanidinomet hylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yi-(l-f-butoxy)]-7-[2-(3-gua nidinomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 15 (±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-[2-(3-guanidi nomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-valine)]-7-[2-(3-guani dinomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-ρhenylalanine)]-7-[2- (3-guanidinomethylphenyl)-l- 20 ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-metlnylethyl)-7-[2-(4-guanidinomethy lthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-methyl-4-(2-carboxy-l-ρlnenylethyI)-7-[2-(4-guanidinometh ylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, 25 (±)-l-methyi-4-[succin-2-yl-(l-t-butoxy)]-7-[2-(4-guanidino methylthiophenol)-l-ethyne]-

3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-glycine)]-7-[2-(4-guanidi nomethylthiophenol)-l-ethyne]-

3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-vaIine)]-7-[2-(4-guanidin omethylthiophenol)-l-ethyne]-3,4- 30 dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(4-g uanidinomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-phenyl-4-(2-carboxy-l-methyletlnyl)-7-[2-(4-guanidinomethy lthiophenol)-l-ethyne]-3,4-

•* * dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

35 l-phenyl-4-(2-carboxy-l -phenylethyl)-7-[2-(4-guanidinomethylthiophenol)-l-ethyne]-3 ,4- ^" * dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(4-guanid inomethylthiophenol)-l-ethyne]-

3,4-dihydro-l H-l, 4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(4-guanidinom ethylthiophenol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate,

(±)-l-phenyl-4-[succϊn-2-yl-(l-vaIine)]-7-[2-(4-guanidi nomethylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-phenyl-4-[sucdn-2-yl-(l-phenylaIanine)]-7-[2-(4-guani dϊnomethyIthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-methylethyl)-7-[2-(4-guanidinomethyl thiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, l-benzyl-4-(2-carboxy-l-phenylethyl)-7-[2-(4-guanidinomethyl thiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yI-(l-t-butoxy)]-7-[2-(4-guanid inomethylthiophenol)-l-ethyne]- 3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-4-[succin-2-yl-(l-glycine)]-7-[2-(4-guanϊd inomethylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-4-[succin-2-yI-(l-vaIϊne)]-7-[2-(4-guanidinom ethylthiophenol)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-I-benzyl-4-[sucdn-2-yl-(l-phenylalanϊne)]-7-[2-(4-g uanidϊnomethyIthϊophenoI)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone trifluoracetate, l-isopropyl-4-(2-carboxy-l-methylethyl)-7-[2-(4-guanϊdinome thyIthiophenol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dϊone trifluoracetate, l-isopropyl-4-(2-carboxy-l-phenyletlnyl)-7-[2-(4-guanidinome thyIthiophenol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-ϊsopropyl-4-[succin-2-yl-(l-t-butoxy)]-7-[2-(4-gu anidinomethylthϊophenol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-4-[succin-2-yl-(l-glycine)]-7-[2-(4-guanidi nomethylthiophenol)-l-ethyne]- 3,4-dihydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yI-(l-valine)]-7-[2-(4-guani dinomethylthiophenol)-l-ethyne]- 3,4-dϊhydro-l H-l ,4-benzodiazepine-2,5-d ione trifluoracetate,

(±)-l-isopropyl-4-[succin-2-yl-(l-phenylaIanine)]-7-[2-( 4-guanidinomethyIthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyI-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-( 3-guanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyI-3-phenyl-4-(2-carboxy-l-phenylethy])-7-[2-(3-g uanidinomethylphenyl)-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succϊn-2-yl-(l-f-butoxy)]-7-[2-(3 -guanidinomethylphenyl)-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyI-4-[succϊn-2-yl-(l-glycine)]-7-[2-(3- guanidϊnomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(3-gu anidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-[succin-2-yI-(l-phenylalanine)]- 7-[2-(3-guanidinomethylphenyl)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-[2-(3-guanid inomethylphenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(3-gua nidinomethylphenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(3-gu anidinomethylphenyl)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(3-gua nidinomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-valine)]-7-[2-(3-guan idinomethylphenyl)-l-ethyne]-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2-(3- guanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methyletlnyI)-7-[2-(3- guanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazeρine-2,5-dione trifluoracetate, (±)-l-benzyl-3-pheny]-4-(2-carboxy-l-phenylethyl)-7-[2-(3-g uanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2- (3-guanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(3-g uanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(3-gu anidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yl-(l-plnenylalanine)]-7- [2-(3-guanidinomethylphenyl)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-metlnylethyl)-7-[2- (3-guanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[ 2-(3-guanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2- (3-guanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-( 3-guanidinomethylphenyl)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(3 -guanidinomethylphenyl)-l- ethyne]-3,4-dilnydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-I-isopropyl-3-phenyl-4-[succin-2-yl-(l-phenylalanine)]- 7-[2-(3- guanidinomethylphenyl)-l-ethyne]-3,4-dihydro-lH-l,4-benzodia zepine-2,5-dione trifluoracetate,

(±)-l-methyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-( 4-guanidinomethylthiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate,

(±)-l-methyI-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-( 4-guanidinomethylthiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(4- guanϊdinomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(4-g uanidϊnomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(4-gu anϊdinomethylthiophenoI)-l- ethyne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l-methyl-3-phenyI-4-[succin-2-yl-(l-phenyIaIanine)]-7-[ 2-(4- guanidinomethylthiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benz odiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-(2-carboxy-l-methylethyl)-7-[2-(4-gua nidinomethylthioρhenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-(2-carboxy-l-phenylethyl)-7-[2-(4-guanϊ dinomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-f-butoxy)]-7-[2-(4-gu anidinomethyIthiophenoI)-l- ethyne]-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dione trifluoracetate, (±)-l,3-dϊphenyl-4-[succin-2-yl-(l-glycine)]-7-[2-(4-guani dinomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoracetate, (±)-l,3-diphenyl-4-[succin-2-yI-(l-vaIine)]-7-[2-(4-guanidi nomethylthiophenol)-l-ethyne]- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l,3-diphenyl-4-[succin-2-yl-(l-phenylalanine)]-7-[2- (4-guanidinomethyIthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benz diazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-(2-carboxy-l-methylethyl)-7-[2-(4-g uanidinomethylthiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoracetate,

(±)-l-benzyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[2-( 4-guanidinomethylthiophenol)- l-ethyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyI-4-[succin-2-yI-(l-t-butoxy)]-7-[2-(4- guanidinomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succin-2-yI-(l-glycine)]-7-[2-(4-g uanidinomethyIthϊophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-benzyl-3-phenyl-4-[succϊn-2-yI-(l-valine)]-7-[2-(4-g uanidinomethyIthiophenol)-l- ethyne]-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate,

(±)-l-benzyl-3-phenyl-4-[succiιn-2-yl-(l-phenylalanine)]-7 -[2-(4- guanidinomethylthiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benz odiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-methylethyI)-7-[ 2-(4- guanidinomethylthiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benz odiazepine-2,5-dione trifluoracetate,

(±)-l-isopropyl-3-phenyl-4-(2-carboxy-l-phenylethyl)-7-[ 2-(4- guanidinomethylthiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benz odiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-t-butoxy)]-7-[2- (4-guanidinomethylthiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyI-4-[succin-2-yl-(l-glycine)]-7-[2-( 4-guanidinomethylthiophenol)- l-ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-phenyl-4-[succin-2-yl-(l-valine)]-7-[2-(4 -guanidinomethylthiophenol)-l- ethyne]-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate, (±)-l-isopropyl-3-plnenyl-4-[succin-2-yl-(l-plnenylalanine) ]-7-[2-(4- guanidinomethyIthiophenol)-l-ethyne]-3,4-dihydro-lH-l,4-benz odiazepine-2,5-dione trifluoracetate.

Example 11

l-wethyl-4-(2-carboxy-l-methylethyl)-7-(5-guanidino-l-μe ntynyl)-3,4-dihydro-lH- l,4,benzodiazepine-2,5-dioιιe trifluoracetate. a) Methyl N-(2-amino-5-iodobenzoyl)-3-amino-3-methylpropanate was prepared using the method described in part (b) of Example 1. Thus, 1.72 grams of 5-iodoisatoic anhydride and 1.73 grams of methyl 3-aminobutanoate p-tosylate yielded 0.65 grams (30%) methyl N-(2- amino-5-iodobenzoyl)-3-aminobutanoate (TLC, Siθ2, 1:1 EtOAc/hexane, Rf=0.63, un positive).

b) Methyl N-(2-methylamino-5-iodobenzoyl)-3-amino-3-methylpropanoate was prepared using the method described in part (c) of Example 1. Thus, 0.32 grams of methyl N-(2-amino- 5-iodobenzoyl)-3-amϊnobutanoate yielded 0.14 grams (43%) of methyl N-(2-methylamino-5- iodobenzoyl)-3-aminobutanoate (TLC, Siθ2, 1:1 EtOAc/hexane, Rf=0.85, un positive).

c) l-methyl-4-(3-methoxy-3-oxobutan-2-yl)-7-ϊodo-3,4-dihydro-l H-l,4-benzo-diazapine- 2,5-dione was prepared using the method described in part (d) of Example 1. Thus, 0.25 grams of N-(2-methylamino-5-iodobenzoyl)-3-aminobutanoate yielded 0.08 grams (29%) of 1- methyl-4-(3-methoxy-3-oxobutan-2-yl)-7-iodo-3,4-dihydro-lH-l ,4-benzo-diazapϊne-2,5- dione (TLC, Siθ2, 1:1 EtOAc/hexane, Rf=0.33, un positive).

d) l-methyl-4-(3-methoxy-3-oxobutan-2-yl)-7-[5-(N-Boc)-amino-l- pentyne]-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione was prepared using the method described in part (f) of Example 1. Thus, 0.08 grams of l-methyI-4-(3-methoxy-3-oxobutan-2-yl)-7-iodo-3,4- dihydro-lH-l,4-benzo-diazapϊne-2,5-dϊone yielded 0.061 grams (68%) of l-methyl-4-(3- methoxy-3-oxobutan-2-yl)-7-[5-(N-Boc)-amϊno-l-pentyne]-3,4- dihydro-lH-l,4- benzodiazepine-2,5-dione (TLC, Siθ2, 1:1 EtOAc/hexane, Rf=0.24, un positive).

e) I-methyl-4-(2-carboxy-l-methylethyl)-7-(5-amino-l-pentyne)-3 ,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoracetate was prepared using the method described in part

(g) of Example 1. Thus, 61mgs of l-methyl-4-(3-methoxy-3-oxobutan-2-yI)-7-[5-(N-Boc)- amino-l-pentyne]-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dion e yielded 40 mgs (87%) of 1- methyl-4-(2-carboxy-l-methylethyI)-7-(5-amino-l-pentyne)-3,4 -dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate (1/2" C-18 reverse-phase column, eluting with a solvent gradient of 10:90 metlnanol(0.1% trifluoracetic acid)/water(0.1% trifluoracetic acid), time 0 to 10 min, to 50:50 methanol(0.1% trifluoracetic acid)/water(0.1% trifluoracetic acid), time 10 min to 40 min, flow lOml/min, R _t =31.2 min, un detection 254nM). HRMS (FAB) molecular ion m/z=358.1765 (cald. C19H24N3O4, 358.1767)

f) l-methyl-4-(2-carboxy-l-methylethyl)-7-(5-guanϊdino-l-penty ne)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dϊone trifluoracetate was prepared using the method described in Example 2. Thus, 15 mgs of l-methyl-4-(2-carboxy-l-methylethyl)-7-(5-amino-l-pentyne)- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate yielded lOmgs (67%) of 1- methyl-4-(2-carboxy-l-methylethyl)-7-(5-guanidino-l-pentyne) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate (1/2" C-18 reverse-phase column, eluting with a solvent gradient of 10:90 methanol(0.1% trifluoracetic acid)/water(0.1% trifluoracetic acid), time 0 to 10 min, to 50:50 methanol(0.1% trifluoracetic acid)/water(0.1% trifluoracetic acid), time 10 min to 40 min, flow lOml/mϊn, Rt=36.9 min, un detection 254nM). HRMS (FAB) molecular ion m/z=400.1999 (cald. C20H26N5O4, 400.1986).

Example 12

l-(4-chlorophenyl)methyl-4-(2-carboxyethyl)-7-(4-(l-piper idin)-phenyl)-3,4-dihydro-lH- l,4-bcnzodiazapine-2,5-dione trifluoro acetate. a) Over a period of 15 minutes samples of iodine (8.62 grams, 0.034mol) and silver benzoate (7.78 grams, 0.034mo!) were added in portions to a magnetically stirred solution of 5 grams of 1-phenylpiperazine in 80mL acetic acid. The mixture stirred for 1 hour. The solvent was evaporated and the residue partioned between 150mL diethyl ether and 150mL 2N sodium hydroxide. The organic layer was washed with lOOmL water, lOOmL brine, then dried over potassium carbonate and concentrated in vacuo to yield 1.0 gram (11%) of l-(4-iodophenyl)- piperzine (110-115°C). The material obtained was used without further purification. 1H NMR (CDC13, dTMS) 7.51 (2H, d, o-ArH), 3.17 (4H, m), 3.04 (4H, m). ¹³ C NMR (CDCI3) 151.36, 137.73, 118.05, 81.35, 49.92, 45.95.

b) The crude material obtained from part (a) (1 gram, 3.47mmol) was dissolved in dry THF (lOmL) and a catalytic amount of dimethylamino-pyridine (lOOmgs) and di-ferf-butyl dicarbonate (0.9 grams, 4.1mmol, 1.2 molar excess) were added, monitoring the reaction by TLC (Siθ2, 1:1 EtOAc/hexane, Rf(product)=0.88). After 12 hours (overnight) the reaction was diluted with diethyl ether and extracted lX75mL water, lX75mL IN HCl, lX75mL sat. sodium bicarbonate, lX75mL brine, dried over potassium carbonate, filtered and concentrated in vacuo. The material was further purified by filtering through a packet of Siθ2 using 1:1 diethyl ether/hexane as the eluting solvent to yield l-(4-iodophenyl)-4-(N-Boc)-piperzine (1 grm, 77%, 142-143°C). 1H NMR (CDC13, dTMS) 7.54 (2H, d, m-ArH), 6.69 (2H, d, 3.04 (4H, t, 1.48 (9H, s, Bu*).

c) A magnetically stirred solution of N-(2-amino-5-iodobenzoyl)-3-aminoproprionate (8.8 grams, 23.4mmoI), prepared using the procedure shown in part (b) of Example 1, dimethylformamide, 2,6-lutidine (1.5 molar equiv., 35.1 mmol, 4.25mL) and 4-chlorobenzyl chloride (1.5 molar equiv., 35.1 mmol, 5.96 grams) was heated to 100°C for 24 hours. The

mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting residue was dissolved in 150mL methylene chloride and washed with 2X100mL 10% dtric add, lXlOOmL water, dried over sodium sulfate, filtered and concentrated in vacuo. The solid obtained was dissolved in a minimum volumn of methylene chloride and a 5 fold excess of hexanes added. The solution was allowed to stand overnight in the refrigerator (5-7°C) to yield 7.56 grams of N-(2-(p-chIorobenzyl)amϊno-5-iodobenzoyI)-3-aminoproprionat e (153- 155°C). Concentration of the mother liquor and repeating the steps for crystallization yielded a second crop (3.32 grams) for a total 92% isolated yield of the desired product. *H NMR (CDCI3, dTMS) 8.10 (IH, bt, ³ JHH=5Hz, NH), 7.60 (IH, d, jRH=2Hz, C6-H), 7.44 (IH, dd, ³ jHH=9Hz, C8-H), 7.29 (4H, m, p-ClC6H4), 6.72 (IH, bt, ³ JHH=6Hz, NH), 6.34 (IH, d, ³ jHH=9Hz, C9-H), 4.35 (2H, d, ³ jHH=9Hz, NCH2Ar), 4.20 (2H, q, CH2CO2), 1.31 (3H, t, ³ J _HH =7Hz, CH2CH3). ¹³ C NMR (CDCI3) 172.6, 168.3, 148.6, 141.0, 137.0, 135.6, 128.8, 128.3, 117.6, 1143, 75.1, 60.9, 46.3, 35.1, 33.9, 14.2

d) To a magnetically stirred bϊphasϊc solution of N-(2-(p-chlorobenzyl)amino-5- iodobenzoyl)-3-aminoproprionate (lOgrams, 20.57mmol), 200mL methylene chloride, and 200mL water was added, at room temperature, a-bromoacetyl bromide (24.7mmol, 1.2 molar equiv., 2.15mL), monitoring the reaction by TLC (Siθ2, 1:1 EtOAc/hexane). The reaction was complete 6 hours. The layers were separated , washing the aqueous layer with 75mL methylene chloride. Tine combined organics were washed lXlOOmL sat. sodium bicarbonate, lXlOOmL Brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was dissolved in 50mL dimethylformamide and added, via an addition funnel, over a period of 30 minutes to a slurry of sodium hydride (1.2 molar equiv., 24.7mmol, 0.60 grams) in lOmL dimethylformamide cooled to 0°C under an atmosphere of nitrogen. The reaction was stirred for an additional 1 hour and then poured over an ice-cold 10% citric acid solution. The cloudy mixture was extracted 3X100mL EtOAc. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification was achieved by column chromatography (S1O2 , 600mL, using 30%EtO Ac/70% hexane to 60%EtOAc/40% hexane as the eluting solvent gradient) to yield 6.5 grams (63%) of l-(p-chlorobenzyl)-7-iodo-4-(2- carboxyethyl)-3,4-dϊhydro-lH-l,4-benzodiazpine-2,4-dione ethyl ester. 1H NMR (CDCI3, dTMS) 8.11 (IH, d, ³ JHH=9HZ, C8-H), 7.23 (2H, d, ArH), 6.87 (IH, d, C9-H), 5.05 (IH, d, 2j _HH =i6Hz, NCHHAr), 4.95 (IH, d, 2JHH=16Hz, NCHHAr), 4.1 (3H, m, OCH2, C3- H), 3.93 (IH, d, ² J _HH =l5Hz, C3-H), 3.9 (2H, m, NCH2CH2), 2.65 (2H, m, CH2CO2), 1.25

e) To a magnetically stirred solution of l-(4-iodoplnenyI)-4-(N-Boc)-piperzine (0.5 grams, 1.29mmoI) in 0.65mL THF at -78°C under an atmosphere of nitrogen was added n-BuLi as a

. so ut on n exane . mmo , . mo ar equ v., . m over a m nu e per o . e mixture was stirred for 15 minutes at -78°C and the treated with triisopropylborate (3 molar equiv., 3.9mmol, 0.9mL). The mixture was allowed to warm to room temperature and stirred overnight (ca. 12 hours). The mixture was cooled to 0°C and acidified to pH 6.5 with 5% aq. HCl and extracted with CH2CI2 (50mL). The organic layer was washed with brine, dried over sodium sulfate, decanted and concentrated in vacuo. The resulting residue, in a minimum volume of ethanol, was added to a prestirred (10 mins) mixture of tetrakistriphenylphosphine palladium (0.03 molar equiv., 0.026mmol, 30mgs), and 0.447 grams of l-(p-chlorobenzyl)-7-iodo-4-(2-carboxyethyl)-3,4-dihydro-lH- l,4-benzodiazpine- 2,4-dione ethyl ester (0.85mmol) in 0.5mL dimetlnylformamide at room temperature. 1.3mL of a 2M solution of sodium carbonate (2 equiv.) was added and tine reaction mixture heated to 80°C for 6 hours. The mixture was allowed to cool to room temperature and is quenched with IN HCl (25mL) and extracted 3X50mL ethyl acetate. The combined organics were washed lX50mL sat NaHCO3, brine, dried over Na2SO4 decanted and concentrated in vacuo. The resulting residue was chromatographed (Siθ2, 1:1 EtOAc/hexane to 9:1 EtOAc/hexane as the eluting solvent) to yield l-(p-chlorobenzyl)-7-[4-(4-N-Boc-l-piperazine)phenyl]-4-(2- carboxyethyl)-3,4-dihydro-lH-l,4-benzodiazpine-2,4-dione ethyl ester (0.137 grams, 24%, Rf (Siθ2, 1:1 EtOAc/hexane)=0.15, mu and ninhydrin positive). 1H NMR (CDCI3, dTMS) 8.00 (IH, d, C8-H), 7.50 (2H, d, CH2-/«-ArH), 7.16 (IH, d, C9- H), 7.10 (2H, d, ³ JHH=9HZ, CH2-o-ArH), 6.95 (2H, d, C7-m-ArH), 5.08 (IH, d, 2j _HH= i6Hz, NCHHAr), 4.99 (IH, d, ² j _HH =i6Hz, NCHHAr), 4.18 (IH, d, ² J _HH =15Hz, C3- H), 4.13 (2H, q, J _H H=7Hz, OCH2), 3.92 (2H, , NCH2CH2), 3.92 (IH, d, ² J _HH =15Hz, C3- H), 3.58 (4H, t, J _{H H} =5Hz, NCH2CH2NH), 3.18 (4H, t, ³ JH H=5HZ, NCH2NCH2NH), 2.68 (2H, m, CH2CO2), 1.47 (9H, s, Bu ^l ), 1.25 (3H, t, 13C NMR 171.3, 168.5, 167.1,

154.7, 150.9, 138.6, 138.0, 135.2, 133.3, 132.1, 130.9, 129.9, 129.7, 128.9, 128.4, 127.5, 121.9, 116.4, 79.9, 60.8, 52.4, 50.6, 48.8, 45.1, 32.8, 28.4, 14.2.

Using the above procedure, but substituting the appropriate 7-iodo-3,4-dihydro-lH- l,4-benzodiazpine-2,4-dione alkyl ester for l-(p-clnlorobenzyI)-7-iodo-4-(2-carboxyethyl)- 3,4-dihydro-lH-l,4-benzodiazpine-2,4-dione ethyl ester and substituting the appropriate iodoarene for l-(4-iodoplnenyl)-4-(N-Boc)-piperzine there may be prepared, for example, the following compounds: l-methyI-7-[4-(4-N-Boc-l-piperazine)phenyl]-4-(2-carboxyethy l)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione ethyl ester, l-(diphenylmethyl)-7-[4-(4-N-Boc-l-piperazine)phenyI]-4-(2-c arboxyethyl)-3,4-dihydro- lH-l,4-benzodiazpine-2,4-dione ethyl ester, l-(2-napthyl)methy]-7-[4-(4-N-Boc-l-piperazine)phenyI]-4-(2- carboxyethyI)-3,4-dihydro- lH-l,4-benzodiazpine-2,4-dione ethyl ester, •

(+)-l-methyI-7-[4-(4-N-Boc-l-piperazine)phenyI]-4-(3-phenyl- 3-proprϊonate)-3,4- dihydro-lH-l,4-benzodiazpine-2,4-dione methyl ester,

(+)-l-(2-napthyl)methyl-7-[4-(4-N-Boc-l-piperazϊne)pheny l]-4-(3-phenyl-3-proprionate)- 3,4-dihydro-lH-l,4-benzodiazpine-2,4-dϊone methyl ester, l-(p-chIorobenzyl)-7-[4-(2-(N-Boc)-aminoethoxy)phenyl]-4-(2- carboxyethyl)-3,4-dihydro- lH-l,4-benzodiazpine-2,4-dione ethyl ester l-methyl-7-[4-(2-(N-Boc)-aminoethoxy)phenyl]-4-(2-carboxyeth yI)-3,4-dihydro-lH-l,4- benzodϊazpine-2,4-dione ethyl ester, l-(diphenylmethyl)-7-[4-(2-(N-Boc)-aminoethoxy)phenyI]-4-(2- carboxyethyI)-3,4- dihydro-lH-l,4-benzodiazpϊne-2,4-dϊone ethyl ester, l-(2-napthyl)methyl-7-[4-(2-(N-Boc)-aminoethoxy)phenyI]-4-(2 -carboxyethyl)-3,4- dihydro-lH-l,4-benzodiazpine-2,4-dione ethyl ester,

(+)-l-methyI-7-[4-(2-(N-Boc)-aminoethoxy)phenyl]-4-(3-phe nyl-3-proprionate)-3,4- dihydro-lH-l,4-benzodiazpine-2,4-dione methyl ester, (±)-l-(2-napthyl)methyl-7-[4-(2-(N-Boc)-aminoethoxy)phenyl] -4-(3-phenyl-3- proprionate)-3,4-dihydro-lH-l,4-benzodϊazpine-2,4-dione methyl ester, l-(p-chlorobenzyl)-7-[4-(N-Boc-aminomethyl)phenyI]-4-(2-carb oxyethyI)-3,4-dihydro-lH- l,4-benzodiazpine-2,4-dione ethyl ester l-methyI-7-[4-(N-Boc-aminomethyl)phenyI]-4-(2-carboxyethyl)- 3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione ethyl ester, l-(diphenylmethyl)-7-4-(N-Boc-aminomethyl)phenyl]-4-(2-carbo xyethyl)-3,4-dihydro- lH-l,4-benzodiazpine-2,4-dione ethyl ester, l-(2-napthyI)methyI-7-[4-(N-Boc-aminomethyI)phenyl]-4-(2-car boxyethyl)-3,4-dihydro- lH-l,4-benzodiazpϊne-2,4-dione ethyl ester, (±)-l-methyl-7-[4-(N-Boc-aminomethyI)phenyl]-4-(3-phenyl-3- proprionate)-3,4-dihydro- lH-l,4-benzodiazpϊne-2,4-dione methyl ester,

(+)-l-(2-napthyI)methyl-7-[4-(N-Boc-amϊnomethyl)phenyl]- 4-(3-phenyl-3-proprionate)- 3,4-dϊhydro-lH-l,4-benzodiazpine-2,4-dione methyl ester.

f) l-(p-chlorobenzyl)-7-[4-(I-piperazϊne)phenyI]-4-(2-carboxye thyl)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate was prepared using the method described in part (c) of Example 1. Thus, 34 mgs (0.052mmol) l-(p-chlorobenzyl)-7-[4-(4-N-Boc-l- piperazine)phenyl]-4-(2-carboxyethyl)-3,4-dihydro-lH-l,4-ben zodiazpine-2,4-dione ethyl ester yielded 25 mgs (90%) of l-(p-chlorobenzyl)-7-[4-(l-piperazϊne)phenyl]-4-(2- carboxyethyl)-3,4-dihydro-lH-l,4-benzodiazpϊne-2,4-dione trifluoroacetate (1/2" C-18 column, eluting with a solvent gradient of 1:9 acetonitrile(0.1%TFA) /water (0.1% TFA) time 0 to 10 minutes, to 1:1 acetonitrile(0.1%TFA)/water (0.1% TFA) time 10 to 40 minutes, flow lOmL/min, Rt=34.9 min, mu detection 254nM). HRMS (FAB) molecular ion m/z=533.1950 (cald. C29H30N4O4C1, 533.1956). 1H NMR (D2O,10%CD3OD) 7.61 (IH, d,

j _HH= 2Hz, C6-H), 7.43 (IH, dd, C8-H), 7.28 (2H, d, C7-o-ArH), 7.10 (IH, d, ³ JHH=8HZ, C9-H), 6.98 (2H, d, CH2-o-ArH), 6.80 (2H, d, NCHHAr), 3.95 (IH, d, 2j _HH =i4Hz, C3-H), 3.84 (IH, dt, NCHHCH2), 3.72 (IH, d, J _HH =i4Hz, C3-H), 3.58 (IH, dt, C3-H), 3.23 (4H, bs, NCH2CH2NH), 3.18 (4H, bs, NCH2CH2NH), 2.58 (2H, t, 3JHH=7Hz, CH2CO2).

Using tine above procedure, but substituting the appropriate 7-aryl-3,4-dihydro-lH- l,4-benzodiazpine-2,4-dione N-Boc amino alkyl ester for l-(p-chlorobenzyl)-7-[4-(4-N-Boc- l-piperazine)phenyl]-4-(2-carboxyethyl)-3,4-dihydro-lH-l,4-b enzodiazpine-2,4-dione ethyl ester there may be prepared, for example, the following compounds: l-methyl-7-[4-(l-piperazine)phenyI]-4-(2-carboxyethyl)-3,4-d ihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate, l-(diphenylmethyI)-7-[4-(l-pip>erazine)phenyl]-4-(2-carbo xyethyl)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate, l-(2-napthyl)methyl-7-[4-(l-piperazine)phenyl]-4-(2-carboxye thyl)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate,

(±)-l-methyI-7-[4-(l-piperazine)phenyI]-4-(3-phenyl-3-pr oprionate)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate,

(±)-l-(2-napthyl)methyl-7-[4-(l-piperazine)plnenyl]-4-(3 -phenyI-3-proprionate)-3,4- dihyd ro-lH-l,4-benzodiazρine-2,4-dione trifluoroacetate, l-(p-chlorobenzyl)-7-[4-(2-aminoethoxy)plnenyl]-4-(2-carboxy ethyl)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate, l-metlnyl-7-[4-(2-aminoethoxy)phenyl]-4-(2-carboxyethyl)-3,4 -dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate, l-(diplneny]methyl)-7-[4-(2-aminoethoxy)phenyl]-4-(2-carboxy ethyl)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate, l-(2-napthyl)methyl-7-[4-(2-aminoethoxy)phenyl]-4-(2-carboxy ethy])-3,4-dihydro-lH- l,4-benzodiazρine-2,4-dione trifluoroacetate,

(±)-l-methyl-7-[4-(2-aminoetlnoxy)phenyl]-4-(3-phenyl-3- proprionate)-3,4-dihydro-lH- l,4-benzodiazpine-2,4-dione trifluoroacetate,

(±)-l-(2-naptlnyl)methyl-7-[4-(2-aminoetlnoxy)phenyl]-4- (3-phenyl-3-proprionate)-3,4- dihydro-lH-l,4-benzodiazpine-2,4-dione trifluoroacetate, l-(p-chlorobenzyl)-7-[4-(aminomethyl)phenyl]-4-(2-carboxyeth yl)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate, l-methyl-7-[4-(aminomethyl)phenyl]-4-(2-carboxyethyl)-3,4-di hydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate, l-(diplnenylmetlnyI)-7-4-(aminomethyl)plnenyl]-4-(2-carboxye thyl)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate,

l-(2-napthyl)methyl-7-[4-(aminomethyl)phenyl]-4-(2-carboxyet hyl)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate, (+)-l-methyI-7-[4-(aminomethyl)phenyl]-4-(3-phenyl-3-proprio nate)-3,4-dihydro-lH-l,4- benzodiazpine-2,4-dione trifluoroacetate, (+)-l-(2-napthyl)methyI-7-[4-(aminomethyl)phenyI]-4-(3-pheny l-3-proprionate)-3,4- dihydro-lH-l,4-benzodϊazpine-2,4-dione trifluoroacetate.

Example 13

l-[3-(N-(4-aιmnobιtturyl))amitτophenyI]methyl-4-(2-car boxyethyl)-7-(6-aminohexyl)-3,4- dilιydro-lH-l _r 4-benzodiazapine-2,5-dione bistrifluoroacetate. a) l-(3-nitrophenyI)methyl-4-(2-carboxyethyI)-7-(N-Boc-6-aminoh exynyI)-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione etlnyl ester (HOmgs, 0.18mmol) was reduced under an atmosphere of nitrogen in 4mL ethyl acetate in the presence of a catalytic amount of 10% Pd on carbon (25mgs), monitoring the reaction by TLC (S1O2, 1:1 ethyl acetate/hexane, Restarting materϊal)=0.33, Rf(product)=0.15, mu and ninhydrin positive). After 3 hours, the reaction was filtered through Celite®, washing with ethyl acetate, and concentrated in vacuo to yield 97mgs (92%) of l-(3-aminophenyl)methyl-4-(2-carboxyethyl)-7-(N-Boc-6- amϊnohexyI)-3,4-dϊhydro-lH-l,4-benzodiazapine-2,5-dione ethyl ester. IH NMR (CDCI3, dTMS) 7.58 (IH, d, C8-H), 7.09 (IH, d, CH2ArH), 7.04 (IH, t, 3JHH=8Hz, CH2ArH), 6.54 (IH, bd, CH2ArH), 6.48 (IH, bs, CH2ArH), 4.99 (IH, d, ² J _HH =i6Hz, CHHAr), 4.90 (IH, d, 2JHH=16Hz, CHHAr), 4.53 (IH, vbs, NHBoc), 4.20-3.96 (4H, m, OCH2, C3-H, NCHHCH2), 3.92-3.80 (2H, m, C3-H, NCHHCH2), 3.55 (2H, bs, NH2), 3.06 (2H, bq, CH2NHB0C), 2.72 (2H, m, CH2CO2), 2.56 (2H, t, ³ JHH=7HZ), 1.66-1.20 (20H, m, (CH2)4, Bu ^l , OCH2CH3). 13C NMR (CDCI3) 171.4, 168.5, 167.4, 146.3, 140.7, 138.1, 137.9, 132.2, 130.1, 129.6, 129.0, 121.6, 117.4, 114.5, 113.6, 79.0, 60.8, 52.4, 51.1, 45.1, 40.5, 34.9, 32.8, 30.8, 29.9, 28.8, 28.4, 26.5, 14.2. Using the above procedure, but substituting the appropriate 7-alkyl or aryl-3,4- dihydro-lH-l,4-benzodiazpine-2,4-dione N-Boc amino alkyl ester for l-(3- nitrophenyl)methyl-4-(2-carboxyethyI)-7-(N-Boc-6-aminohexyny l)-3,4-dihydro-lH-l,4-

benzodiazapine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-(2-aminophenyl)methyl-4-(2-carboxyethyl)-7-(N-Boc-6-aminoh exyl)-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione ethyl ester, l-(4-aminophenyl)methyl-4-(2-carboxyethyl)-7-(N-Boc-6-aminoh exyl)-3,4-dihydro-lH- l,4-benzodiazapine-2,5-dione ethyl ester, l-(3-aminophenyl)methyl-4-(2-carboxyethyl)-7-[4-(4-N-Boc-l-p iperazine)phenyl]-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione ethyl ester, l-(3-aminophenyl)methyl-4-(3-phenyl-3-proprionate)-7-[4-(4-N -Boc-l- piperazine)phenyl]-3,4-dihydro-lH-l,4-benzodiazapine-2,5-dio ne ethyl ester, l-(3-aminophenyl)methyl-4-(3-ρhenyl-3-proprionate)-7-(N-Boc -6-aminohexyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione ethyl ester,

b) A solution of the aniline l-(3-aminophenyl)methyl-4-(2-carboxyethyl)-7-(N-Boc-6- aminohexyI)-3,4-dihydro-lH-l,4-benzodiazapine-2,5-dione ethyl ester (50mgs, 0.09mmol) and 0.5mL dimethylacetamide was added to a prestirred solution of N-Boc-4-aminobutyric acid (0.16mmol, 32.5mgs), 0.5mL dimethylacetamide, 0.5mL pyridine, and benztriazol-1-yl- oxy-tris-(dimetlnylamino)phosphoniurn hexafluorophosphate (BOP Reagent) and a catalytic amount of dimethylaminυpyridine (DMAP, 5mgs), monitoring by TLC (8:2 ethyl acetate/hexane). After 6 hours, the reaction was poured over 50mL IN HCl and extracted 2X50mL ethyl acetate. The combined organics was dried over sodium sulfate, decanted, and concentrated in vacuo. The resulting residue was purified by column chromatography, Siθ2, using 7:3 ethyl acetate/hexane to 9:1 ethyl acetate/hexane, Rf(8:2 ethyl acetae/hexane, product)=0.15, to yield 59mgs (86%) of l-[3-(4-N-Boc-aminobutyryl)aminophenyl]methyl-4- (2-carboxyethy l)-7-(N-Boc-6-aminohexyl)-3,4-d ihyd ro-1 H-l, 4-benzodiazapine-2,5-dione ethyl ester. ^J H NMR (CDCI3, dTMS) 8.78 (IH, bs, ArNHCO), 7.56 (IH, d, ⁴ JHH=2Hz, C6- H), 7.44 (IH, bd, j _H H=8Hz, C8-H), 7.36 (IH, bs, CH2ArH), 7.17 (2H, m, CH2ArH), 7.09 (IH, t, ³ J _HH =8Hz, CH2ArH), 6.81 (IH, bd, J _H H=8Hz, C9-H), 5.1-4.9 (3H, m, NHBoc, CH2Ar), 4.58 (IH, bs, NHBoc), 4.20-4.05 (4H, m, OCH2, C3-H, NCHHCH2), 3.87 (IH, d, ² JHH=15HZ, C3-H), 3.80 (IH, dt, NCHHCH2), 3.16 (2H, bq, j _H H=6Hz, CH2NHB0C), 3.04 (2H, bq,

³ J _HH =6Hz, CH2NHB0C), 2.71 (2H, m, CH2CO2), 2.54 (2H, t, ³ J _H H=7Hz, NCOCH2), 2.32 (2H, t, NCOCH2CH2), 1.6-1.2 (20H, m, (CH2)4, But, OCH2CH3).

Using the above procedure, but substituting the appropriate 7-alkyl or aryl-3,4- dihydro-lH-l,4-benzodiazpine-2,4-dione N-Boc amino alkyl ester for l-(3- aminophenyI)methyl-4-(2-carboxyethyl)-7-(N-Boc-6-aminohexyl) -3,4-dihydro-lH-l,4- benzodiazapine-2,5-dione ethyl ester there may be prepared, for example, the following compounds:

l-[2-(4-N-Boc-aminobutyryl)aminophenyI]methyl-4-(2-carboxyet hyl)-7-(N-Boc-6- aminohexyl)-3,4-dihydro-lH-l,4-benzodiazapine-2,5-dione ethyl ester, l-(4-(4-N-Boc-aminobutyryl)aminophenyl)methyl-4-(2-carboxyet hyl)-7-(N-Boc-6- aminohexyl)-3,4-dihydro-lH-l,4-benzodiazapine-2,5-dione ethyl ester, l-(3-(4-N-Boc-aminobutyryl)aminophenyl)methyl-4-(2-carboxyet hyl)-7-[4-(4-N-Boc-l- piperazine)phenyl]-3,4-dihydro-lH-l,4-benzodiazapine-2,5-dio ne ethyl ester, l-(3-(4-N-Boc-aminobutyryl)aminophenyl)methyl-4-(3-phenyl-3- proprionate)-7-[4-(4-N- Boc-l-pϊperazϊne)phenyI]-3,4-dihydro-lH-l,4-benzodϊazapin e-2,5-dione ethyl ester, l-(3-(4-N-Boc-amϊnobutyryl)amϊnophenyl)methyl-4-(3-phenyl- 3-proprionate)-7-(N-Boc-6- aminohexyl)-3,4-dihydro-lH-l,4-benzodϊazapine-2,5-dione ethyl ester, l-[3-(3-N-Boc-aminopropϊonyI)aminophenyl]methyl-4-(2-carbox yethyl)-7-(N-Boc-6- aminohexyl)-3,4-dihydro-lH-l,4-benzodϊazapine-2,5-dione ethyl ester, l-[2-(3-N-Boc-aminopropionyl)amϊnophenyl]methyl-4-(2-carbox yethyl)-7-(N-Boc-6- aminohexyI)-3,4-dihydro-lH-l,4-benzodiazapine-2,5-dione ethyl ester, l-(4-(3-N-Boc-aminopropionyl)aminophenyI)methyl-4-(2-carboxy ethyI)-7-(N-Boc-6- amϊnohexyl)-3,4-dihydro-lH-l,4-benzodtazapine-2,5-dione ethyl ester, l-(3-(3-N-Boc-aminopropionyI)aminophenyl)methyl-4-(2-carboxy ethyl)-7-[4-(4-N-Boc-l- piperazine)phenyl]-3,4-dihydro-lH-l,4-benzodiazapine-2,5-dio ne ethyl ester, l-(3-(3-N-Boc-aminopropionyl)amϊnophenyl)methyl-4-(3-phenyl -3-proprionate)-7-[4-(4- N-Boc-l-piperazine)phenyI]-3,4-dihydro-lH-l,4-benzodiazapine -2,5-dione ethyl ester, l-(3-(3-N-Boc-aminopropionyl)aminophenyI)methyl-4-(3-phenyl- 3-proprionate)-7-(N- Boc-6-aminohexyl)-3,4-dihydro-lH-l,4-benzodiazapine-2,5-dϊo ne ethyl ester.

c) l-[3-(N-(4-aminobuturyl))aminophenyI]methyl-4-(2-carboxyethy l)-7-(6-aminohexyl)- 3,4-dihydro-IH-l,4-benzodiazapine-2,5-dione trifluoroacetate was prepared using the method described in part (c) of Example 1. Thus, 59 mgs (0.074mmol) l-[3-(4-N-Boc- aminobutyryl)aminophenyI]methyl-4-(2-carboxyethyl)-7-(N-Boc- 6-aminohexyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione ethyl ester yielded 50 mgs (99%) of l-[3-(N-(4- aminobuturyI))aminophenyl]methyl-4-(2-carboxyethyl)-7-(6-ami nohexyl)-3,4-dihydro- lH-l,4-benzodiazapine-2,5-dione trifluoroacetate (1/2" C-18 reverse-phase column, eluting with a solvent gradient of 1:9 acetonϊtrile(0.1%TFA)/water (0.1% TFA) time 0 to 10 minutes, to 1:1 acetonitrile(0.1%TFA)/water (0.1% TFA) time 10 to 40 minutes, flow lOmL/min, Rχ=30.5 min,mu detection 254nM). HRMS (FAB) molecular ion m/z=538.3032 (cald. C29H39N5O5, 538.3030). 1H NMR (D2O) 7.21 (IH, bs, C6-H), 7.05-6.85 (5H, m, CH2ArH, C8- H), 652 (IH, bd, ³ J _H H=8Hz, C9-H), 5.03 (IH, d, ² J _HH =i6Hz, CHHAr), 4.47 (IH, d, ² JHH=16Hz, CHHAr), 3.86 (IH, d, ² J _HH =l5Hz, C3-H), 3.80 (IH, dt, ³ J _H H=7Hz, ² JHH=15Hz, NCHHCH2), 3.63 (IH, d, ² J _HH =i5Hz, C3-H), 3.51 (IH, dt, ³ J _H H=7Hz, ² JHH=15Hz, NCHHCH2), 2.83 (2H, t, J _H H=8Hz, CH2NH2), 2.68 (2H, t, ³ J _H H=8Hz,

CH2NH2), 2.43 (2H, t, NCOCH2CH2),

1.35 (2H, p, ³ JHH=7HZ), 1.22 (2H, _P , J _H H=7Hz), 1.1-0.9 (4H, m).

Using the above procedure, but substituting the appropriate 7-alkyl or aryl-3,4- dihydro-lH-l,4-benzodiazpine-2,4-dione bis-N-Boc diamino alkyl ester for l-[3-(4-N-Boc- aminobutyryl)aminophenyl]methyl-4-(2-carboxyethyl)-7-(N-Boc- 6-aminohexyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-[2-(4-aminobutyryl)aminophenyl]methyl-4-(2-carboxyethyl)-7 -(6-aminohexyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione bistrifluoroacetate, l-(4-(4-aminobutyryl)aminophenyl)methyl-4-(2-carboxyethyl)-7 -(6-aminohexyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione bistrifluoroacetate, l-(3-(4-aminobutyryl)aminophenyl)methyl-4-(2-carboxyethyl)-7 -[4-(l-piperazine)phenyl]-

3,4-dihydro-lH-l,4-benzodiazapine-2,5-dione bistrifluoroacetate, l-(3-(4-aminobutyryl)aminoplnenyl)methyl-4-(3-phenyl-3-propr ionate)-7-[4-(l- piperazine)phenyl]-3,4-d ihyd ro-1 H-l, 4-benzodiazapine-2,5-dione bistrifluoroacetate, l-(3-(4-aminobutyryl)aminoplnenyl)methyl-4-(3-phenyl-3-propr ionate)-7-(6-aminohexyl)-

3,4-dihydro-lH-l,4-benzodiazapine-2,5-dione bistrifluoroacetate, l-[3-(3-aminopropionyl)aminophenyI]metlnyl-4-(2-carboxyethyl )-7-(6-aminohexyl)-3,4- dihydro-1 H-l, 4-benzodiazapine-2,5-d ione bistrifluoroacetate, l-[2-(3-aminopropionyl)aminophenyl]methyl-4-(2-carboxyethyl) -7-(6-aminohexyl)-3,4- dihydro-lH-l,4-benzodiazapine-2,5-dione bistrifluoroacetate, l-(4-(3-aminopropionyl)aminophenyl)methyl-4-(2-carboxyethyl) -7-(6-aminohexyl)-3,4- dihydro-1 H-l, 4-benzodiazapine-2,5-d ione bistrifluoroacetate, l-(3-(3-aminopropionyl)aminophenyl)methyl-4-(2-carboxyethyl) -7-[4-(l- piperazine)phenyl]-3,4-dihydro-l H-l, 4-benzodiazapine-2,5-d ione bistrifluoroacetate, l-(3-(3-aminopropionyl)aminophenyl)methyl-4-(3-phenyl-3-prop rionate)-7-[4-(4-(l- piperazine)phenyl]-3,4-d ihyd ro-1 H-l, 4-benzodiazapine-2,5-d ione bistrifluoroacetate, l-(3-(3-aminopropionyl)aminophenyl)methyl-4-(3-phenyI-3-prop rionate)-7-(6- aminohexyl)-3,4-dilnydro-l H-l,4-benzodiazapine-2,5-dione bistrifluoroacetate.

Example 14

l-(diphenylmethyl)-4-(2-carboxyethyl)-7-(5-aminopentyl)-3 _r 4-dihydro-lH-l,4- benzodiazepinc-2,5-dione trifluoroacetate a) A magnetically stirred solution of 1.1 gram of N-(2-amino-5-iodobenzoyl)-b-alanine ethyl ester (3.1mmol), prepared by the method shown in part (b) of Example 1, 0.48mL of 2,6- lutϊdine (4.1mmol), 1.2 grams of chlorodiphenylmethane (4.7mmoI), and lOmL of dimethylformamide was heated to 50°C for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting oil was dissolved in 35mL of methylene chloride and washed witln 2x50mL 10% citric acid, lx50mL water, dried over sodium sulfate, decanted and concentrated in vacuo. The resulting oil was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 10/90 ethyl acetate/hexane to 25/75 ethyl acetate/hexane (TLC, SiU2, 1:1 EtOAc/hexane, Rp 0.82, uv positive) to yield 0.92 gram (56%) of N-(2-diphenylmethylamino-5-iodobenzoyl)-b-alanine ethyl ester. NHCHAr2), 7.56 (IH, d, ArH Ph, ArH p-CON), 6.73 (IH, t, ³ J _HH =6Hz, NHCH2), 6.29 (IH, d, ³ J _HH =9Hz, ArH m-CON), 5.52 (IH, d, ³ J _HH =5Hz, CHNH), 4.15 (2H, q, ³ J _HH =7Hz, OCH2), 3.61 (2H, q, ³ J _HH =6Hz, CH2NH), 2.58 (2H, t, ³ J _HH =6Hz, CH2CO), 1.25 (3H, t, JHH=6Hz, CH3CH2O). Using the above procedure, but substituting the appropriate alkyl or aryl halide there may be prepared, for example, the following compounds: N-(2-(l-napthyl)methyIamino-5-iodobenzoyl)-b-alanine ethyl ester, N-(2-(2-napthyl)methylamino-5-iodobenzoyI)-b-alanine ethyl ester, N-(2-(p-phenoxybenzyl)amino-5-iodobenzoyl)-b-alanine ethyl ester, N-(2-(m-phenoxybenzyl)amino-5-iodobenzoyl)-b-aIanϊne ethyl ester,

N-(2-(p-trifluoromethylbenzyl)amϊno-5-iodobenzoyl)-b-ala nϊne ethyl ester, N-(2-(ethyI-5-vaIeroyI)amino-5-iodobenzoy])-b-alanιne ethyl ester, N-(2-(p-methoxybenzyl)amino-5-iodobenzoyI)-b-alanine ethyl ester, Methyl 3(S)-N-(2-(2-methylnapthyl)amino-5-iodobenzoyl)-3-amino-3-me thylpropionate, Methyl 3(R)-N-(2-(2-napthyl)methylaminυ-5-iodobenzoyl)-3-amino-3-m ethyIpropionate, Methyl (+/-)-N-(2-(2-napthyl)methylamϊno-5-iodobenzoyl)-3-amϊno-3 -methylpropionate, Methyl 3(S)-N-(2-(2-napthyl)methylamino-5-iodobenzoyI)-3-amino-3-ph enylpropionate,

Methyl 3(R)-N-(2-(2-napthyl)methylamiιno-5-iodobenzoyI)-3-amino-3- phenylpropionate, Methyl (+/-)-N-(2-(2-napthyl)methylamino-5-iodobenzoyI)-3-amino-3-p henylpropionate,

b) To a magnetically stirred solution of 0.93 gram of N-(2-diphenyl-methylamino-5- iodobenzoyl)-b-alanine ethyl ester (1.8mmol) in 15mL of methylene chloride and 15mL water, was added 183mL a-bromoacetylbromide (2.1 mmol). The reaction mixture was stirred overnight. The layers were separated, the aqueous fraction was washed lxl5mL methylene chloride, and the two methylene chloride fractions were combined and washed with lx20mL of saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was dissolved in 7mL of dimetlnylformamide and added, via an addition funnel, to a slurry of 57 mgs of 95% sodium hydride (2.2mmol) in 5mL dimethylformamide that was cooled at 0°C. After 2 hours, the mixture was poured over 40mL of ice cooled 10% citric acid and extracted 3x40mL methylene chloride. The combined organic layers were washed witln 2x50mL of 10% citric acid and lx50mL water, dried over sodium sulfate, decanted, concentrated in vacuo and further purified by column chromatography, using silica gel, eluting witln a 1:1 mixture of ethyl acetate and hexane (TLC, Siθ2, 1:1 EtOAc/hexane, R = 0.61, uv positive) to yield 474 mgs (48%) of 1-

(diphenylmethyl)-4-(2-carboxyethyl)-8-iodo-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione ethyl ester. *H NMR (CDCI3, dTMS) 8.03 (IH, d, ³ JHH=2Hz, ArH o-CON), 7.45 (IH, dd, ArH Ph), 6.79 (IH, d, ³ JHH ⁼ 9Hz, ArH m-CON), 6.70 (IH, s), 4.13 (2H, q, ³ J _HH =7Hz, OCH2), 3.98 (2H, dd, CH2N), 2.58 (2H, dm, ³ JHH=40HZ, CH2CO), 1.27 (3H, t, CH3CH2O). ¹³ C NMR (CDCI3) 171.2, 168.0, 165.6, 139.9, 139.3, 138.8, 138.1, 137.5, 132.0, 129.1, 128.5, 128.4, 128.0, 128.0, 128.0, 127.9, 127.6, 125.4, 90.6, 67.2, 60.8, 53.1, 45.0, 32.6, 14.2.

Using the above procedure, but substituting the appropriate N-(2-amino-5- iodobenzoyl)-b-alanine ethyl ester for N-(2-diplnenylrnethylamino-5-iodobenzoyl)-b- alanine ethyl ester there may be prepared, for example, the following compounds: l-(l-napthyl)methyl-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione ethyl ester, l-(2-napthyl)methyl-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione ethyl ester, l-(m-phenoxybenzyl)-4-(2-carboxyethyl)-7-iυdo-3,4-dilnydro- lH-l,4-benzodiazepine-2,5- dione ethyl ester, l-(p-phenoxybenzyl)-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione ethyl ester, l-(p-trifluorometInylbenzyl)-4-(2-carboxyethyl)-7-iodo-3,4-d ihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester,

l-(ethyl-5-valeroyl)-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-l H-l,4-benzodiazepine-2,5- dione ethyl ester, l-(p-methoxybenzyl)-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione ethyl ester, l-(p-methylmethylbenzoyl)-4-(2-carboxyethyl)-7-iodo-3,4-dihy dro-lH-l,4- benzodϊazepine-2,5-dione ethyl ester, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-iodo-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione methyl ester, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-iodo-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione methyl ester, l-(2-napthyI)methyl-4-((+/-)3-butanoate)-7-iodo-3,4-dihydro- lH-l,4-benzodiazepine-2,5- dione methyl ester, l-(2-napthyI)methyl-4-(3(S)-phenyl-3-proprionate)-7-iodo-3,4 -dihydro-lH-l,4- benzodϊazepine-25-dione methyl ester, l-(2-napthyl)methyl-4-(3(R)-phenyl-3-proprionate)-7-iodo-3,4 -dihydro-lH-l,4- benzodiazepine-25-dϊone methyl ester, l-(2-napthyl)methyl-4-((+/-)3-phenyI-3-proprionate)-7-ϊodo- 3,4-dihydro-lH-l,4- benzodiazepine-25-dϊone methyl ester.

c) To a magnetically stirred solution of 208 mgs of l-(diphenyImethyI)-4-(2-carboxyethyl)-7- iodo-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester (0.37mmol) in 6mL ethyl acetate, degassed of oxygen, under an atmosphere of nitrogen, was added 134 mgs of N-boc-5- amino-1-pentyne (0.74mmol), prepared as described in part (e) of Example 1, 10 mgs of bistriphenylphosphine palladium dichloride (0.014mmol), 5 mgs of cuprous iodide (0.026mmol) and 250uL of triethylamine (1.75mmol). After 1.5 hours, the reaction mixture was diluted witln 35mL of ethyl acetate and washed with lxlδmL 5% EDTA-Na2, dried over sodium sulfate, decanted, concentrated in vacuo, and further purified by column chromatography, using silica gel, eluting witln a 1:1 mixture of ethyl acetate and hexane (TLC, SiO ₂ , 1:1 EtOAc/hexane, R = 0.46, uv positive) to yield 131 mgs (60%) of 1- (dϊphenylmethyl)-4-(2-carboxyethyl)-8-(N-boc-5-amino-l-pent ynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester. 1H NMR (CDCI3, TMS) 7.71 (IH, d, ArH o-CON), 7.10-7.36 (11H, m, ³ J _H H=2Hz, ArH Ph, ArH p-CON), 6.94 (IH, d, ⁴ jHH=9Hz, ArH p-CON), 6.67 (IH, s, CHAr2), 4.78 (IH, s, NHBoc), 4.10 (2H, q, ³ J _HH =7Hz, CH2O) 3.95 (2H, dd, 2j _HH =l()6Hz, 2j _HH =l5Hz, COCH2CN), 3.82 (2H, dm, ² > ⁵ } _HH =7Hz, ² , ³ J _HH =59Hz, CH2N), 3.19 (2H, q, ³ J _HH =3Hz, CH2NHB0C), 2.54 (2H, dm, ³ J _HH =7Hz, ³ J _HH =21Hz,

CH2CO), 2.37 (2H, t, CH2CH ₂ CH2), 1.38 (9H, s, Ch3 Boc), 122 (3H, t, ³ J _H H=7Hz, CH3CH2O).

Using the above procedure, but substituting the appropriate 7-iodo-3,4-dihydro-lH- l,4-benzodϊazepϊne-2,5-dione for l-(diphenylmefhyI)-4-(2-carboxyethyI)-7-iodo-3,4-

dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester and alkyne for N-boc-5-amino-l- pentyne there may be prepared, for example, the following compounds: l-(diphenylmethy])-4-(2-carboxyethyl)-7-(N-boc-6-amino-l-hex ynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(diphenylmethyl)-4-(2-carboxyetlnyl)-7-(N-boc-4-amino-l-bu tynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(l-napthyl)methyl-4-(2-carboxyethyI)-7-(N-boc-5-amino-l-pe ntynl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione ethyl ester, l-(l-napthyl)methyl-4-(2-carboxyethyl)-7-(N-boc-6-amino-l-he xynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(2-napthyl)methyl-4-(2-carboxyethyl)-7-(N-boc-5-amino-l-pe ntynI)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione ethyl ester, l-(2-napthyl)methyl-4-(2-carboxyethyI)-7-(N-boc-6-amino-l-he xynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-phenoxybenzyl)-4-(2-carboxyethyI)-7-(N-boc-5-amino-l-pe ntynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-phenoxybenzyl)-4-(2-carboxyethyl)-7-(N-boc-6-amino-l-he xynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(m-phenoxybenzyl)-4-(2-carboxyethyI)-7-(N-boc-5-amino-l-pe ntynl)-3,4-dihydro-lH- l,4-benzodiazeρine-2,5-dione ethyl ester, l-(m-phenoxybenzyl)-4-(2-carboxyethyI)-7-(N-boc-6-amino-l-he xynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-trifluoromethyIbenzyl)-4-(2-carboxyethyl)-7-(N-boc-5-am ino-l-pentynl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione ethyl ester, l-(p-trifluorometlnylbenzyl)-4-(2-carboxyethyI)-7-(N-boc-6-a mino-l- hexynl)-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione ethyl ester, l-(ethyl-5-valeroyl)-4-(2-carboxyetlnyI)-7-(N-boc-5-amino-l- pentynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(ethyl-5-valeroyl)-4-(2-carboxyethyl)-7-(N-boc-6-amino-l-h exynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-methoxybenzyl)-4-(2-carboxyethyl)-7-(N-boc-5-amino-l-pe ntynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-methoxybenzyl)-4-(2-carboxyetlnyl)-7-(N-boc-6-amino-l-h exynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-methylmethyIbenzoyl)-4-(2-carboxyetlnyl)-7-(N-boc-5-ami no-l-pentynl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione ethyl ester, l-(p-methy]methylbenzoyl)-4-(2-carboxyethyl)-7-(N-boc-6-amin o-l-hexynI)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione ethyl ester,

l-(2-napthyl)mel yl-4-(3(S)-butanoate)-7-(N-boc-5-amino-l-pentynl)-3,4-dihydr o-lH-l,4- benzodiazepine-25-dione methyl ester, l-(2-napthyl)methyI-4-(3(S)-butanoate)-7-(N-boc-6-amino-l-he xynl)-3,4-dihydro-lH-l,4- benzodiazepine-25-dϊone methyl ester, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(N-boc-5-amϊno-l-p entynl)-3,4-dihydro-lH-l,4- benzodiazepine-2^-dione methyl ester, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(N-boc-6-amino-l-he xynl)-3,4-dihydro-lH-l,4- benzodiazepine-25- ϊone methyl ester, l-(2-napthyl)methyl-4-((+/-)3-butanoate)-7-(N-boc-5-amino-l- pentynl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-((+/-)3-butanoate)-7-(N-boc-6-amino-l- hexynl)-3,4-dihydro-lH- l,4-benzodiazεpϊne-25-dϊone methyl ester, l-(2-napthyl)methyl-4-(3(S)-phenyl-3-proprionate)-7-(N-boc-5 -amino-l-pentynI)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyI-4-(3(S)-phenyl-3-proprionate)-7-(N-boc-6 -amino-l-hexynl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-(3(R)-phenyl-3-proprϊonate)-7-(N-boc- 5-amino-l-pentynl)-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone methyl ester, l-(2-napthyl)mεthyl-4-(3(R)-phenyl-3-proprionate)-7-(N-boc- 6-amino-l-hexynl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-((+/-)3-phenyI-3-proprionate)-7-(N-boc -5-amino-l-pentynl)-3,4- dϊhydro-lH-l,4- enzodiazepine-2,5-dϊone methyl ester, l-(2-napthyl)methyl-4-((+/-)3-phenyl-3-proprionate)-7-(N-boc -6-amino-l-hexynl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone methyl ester.

d) To a magnetically stirred solution of 66 mgs of l-(diphenyImethyl)-4-(2-carboxyethyl)-8- (N-boc-5-amino-l-pentynl)-3,4-dihyd ro-1 H-l,4-benzodiazepine-2,5-dione ethyl ester (O.llmmol) in 2mL ethyl acetate, covered with an.atmosphere of hydrogen, was added 23 mgs of palladium/carbon catalyst. The mixture was stirred for 1 hr. before filtering the mixture through Celite© and concentrating in vacuo to yield quantitative yield of 1-

(diphenylmethyl)-4-(2-carboxyethyl)-8-(N-boc-5-aminopenty l)-3,4-dihydro-lH-l,4- benzodiazepine-25-dione ethyl ester. 1H NMR (CDCI3, dTMS) 7.54 (IH, d, Ar- H o-CON), 6.90-738 (12H, m, Ar-H Ph, ArH p-CON, ArH m-CON), 6.54 (IH, s, NCHAr2), 4.64 (IH, s, NHBoc), 4.12 (2H, q, ³ J _HH =7Hz, CH ₂ O) 3.97 (2H, dd, ² J _HH =i29Hz, CH2N), 3.07 (2H, q, ³ J _H H= Hz, CH2NHB0C), 2.55 (4H, dm, t, ³ J _HH =7Hz, ³ J _HH =30Hz, ³ J _HH =7Hz, CH ₂ CO, CH ₂ Ar), 1.3-1.6 (4H, m, , ³ J _HH =7Hz, J _HH =7Hz, CH2CH2Ar, CH2CH2NHB0C), 1.1-1.3 (14H,s, m,t, JHH=7Hz, J _HH =7Hz, CH3 Boc, CH2CH2CH2NHB0C, CH3CH2).

Using the above procedure, but substituting tine appropriate 4-(2-carboxyethyl)-7-

(N-boc-amino-l-alkynl)-3,4-dilnydro-lH-l,4-benzodiazepine -2,5-dione ethyl ester for 1-

(diphenylmethyl)-4-(2-carboxyethyl)-7-(N-boc-5-amino-l-pe ntynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-(diphenylmethyl)-4-(2-carboxyethyI)-7-(N-boc-6-aminohexyl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(diphenylmethyl)-4-(2-carboxyethyl)-7-(N-boc-4-aminobutyl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(l-napthyl)methyl-4-(2-carboxyethyl)-7-(N-boc-5-aminopenty l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(l-napthyl)methyl-4-(2-carboxyethyl)-7-(N-boc-6-aminohexyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(2-napthyl)methyl-4-(2-carboxyethyl)-7-(N-boc-5-aminopenty l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(2-napthyl)methyl-4-(2-carboxyetlny])-7-(N-boc-6-aminohexy l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-phenoxybenzyl)-4-(2-carboxyethyl)-7-(N-boc-5-aminopenty l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-phenoxybenzyl)-4-(2-carboxyethyI)-7-(N-boc-6-aminohexyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(m-phenoxybenzyl)-4-(2-carboxyethyl)-7-(N-boc-5-aminopenty l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(w-phenoxybenzyl)-4-(2-carboxyethyl)-7-(N-boc-6-aminohexyI )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-trifluoromethylbenzyl)-4-(2-carboxyethyl)-7-(N-boc-5-am inopentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione ethyl ester, l-(;j-trifluoromethylbenzyl)-4-(2-carboxyethyl)-7-(N-boc-6-a mino hexyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester, l-(ethyl-5-valeroyl)-4-(2-carboxyetlnyl)-7-(N-boc-5-aminopen tyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(ethyl-5-valeroyl)-4-(2-carboxyethyl)-7-(N-boc-6-aminohexy l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-methoxybenzyl)-4-(2-carboxyethyl)-7-(N-boc-5-aminopenty l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-methoxybenzyl)-4-(2-carboxyethyI)-7-(N-boc-6-aminohexyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(p-methylmethylbenzoyl)-4-(2-carboxyethyl)-7-(N-boc-5-amin o pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione ethyl ester,

l-(p-methylmethylbenzoyl)-4-(2-carboxyethyl)-7-(N-boc-6-amin o hexyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione ethyl ester, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-(N-boc-5-amino-l-pe ntyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-(N-boc-6-amϊno-l-h exyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(N-boc-5-amino-l-pe ntyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(N-boc-6-amino-l-he xyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-((+/-)3-butanoate)-7-(N-boc-5-amino-l- pentyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyI-4-((+/-)3-butanoate)-7-(N-boc-6-amino-l- hexyI)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-(3(S)-phenyI-3-proprϊonate)-7-(N-boc- 5-amino-l-pentyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyI-4-(3(S)-phenyl-3-proprϊonate)-7-(N-boc- 6-amino-l-hexyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-(3(R)-phenyl-3-proprionate)-7-(N-boc-5 -amino-l-pentyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone methyl ester, l-(2-napthyl)methyl-4-(3(R)-phenyl-3-proprionate)-7-(N-boc-6 -amino-l-hexyl)-3,4- dihydro-lH-l,4-benzodϊazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-((+/-)3-phenyl-3-proprionate)-7-(N-boc -5-amino-l-pentyl)-3,4- dϊhydro-lH-l,4-benzodiazepine-2,5-dione methyl ester, l-(2-napthyl)methyl-4-((+/-)3-phenyI-3-proprionate)-7-(N-boc -6-amino-l-hexyl)-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dϊone methyl ester.

e) To a solution of 33 mgs of l-(dϊphenylmethyl)-4-(2-carboxyethyl)-7-(N-boc-5- aminopentyl)-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione ethyl ester (0.05mmol) in 2mL ethyl acetate was added 0.4mL triethylsilane (2.5mmol) and 6mL of saturated HCl/ethyl acetate at 5°C. After 1 hour at 5°C the mixture was concentrated in vacuo and diluted with 2mL of methanol. To the methanolic solution was added 2mL of 2N sodium hydroxide. After 1 hour, the reaction was quenched with l/2mL of acetic acid, concentrated in vacuo, diluted with 5mL of methanol and water and purified by high pressure liquid chromatography, using a 1/2" C-18 reverse phase column, eluting with a solvent gradient of 30:70 methanol (0.1% trifluoroacetic acid)/water (0.1% trifluoroacetic acid), time 0 to 10 minutes, to 70:30 methanol (0-1% trifluoroacetic acid)/water (0.1% trifluoroacetic acid), time 10 minutes to 40 minutes, flow = lOmL/mϊn. (R _t = 37.5 min., uv detection 254nm) to yield 14 mgs (46%) of 1-

(diphenylmethyl)-4-(2-carboxyethyl)-7-(5-aminopentyl)-3,4 -dihydro-lH-l,4-

benxodiazepine-2,5-dione trifluoroacetate. HRMS (FAB) molecular ion m/z=500.2529 (calc.

C30N3O4H33, 500.2549). 1H NMR (CDCI3, TMS) 6.60-7.20 (13H, m, ArH Ph,

ArH p-CON, ArH o-CON, ArH m-CON), 6.33 (IH, s, NCH-Ar2), 3.65 (2H, dd, ² J _HH =H3Hz,

² J _HH =15Hz, COCH ₂ CN), 3.50 (2H, dm, ² , J _HH =7Hz, ,3j _HH=59 Hz, CH2N), 2.66 (2H, t, ³ J _HH =8Hz, CH ₂ NH ₂ ) 2.22-2.39 (4H, m, t, ³ J _HH =6Hz, ³ J _HH =8Hz, CH ₂ CO, CH ₂ Ar), 1.20-

133 (4H, m, m, ³ J _H H=7Hz, CH2CH ₂ Ar, CH2CH ₂ NH ₂ ), 1.00 (2H, m, ³ J _HH =7Hz,

CH2CH2CH2NH2).

Using the above procedure, but substituting the appropriate 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione for l-(diphenylmethyl)-4-(2-carboxyethyl)-7-(N-boc-5- aminopentyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-(diphenylmethyl)-4-(2-carboxyethyl)-7-(6-aminohexyI)-3,4-d ihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(diphenylmethyl)-4-(2-carboxyethyI)-7-(4-aminobutyl)-3,4-d ihydro-lH-l,4- benzodiazepine-2,5- ione trifluoroacetate, l-(l-napthyl)methyl-4-(2-carboxyethyl)-7-(5-aminopentyl)-3,4 -dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(l-napthyl)methyl-4-(2-carboxyethyl)-7-(6-aminohexyI)-3,4- dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(2-carboxyethyl)-7-(5-aminopentyI)-3,4 -dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(2-carboxyethyl)-7-(6-aminohexyI)-3,4- dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-phenoxybenzyl)-4-(2-carboxyethyl)-7-(5-arninoρentyl)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5- ione trifluoroacetate, l-(p-phenoxybenzyl)-4-(2-carboxyethyl)-7-(6-aminohexyl)-3,4- dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-( -phenoxybenzyl)-4-(2-carboxyethyI)-7-(5-aminopentyl)-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(m-phenoxybenzyl)-4-(2-carboxyethyI)-7-(6-aminohexyl)-3,4- dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-trifluoromethylbenzyl)-4-(2-carboxyethyl)-7-(5-aminopen tyI)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-trifluoromethylbenzyl)-4-(2-carboxyethyI)-7-(6-aminohex yl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(ethyl-5-vaIeroyl)-4-(2-carboxyethyl)-7-(5-aminopentyl)-3, 4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(ethyl-5-vaIeroyl)-4-(2-carboxyetlnyl)-7-(6-aminohexy l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate,

l-(p-methoxybenzyI)-4-(2-carboxyethy])-7-(5-aminopentyl)-3,4 -dihydro-lH-l,4- benzodϊazepine-2,5-dione trifluoroacetate, l-(p-methoxybenzyl)-4-(2-carboxyethyl)-7-(6-aminohexyl)-3,4- dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoroacetate, l-(p-methylmethylbenzoyl)-4-(2-carboxyethyl)-7-(5-aminopenty l)-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoroacetate, l-(p-methylmethylbenzoyl)-4-(2-carboxyethyl)-7-(6-aminohexyl )-3,4-dihydro-lH-l,4- benzodiazepine-25-dione trifluoroacetate, l-(diphenylmethyl)-4-(2-carboxyethyl)-7-(6-amino-l-hexynl)-3 ,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(diphenylmethyl)-4-(2-carboxyethyl)-7-(4-amino-l-butynl)-3 ,4-dihydro-lH-l,4- benzodϊazepϊne-2,5-dϊone trifluoroacetate, l-(l-napthyl)methyl-4-(2-carboxyethyl)-7-(5-amino-l-pentynl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(l-napthyI)methyl-4-(2-carboxyethyl)-7-(6-amino-l-hexynl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(2-carboxyetlnyI)-7-(5-amino-l-pentynl )-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(2-carboxyethyl)-7-(6-amϊno-l-hexynI) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dϊone trifluoroacetate, l-(p-phenoxybenzyl)-4-(2-carboxyethyl)-7-(5-amϊno-l-pentynl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(ρ-phenoxybenzyI)-4-(2-carboxyethyl)-7-(6-amino-l-hexynl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-d ione trifluoroacetate, l-(m-phenoxybenzyl)-4-(2-carboxyethyl)-7-(5-amϊno-l-pentynl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(w-phenoxybenzyI)-4-(2-carboxyethyI)-7-(6-amϊno-l-hexynl) -3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dione trifluoroacetate, l-(p-trifluoromethylbenzyl)-4-(2-carboxyethyI)-7-(5-amino-l- pentynl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(p-trifluoromethylbenzyl)-4-(2-carboxyethyI)-7-(6-amino-l- hexynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(ethyI-5-valeroyl)-4-(2-carboxyethyl)-7-(5-amino-l-pentynI )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(ethyl-5-valeroyl)-4-(2-carboxyethyI)-7-(6-amino-l-hexynl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-methoxybenzyl)-4-(2-carboxyethyl)-7-(5-amino-l-pentynI) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate.

l-(p-methoxybenzyl)-4-(2-carboxyethyI)-7-(6-amino-l-hexyn )-3,4- i y ro- -l, - benzodiazepine-2,5-dione trifluoroacetate, l-(p-methylmethylbenzoyl)-4-(2-carboxyethyl)-7-(5-amino-l-pe ntynl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(p-methylmethylbenzoyl)-4-(2-carboxyethyl)-7-(6-amino-l-he xynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-d ione tri f luoroaceta te, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-(5-amino-l-pentyl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-(6-amino-l-hexyl)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dionetrifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(5-amino-l-pentyl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dionetrifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(6-amino-l-hexyl)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyI-4-((+/-)3-butanoate)-7-(5-amino-l-pentyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-butanoate)-7-(6-amino-l-hexyl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-phenyI-3-proprionate)-7-(5-amino -l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)metlnyl-4-(3(S)-phenyl-3-proprionate)-7-(6-amin o-l-hexyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-phenyl-3-proprionate)-7-(5-amino -l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-phenyI-3-proprionate)-7-(6-amino -l-hexyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-ρhenyl-3-proprionate)-7-(5-am ino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-phenyl-3-proprionate)-7-(6-ami no-l-hexyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-(5-amino-l-pentynl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-(6-amino-l-hexynl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-butant)ate)-7-(5-amino-l-pentynl )-3,4-dihydro-lH-l,4- benzod iazep i ne-2,5-d ione tri f 1 uoroaceta te, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(6-amino-l-hexynl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate,

l-(2-naprhyl)methyl-4-((+/-)3-butanoate)-7-(5-amino-l-pentyn l)-3,4-dihydro-lH-l,4- benzodiazepine-25-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-butanoate)-7-(6-amino-l-hexynl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-phenyI-3-proprionate)-7-(5-amino -l-pentynl)-3,4-dihydro- lH-l,4-benzodϊazepine-25-dϊone trif luoroaceta te, l-(2-napthyl)methyl-4-(3(S)-phenyl-3-proprionate)-7-(6-amino -l-hexynI)-3,4-dihydro- lH-l,4-benzodiazepine-25-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-phenyI-3-proprionate)-7-(5-amino -l-pentynl)-3,4-dihydro- lH-l,4-benzodiazepine-25-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-phenyl-3-proprionate)-7-(6-amino -l-hexynl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyI-4-((+/-)3-phenyI-3-proprϊonate)-7-(5-am ino-l-pentynl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-phenyl-3-proprionate)-7-(6-ami no-l-hexynl)-3,4-dihydro- lH-l,4-benzodϊazepine-2,5-dϊone trifluoroacetate.

Example 15

l-(diphenyl ethyl)-4-(2-carboxyetlιy0-7-(5-guanidinopentyl)-3 _r 4-dihydro-lH-l,4- benxodiazepina-2,5-dione trifluoroacetate a) To a solution of 11 mgs of l-(diphenylmethyl)-4-(2-carboxyethyI)-7-(5-aminopentyl)-3,4- dihydro-lH-l,4-benxodϊazepϊne-2,5-dione trifluoroacetate (0.02mmol) in 2mL of methanol was added ImLof 5% potassium bicarbonate and 17 mgs of aminoiminomethanesulfonic acid (0.12mmol). After 30 minutes, the reaction mixture was quenched with 0.5mL of acetic acid and concentrated in vacuo. The resulting residue was diluted with 5mL of water and methanol and purified by high pressure liquid chromatography, using a 1/2" C-18 reverse phase column, eluting witln a solvent gradient of 30:70 methanol (0.1% trifluoroacetic acid)/water (0.1% trifluoroacetic acid), time 0 to 10 minutes, to 70:30 methanol (0.1%

trifluoroacetic acid)/water (0.1% trifluoroacetic acid), time 10 minutes to 40 minutes, flow = lOmL/min. (R _t = 40.5 min., uv detection 254nm) to yield 9.3 mg (71%) of l-(diphenylmethyl)-

4-(2-carboxyethyl)-7-(5-guanidinopentyl)-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione trifluoroacetate. HRMS (FAB) molecular ion m/z=542.2750 (calc. C31N5O4H35, 542.2767). 1H NMR (CDCI3, dTMS) 6.78-7.22 (13H, m, ArH Ph, ArH p-CON, ArH o-CON,

ArH m-CON), 6.45 (IH, s, NCHAr2), 3.83 (2H, dd, ² J _HH =113Hz, ² j _HH= i5Hz, COCH2CN),

3.65 (2H, dm, 2, ³ j _HH -. _7Hz , ,3j _HH=59Hz> CH2N), 2.85 (2H, t, ³ J _HH =8Hz, CH ₂ NH ₂ ) 2.25-

2.45 (4H, t, t, CH ₂ CO, CH ₂ Ar), 1.31 (4H, m, , ³ J _HH =7Hz, CH2CH ₂ Ar, CH2CH ₂ NH ₂ ), 0.98

(2H, m, ³ J _HH =7Hz, CH2CH ₂ CH ₂ NH ₂ ).

Using the above procedure, but substituting the appropriate amino acid for 1-

(dipheriylmethyl)-4-(2-carboxyethyl)-7-(5-aminopentyl)-3, 4-dihydro-lH-l,4- benxodiazepine-2,5-dione trifluoroacetate there may be prepared, for example, the following compounds: l-(diphenyl methyl )-4-(2-carboxyethy I )-7-(6-guanidinolnexyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(diphenylmethyl)-4-(2-carboxyethyl)-7-(4-guanidinobutyl)-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(l-napthyl)methyl-4-(2-carboxyethyl)-7-(5-guanidinopentyl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(l-napthyl)methyl-4-(2-carboxyethyl)-7-(6-guanidinohexyI)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5- ione trifluoroacetate, l-(2-napthyl)methyl-4-(2-carboxyetlnyI)-7-(5-guanidinopentyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5- ione trifluoroacetate, l-(2-napthyl)methyl-4-(2-carboxyethyI)-7-(6-guanidinohexyl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5- ione trifluoroacetate, l-(p-phenoxybenzyl)-4-(2-carboxyethyl)-7-(5-gιιanidinopent yl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-phenoxybenzyl)-4-(2-carboxyetlnyl)-7-(6-guanidinolnexyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(m-phenoxybenzyl)-4-(2-carboxyethyl)-7-(5-guanidinopentyl) -3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(m-phenoxybenzyl)-4-(2-carboxyethyl)-7-(6-guanidinohexyl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-trifluoromethylbenzyl)-4-(2-carboxyetlnyl)-7-(5-guanidi nopentyI)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(p-triflLioronnethylbenzyl)-4-(2-carboxyetlnyl)-7-(6-guani dinohexyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate,

l-(ethyl-5-valeroyl)-4-(2-carboxyethyl)-7-(5-guanidinopentyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(ethyl-5-valeroyl)-4-(2-carboxyethyI)-7-(6-guanidinohexy l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-methoxybenzyl)-4-(2-carboxyethyl)-7-(5-guanϊdinopentyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-methoxybenzyI)-4-(2-carboxyethyl)-7-(6-guanidinohexyl)- 3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dione trifluoroacetate, l-(p-methylmethylbenzoyl)-4-(2-carboxyethyl)-7-(5-guanidinop entyl)-3,4-dihydro-lH- l,4-benzodϊazepine-2,5-dione trifluoroacetate, l-(p-methyImethylbenzoyl)-4-(2-carboxyethyl)-7-(6-guanidinoh exyl)-3,4-dihydro-lH-l,4- benzodi ^' azepϊne-2,5-dϊone trifluoroacetate, l-(diphenylmethyI)-4-(2-carboxyethyl)-7-(6-guanidino-l-hexyn l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(diphenyImethyl)-4-(2-carboxyethyI)-7-(4-guanidino-l-butyn l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(l-napthyl)methyl-4-(2-carboxyethyl)-7-(5-guanidϊno-l-pen tynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(l-napthyI)methyl-4-(2-carboxyethyI)-7-(6-guanidϊno-l-hex ynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyI-4-(2-carboxyethyl)-7-(5-guanidino-l-pent ynl)-3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dϊone trifluoroacetate, l-(2-napthyI)methyl-4-(2-carboxyethyl)-7-(6-guanidino-l-hexy nl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-phenoxybenzyl)-4-(2-carboxyethyI)-7-(5-guanidino-l-pent ynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dϊone trifluoroacetate, l-(p-phenoxybenzyl)-4-(2-carboxyethyl)-7-(6-guanidino-l-hexy nl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(m-phenoxybenzyl)-4-(2-carboxyethyl)-7-(5-guanidino-l-pent ynI)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(m-phenoxybenzyl)-4-(2-carboxyethyI)-7-(6-guanidino-l-hexy nl)-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoroacetate, l-(p-trifIuoromethylbenzyI)-4-(2-carboxyethyl)-7-(5-guanidin o-l-pentynI)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(p-trifluoromethylbenzyl)-4-(2-carboxyethyl)-7-(6-guanidin o-l-hexynl)-3,4-dihydro-lH- l,4-benzodϊazep>ine-2,5-dione trifluoroacetate, l-(ethyl-5-valeroyl)-4-(2-carboxyethyl)-7-(5-guanϊdino-l-pe ntynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate.

l-(ethyl-5-valeroyl)-4-(2-carboxyethyl)-7-(6-guanidino-l-hex ynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-methoxybenzyl)-4-(2-carboxyethyl)-7-(5-guanidino-l-pent ynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-methoxybenzyl)-4-(2-carboxyethy])-7-(6-guanidino-l-hexy nl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(p-methylmethyIbenzoyl)-4-(2-carboxyethyl)-7-(5-guanidino- l-pentynl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(p-methylmethylbenzoyl)-4-(2-carboxyethyI)-7-(6-guanidino- l-hexynl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-(5-guanidino-l-pent yl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-(6-guanidino-l-hexy l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dionetrifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(5-guanidino-l-pent yl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dionetriflιιoroacetate, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(6-guanidino-l-hexy l)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-butanoate)-7-(5-guanidino-l-pe ntyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-butanoate)-7-(6-guanidino-l-he xyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-phenyl-3-proprionate)-7-(5-guani dino-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-phenyl-3-proprionate)-7-(6-guani dino-l-hexyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-phenyl-3-proprionate)-7-(5-guani dino-l-pentyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5- ione trifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-phenyl-3-proprionate)-7-(6-guani dino-l-hexyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-phenyl-3-proprionate)-7-(5-gua nidino-l-pentyl)-3,4- dihydro-1 H-l, 4-benzodiazepine-2,5-d ione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-phenyl-3-proprionate)-7-(6-gua nidino-l-hexyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-(5-guanidino-l-pent ynl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-butanoate)-7-(6-guanidino-l -hexynI)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoroacetate,

l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(5-guanidino-l-pent ynl)-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-butanoate)-7-(6-guanidino-l-hexy nl)-3,4-dihydro-IH-l,4- benzodiazepϊne-25-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-butanoate)-7-(5-guanidino-l-ρ entynl)-3,4-dihydro-lH-l,4- benzodiazepine-25-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-butanoate)-7-(6-guanidino-l-he xynI)-3,4-dihydro-lH-l,4- benzodϊazepine-25-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-phenyI-3-proprionate)-7-(5-guani dino-l-penrynl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(S)-phenyl-3-proprionate)-7-(6-guani dino-l-hexynl)-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-(3(R)-phenyl-3-proprionate)-7-(5-guani dino-l-pentynl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyI)methyl-4-(3(R)-phenγI-3-proprionate)-7-(6-guan idino-l-hexynl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyl)methyl-4-((+/-)3-phenyl-3-proprϊonate)-7-(5-gu anidino-l-pentynl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoroacetate, l-(2-napthyI)methyl-4-((-t-/-)3-phenyl-3-proprionate)-7-(6-g uanidino-l-hexynl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoroacetate.

Example 16

l-vιethyl-4-(2-carboxyethyl)-8-(3-amino-l-proμynyI)-3,4 -dihydro lH-l,4-naptlιodiazepine-2,4-dione trifluoracetate

^a ) [4,5]-Benzoϊsatoic anhydride was prepared according to tine method described in part (a) of Example 1. Thus, 35g of 3-amino-2-naphthoϊc acid (187mMol) was dissolved in 500mL of water containing 20g of potassium carbonate. A solution of phosgene in toluene (1.93M, 290mL) was added slowly with vigorous stirring. A precipitate appeared along with evolution of gas. Stirring was continued for 30 min after complete addition of the phosgene. The precipitate was collected by suction filtration. The solid material was washed thoroughly

with water and hexane and air dried yielding 37.7g (95%) of [4,5]-benzoisatoic anhydride. M.p. >400°C 1H NMR (CDCL3): 12.0, s, IH; 8.95, s, lH; 8.3, d, J=7Hz, IH; 8.15, d, J=7Hz, IH; 7.85, t, J=7Hz, IH; 7.7, t, J=7Hz, IH; 7,7, s, IH.

5 b) 10.3g (48.3mMol) of [4,5]-benzoisatoic anhydride was dissolved in 50mL of anhydrous ar N,N-dimethylformamide (DMF) and added dropwise to an ice-cooled suspension of sodium hydride (97%, 1.25g) in 50mL of DMF witln gas evolution. After stirring an additional 30min, 3.16mL (105mol%) of methyl iodide was added to the solution. After one hour, the reaction mixture was poured over ice and the precipitated product was collected by suction filtration

10 and air dried, yielding 9.3g (85%) of N-methy!-[4,5]-benzoisatoic anhydride, a tan solid.

M.p. 219-222°C. 1H NMR (d ⁶ -DMSO): 8.8, s, lH; 8.15, d, J=7Hz, IH; 8.0, d, J=7Hz, IH; 7.85, s, IH; 7.7, t, J=7Hz, IH; 7.55, t, J=7Hz, IH; 3.35, s, 3H.

Using the above procedure, but substituting the appropriate alkyl halide for methyl iodide there may be prepared, for example, the following compounds:

15 N-benzyl-[4,5]-benzoisatoic anhydride, N-(2,4-diflurobenzyl)-[4,5]-benzoisatoic anhydride, N-(b-napthyl)methyI-[4,5]-benzoisatoic anhydride.

c) A solution of 20.0g (89mMol) of N-methyI-[4,5]-benzoisatoic anhydride, 20.5g (133.5mMoI) of the hydrochloride salt of ethyl 3-aminopropionate, and 18.6mL (133.5mMol) of

20 triethylamine in lOOmL of DMF was stirred at 80°C for four hr. The reaction mixture was then poured over ice containing citric acid and the precipitated product was collected by suction filtration. The crude product was recrystallized from benzene /hexane, yielding 24g (60%) of 3-(N-methylamino)-2-[N-(2-carboxyethyl)]-naphthocarboxamide ethyl ester, a yellow crystalline solid. MS (FAB) 300.1. H NMR (CDCL3): 7.8, s, IH; 7.65, d, J=7Hz, IH;

25 7.6, d, I=7Hz, IH; 7.4, t, J=7Hz, IH; 7.2, t, J=7Hz, IH; 6.9, br s, IH; 6.8, s, IH; 4.2, q, J=7Hz, 2H; 3.75, q, ]=5Hz, 2H; 2.95, s, 3H; 2.65, t, J=5Hz, 2H; 1.3, t, J=7Hz, 3H.

Using the above procedure, but substituting the appropriate 3-aminopropionate for ethyl 3-aminopropionate there may be prepared, for example, the following compounds:

30 (±)-3-(N-methyl)amino-2-[N-(3-butanoate)]-naphthocarboxamid e ethyl ester,

(±)-3-(N-methyl)amino-2-[N-(3-plnenyl-3-proprionate)]-na phthocarboxamide ethyl ester, (±)- ³ -(N-benzyl)amino-2-[N-(3-butanoate)]-naphthocarboxamid e ethyl ester, (±)-3-(N-benzyl)amino-2-[N-(3-phenyl-3-proprionate)]-naphth ocarboxamide ethyl ester, (±)-3-(N-2,4-diflurobenzyl)amino-2-[N-(3-butanoate)]-naphth ocarboxamide ethyl ester,

35 (±)-3-(N-2,4-diflurobenzyl)amino-2-[N-(3-plnenyl-3-proprion ate)]-naphthocarboxamide ethyl ester,

(±)-3-(N-(b-napthyl)methyl)amino-2-[N-(3-butanoate)]-nap hthocarboxamide ethyl ester, (±)-3-(N-(b-napthyl)methyl)amino-2-[N-(3-pheιnyl-3-proprio nate)]-naphthocarboxamide ethyl ester.

d) To an ϊce-cooled solution of 5.0g (17.5mMoI) of 3-(N-methyl)amino-2-[N-(2- carboxyethyl)]-naphthocarboxamide ethyl ester and 2.68mL (19mMol) of triethylamine in 50mL of methylene chloride was added dropwise a solution of 1.59mL 19(mMol) of bromoacefyl bromide. After warming to room temperature, the solution was washed with aqueous dtric acid and aqueous sodium bicarbonate solution, dried over sodium sulfate and evaporated- This material was dissolved in DMF (20mL) and added dropwise to a suspension of 97% sodium hydride (462mg, 19mMoI) at -15°C. After warming to room temperature the solution was poured over ice/citric acid and extracted into ether. 3.1g (52%) of l-methyl-4- (carboxyethyl)-3,4-dihydro-lH.-l,4-naphthodϊazepine-2,5-dio ne ethyl ester, a yellow oil, was obtained after column chromatography on silica gel. MS (FAB) 341. Η NMR (CDCL3): 8.4,s,lH; 7.9,d,J=8.5, lH; 7.8, d, J=8.5, IH; 7.6,s, lH; 7.45-7.6, m, 2H; 4.15, q, J=7Hz, 2H; 4.1, d, J=14Hz, lH; 3.95, t, J=7Hz, 2H; 3.85, d,J=14Hz, IH; 3.5, s, 3H; 2.75, m, 2H; 1.25, t, J=7Hz, 3H- Using the above procedure, but substituting the appropriate naphthocarboxamide for

3-(N-methyl)amino-2-[N-(2-carboxyethyl)]-naphthocarboxami de ethyl ester' there may be prepared, for example, the following compounds: l-benzyI-4-(carboxyethyl)-3,4-dihydro-lH.-l,4-naphthodϊazep ine-2,5-dione ethyl ester l-(2,4-diflurobenzyl)-4-(carboxyethyI)-3,4-dϊ!nydro-lH-l,4- naphthodiazepine-2,5-dione ethyl ester l-(b-napthyl)methyl-4-(carboxyetlnyl)-3,4-dihydro-lH.-l,4-na phthodiazepine-2,5-dione ethyl ester

(±)-l-methyl-4-(3-butanoate)-3,4-dilnydro-lH_-l,4-naphth odiazepine-2,5-dione ethyl ester, C+)-l-methyl-4-(3-phenyl-3-proprionate)-3,4-dihydro-lH.-l,4- naphthodiazepine-2,5-dione ethyl ester,

(±)-l-benzyl-2-(3-butanoate)-3,4-dihydro-lH.-l,4-naphtho diazeplne-2,5-dione ethyl ester, (±)-l-benzyl-2-(3-phenyl-3-proprionate)-3,4-dihydro-lH.-l/4 -naphthodiazepine-2,5-dione ethyl ester,

Ct)-l-(2,4-diflurobenzyI)-2-(3-butanoate)-3,4-dihydro-lH_ -l,4-naphthodiazepine-2,5-dione ethyl ester,

(±)-l-(2,4-difIurobenzyl)-2-(3-phenyI-3-proprϊonate)-3, 4-dihydro-lI±-l,4- naphthodiazepine-2,5-dione ethyl ester,

(+)-l-(b-naptInyl)metlnyl-2-(3-butanoate)-3,4-dihydro-lH- l,4-naphthodiazepine-2,5-dione ethyl ester, (+)-l-(b-napthyl)metlnyl-4-(3-phenyl-3-proprionate)-3,4-dihy dro-lH-l,4- naphthodiazepine-2,5-dione ethyl ester.

e) l-Methyl-4-(ethoxycarbonylethyl)-3,4-dihydro-lH.-l,4-naphtho diazepine-2,5-dione (3.1g, 9.1mMol) was placed in an ice bath and 4mL of fuming nitric acid was added. After

stirring for lhr at 0°C the reaction was allowed to warm to room temperature and stirred for an additional 2hr. The reaction mixture was poured into ice water and extracted with ethyl acetate, dried (sodium sulfate) and evaporated to yield a yellow solid. Thin layer chromatography (TLC) and *H NMR analysis indicated a mixture of nitrated products. The crude mixture was purified by column chromatography (SiC>2) to yield 600mgs (17%) of 8- Nitro-l-methyl-4-(ethoxycarbonylethyl)-3,4-dihydro-lH.-l,4-n aphthodiazepine-2,5- dione. 1H NMR (CDCI3, dTMS) 8.8 (IH, d, ⁴ j _HH =2Hz), 8.6 (IH, s), 8.3 (IH, dd, ² T _HH =9Hz, ⁴ lHH=2Hz), 7.95 (IH, d, ³ J _H H=9Hz), 7.7 (IH, s), 4.15 (2H, q, ³ J _H H=8Hz), 4.1 (IH, d, 3.5 (3H, s), 2.75 (2H, m), 1.25 (3H, t, ³ JHH=8Hz).

Using the above procedure, but substituting the appropriate naphthocarboxamide for 3-(N-methyl)amino-2-[N-(2-carboxyethyl)]-naρhtlnocarboxamid e ethyl ester there may be prepared, for example, the following compounds: l-(2,4-diflurobenzyl)-4-(carboxyethyl)-8-nitro-3,4-dihydro-l H.-l _/ 4-naphthodiazepine-2,5- dione ethyl ester,

(±)-l-methyl-4-(3-butanoate)-8-nitiO-3,4-dihydro-l H.-l,4-naphthodiazepine-2,5-dione ethyl ester,

(±)-l-(2,4-diflurobenzyl)-2-(3-butanoate)-8-nitro-3,4-di hydro-lH.-l,4-naphthodiazepine- 2,5-dione ethyl ester.

f) l-Methyl-4-(carboxylethyl)-8-nitro-3,4-dihydro-l H.-l,4-naphthodiazepine-2,5-dione ethyl ester (600mg, 1.56mMol) was hydrogenated in ethanol witln 200mg of 10% palladium on carbon catalyst at 50psi hydrogen for 24hr after which time tic indicated that reduction was complete. The catalyst was removed by filtration through Celite®, and the filtrate was evaporated yielding ca. 500mg of l-methyl-4-(carboxylethyl)-8-amino-3,4-dihydro-lH.-l,4- naphthodiazepine-2,5-dione ethyl ester. » H NMR (CDCL3): 8.1, s, IH; 7.6, d, J=9.5Hz, IH; 7.45, s, IH; 7.15, s, IH; 7.1, d, J=9.5Hz, IH; 4.15, q, J=8Hz, 2H; 4.1, d, J=14Hz, IH; 3.95, t, J=7Hz, 2H; 3.8, d, J=14Hz, IH; 34, s, 3H; 2.7, , 2H; 1.2, t, J=8Hz. This material was dissolved in 4mL of water containing 117mL of concentrated sulfuric acid and cooled to 0°C with an ice bath. Sodium nitrite (97nng, 1.5mMol) in 2mL of water was added to the solution dropwise, and the temperature of the solution was allowed to rise to room temperature over one hour. 2.6g (14mMoI) of potassium iodide was added to the solution and stirring was continued for 24hr. The reaction mixture was diluted witln water and extracted with ethyl acetate, and the ethyl acetate was dried (sodium sulfate) and evaporated. Chromatography on silica gel yielded ca. 240 mg of 8-Iodo-l-metlnyl-4-(ethoxycarbonylethyl)-3,4-dihydro- lH-l,4-naphthodiazepine-2,5-dione as an amber oil. MS (FAB) 466.9. ^l H NMR (CDCL3): 8.3, s, 2H; 7.8, dd, J=8.5Hz, J'=1.5Hz, I H; 7.55, s, I H; 7.55, d, J=8.5Hz, IH; 4.15, q, J=7Hz, 2H; 4.1, d, J=14Hz, IH; 3.95, t, J=7Hz, 2H; 3.9, d, J=14Hz, IH; 3.5, s, 3H; 2.75, m, 2H; 1.25, t, I=7Hz.

Using the above procedure, but substituting the appropriate 8-nitro-3,4-dihydro-lH_- l,4-naphthodiazepϊne-2,5-dione for l-methyl-4-(2-carboxylethyl)-8-nitro-3,4-dihydro-lH,- l,4-naphthodiazepine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-(2,4-dϊflurobenzyl)-4-(carboxyethyI)-8-iodo-3,4-dihydro-l H-l,4-naphthodiazepine-2,5- dione ethyl ester,

(±)-l-methyI-4-(3-butanoate)-8-iodo-3,4-dihydro-lH-l,4-n aphthodiazepϊne-2,5-dione ethyl ester,

(±)-l-(2,4-diflurobenzyl)-2-(3-butanoate)-8-iodo-3,4-dih ydro-lH-l,4-naphthodiazepine- 2,5-dione ethyl ester.

g) l-Methyl-4-(ethoxycarbonylethyl)-8-Iodo-3,4-dihydro-lH.-l,4- naphthodiazepine-2,5- dione (lOOmg, 215mM) was combined in lmL of ethyl acetate with 166mg (500m%) of N-t- butoxycarbonylpropargyl amine, 15mg (10mol%) of bistriphenylphosphine palladium dichloride, and 299mL (10X excess) of triethylamine. The apparatus was degassed and an atmosphere of nitrogen was introduced. 8.2mg (20mol%) of cuprous iodide was added and the solution was again degassed and nitrogen atmosphere was replaced. After 24hr the reaction mixture was diluted witln ethyl acetate and washed succesively with aqueous citric acid and aqueous sodium bicarbonate, dried (sodium sulfate) and evaporated. The residue was chromatographed on silica gel, yielding HOmg of l-methyl-4-(crboxylethyl)-8-(3-t- butyloxycarbonylamino-l-propynyl)-3,4-dihydro-lH-l,4-naphtho diazepine-2,5-dione. MS (FAB) 494.1. 1H NMR (CDCL3): 8.35, s, lH; 7.95, S, 1H; 7.75, d, J=8.5Hz, IH; 7.55, s, IH; 7.5, d,J=8.5Hz, lH; 4.9, brs, lH; 4.2, br s, 2H; 4.2, q, ]=7Hz, 2H; 4.1, d, J=14Hz, IH; 4.0, t, J=7Hz, 2H; 3.9, d, J=7Hz, 1 H; 3.5, s, 3H; 2.75, m, 2H; 1.5, s, 9H; 1.25, t, J=7Hz, 3H. Using the above procedure, but substituting the appropriate 8-iodo-3,4-dihydro-lH- l,4-naphthodϊazepϊne-2,5-dϊone for l-methyl-4-(2-carboxyIethyI)-8-iodo-3,4-dihydro-lH- l,4-naphthodϊazepϊne-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-(2,4-diflurobenzyl)-4-(carboxyethyl)-8-(3-t-butyloxycarbon ylamino-l-propynyl)-3,4- dihydro-lH.-l,4-naphthodϊazepine-2,5-dione ethyl ester,

(±)-l-methyl-4-(3-butanoate)-8-(3-t-butyloxycarbonyIamϊ no-l-propynyl)-3,4-dihydro-lH- l,4-naphthodiazepine-2,5-dione ethyl ester,

(±)-l-(2,4-diflurobenzyl)-2-(3-butanoate)-8-(3-t-butylox ycarbonylamino-l-propyny])-3,4- dihydro-lH.-l,4-naphthodϊazepϊne-2,5-dione ethyl ester, l-(2,4-diflurobenzyl)-4-(carboxyethyl)-8-(4-t-butyloxycarbon ylamino-l-butynyl)-3,4- dihydro-1 H-l ,4-naphthodϊazepine-2,5-d ione ethyl ester,

(+)-l-methyl-4-(3-butanoate)-8-(4-t-butyioxycarbonylamino -l-butynyI)-3,4-dihydro-lH- l,4-naphthodiazepine-2,5-dione ethyl ester.

(+)-l-(2,4-diflurobenzyl)-2-(3-butanoate)-8-(4-t-butyloxycar bonylamino-l-butynyl)-3,4- dihydro-lH.-l/4-naphthodiazepine-2,5-dione ethyl ester.

h) To a stirred solution of l-methyl-4-(carboxyethyl)-8-(3-t-butyloxycarbonylamino-l- propynyl)-3,4-dihydro-lH.-l _/ 4-naphthodiazepine-2,5-dione ethyl ester (llOmg, 0.22mMoI) in 8mL of methanol was added lmL of IN sodium hydroxide solution. After 4hr no more starting material was detected by tic. The solvent was removed in vacuo and the residue was treated with lOmL of 4N HCl in dioxane. After 2hr the solvent was removed in vacuo and the residue was purified by reverse phase HPLC, yielding 25mg of l-methyI-4-(carboxyethyl)-8- (3-amino-l-propynyl)-3,4-dihydro-lH.-l,4-naphthodiazepine-2, 5-dione . HRMS (FAB) molecular ion m/z=366.1454 (cald. C20H2 N3O4, 366.4004). 1H NMR (CD3OD): 7.9, s, lH;

7.7, s, IH; 7.55, d, J=8Hz, IH; 7.45, s, lH; 7.2, d, J=8Hz, IH; 3.75, d, J=14Hz, IH; 3.65, s, 2H; 3.55, d, J=14Hz, IH; 3.5, m, 2H; 3.05, s, 3H; 2.2, q, J=7Hz, 2H.

Using the above procedure, but substituting the appropriate 8-(t- butyloxycarbonylamino-l-alkynyl)-3,4-dihydro-l H.-L4-naphthodiazepine-2 _/ 5-dione for 1- methyl-4-(carboxyethyl)-8-(3-t-butyloxycarbonylamino-l-propy nyl)-3,4-dihydro-lH.-l,4- naphthodiazepine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-(2,4-di lurobenzyl)-4-(carboxyethyl)-8-(3-amino-l-propynyl)-3,4-dihy dro-lH.-l/4- naphthodiazepine-2,5-dione,

(±)-l-methyI-4-(3-butanoate)-8-(3-amino-l-propynyl)-3,4- dihydro-lH.-l/4- naphthodiazepine-2,5-dione,

(±)-l-(2,4-diflurobenzyl)-4-(3-butanoate)-8-(3-amiιno-l -propynyl)-3,4-dihydro-lH-l,4- naphthodiazepine-2,5-dione, l-(2,4-diflurobenzyl)-4-(carboxyetlnyl)-8-(4-amino-l -butynyl)-3,4-dihydro-lH.-l,4- naphthodiazepine-2,5-dione,

(±)-l-methyl-4-(3-butanoate)-8-(4-amino-l-butynyl)-3,4-d ihydro-lH_-l,4- naphthodiazepine-2,5-dione, (+)-l-(2 _/ 4-diflurobenzyl)-4-(3-butanoate)-8-(4-amino-l-butynyl) -3,4-dihydro-lH-l,4- naphthodiazepine-2,5-dione.

Example 17

l-Methyl-4-(carboxyethyl)-8-(3-guanidino-l-propynyl)-3,4- dihydro-lK-l,4- naphtbodiazepine-2,5-dione The title compound was prepared from l-methyI-4-(carboxyethyl)-8-(3-amino-l-propynyl)- 3,4-dihydro-lH-l,4-naphthodiazepine-2,5-dione (50mg) according to the procedure described in Example 2. HRMS (FAB) molecular ion m/z=408.1672 (cald. C21H22N5O4, 408.1672). 1H NMR (CD3OD): 7.9, s, IH; 7.7, s, lH; 7.55, d, J=8Hz, IH; 7.45, s, IH; 7.2, d, J=8Hz, lH; 3.75, d, J=14Hz, lH; 3.65, s, 2H; 3.55, d, J=I4Hz, IH; 3.5, m, 2H; 3.05, s, 3H; 2.2, q,J=7Hz, 2H. Using the above procedure, but substituting the appropriate 8-(amino-l-alkynyl)-3,4- dihydro-lH-l,4-naphthodiazepine-2,5-dione for l-methyl-4-(carboxyethyl)-8-(3-amino-l- propynyl)-3,4-dihydro-lϋ-l,4-naphtInodiazepine-2,5-dione there may be prepared, for example, the following compounds: l-(2,4-diflurobenzyl)-4-(carboxyethyl)-8-(3-guanidϊno-l-pro pynyl)-3,4-dϊhydro-lH.-l,4- naphthodiazepϊne-2,5-dϊone,

(+)-l-methyI-4-(3-butanoate)-8-(3-guanidiιno-l-propynyl) -3,4-dihydro-lFI-l,4- naphthodiazepine-2,5-dione,

(±)-l-(2,4-difiurobenzyl)-2-(3-butanoate)-8-(3-guanidino -l-propynyl)-3,4-dihydro-lH-l/4- naphthodϊazepϊne-2,5-d ione, l-(2,4-diflurobenzyI)-4-(carboxyethyl)-8-(4-guanidino-l-buty nyl)-3,4-dihydro-lH.-l,4- naphthodiazepine-2,5-dione,

(+)-l-methyl-4-(3-butanoate)-8-(4-guanidϊno-l-butynyl)-3 ,4-dihydro-lIi-l,4- naphthod iazepϊne-2,5-d ione,

(±)-l-(2,4-diflurobenzyl)-2-(3-butanoate)-8-(4-guanϊdin o-l-butynyl)-3,4-dihydro-lE-l,4- naphthodiazepine-2,5-dϊone.

Example 18

l-Methyl-4-(carboxyethyl)-8-(3-amino-I-propyl)-3,4,7,8,9, 10-hexahydroUydro-lH-l,4- naphthodiazepine-2,5-dione l-Methyl-4-(carboxyethyl)-8-(3-amino-l-propynyl)-3,4-dihydro -lH_-l,4- naphthodiazepine-2,5-dione (50mg) was reduced witln lOmg of 10% Pd/C in lOmL of 5:1 water ethanol at 45psi of hydrogen in a Parr hydrogenation apparatus for 24hr yielding, after filtration through Celite® and purification by reverse phase HPLC, the title compound. MS (FAB) 374.1. ^l NMR (CD3OD): 7.4, s, IH; 7.0, s, IH; 3.95, d, J=14Hz, IH; 3.8, d, J=14Hz, IH; 3.6, m, 2H; 3.2, s, 3H; 2.85, t, J=7Hz, 2H; 2.4, t, J=7Hz, 2H; 1.9, m, lH; 1.65, m, 4H; 1.4, m, 4H.

Using the above procedure, but substituting the appropriate 8-(amino-l-alkynyI)-3,4- dihydro-lH.-l,4-naphthodiazepine-2,5-dione for l-methyl-4-(carboxyethyl)-8-(3-amino-l- propynyI)-3,4,7,8,9,10-hexahydrohydro-lH.-l _/ 4-naphthodiazepine-2,5-dione there may be prepared, for example, the following compounds: l-(2,4-diflurobenzyl)-4-(carboxyethyl)-8-(3-guanidino-l-prop ynyl)-3,4,7,8,9,10- hexahydrohydro-lH.-l,4-naphthodiazepine-2,5-dione,

(±)-l-methyl-4-(3-butanoate)-8-(3-guanidino-l-propynyl)- 3,4,7,8,9,10-hexahydrohydro- lH.-l,4-naphthodiazepine-2,5-dione,

(±)-l-(2,4-diflurobenzyl)-2-(3-butanoate)-8-(3-guanidino -l-propynyl)-3,4,7,8,9,10- hexahydrohydro-lH.-l,4-naphthodiazepine-2,5-dione,

Example 19

2-(2-carboxyethyl)-8-(4-amidinobeiJzyloxy)-2,3,4,5-tetrah ydro-lH-2-benzazepin-l-one trifluoroacetate.

a) A solution of 7-methoxytetralone (Fluka Chemical, 100.0 g, 0.567 mol) in dry pyridine (600 L) was treated with hydroxylamine hydrochloride (Fluka, 43.0 g, 0.618 mol) and the resulting dark yellow solution was stirred at room temperature for 1 hour. The solution was then concentrated in vacuo, and azeotroped with several volumes of toluene, then partitioned between ethyl acetate and brine. The combined organic layers were dried (K2CO3), filtered, and concentrated in vacuo. The residue was crystallized from ethyl acetate/hexanes to yield 88 g (81%) of the oxime as a waxy solid.

b) Following a procedure of Tomita, et. al., J. Chem. Soc. C 1969, 183, 7-methoxytetralone oxime (45.0 g, 0.235 mol) was mixed with solid trichloroacetic acid (150 g), and the resulting suspension heated to ca. 80 C, at which time a violent exotherm ensued, yielding a black solid mixture.' The residue was cooled, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the combined organic layers were concentrated in vacuo. The residue was purified by chromatography over silica gel to yield 10.0 g (22%) of 8-methoxy- 2,3,4,5-tetrahydro-lH-2-benzazepin-l-one. An analytical sample was obtained by recrystallization from CH2CI2 /hexanes to yield colorless crystals: mp. 99-101°C (lit. (see above) 100-101°C); !H NMR(CDCl3) d7.35(brs, IH), 7.30(d, J=3Hz, IH), 7.10(d, J=9Hz, IH), 6.95(dd, J=3, 9Hz, IH), 3.82(s, 3H), 3.1 (q, J=6Hz, 2H), 2.80(t, J=6Hz, 2H), 1.98(m, 2H).

c) A solution of 8-methoxy-2,3,4,5-tetrahydro-l.H-2-benzazepin-l-one (10.0 g, 0.052 mol) in N,N-dimethylformamide (30 mL) and allylbromide (23 mL, 0.260 mL) was treated with NaH (60% by wt. dispersion in oil, 2.50 g, 0.063 mol) and the resulting grey suspension stirred at room temperature under an atmosphere of argon. Gas evolution was noted. After 15 minutes, the solution was diluted with brine and partitioned between ethyl acetate and brine. The combined organic layers were concentrated in vacuo and purified by chromatography over silica gel eluting with a gradient of hexane to 1:1 ethyl acetate/hexane to yield 8 g (83%) of 2-allyI-8-methoxy-2,3,4,5-tetrahydro-lH-2- benzazepϊn-1-one as a colorless oil: 1H NMR(CDCl3) d7.23(m, IH), 7.03(d, J=9Hz, IH), 6.90(dd, 1=3, 9Hz, IH), 5.91(m, IH), 5.23(m, 2H), 4.20(d, ]=6Hz, 2H), 3.82(s, 3H), 3.18(t, J=6Hz, 2H), 2.72(t, J=6Hz, 2H), 1.96(pentet, J=6Hz, 2H); ¹³ C NMR(CDCl3) dl70.59(£O), 158.42(NCO), 136.88, 133.81, 129.43, 129.35, 129.33, 117.56, 117.54, 112.98, 55.26, 49.43, 5.37, 29.57, 29.22; MS(FAB) m/z= 232.1 (MH ⁺ ).

d) A solution of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-lH-2-benzazepϊn-l-one (8.0 g, 0.043 mol) in dry tetrahydrofuran (40 mL) was treated witln 9-borabicyclononane (1.0 M in THF) and the resulting mixture was stirred for 18 hours at room temperature. The solution was then diluted with EtOH (50 mL), cooled to 0°C (ice bath), and treated with 15% aqueous NaOH (15 mL) followed by 30% aqueous H2O2 (10 mL). The resulting mixture was stirred for 1 hour

at 0°C, then treated cautiously with saturated aqueous sodium thiosulfate (50 mL). The mixture was partitioned between ethyl acetate and brine, and the combined organic layers were concentrated in vacuo, and the residue was purified by chromatography over silica gel eluting with ethyl acetate to yield 6.5 g (60%) of 2-(3-hydroxypropyl)-8-methoxy-2,3,4,5- tetrahydro-lH-2-benzazepin-l-one as a colorless oil; 1H NMR(CDCl3) d7.19(s, IH), 7.06(d, J=9Hz, IH, 6.92(dd, J=3, 9Hz, IH), 4.30(brs, IH), 3.82(s, 3H), 3.71(t, J=6Hz, 2H), 3.61(brs, 2H), 3.18(t, J=6Hz, 2H), 2.72(t, J=6Hz, 2H), 2.02(pentet, J=6Hz, 2H), 1.79(pentet, J=6Hz, 2H); ¹³ C NMR(CDCl3) dl72.25(CO), 158.51(N O), 136.34, 129.53, 117.46, 112.94, 58.19, 55.42, 46.16, 43.30, 30.91, 29.45, 29.12; MS (FAB) m/z=250.1(MH+); HRMS (FAB, MH+) m/z=249.1364 (cald C14H19NO3: 249.1364).

e) A solution of 2-(3-hydroxyproρyl)-8-methoxy-2,3,4,5-tetrahydro-lH.-2-benz azepin-l-one (6.50 g, 0.026 mol) in CH2CI2 was added, at -78°C (CO2 /acetone), to a solution of (COCl)2 (4.50 mL, 0.052 mol) and DMSO (7.4 mL, 0.104 mol) in CH2O2 (100 mL) at -78°C. After stirring for 15 minutes at -78°C, the mixture was treated with NEt3 (30 mL, 0.208 mol), and the bath removed. The CH2CI2 solution was washed witln brine, dried (MgSO4) and concentrated in vacuo. The residue was immediately dissolved in N,N-dimethylformamide (30 mL) and MeOH (30mL), and treated, in portions, with pyridinium dichromate (30 g total). After stirring for 24 hours, the dark brown suspension was diluted with ethyl acetate and filtered, and the filtrate was partitioned between ethyl acetate and brine. The combined organic layers were washed witln water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography over silica gel eluting with a gradient of 10% ethyl acetate/hexane to 100% ethyl acetate to yield 2.5 g (35%) of 2-(2-carboxyethyl)-8-methoxy- 2,3,4,5-tetrahydro-lH.-2-benzazepin-l-one methyl ester as a colorless oil; *H NMR(CDCl3) d7.18(d, J=3Hz, IH), 7.02(d, J=9Hz, IH), 6.88(dd, J=3, 9Hz, IH), 3.83(t, J=6Hz, 2H), 3.80(s, 3H), 3.69(s, 3H), 3.23(t, J=6Hz, 2H), 2.78(t, J=6Hz, 2H), 2.67(t, J=6Hz, 2H), 1.96(m, 2H); ¹³ C NMR(CDCl3) dl72.41(CO), 171.15(£O), 158.50, 136.80, 129.58, 129.40, 117.34, 112.86, 55.42, 51.78, 47.37, 44.13, 33.64, 29.85, 29.14; MS(FAB) m/z=278.1 (MH+); HRMS(FAB, MH ⁺ ) m/z= 278.1392 (cald for C15H19NO4: 277.1313).

f) A solution of 2-(2-carboxyethyl)-8-methoxy-2,3,4,5-tetrahydro-lH-2-benzaze pin-l-one methyl ester (3.20 g, 0.011 mol) in CH2CI2 was added to a suspension of AICI3 (4.70 g, 0.034 mol) and »-propanethiol (5.3 mL, 0.057 mol) at 0°C (ice bath), and the resulting mixture stirred for 10 minutes at room temperature. The mixture was diluted with saturated aqueous sodium bicarbonate (50 mL), and the resulting white suspension stirred for 1 hour. The gelatinous mixture was filtered, and the filtrate was dried (MgSO4) and concentrated in vacuo to yield 2.0 g (85%) of 2-(2-carboxyethyl)-8-hydroxy-2,3,4,5-tetrahydro-lH-2-

benzazepin-1-one methyl ester as a colorless oil; 1H NMR(CD3OD) d7.08(d, J=9Hz, IH, 7.02(d, J=3Hz, IH), 6.87(dd, J=3, 9Hz, IH), 3.05(t, J=6Hz, 2H), 2.72(t, J=6Hz, 2H), 1.97(t, J=6Hz, 2H). g) A suspension of 2-(2-carboxyethyl)-8-hydroxy-2,3,4,5-tetrahydro-lH.-2-benzaz epin-l-one methyl ester (250 mg, 0.950 mmol), p-cyanobenzylbromide (186 mg, 0.950 mmol) and K2CO3 (500 mg) in N,N-dϊmethylformamide (20 mL) was stirred vigorously at room temperature under an atmosphere of argon. After 1 hour, the suspension was diluted with ethyl acetate (100 L), washed with water and brine, dried (Na2SO ) and concentrated in vacuo. The residue was purified by chromatography over silica gel to yield 150 mg (40%) of 2-(2- carboxyethyl)-8-(4-cyanobenzyioxy)-2,3,4,5-tetrahydro-lH-2-b enzazepin-l-one methyl ester as a colorless oil; 1H NMR(CDC1 ) d7.66(d, J=6Hz, IH), 7.54(d, J=6Hz, IH), 7.00(dd, J=3, 9Hz, IH), 5.13(s, 2H), 3.84(t, J=6Hz, 2H), 3.70(s, 3H), 3.24(t, J=6Hz, 2H), 2.72(m, 4H), 1.98(pentet, ]=6Hz, 2H); ¹³ C NMR(CDCl3) dl72.27(CO), 170.82(£O), 157.05, 142.32, 137.01,

132.39, 132.32, 130.45, 129.63, 127.52, 118.66, 117.83, 113.98, 111.53, 68.90, 51.76, 47.31, 44.14, 33.58, 29.76, 29.13; MS(FAB) mfz= 379.1(MH ⁺ ).

h) A solution of 2-(2-carboxyethyl)-8-(4-cyanobenzyloxy)-2,3,4,5-tetrahydro-l H-2- benzazepin-1-one methyl ester (150 mg, 0.400 mmol) in 50 mL of 1:1 pyridine-NEt3 was saturated with H2S, and heated at 50°C under argon. After 1 hour, the solvents were removed in vacuo. The residue was dissolved in CH2CI2 (20 mL) and treated with iodomethane (4 mL), and the resulting mixture heated at reflux for 1 hour. The solvents were removed in vacuo, and the residue was dissolved in MeOH and treated with an excess of NH4OAC (1 g). Tine resulting suspension was stirred for 15 minutes at60°C. The MeOH was then removed, and the residue was treated witln 50% NaOH (3 mL) in tetrahydrofuran (20 mL), and stirred for 15 minutes at room temperature. The mixture was then diluted with trifluoroacetic acid, and the volatiles were removed in vacuo. The residue was purified by HPLC (1/2" C-18 reverse-phase column, eluting with a solvent gradient of 1:9 acetonitrile(0.1%TFA)/water (0.1% TFA) time 0 to 10 minutes, to 1:1 acetonitriIe(0.1%TFA)/water (0.1% TFA) time 10 to 40 minutes, flow lOmL/min, R _t =30.5 min, mu detection 254nM), to give 18.5 mg (9 %) of 2-(2-carboxyethyl)-8-(4-amidinobenzyloxy)- 2,3,4,5-tetrahydro-lH-2-benzazepin-l-one trifluoroacetate as a yellowish-brown solid after lyophylization; *H NMR(CD3OD) d7.66(d, J=6Hz, IH), 7.54(d, J=6Hz, IH), 7.00(dd, J=3, 9Hz, IH), 5.13(s, 2H), 3.84(t, J=6Hz, 2H), 3.70(s, 3H), 3.24(t, ]=6Hz, 2H), 2.72(m, 4H), 1.98(m, J=6Hz, 2H); MS(FAB) m/z= 381.1688 (MH ⁺ ).

Example 20

2-(2-carboxyethyl)-8-(8-aminooctyloxy)-2,3,4,5-tetrahydro -lH-2-benzazepin-l-one trifluoroacetate.

a) A solution of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-lH-2-benzazepin-l-one (1.10 g, 0.0047 mol) in CH2C12 (20 mL) was treated at 0°C witln BBr3 (IM in CH2CI2, 9.50 mL), and the resulting mixture stirred at 0°C for 30 minutes. The solution was poured over ice, NaHCO3 was added, and the solution was extracted with CH2CI2- Tine combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo to yield ca. 1.0 g (100%) of 2-allyl-8- hydroxy-2,3,4,5-tetrahydro-lH-2-benzazepin-l-one as a colorless oil; *H NMR(CDCl3) d8.2(brs, IH), 7.47(s, IH), 6.95(d, ]=6Hz, IH), 6.84(dd, J=3, 6Hz, IH), 5.89(m, IH), 5.22(m, complex, 2H), 4.20(d, J=6Hz, 2H), 3.18(t, ]=6Hz, 2H), 2.66(t, J=6Hz, 2H), 2.15(s, IH), 1.96(m, 2H); ¹³ C NMR(CDCl3) dl71.65(CO), 156.01, 135.68, 133.27, 129.55, 128.46, 118.51, 118.05, 115.91, 53.46, 49.81, 45.83, 30.87, 29.76, 29.12.

b) A suspension of 2-allyl-8-hydroxy-2,3,4,5-tetrahydro-lH.-2-benzazepin-l-one (1.0 g, 0.0049 mol), 8-azido-l-(toluenesulfonyloxy)octane (1.50 g, 0.0049 mol) and K2CO3 in N,N- dimethylformamide (20 mL) was stirred vigorously under argon, and heated at 65°C for 18 hours. Tine solution was then partitioned between ethyl acetate and brine, and the combined organic layers were washed witln water, dried ( 2CO3), filtered, and concentrated in vacuo. Tine residue was purified by chromatography over silica gel to yield 920 mg (51%) of 2-allyl- 8-(8-azidooctyloxy)-2,3,4,5-tetrahydro-l H.-2-benzazepin-l-one as a colorless oil; 1H NMR(CDCl3) d7.47(s, IH), 6.95(d, J=6Hz, IH), 6.84(dd, J=3, 6Hz, IH), 5.89(m, IH), 5.22(m, complex, 2H), 4.20(d, J=6Hz, 2H), 3.95(t, J=6Hz, 2H), 3.22(t, J=6Hz, 2H), 3.18(t, J=6Hz, 2H), 2.66(t, J=6Hz, 2H), 1.90(t, J=6Hz, 2H), 1.79(t, J=6Hz, 2H), 1.60(m, 4H), 1.35(m, 6H).

c) A solution of 2-allyl-8-(8-azidooctyloxy)-2,3,4,5-tetrahydro-lH.-2-benzaze pin-l-one (920 mg, 2.48 mmol) in tetrahydrofuran (20 mL) was treated witln 9-borabicyclononane (0.5 M/THF, 10 mL, 5.00 mmol), and the mixture was stirred under argon at room temperature for 18 hours. The mixture was then cooled in an ice bath, and EtOH (5 mL) followed by 15% aqueous NaOH (10 mL) and 30% H2O2 (15 mL) were added. The mixture was stirred for 1

hour, then saturated aqueous sodium tlniosulfate was added (20 mL). The solution was partitioned between ethyl acetate and brine, and the combined ethyl acetate layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel to yield 400 mg (42%) of 2-(3-hydroxypropyl)-8-(8- azϊdooctyloxy)-2,3,4,5-tetrahydro-lH-2-benzazepin-l-one as a colorless oil; *H

NMR(CDCl3) d7.20(d, J=3Hz, IH), 7.04(d, J=6Hz, IH), 6.91 (dd, J=3, 6Hz, IH), 3.96(t, J=6Hz, 2H), 3.72(t, J=6Hz, 2H), 3.61(t, J=6Hz, 2H), 3.26(t, J=6Hz, 2H), 3.18(t, J=6Hz, 2H), 2.73(t, J=6Hz, 2H), 2.02(t, J=6Hz, 2H), 1.77(m,4H), 1.60(m, 2H), 1.36(m, 8H).

d) 2-(3-hydroxypropyl)-8-(8-azidooctyloxy)-2,3,4,5-tetrahydro-I H-2-benzazepin-l-one was subjected to standard Swern conditions followed by PDC oxidation as described in part (e) of Example 14 to yield 140 mg (45%) of 2-(2-carboxyethyl)-8-(8-azidooctyloxy)-23,4,5- tetrahydro-lH.-2-benzazepin-l-one methyl ester as a colorless oil; *H NMR(CDCl3) d7.18(d, J=3Hz, IH), 7.00(d, J=9Hz, IH), 6.89(dd, J=3, 9Hz, IH), 3.96(t, J=6Hz, 2H), 3.84(t, J=6Hz, 2H), 3.70(s, 3H), 3.26(m, 4H), 2.74(m, 4H), 1.97(t, J=6Hz, 2H), 1.77(t, l=6Hz, 2H), 1.60(t, J=6Hz, 2H), 1.35(m, 6H); ¹³ C NMR(CDCl3) dl72.38(£O), 171.21(£O), 158.04, 136.72, 129.40, 129.34, 117.78, 113.57, 68.05, 51.76, 51.41, 47.37, 44.13, 33.64, 29.86, 29.13, 19.02, 28.77, 26.59, 25.87; MS(FAB) 417.2(MH ⁺ ).

e) A solution of 2-(2-carboxyethyl)-8-(8-azidooctyloxy)-2,3,4,5-tetrahydro-lH -2- benzazepϊn-1-one methyl ester (70 mg, 0.168 mmol) in MeOH (1 mL) was treated with 10% Pd/C (20 mg) and the resulting suspension was reduced under an atmosphere of hydrogen (30psi) for 2 hours. The solution was then filtered through Celite®, and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (1 mL) and treated with 50% NaOH (0.5 mL), and the resulting mixture was stirred at room temperature. After 1 hour, the solution was treated witln trifluoroacetic acid (1 mL), and concentrated in vacuo. The white paste remaining was purified by HPLC (1/2' C-18 reverse-phase column) eluting with a gradient of 3:7 methanol (0.1% trϊfluoroaceate)/water (0.1% trifluoroaceate), time 0 to 10 min, to 7:3 methanol(0.1% trifluoroaceate)/water(0.1% trifluoroaceate), time 10 to 40 min, to yield 30 mg (36%) of 2-(2-carboxyethyl)-8-(8-aminooctyloxy)-2,3,4,5-tetrahydro-lH -2- benzazepϊn-1-one as a colorless oil; ¹ H NMR(CD3OD) d7.095(m, 2H), 6.96(dd, J=3, 9Hz, IH), 3.98(t, ]=6Hz, 2H), 3.83(t, J=6Hz, 2H), 3.27(m, 4H), 2.90(t, J=6Hz, 2H), 2.69(m, 4H), 2.03(t, J=6Hz, 2H), 1.78(t, ]=6Hz, 2H), 1.64(t, J=6Hz, 2H), 1.40(m, 6H); MS(FAB) m/z= 377.1(MH+- TFA).

Example 21

2-(2-carboxyethyl)-8-(8-guanadinooctyloxy)-2,3,4,5-tetrah ydro-lH-2-benzazeρin-l-one trifluoroace ta te. a) A solution of 2-(2-carboxyethyl)-8-(8-aminooctyloxy)-2,3,4,5-tetrahydro-lH .-2- benzazepin-1-one trifluoroacetate (30 mg, 0.061 mmol) in saturated aqueous KHCO3 (2 mL) was treated witln formamidine sulfonic acid (85 mg, 1.08 mmol) and the resulting mixture was stirred at room temperature for 20 minutes. The mixture was neutralized with acetic acid, and the residue was purified by HPLC (1/2' C-18 reverse-phase column) eluting with a gradient of 3:7 methanol (0.1% trifluoroaceate) /water (0.1% trifluoroaceate), time 0 to 10 min, to 7:3 methanol(0.1% trifluoroaceate)/water(0.1% trifluoroaceate), time 10 to 40 min, to yield 7.3 mg (25%) of 2-(2-carboxyethyl)-8-(8-guanadinooctyloxy)-2,3,4,5-tetrahydr o-lH_-2- benzazepin-1-one trifluoroacetate as a light brown solid; 1H NMR(CD3OD) d7.09(m, 2H), 6.96(dd, J=3, 9Hz, IH), 3.98(t, J=6Hz, 2H), 3.83(t, J=6Hz, 2H), 3.33(m, 4H), 2.91(t, J=6Hz, 2H), 2.69(t, J=6Hz, 4H), 2.30(m, 2H), 1.75(m, 2H), 1.65(m, 2H), 1.40(m, 6H); ¹³ C NMR(CD3OD) dl75.9(£O), 173.8(£O), 160.0, 137.0, 131.16, 130.79, 118.66, 114.81, 69.17, 45.33, 40.78, 34.32, 31.15, 30.27, 30.18, 30.15, 30.04, 28.59, 27.39, 27.06; MS(FAB) m/z= 419.2(MH ⁺ ).

Example 22

2-(2-carboxyethyl)-8-(5-aιninoμentyιη _/ l)-2,3,4,5-tetrahydro-lH-2-benzazepin-l-one trifluoroacetate. a) A solution of 2-(2-carboxyethyl)-8-hydroxy-2,3,4,5-tetrahydro-lH.-2-benzaz epin-l- one methyl ester (2.20 g, 0.00836 mol) and NEt3 (1.40 mL, 0.0100 mol) in CH2CI2 (20 mL) was cooled to 0°C (ice bath) and treated witln trifluoromethanesulfonic anhydride (1.70 mL, 0.0100 mol), and the resulting mixture stirred to 30 minutes. The mixture was then partitioned between ethyl acetate and saturated aqueous aHCO3. The combined organic layers were

dried (MgSO4), filtered, and concentrated in vacuo to an oil, used immediately without purification. A solution of the triflate (400 mg, 1.00 mmol) and 5-((rerf- butyloxy)carbonyl)amino-2-pentyne (366 mg, 2.00 mmol) in NEt3 (10 mL) was treated with 6/s-triphenylphosphine palladium dichloride (20 mg) and Cul (10 mg), and the resulting mixture was de-gassed thoroughly with argon, and heated at reflux for 12 hours. The solution was then cooled, and volatiles removed in vacuo, and the residue was purified by chromatography over silica gel eluting with 1:1 ethyl acetate/hexanes to yield 400 mg (93%) of 2-(2-carboxyethyl)-8-(5-N-Boc-aminopentynyI)-2,3,4,5-tetrahy dro-lH-2-benzazepin-l- one methyl ester as a colorless oil; H NMR(CDCl3) d7.68(s, IH), 7.37(d, J=6Hz, IH), 75Q(d, J=6Hz, IH), 4.7(brs, IH), 3.84(t, J=6Hz, 2H), 3.71(s, 3H), 3.25(q, J=6Hz, 4H), 2.73(t, J=6Hz, 4H), 2.46(t, J=6Hz, 2H), 2.00(m, 2H), 1.78(m, 2H); ¹³ C NMR(CDCl3) dl71.38(£O), 170.49(£O), 155.92, 136.83, 136.06, 133.61, 131.68, 128.25, 122.55, 89.55, 80.43, 51.78, 47.18, 44.11, 39.75, 33.58, 29.92, 29.57, 28.72, 28.37, 16.88; MS(FAB) m/z= 429.1(MH ⁺ ).

b) A solution of 2-(2-carboxyethyl)-8-(5-N-Boc-aminopentynyl)-2,3,4,5-tetrahy dro-lH-2- benzazepϊn-1-one methyl ester (66 mg, 0.154 mmol) in EtOH (1 mL) was treated with trifluoroacetic acid (0.5 mL), and the resulting mixture stirred for 18 hours. The volatiles were then removed, and the residue was dissolved in tetrahydrofuran (1 mL), and treated with 50% NaOH (0.5 mL), and the mixture was stirred for 20 minutes at room temperature. Trifluoroacetic acid was then added (3 mL), and the solution was concentrated in vacuo. The residue was purified by HPLC (1 /2' C-18 reverse-phase column) eluting with a gradient of 3:7 methanol (0.1% trifluoroaceate)/water (0.1% trifluoroaceate), time 0 to 10 min, to 7:3 methanol(0.1% trifluoroaceate)/water(0.1% trifluoroaceate), time 10 to 40 min, to yield 46 mg (95%) of 2-(2-carboxyethyl)-8-(5-aminopentynyl)-2,3,4,5-tetrahydro-lH -2-benzazepin- 1-one trifluoroacetate as a light brown solid; 1H NMR(D2θ) d732(s, IH), 7.25(d, J=6Hz, IH), 7.00(d, J=6Hz, IH), 3.63(t, J=6Hz, 2H), 2.95(m, 4H), 2.58(t, J=6Hz, 2H), 2.50(t, J=6Hz, 2H), 2.38(t, J=6Hz, 2H), 1.80(m, 4H); MS(FAB) m/z= 315(MH ⁺ ).

Example 23

2-(2-carboxyethyl)-8-(5-guamdinopcιιtytιyl)-2,3,4,5-te trahydro-lH-2-benzazeμin-l-one trifluoroacetate. a) A solution of 2-(2-carboxyethyl)-8-(5-amin.opentynyl)-2,3,4,5-tetrahydro-l H-2- benzazepϊn-1-one trifluoroacetate (20 mg, 0.063 mmol) in saturated aqueous KHCO3 (1 mL)

was treated with formamidine sulfonic acid (80 mg, 1.0 mmol), and the resulting mixture stirred for 2 hours. The mixture was then treated with acetic acid, and the volatiles were removed. The residue was purified by HPLC (112' C-18 reverse-phase column) eluting with a gradient of 3:7 methanol (0.1% trifluoroaceate)/water (0.1% trifluoroaceate), time 0 to 10 min, to 7:3 methanol(0.1% trifluoroaceate)/water(0.1% trifluoroaceate), time 10 to 40 min, to yield 4.5 mg (15%) oι2-(2-carboxyethyl)-8-(5-guanidinopentynyl)-2,3,4,5-tetrah ydro-lH-2- benzazepin-1-one trifluoroacetate as a light brown solid; 1H NMR(D2θ) d7.40(s, IH), 725(dd, J=3, 6Hz, IH), 7.15(d, J=6Hz, IH), 3.80(t, J=6Hz, 2H), 3.30(m, 4H), 3.15(t, J=6Hz, 2H), 2.00(t, J=6Hz, 2H), 1.80(m, 2H); MS(FAB) m/z=357.1(MH ⁺ ).

Example 24

2-(2-carboxyethyl)-8-(4-(2-aminoethoxy)μhenyl)-2,3,4,5-t etrahydro-lH-5-oxa-2- benzazepin-1-one trifluoroacetate. a) A solution of 1-aminopropylene (10.6 grams, 0.186mol) in methanol was added to a methanolic solution of 3-phenylpropyleneoxide (5.07 grams, 0.037mol) and the mixture heated to reflux for 30 minutes. The mixture was allowed to warm to room temperature and concentrated in vacuo to yield 7.2 grams (99%) of N-allyI-3-phenyl-2-hydroxypropylamine. 1H NMR (CDCI3, dTMS) 7.34-7.18 (5H, m, Ar-H), 5.84 (IH, ddt, CH2CH), 5.2-5.0 (2H, m, CH=CH2), 3.86 (IH, m, CHOH), 3.19 (2H, m, NCH2CH=CH2), 2.76-2.66 (3H, m, NCH2CH(OH)CHHPh), 2.50 (IH, dd ¹³ C NMR (CDCI3) 138.4, 136.5, 129.3, 128.4, 126.3, 116.0, 70.6, 54.0, 51.9, 41.7.

Using the above procedure, but substituting the appropriate alkenyloxide or allyl amine for 3-phenylpropyleneoxide or 1-aminopropylene, respectively, there may be prepared, for example, the following compounds: N-allyl-2-hydroxypropylamine, N-(3-but-l-ene)-3-phenyl-2-hydroxypropylamine, N-(3- but-l-ene)-2-hydroxypropylamine.

b) To a magnetically stirred suspension of 5-iodosalisylic acid (Aldrich, 85 grams, 0.032mol), was added oxalyl chloride (8.6 grams, 0.064 mol) and one drop of dimethylformamide. The mixture was stirred until effervescence had ceased and concentrated in vacuo. The resulting residue was diluted with diethyl ether and added to a solution of N-aIlyI-3-phenyl-2- hydroxypropyl-amine (6.4 grams, 0.034 mol) in diethyl ether over a period of 30 minutes. The reaction was stirred for 1 hour, filtered, and concentrated in vacuo. the resulting residue was dissolved in methylene chloride and washed with IN HCl, sat sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to yield 12.26 grams (87%) of N- allyl-N-(2-hydroxy-5-iodobenzoyl)-2-hydroxy-3-phenylpropylam ine. The material was used without further purification.

Using the above procedure, but substituting the appropriate hydroxypropylamine for N-allyl-3-phenyl-2-hydroxypropylamine there may be prepared, for example, the following compounds: N-aIlyl-N-(2-hydroxy-5-iodobenzoyI)-2-hydroxypropylamine, N-(3-but-l-ene)-N-(2-hydroxy-5-ϊodobenzoyI)-2-hydroxy-3-phe nylpropylamine, N-(3-but-l-ene)-N-(2-hydroxy-5-ϊodobenzoyl)-2-hydroxypropyl amine.

c) To a magnetically stirred solution of N-alIyl-N-(2-hydroxy-5-ϊodobenzoyl)-2-hydroxy-3- phenylpropyiamine (12.05 grams, 0.027 mol) in lOOmL THF was added triphenylphosphine (7.24 grams , 0.027 mol), and diethyl azodicarboxylate (4.7 grams, 0.027 mol). The mixture was heated to reflux overnight, allowed to cool to room temperature, and concentrated in vacuo. the resulting residue was dissolved in ethyl acetate (lOmL) and diluted with diethyl ether. The solids that form were filtered and the mother liquor was concentrated in vacuo. The yellow oil was purified by column chromatography (Siθ2, using 15% diethyl ether/85% hexane to 1:1 diethyl ether/hexane as the eluting solvent gradient, Rf(product, 1:1 Et2O/heaxane)=0.64) to yield 4.31 grams (38%) of 2-allyl-4-benzyl-8-iodo-2,3,4,5- tetrahydro-lH-5-oxa-2-benzazepin-l-one. 1H NMR (CDCI3, dTMS) 8.10 ( IH, d, C9-H), 7.69 (IH, dd, ⁴ JHH=2HZ, C7-H), 7.4-7.2 (5H, m, C6H5), 6.76 (IH, d, ³ JHH=9Hz, C6-H), 5.79 (IH, ddt, ³ J _H H=17Hz, ³ J _H H=HHz, ³ J _H H=6Hz, CH ₂ CH=CH ₂ ), 5.2-5.0 (2H, m, CH=CH2), 5.71 (1 H, m, CHOH), 4.31 (1 H, d t, NCHHCH=CH2), 3.34 (IH, dd, C3-H), 3.25 (IH, dd, CHHPh), 2.73 (IH, dd, 2j _HH =i4Hz, J _H H=7Hz, CHHPh). ¹³ C NMR (CDCI3) 166.9, 152.7, 141.4, 139.6, 136.5, 132.6, 129.8, 129.1, 128.8, 127.0, 124.6, 118.4, 86.7, 84.7, 50.4, 48.9, 38.9. IR (NaCl, cm" ¹ ) 1641, 1589, 1463, 1430, 1264, 1217, 699.

Using the above procedure, but substituting the appropriate hydroxypropylamine for N-allyl-N-(2-hydroxy-5-iodobenzoyl)-2-hydroxy-3-phenylpropyl amine there may be prepared, for example, the following compounds:

2-alIyl-4-methyl-8-iodo-2,3,4,5-tetrahydro-lH-5-oxa-2-benzaz epin-l-one,

2-(3-but-l-ene)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-lH-5-o xa-2-benzazepin-l-one,

2-(3-but-l-ene)-4-methyl-8-iodo-2,3,4,5-tetrahydro-lH-5-o xa-2-benzazepin-l-one.

d) To a magnetically stirred solution of 2-alIyl-4-benzyl-8-iodo-2,3,4,5-tetrahydro-lH-5- oxa-2-benzazepin-l-one (0.9234 grams, 2.2mmol) in 4mL THF at room temperature under an atmosphere of nitrogen was added 6.0mL of a 0.5M solution of 9-borabicylo[33.1]nonane in THF (3 mmol) and tine mixture stirred for 1 hour. The reaction was quenched with 6mL of a solution of 2 grams of sodium hydroxide and 22mL of a 1:1 mixture of ethanol and water. To the resulting solution was added 7mL of a 30% solution hydrogen peroxide in water. After 30 minutes the mixture was partitioned between dietlnyl ether and water. The organic layer was washed witln 10% citric acid and brine, dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (SiO2, using 1:5 ethyl acetate/methylene chloride as the eluting solvent, Rf(product)=0.22) to yield 0.74 grams (77%) of 2-(3-hydroxypropyl)-4- benzyl-8-iodo-2,3,4,5-tetrahydro-lH-5-oxa-2-benzazepin-l-one . IH NMR (CDCI3, dTMS) 8.08 (IH, d, C7-H) _> 7.4-7.2 (5H, m, C6H5), 6.78 (IH, d, C6-H), 4.64 (IH, m, ArOCH), 3.70 (2H, m, CH2OH), 3.58 (2H, bt, C3-H), 3.24 (IH, dd, CHHPh), 2.76 (IH, dd, 2j _HH= i4Hz, j _HH =7Hz, CHHPh), 1.68 (2H, m, CH2CH2OH). ¹³ C NMR (CDCI3) 168.3, 152.6, 141.6, 139.4, 136.2, 132.1, 131.9, 129.2, 129.0, 128.8, 128.4, 127.0, 124.7, 86.8, 85.7, 58.0, 49.9, 44.5, 38.8, 30.3. IR (NaCl, cm" ¹ ) 3422 (b), 1636, 1463, 1436, 1217, 1064.

Using the above procedure, but substituting the appropriate 5-oxa-2-benzazepin-l- one for 2-allyl-4-benzyl-8-iodo-2,3,4,5-tetrahvdro-lH-5-oxa-2-benzaz epin-l-one there may be prepared, for example, the following compounds:

2-(3-hydroxypropyl)-4-methyl-8-iodo-2,3,4,5-tetrahydro-lH -5-oxa-2-benzazepin-l-one, 2-(4-hydroxybut-2-yl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-lH- 5-oxa-2-benzazepin-l-one, 2-(4-hydroxybut-2-yl)-4-methyl-8-iodo-2,3,4,5-tetrahydro-lH- 5-oxa-2-benzazepin-l-one.

e) To a magnetically stirred solution of 2-(3-hydroxyproρyl)-4-benzyl-8-iodo-2,3,4,5- tetrahydro-lH-5-oxa-2-benzazepin-l-one (0.75 grams, 1.7mmol) in 5mL dimethylformamide at room temperature was added a solution of pyridinium dichromate (2.58 grams, 6.86mmoI) in 5mL dimethylformamde. The reaction mixture was stirred overnight, diluted with 75mL water, washed 3X75mL dietlnyl ether, made acidic to a pH of 2 with cone. HCl and extracted 3X75mL dietlnyl ether. The combined organics were extracted 3X40mL IN sodium hydroxide. One combined aqueous layers were acidified to a pH of 2 with cane HCl and extracted 3X50mL diethyl ether. These ether layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 0.557 grams (73%) of 2-(2-carboxyethyl)-4-benzyl-8-iodo- 2,3,4,5-tetrahydro-lH-5-oxa-2-benzazepin-l-one. H NMR (CDCI3, dTMS) 8.07 (IH, d,

C7-H), 7.4-7.2 (5H, m, H5), 6.75 (IH, d, ³ JHH=8Hz, C6-H), 4.75 (IH, m, ArOCH), 3.89 (IH, dt, ² J _HH =l4Hz, J _H H=θHz, NCHHCH2CO2), 3.69 (IH, dt, NCHHCH2CO2), 3.44 (2H, d, C3-H), 2.8-2.7 (3H, m, C3-H, CH2CO2). ¹³ C NMR (CDC13) 176-1, 167.6, 164.4, 152.8, 141.7, 139.5, 136.4, 129.4, 129.1, 128.9, 128.8, 127.0, 124.7, 86.7, 84.7, 51.4, 45.0, 38.8, 33.0.

Using the above procedure, but substituting the appropriate 5-oxa-2-benzazepin-l- one for 2-(3-hydroxypropyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-lH-5- oxa-2-benzazepin-l- one there may be prepared, for example, tine following compounds: 2-(2-carboxyethyl)-4-methyl-8-iodo-2,3,4,5-tetrahydro-lH-5-o xa-2-benzazepin-l-one, 2-(3-carboxy-2-propyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-lH -5-oxa-2-benzazepin-l-one, 2-(3-carboxy-2-propyl)-4-methyl-8-iodo-2,3,4,5-tetrahydro-lH -5-oxa-2-benzazepϊn-l-one.

f) A solution of dϊazomethane in ether, prepared by allowing a slurry of 2.98 grams of N- nitroso-N-methylurea and lOmL ether to react witln a solution of 20 grams of KOH in 20mL water, was carefully added via a pipet to solution of 2-(2-carboxyethyl)-8-iodo-2,3,4,5- tetrahydro-lH-5-oxa-2-benzazepin-l-one (0.42 grams, 0.93mmol) in 20mL diethyl ether until yellow color persists. The mixture was allowed to stand overnight and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 1:9 ethyl acetate/hexane, Rf(product)=0.2) to yield 0.275 grams (64%) of 2-(2-carboxyethyl)-8-iodo- 2,3,4,5-tetrahydro-lH-5-oxa-2-benzazepin-l-one methyl ester. 1H NMR (CDCI3, dTMS) 8.06 (IH, d, C7-H), 7.4-7.2 (5H, m, C H5), 6.75 (IH, d, ³ JHH=8HZ, C6-H), 4.76 (IH, m, ArOCH), 3.88 (IH, dt, ² J _HH =i4Hz, ³ J _HH =6Hz, NCHHCH2CO2), 3.69 (4H, m, NCHHCH2CO2CH3), 3.44 (2H, m, C3-H), 3.06 (IH, dd, ³ JHH=7HZ, CHHPh), 2.69 (2H, m, CHHPh, CH2CO2). ¹³ C NMR (CDC13) 172.4, 167.2, 164.4, 152.6, 141.4, 139.4, 136.5, 129.6, 129.1, 121.0, 128.8, 127.0, 124.6, 6.6, 84.7, 51.8, 51.3, 45.1, 38.7, 33.0.

Using the above procedure, but substituting the appropriate 5-oxa-2-benzazepin-l- one for 2-(2-carboxyethyI)-8-iodo-2,3,4,5-tetrahydro-l H-5-oxa-2-benzazepin-l-one there may be prepared, for example, the following compounds:

2-(2-carboxyethyl)-4-metlnyI-8-iodo-2,3,4,5-tetrahydro-lH -5-oxa-2-benzazepin-l-one methyl ester,

2-(3-carboxy-2-propyl)-4-benzyI-8-iodo-2,3,4,5-tetrahydro -lH-5-oxa-2-benzazepin-l-one methyl ester, 2-(3-carboxy-2-propyI)-4-methyl-8-iodo-2,3,4,5-tetrahydro-lH -5-oxa-2-benzazepin-l-one methyl ester.

g) To a magnetically stirred solution of 4-iodophenol (15 grams, 0.068mol) in lOOmL THF was sequentially added trϊphenylphosphine (19.67 grams, 0.075mol), diethyl azodicarboxylate

(13.06 grams, 0.073mol), and 2-azidoethanol (5.93 grams, 0.068mol). The mixture was stirred overnight, concentrated in vacuo, diluted witln 90mL ethyl acetate and diluted with hexane (400mL), and the resulting solids filtered away. The filtrate was concentrated in vacuo, diluted with diethyl ether, and extracted witln IN NaOH and water. Pentane was added to induce precipitation of a white solid that was again filtered away. The filtrate was concentrated in vacuo, and dissolved in methanol (60mL). Triethylamine (27 grams, 0.267mol) and propanedithiol (23 grams, 0.215mol) were added and the mixture stirred at room temperature overnight. Tine solution was diluted witln lOOmL water and partitioned between methylene chloride and IN NaOH. The organic layer was extracted with 2X200mL IN HCl and the aqueous layer washed witln lOOmL methylene chloride, made basic with 2N NaOH and extracted 3X75mL methylene chloride. The combined organics were dried over sodium carbonate, filtered and concentrated in vacuo to yield 12.97 grams of 2-(4-iodophenoxy)ethyl amine (72%). *H NMR (CDCI3, dTMS) 7.56 (2H, d, ³ JHH= 9HZ, Ar-H), 6.63 (2H, d, ³ JHH= 9Hz, Ar-H), 4.03 (2H, t, OCH2). ¹³ C NMR (CDCI3) 158.0, 138.2, 116.9, 83.4, 66.9, 49.9. IR (NaCl, cm' ¹ ) 2930, 2107 (s), 1589, 1483, 1284, 1237, 1058, 819.

h) 2-(4-iodophenoxy)ethylamine (10 grams, 0.038mol) dissolved in THF (50mL) was allowed to react witln di-f-butyl dicarbonate (9.13 grams, 0.041 mol) at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to yield 17.7 grams (99%) of N-Boc-2-(4- iodophenoxy)ethyiamine.

i) A slurry of 2-(2-carboxyethyl)-4-benzyl-8-iodo-2,3,4,5-tetrahydro-lH-5-o xa-2- benzazepin-1-one methyl ester (0.155 grams, 0.334mmol), N-Boc-2-(4- iodophenoxy)ethylamine (0.246 grams, 0.664mmol), degassed triethylamine (2mL), bis(triphenylphosphine)palladium dichloride (11 mgs, 10 mol %), and coprous iodide (6mgs, 20 mol %) was heated to reflux overnight. The reaction was concentrated in vacuo, triturating the resulting residue with dietlnyl ether (30mL). The ethereal solution was concentrated in vacuo and the residue purified by column chromatography (Siθ2, using 1:1 ethyl acetate/hexane to ethyl acetate as the eluting solvent gradient, Rf(product)=0.08) to yield 19.1mgs (10%) of 2-(2-carboxyetlnyl)-4-benzyl-8-(4-(2-N-Boc-amino)ethoxypheny l)-2,3,4,5- tetrahydro-lH-5-oxa-2-benzazepin-l-one methyl ester. IH NMR (CDCI3, dTMS) 7.94 (IH, d, C8- o-Ar-H), 7.40-7.25 (5H, , QjHs), 7.05 (IH, d, ³ J _H H=8Hz, C6-H), 6.96 (2H, d, ³ JHH=9Hz, Cβ-MJ-Ar-H), 5.03 (IH, bs, NH), 4.76 (IH, m, OCH), 4.06 (2H, t, OCH2CH2N), 3.92 (IH, dt, 2j _HH =χ4Hz, J _H H=7Hz, NCHHCH2CC7), 3.73 (IH, dt, ² J _HH =14Hz, ³ J _HH =7Hz, NCHHCH2CO2), 3.67 (3H, s, CH3), 3.56 (2H, bq, ³ JHH=6Hz, CH2NH), 3.51 (IH, dd, 2j _H -H), 3.12 (IH, dd, 2j _H

CHHPh), 2.72 (2H, m, CH2CO2), 1.48 (9H, s, Bu ^l ), ¹³ C NMR (CDCI3) 172.6, 168.9, 136.8, 136.5, 130.8, 129.1, 128.8, 128.7, 128.3. 126.9, 123.0, 114.8, 84.6, 60.4, 51.8, 51.5, 45.0, 38.8, 33.2, 28.3.

Using the above procedure, but substituting the appropriate 5-oxa-2-benzazepin-l- one for 2-(2-carboxyethyl)-8-iodo-2,3,4,5-tetrahydro-lH-5-oxa-2-benz azepin-l-one there may be prepared, for example, the following compounds:

2-(2-carboxyethyl)-4-methyl-8-(4-(2-N-Boc-amino)ethoxyphe nyI)-2,3,4,5-tetrahydro-lH- 5-oxa-2-benzazepin-l-one methyl ester,

2-(3-carboxy-2-propyl)-4-benzyl-8-(4-(2-N-Boc-amino)ethox yphenyl)-2,3,4,5-tetrahydro- lH-5-oxa-2-benzazepin-l-one methyl ester,

2-(3-carboxy-2-propyI)-4-methyl-8-(4-(2-N-Boc-amino)ethox yphenyl)-2,3,4,5-tetrahydro- lH-5-oxa'-2-benzazepin-l-one methyl ester,

2-(2-carboxyethyI)-4-benzyI-8-[4-(4-N-Boc-piperazine)phen yI]-2,3,4,5-tetrahydro-lH-5- oxa-2-benzazepin-l-one methyl ester, 2-(2-carboxyethyl)-4-methyl-8-[4-(4-N-Boc-piperazine)phenyl] -2,3,4,5-tetrahydro-lH-5- oxa-2-benzazepin-l-one methyl ester,

2-(3-carboxy-2-propyl)-4-benzyl-8-[4-(4-N-Boc-pϊperazine )phenyI]-2,3,4,5-tetrahydro-lH- 5-oxa-2-benzazepin-l-one methyl ester,

2-(3-carboxy-2-propyl)-4-methyI-8-[4-(4-N-Boc-piperazine) phenyl]-2,3,4,5-tetrahydro-lH- 5-oxa-2-benzazepin-l-one methyl ester,

2-(2-carboxyethyl)-4-benzyl-8-[4-(4-N-Boc-aminomethyl)phe nyl]-2,3,4,5-tetrahydro-lH-5- oxa-2-benzazepin-l-one methyl ester,

2-(2-carboxyethyl)-4-metInyl-8-[4-(4-N-Boc-aminomethyl)ph enyl]-2,3,4 _/ 5-tetrahydro-lH- 5-oxa-2-benzazepin-l-one methyl ester, 2-(3-carboxy-2-propyI)-4-benzyl-8-[4-(4-N-Boc-amϊnomethyI)p henyl]-2,3,4,5-tetrahydro- lH-5-oxa-2-benzazepin-I-one methyl ester,

2-(3-carboxy-2-propyl)-4-methyI-8-[4-(4-N-Boc-aminomethyI )phenyl]-2,3,4,5-tetrahydro- lH-5-oxa-2-benzazepϊn-l-one methyl ester.

j) To a solution of 2-(2-carboxyethyl)-4-benzyl-8-(4-(2-N-Boc-amϊno)ethoxypheny l)-2,3,4,5- tetrahydro-lH-5-oxa-2-benzazepin-l-one methyl ester (19.1mgs, 0.03mmoi) in 0.5mL acetonitrile and 0.5mL water was added a concentrated solution of HCl in ethyl acetate (lmL) and the reaction allowed to stand for 15 minutes, concentrated in vacuo, dissolved in methanol (lmLO and allowed to react with 2N NaOH (lmL). The reaction was quenched with acetic acid (0.5mL) and concentrated in vacuo, dissolved in a minimum of water and purified by high-pressure column chroma ography (HPLC, 1 /2" reverse-phase C-18 column, 1:4 acetonitrile(0.1%TFA)/water (0.1%TFA) to 3:2 acetonitrile(0.1%TFA)/water (0.1%TFA) as the eluting solvent gradient) to yield 4.2mgs (30%) of 2-(2-carboxyethyl)-8-(4-(2- aminoethoxy)phenyl)-2,3,4,5-tetrahydro-lH-5-oxa-2-benzazepin -l-one. *H NMR (CD3OD)

7.80 (IH, d, C7-H), 7.58 (2H, d, ³ JHH=9Hz, C8-o-Ar-H), 7.40-7.35 (5H, m, C H5), 7.10 (2H, d, ³ ] _H H=9Hz, C8-m-Ar-H), 7.03 (IH, d, ³ J _HH =8Hz, C6-H), 4.28 (2H, t, 3]HH=4Hz, OCH2CH2), 3.81 (2H, m, NCH2CH2CO2), 3.61 (IH, dd, C3-H), 3.44 (IH, dd, ³ J _H H=4Hz, C3-H), 3.41 (2H, t, J _H H=5Hz, CH ₂ Ph), 2.87 (2H, t, ³ jHH=7Hz, CH NH ₂ ), 2.50 (2H, t, JHH=7Hz, CH2CO2). HRMS (FAB, MH ⁺ ) m/z= 461.2109 (cald for C27H29N2O5: 461.2076).

Using the above procedure, but substituting the appropriate 5-oxa-2-benzazepin-l- one for 2-(2-carboxyethyI)-4-benzyl-8-(4-(2-N-Boc-amino)ethoxyphenyl )-2,3,4,5- tetrahydro-lH-5-oxa-2-benzazepin-l-one methyl ester there may be prepared, for example, the following compounds:

2-(2-carboxyetlnyI)-4-metlnyl-8-(4-(2-amino)ethoxyphenyl) -2,3,4,5-tetrahydro-lH-5-oxa-2- benzazepin-1-one,

2-(3-carboxy-2-propyl)-4-benzyl-8-(4-(2-amino)ethoxypheny l)-2,3,4,5-tetrahydro-lH-5- oxa-2-benzazepin-l-one,

2-(3-carboxy-2-propyl)-4-methyl-8-(4-(2-amino)ethoxypheny I)-2,3,4,5-tetrahydro-lH-5- oxa-2-benzazepin-l-one, 2-(2-carboxyethyl)-4-benzyl-8-[4-(l -piperazine)phenyl]-2,3,4,5-tetrahydro-lH-5-oxa-2- benzazepin-1-one,

2-(2-carboxyethyl)-4-methyl-8-[4-(l-pi eraziιne)phenyl]-2,3,4,5-tetrahydro-lH-5-oxa-2- benzazepin-1-one,

2-(3-carboxy-2-propyl)-4-benzyl-8-[4-(l-piperazine)phenyl ]-2,3,4,5-tetrahydro-lH-5-oxa- 2-benzazepin-l-one,

2-(3-carboxy-2-propyl)-4-metlnyl-8-[4-(l-pi erazine)phenyl]-2,3,4,5-tetrahydro-lH-5-oxa-

2-benzazepin-l-one,

2-(2-carboxyethyI)-4-benzyl-8-[4-(4-aminomethyl)phenyl]-2 ,3,4,5-tetrahydro-lH-5-oxa-2- benzazepin-1-one, 2-(2-carboxyethyi)-4-methyl-8-[4-(4-aminomethyl)phenyl]-2,3, 4,5-tetrahydro-lH-5-oxa-2- benzazepin-1-one,

2-(3-carboxy-2-propyl)-4-benzyl-8-[4-(4-aminomethyl)pheny l]-2,3,4,5-tetrahydro-lH-5- oxa-2-benzazepin-l -one,

2-(3-carboxy-2-propyl)-4-methyl-8-[4-(4-aminomethyl)pheny l]-2,3,4,5-tetrahydro-lH-5- oxa-2-benzazepin-l-one.

Example 25

l-MethyI-4-(2-carboxyethyl)-7-(4-amidino)benzamido-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dione acetate

a) A solution of N-methyl isatoic anhydride (64.0 g, 0.325 mol) and b-alanine ethyl ester hydrochloride (50.0 g, 0.325 mol) in N,N-dimethyIformamide (325 mL) was treated with N,N-dϊmethylaminopyridϊne (2.0 g), the resulting mixture cooled to 0°C (ice bath), and triethylamine (46.0 mL, 0.325 mol) was added in one batch. Vigorous CO2 evolution was noted. The mixture was stirred for 18 In at room temperature, then diluted with 400 mL ethyl acetate. The solution was washed exhaustively witln water and brine to remove the N,N- dϊmethylformamide, then dried over MgSO4, filtered and concentrated in vacuo. The residue was adsorbed on silica gel, and elution witln a gradient of hexane to 1:1 ethyl acetate-hexane yielded 80 g (98%) of an oil. *H NMR (CDCI3, dTMS) 7.28 (3H, m), 6.75 (IH, s, NHCH3), 6.62 (IH, d, J=9Hz, ArH), 6.55(1 H, t, J=9Hz, ArH), 4.14 (q, J=9Hz, 2H, CH2O), 3.63 (q, J=6Hz, NCH2CH2), 2.83 (s, 3H, NCH3), 2.59(2H, t, J=6Hz, CH2CO2E.), 1.24 (3H, t, J=9Hz, CH2CH3); ¹³ C NMR(CDCl3, dTMS) 172.88, 169.89, 150.71, 132.96, 127.42, 115.01, 114.60, 111.16, 60.87, 35-11, 34.19, 29.74, 14.28.

b) A solution of N-(N-methyl-2-aminobenzoyI)-b-alanine ethyl ester (80.0 g, 0.319 mol) in CH2CI2 (400 mL) and H2O (200 mL) was cooled to 0°C (ice bath) and treated rapidly dropwise with bromoacetylbromide (42 mL, 0.478 mol). After the addition was complete, the phases were separated, and the aqueous phase was washed twice with CH2CI2, and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to yield 105 g (89%) of an oil. This material was dissolved in N,N-dimethylformamide (200 mL), and with rapid stirring, was treated in one portion witln CS2CO3 (93.0 g, 0.283 mol). The mixture was stirred for 1/2 In at room temperature, then diluted with ethyl acetate and washed exhaustively with brine and water to remove N,N-dimethyIformamϊde. The solution was then dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in minimal ethyl acetate and diluted with hexane until cloudy. A small amount of ethyl acetate was then added, and the mixture stored at -20°C. The crystals that had formed were

collected and washed with hexane, then dried in vacuo to yield 43 g (52%) of colorless crystals, mp. 119-121°C. H NMRCCDCtø, dTMS) 7.83 (IH, dd, J=1.5, 8Hz, ArH), 7.51 (IH, td, J=1.5, 6Hz, ArH), 7.28 (IH, t, J=6Hz, ArH), 7.18 (IH, d, J=9Hz, ArH), 4.13(2H, q, J=9Hz, CH2O), 4.03 (IH, B part, ABq, ]=15Hz, CH2CO), 3.92 (2H, t, J=6Hz, NCH2), 3.84 (IH, A part, ABq, J=15Hz, CH2CO), 3.37 (s, 3H, NCH3), 2.71 (2H, m, complex, CH2Cθ2Et), 1.24 (3H, t, J=6Hz, CH2CH3), 171.43, 169.16, 167.26, 141.08, 132.25, 130.92, 128.74, 125.75, 121.07, 60.89, 52.31, 45.18, 35.03, 32.97, 14.29; MS(FAB) m/z 291(MH ⁺ ).

c) Fuming nitric acid (200 mL) was cooled to 0°C and treated portionwise with l-methyl-4-(2- carboxyethyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester (43.0 g, 0.148 mol), and the resulting dark yellow mixture was stirred for 24 h at room temperature. The solution was then poured over ice onto solid NaHCO3 and extracted exhaustively with ethyl acetate.

The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to yield

36 g (73% ) af an orange oil; ^! H NMR(CDCl3, dTMS) 8.70 (IH, d, J=3Hz, ArH), 8.34 (IH, dd, ]=3, 9Hz, ArH), 7.38 (IH, d, J=9Hz, ArH), 4.14 (2H, q, J=6Hz, CH2O), 4.04 (2H, d, J=6Hz,

CH2CO), 3.93 (2H, t, J=6Hz, NCH2), 3.44 (3H, s, NCH3), 2.74 (2H, m, complex, CH2CO2Et),

1.26 (3H, t, J=6Hz, CH2CH3); ¹³ C NMR(CDC ) dl94.51, 191.54, 188.52, 168.96, 167.69, 152.58,

150.31, 150.05, 145.12, 84.22, 75.21, 68.61, 58.39, 55.97, 37.44; MS(FAB) m/z 336.1(MH+). Using the same above method, but substituting the appropriate l-alkyl-4-(2- carboxyethyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester for l-methyl-4-(2- carboxyethyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester there may be prepared, for example, the following compounds:

1 -ethyl-4-(2-carboxyetlnyl)-7-nitro-3,4-d ihyd ro-1 H-l, 4-benzodiazepine-2,5-dione ethyl ester, l-isopropyl-4-(2-carboxyethyl)-7-nitro-3,4-dihydro-l H-l,4-benzodiazepine-2,5-dione ethyl ester, l-isobytyl-4-(2-carboxyethyI)-7-nitro-3,4-d ihyd ro-1 H-l, 4-benzodiazepine-2,5-dione ethyl ester, l-cycIohexyl-4-(2-carboxyethyl)-7-nitro-3,4-dilnydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester.

d) A solution of l-metInyI-4-(2-carboxyethyl)-7-nitro-3,4-dihydro-lH-l,4-benz odiazepine- 2,5-dione ethyl ester (36.0 g, .107 mol) in ethyl acetate (200 L) and absolute ethanol (150 L) was hydrogenated over Pd on carbon (4 g) at 40 PSI for 24 In. The black suspension was then filtered and concentrated in vacuo to give 32.3 g (100%) of a colorless foam. This foam was dissolved in CH2CI2, cooled to 0°C (ice bath) and treated with NEt3 (17.5 mL, 0.126 mol) followed by 4-cvanobenzoyl chloride (20.86 g, 0.126 mol), and the resulting mixture was stirred for 24 h at room temperature. The mixture was then washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to yield a light brown solid.

Recrystallization of the solid from CH2Cl2/hexanes yielded 33 g (76%) of a white granular solid: mp. 158-160°C; ² H NMR(CDCl3, dTMS) 8.76 (IH, s, NH), 8.00 (IH, dd, J=3, 9Hz, ArH), 7.72 (IH, d, J=9Hz, ArH), 7.58 (IH, d, J=3Hz, ArH), 7.47 (IH, d, J=9Hz, ArH), 6.94 (IH, d, J=9Hz, ArH), 3.83 (2H, q, J=6Hz, OCH2CH3), 3.77 (IH, B part, ABq, T=15Hz, CH2CO), 357 (IH, A part, ABq, J=15Hz, CH2CO), 3.53 (2H, t, J=6Hz, NCH2), 3.09 (3H, s, NCH3), 2.34 (2H, m, complex, CH2CO2E.), 0.95 (3H, t, J=6Hz, OCH2CH3); ^I3 C NMR(CDCl3) dl71.04, 168.57, 166.90, 164.31, 138.24, 137.34, 135.51, 132.47, 128.60, 128.05, 124.64, 121.85, 117.83, 115.51, 60.94, 52.09, 5.01, 34.92, 32.60, 14.13; MS(FAB) m/z 435(MH+).

Using the same above procedure, but substituting the appropriate cyano acid chloride or amino protected amino acid chloride for 4-cyanobenzoyl chloride there may be prepared, for example, the following compounds: l-methyl-4-(2-carboxyethyl)-7-(3-cyano)benzamϊdo-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione ethyl ester, l-methyl-4-(2-carboxyethyl)-7-(4-cyano)butanamidυ-3,4-dihyd ro-lH-l,4-benzodiazepine- 2,5-dϊone ethyl ester, l-methyI-4-(2-carboxyethyl)-7-(5-cyano)pentamido-3 _/ 4-dihydro-lH-l,4-benzodiazepϊne- 2,5-dione ethyl ester, l-methyl-4-(2-carboxyethyI)-7-4-(N-Boc)-aminobutanamido-3,4- dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-methyl-4-(2-carboxyethyl)-7-5-(N-Boc)-aminopentamido-3,4-d ihydro-lH-l,4- benzodiazepine-25-dione ethyl ester. Furthermore, using the same procedure but substituting the appropriate l-aIkyI-4-(2-carboxyethyl)-7-nitro-3,4-dihydro-lH-l,4-benzod iazepine- 2,5-dione ethyl ester for l-methyI-4-(2-carboxyethyI)-7-nitro-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-ethyI-4-(2-carboxyethyl)-(4-cyano)benzamido-3,4-dϊhydro-l H-l,4-benzodiazepine-2,5- dione ethyl ester, l-isopropyI-4-(2-carboxyethyl)-(4-cyano)benzamϊdo-3,4-dihyd ro-lH-l,4-benzodiazepine- 2,5-dione ethyl ester, l-isobytyI-4-(2-carboxyethyl)-(4-cyano)benzamido-3,4-dihydro -lH-l,4-benzodiazepine- 2,5-dϊone ethyl ester, l-cycIohexyl-4-(2-carboxyethyI)-(4-cyano)benzamϊdo-3,4-dihy dro-lH-l,4-benzodiazepine- 2,5-dione ethyl ester.

e) A solution of l-methyl-4-(2-carboxyethyI)-7-(4-cyano)benzamido-3,4-dihydro -lH-l,4- benzodiazepine-2,5-dione ethyl ester (10.0 g, 0.023 mol) in NEt3 (50 mL) and pyridine (70 mL) was saturated with H2S, then heated at 70°C for 24 In. The solvents were removed in vacuo, and tine residue remaining was suspended in CH2CI2 (200 mL) and treated with iodomethane (10 mL). The resulting solution was heated at reflux for 24 h. The volatiles were then

removed in vacuo, and the resulting residue was dissolved in EtOH (100 mL) and treated with

NH4OAC (3.2 g), and the resulting suspension heated to 50°C with stirring for 24 h. The mixture was concentrated in vacuo, and the product was dissolved in 0.5% aqueous HOAc, and isolated by HPLC to yield a white solid; 1H NMR (EfeO, TFA salt) d7.72 (2H, d, J=12Hz, ArH), 7.65 (2H, d, J=12Hz, ArH), 7.63 (IH, d, J=3Hz, ArH), 7.53 (IH, dd, 1=3, 9Hz, ArH), 7.12

(IH, d, J=12Hz, ArH), 4.40 (2H, B part, ABq, J=15Hz, C3-H and m, CHHCH2CO2), 3.91(2H, q, J=6Hz, OCH2), 3.68 (IH, A part, ABq, C3-H), 3.48 (IH, m, CHHCH2CO2), 3.18 (3H, s,

NCH3), 2.54 (2H, m, CH2CO2), 0.98 (3H, t, ]=6Hz, OCH2CH3); MS (FAB) m/z 452(MH+).

Using the above procedure, but substituting the appropriate l-alkyl-4-(2-carboxyethyl)-7-(4- cyano)alkyl/benzamido-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione ethyl. ester for 1- methyl-4-(2-carboxyethyl)-7-(4-cyano)benzamido-3,4-dihydro-l H-l,4-benzodiazepine-2,5- dione ethyl ester, there may be prepared, for example, the following compounds. l-methyl-4-(2-carboxyethyI)-7-(3-amidino)benzamido-3,4-dihyd ro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-methyl-4-(2-carboxyethyl)-7-(4-amidino)butanarnido-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-methyl-4-(2-carboxyethyl)-7-(5-amidino)pentamido-3,4-dihyd ro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-ethyl-4-(2-carboxyethyl)-(4-a mid ino)benzamido-3,4-d ihyd ro-lH-l,4-benzodiazepine- 2,5-dione ethyl ester, l-isopropyl-4-(2-carboxyetlnyl)-(4-amidino)benzarnido-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-isobytyl-4-(2-carboxyethyl)-(4-amidino)benzamido-3,4-dihyd ro-lH-l,4-benzodiazepine-

2,5-dione ethyl ester, l-cycIohexyl-4-(2-carboxyethyl)-(4-amidino)benzamido-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester.

f) A solution of l-methyl-4-(2-carboxyethyl)-7-(4-amidino)benzamido-3,4-dihyd ro-lH-l,4- benzodiazepine-2,5-dione ethyl ester acetate (0.2 g, 0.456 mmol) in THF (20 mL) and 50% aqueous NaOH (3 L) was stirred for 24 In at room temperature. Acetic acid was then added, and tine solution was concentrated in vacuo. The residue remaining was purified by HPLC to yield 122 mg (57%) of a white foam (isolated by lyophylization); ^X H NMR(D2θ) d7.73 (2H, d, J=6Hz, ArH), 7.63 (2H, d, J=6Hz, ArH), 7.62 (IH, m, ArH), 7.54 (IH, dd, 1=3, 9Hz, ArH), 7.12 (IH, d, J=9Hz, ArH), 3.87 (IH, B part, ABq, J=15Hz, CH2CO) overlapping 3.84 (IH, m, complex), 3.20 (IH, A part, ABq, J=15Hz, CH2CO), 3.48 (IH, m), 3.03 (3H, s, NCH3), 2.50

(2H, m, complex, CH2CO); MS(FAB) /z 424.3(MH ⁺ ); High Resolution MS(FAB) calculated for C21H22N5O5424.1620, found 424.1647.

Using the above method, but substituting the appropriate l-alkyl-4-(2- carboxyethyl)-7-(4-amidino)alkyl /benzamido-3,4-dilnydro-lH-l,4-benzodiazepine-2,5-

dione ethyl ester for l-methyl-4-(2-carboxyethyl)-7-(4-amidino)benzamido-3,4-dihyd ro- lH-l,4-benzodiazepine-2,5-dione ethyl ester, there may be prepared, for example, the following compounds: l-methyl-4-(2-carboxyethyI)-7-(3-amϊdino)benzamϊdo-3,4-dih ydro-lH-l,4- benzodϊazepϊne-2,5-dione acetate, l-methyI-4-(2-carboxyethyI)-7-(4-amidϊno)butanamido-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione acetate, l-methyl-4-(2-carboxyethyl)-7-(5-amidino)pentamido-3,4-dihyd ro-lH-l,4- benzodϊazepine-2,5-dione acetate, l-ethyl-4-(2-carboxyethyl)-(4-amidino)benzamido-3,4-dihydro- lH-l,4-benzodiazepine-

2,5-dione acetate, l-isopropyI-4-(2-carboxyethyl)-(4-amidino)benzamido-3,4-dihy dro-lH-l,4- benzodiazepϊne-2,5-dione acetate, l-isobytyl-4-(2-carboxyethyl)-(4-amidϊno)benzamido-3,4-dihy dro-lH-l,4-benzodiazepine- 2,5-dϊone acetate, l-cycIohexyl-4-(2-carboxyethyI)-(4-amidino)benzamido-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione acetate.

Example 26

l-mefhyl-4-(2-carboxyethyl)-7-(4-amidiιwbeιιzyloxy)-3, 4-dihydro-lH-l,4-benzodiazepine-

2,5-dioue trifluoroacetate.

a) To a stirred solution of 643 mg (2.11 mmol) of l-methyl-4-(2-carboxyethyl)-7-amino-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester (prepared from l-methyl-4-(2- carboxyethyl)-7-nitro-3,4-dϊhydro-lH-l,4-benzodiazepine-2,5 -dione ethyl ester as a colorless foam as described in part (d) of example 26) in 60 mL of 0.1 N sulfuric acid at 0 ^C C was added a solution of 153 mg (2.21 mmol) of sodium nitrite in 5 ml of water. After 10 min., a solution of 49.0 g (211 mmol) of copper (II) nitrate hemipentahydrate in 90 mL of water was added followed by 287 mg (2.00 mmol) of copper (I I) oxide. The mixture was warmed to ambient temperature and extracted with three portions of methylene chloride. The combined

extracts were washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Chromatography (silica gel 60, gradient elution from 1:2 ethyl acetate/hexane to ethyl acetate, Rf = 0.2 in 2:1 ethyl acetate/hexane on silica) gave 353 mg (55%) of l-methyI-4-(2-carboxyethyl)-7-hydroxy-3,4-dihydro-lH-l,4-ben zodiazepine-2,5- dione ethyl ester as a colorless stable foam. ^J H NMR (300 MHz, CDCI3) d 8.60 (IH, bs, Ar- OH), 7.52 (IH, bs, Ar-H), 7.1-7.0 (2H, m, Ar-H), 4.12 (2H, q, J=73 Hz, OCH2CH3), 4.07 (IH, d, J=14.7 Hz, NCHHCON), 3.90 (2H, m, NCH2CH2), 3.86 (IH, d, J=14.7 Hz, NCHHCON), 3.33 (3H, s, NCH3), 2.70 (2H, m, NCH2CH2), 123 (3H, t, J=7.3 Hz, OCH2CH3)); Exact mass (FAB, M+H ⁺ ) calcd for C15H19 N2O5: 307.1294; Found: 307.1289. Using the above procedure, but substituting the appropriate l-aIkyl-4-(2- carboxyethyl)-7-nitro-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione ethyl ester for 1- methyI-4-(2-carboxyethyl)-7-nitro-3,4-dihydro-lH-l,4-benzodi azepine-2,5-dione ethyl ester, there can be prepared, for example, the following compounds: l-ethyl-4-(2-carboxyethyl)-7-hydroxy-3,4-d ihyd ro-1 H-l, 4-benzodiazepine-2,5-dione ethyl ester, l-isopropyl-4-(2-carboxyethyl)-7-hydroxy-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-isobytyl-4-(2-carboxyethy I)-7-hydroxy-3,4-d i hyd ro-1 H-l ,4-benzodiazepine-2,5-dione ethyl ester, l-cyclohexyl-4-(2-carboxyethyl)-7-hydroxy-3,4-dihydro-lH-l,4 -benzodiazepine-2,5-dione ethyl ester.

b) To a stirred solution of 121 mg (0.395 mmol) of l-methyl-4-(2-carboxyethyl)-7-hydroxy- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester and 93.0 mg (0.474 mmol) of a- bromo-p-tolylnitrile in 2 ml of dry dimetlnylformamide was added 60.0 mg (0.434 mmol) of potassium carbonate. The mixture was stirred overnight at ambient temperature then partitioned between ethyl acetate and water. The organic phase was separated and washed witln water, brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Chromatography (silica gel 60, gradient elution from 2:1 ethyl acetate/hexane to ethyl acetate, Rf = 0.35 in 2:1 ethyl acetate/hexane on silica) gave 125 mg (75%) of l-methyl-4-(2- carboxyethyl)-7-(4-cyanobenzyloxy)-3,4-d ihyd ro-1 H-l, 4-benzodiazepine-2,5-dione ethyl ester as a colorless foam. ^] H NMR (300 MHz, CDCI3) d 7.68 (2H, d, 1=8.8 Hz, NC-Ar-H2), 7.54 (2H, d, J=8.8 Hz, NC-Ar-H2), 7.52 (IH, bs, O-Ar-H), 7.13 (2H, bs, O-Ar-H), 5.16 (2H, ABq, J=12.7 Hz, ArCH2θ), 4.13 (2H, q, J=7.3 Hz, OCH2CH3), 4.03 (1 H, d, J=14.7 Hz, NCHHCON), 3.92 (2H, m, NCH2CH2), 3.84 (IH, d, J=14.7 Hz, NCHHCON), 3.34 (3H, s, NCH3), 2.70 (2H, m, NCH2CH2), 1.24 (3H, t, J=7.3 Hz, OCH2CH3); Exact mass (FAB, M+H ⁺ ) calcd for Q23H24 N3O5: 422.1716; Found: 422.1744.

Using the above procedure, but substituting the appropriate l-alkyl-4-(2- carboxyethyl)-7-hydroxy-3,4-dϊhydro-lH-l,4-benzodiazepine-2 ,5-dione ethyl ester for 1- methyl-4-(2-carboxyethyl)-7-hydroxy-3,4-dihydro-lH-l,4-benzo diazepine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-ethyl-4-(2-carboxyethyI)-7-(4-cyanobenzyl)oxy-3,4-dihydro- lH-l,4-benzodiazepine-2,5- dione ethyl ester, l-isopropyI-4-(2-carboxyethyl)-7-(4-cyanobenzyl)oxy-3,4-dϊh ydro-lH-l,4-benzodiazepine- 2,5-dione ethyl ester, l-isobytyl-4-(2-carboxyethyl)-7-(4-cyanobenzyI)oxy-3,4-dihyd ro-lH-l,4-benzodiazepine- 25-dione ethyl ester, l-cyclohexyI-4-(2-carboxyethyl)-7-(4-cyanobenzyI)oxy-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dϊone ethyl ester, l-ethyl-4-(2-carboxyethyl)-7-(3-cyanobenzyl)oxy-3,4-dihydro- lfY-l,4-benzodiazepine-2,5- dione ethyl ester, l-isopropyl-4-(2-carboxyethyl)-7-(3-cyanobenzyl)oxy-3,4-dihy dro-lH-l,4-benzodiazepine- 2,5-dϊone ethyl ester,

I-ϊsobytyl-4-(2-carboxyethyI)-7-(3-cyanobenzyI)oxy-3,4-d ihydro-lH-l,4-benzodiazepine- 2,5-dione ethyl ester, l-cycIohexyl-4-(2-carboxyethyl)-7-(3-cyanobenzyI)oxy-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-ethyl-4-(2-carboxyethyI)-7-(4-cyanobutyl)oxy-3,4-dihydro-l H-l,4-benzodlazepine-2,5- dione ethyl ester, l-isopropyI-4-(2-ca rboxyethyl )-7-(4-cyanob u ty 1 )oxy-3,4-d ihyd ro-lH-l,4-benzodiazepine- 2,5-dione ethyl ester, l-isobytyl-4-(2-carboxyethyI)-7-(4-cyanobutyl)oxy-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione ethyl ester, l-cyclohexyl-4-(2-carboxyethyl)-7-(4-cyanobutyl)oxy-3,4-dihy dro-lH-l,4-benzodiazepine- 2,5-dione ethyl ester.

c) Hydrogen sulfide gas was bubbled into a solution of 83.6 mg (0.198 mmol) of l-methyI-4-(2- carboxyethyI)-7-(4-cyanobenzyIoxy)-3,4-dihydro-lH-l,4-benzod iazepine-2,5-dione ethyl ester in 3 mL of 1:1 pyrϊdine/trϊethylamine for 15 min and tine mixture was warmed in a 50 °C oil bath for 4 h. After evaporation of the solvent, the residue was taken up in 6 mL of 5:1 methylene chloride/methyl iodide and warmed at 50 °C for 1 In. The solution was again concentrated and the residue redissolved in 3 mL of methanol containing 0.5 g of ammonium acetate. The mixture was heated at 50 °C for 12 In, concentrated to a volume of 1 mL, and purified by reverse phase HPLC (Rainin Microsorb 1/2" C-18). The product was eluted with a solvent gradient of 0:100 acetonitrile (0.1% trifluoroacetic acid) /water (0.1% trifluoroacetic acid), time 0 to 10 min, to 50:50 acetonitrile (0.1% trifluoroacetic acϊd)/water (0.1%

trifluoroacetic acid), time 10 to 40 min, flow=12 ml/min, Rt=35.2 min, uv detection at 254 nM. Concentration of the clean fractions gave 70.0 mg (65%) of l-methyl-4-(2-carboxyethyl)-7-(4- amidinobenzyloxy)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dion e ethyl ester trifluoroacetate as a colorless amorphous solid. 1H NMR (300 MHz, 1:1 D2θ/d°-acetone) d 7.85 (2H, d, J=7.5 Hz, HNC-Ar-H2), 7.68 (2H, d, ]=7.5 Hz, HNC-Ar-H2), 7.40-7.25 (3H, m, O- Ar-H3), 5.24 (2H, s, ArCH2θ), 4.07 (IH, d, J=15.1 Hz, NCHHCON), 4.04 (IH, m, NCHHCH2), 4.02 (2H, q, 1=7.3 Hz, OCH2CH3), 3.82 (IH, d, J=15.1 Hz, NCHHCON), 3.71 (IH, ddd, 1=14.2, 5.9, 5.9 Hz, NCHHCH2), 3.29 (3H, s, NCH3), 2.65 (2H, m, NCH2CH2), 1.11 (3H, t, J=73 Hz, OCH2CH3); Exact mass (FAB, M+H+) calcd for C23H27 N4O5: 439.1981; Found: 439.1977.

Using the above procedure, but substituting the appropriate l-alkyl-4-(2- carboxyethy l)-7-(cya nobenzy 1 /a 1 ky I )oxy-3,4-d i hyd ro-1 H-l ,4-benzodiazepine-2,5-dione ethyl ester for l-methyl-4-(2-carboxyethyl)-7-(4-cyanobenzyl)oxy-3,4-dihydro -lH-l,4- benzodiazepine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-ethyI-4-(2-carboxyethyl)-7-(4-amidinobenzyl)oxy-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione ethyl ester, l-isopropyl-4-(2-carboxyethyI)-7-(4-amidinobenzyl)oxy-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-isobytyl-4-(2-carboxyethyl)-7-(4-annidinobenzyl)oxy-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-cyclohexyl-4-(2-carboxyethyl)-7-(4-amidinobenzyl)oxy-3,4-d ihydro-lH-l _/ 4- benzodiazepine-2,5-dione ethyl ester, l-ethyl-4-(2-carboxyethyl)-7-(3-amidinobenzyl)oxy-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione ethyl ester, l-isopropyl-4-(2-carboxyethyl)-7-(3-amidinobenzyl)oxy-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-isobytyl-4-(2-carboxyethyI)-7-(3-cimidinobenzyl)oxy-3,4-di hydro-lH-l,4- benzodiazepine-2,5- ione ethyl ester, l-cycIohexyl-4-(2-carboxyethyl)-7-(3-amidinobenzyl)oxy-3,4-d ihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-ethyl-4-(2-carboxyethyl)-7-(4-amidinobutyl)oxy-3,4-dihydro -lH-l,4-benzodiazepine- 2,5-dione ethyl ester, l-isopropyl-4-(2-carboxyethyl)-7-(4-amidinobutyl)oxy-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, ^' l-isobytyl-4-(2-carboxyethyI)-7-(4-amidinobutyl)oxy-3,4-d ihyd ro-1 H-l, 4-benzodiazepine- 2,5-dione ethyl ester, l-cyclohexyl-4-(2-carboxyethyl)-7-(4-amidinobutyl)oxy-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester.

d) To a stirred, 0 °C solution of 37.3 mg (0.0690 mmol) of l-methyl-4-(2-carboxyethyl)-7-(4- amidinobenzyloxy)-3,4-dihydro-lH-l,4-benzodϊazepine-2,5-dio ne ethyl ester trifluoroacetate in I L of tetrahydrofuran was added 0.28 mL of 1 N aqueous sodium hydroxide and the mixture warmed to ambient temperature over 1 h. The reaction was acidified with 50 mL of acetic add, concentrated in vacuo, and purified by reverse phase HPLC (Raϊnin Mϊcrosorb 1/2" C-18). The product was eluted with a solvent gradient of 0:100 acetonitrile (0.1% trifluoroacetic acid) /water (0.1% trifluoroacetic acid), time 0 to 10 min, to 50:50 acetonitrile (0.1% trifluoroacetic acid)/water (0.1% trifluoroacetic acid), time 10 to 40 min, flow=12 ml /min, Rt=32.4 min, uv detection at 254 nM. Concentration of the clean fractions gave 26.6 mg (75%) of l-methyl-4-(2-carboxyethyI)-7-(4-amidinobenzyloxy)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dϊone trifluoroacetate as a colorless amorphous solid. ^α H NMR (300 MHz, 1:1 D2θ/d ⁶ -acetone) d 7.75 (2H, d, J=8.3 Hz, HNC-Ar-H2), 7.60 (2H, d, J=83 Hz, HNC-Ar-H2), 732-7.18 (3H, m, O-Ar-H3), 5.16 (2H, s, ArCH2θ), 4.01 (IH, d, J=15.1 Hz, NCHHCON), 4.04 (IH, ddd, J=14.2, 7.3, 7.3 Hz, NCHHCH2), 3.77 (IH, d, J=15.1 Hz, NCHHCON), 3.67 (IH, ddd, J=14.2, 5.8, 5.8 Hz, NCHHCH2), 3.20 (3H, s, NCH3), 2.59 (2H, m, NCH2CH2) Exact mass (FAB, M+H ⁺ ) calcd for C21H23 N4O5: 11.1668; Found: 411.1701.

Using the above procedure, but substituting the appropriate l-alkyl-4-(2- carboxyethyI)-7-(amϊdinobenzyl/alkyl)oxy-3,4-dihydro-lH-l,4 -benzodiazepine-2,5-dione ethyl ester for l-methyl-4-(2-carbυxyethyI)-7-(4-amidϊnobenzyl)oxy-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione etinyl ester there may be prepared, for example, the following compounds: l-ethyl-4-(2-carboxyethyI)-7-(4-amϊdϊnobenzyl)oxy-3,4-dihy dro-lH-l,4-benzodiazepine- 2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxyethyI)-7-(4-amidϊnobenzyI)oxy-3,4-d ihydro-lH-l,4- benzodiazepine-25-dϊone trifluoracetate, l-isobytyl-4-(2-carboxyetlnyl)-7-(4-amidinobenzyI)oxy-3,4-di hydro-lH-I,4- benzodiazepine-2,5-dione trifluoracetate, l-cycIohexyI-4-(2-carboxyethyI)-7-(4-amidϊnobenzyI)oxy-3,4- dihydro-lH-l,4- benzodiazepϊne-25-dione trifluoracetate, l-ethyI-4-(2-carboxyethyI)-7-(3-amidinobenzyl)oxy-3,4-dihydr o-lH-l,4-benzodiazepine- 2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxyethyl)-7-(3-amidinobenzyl)oxy-3,4-di hydro-lH-l,4- benzodiazepine-25-dione trifluoracetate, l-isobytyl-4-(2-carboxyethyl)-7-(3-amϊdinobenzyl)oxy-3 _/ 4-dihydro-lH-l,4- benzodiazepine-25-dϊone trifluoracetate, l-cyclohexyI-4-(2-carboxyetlnyI)-7-(3-amidϊnobenzyI)oxy-3,4 -dihydro-lH-l,4- benzodϊazepine-25-dione trifluoracetate.

l-ethyl-4-(2-carboxyethyl)-7-(4-amidinobutyl)oxy-3,4-dihydro -lH-l,4-benzodiazepine- 2,5-dione trifluoracetate, l-isopropyl-4-(2-carboxyethyl)-7-(4-amidinobutyl)oxy-3,4-dih ydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-isobytyl-4-(2-carboxyethyI )-7-(4-a mid i nobu ty 1 )oxy-3,4-dihyd ro-lH-l,4-benzodiazepine- 2,5-dione trifluoracetate, l-cyclohexyl-4-(2-carboxyethyl)-7-(4-amidinobutyl)oxy-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate.

Example 27

l-(4-chlorobeιtzyl)-4-(2-carboxyethyl)-7-(4-aιuidinobe� �ιzyloxy)-3,4-dibydro-lH-l,4- benzodiazepine-2,5- ione trifluoroacetate.

a) To a stirred solution of 10.0 g (59.8 mmol) of 5-hydroxy-2-nitrobenzaldehyde and 12.3 g (62.8 mmol) of a-bromo-p-tolylnitrile in 50 ml of dry dimethyl-formamide was added 9.10 g (65.8 g) of anhydrous potassium carbonate. The mixture was warmed to 50 °C for 2 h and partitioned between water and ethyl acetate. The organic phase was washed with 1 N sodium bicarbonate, water, brine, and dried over anhydrous magnesium sulfate. Concentration gave 13.8 g (82°/.) of 5-(4-cyanobenzyloxy)-2-nitrobenzaldehyde. ² H NMR (300 MHz, d ⁶ -acetone) d 10.39 (IH, s, Ar-CHO), 8.23 (IH, d, J=9.0 Hz, O-Ar-H), 7.85 (2H, d, 1=8.3 Hz, NC-Ar-H2), 7.77 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.48 (IH, dd, ]=9.0, 2.9 Hz, O-Ar-H), 7.43 (IH, d, ]=2.9 Hz, O-Ar-H), 5.50 (2H, s, ArCH2θ).

b) Potassium permanganate (6.18 g, 39.1 mmol) was added in portions to a stirred solution of 13.8 g (48.9 mmol) of 5-(4-cyaιnobenzyloxy)-2-nitrobenzaIdehyde and 1.58 g (4.89 mmol) of tetrabutylammonium bromide in 70 nnL of pyridine. After 1 In, the solvent was removed in vacuo and the residue was partitioned between etinyl acetate and water. Sodium hydrogen

sulfite was added to destroy excess permanganate and the aqueous phase was separated and extracted with ethyl acetate. The combined organics were washed with 1 N sodium hydrogen sulfate, brine, dried over anhydrous magnesium sulfate, and concentrated to give 14.6 g of 5-(4-cyanobenzyloxy)-2-nitrobenzoϊc acid as a powder, used without further purification. H NMR (300 MHz, d ⁶ -acetone) d 8.07 (IH, d, J=8.8 Hz, O-Ar-H), 7.86 (2H, d, J=83 Hz, NC-Ar-H2), 7.78 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.39 (IH, d, J=2.9 Hz, O-Ar-H), 7.36 (IH, dd, J=8.8, 2.9 Hz, O-Ar-H), 5.48 (2H, s, A1CH2O)-

c) Oxalyl chloride (5.70 mL, 65.4 mmol) was added slowly to a rapidly stirred suspension of 14.6 g (48.9 mmol) of 5-(4-cyanobenzyloxy)-2-ni trobenzoic acid and 2 mL of dimethylformamide in 100 mL of benzene. When gas evolution ceased, the solution was heated briefly to 60 °C, concentrated in vacuo, and redissolved in 75 mL of tetrahydrofuran. This solution was added dropwise to a rapidly stirred suspension of 8.50 g (55.3 mmol) of b- alanine ethyl ester hydrochloride and 21.1 g(251 mmol) of sodium bicarbonate in 325 mL of 2:1 tetrahydrofuran /water at 0 °C. Tine mixture was warmed to ambient temperature for 12 h and the tetrahydrofuran was removed in vacuo. The residue was partitioned between ethyl acetate and 1 N sodium bicarbonate and the aqueous phase was separated and extracted with ethyl acetate. The combined organics were washed with 1 N sodium hydrogen sulfate, water, brine, dried over anhydrous magnesium sulfate, and concentrated to give 17.7 g (91%) of N-(5- (4-cyanobenzyloxy)-2-nitrobenzoyl)-b-alanine ethyl ester as a tan powder. ^H NMR (300 MHz, CDCI3) d 8.11 (IH, d, J=83 Hz, O-Ar-H), 7.71 (2H, d, J=83 Hz, NC-Ar-H2), 7.52 (2H, d, J=83 Hz, NC-Ar-H2), 7.01 (2H, m, O-Ar-H2), 6.50 (IH, bt, J=5.9 Hz, N-H), 5.21 (2H, s, ArCH2θ), 4.14 (2H, q, J=7.3 Hz, OCH2CH3), 3.69 (2H, bq, J=5.8 Hz, NCH2CH2), 2.70 (2H, t, 1=5.8 Hz, NCH2CH2), 1.26 (3H, t, J=73 Hz, OCH2CH3); Exact mass (FAB, M+H+) calcd for C20H20 N3O6: 398.1352; Found: 398.1343.

d) Tin(II) chloride (12.2 g, 64.4 mmol) was added to a solution of 5.12 g (12.9 mmol) of N-(5- (4-cyanobenzyloxy)-2-nitrobenzoyl)-b-aIanϊne etinyl ester in 40 mL of 1:1 ethyl acetate/ethanol and the mixture heated to 70 ^σ C for 15 min, cooled, and poured into a mixture of ice water, 1 N sodium bicarbonate, and etinyl acetate. 1 N sodium hydroxide was added carefully until a clear solution resulted and the aqueous phase was separated and extracted with ethyl acetate. The combined organics were washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated to give a dark solid that was purified by chromatography (silica gel-60, 1:1 etinyl acetate/hexane) to give 2.51 g (53%) of N-(5-(4- cyanobenzyIoxy)-2-amϊnobenzoyl)-b-alanϊne ethyl ester as a light yellow solid. ^X H NMR (300 MHz, CDCI3) d 7.67 (2H, d, J=8.3 Hz, NC-Ar-H2), 7.52 (2H, d, J=83 Hz, NC-Ar-H2), 6.94 (IH, d, J=2.9 Hz, O-Ar-H), 6.89 (IH, dd, J=2.9, 8.8 Hz, O-Ar-H), 6.78 (IH, b, N-H), 6.66 (IH, d, J=8.8 Hz, O-Ar-H), 5.04 (2H, s, ArCH2θ), 4.16 (2H, q, J 7.3 Hz, OCH2CH3), 3.66 (2H,

bq, J=5.8 Hz, NHCH2CH2), 2.62 (2H, t, J=5.8 Hz, NHCH2CH2), 1.27 (3H, t, J=73 Hz, OCH2CH3); Exact mass (FAB, M+H ⁺ ) calcd for C20H22 3O4: 368.1610; Found: 368.1603.

e) A solution of 1.03 g (2.80 mmol) of N-(5-(4-cyanobenzyloxy)-2-aminobenzoyI)-b-alanine ethyl ester, 394 mg (2.80 mmol) of p-chlorobenzaldehyde, and 20 mg of p-toluenesulfonic acid in 30 mL of toluene was heated at reflux through a Dean-Stark trap for 45 min. The solvent was removed in vacuo and the residue was dissolved in 15 mL of trifluoroacetic acid. Triethylsilane (1.34 mL, 8.40 mmol) was added and tine mixture was stirred at room temperature for 12 h, concentrated in vacuo, and partitioned between 1 N aqueous sodium bicarbonate and etinyl acetate. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. Chromatography (silica gel-60, 2:3 ethyl acetate/hexane) gave 820 mg (59%) of N-(5-(4-cyanobenzyloxy)-2-(4- chlorobenzylamino)benzoyl)-b-alanine etinyl ester as a colorless solid. -1H NMR (300 MHz, CDCI3) d 7.66 (2H, d, )=7.8 Hz, NC-Ar-H2), 7.51 (2H, d, J=7.8 Hz, NC-Ar-H2), 7.27 (4H, s, ClArH4), 6.98 (IH, d, J=2.0 Hz, O-Ar-H), 6.89 (1 H, dd, J=2.0, 9.3 Hz, O-Ar-H), 6.78 (IH, b, N- H), 6.66 (IH, d, ]=9.3 Hz, O-Ar-H), 5.03 (2H, s, ArCH2θ), 4.32 (2H, s, ClArCH2), 4.17 (2H, q, 1=7.3 Hz, OCH2CH3), 3.65 (2H, bq, J=5.7 Hz, NHCH2CH2), 2.62 (2H, t, 1=5.7 Hz, NHCH2CH2), 1.28 (3H, t, J=7.3 Hz, OCH2CH3); Exact mass (FAB, M+H ⁺ ) calcd for C27H27CIN3O4: 492.1690; Found: 492.1681.

f) To a rapidly stirred mixture of 820 mg (1.67 mmol) of N-(5-(4-cyanobenzyloxy) -2-(4- chlorobenzylamino)benzoyl)-b-alanine etinyl ester in 20 mL of 3:1 methylene chloride/water at ambient temperature was added 174 mL (2.1X) mmol) of bromoacetyl bromide via syringe. After 6 In, an additional 100 L (1.15 mmol) was added and the mixture stirred for 12 h. The aqueous phase was discarded and the organic layer washed witln 1 N aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in 5 L of imethylformamide, 1.08 g (3.33 mmol) of cesium carbonate was added, and the mixture warmed briefly to 60 °C and allowed to stir at ambient temperature for 12 h. The resulting suspension was partitioned between ethyl acetate and water and the organic phase was separated and washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. Chromatography (silica gel-60, 1:1 ethyl acetate/hexane) gave 574 mg (65%) of l-(4-chlorobenzyl)-4-(2-carboxyethyl)-7-(4- cyanobenzyloxy)-3,4-dihydro-lH-l ,4-benzodiazepine-2,5-dione etinyl ester as a colorless foam. 1H NMR (300 MHz, CDCI3) d 7.68 (2H, d, J=83 Hz, NC-Ar-H2), 7.51 (2H, d, J=83 Hz, NC-Ar-H2), 7.35 (IH, d, J=3.0 Hz, O-Ar-H), 7.24 (2H, d, J=9.7 Hz, ClArH2), 7.10 (IH, d, 1=8.8 Hz, O-Ar-H), 7.07 (2H, d, J=9.7 Hz, ClArH2), 7.01 (IH, dd, J=3.0, 8.8 Hz, O-Ar-H), 5.15 (IH, d, J=13.2 Hz, ArCHHO), 5.10 (I H, d, J=13.2 Hz, ArCHHO), 5.08 (IH, d, ]=15.6 Hz, ClArCH2), 5.91 (IH, d, J=15.6 Hz, ClArCH2), 4.14 (2H, q, J=7.3 Hz, OCH2CH3), 4.13 (IH, d, J=14.7 Hz, NCHHCON), 4.00 (I H, m, NCHHCH2), 3.89 (I H, d, J=14.7 Hz, NCHHCON), 3.88

(NCHHCH2), 2.68 (2H, m, NHCH2CH2), 1.26 (3H, t, J=73 Hz, OCH2CH3); Exact mass (FAB, M+H+) calcd for C29H27CIN3O5: 532.1639; Found: 532.1628.

g) Hydrogen sulfide gas was bubbled into a solution of 295 mg (0.555 mmol) of l-(4- chlorobenzyl)-4-(2-carboxyethyI)-7-(4-cyanobenzyloxy)-3,4-di hydro-lH-l,4- benzodiazepine-2,5-dϊone ethyl ester in 4 mL of 1:1 pyrϊdine/triethylamine for 15 min and the mixture was warmed in a 50 °C oil bath for 12 h. After evaporation of the solvent, the residue was taken up in 4 mL of 3:1 methylene chloride/methyl iodide and heated at reflux for 1 h. The solution was again concentrated and tine residue redissolved in 3 mL of methanol containing 0.5 g of ammonium acetate. The mixture was heated at 50 °C for 4 h, concentrated to a volume of 1 mL, and purified by reverse phase HPLC (Rainin Microsorb 1/2" C-18). The productwas eluted with a solvent gradient of 0:100 acetonitrile (0.1% trifluoroacetic acid) /water (0.1% trifluoroacetic acid) to 50:50 acetonitrile (0.1% trifluoroacetic acid)/water (0.1% trifluoroacetic acid), time 0 to 30 min, flow=12 ml/min, Rt=39.9 min, uv detection at 230 nM. Concentration of the clean fractions gave 215 mg (60%) of l-(4-chlorobenzyl)-4-(2- carboxyethyl)-7-(4-amidinobenzyIoxy)-3,4-dihydro-lH-l,4-benz odiazepine-2,5-dione ethyl ester trifluoroacetate as a colorless amorphous solid- 1H NMR (300 MHz, d^-acetone) d 8.60 (IH, b, NH), 7.95 (2H, d, J=8.3 Hz, HNC-Ar-H2), 7.73 (2H, d, J=83 Hz, HNC-Ar-H2), 7.40 (IH, d, 1=9.3 Hz, O-Ar-H), 7.32-7.16 (6H, m, O-Ar-H, ArH θ), 5.34 (IH, d, J=16.1 Hz, NCHHAr), 5.27 (2H, s, ArCH2θ), 4.94 (1 H, d, J=16.1 Hz, NCHHAr), 4.24 (IH, d, J=14.7 Hz, NCHHCON), 4.11 (2H, q, J=7.3 Hz, OCH2CH3), 4.04 (IH, m, NCHHCH2), 3.94 (IH, d, J=14.7 Hz, NCHHCON), 3.80 (IH, m, NCHHCH2), 2.68 (2H, bt, J=6.8 Hz, NCH2CH2), 1.22 (3H, t, J=7.3 Hz, OCH2CH3); Exact mass (FAB, M+H ⁺ ) calcd for C29H30CI N4O5: 549.1905; Found: 549.1912.

h) To a stirred, 0 °C solution of 104 mg (0.160 mmol) of l-(4-chlorobenzyI)-4-(2- carboxyethyI)-7-(4-amidinobenzyloxy)-3,4-dihydro-lH-l,4-benz odiazepine-2,5-dione ethyl ester trifluoroacetate in 1.5 mL of tetrahydrofuran was added 0.48 mL of 1 N aqueous sodium hydroxide and the mixture warmed to ambient temperature over 2 h. The reaction was acidified with 0.10 mL of acetic acid, concentrated in vacuo, and purified by reverse phase HPLC (Rainin Microsorb 1/2" C-18). The product was eluted with a solvent gradient of 0:100 acetonitrile (0.1% trifluoroacetic acid) /water (0.1% trifluoroacetic acid) to 50:50 acetonitrile (0.1% trifluoroacetic acid)/water (0.1% trifluoroacetic acid), time 0 to 30 min, flow=12 ml/min, Rf=29.1 min, uv detection at 230 nM. Lyophilization of the clean fractions gave 90.0 mg (90%) of l-(4-chlorobenzyl)-4-(2-carboxyethyI)-7-(4-amidinobenzyloxy) -3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione trifluoroacetate as a colorless powder. 1H NMR (300 MHz, d ⁶ -acetone) d 10.80 (IH, b, NH), 8.70 (IH, b, NH), 7.94 (2H, d, 1=8.8 Hz, HNC-Ar- H2), 7.71 (2H, d, J=8.8 Hz, HNC-Ar-H2), 7.41 (IH, d, J=8.8 Hz, O-Ar-H), 732-7.16 (6H, m, O- Ar-H, ArH4CI), 5.36 (IH, d, J=15.6 Hz, NCHHAr), 5.24 (2H, s, ArCH2θ), 4.92 (IH, d, J=15.6

Hz, NCHHAr), 4.23 (IH, d, J=14.7 Hz, NCHHCON), 4.03 (IH, m, NCHHCH2), 3.98 (IH, d, J=14.7 Hz, NCHHCON), 3.81 (IH, m, NCHHCH2), 2.71 (2H, bt, J=6.8 Hz, NCH2CH2); Exact mass (FAB, M+H+) calcd for C27H26CI N4O5: 521.1592; Found: 521.1581.

Example 28

1-(mcthyl)-4-(2-carboxycthyl)-7-(4-auιidinoμlιcnyl)etl ιynyl-3,4-dihydro-lH-l,4- benzodiazepm' e-2,5-dione trifluoracetate.

a) l-methyl-4-(2-carboxyethyl)-7-(4-amidinophenyl)ethynyl-3,4-d ihydro-lH-l,4- benzodiazepine-2,5-dione etinyl ester was prepared using the method employed in part (h) of example 19. Thus, from 0.242 grams of l-methyi-4-(2-carboxyethyl)-7-(4- cyanophenyI)ethynyl-3,4-dihydro-lH-l,4-benzodiazepine-2,5,di one ethyl ester was prepared 0.145 grams (56%) of l-methyl-4-(2-carboxyethyl)-7-(4-amidinophenyl)ethynyl- 3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester. The product was purified by reverse phase HPLC (Column: Dynamax 60A C18, Method: 30:70 acetonitrile (0.1% trifluoroacetic acid) /water (0.1% trifluoroacetic acid), time 0 to 10 min, 30:70 acetonitrile (0.1% trifluoroacetic acid) /water (0.1% trifluoroacetic acid) to 70:30 acetonitrile (0.1% trifluoroacetic acid)/water (0.1 % trifluoroacetic acid), time 10-40 min, 70:30 acetonitrile (0.1% trifluoroacetic acid)/water (0.1% trifluoroacetic acid), time 40-55min, flow=10 ml/min, R _t =28.9 min, uv detection at 254 nM). » H NMR (300 MHz, D2O) d 7.89 (IH, d, 3]HH=2Hz, C6-H), 7.80 (5H, m, C8-H, o,m-ArH), 7.46 (IH, d, 3JHH=9 Hz, C9-H), 4.17 (IH, d, ]=15Hz, C3-H), 4.06 (IH, dt, 2JHH=14Hz, 3JHH=7Hz, NCHHCH2CO2), 3.92 (IH, d, 1=15 Hz, C3-H), 3.77 (IH, dt, 2JHH=14Hz, 3JHH=7Hz, NCHHCH2CO2), 3.37 (3H, s, NCH3), 2.71 (2H, m, NCH2CH7CO2); Mass spectrum (FAB, M+H ⁺ ) calcd for C24H25N4O4: 433.2; Found: 431.2.

Using the above procedure, but substituting the appropriate 4-(2-carboxyethyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester for l-methyI-4-(2-carboxyethyl)-7-(4- cyanophenyl)ethynyI-3,4-dihydro-l H-l,4-benzodiazepine-2,5,dione ethyl ester there was prepared, for example, the following compounds:

l-methyl-4-(2-carboxyethyl)-7-(3-amidinophenyI)ethynyl-3,4-d ihydro-lH-l,4- benzodiazepine-2,5,dione ethyl ester l-ethyI-4-(2-carboxyethyl)-7-(4-amϊdinophenyl)ethynyl-3,4-d ihydro-lH-l,4- benzodiazepine-2,5,dione ethyl ester l-isopropyl-4-(2-carboxyethyl)-7-(4-amidinophenyl)ethynyl-3, 4-dihydro-lH-l,4- benzodiazepine-2,5,dione ethyl ester l-isobutyl-4-(2-carboxyethyI)-7-(4-amidinophenyl)ethynyl-3,4 -dihydro-lH-l,4- benzodiazepine-2,5,dione ethyl ester l-phenyl-4-(2-carboxyethyl)-7-(4-amidinophenyl)ethynyI-3,4-d ihydro-lH-l,4- benzodiazepine-2,5,dione ethyl ester

b) A magnetically stirred solution of l-methyl-4-(2-carboxyethyl)-7-(4- amidinophenyl)ethynyl-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5 -dϊone ethyl acetate (0.045 grams, 0.104 mmol) in 0.5mL methanol at room temperature was added 0.5mL 2N sodium hydroxide. After 30 mins, the reaction was quenched with lmL acetic acid, concentrated in vacuo, diluted in a minimum of a 1:3 methanokwater mixture and purified by HPLC (Column: Dynamax 60A C18, Method: 10-50% MeCN/H2O lOml/min. Detector: 254nm. Time(%MeCN): 0:00(10), 00:15(10,inj.,detect on), 10:00(10), 40:00(50), 55:00(50), 59:58(10, detect off), 60:00(off), Rf=32.3mϊn) to yield 27mgs of l-(methyI)-4-(2-carboxyethyI)-7-(4- amidinophenyl)ethynyl-3,4-dihydro-lH-l,4-benzodiazepinedϊon e-2,5,dϊone trifluoracetate- Exact mass (FAB, M+H ⁺ ) calcd for C22H22N O4: 405.1563, found: 405.1562 Using the above procedure, but substituting the appropriate 4-(2-carboxyethyl)-3,4- dihydro-lH-l,4-benzodiazepϊne-2,5-dione etinyl ester for l-methyl-4-(2-carboxyerhyl)-7-(4- amϊdinophenyI)ethynyl-3,4-dϊhydro-lH-l,4-benzodiazepine-2, 5,dione ethyl ester there was prepared, for example, the following compounds: l-methyI-4-(2-carboxyethyI)-7-(3-amϊdinophenyI)ethynyI-3,4- dihydro-IH-l,4- benzodiazepine-2,5,dione trifluoracetate l-ethyl-4-(2-carboxyethyI)-7-(4-amidinophenyl)ethynyl-3,4-di hydro-lH-l,4- benzodiazepine-2,5,dϊone trifluoracetate l-isopropyl-4-(2-carboxyethyI)-7-(4-amidϊnophenyI)ethynyl-3 ,4-dihydro-lH-l,4- benzodiazepine-2,5,dione trifluoracetate l-isobutyI-4-(2-carboxyethyl)-7-(4-amϊdϊnophenyl)ethynyl-3 ,4-dihydro-lH-l,4- benzodiazepϊne-2,5,dioιne trifluoracetate l-phenyl-4-(2-carboxyethyl)-7-(4-amidϊnophenyI)ethynyI-3,4- dihydro-lH-l,4- benzodϊazepine-2,5,dϊone trifluoracetate

Example 29

l-(4-c lorobenzyl)-4-(2-carboxιjctlιyI)-7-(4-aιnidinoμhcnyl)eth ynyl-3,4-dihydro-lH-l,4- benzodiazepine-2,5, dione trifluoracetate.

a) l-(4-chlorobenzyl)-4-(2-carboxyetlnyI)-7-(4-cyanophenyl)ethy nyl-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione etinyl ester was prepared using the method described in part (f) of example 1. Thus, from 0.265 grams (0.46mmol) of l-(4-chlorobenzyl)-4-(2-carboxyethyl)-7- iodo-3,4-dihydro-lH-l,4-benzodiazepinedione ethyl ester and 0.127 grams (4- cyanophenyl)ethyne was prepared 0.296 grams of l-(4-chlorobenzyl)-4-(2-carboxyethyl)-7- (4-cyanophenyl)etynyl-3,4-dihydro-lH-l,4-benzodiazepine-2,5- dione ethyl ester (99%, TLC, Siθ2, 1:1 ethyl acetate/hexane, Rf=0.38, uv positive). 1H NMR (CDCI3, dTMS) 7.99 (IH, d, ArH), 7.52 (IH, dd, 4j _{H H=} 2Hz, J _{H H} =8Hz, C8-H), 7.24 (2H, d, J _HH =8Hz, o-ArH NBn), 7.14 (IH, d, J _HH =8Hz, C9-H), 7.02 (2H, d, J _H H=8Hz, m-ArH NBn) 5.09 (IH, d, ² J _HH =15Hz, NCHHAr), 4.98 (IH, d, ² J _HH =l5Hz, NCHHAr), 4.12 (4H, m, OCH2, C3-H, NCHHCH2CO2), 3.95 (IH, d, 2j _HH= i5Hz, C3-H), 3.92 (IH, m, NCHHCH2CO2), 2.68 (2H, m, CH2C02), 1.24 (3H, t, J _H H=7Hz, CH3)

b) l-(4-chlorobenzyl)-4-(2-carboxyethyl)-7-(4- midinoplnenyl)etynyl-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester was prepared using the method described in part (h) of example 19. Thus, from 0.15 grams (0.286mmol) of l-(4-chlorobenzyl)-4-(2-carboxyethyl)-7- (4-cyanophenyl)etynyl-3,4-dihydro-lH-l,4-benzodiazepinedione ethyl ester was prepared 0.03 grams (20%) of 1-(4-chlorobenzyl)-4-(2-carboxyethyI)-7-(4-amidinophenyl)ety nyl-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester purified by HPLC (30-70% MeOH/H20 lOml/min. Detector: 254nm. Time(%MeOH): 0:00(30), 00:15(30,inj.,detect on), 10:00(30), 40:00(70), 55:00(70), 59:58(30, detect off), 60:00(off), Rf=38.0min). H NMR (CDCI3, dTMS) 7.99 (IH, d, ⁴ j _{H H} =2Hz, C6-H), 7.74 (2H, d, ³ JHH=8Hz, ArH), 7.63 (2H, d,

C8-H), 7.26 (2H, d, o- ArH NBn), 7.16 (lH d, ³ JHH=8HZ, C9-H), 7.07 (2H, d, m-ArH NBn) 5.10 (IH, d, ² JHH=16Hz, NCHHAr), 4.98 (IH, d, ² J _HH =l6Hz, NCHHAr), 4.13 (4H, m, OCH2, C3-H, NCHHCH2CO2), 3.95 (2H, m, C3-H, NCHHCH2CO2), 2.68 (2H, m, CH2CO2), 1.25 (3H, t, ³ JHH=7Hz, CH3)

c) l-(4-chlorobenzyl)-4-(2-carboxyethyI)-7-(4-amidinophenyl)ety nyl-3,4-dihydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoracetate was prepared using the method described in part (b) of example 27. Thus, 30mgs of l-(4-chlorobenzyl)-4-(2-carboxyethyI)-7-(4- amidinophenyl)etynyl-3,4-dihydro-lH-l,4-benzodiazepinedione ethyl ester was saponified to yield 20mgs of l-{4-chlorobenzyl)-4-(2-carboxyethyl)-7-(4-amidinophenyl)ety nyl-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate purified by HPLC (Column: Dynamax 60A C18, Method: 10-50% MeCN/H2O lOml/min. Detector: 254nm. Time(%MeCN): 0:00(10), 00:15(10,ϊni.,detect on), 10:00(10), 40:00(50), 55:00(50), 59:58(10, detect off), 60:00(off), Rf=383mm). 'H NMR (D2O) 7.25 (6H, m, C6-H, ArH, C8-H), 6.98 (IH, d, o-ArH NBn), 6.57 (2H, d, m-ArH NBn) 4.92 (IH, d, ² JHH=16Hz, NCHHAr), NCHHAr overlaps with HOD, 3.70 (IH, d, 2j _HH= i5Hz, C3-H), 354 (IH, m, NCHHCH2CO2), 3.43 (IH, d, J _HH =l5Hz, C3-H), 3.30 (IH, m, NCHHCH2CO2), 2.59 (2H, m, CH2CO2). Exact mass (FAB, M+H ⁺ ) calcd for C28H24N4O4CI 515.1514, found: 515.1486

Example 30

l-phenyl-4-(2-carboxyethyl)-7-(5-guaιtidinoμcntyl)-3,4- dihydro-lH-l,4-benzodiazepine-

2,5-dione trifluoracetate.

a) A solution of 2-chloro-5-nϊtrobenzoic acid (5,24 grams, 0.026mol), aniline (0.166mol, 15.5 grams), potassium carbonate (4.1 grams) and 0.1 grams copper oxide is heated refluxed for 2 hrs. The reaction mixture was allowed to cool to room temperature and diluted with water (lOOmL), and extracted with lX50mL ether. The aqueous layer was made acidic by the

addition of cone. HCl and the mixture extracted 3X50mL ethyl acetate. The combined organics were dried over magnesium sulphate, filtered and concentrated in vacuo. The resulting residue, N-phenyl-5-nitroanthranilic acid (0.8 grams, 12%), was used without further purification. 1H NMR (D2O, CD3OD) 8.84 (IH, d, C6-H), 8.15 (IH, dd, 2j _HH= 2H _2/ ³ JHH=8HZ, C4-H), 7.42 (2H, d, -NPh-H), 7.31 (3H, m,ø,r NPh-H), 7.15 (IH, d, ³ JHH=8Hz, C3-H).

Using the above method, but substituting the appropriate substituted aniline for aniline there may be prepared, for example, the following compounds:

N-(4-methoxy)phenyl-5-nitroanthranilic acid, N-(4-chloro)phenyl-5-nitroanthranilic acid, N-(3-trifluromethyl)phenyl-5-nitroanthranilic acid.

b) To a solution of N-phenyl-5-nitroanthranilic acid (0.8 grams, 3.1mmoI), in lOmL methylene chloride and two drops dimethylformamide was added oxalyl chloride (0.3mL, 3.4mmol), and the reaction stirred for 30 mins. The mixture was concentrated in vacuo, diluted with 15mL methylene chloride cooled to 0°C and allowed to react witln b-alanine ethyl ester

(3.4mmol, 0.522grams) and triethylamine (3.5mmol, 0.49mL). After 1 hour, the reaction was concentrated in vacuo and the resulting residue purified by column chromatography on Si02 using 25% ethyl acetate in hexane to 40% etinyl acetate in hexane (TLC, 1:2 ethyl acetate/hexane Rf=0.31, uv positive) to yield 1 gram (90%) of N-(N-phenyl-5- nitroanthranoyl)-b-alanine ethyl ester. *H NMR (CDCI3, dTMS) 10.38 (IH, bs, CO2H), 8.40 (IH, d, C4-H anthranoyl), 7.41 (2H, t, ³ J _H H=8Hz, m-NPh-H), 7.24 (3H, m, o,p-NPh-H), 7.15 (IH, d, ³ ] _HH =9Hz, C3-H anthranoyl), 7.10 (IH, bt, ³ J _H H=5Hz, C(O)NH), 4.21 (2H, q, J _H H=7Hz, OCH2), 3.75 (2H, q, ³ J _H H=6Hz, NCH2CH2CO2), 2.71 (2H, t, J _H H=6Hz, CH2CO2), 131 (3H, t, CH3); ¹³ C NMR (CDCI3, dTMS) 172.5, 167.9, 151.9, 138.7, 137.1, 129.7, 128.1, 125.5, 124.6, 123.6, 114.8, 113.2, 61.1, 35.5, 33.7, 14.2.

Using the above method, but substituting the appropriate substituted N-aryl-5- nitroanthranilic acid for N-phenyl-5-nitroanthranilic acid there may be prepared, for example, the following compounds: N-(N-(4-methoxy)phenyl-5-nitroanthranoyl)-b-alanine etinyl ester, N-(N-(4- chloro)phenyl-5-nitroanthranoyl)-b-alanine ethyl ester, N-(N-(4-trifluromethyl)phenyl-5- nitroanthranoyl)-b-alanine ethyl ester.

c) A solution of 0.8 grams (2.3mmoI) of N-(N-phenyl-5-nitroanthranoyl)-b-alanine ethyl ester in 5mL ethanol, 2.5nnL IN HCl, and 0.1 grams 10% palladium on carbon was placed under an atmosphere of hydrogen and stirred for 2 hrs. The mixture was filtered through Celite® washing witln ethanol water mixture. The filtrate was concentrated in vacuo and the resulting residue diluted witln lOmL water. The mixture was cooled to 0°C and allowed to react witln sodium nitrite (158mgs, 2.3mmol) dissolved in lmL water. After 2 hrs potassium

iodide (2.3 grams) in 3mL water was added and the reaction warmed to 50°C for 05 hrs. The cooled mixture was diluted with sat sodium bicarbonate and extracted 3X50mL ethyl acetate. The combined organics were dried over magnesium suphate, filtered, concentrated in vacuo. and chromatographed on SiO2, using 20% etinyl acetate in hexane to 60% ethyl acetate and hexane (TLC, 25%ethyl acetate/hexane, Rf=0.52 uv positive) to give 0.18 grams (18%) of N- (N ² -phenyl-5-iodoanthranoyl)-b-alanine ethyl ester. *H NMR (CDCI3, dTMS) 9.31 (IH, bs, NH), 7.66 (IH, d, C4-H anthranoyl), 7.32 (2H, m, NPh-H), 7.17 (2H, m, NPIn-H), 7.10 (IH, d, C3-H anthranoyl), 7.04 (IH, m, NPh-H), 6.85 (IH, bt, C(O)NH), 4.20 (2H, q, NCH2CH2CO2), 2.65 (2H, t, ³ JHH=6HZ,

CH2CO2), 1.29 (3H, t, CH3); ¹³ C NMR (CDCI3, dTMS) 172.7, 168.0, 151.2, 140.7, 140.5, 135.9, 129.4, 123.0, 121.2, 120.2, 117.2, 77.9, 60.9, 353, 33.9, 14.2.

Using the above method, but substituting the appropriate substituted N-(N-aryl-5- nitroanthranoyl)-b-alanϊne etinyl ester for N-(N-phenyl-5-nϊtroanthranoyl)-b-alanine ethyl ester there may be prepared, for example, the following compounds:

N-(N-(4-methoxy)phenyl-5-iodoanthranoyI)-b-alanine etinyl ester, N-(N-(4- chloro)phenyl-5-iodoanthranoyI)-b-alanine etinyl ester, N-(N-(4-trifluromethyl)phenyl-5- ϊodoanthranoyI)-b-alanine etinyl ester.

d) To a magnetically stirred biphasic mixture of N-(N-phenyl-5-iodoanthranoyI)-b-alanine ethyl ester (180mgs, 0-41mmol), lOmL methylene chloride, lOmL water was added bromoacetyl bromide (0.054mL, 0.45mmol). After 2 hrs, the layers were separated. The organic layer was dried over sodium sulphate, decanted, and concentrated in vacuo. The resulting residue was dissolved in dimethylformamide (3mL) and cesium carbonate (2.5 molar excess, l.OmmoI) added. After 30 mins, the mixture was diluted with 75mL water and extracted witln 3X50mL etinyl acetate. The combined organics were dried over sodium sulphate, decanted, and concentrated in vacuo- The resulting residue was further purified by column chromatography on SIO2, using 35% ethyl acetate in hexane to 65% ethyl acetate and hexane to yield 0.142 grams (72%) of l-phenyl-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-lH- l,4-benzodiazepϊne-25-dϊone etinyl ester (TLC, 1:1 ethyl acetate/hexane, Rf=0.29, uv positive). *H NMR (CDCI3, dTMS) 8.20 (IH, d, ⁴ J _HH =2Hz, C6-H), 7.60 (IH, dd, ² J _HH =2Hz, 3j _HH= 8Hz, C8-H), 7.38 (3H, m, NPh-H), 7.20 (2H, m, NPh-H), 6.53 (IH, d, ³ JHH=9Hz, C9- H), 4.21 (IH, d, 2JHH=15Hz, C3-H), 4.11 (2H, q, j _H H=7Hz, OCH2), 4.01 (IH, d, 2JHH=15Hz, C3-H), 3.95 (2H, t, ³ J _HH =7Hz, NCH2CH2CO2), 2.72 (2H, m, CH2CO2), 1.24 (3H, t, ³ J _H H=7Hz, CH3); ¹³ C NMR (CDCI3, dTMS) 171.2, 167.2, 165.6, 140.7, 140.5, 139.8, 139.3, 130.7, 129.5, 128.1, 128.0, 126.1, 89.9, 60.8, 52.6, 45.2, 32.6, 14.1.

Using the above method, but substituting the appropriate substituted N-aryl-5- iodoanthranilic acid for N-(N-phenyl-5-iodoanthranoyl)-b-alanine ethyl ester there may be prepared, for example, the following compounds:

l-(4-methoxy)phenyl-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione ethyl ester, l-(4-chloro)phenyl-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-lH- l,4- benzodiazepine-2,5-dione etinyl ester, l-(4-trifluromethyl)phenyl-4-(2-carboxyethyl)-7- iodo-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione etinyl ester.

e) l-phenyl-4-(2-carboxyethy])-7-(N-Boc-5-amino-l-pentynyl)-3,4 -dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester was prepared using the method described in part (f) of example 1. Thus, 71mgs of l-phenyl-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-lH-l,4- benzodiazepinedione-2,5,dione etinyl ester and 30mgs of N-Boc-5-amino-l-pentyne yielded 61mgs (76%) of l-phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-amino-l-pentynyI)-3,4 -dihydro- lH-l,4-benzodiazepine-2,5-dione ethyl ester. ^] H NMR (CDCI3, dTMS) 7.90 (IH, d, C9-H), 4.72 (IH, bs, NH), 4.21 (IH, d, 2JHH=15Hz, C3-H), 4.11 (2H, q, J _{H H} -.7Hz, OCH2), 4.00 (IH, d, 2j _HH= i5Hz, C3-H), 3.96 (2H, t, ³ J _H H=7Hz, NCH2CH2CO2), 3.25 (2H, bq, ³ jHH=7Hz, CH2NH), 2.72 (2H, , CH2CO2), 2.44 (2H, t, J _H H=7Hz, CCCH2), 1.76 (2H, p, ³ JHH=7HZ, CH2CH2CH2), 1.43 (9H, s, C(CH3)3), 1.23 (3H, t, j _H H=7Hz, CH3); ¹³ C NMR (CDCI3, dTMS) 1713, 167.3, 166.4, 155.9, 140.0, 139.7, 134.5, 133.8, 129.4, 129.1, 128.1, 127.9, 124.3, 121.7, 90.0, 79.5, 60.8, 52.6, 45.1, 39.7, 32.7, 28.7, 28.4, 16.9, 14.1.

Using the above procedure, but substituting the appropriate l-aryl-4-(2- carboxyethyl)-7-iodo-3,4-dihydro-l H-l,4-benzodiazepinedione-2,5,dione etinyl ester for 1- phenyl-4-(2-carboxyethyl)-7-iodo-3,4-dihydro-lH-l,4-benzodia zepinedione-2,5,dione ethyl ester and amino or cyano alkyne for N-Boc-5-amino-l-pentyne there may be prepared, for example, the following compounds: l-(4-methoxy)phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-amino-l-pe ntynyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5- ione ethyl ester, l-(4-chloro)phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-amino-l -pentynyI)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione ethyl ester , l-(3-triflurophenyl)phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-ami no-l-pentynyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione ethyl ester l-(4-methoxy)phenyl-4-(2-carboxyethyI)-7-(N-Boc-6-amino-l-he xynyl)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione ethyl ester, l-(4-chloro)phenyl-4-(2-carboxyetlnyl)-7-(N-Boc-6-amino-l-he xynyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester , l-(3-triflurophenyl)phenyl-4-(2-carboxyethyl)-7-(N-Boc-6-ami no-l-hexyny])-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione ethyl ester l-(4-methoxy)phenyl-4-(2-carboxyethyl)-7-(4-cyanophenyl)ethy nyl-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione etinyl ester, l-(4-chloro)phenyl-4-(2-carboxyethyl)-7-(4-cyanophenyl)ethyn yl-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester ,

l-(3-triflurophenyl)phenyl-4-(2-carboxyethyl)-7-(4-cyanophen yl)ethynyl-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione ethyl ester

f) Using the method described in part (a) of example 3 l-phenyl-4-(2-carboxyethyl)-7-(N- Boc-5-aminopeπtyl)-3,4-dihydro-lH-l,4-benzodiazepinedione-2 ,5,dione ethyl ester was prepared from l-phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-amino-l-pentynyl)-3,4 -dihydro- lH-l,4-benzodiazepine-2,5-dϊone etinyl ester in quantitative yield. 1H NMR (CDCI3, dTMS) 7.67 (IH, d, C8-H), 6.70 (IH, d, ³ JHH=8HZ, C9-H), 4.55 (IH, bs, NH), 4.24 (IH, d, 2JHH=15Hz, C3-H), 4.11 (2H, q, ³ jHH=7Hz, OCH2), 3.97 (2H, m, C3-H, NCH2CH2CO2), 3.10 (2H, bq,

³ JHH=7Hz, CH2NH), 2.72 (2H, m, CH2CO2), 2.60 (2H, t, ³ jHH=7Hz, ArCH^), 1.62 (2H, p, ³ JHH^7Hz), 1.47 (2H, p, ³ J _H H=7Hz), 1.41 (9H, s, C(CH ₃ ) ₃ ), 1.34 (2H, m), 1.23 (3H, t, ³ J _HH =7Hz, CH3); ¹³ C NMR (CDCI3, dTMS) 171.3, 167.6, 167.2, 155.9, 140.4, 140.3, 138.6, 132.0, 130.1, 129.3, 128.9, 128.1, 127.6, 124.3, 60.7, 52.7, 45.1, 40.4, 34.9, 32.7, 30.6, 29.9, 28.4, 26.4, 14.1.

Using the above procedure, but substituting the appropriate l-aryl-4-(2- carboxyethyl)-7-alkynyl-3,4-dihydro-lH-l,4-benzodiazepinedio ne-2,5,dione ethyl ester for l-phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-amino-l-pentynyf)-3,4 -dihydro-lH-l _/ 4- benzodiazepine-2,5-dione etinyl ester there may be prepared, for example, the following compounds: l-(4-methoxy)phenyI-4-(2-carboxyethyI)-7-(N-Boc-5-amino-l-pe ntyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione etinyl ester, l-(4-chloro)phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-amino-l-pen tyI)-3,4-dϊhydro-lH-l,4- benzodiazepϊne-2,5-dione ethyl ester , l-(3-triflurophenyl)phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-ami no-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione etinyl ester l-(4-methoxy)phenyl-4-(2-carboxyethyl)-7-(N-Boc-6-amino-l-he xyI)-3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dione ethyl ester, l-(4-chloro)phenyI-4-(2-carboxyethyl)-7-(N-Boc-6-amino-l-hex yI)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione etinyl ester , l-(3-triflurαphenyI)phenyl-4-(2-carboxyethyI)-7-(N-Boc-6-am ino-l-hexyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione etinyl ester

g) To a solution of 13.3mgs (0.025mmol) l-phenyI-4-(2-carboxyethyl)-7-(N-Boc-5- amϊnopentyl)-3,4-dihydro-lH-l,4-benzodiazepϊne-2,5-dione ethyl ester in lmL ethyl acetate and 0.5mL triethylsilane was added 2mL sat. solution of HCl in ethyl acetate. After 30 mins, the reaction mixture was concentrated in vacuo , diluted in a minimum of THF and 18mL of a 30% by weight hydrogen peroxide. n equivalent of lithium hydroxide was added and the reaction stirred for 1 hrs. The reaction was quenched with sodium sufite and

concentrated to yield a residue, which was diluted in a methanol water mixture and purified by HPLC (10-50% MeCN/H20 lOml/min. Detector: 254nm. Time(%MeCN): 0:00(10), 00:15(10,inj.,detect on), 10:00(10), 40:00(50), 55:00(50), 59:58(10, detect off), 60:00(off), Rf=33.5min) to yield l-phenyl-4-(2-carboxyethyI)-7-(5-amino-l-pentyl)-3,4-dihydro -lH- l,4-benzodiazepine-25-dione (6mgs). 1H NMR (CDC13, dTMS) 7.12 (IH, bs, C6-H), 6.97 (3H, m, m,p-NPh-H), 6.79 (IH, bd, ³ JHH=8Hz, C8-H), 6.74 (2H, d, ³ JHH=8Hz, o-NPh-H), 6.36 (IH, d, ³ JHH=8Hz, C9-H), 3.89 (IH, d, ² JHH=15Hz, C3-H), 3.74 (IH, dt, ² JHH=14Hz, ³ JHH=7Hz, NCHHCH2C02), 3.47 (IH, d, ² JHH=15Hz, C3-H), 3.21 (IH, dt, ² JHH=14Hz, ³ JHH=7Hz, NCHHCH2CO2), 2.43 (2H, t, ³ JHH=7Hz, CH2NH2), 2.25 (2H, m, CH2CO2), 2.15 (2H, t, ³ JHH=7Hz, ArCH2), 1.12 (4H, m,), 0.83 (2H, m)

Using the above procedure, but substituting the appropriate l-aryl-4-(2- carboxyethyI)-7-alkynyl-3,4-dihydro-lH-l,4-benzodiazepinedio ne-2,5,dione ethyl ester for l-phenyl-4-(2-carboxyethyI)-7-(N-Boc-5-amino-l-pentynyl)-3,4 -dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-(4-methoxy)phenyl-4-(2-carboxyethyI)-7-(N-Boc-5-amino-l-pe ntyl)-3,4<Iihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(4-chIoro)phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-amino-l-pen tyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione etinyl ester , l-(3-triflurophenyl)phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-ami no-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione ethyl ester l-(4-methoxy)phenyl-4-(2-carboxyethyl)-7-(N-Boc-6-amino-l -hexyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester, l-(4-chloro)phenyl-4-(2-carboxyetlnyl)-7-(N-Boc-6-annino-l-h exyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione etinyl ester , l-(3-triflurophenyl)phenyl-4-(2-carboxyethyl)-7-(N-Boc-6-ami no-l-hexyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione etinyl ester

h) 6mgs of l-phenyl-4-(2-carboxyethyI)-7-(5-amino-l-pentyI)-3,4-dihydro -lH-l,4- benzodiazepine-2,5,dione was dissolved in sat 5% potassium carbonate and an excess of formamidine sulphonic acid (15mgs). After 30mins, the reaction was quenched with acetic acid , concentrated in vacuo, diluted in a minimum of a water/methanol mixture and purified by HPLC (Column: Dynamax 60A C18, Method: 10-50% MeCN/H2O lOml/min. Detector: 254nm. Time(%MeCN): 0:00(10), 00:l5(10,inj.,detect on), 10:00(10), 40:00(50), 55:00(50), 59:58(10, detect off), 60:00(of f), Rf=37.1 min). ^] H NMR (D20) 7.08 (IH, bs, ArH C6-H), 6.93 (3H, m), 6.63 (IH, bd, J _H H=4Hz), 6.21 (2H, d, J _H H=«Hz), 3.79 (IH, d, ² JHH=15HZ, C3-H), 3.74 (IH, dt, 2j _{H H=} i4Hz, ³ J _H H=7Hz, NCHHCH2CO2), 3.42 (IH, d, ² J _HH =l5Hz, C3-H), 3.19 (IH, dt, CH2NH),

223 (2H, m, CH2CO2), 2.12 (2H, bt, ³ JHH=7Hz), 1.02 (4Hz, m), 0.79 (2H, m) Exact mass (FAB, M+H ⁺ ) calculated for C24H30N5O4; 452.2298, found 452.2270.

Using the above procedure, but substituting the appropriate l-aryl-4-(2- carboxyethyl)-7-alkyl-3,4-dihydro-lH-l,4-benzodiazepϊnedion e-2,5,dione ethyl ester for 1- phenyl-4-(2-carboxyethyl)-7-(N-Boc-5-amino-l -pentyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione ethyl ester there may be prepared, for example, the following compounds: l-(4-methoxy)phenyl-4-(2-carboxyethyl)-7-(5-amino-l-pentyl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-(4-chloro)phenyl-4-(2-carboxyethyl)-7-(5-amϊno-l-pentyl)- 3,4-dϊhydro-lH-l,4- benzodiazepϊne-2,5-dione trifluoracetate , l-(3-trϊflurophenyl)phenyl-4-(2-carboxyethyl)-7-(5-amino-l- pentyl)-3,4-dihydro-lH-l,4- benzodϊazepine-2,5-dione trifluoracetate l-(4-methoxy)phenyl-4-(2-carboxyethyl)-7-(6-amϊno-l-hexyl)- 3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate, l-(4-chloro)phenyI-4-(2-carboxyethyl)-7-(6-amino-l-hexyI)-3, 4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate , l-(3-triflurophenyl)phenyl-4-(2-carboxyethyI)-7-(6-amino-l-h exyl)-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dϊone trifluoracetate

Example 31

(±l-l-uιethyl-4-(2-carboxy-2-methylethyl)-7-(6-amino-i- hexyl)-3,4-dihydro-tH.-l,4- benzodiazeμiιte-2,5-dioπe trifluoracetate.

a) In a IL beaker was placed 40 grams (0.267mmol) of N-methylanthranilic acid dissolved in 300mL water and 26.7mL cone. HCl cooled to 20°C A solution of ICL, prepared by dissolving 44grams of ICl to a cooled (0°C) solution of 167mL water and 45ml cone. HCl, was rapidly added to the stirred N-methylanthranilc acid solution. The reaction was allowed to stir for 2hrs, filtered on a medium glass frit funnek washing the solids with water. The green powder isolated was dried under vacuum to yield 70 grams (96%) of 5-iodo-N- methylanthranϊlic acid. ^l H NMR (DMSO-d6) 7.61 (IH, bs, C6-H), 7.21 (IH, bd,

C4-H), 6.19 (IH, d, C3-H), 2.43 (3H, s, NCH3); ¹³ C NMR (DMSO-dβ) 169.0, 151.4, 142.7, 139.6, 114.2, 112.7, 74.2, 29.6.

b) To a mechanically stirred solution of 5-iodo-N-methylanthranilic acid (40 grams 0.144 mol), potassium carbonate (19.95 grams, 0.144mol), and 500ml water at 0°C was added phosgene (1.93M solution in toluene, 0.2mol, 104mL) over a period of lhr. the resulting slurry was stirred for an additional 3 hrs and the solids isolated by filtration, washing with water, and a small amount (70mL) of ether. The solids were dried overnight in vacuo to yield 34 grams (78%) of 5-iodo-N-methyIisatoic anhydride. 1H NMR (DMSO-dό) 8.18 (IH, bs, C6- H), 8.08 (IH, bd, C4-H), 7.12 (IH, d, C3-H), 3.42 (3H, s, NCH3).

c) A solution of (+)-3-amino-2-methylpropionic acid (1.9 grams, 18.77mmol), p- toluenesulphonic acid, in 50mL methanol was heated to reflux for 62hrs. the reaction was allowed to cool to room temperature, concentrated in vacuo to yield an oil. 1/2 by volume of this oil was dissolved in 10 L dimethylformamide and allowed to react with 5-iodo-N- methylisatoic anhydride (2.5 grams, 8.4mmol) and 7.0mL triethylamine (5-fold excess) and a catalytic amount of dimethylaminopyridine (50mgs). the reaction was heated to 50°C for lhr. The reaction was allowed to cool to room temperature, diluted with lOOmL water and extracted 3X50mL etinyl acetate. The combined organics were dried over sodium sulphate, decanted, and concentrated in vacuo. The resulting residue was further purified by column chromatography (Siθ2, 25%ethyl acetate in hexane to 50% ethyl acetate and hexane) to yield 1.5 grams (47%) of (±)-N-(N2-methyl-2-amino-5-iodobenzoyl)-3-amino-2- methylproprionate methyl ester. 'H NMR (CDCI3, dTMS) 7.50 (IH, d, ⁴ ] _HH =2Hz, C6-H), 7.43 (IH, dd, C3-H), 3.64 (3H, s, OCH3), 3.51 (IH, ddd, ² j _H

NHCHHCH), 3.40 (I H, ddd, 2j _H NHCHHCH), 2.75 (4H, m, CHCO2, NCH3), 1.15 (3H, d, ³ J =7Hz, CHCH ); ¹³ C NMR 175.9, 168.7, 149.9, 141.0, 135.7, 117.6, 113.4, 74.2, 52.1, 42.1, 39.6, 29.7, 15.1

d) To a biphasic mixture of (±)-N-(N-methyl-2-amino-5-iodobenzoyl)-3-amino-2- methylpropionate methyl ester (2.0mmol, 0.752grams), 8mL methylene chloride, and 8mL water was added bromoacetylbromide (0.174nnL, 1.5 molar equivalents) and the reaction stirred for 2hrs. The layers were separated and the organics were dried over sodium sulphate, decanted, and concentrated in vacuo. The resulting residue was diluted in lOmL dimetlnylformamide and a 3-fold excess of cesium carbonate (6.0mmol, 1.95 grams). After 30 mins the mixture was diluted with 75nnL water and extracted 2X50mL ethyl acetate. The combined organics were dried over magnesium sulphate, filtered, and concentrated in vacuo. The resulting residue was further purified by column chromatography (Si02, 50% ethyl acetate/hexane to 70% ethyl acetate/hexane, TLC, Rf=0.21, uv positive) to yield (±)-l-

methyl-4-(2-carboxy-2-methylethyl)-7-iodo-3,4-dϊhydro-lH-l, 4-benzodiazepine-2,5-dione methyl ester (05 grams, 61%, mp=138-140°C). ¹ H NMR (CDCI3, dTMS) 8.13 (IH, d, ⁴ JHH=2Hz, C6-H), 7.79 (IH, dd, ⁴ J _H H=2Hz, j _H H=9Hz, C8-H), 6.92 (IH, d, ³ jHH=9Hz, C9- H), 3.80 (7H,s, NCH2CHCO2, C3-H, OCH3), 3.34 (3H, two s, NCH3, diastereotopic resonances are observed), 1.19 (1.5H, d, ³ jHH=7Hz, CHCH3), 1.16 (1.5H, d, ³ jHH=7Hz, CHCH3).

e) (±)-l-methyl-4-(2-carboxy-2-methylethyl)-7-(N-Boc-5-amino-l -hexynyI)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione methyl ester was prepared using the method described in part (f) of example 1. Thus, 0.15 grams (036mmol) of (±)-l-methyl-4-(2-carboxy-2- methyIethyl)-7-ϊodo-3 _; 4-dihydro-lH-l,4-benzodiazepinedione-2,5,dione methyl ester and 0.11 grams (054mmol) of N-Boc-6-amino-l-hexyne yielded 0.164 grams (94%) of (±)-l- methyl-4-(2-carboxy-2-methylethyl)-7-(N-Boc-5-amino-l-hexyny l)-3,4-dihydro-lH-l,4- benzodiazepine-25-dione methyl ester (TLC, 1:1 ethyl acetate/hexane, Rf=0.23). 1H NMR (CDCI3, dTMS) 7.79 (IH, d, ³ JHH=8HZ, C8-H), 7.06 (IH, d, ³ JHH=8Hz, C9-H), 4.67 (IH, bs, NHBoc), 4.04 (0.5H, d, ² ] _HH =15Hz, C3-H), 3.94 (05H, d, C3-H), 3.73 (2.5H, m, NCH2CH, C3-H), 3.66 (15H, s, OCH3), 3.59 (1.5H, s, OCH3), 3.30 (3H, bs, NCH3), 3.10 (2H, bq, CH ₂ NH), 2.93 (IH, m, CHCO2), 2.38 (2H, bt, J _H H=7Hz, CCCH2), 158 (4H, m), 1.38 (9H, s, C(CH3)3), 1.14 (1.5H, d, CHCH3), 1.11 (1.5H, d, CHCH3); ¹³ C NMR 175.1, 174.6, 168.7, 166.9, 156.1, 139.9, 134.9, 134.0, 128.7, 121.8, 120.9, 91.5, 79.3, 79.1, 52.5, 52.1, 52.0, 515, 402, 38.5, 38.4, 34.9, 34.8, 29.4, 28.5, 25.8, 19.2, 16.1, 14.6.

f) (±)-l-methyi-4-(2-carboxy-2-methvlethyI)-7-(N-Boc-5-amino-l -hexyI)-3,4-dihydro-lH- l,4-benzodiazepine-2,5-dione methyl ester was prepared using the method described in part (a) of example 3. Thus, 0.085 grams (0.17mmol) of (+)-l-methyI-4-(2-carboxy-2- methylethyl)-7-iodo-3,4-dilnydro-lH-l,4-benzodiazepinedione- 2,5,dione methyl ester yielded 0.081 grams (95%) of (±)-l-methyI-4-(2τcarboxy-2-methylethyl)-7-(N-Boc-5-amino- l-hexyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dϊone methyl ester (TLC, 3:1 ethyl acetate/hexane, C6-H), 7.27 (IH, dd, C9-H), 4.60 (IH, bs, NHBoc), 4.07 (0.5H, d, ² j _HH= χ5H _z , C3-H), 3.98 (0.5H, d, ² J _HH =i5Hz, C3-H), 3.97 (0.5H, d, ² JHH=15Hz, C3-H), 3.75 (2.5H, m, NCH2CH, C3-H), 3.67 (1.5H, s, OCH3), 3.60 (1.5H, s, OCH3),3.33 (3H, two s, NCH3), 3.06 (2H, bq, CH2NH), 2.95 (IH, m, CHCO2), 2.58 (2H, bt, ³ JHH=7Hz, ArCH2), 1.59 (2H, m), 1.40 (11H, m, C(CH3)3), 1.30 (4H, m), 1.15 (1.5H, d,

³ JHH=7Hz, CHCH3), 1.13 (1.5H, d, j _H H=7Hz, CHCH3); ¹³ C NMR 174.9, 174.5, 168.8, 167.4, 155.9, 140.2, 138.6, 132.1, 130.1, 128.2, 120.7, 78.8, 52.4, 52.0, 51.9, 51.2, 40.3, 38.4, 34.8, 34.7, 30.8, 29.8, 28.7, 283, 26.4, 14.9, 14.4.

g) (±l-l-methyI-4-(2-carboxy-2-methylethyI)-7-(6-amino-l-hexyl )-3,4-dihydro-lH-l,4- benzodiazepine-2,5-dione trifluoracetate was prepared using the method described in part (g) of example 1. Thus 0.04grams of (±)-l-methyl-4-(2-carboxy-2-methylethyl)-7-(N-Boc-5- amino-l-hexyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione methyl ester yielded 27mgs (88%) of the desired product, purified by HPLC (Column: Dynamax 60A C18, Method: 10-50% MeCN/H2O lOml/min. Detector: 254nm. Time(%MeCN): 0:00(10), 00:15(10,inj.,detect on), 10:00(10), 40:00(50), 55:00(50), 59:58(10, detect off), 60:00(off), Rf=32.1min). 1H NMR (D2O) 7.30 (IH, d, 4] _HH =2Hz, ArH C6-H), 7.24 (IH, dd, 4JHH-.2HZ, ³ J _H H=8Hz, ArH C8-H), 7.08 (IH, d, ³ J _H H=8Hz, ArH C9-H), 3.85 (1.6H, m, C3-H, NCHHCH(Me)CO2), 3.57 (1.8H, m, C3-H, NCHHCH(Me)Cθ2), 3.25 (0.6H, dd, ² j _H 3.10 (3H, s, NCH3),

2.74 (3H, m, CH(Me)Cθ2, CH2NH2), 2.40 (2H, t, J _H H=7Hz, ArCH2), 138 (4H, m), 1.13 (4H, m), 0.95 (1.8H, d, ³ J _H H=7Hz, CHCH3), 0.88 (1.2H, d, ³ J _H H=7Hz, CHCH3). Exact mass (FAB, M+H ⁺ )calculated for C20H30N3O4 376.2236, found 376.2228.

Example 32

(+l-l-methyl-4-(N-Cbz-2-carboxy-2- niιwIctIιyl)-7-(6-aιniιw-l-]ιexyl)-3,4-dihydro-lH- l,4-benzodiazeμine-2,5-dione trifluoracetate.

a) A solution of (±)-2-(N-Cbz-amino)-3-aminopropionic acid (lgram, 4.22mmol), lOmL methanol, 1.6mL of a 4N HCl in dioxane was stirred at room temperature for 24 hrs. The reaction mixture was concentrated in vacuo, triturated witln ether (50mL). The resulting residue was dissolved in dimethylformamide (6mL) and allowed to react with N-methyl-6- iodoisatoic anhydride (1.34grams, 4.5mmol) and triethylamine (1.9mL, 14mmol). The reaction was heated to 5( ⁾ °C for 1.51nrs, cooled to room temperature, diluted with lOOmL water and extracted witln 2X75nnl_ ethyl acetate. The combined organics were dried over sodium sulphate, decanted, and concentrated in vacuo. The resulting residue was purified by column chromatography (Si02, 35%ethyl acetate/hexane to 65%ethyl acetate/hexane) to yield (+)-N2-(N -methyl-2-amino-5-iodobenzoyl)-3-amino-2-(N ^J -Cbz)-aminopropionate methyl ester (1.65 grams, 77%).

b) (±)-l-methyl-4-(2-carboxy-2-(N-Cbz)-amrnoethyl)-7-iodo-3,4- dihydro-lH-l,4- benzodiazepine-2,5-dione methyl ester was prepared using the method described in part(d) of example 31. Thus, 0.825 grams (1.6mmol) of (+)-N ² -(N ³ -methyl-2-amϊno-5-iodobenzoyl)- 3-amino-2-(N ¹ -Cbz)-aminopropϊonate methyl ester yielded 0.756 grams (86%) of (±)-l- methyl-4-(2-carboxy-2-(N-Cbz)-aminoethyI)-7-iodo-3,4-dihydro -lH-l,4-benzodiazepine- 25-dione methyl ester (TLC, SiO2, 1:1 ethyl acetate/hexane, Rf=0.21, uv positive). H NMR (CDCI3, dTMS) 8.09 (0.5H, d, C6-H), 7.76 (IH, dd, C9-H), 6.87 (05H, d, ³ jHH=8Hz, C9-H), 6.22 (0.5H, d, ³ J H H=8Hz, CbzNH), 5.90 (0.5H, d, ³ jHH=8Hz, CbzNH), 4.67 (IH, bs, NHBoc), 5.05 (2H, OCH2), 4.63 (IH, m, CHCO2), 4.2-3.6 (7H, m, C3-H, NCH2CH, C3-H, OCH3), 3.29 (1.5H, bs, NCH3), 3.24 (1.5H, bs, NCH3); ¹³ C NMR 1705, 170.4, 168.4, 168.3, 166.8, 166.7, 156.1, 141.3, 140.7, 139.6, 139.4, 136.5, 136.2, 129.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.1, 123.1, 122.9, 89.5, 76.9, 67.0, 52.6, 52.4, 35.0.

c) (+)-l-methyl-4-(2-carboxy-2-(N-Cbz)aminoethyl)-7-(N-Boc-5-am ino-l-pentynyl)-3,4- dihydro-lH-l,4-benzodiazepine-2,5-dione methyl ester was prepared using the method described in part (f) of example 1. Thus, 0.2 grams (036mmol) of (+)-l-methyl-4-(2-carboxy- 2-(N-Cbz)-aminoethyI)-7-iodo-3,4-dihydro-lH-l,4-benzodiazepi ne-2,5-dione methyl ester yielded 0.187 grams (85%) of the desired product (TLC, 1:1 ethyl acetate/hexane Rf=0.17 uv and ninhydrin positive). ^J H NMR (CDCI3, dTMS) 7.83 (0.5H, d, C6-H), 7.79 (0.5H, d, ]HH=2Hz, C6-H), 7.50 (IH, bd, ³ J _H H=8Hz, C8-H), 7.30 (5H, m, Ph), 7.10 (0.5H, d, CbzNH), 5.84 (0.5H, d, CbzNH), 5.09 (2H, OCH2), 4.66 (2H, m, NHBoc, CHCO2), 4.2-3.6 (7H, m, C3-H, NCH2CH, C3-H, OCH3), 3.34 (1 H, bs, NCH3), 3.29 (1.5H, bs, NCH3) 3.24 (2H, m, CH2NHB0C), 2.43 (2H, CCCH>), 1.78 (2H, m, CH2CH2CH2), 1.44 (9H, s, C(CH3)3); ¹³ C NMR 170.3, 170.2, 168.2, 168.1, 167.5, 167.4, 155.9, 139.7, 135.1, 135.0, 133.9, 133.8, 128.4, 123.3, 128.0, 127.9, 127.8, 121.4, 120.9, 90.9, 79.1, 79.0, 66.9, 66.8, 53.7, 52.9, 52.8, 52.7, 51.9,49.6, 34.8, 28.7, 28.3, 16.8.

d) (±)-l-methyl-4-(2-carboxy-2-(N-Cbz)aminoethyl)-7-(N-Boc-5-a mino-l-pentyl)-3,4- dihydro-lH-l,4-benzodϊazepine-25-dϊone methyl ester was prepared using the method described in part (a) of example 3. Thus, 93mgs of (+)-l-methyl-4-(2-carboxy-2-(N- Cbz)aminoethyl)-7-(N-Boc-5-amϊno-l-peιntyI)-3,4-dihydro-lH -l,4-benzodiazepine-2,5- dione methyl ester yielded 93mgs (99%) of the desired product. 1H NMR (CDCI3, dTMS) 7.60 (0.6H, d, 4j _HH =2Hz, C6-H), 7.55 (0.4H, d, ⁴ J _HH =2Hz, C6-H), 7.30 (6H, m, Ph, C8-H), 7.07 (0.6H, d, CbzNH), 5.89 (0.4H, d, ³ J _H H=8Hz, CbzNH), 5.09 (2H, m, OCH2), 4.60 (2H, bs, CHCO2, NHBoc), 4.2-3.6 (7H, m, C3-H, NCH2CH, C3-H, OCH3), 3.33 (1.5H, bs, NCH3), 3.30 (1.5H,

bs, NCH3) 3.07 (2H, m, CH2NHB0C), 2.60 (2H, m, ArCH2), 1.60 (2H, m), 1.45 (2H, m), 1.40 (9H, s, C(CH3)3), 1.33 (2H, m); ¹ C NMR 170.4, 168.5, 168.4, 155.9, 140.3, 138.7, 132.4, 130.4, 128.4, 128.3, 128.0, 121.0, 66.9, 60.3, 53.9, 53.0, 52.8, 52.7, 52.0, 50.5, 49.7, 40.4, 34.8, 30.7, 29.9, 283, 263, 20.9, 14.1.

e) (±}-l-methyl-4-(2-carboxy-2-(N-Cbz)aminoethyl)-7-(5-amino-l -pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate was prepared using the method described in part (g) of example 1. Thus 46mgs of (±)-l-methyl-4-(2-carboxy-2-(N-Cbz)aminoethyl)-7- (N-Boc-5-amino-l-pentyl)-3,4-dihydro-lH-1,4-benzodiazepine-2 ,5-dione methyl ester yielded 16mgs (40%) of the desired product, purified by HPLC (Column: Dynamax 60A C18, Method: 10-50% MeCN/H20 lOml/min. Detector: 254nm. Time(%MeCN): 0:00(10), 00:15(10,inj.,detect on), 10:00(10), 40:00(50), 55:00(50), 59:58(10, detect off), 60:00(off) Rf=383min). *H NMR (D2O) 7.38 (2H, bs), 7.18 (3H, m), 6.95 (2H, m), 6.78 (IH, m), 4.94 (2H, m, OCH2Ph), 4.0-3.3 (4H, m), 3.11 (1 H, s, NCH3), 2.86 (2H, s, NCH3), 2.81 (2H, m, CH2NH2), 2.58 (1.3H, t, ArCH2), 157 (4H, m), 1.23 (2H, m).

f) (±l-l-methyl-4-(2-carboxy-2-(N-Cbz)aminoethyI)-7-(5-guanidi no-l-pentyI)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate was prepared using the method described in example 2. Thus 8mgs of (+}-l-methyl-4-(2-carboxy-2-(N-Cbz)aminoethyl)-7-(5-amino-l- pentyl)-3,4-dihydro-lH-l,4-benzodiazepine-2,5-dione trifluoracetate yielded 6mgs (69%) of (+i-l-methyl-4-(2-carboxy-2-(N-Cbz)aminoethyl)-7-(5-guanidin o-l-pentyl)-3,4-dihydro- lH-l,4-benzodiazepine-2,5-dione trifluoracetate (HPLC, Column: Dynamax 60A C18, Method: 10-50% MeCN/H20 lOml/min. Detector: 254nm. Time(%MeCN): 0:00(10), 00:15(10,inj.,detect on), 10:00(10), 40:00(50), 55:00(50), 59:58(10, detect off), 60:00(off), Rf=45.4min). ^" Η NMR (D?0) 7.40 (2H, bs), 7.20 (3H, m), 6.96 (2H, m), 6.78 (lH,t, 3j _HH= 8Hz), 4.98 (2H, m, OCH2Ph), 4.0-33 (4H, m), 3.13 (IH, s, NCH3), 2.94 (2H, m, CH2NH), 2.83 (2H, s, NCH3), 2.59 (1.3H, t, ArCH2), 1.42 (4H, m), 1.20 (2H, ). Exact mass calculated for C27H35N6O6539.2618, found 539.2618.

Example 33

Fibrinogen-GP Il HIa Receptor ELISA Binding Assay

The method used is essentially that described in Nachman and Leung (J. Clin. Invest.,

69: 263-269 [1982]). The GP 11 111 a is essentially purified as described in Fitzgerald et al, (Anal. Bioche . 151: 169-177 [1985]).

A. GP Ilfrlliypurification

Outdated human platelets are washed 3 times witln 10 mM tris-HCl, 150 mM NaCl (TBS), 1 mM EDTA, pH 7.5, and centrifuged at 2000 x g to pellet cells. Cells are lysed in 5 pellet volumes of TBS, 1% Triton X-100, 1 M Ca2Cl2, and followed by centrifugation at 30,000 x g. The supernatant fraction is collected and the supernatant is loaded onto a concanavalin-A column, previously equilibrated in TBS, 1 mM Ca2θ2, 0.1% Triton, 0.05% aN3 and eluted with 0.2 M a-methylmannoside. Fractions are pooled and loaded onto a heparin-agarose column. The flowthrough is collected and concentrated on an Amicon YM 30 filter to a volume of approximately 5-10 ml. The concentrate is then applied to an S-300 column (500 ml) and 6 ml fractions are collected. The GP IIbIII _a containing fractions are collected, pooled, and stored at -80° C. B. Purification of Low Solubility Fraction of Fibrinogen

The purification of fibrinogen is conducted essentially as described by Lipinska et al, (J. Lab. Clin. Med. 507, [1974]). Briefly, a 0.3 % w/v solution of human fibrinogen (Kabi #5302) is dissolved in 150 mM NaCl. Saturated (NH4)2SO4 is added dropwise with stirring to the fibrinogen solution to obtain about 16% saturation. The precipitate is spun down in appropriate size bottles at 2000 x g. The supernatant is decanted and the precipitate resuspended in 150 mM NaCl (approximately 50% of the original volume). NH4SO4 is again added dropwise to obtain 16% saturation. The suspension is spun down and the precipitate is resuspended in Tris-saline in a minimal volume (approximately 5% of the original volume). Any remaining insoluble material is spun down at 2000 rpm in a Sorval type centrifuge and the fibrinogen supernatant is decanted and dialyzed overnight at 4"C against Tris-saline. Characterization of the fibrinogen is by the Bradford protein assay, SDS-PAGE, and /or Western blotting using well known standard procedures. C. ELISA Assay

Briefly, 96 well plates are coated (Type Nunc 1 Maxisorp™) witln 10 mg/ml purified fibrinogen (100 ml/well), and allowed to stand overnight at 4°C. The plates are washed three times with PBS Tween (0.137 M NaCl, 0.003 M KCl, 0.008 M Na2HPO4, 0.001 M KH2PO4, pH 7-4 at room temperature, 0.05% Tween-20) and blocked for 1 to 2 hours at room temperature witln 200 ml/well TNCNT (which is 0.5% BSA, 20mM Tris, pH 75 at room temperature, I20mM NaCl, 0.2% Na 3, 2mM CaCb, 0.05% Tween 20, 0.5% BSA [Calbiochem RIA grade or better]) on a plate shaker. The plates are again washed three times with PBS/Tween and then 50 ml of sample in TNCNT is added. The mixture is incubated for 15 minutes at room temperature on a plate shaker. The stock solution of purified GP flbHIa receptor from human platelets, (0.4 - 1.0 mg/ml GP IlbHIa in 0.1% Triton X-100, ImM CaCl2, 20 mM Tris, 150 mM NaCl, 0.05% in 0.3 M N-acetyl glucosamine pH 7.5, stored at -70°C), is reconstituted to about 40 mg/ml in TNCNT. Fifty ml of this diluted GP H III _a is then added to each well and incubated on a plate shaker at room temperature. After one hour, the plates are washed four times with PBS/Tween and 100 ml of a polyclonal or

monoclonal antibody specific for GP Ilia such as AP3 (lmg/ml) (See e.g. Newman et al, Blood, 65: 227-232 [1985]) in ELISA buffer (PBS, 0.5% BSA, 0.05% Tween 20, 0.01% Thimerasol) is added. After a one hour incubation at room temperature on a plate shaker, the samples are washed 4 times with PBS/Tween. One hundred ml of GAM-HRP (horse radish peroxidase conjugate of goat anti-mouse IgG [Pel-Freeze Cat. 715305-1] dissolved in ELISA buffer) previously diluted to 1:10,000 is then added and the samples are incubated 1 hour at room temperature on a plate shaker. The samples are then washed 4 times with PBS/Tween and 100 ml OPD/H2O2 substrate is added (OPD/H2O2 substrate: 10 mg 0- phenylenediamine in 15 ml phosphate/citrate buffer, at room temperature and covered with foil; just before use, 6.25 ml of 30% H2O2 is added to give a final solution of 0.67 mg OPD/ml in 0.0125% H2O2 )• (The phosphate/citrate buffer consists of 16 mM Citric Acid, 50 mM Na2 HPO4 _; pH 5.0). The color develops within about 3 to 20 minutes and the reaction is stopped witln 100 mi 1 M H2SO4. The optical density at 492 nnn vs 405 nm is recorded and IC50 values are determined.

Example 34 Human Vitronectin- Vitronectin Receptor (a _v b3) ELISA Assay

A. Human Vitronectin Purification Human vitronectin (Vn) is isolated from human plasma and purified by affinity chromatography by the method of Yatohgo et. al, (Cell Structure and Function 13: 281-292 [1988]).

B. Human Vitronectin receptor (a _v b^ Purification Human vitronection receptor (VnR) is purified from human placenta by the method of

Pytela et al, (Methods EnzymoL, 144: 475 [1987]). Alternatively the a _v b3 receptor can be purified from some cell lines (e.g., human embryonic kidney 293 cells) transfected with DNA sequences for both the a and b3 subunits. The subunits are purified by employing octylglucoside extraction followed by Con-A, Heparin-Sepharose, and S-300 Chromatography.

C. Monoclonal Antibodies

Anti-GP Hbllla monoclonal antibodies specific for human GP III _a are prepared by the method of Newman ct al (Blood, 65: 227-232 [1985]), or a similar procedure. This mouse Mab is specific for the b subunit of the vitronectin receptor.

Rabbit Fab 2 anti-mouse Fc fragment horse radish peroxidase conjugate (anti-MuFc HRP) is obtained from PelFreeze (cat. no. 715305-1).

D. ELISA Assay

Maxisorp microtiter plates are coated witln 2 mg/ml human vitronectin dissolved in PBS (50 ml/well) and stored overnight at 4°C The plates are washed two times with PBS- 0.05% Tween-20 (wash buffer) and blocked by incubating with about 150 ml/well of assay buffer (1%, BSA [RIA grade or betterl in 50 mM Tris-HCl, 100 mM NaCl, ImM MgCl2, CaC-2, MnCl2 pH 7.4) for 60 minutes. Dilutions of standards are prepared and putative inhibitors (Table 3) are dissolved in assay buffer. The blocked plates are emptied and 25 ml/well of inhibitor or standard solution is added to each well. Twenty-five ml of a 30 mg/ml solution of purified ayb3 in assay buffer is pipetted into the coated plate. The final concentration of receptor in the assay well is about 15 mg/ml. The plate is incubated on a shaker for 60 minutes. Meanwhile , for each microtite plate, 6 ml buffer solution containing 1.5 mg/ml of mouse monoclonal antibody specific for b3 is prepared. To this solution is added ml of the secondary antibody, which is anti-mouse-Fc-HRP antibody conjugate. For example, for one plate, prepare 6 ml of a 1.5 mg/ml mouse Mab solution to which is added 1 ml of anti-mouse- Fc-HRP antibody stock, (this represents a 1:6000 dilution of the antibody - HRP conjugate). This mixture is allowed to incubate during the receptor-inhibitor incubation. The assay plates are washed 4 times witln PBS-Tween and 50 ml /well of the antibody mixture is then pipetted into the plate for a 60 minute incubation. The plate is washed 4 times and the color reaction is developed witln 50 ml/well of 0.67 mg/ml o-phenyldiamine in PBS containing 0.012% H2O2. Alternatively, 16 mM citric acid , 50 mM Na2Pθ at pH 5.0 can be used as a substrate buffer. The reaction is stopped witln 50 ml/well 1 M H2SO4. The plates are read at 492-405 nm and the data analyzed by four-parameter fit.

Example 35 GP IlblHa-von Willebrand factor (vWF) ELISA Assay

A. ELISA Assay

Microtiter plates are coated with 1.0 mg/ml GP Ilb'IIa, prepared by the method of Fitzgerald et al., (Anal Biochem. 151: 169-177 [1985]) and allowed to incubate overnight in coat buffer. The plates are then washed three times in wash buffer (0.05% Tween 20 in PBS) and 150 ml of assay buffer is added and allowed to incubate for 1-2 hours at room temperature on plate shaker. The plates are washed three times and 50 ml of 2x inhibitor in assay buffer (Assay buffer: 0.5% BSA/50mM Tris, lOO M NaCl, l.OmM CaCl2, l.OmM MgCl2, l.OmM MnCto; coat buffer is the same but without BSA) is added. Fifty ml of 4.0 mg/ml vWF ( prepared as described by Ledford et al., Thrombosis and Haemostasis, 64(4): 569-575 [1990]) in assay buffer is then added and allowed to incubate for one hour at room temperature on plate-shaker. The plates are washed three times and the antibody mixture is added (1:5000 of mouse anti-vWF and 1:5000 of rabbit-anti-mouse-Fc-HRP, both commercially available) in assay buffer and incubated for 1 hour at room temperature on plate-shaker. Plates are again washed three times and 100 ml of substrate solution (10 mg OPD, 6.5 ml H2 O2, 15 ml

phosphate citrate buffer) is added and incubated at room temperature. The color change of OPD/H2O2 reagent is read at 492 nm with a 405 nm reference wavelength on the filter photometer.

Example 36

In Vitro Human Platelet Aggregation Assay

Platelet aggregation assays are performed in human platelet rich plasma (PRP).

Fifty milliliters of whole human blood (9 parts) is drawn on 3.6% sodium citrate (1 part) from a donor who has not taken aspirin or related medications for at least two weeks. The blood is centrifuged at 160 x g for 10 minutes at 22°C and allowed to stand for 5 minutes after which the PRP is decanted. Platelet poor plasma (PPP) is isolated from the remaining blood after centrifugation at 2000 x g for 25 minutes. The platelet count of the PRP is diluted to about

300,000 platelets per microliter with PPP. A 225 ml aliquot of PRP plus 25 ml of either a dilution of the test inhibitor sample or a control (PBS) is incubated for 5 minutes in a Chrono-log Whole Blood Aggregometer at 25°C.

An aggregating agent (collagen, lmg/ml; U46619, 100 ng/ml; or ADP, 17 mM) is added and the transmission is recorded.

Example 37 Representative 1, 3, , and 7 substituted Benzodiazepinediones

Cmpd# _Q_ R

1 amine 2 guanidine 3 guanidi e 4 guanidine 5 amine 6 amine 7 amine 8 guanidine

Crnpd# M. M

63 guanidine 64 guanidine 65 guanidine 66 guanidine 67 amine 68 amine 69 amine 70 guanidine 71 amine 72 amine 73 amine 74 guanidine

Cmpdt

82 amine 83 guanidine

CCfeH

Cmpd#

84 amine 85 guanidine

d#

Cmpd# n

91 92 93 94 95 96 97 98 99

Cmpdft Q L R 100 amine (CH2)6 CH2( NH2CόH )

101 amine (CH2)6 CH2( H2C6H ₄ )

102 amine (CH2)6 CH2 nNHCOBu ⁿ C6H ₄ )

103 amine (CH2)6 (CH ₂ )sNH2

104 guanidine ( H2)6 (CH2)sNHC(NH)NH2 105 amine (CH ₂ )6 CH2(mNHCO(pgC6H4)C6H ₄ )

Cmpd# -Ci-

106 amine 107 guanidine 108 amine 109 amine

Gnpd# _Q_

110 amine (CH ₂ )6 4 111 guanidine (CH ₂ )6 4

Cmpd#

112 amine (CH ₂ )6 113 guanidine (CH ₂ )6

Gn d# R

Example 38

Results of ELISA and Platelet Aggregation (PA) Assays for 1, 3, , and 7 substituted

Benzodiazepinediones

IC ₅ o(mM) IC ₅₀ (mM) IC ₅ o(mM)

Cmpd# Fg/IIblHa PA(citrate) PA(heparin)

1 8.3

2 0.204

3 0.254

4 0.466

5 7.0

6 5.0

7 6.0

8 0.055 4.58

9 0.0036 3.1(2) 7.5

10 0.070 7.99

11 0.060

12 0.030 6.72

13 0.008 1.86

14 0.012 1.7 3.34

15 0.011 0.59

16 0.014 1.51

17 0.011 2.55

18 0.062

19 0.014 1.20 4.76

20 0.014 2.12

21 0.200

22 0.010 0.52

23 0.056 0.59

24 0.013 0.78 1.60

25 0.015 1.78(2)

IC ₅₀ (mM) IC ₅₀ (mM) IC ₅₀ (mM)

Cmpd# Fg/IIblHa (citrate) (heparin)

63 80.0

64- 2.30

65 25.0

66 0.018 1.19

67 0.052(2) 2.3 4.03

68 0.040(2)

69 0.200

70 0.100

71 0.097(2) 11.4 41.3

72 0.190(2)

73 > 100.0

74 > 100.0

IC ₅₀ (mM) IC ₅₀ (mM) IC ₅ o(mM)

Cmpd# Fg/Ilbllla (citrate) (heparin)

75 0.022 2.29 76 0.023 2.25 77 0.192 78 1.27 79 0.149 80 0.211 81 0.308

IC ₅₀ (mM) IC ₅₀ (mM) IC ₅ o(mM) Cπφd Fg/IIbIIIa PA (citrate) PA (heparin)

82 0.007 0.67 2.3 83 0.019 1.80 4.8

IC ₅₀ (mM) IC ₅₀ (mM) IC ₅₀ (mM)

Cmpd# Fg/IIbllla PA (citra e) PA (heparin)

86 0.035 0.12 0.35 87 0.007 0.45 0.36 88 0.008 0.059 0.080 89 0.005 0.091 0.130 90 0.015 0.136

Cmpd#

91 92 93 94 95 96 97 98 99

IC ₅₀ (mM) Cmpd# PA(heparin)

100 0.49 101 102 0.82 103 104 105 0.54

ICsoGnM) IC ₅₀ (mM) IC50(mM) Cmpd# Fg/IIbllla PA(ci rate) PA(heparin)

106 0.019 0.13 0.49 107 0.013 108 0.015 0.59 0.89 109 0.027 1.04 3.4

IC5o(mM) IC ₅₀ (mM) IC ₅₀ (mM)

Cmpd# Fg/IIbllla PA(citrate) PA(heparjn)

110 0.024 0.70 111 0.020 1.65

ICso(mM) IC ₅₀ (mM)

Cmpd# Fg/IIbllla PA(citrate) 112 0.006 0.48

113 0.012

IC ₅₀ (mM) IC ₅ o(mM) IC ₅ o(mM)

Cmpd# Fg/IIbllla PA(citrate) PA(heparin)

114 0.014 5.56 115 0.053 18.8 116 0.016 1.68 117 0.008 1.71 1.80 118 0.019 2.84

While tine invention has necessarily been described in conjunction with preferred embodiments, one of ordinary skill, after reading the foregoing specification, will be to effect various changes, substitutions of equivalents, and alterations to the subject matter set forth herein, without departing from the spirit and the scope thereof. Hence, the invention can be practiced in ways other than those specifically described herein. It is therefore intended that the protection granted by Letters Patent hereon be limited only by the appended claims and the equivalents thereof.