Background of the Invention Field of the Invention The present invention relates to novel oligomeric amino acid derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.

Related Art It has been known since the early 1980's that the vascular relaxation caused by acetylcholine is dependent on the presence of the vascular endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years. In addition, NO is the active component of amylnitrite, glyceryltrinitrate and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid L- arginine by the enzyme NO synthase.

Nitric oxide is the endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al., Biochemical Pharmacology, 38,1709-1715, 1989; Moncada et al., Pharmacological Reviews, 43,109-142,1991). Excess NO production appears to be involved in a number of pathological conditions, particularly conditions which involve systemic hypotension such as toxic shock, septic shock and therapy with certain cytokines (Kerwin et al., J. Medicinal Chemistry, 38,4343-4362, 1995).

The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, L-N-monomethyl-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of toxic shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A-0446699.

It has recently become apparent that there are at least three types of NO synthase as follows: (i) a constitutive, Ca++/calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or physical stimulation.

(ii) a constitutive, Ca++/calmodulin dependent enzyme, located in the brain, that releases NO response to receptor or physical stimulation.

(iii) a Ca++ independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed this inducible NO synthase generates NO continuously for long periods.

The NO released by the two constitutive enzymes acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the inducible NO synthase (Knowles and Moncada, Biochem J., 298,249-258,1994 Billiar et al., Annals of Surgery, 221,339-349,1995; Davies et al., 1995) There is also a growing body of evidence that NO may be involved in the degeneration of cartilage which takes place in cerain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis (McInnes et al., J. Exp. Med, 184,1519-1524,1996; Sakurai et al., J. Clin. Investig., 96,

2357-2363,1995). Accordingly, conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune and/or inflammatory conditions affecting the joints, for example arthritis, and also inflammatory bowel disease, cardivascular ischemia, diabetes, congestive heart failure, myocarditis, atherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (secondary to cardiac arrest), multiple sclerosis and other central nervous system disorders mediated by NO, for example Parkinson's disease and Alzheimer's disease, and other disorders mediated by NO including opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviour, for example, nicotine and eating disorders (Kerwin et al., J. Medicinal Chemistry, 38,4343-4362,1995; Knowles and Moncada, Biochem J., 298,249-258, 1994; Davies et al., 1995; Pfeilschifter et al., Cell Biology International, 20,51-58, 1996).

Further conditions in which there is an advantage in inhibiting NO production from L-arginine include systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy (E. Kelly et al., J. Partent. Ent. Nutri., 19,234-238,1995; S. Moncada and E. Higgs, FASEB J., 9,1319- 1330,1995; R. G. Kilboum et al, Crit. Care Med., 23,1018-1024,1995).

Some of the NO synthase inhibitors proposed for therapeutic use so far, and in particular L-NMMA, are non-selective; they inhibit both the constitutive and the inducible NO synthases. Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over- inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment. Thus, while non- selective NO synthase inhibitors have therapeutic utility provided that appropriate

precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S.

Moncada and E. Higgs, FASEB J., 9,1319-1330,1995).

WO 96/35677, WO 96/33175, WO 96/15120, WO 95/11014, WO 95/11231 WO 95/25717, WO 95/24382, W094/12165, W094/14780, W093/13055, EP0446699A1 and U. S. Patent No. 5,132,453 disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase. The disclosures of which are hereby incorporated d by reference in their entirety as if written herein.

Summary of the Invention In a broad aspect, the present invention is directed to novel compounds, pharmaceutical compositions and methods of using said compounds and compositions for inhibiting or modulating nitric oxide synthesis in a subject in need of such inhibition or modulation by administering a compound which preferentially inhibits or modulates the inducible isoform of nitric oxide synthase over the constitutive isoforms of nitric oxide synthase. It is also another object of the present invention to lower nitric oxide levels in a subject in need of such lowering.

Compounds of the present invention are represented by the following chemical formula: or a pharmaceutically acceptable salt thereof, wherein; IaX Ib, Ic, and Id are independently selected from a structure of Formula II:

wherein Formula (II) has a point of attachment for bonding to a linker B by replacement of a substituent group of Formula (II) independently selected form the group consisting J1. andaremovablehydrogenfromasubstituentindependentlyselectedfr omtheJ2,A-R7, group R1,R2,R3,R4,R7undR8;of J1 and J2 are independently selected from the group consisting of OR23, SR23, N(R24)R25NHR24and with the proviso that A is 26; J2J1and can be taken together forming a group selected form the group consisting of OR28O, OR28NR24andSR28NR24withSR28S, the proviso that A is R26; J2J1and can be taken together forming J wherein J is connected to the carbon of J2J1and by a covalent double bond and wherein J is independently selected form the gorup consisting of O, NR22 and S with the proviso that A is selected from other than R26; G is independently selectd from the group consisting of O, S, CH2, CHR15, C(R15)2, NH, NR15;

A is independently selected from the group consisting of O, N (R), S and heterocyclyl; A can be independently selected from the group consisting of O, N(R5) and S connected to the point of attachment of any one of R1 byaspacergroupselectedR2 from a linear moiety having a chain length of 1 to 6 atoms to form a heterocyclyl having from 5 to 10 members; A can be independently selected from the group consisting of O, N(R5) and S connected to the points of attachment of R1 byaspacergorupselectedfromaR2 linear moiety having a chain length of 1 to 6 to form a heterocyclyl having from 5 to 10 members; A can be indenepdently selected from the group consisting of O, N(R5) and S connected to the point of attachment of R3 bya a spacer group selected from a linear moiety having a chain length of 1 to 3 atoms to form a heterocyclyl having from 7 to 10 members; A can be independently selected from the group consisting of O, N(R5) and S connected to the points of attachment of aspacergorupselectedfromalinearmoietyby having a chain length of 1 to 4 atoms to form a heterocyclyl having from 6 to 10 members; A can be independently selected from the group consisting of O, N (R) and S connected to X by a substituent selected from hydroxyl, sulfhydryl, amino, carboxyl, and carbonyl substituents of group X by a spacer selected from the group consisting of a covalent bond and a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 to 10 members;

A can be R, wherein R is independently selected from the group consisting of hydrogen, formyl, hydroxyalkyl, alkenyl, alkynyl, acyl, aroyl, aralkanoyl, heteroaroyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaralkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkylalkenyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkenyloxyalkyl, cyanoalkyl, carboxy, carboxamido, carboalkoxy, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, formylalkyl, and acylalkyl; A can be R, wherein R is independently selected from the group consisting of N(R5)N(R7)R25,N(R5)SO2R13,N(R5)C(O)R15,N(R5)OR7,N(R5)SR7, R19(R20)C=N-O,naturalaminoacids,syntheticN(R5)C(S)R15,R19(R2 0)C=N-N(R5), amino acids, N(R5)P(O)(OR13)2;and R1 and R2 are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S (O) R S02R, C (O) R, CH20C (O) R, hydroxyl, sulfhydryl, OR, SR6, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH2S03M, CH2CH2S03'MCH2P03'2M,CH2CH2P03'2MCH (OR)(OR) CF3, P (O) R R CH2NR19C(O)R15,CH2NR19C(S)R15,CH2SC(O)R15,P(O)(R30)2R31,C(S) R15, CH2SC (S) RI, CH20C (O) GR, CH2NR19C(O)GR15, CH2NR19C (S) GR CH20C (S) GR15, CH2SC (S) GR15, OSO2R, OS (O) RI, OC (S) RI, SC (S) RI

OC (S) GR, SC (S) GR15. OC (O) R, SC (O) R, OC (O) GR, SC (O) GR, and <BR> <BR> <BR> <BR> <BR> R19(R20)CH;<BR> R1 canR2 be taken together forming a group selected from the group R19(R20)C=,D(C(R30)(R31))2D,andD((R19)R20C)eW(C(R19)r20)kDco nsistingof wherein z is 2 to 5, e is 1 to 2, k is 1 to 2, D is selected from the group consisting of oxygen, C=O, C=S, S(O)m wherein m is 0 to 2, OP(OR31)R30, P(S)R30 and Si(R19)R20 and W is selected from the group consisting of oxygen, C=O, C=S, S(O)m, S (O) m where m is 0 to 2, P (O) R, P (S) R, N (R), and Si (R) R with the proviso that only one D can be oxygen or sulfur at any time; R1 canR2 be taken together forming a group selected from the group consisting of cycloalkyl radicals, cycloalkenyl radicals wherein said cycloalkyl radicals and cycloalkenyl radicals may be optionally substituted with one or more R30 or R31 substituents, aryl radicals, heteroaryl radicals, saturated heterocyclic radicals and partially saturated heterocyclic radicals wherein said radicals are 1,2-disubstituted and said 1,2- 19 32 substitutents are independently selected from C=O, C=S, C (R) R, S (O), S (O) 2, P(S)R30andSi(R19)R20;OP(OR31)R30,P(O)R30, R2canR1and be taken together forming a group selected from the group consisting of cis-1,2-disubstituted alkyls and cis-1,2-disubstituted alkenyls wherein said 19 32 1, 2-substitutents are independently selected from C=O, C=S, C (R) R, S (O), S (O) 2, OP (OR31)R30, P(O)R30, P(S)R30, and Si (R) R and said alkyl and alkenyl may be 30 31 optionally substituted with one or more R or R substituents;

R4areindependentlyR3and selected from the group consisting of hydrogen, hydroxyl, sulfhydryl, OR, SR, CH2S03'M,CH2CH2S03'M+,CH2P03'2M, S(O)R13,SO2R13,P(O)R30R31,P(O)(R30)2R31,CH2CH2PO3-22M+,CH(OR 6)CF3, C (O) R, C (S) R, CH20C (O) RI, CH2NR19C(O)R15, CH2NR19C (S) RI CH2SC (O) RI, CH2SC (S) R, CH20C (O) GR15, CH2NR19C(O)GR15, CH2NR C (S) GR15, CH20C (S) GR15, CH2SC (S) GR, OSO2R13, OS (O) R OC (S) R, SC (S) RI, OC (S) GR, SC (S) GR, OC (O) R15, SC (O) R, OC (O) GR and SC(O)GR15; R4canR3and be taken together to form the group L-U-V wherein L is not identical to V, and L, U, and V are independently selected from the group consisting of O, S, C(O), C(S), C(JH)2 wherein JH is independently selected from NH24,SR23, and N(R24)R25, CR29, S (O), S02, OP (OR31) R, P (O) R, P (S) R C (R) R31 R30(O)POP(O)R30,Si(R19)R20,Si(R19)R20Si(R19)R20,C=C(R30)R31, (O)2POP(O)2, (R19)R20CSC(R19)R20,Si(R19)R20OSi(R19)R20,(R19)R20COC(R19)R2 0, S(O)C(R30)=C(R31),SO2C(R30)=C(R31),C(O)C(R30)=C(R31),C(S)C(R 30)=C(R31), P(S)R30C(R30)=C(R31).PR30C(R30)=C(R31),P(O)R30C(R30)=C(R31), DC (R) (R) D wherein D is selected from the group consisting of oxygen, C=O, C=S, mis0to2,OP(OR31)R30,P(O)R30,P(S)R30,Si(R19)R20andN(R30),S(O) mwherein and a covalent bond with the proviso that no more than any two of L, U and V are simultaneously covalent bonds and the heterocycle comprised of by L, U, and V is greater than a 4-membered ring;

R3 and R4 can be taken together to form the group L-U-V wherein L is not identical to V, and L, U, and V are independently selected from the group consisting of cycloalkyl radical, cycloalkenyl radical wherein said cycloalkyl radical and cycloalkenyl radical may be optionally substituted with one or more R and R31 substituents, aryl radical, heteroaryl radical, saturated heterocyclic radical and partially saturated heterocyclic radical wherein said radicals are 1,2-disubstituted and said 1,2-substitutents are independently selected from C=O, C=S, C (R) R, S (O), S (O) 2, OP (OR) R P(O)R30, P(S)R30 and Si(R19.)R20; R4canbetakentogethertoformthegroupL-U-Vwherein,L,U,andVareR3 and independently selected from the group consisting of cis-1,2-disubstituted alkanyl and cis- 1,2-disubstituted alkenyl radicals wherein said 1,2-substitutents are independently selected from C=O, C=S, C(R19)R32, S(O), S(O)2, P(S)R30,P(O)R30, and Si(R19)R20 and said alkanes and alkenes may be optionally substituted with ont or more R30 or R31 substituents; R is independently selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S (O) R S02R, P (O) R30R31, P(O)(R30)2R31, C(O)R15, C(S)R15, CH2OC(O)R15, CH2NR19C(O)R15, CH2NR19C (S) RI, CH2SC (O) RI, CH2SC (S) R15 CH20C (O) GR, CH2NR C (O) GR, CH2NR C (S) GR 15, CH20C (S) GR 15

CH2SC (S) GR, heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino; R, R and R can be taken together to form a spacer group consisting of a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 through 8 members; R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,

heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino ; R is independently selected from the group consisting of hydroxyalkyl, aminoalkyl, heteroaryloxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, synthetic amino acid, and a polyhydroxy compound of carbon; R7 is selected from the group consisting of hydrogen, aryl, heteroaralkyl, hydroxy, alkyl, alkenyl, alkynyl, amino, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, hydroxyalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl,

cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S (O) R, S02R, P (O) R30,R31, P(O)(R30)2R31 C(O)R15, C (S) R, CH20C (O) R, CH2NR C (O) R, CH2NR C (S) RI, CH2SC (O) R CH2SC (S) R, CH20C (O) GR, CH2NR C (O) GR, CH2NR C (S) GR CH20C (S) GR, CH2SC (S) GR, heteroaryloxyalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino and sulfonylalkylamino; R, R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a heterocyclyl having from 5 to 8 members; R can be selected from a heterocyclyl radical in which there is at least one carbon in one ring and in which 1 to about 4 members of said ring are heteroatoms independently selected from oxygen, nitrogen and sulfur and said heterocyclyl radical may be optionally substituted with heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,

arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, guanidino, amidino, and acylamino; R8 is selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylthioalkyl, cyanoalkyl, sulfhydrylalkyl, formyl, C (O) A- R, C (S) A-R, CH20C (O) A-R, CH2NR C (O) A-R, CH2NR C (S) A-R7, CH2SC (O) A-R, CH2SC (S) A-R, CH20C (O) GR, CH2NR C (O) GR CH2NR19C(S)GR15, CH2OC(S)GR15, CH2SC(S)GR15 and acyl; R8 may be taken together with X to form a carbocyclic or a heterocyclic ring having from 3 to 8 members; R is independently selected from aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,

aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, synthetic amino acid, and a polyhydroxy compound of carbon; R 15 is independently selected from hydrido, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl,

alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, a synthetic amino acid, and a polyhydroxy compound of carbon; M is a pharmaceutically acceptable cation; X is selected from the group consisting of alkylene, alkenylene, alkynylene,- (CH2) pQ (CH2) r- wherein p is 1 to 3, r is 1 to 3 and Q is selected from oxygen, C=O, N (R) SO2, SO2N (R), S (O) t, Se (O) t wherein t is 0 to 2, P (O) R,- (CH2) sT (CH2) v- wherein s is O to 2, v is 0 to 2 and T is selected from 3 to 6 membered carbocyclic radicals, aryl radicals and heterocyclyl radicals, and N(R12) wherein n is 1 to 2, wherein all positions on X may be optionally substituted with one or more selected from the group consisting of halogen, Cl-Clo alkyl, Cl-Clo alkoxy, hydroxy, haloalkyl, nitro, cyano, and amino; R12 is selected from hydrogen, hydroyl, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, haloalkyl, aryl, aralkyl, cycloalkylalkyl, and heterocyclylalkyl; R21 is selected from hydroxyl and alkyl; Y is selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkenyl, cycloalkenyloxy, alkenyloxyalkyl, alkylthioalkyl, alkylaminoalkyl and R9andR10arewherein independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, hydroxy, alkoxy, aryl, heterocyclyl, and aralkyl;

R9 and R10 can be taken together to form a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a heterocyclyl having from 3 through 8 members; R19 and R20 are indenpendently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and diaralkoxyphosphonoalkyl; R19 and R20 can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms and selected from the group consisting of a cycloalkyl having from 3 through 8 members, a cycloalkenyl having from 3 through 8 members, and a heterocyclyl having from 3 through 8 members; R22 and R23 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,

heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl and aralkylsulfonylalkyl; R24 and R25 are independently selected from the group consisting of hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkoxy, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, cycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinylalkyl, aralkylsulfonylalkyl;aralkylsulfinylalkyland R24 and R25 can be taken to form a linear moiety spacer group having a chain length of 4 to 7 atoms to form a heterocyclyl having from 5 through 8 members; R26 is independently selected from hydrogen, formyl, hydroxyalkyl, alkenyl, alkynyl, acyl, aroyl, aralkanoyl, heteroaroyl, alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaralkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, alkylthioalkyl, cycloalkylalkenyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkenyloxyalkyl, cyanoalkyl, carboxy, carboxamido, carboalkoxy, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, formylalkyl and acylalkyl;

R28 is independently selected from a group consisting of CH(R23)CH2, CH(R23)CH2CH2, CH2CH(R23)CH2,cycloalkylene, and heterocyclylene; R and R are independently selected from hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, a synthetic amino acid, and polyhydroxy compound of carbon; R and R can be taken to form a linear moiety spacer group having a chain length of 2 to 7 atoms to form a group selected from the group consisting of a cycloalkyl having from 3 through 8 members, a cycloalkenyl having from 3 through 8 members, and a heterocyclyl having from 3 through 8 members; B is a linker selected from the group consisting of B 1, B2, B3, B4, B5, B6, B7, B8, Bg, B10,B11,B12,B13,B14, and B15 wherein f, g, h, and i are integers independently

selected from the group consisting of 0, 1,2,3,4, and 5 representing the number of attachments to B, with the proviso that the sum of f, g, h, and i must be at least two; B 1 is a linker connecting a first group independently selected from the group consisting of Ia, Ib, Ic, and Id through the point of bonding of a removable hydrogen of a group selected independently from the group consisting of A and R to a second group independently selected from the group consisting of Ia, Ib, Ic, and Id through the point of bonding of a removable hydrogen of a group selected independently from the group consisting of A and R wherein said linker is selected from the group consisting of a covalent single bond with the proviso that only one A is simultaneously O and S, (CR19R20)uQQ(CCR19R20(CR19R20)jCR19R20,CR7R20(CR7R20)jCR7R20 , R19R20)w,R19R20)w,(CR7R20)uQQ(CR7R20)w, (CH2)xT(CH2)y, and (CR7R20)xT(CR7R20)y wherein j is selected from an integer of 0 to 18, x and y are selected from an integer of 0 to 8, and u and w are selected from an integer of 1 to 8; B2 is a linker connecting a first group independently selected from the group consisting of Ia, andIc, Id from the point of attachment of A-R7to a second group independently selected from the group consisting of la, Ib, Ic, and Id from the point of attachment of A-R wherein said 19 20 19 20 19 20 linker is selected from the group consisting of Hjjnk-CR R (CR R) jCR R-Hnk Hlink-(CH2)uQQ(CH2)w-Hlink,Hlink-,Hlink-CR7R20(CR7R20)jCR7R2 0-Hlink, (CR19R20)uQQ(CR19R20)w-Hlink,Hlink- andHlink-(CH2)xt(CH2)y-Hlink,Hlink-(CR19R20)xT(CR19R20)y-Hli nk,

(CR7R20)xT(CR7R20)y-Hlink(CR7R20)xT(CR7R20)y-Hlinkwherein j is selected from an integer to0 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the proviso that only one Hlink can be simultaneously a covalent single bond; B2 can be a linker selected from the group consisting of natural amino acids and synthetic amino acids wherein said amino acids have two or more acylateable functional groups selected from the group consisting of primary amino, secondary amino, thiol, and hydroxy; B3 is a linker connecting groups indenendently selected from the group consisting of Ia, Ib, Ic,and Id from the point of attachment of A-R7of said Ia, Ib, Ic, and Id groups wherein the number of groups attached to said linker from the point of attachment of A- R is kk wherein kk is an integer selected from 2 to 20 wherein said integer represents the number of acylateable functions present on said linker with a range of from two to the maximum number of acylateable functions present on said linker with the proviso that no more than 5 each of la, Ib, Ic, and Id are simultaneously. present on said linker and wherein said linker is selected from the group consisting of polyhydroxy compound of carbon selected from the group consisting of polyhydroxyalkanes, saccharides, disaccharides, polysaccharides, inositols, alditols, alditol acetals, alditol ketals, aldaric acids, aldonic acids, aldonic acid lactones, and hydroxyalkylamines having 2 to 20 acylateable hydroxy groups; B3 can be a linker selected from the group consisting of polyamino compounds of carbon selected from the group consisting of diaminoalkanes, diaminocycloalkanes, diaminoaryls, diaminoheterocycyls, diaminoalkylamines, triaminoalkylamines, diaminoalkylaminoalkylamines, and triaminoalkylaminoalkylamines, wherein said polyamino compounds have two to twenty acylateable amino groups, and compounds of

carbon having one to nineteen hydroxy functions, one to nineteen amino functions and zero to eighteen thiol fanctions; B4 is a linker connecting a first group independently selected from the group consisting of Ia, Ib, Ic, and Id through the point of bonding of a removable hydrogne of a substituent independently afrom group of substituents consisting of R4R3, and R8 wherein R1, R3 and R4 are indenpendently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and R8 is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl to a second group independently selected from the group consisting of Ia, Ib, Ic, and Id through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting of R1, R3, R4 and R8 whrein R1, R3 and R4 are indenepdently selected fron the group consisting of hydrogen, hydroxy, and sulfhydryl and R8 is selected form the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl wherein said linker is selected from the group consisting of C=O, S=O,SO2,Si(R24)(R25),P(O)R30,P(S)R30,(O)2POP(O)2,C(O)C(O),C= S, R30(O)POP(O)R30, Si(R19)R20OSi(R19R20; B4 can be a linker selected form the group consisting of Alink- Alink-CR19R20(CR19R20)jCR19R20-Alink,Alink-CR7R20(CR7R20)jCR 7R20-Alink, (CR19R20)uQQ(CR19R20)w-Alink,Alink- andAlink-(CH2)xT(CH2)y-Alink,Alink-(CR19R20)xT(CR19R20)y-Ali nk (CR7R20)xT(CR7R20)y-Alink,(CR7R20)xT(CR7R20)y-Alink,wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8 and x and y are independently selected

from an integer of 0 to 8 with the proviso that only one Alink can be a covalent single bond; B5 is a linker connecting a first group independently selected from the group consisting of Ia, Ib, Ic, and Id through thepoint of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting of R1, R3, R4 and R8 wherein R1, R3 and R4 are indenepdently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and R8 is selected form the gorup consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl to a second group independently selected from the group consisting of Ia, Ib, Ic, and Id through the points of bonding of both substituents R1 and R2 wherein R1 and R2 are both removable hydrogens wherein said linker is selected from the group consisting of Dlink- CR19R20(CR19R20)jCR19R20-Alink,Dlink- Dlink-(CR19R20)uQQ(CR19R20)W-Alink,Dlink-(CR7R20)uQQ(CR7R20) w-Alink, (CH2)xT(CH2)y-Alink, Dlink- Elink-T(CR19R20)y-AlinkandElink-(CR7R20)xT(CR7R20)y-Alink,El ink-T(CH2)y-Alink, T(CR7R20)y-Alink,T(CR7R20)y-Alink,wherein j is selected from an integer to0 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer to0 8, T is selected from the group consisting of a carbocyclic radical, aryl radical and a heterocyclyl radical, Dlink is selected from a covlent single bond and =C(R15), and Elink is selected from the group consisting of a covalent single bond and covalent double bond with the provisos that only one of Alink,Dlink and becan

simultaneously a covalent single bond and that only Elinkand can bond to the points of bonding of R1 R2; B6 is a linker connecting a first group independently selected from the group consisting of Ia, Ib, Ic, and Id through the points of bonding of both substituents R1 and R2 wherein R1 andR2 are both removeable hydrogens to a second group independently selected from the group consisting of la, Ib, Ic, and Id through the points of bonding of both substituents R and R wherein R and R are both removeable hydrogens wherein 19 20 19 20 19 20 said linker is selected from the group consisting of Flink-cR R (CR R) jCR R- Flink-(CR19R20)uQQ(CR19R20)w-Flink,Flink,Flink-CR7R20(CR7R20 )jCR7R20-Flink, Flink-Flink-(CR7R20)uQQ(CR7R20)w-Flink,Flink-(CR19R20)xT(CR1 9R20)y-Flink, Elink-T(CR7R20)y-Flink,Elink-(CR7R20)xT(CR7R20)y-Flink,Elink -T(CR19R20)y-Flink, T-Glink and Glink-T-Elink wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of 0 to 8, Elink is selected from the group consisting of a covalent single bond and covalent double bond, Flink is =C (R), and Glink is a covalent double bond; B7 is an amide and ester forming linker connecting groups independently selected from the group consisting of Ia, Ib, Ic, and Id through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting of the group R1, R3, R4 and R8 wherein R1, R3 and R4 are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and R8 is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl of said

la, Ib, Ic, and Id groups wherein the number of groups attached to said linker through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting of R, R, R and R wherein R, R and R are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and R is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl is kk wherein kk is an integer selected from 2 to 20 wherein said integer represents the number of amide and ester forming functions present on said linker with a range of from two to the, maximum number of amide and ester forming functions present on said linker with the proviso that no more than 5 each of la, Ib, Ic, and Id are connected by said amide and ester forming linker wherein said amide and ester forming linker is selected from the group consisting of carboxylic acid compounds of carbon selected from synthetic amino acids, natural amino acids, aldaric acids, citric acid cycle intermediates, alkylpolycarboxylic acids, arylpolycarboxylic acids and heteroarylpolycarboxylic acids wherein 2 to 20 acylating groups are present, said carboxylic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of phosphates, phosphonates, sulfonates, and sulfates, and said carboxylic acid compounds can be optionally substituted with acylateable substituents selected from the group consisting of amino, hydroxy, and sulfhydryl; B7 can be an amide and ester forming linker selected from the group consisting of phosphoric acid compounds of carbon selected from the group consisting of phosphoric acid esters of saccharides, hydroxyaryls and heterocycles, phosphoric acid amides of amines, anilines, and aminoheterocycles wherein 2 to 20 acylating groups are present and said phosphoric acid compounds of carbon may be optionally substituted with acylating substituents selected from the group consisting of carboxylates, phosphonates, sulfonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl;

B7 can be an amide and ester forming linker selected from the group consisting of phosphonic acid compounds of carbon selected from the group consisting of multiply phosphonoalkylated ammonia, primary amines, primary and secondary diamines, primary and secondary triamines, primary and secondary tetramines, primary and secondary ethyleneimines, and primary and secondary propyleneiminines and multiphosphonated alkanes, alkenes, alcohols, carboxylic acids, arenes, heterocyclyl radicals, and amino acids wherein 2 to 20 acylating groups are present and said phosphonic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, sulfonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl; B7 can be an amide and ester forming linker selected from the group consisting of sulfonic acid compounds of carbon selected from the group consisting of multiply sulfonoalkylated ammonia, primary amines, primary and secondary diamines, primary and secondary triamines, primary and secondary tetramines, primary and secondary ethyleneimines, and primary and secondary propyleneiminines and multisulfonated alkanes, alkenes, alcohols, carboxylic acids, arenes, heterocyclyl radicals, and amino acids wherein 2 to 20 acylating groups are present and said sulfonic acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates, phosphonates, and sulfates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl; B7 can be an amide and ester forming linker selected from the group consisting of sulfuric acid compounds of carbon selected from the group consisting of sulfuric acid esters of saccharides, hydroxy aryls and heterocycles, and sulfuric acid amides of amines, anilines, and aminoheterocycles wherein 2 to 20 acylating groups are present and said sulfuric acid compounds of carbon may be optionally substituted with one or more acylating substituents selected from the group consisting of carboxylates, phosphates,

sulfonates, and phosphonates and optionally substituted with one or more acylateable substituents selected from the group selected from amino, hydroxy, and sulfhydryl; B8 is a linker connecting a first group independently selected from the group consisting of la, Ib, Ic, and Id through the point of bonding of a removable hydrogen of a group selected independently from A and R to a second group independently selected from the group consisting of Ia, Ib, Ic, and Id through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting of R1, R and R wherein R, R and R are independently selected from hydrogen, hydroxy, and sulfhydryl wherein said linker is selected from the group consisting of a covalent single bond with the proviso that R is other than hydroxy and sulfhydryl, (CR19R20)uQQ(CCR19R20(CR19R20)jCR19R20,CR7R20(CR7R20)jCR7R20 , (CR19R20)xT(CR19R20)yandR19R20)w,(CR7R20)uQQ(CR7R20)w, (CR7R20)xT(CR7R20)y wherein j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8; B9 is a linker connecting a first group independently selected from the group consisting of Ia, Ib, Ic, and Id from the point of attachment of A-R to a second group independently selected from the group consisting of Ia, Ib, Ic, and Id through the point of bonding of a removable hydrogen of a substituent independently selected from a group of substituents consisting of R1, R3, R4 and R8 wherein R1, R3 and R4 are independently selected from the group consisting of hydrogen, hydroxy, and sulfhydryl and is selected from the group consisting of hydroxyalkyl, aminoalkyl, alkylaminoalkyl and sulfhydrylalkyl and wherein said linker is selected from the group consisting of Hljnk-

Hlink-CR19R20(CR19R20)jCR19R20-Alink,Hlink-CR7R20(CR7R20)jCR 7R20-Alink, Hlink-(CR19R20)uQQ(CR19R20)w-Alink,Hlink-(CR7R20)uQQ(CR7R20) w-Alink, Hlink-(CR7R20)xT(CR7R20)y-Alinkwherein(CR190R20)xT(CR19R20)y -Alink,and j is selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0 to 8 with the provisos that only one Alink and Hlink can be simultaneously a covalent single bond, Alink is connected to the point of bonding of a removable hydrogen of a group of substituents consisting of R, R, R and R, and Hlink is connected only to the point of bonding of A- R7 ; Bg can be selected from the group consisting of bifunctional compounds of carbon wherein said compounds of carbon have one or more acylateable groups selected from the group consisting of primary amino, secondary amino, hydroxy, and sulfhydryl and one or more acylating groups selected from carboxy, thionocarboxy, sulfonyl, sulfate, sulfinyl, phosphate, and phosphonyl, wherein said compounds of carbon may be optionally substituted with one or more R31 groups, wherein said acylateable group is connected to the point of bonding of A-R and wherein said acylating group is connected to the point of bonding of a removable hydrogen of a substituent group selected from R, R, R and R ; B 10 is a linker connecting a first group independently selected from the group consisting of la, Ib, Ic, and Id through the point of bonding of a removable hydrogen of a group selected independently from A and R to a second group independently selected from the group consisting of la, Ib, Ic, and Id through the points of bonding of both 12 12 substituents R and R wherein R and R are both removable hydrogens and wherein

said linker is selected from the group consisting of CR19R20(CR19R20)jCR19R20-Dlink (CR19R20)uQQ(CR19R20)w-Dlink,andCR7R20(CR7R20)jCR7R20-Dlink, (CR7R20)uQQ(CR7R20)w-Dlink,(CR19R20)xT(CR19R20)y-Dlink, andElink-T(CR7R20)ywhereinjis(CR7R20)xT(CR7R20)y-Dlink,Elink -T(CR19R20)y selected from an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independently selected from an integer of0 to 8, Dlink is selected from a group consisting of a covalent single bond and =C(R15), and selectedfromais group consisting of a covalent single bond and a covalent double bond with the proviso that only Dlink and Elink can bond to the points of bonding of R1 and R2; B11B11is a linker connecting a first group independently selected from the group consisting of Ia, Ib, Ic,and Id from the point of attachment of A-R7 to a second group independently selected from the group consisting of Ia, Ib, Idthroughthepointsofand bonding of both substituents R1 and R2 whrein R1 and R2 are both removable hydrogens and wherein said linker is selected from the group consisting of Hlink- Hlink-CR19R20(CR19R20)jCR19R20-Dlink,Hlink-CR7R20(CR7R20)jCR 7R20-Dlink, Hlink-(CR19R20)uQQ(CR19R20)w-Dlink,Hlink-(CR7R20)uQQ(CR7R20) w-Dlink, Hlink-(CR19R20)xT(CR19R20)y-Dlink,Hlink-(CR7R20)xT(CR7R20)y- Dlink, Hlin-(CR7R20)xT-Elinkwhereinjisselectedfromanintegerof(CR19R 20)xT-Elinkand 0 to 18, u and w are independently selected from an integer of 1 to 8, x and y are independentlyindependentlyselected from an integer of0 to 8, Dlink is selected form a covalent single bond and Elinkisselectedfromthegroupconsistingofacovalentsingleand bond and covalent double bond with the provisos that only one Hlinkand can be

simultaneously a covalent single bond, and Hljnk is connected only to the point of bonding of A-R7 ; B l 2 is a linker connecting a first group independently selected from the group consisting of la, Ib, In, rand Id from the point of attachment of A-R to a second group independently selected from the group consisting of Ia, Ib, Ic, and Id through the point of bonding of a removable hydrogen of a group selected independently from the group consisting of A and R wherein said linker is selected from the group consisting of covalent single bond, Hlink-CR7R20(CR7R20)jC Hlink-(CR7R20)uQQ(CR7R20)w,Hlink-R7R20,Hlink-(CR19R20)uQQ(CR 19R20)w, Hlink-(CR7R20)XT(CR7R20)ywhereinjisselectedfrom(CR19R20)xT(C R19R20)yand an integer of 0 to 18, u and w are independently selected from an integer of 1 to 8, and x and y are independently selected from an integer of 0to 8 with the proviso that only Hlink can be bonded to the point of attachment of A-R7; B 13 is a linker connecting a first group independently selected from the group consisting of Ia, Ib, Ic, and Id from the points of attachment of A-R and R to a second group independently selected from the group consisting of Ia, Ib, Ic, and Id from the point of attachment of A-R and R wherein said linker consists of a single covalent bond connecting A-R7 point of attachment of said first group to the point of attachment of R1 of said second group and a single covalent bond connecting A-R7point of attachment of said second group to the point of attachment of R of said first group;

B14 is a linker connecting a first group independently selected from the group consisting of Ia, Ib, Id,whereinand A is R26, from the points of attachment of J2, R1 and R2 to a second group independently selected from the group consisting of Ib, Ic, and Id, wherein A is R26, from the points of attachment of J1, andR2whereinR1 said linker consists of a double covalentbond connecting the point of attachment of J1 and J2 of said first group to the points of attachment of R1 and R2 of said second group and a double covalent bond conncting the point of attachment of J1 and J2 of said second group to the points of attachment of R1 and R2 of said first group; B15 is a liker connecting a first group independenlty selected from the group consisting of Ia, Ib, Ic, and Id from the points of attachment of A-R7, R1 and R2 to a second group independently selected from the group consisting of Ia, Ib, and Id, wherein A is R26, from the points of attachment of J1, R1wheresaidlinkerand consists of a single covalent bond connecting A-R7 point of attachment of said first group to the point of attachment of R1 of said second group and a double covalent bond connecting the point of attachment of J1 and saidsecondgrouptothepointsofof attchment of R1 and R2 of said first group; Alink is independently selected from the group consisting of covalent single bond, C=O, C(O)C(O), C=S, S=O, SO2, S(O)2O, Si(R24R25)2, P(O)R30, and C(OR6)(R19);

Hlink is independently selected from the group consisting of a covalent single bond, N(R30),ON(R30),SN(R30),N(R30)O,N(R30)S,N(R30)N(R31),S, ON(R30)C(O),ON(R30)C(S),N(R30)N(R31)C(O),N(R30)C(O),N(R30)C( S), N(R30)N(R31)P(O)R30,N(R30)N(R31)C(S),N(R30)N(R31)P(OR31)R30, N (R) N(R31)P(S)R30, ON(R30) P (O) R30 ON (R30) P (S) R, SN (R) P (O) R, SN (R) P (S) R30, ON (R) C (O) O, ON (R) C (S) O, ON (R) C (O) N (R39), ON (R) C (S) N(R30)N(R31)C(O)O,N(R30)N(R31)C(O)S,N(R30),ON(R30)C(S)S, N(R30)N(R31)C(S)S,N(R30)N(R31)C(O)N(R31),N(R30)N(R31)C(S)O, N(R30)N(R31)P(O)R30,N(R30)N(R31)C(S)N(R31),N(R30)N(R31)P(OR3 1)R30, N(R30)N(R31)P(S)R30O,N(R30)N(R31)P(S)R30,N(R30)N(R31)P(O)R30 O, N(R30)N(R31)P(OR31)R30,N(R30)N(R31)P(O)R30S,N(R30)N(R31)P(S) R30S, N(R31)P(O)R30, N(R31)P(S)R30, N(R31)P(O)R30O, N(R31)P(S)R30O, N(R31)P(OR31)R30,N(R31)P(O)R30,N(R31)P(O)R30S,N(R31)P(S)R30S , ON(R30)P(S)R30,SN(R30)P(O)R30,N(R31)P(S)R30,ON(R30)P(O)R30, SN (R30) P (S) R30, ON (R30) S (O) tt, SN (R30) S (O) tt, andN (R) S (O) tt, N (R30) N (R31) S (O) tt where tt is 1 to 2; QQ is selected from the group consisting of O, ON (R30), C=O, C=S, S (O) t, Se (O) t wherein t is 0 to 2, N(R30)Se(O)tt,ON(R30)Se(O)ttN(R30)S(O)tt, wherein tt is 1 to 2, Si(R24R25)2, N(R30)n wherein 1to2,P(O)R30andOP(O)(R30).=

It is an object of the present invention to provide compounds that have usefulness as inhibitors of nitric oxide synthase. These compounds also preferentially inhibit the inducible form over the constitutive form by at least 3 fold- It is an advantage of the present invention that the compounds are more selective than those known in the art.

It is an object of the present invention to provide compounds that also are more selective man those known in the art.

It is an object of the present invention to provide compounds that have usefulness as inhibitors of nitric oxide synthase for longer periods of time.

It is an advantage of the present invention that the compounds are more useful for longer period of time than those known in the art.

It is an object of the present invention to provide compounds that have usefulness as inhibitors of nitric oxide synthase with control of the concentration of the inhibitor in the body.

It is an advantage of the presenti, nvention that the compounds control the concentration of the inhibitor in the body better than those known in the art.

It is also an advantage in that compounds of the present invention have preferred physical properties as compare to compounds known in the art. In contrast, NIL, which is disclosed in WO 93/13055 when the hydrochloride salt can be isolated as a colorless crystal, but has the property of deliquescence. The compound quickly becomes a very viscous sticky oil upon exposure to moisture in normal room air which makes it difficult to handle.

Also included in the family of compounds of Formula I, are the pharmaceutically- acceptable salts thereof. The term"pharmaceutically-acceptable salts"embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.

Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically- acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N, N'-dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.

While it may be possible for the compounds of Formula I to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition.

According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier (s) must be ! acceptable ! in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods

include the step of bringing into association a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof (active ingredienti) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use. Extemporaneous injection

solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.

Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day. The dose range for adult humans is generally from 0.005 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

The compounds of Formula I are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.

The use of generic terms in the description of the compounds are herein defined for clarity.

As utilized herein, the term"alkyl", either alone or within other terms such as "haloalkyl"and"alkylthio", means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms.

Said alkyl radicals may be optionally substituted with groups as defined below. Examples of such radicals include methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso- amyl, hexyl, octyl and the like., The term"alkenyl"refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Said alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propylenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2-2-methylbuten-1-yl, 3- methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.

The term"alkynyl"refers to an unsaturated, acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Said alkynyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.

The term"hydrido"denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a"hydroxyl"radical, one

hydrido radical may be attached to a carbon atom to form a"methine"radical , or two hydrido radicals may be attached to a carbon atom to form a"methylene" (-CH2-) radical.

The term"carbon"radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.

The term"cyano"radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.

The term"hydroxyalkyl"embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with a hydroxyl as defined above. Specifically embraced are monohydroxyalkyl, dihydroxyalkyl and polyhydroxyalkyl radicals.

The term"alkanoyl"embraces radicals wherein one or more of the terminal alkyl carbon atoms are substituted with one or more carbonyl radicals as defined below. Specifically embraced are monocarbonylalkyl and dicarbonylalkyl radicals.

Examples of monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl.

Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and succinyl.

The term"alkylene"radical denotes linear or branched radicals having from 1 to about 10 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, methylethylene, and isopropylidene.

The term"halo"means halogens such as fluorine, chlorine, bromine or iodine atoms.

The term"haloalkyl"embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are

monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical.

Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are"lower haloalkyl"radicals having one to about six carbon atoms.

Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

The term"hydroxyhaloalkyl"embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above.

The term"haloalkylene radical"denotes alkylene radicals wherein any one or more of the alkylene carbon atoms is substituted with halo as defined above. Dihalo alkylene radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkylene radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkylene radicals are"lower haloalkylene"radicals having one to about six carbon atoms. Examples of"haloalkylene"radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.

The term"haloalkenyl"denotes linear or branched radicals having from 1 to about 10 carbon atoms and having one or more double bonds wherein any one or more of the alkenyl carbon atoms is substituted with halo as defined above. Dihaloalkenyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkenyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.

The terms"alkoxy"and"alkoxyalkyl"embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term"alkoxyalkyl"also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy radicals are"lower alkoxy"radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy alkyls. The"alkoxy"radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy"radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethóxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.

The term"haloalkoxyalkyl"also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals. The term"haloalkenyloxy"also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals. The term "haloalkenyloxyalkyl"also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxyalkyl and dihaloalkenyloxyalkyl radicals.

The term"alkylenedioxy"radicals denotes alkylene radicals having at least two oxygens bonded to a single alkylene group. Examples of"alkylenedioxy" radicals include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy. The term"haloalkylenedioxy"radicals denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group. Examples of"haloalkylenedioxy"radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachluoroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.

The term"aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term"aryl"embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

The term"perhaloaryl"embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein the aryl radical is substituted with 3 or more halo radicals as defined below.

The term"heterocyclyl"embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e. g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e. g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e. g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed"heteroaryl"radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e. g., 4H-1,2,4-triazolyl, lH-1,2,3-triazolyl, 2H-1,2,3- triazolyl, etc.] tetrazolyl [e. g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e. g., tetrazolo [1,5-b] pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5-to 6-membered heteromonocyclic group containing 1 to 2 oxygen

atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e. g., 1, 2, 4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e. g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e. g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5- thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e. g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said"heterocyclyl"group may have 1 to 3 substituents as defined below. Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. Non-limiting examples of heterocyclic radicals include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4- thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4- dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo (b) thiophenyl, benzimidazonyl, quinolinyl, tetraazolyl, and the like.

The term"sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals-SO2-."Alkylsulfonyl", embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above.

"Alkylsulfonylalkyl", embraces alkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfonyl", embraces haloalkyl radicals attached to a sulfonyl radical, where haloalkyl is defined as above.

"Haloalkylsulfonylalkyl", embraces haloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term"aminosulfonyl"denotes an amino radical attached to a sulfonyl radical.

The term"sulfinyl", whether used alone or linked to other terms such as alkylsulfinyl, denotes respectively divalent radicals-S (O)-."Alkylsulfinyl", embraces alkyl radicals attached to a sulfinyl radical, where alkyl is defined as above.

"Alkylsulfinylalkyl", embraces alkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. "Haloalkylsulfinyl", embraces haloalkyl radicals attached to a sulfinyl radical, where haloalkyl is defined as above.

"Haloalkylsulfinylalkyl", embraces haloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term"aralkyl"embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are"lower aralkyl"radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable.

The term"heteroaralkyl"embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals. The term"perhaloaralkyl"embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.

The term"aralkylsulfinyl", embraces aralkyl radicals attached to a sulfinyl radical, where aralkyl is defined as above."Aralkylsulfinylalkyl", embraces aralkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term"Aralkylsulfonyl", embraces aralkyl radicals attached to a sulfonyl radical, where aralkyl is defined as above."Aralkylsulfonylalkyl", embraces aralkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term"cycloalkyl"embraces radicals having three to ten carbon atoms.

More preferred cycloalkyl radicals are"lower cycloalkyl"radicals having three to

seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term"cycloalkylalkyl"embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are"lower cycloalkylalkyl"radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclohexylhexyl. The term"cycloalkenyl"embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. Preferred cycloalkenyl radicals are"lower cycloalkenyl"radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term "halocycloalkyl"embraces radicals wherein any one or more of the cycloalkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl radicals. A monohalocycloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhalocycloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred halocycloalkyl radicals are"lower halocycloalkyl"radicals having three to about eight carbon atoms. Examples of such halocycloalkyl radicals include fluorocyclopropyl, difluorocyclobutyl, trifluorocyclopentyl, tetrafluorocyclohexyl, and dichlorocyclopropyl. The term"halocycloalkenyl" embraces radicals wherein any one or more of the cycloalkenyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl radicals. The term"halocycloalkoxy"also embraces cycloalkoxy radicals having one or more halo radicals attached to the cycloalkoxy radical, that is, to form monohalocycloalkoxy, dihalocycloalkoxy, and polycycloalkoxy radicals.

The term"Cycloalkylsulfinyl", embraces cycloalkyl radicals attached to a sulfinyl radical, where cycloalkyl is defined as above."Cycloalkylsulfinylalkyl", embraces cycloalkylsulfinyl radicals attached to an alkyl radical, where alkyl is defined as above. The term"Cycloalkylsulfonyl", embraces cycloalkyl radicals

attached to a sulfonyl radical, where cycloalkyl is defined as above.

"Cycloalkylsulfonylalkyl", embraces cycloalkylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term"alkylthio"embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are"lower alkylthio"radicals having one to six carbon atoms. An example of"lower alkylthio"is methylthio (CH3-S-). The term"alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent-S (=O)- atom.

The terms alkylamino denotes"monoalkylamino"and"dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical. The terms arylamino denotes"monoarylamino"and"diarylamino"containing one or two aryl radicals, respectively, attached to an amino radical. The term"Aralkylamino", embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above. The term aralkylamino denotes"monoaralkylamino"and"diaralkylamino" containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes"monoaralkyl monoalkylamino"containing one aralkyl radical and one alkyl radical attached to an amino radical.

The term"arylsulfinyl"embraces radicals containing an aryl radical, as defined above, attached to a divalent-S (=O)- atom. The term"arylsulfinylalkyl"denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.

The term"Arylsulfonyl", embraces aryl radicals attached to a sulfonyl radical, where aryl is defined as above. "Arylsulfonylalkyl", embraces arylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above. The term "heteroarylsulfinyl"embraces radicals containing an heteroaryl radical, as defined above, attached to a divalent-S (=O)- atom. The term"heteroarylsulfinylalkyl"denotes

heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms. The term"Heteroarylsulfonyl", embraces heteroaryl radicals attached to a sulfonyl radical, where heteroaryl is defined as above."Heteroarylsulfonylalkyl", embraces heteroarylsulfonyl radicals attached to an alkyl radical, where alkyl is defined as above.

The term"aryloxy"embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.

The term"aroyl"embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.

The term"aralkanoyl"embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.

The term"aralkoxy"embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy"radicals having phenyl radicals attached to lower alkoxy radical as described above.

The term"aryloxyalkyl"embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl.

The term"haloaryloxyalkyl"embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group. The term "heteroaryloxy"embraces heteroaryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include pyridyloxy and furyloxy.

The term"heteroaroyl"embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.

The term"heteroaralkanoyl"embraces heteroaralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, pyridylacetyl and furylbutyryl.

The term"heteroaralkoxy"embraces oxy-containing heteroaralkyl radicals attached through an oxygen afom to other radicals. More preferred heteroaralkoxy radicals are"lower heteroaralkoxy"radicals having heteroaryl radicals attached to lower alkoxy radical as described above.

The term"heteroaryloxyalkyl"embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridyloxymethyl.

The term"haloheteroaryloxyalkyl"embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.

The term"arylthio"embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.

The term"arylthioalkyl"embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.

The term"alkylthioalkyl"embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl. The term"alkoxyalkyl"embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.

The term"carbonyl"denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom. The term"carboxy"embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group. The term"carboxamide"embraces amino, monoalkylamino, and dialkylamino radicals, attached to one of two unshared bonds in a carbonyl group. The term "carboxamidoalkyl"embraces carboxamide radicals, as defined above, attached to an alkyl group. The term"carboxyalkyl"embraces a carboxy radical, as defined above, attached to an alkyl group. The term"carboalkoxy"embraces alkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term "carboaralkoxy"embraces aralkoxy radicals, as defined above, attached to one of two unshared bonds in a carbonyl group. The term"monocarboalkoxyalkyl"embraces one carboalkoxy radical, as defined above, attached to an alkyl group. The term "dicarboalkoxyalkyl"embraces two carboalkoxy radicals, as defined above, attached to an alkylene group. The term"monocyanoalkyl"embraces one cyano radical, as defined above, attached to an alkyl group. The term"dicyanoalkylene"embraces two cyano radicals, as defined above, attached to an alkyl group. The term "carboalkoxycyanoalkyl"embraces one cyano radical, as defined above, attached to an alkylene group.

The term"acyl", alone or in combination, means a carbonyl or thionocarbonyl group bonded to a radical selected from, for example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino, alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl. Examples of"acyl"are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like. The term"haloalkanoyl"embraces one or more halo radicals, as defined herein, attached to an alkanoyl radical as defined above.

Examples of such radicals include, for example, chloroacetyl, trifluoroacetyl, bromopropanoyl, and heptafluorobutyryl.

The term"phosphono"embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical. The term"dialkoxyphosphono"denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term"diaralkoxyphosphono"denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds. The term"dialkoxyphosphonoalkyl" denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical. The term"diaralkoxyphosphonoalkyl"denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.

The structural term, H (W) C=C (K) E, alone or in combination, means cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, cyanocarboalkoxycycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, or acylalkyl wherein at least one of W, E, and K are independently selected from carboxy, thionocarboxy, thiolcarboxy, cyano, carboxamido, thionocarboxamido, carboalkoxy, thionocarboalkoxy, thiocarboalkoxy, acyl, thionoacyl, formyl or thionoformyl provided any two of W, E, or K may be taken together to form a spacer group selected from a linear moiety having a chain length of 1 to 4 atoms to form a C5 to C8 saturated carbocyclyl, a C5 to C8 partially saturated carbocyclyl, a C5 to C8 saturated heterocyclyl or a C5 to C8 partially saturated heterocyclyl substituted independently and optionally with, for example, one or more alkyl, haloalkyl, aryl, heteroaryl, alkoxyalkyl, alkoxy, haloalkoxy, cyano, carboalkoxy, hydroxy, hydroxyalkyl, and halo groups.

Said"alkyl","alkenyl","alkynyl","alkanoyl","alkylene","hydro xyalkyl", "haloalkyl","haloalkylene","haloalkenyl","alkoxy","alkoxyalk yl","aryl", <BR> <BR> <BR> "haloalkoxyalkyl","alkylenedioxy","heterocyclyl","heteroaryl ","hydroxyhaloalkyl",<BR> <BR> <BR> <BR> <BR> <BR> "alkylsulfonyl","alkylsulfonylalkyl","haloalkylsulfonylalkyl ","alkylsulfinyl",<BR> <BR> <BR> <BR> <BR> <BR> "alkylsulfinylalkyl","haloalkylsulfinylalkyl","aralkyl","het eroaralkyl","perhaloaralkyl",<BR> <BR> <BR> <BR> <BR> "aralkylsulfonyl","aralkylsulfonylalkyl","aralkylsulfinyl"," aralkylsulfinylalkyl",<BR> <BR> <BR> <BR> <BR> <BR> "cycloalkyl","cycloalkenyl","halocycloalkyl","halocycloalken yl","cycloalkylsulfinyl",<BR> <BR> <BR> <BR> <BR> <BR> "cycloalkylsulfinylalkyl","cycloalkylsulfonyl","cycloalkylsu lfonylalkyl","cycloalkoxy",

"alkylthio","alkylsulfinyl","alkylamino","arylamino","aralky lamino","arylsulfinyl",<BR> <BR> <BR> <BR> <BR> <BR> "arylsulfinylalkyl","arylsulfonyl","arylsulfonylalkyl","hete roarylsulfinyl",<BR> <BR> <BR> <BR> <BR> <BR> "heteroarylsulfinylalkyl","heteroarylsulfonyl","heteroarylsu lfonylalkyl","aryloxy",<BR> <BR> <BR> <BR> <BR> "aroyl","aralkanoyl","aralkoxy","aryloxyalkyl","haloaryloxya lkyl","heteroaroyl", "heteroaralkanoyl","heteroaralkoxy","heteroaralkoxyalkyl","a rylthio","arylthioalkyl", "alkoxyalkyl", and"acyl"groups defined above may optionally have 1 to 3 substituents such as heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy.

The term"spacer"can include a covalent bond and a linear moiety having a backbone of 1 to 7 continuous atoms. The spacer may have 1 to 7 atoms of a univalent or multi-valent chain. Univalent chains may be constituted by a radical selected from =C (H)- , =C (R6)-,-O-,-S-,-S (O)-,-S (O) 2-,-NH-,-N (R6)-,-N=,-CH (OH)-, =C (OH)-,-CH (OR6)-, =C (OR6)-, and-C (O)-. Multi-valent chains may consist of a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4 or 5 or 6 or 7 atoms with a side chain. The chain may be constituted of one or more radicals selected from: lower alkylene, lower alkenyl,-O-,-O-CH2-,-S-CH2-,-CH2CH2-, ethenyl,-CH=CH (OH)-,- <BR> <BR> <BR> OCH2O-,-O (CH2) 2O-,-NHCH2-,-OCH (R6) 0-,-O (CH2CHR6) 0-,-OCF2O-,-O (CF2) 20-, -S-,-S (O)-,-S (O) 2-,-N (H)-,-N (H) O-,-N (R6) O-,-N (R6)-,-C (O)-,-C (O) NH-,-C (O) NR6-,

-N=,-OCH2-,-SCH2-, S (O) CH2-,-CH2C (O)-,-CH (OH)-, =C (OH)-,-CH (OR6)-, =C (OR6)-, S (O) 2CH2-, and-NR6CH2-and many others radicals defined above or generally known or ascertained by one of skill-in-the art. Side chains may include substituents such as heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, alkoxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, hydroxy, amino, thio, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heferoarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboalkoxy, carboaralkoxy, cyano, and carbohaloalkoxy.

The term"prodrug"refers to a compound that is made more active in vivo.

As used herein, reference to"treatment"of a patient is intended to include prophylaxis.

All references, patents or applications, U. S. or foreign, cited in the application are hereby incorporated by reference as if written herein.

Compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis-and trans-geometric isomers, E-and Z-geometric isomers, R-and S-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention. Pharmaceutically acceptable sales of such tautomeric, geometric or stereoisomeric forms are also included within the invention.

The terms"cis"and"trans"denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have two highes ranking groups on the same side of the double bond ("cis") or on opposite sides of the double bond ("trans").

Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or"E"and"Z"geometric forms.

The term"oligomeric"denotes a form of compound in which two to about twenty analogous units of similar function and biological activity are covalently joined one to another directly, through a linker compound, through a mixture of linker compounds, or through a combination of the aforementioned means.

The term"linker"denotes a covalent bond and any group of atoms that covalently joins together two to twenty analogous units of similar function and biological activity.

The term"linker compound"denotes any inorganic and organic material and compound able to covalently join together two to twenty analogous units of similar function and biological activity.

The term"removable hydrogen"denotes a hydrogen that can be removed by reaction with a base or removed by replacement by an alkylating or acylating reagent.

Said hydrogen removing base will have a pKa of a minimum of about 15 relative to water when, for example, a hydrogen is to be removed from a carboxylic acid, a phenol, a sulfate acid, a phosphate acid, an acetoacetate, a malonate, mercaptan, dinitriles, nitroalkane, and the like. Suitable bases having a pKa of about 15 include potassium hydroxide, sodium carbonate, sodium methoxide, triethylamine, sodium ethoxide, tetrabutylammonium hydroxide, and the like. Preferably, the base will have a pKa up to about 30 so that a hydrogen can be removed in a substantially complete manner from alcohols, amides, mononitriles, monoesters, and the like. Examples of preferable bases include potassium tert-butoxide, sodium hydride, sodium amide, lithium diisopropylamine and the like. Acylating reagents able to remove a hydrogen by replacement include anhydrides of carboxylic acids and halides (for example, chloride) of carboxylic acids, sulfate acids, phosphate acids, phosphonate acids and the like.

The term"bifunctional compounds of carbon"denotes linker compounds having two types of functional substituents. One type of functional substituent group can be acylated. Acylateable groups include primary amino, secondary amino, hydroxy, sulfhydryl, and the like. The second type of functional substituent are those that can acylate functional substituents. Acylating groups include carboxy, thionocarboxy, sulfonyl, sulfate, sulfinyl, phosphate, and phosphonyl. Most preferred are activated forms of the said acylating groups where the hydroxy function or salt form are converted into more reactive intermediates such as esters, chlorides, azides, cyanides, oxyimides, isoureas, mixed anhydrides, and the like. Examples of"bifunctional compounds of carbon"include natural and synthetic amino acids such as glycine, alanine, lysine, glutamate, ornithine, serine, threonine, phenylalanine, tyrosine, valine, 4-aminobutanoic acid, and the like, peptides, sugar phosphates such as glycerol phosphate, glucose-6- phosphate, aldonic acids such glucuronic acid, aldaric acids such as glucaric acid, aminoalkylphosphonic acids such as aminomethylphosphonic acid, N, N-bis- phosphonomethylamine, aminoarylcarboxylic acids such as 4-aminobenzoic acid.

Some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures of R and S forms for each stereocenter present.

Some of the compounds described herein may contain one or more ketonic or aldehydic carbonyl groups or combinations thereof alone or as part of a heterocyclic ring system. Such carbonyl groups may exist in part or principally in the"keto"form and in part or principally as one or more"enol"forms of each aldehyde and ketone group present. Compounds of the present invention having aldehydic or ketonic carbonyl groups are meant to include both"keto"and"enol"tautomeric forms.

Some of the compounds described herein may contain one or more imine or enamine groups or combinations thereof. Such groups may exist in part or principally in the"imine"form and in part or principally as one or more"enamine"forms of each group present. Compounds of the present invention having said imine or enamine groups are meant to include both"imine"and"enamine"tautomeric forms.

The following general synthetic sequences are useful in making the present invention. Abbreviations used in the schemes are as follows:"AA"represents amino acids,"Boc"represents tert-butyloxycarbonyl,"BOP"represents benzotriazol-1-yl-oxy- tris- (dimethylamino) phosphonium hexafluorophosphate,"Bz"represents a benzyl group, "CMR-Cl"represents a chloromethylation or bromomethylation reagent such as Cl- CH20C (O) R15, Cl-CH2NR9C (O) R'S, Cl-CH2NR'9C (S) R", Cl-CH2SC (O) R", Cl- CH2SC (S) R'S, Cl-CH2OC (O) GRS, Cl-CH2NR'9C (O) GR'S, Cl-CH2NR'9C (S) GRl5, Cl-CH20C (S) GR15, or Cl-CH2SC (S) GRl5,"DCC"represents 1,3- dicyclohexylcarbodiimide,"DIBAH"represents diisobutylaluminum hydride,"DIPEA" represents diisopropylethylamine,"DMF"represents dimethylformamide,"DMSO" represents dimethylsulfoxide,"Fmoc"represents 9-fluorenylmethoxycarbonyl,"LDA" represents lithium diisopropylamide,"PHTH"represents a phthaloyl group,"pnZ" represents 4-nitrobenzyloxycarbonyl,"PTC"represents a phase transfer catalyst,"TCC" represents trichloroethoxy carbonyl,"p-TsOH"represents paratoluenesulfonic acid, "TBTU"represents 2- (lH-benzotriozole-l-yl)-1, 1, 3,3-tetramethyl uronium tetrafluoroborate,"TEA"represents triethylamine,"TFA"represents trifluoroacetyl, "THF"represents tetrahydrofuran,"THP"represents tetrahydropyranyl, and"Z"represents benzyloxycarbonyl.

Disclosed are eighty-eight synthetic processes useful in the preparation of intermediates (ie, precursors) to the compounds of the present invention. The use of"E" in the structures of these preparatory methods refers to the substituent"E"as defined in structural term, H (W) C=C (K) E, above. The use of"Z"in the structures of these preparatory methods refers to the use of"Z"refers to the benzyloxycarbonyl group as defined in the paragraph immediately above. I The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. Scheme 1 R3 0 O \ HN \ A-R 1. a Y R8 H 2, au . 3 aR3 N (2) e p 3 R N \ A_R7 d Y Cl N 0 y Cl N 0 YR8 BOCHN (5) (6) Boc HN c 0 0 . c 0 0 y u i y U Z-HN 8 A-R Z-HN OH 8 BocHN (4) BocHN (3) (a) R3 -NH2 (aa) N-chlorosuccimide, DMF (b) BOP, DIPEA, DMF (c) Pd, H2, Ethanol/Acetic Acid (d) H20, pH 9-10 (e) HC1, dioxane or trifluoroacetic acid. Scheme 2 N--*, H 0 N O JL or (2a) (7) R a a H2N \a ZON (2b) 0/H \ OCH3 N \A-R7 d W R8 Y HN \ A_R7 8 BocHN (5) (6) BocHN 0 H-A-R7 Z-HN OH 7.. * 8 BocHN (3) BocHN (4) (a) HC1, Methanol (b) BOP, DIPEA, DMF (c) Pd, H2, Ethanol/Acetic Acid (d) TEA, DMF (e) HC1, dioxane or trifluoroacetic acid /R3 Scheme 3 N O 1 O R8 H2N Aa y H a2. aa (7) H2N a, (1) \ s/R3 i N e (2) O 3 R Y"Cl N 0 y ci N 0 HZ \ A_R7 d 8 A_R7 W 8 z-HN (10) j (11) Z-HN c O O Boc-8 OH BocHN X \A-R7 R R Z-HN (8) Z-HN (9) (a) R3-NH2 (aa) N-chlorosuccimide, DMF (b) BOP, DIPEA, DMF (c) HC1, dioxane or trifluoroacetic acid (d) H20, pH 9-10 (e) Pd, H2, Ethanol/Acetic Acid Scheme 4 (a) HC1, Methanol (b) BOP, DIPEA, DMF (c) HC1, dioxane or trifluoroacetic acid (d) TEA, DMF (e) Pd, H2, Ethanol/Acetic Acid /Boc N Scheme 5 (13) 7 -ruz HAN WE_1E 8 /Boc N O Boc (14) N O I Y HN \ A_R7 b Boc- (14) HN A-R 8 Y JX HN < A 1t//< A-R 7(12 i ! Z HN W/~ EZ-HN w E W- H ah N O 1 JL y HN < A-R7 p8 (11) R8 Z-HN (a) t-Butoxycarbonyl azide, H2O, dioxane, MgO (b) Pd, H2, Ethanol/Acetic Acid (c) TEA, 0-80 °C Boc o Scheme 6 (14) y \ -ruz un \au b w E w (E-1) E H boy Boc ? H HN A-R7 I y w R8 O e K H K b Y HNA_R7 N \ R8 H H HN K H E w H K b H N 0 R /H zips A-R R8 (17) W H : N E H K H K w E E E H K (a) TEA, 0-80 °C (b) HC1, dioxane Scheme 7 OH 0 H3C H2 < C02H a H3 C O H02C NH-Boc (19) O H-A-R7 b . t CH3 NH-Boc C (O)-A-R7 c c OH R7_A- (O) C NH-Boc (21) d if R7-A-(o) C NH-Boc (22) N-R1 e II t rR7 _A- (0) NH-Boc (23) (R1 = hydroxyl, sulfhydryl, OR 6 or SR6) (a) 1. t-butoxycarbonylazide, H 20, dioxane, MgO 2. acetic anhydride, TEA (b) BOP, DIPEA, DMF (c) 1 equiv. NaOH, ethanol (d) DMSO, DCC, H 3PO4 (e) R1-NH2, ethanol, sodium carbonate Scheme 8 hydroxyl,sulfhydryl,OR6orSR6)(a)BH3,THF(R1= (b) Acylation with R2: a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions (c) HCl, dioxane or trifluoroacetic acid . (d) H20, pH 9-10 with (2) or TEA, DMF with (2b) Scheme 9 (a) 1. t-butoxycarbonylazide, H2O, dioxane, MgO 2. acetic anhydride, TEA (b) BOP, DIPEA, DMF (c) 1 equiv. NaOH, ethanol (d) DMSO, DCC, H3PO4 (e) R2-NH2 (R2 = hydroxyl, sulfhydryl, OR6 or SR6), . ethanol, sodium carbonate Scheme 10 (R2= hydroxyl, sulfhydryl, OR6 or SR6) (a) BH3, THF (b) Acylation with R : a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions (c) HC1, dioxane or trifluoroacetic acid (d) H20, pH 9-10 with (2) or TEA, DMF with (2b) R3 O N 0 Scheme 11) ! y HNA-R 8 O < (31) R1-HN V a, 8 H 2. au NR 0 1 (2) y cri y C1 Z-H A-R7 1. d, then 2. e i R1- RI-HN (30) c 0. ? Z-H A-R7 Z-HN A-R7 8 R Boc HN H2N (29) BocHN (4) (a) R3-NH2 (aa) N-chlorosuccimide, DMF (b) HCl, dioxane or trifluoroacetic acid (c) Acylation with R1 : a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions (d) Pd, H2, Ethanol/Acetic Acid (e) H20, pH 9-10 Scheme 12 H N O Y-CN y liN A-R 7 R (2a) a (31) R1-HN a \, N/ 2b) 0 1 (2b) onc OCH 3 Z-H < A-R w 8 1. d, then 2. e R-HN oo) c 0 n cZ-H A-R b 8 8 BOCHE (29) (a) HC1, Methanol (b) HC1, dioxane or trifluoroacetic acid (c) Acylation with R : a carboxylic acid choride or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions (d) Pd, H2, Ethanol/Acetic Acid (e) TEA, DMF Scheme 13 R3 / l y HN \ A-R R8 R2-HN y 2. aa R3 (2 ! y Cl 1. d, then 2. e 2R-HN (32) R8 R-HN c Z-HII/) < < A-R7 8 "n0. K H2N (29) BocHN (a) R3-NH2 (aa) N-chlorosuccimide, DMF b) HCl, dioxane or trifluoroacetic acid (c) Acylation with R2: carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating eagent with standard conditions (d) Pd, H2, Ethanol/Acetic Acid (e) H20, pH 9-10 Scheme 14/H OR Y-CN y HN R8 A-R7 \ R8 (2a) (35) R2_HN a /H H (2b) 0 8 y OCH3 Z-H 8 A-R 1. d, then 2. e d i R2-HN (34)c O R8 ranz 2 O Z-HN Z-HN A-R7 "I \ Rg b R (29) BocHN H2N (29) ; (a) HC1, methanol (b) HCl, dioxane or trifluoroacetic acid (c) Acylation with R2: carboxylic choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions (d) Pd, H2, Ethanol/Acetic Acid (e) TEA, DMF Scheme 15 H N O /y/i\ HN < A-R 7z a/ (6) | R8l O Boc HNy HN A-R7 R8 ßb BocHN A-R R \ Z (36) goc HN N/ " ! N O \ A-R R (37) j i R8 H2 N 0 (40; R) N-R1 or-R2 c e LL (41; R2) R19 R20 N R R20 N RZ ! ! ii N 0 N z 0 (39) NH \R8 d N 8 Rl91R20 JX (38) Rl9 R20 (a) Benzyl chloroformate, Na 2CO3, THF, Water (b) HC1, dioxane or trifluoroacetic acid (c) catalytic p-TsOH, hexane or toluene, azeotropic distillation (d) Pd, H 2, Ethanol/Acetic Acid (e) Acylation with R 1 or R2 : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride or sulfinyl chloride with standard conditions. 3 Scheme 16 HN A-R \ R8 (7) H2N R319 R2 0 R3 1 y HN A-R 7 8 N JLL (42) R3 R19 R2 0 1 (R 1 ! t8 / ! ! NR I N_R1 or _R2 y HNA-R \R8 c R 19 R2 0 (43) nu YHNA-R y! 8 c J "---19R20 (43) NH" (44; Ri) R19R2 (45 ; R2) (a) catalytic p-TsOH, hexane or toluene, azeotropic distillation (b) Pd, H2, Ethanol/Acetic Acid (c) Acylation with R2:or carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride or sulfinyl chloride with standard conditions. Ruz O M 0 Scheme 17 R3 y HN A-R7 or Na0 SC H HN (4 6) or p8 8 HN b, 3 N')) \ O N < HN X A-R 7 R3 (31) NH R1 y HN A-R7 R3 b w R8 \ (33 ruz "/ B pizza A-R /ruz R2 _N-R 1 (a) NaO3SCH20H, pH 10-11 [see L. Maier, Phosphorus, Sulfur Silicon Related Elements (1990), 47,43-46] (b) 1. Aldehyde, acetal with trace of acid, or ketone, methanol or ethanol, 2. NaCNBH3, methanol, KOH [see R. F. Borch, Organic Synthesis, 52,124 (1972) 3 Scheme 18 8/R3 R3 a p y HNA-R I \R8 I CC13CH20C (O) H (48) HN z N Z 1 (7) N/H2 N S N R3 H2Ns (52)/R3 N A-R N R3 \ | R8 R2 ho y HNA-R R3 y R8 N CC13CH20C (S) HN (49) e HN \ A-R 7 e NOS J R e S y HN < A-R7 R 2 1 (51) R8 d H2N (50) R HN (a) Trichloroethyl chloroformate, Na 2CO3, H2O, THF [see D. Gravel et al., Canadian Journal of Chemistry, 50, 3846 (1972] (b) Lawesson's Reagent, [Jones and Bradshaw, Chem. Reviews (1984), 84,17-30 and cited references.

(c) 1. Zinc dust, Acetic Acid, 2. Na 2CO3, H20 (d) Acylation with R 1 carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, or sulfinyl chloride with standard conditions (e) Acylation with R 2 with (d)-conditions. R Scheme 19 N/R s "I HN A-R 0 || R8 a (50 H2N R 1 R2 0 R3 .N \ S R (l 9 N R2 01 R3 syHN R8 A-R7 (54)/R3 /"' b R 19 R2 0 N-R1 or-R2 A-ru \ Rg R 19 R2 0 (55) NH (56 ; R) \ S I l; R2) Rl9 R2 o 5) NH (5 1) plRO (a) catalytic p-TsOH, hexane or toluene, azeotropic distillation (b) NaCNBH3, methanol, KOH [see R. F. Borch, Organic Synthesis, 52, 124 (1972) (c) Acylation with R2:or carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, or sulfinyl chloride with standard conditions. Scheme 20 R3 1 N 0 R N O y JX HN/< NR5 R7;(6R H) /Boc-HN R3 a N 0 y HN NR 7 N Q ° R8 (58/ Boc- Boy-HN R8 I (60) Boc-HN 0 19 b R R N O R3 0 N \ NR /R3 Y Rg 1 (59) N 0 H- J y H'lq NR7 R8 (61) HN 19 0 (a) 2 equivalents of Lithium Diisopropylamide, THF, C (0) Cl2 or C (S) Cl2 (b) HC1, dioxane or trifluoroacetic acid (c) 1. Lithium Diisopropylamide, THF, 2.2-haloalkanoate ester (R) (d) Na2CO3, toluene, heat 3 N (6 ; R5= H) 0 Scheme 21 1 Scheme 21 y HNNRSR R8 3 R3/| R8Boc-HN N"0 y HN NR7 R8 (62) Boc-HN c OR RO OR ! ii N B RO $ C b (6 4)- y HN NR7 8 N Boc-HN I ru PRO HN NR) OR R8 I (63) N /R3 je R 19 H 3 y HN NR 7 R (65) R (65) R19 (a) Lithium Diisopropylamide, THF, R19 then dialkyl acetal of a bromoalkanal 20 (b) HC1, dioxane or trifluoroacetic acid R20 (c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone o Scheme 22 axa 2. axa (1) R3 N 3 R 0 y Cl N 0 D-) 0- 1 R8 \ R8 4 BocHN (66) BocHN (67) (67) t 1. b 2. c R3 e O N O 1 N" H2 A-R7 y A-R7 4 BocHN (5) R H2N (68) (a) R3-NH2 (aa) N-chlorosuccimide, DMF (b) an aldehyde or ketone precursor toR4, catalytic p-TsOH, hexane or toluene, azeotropic distillation (c) NaCNBH3, methanol, KOH [see R. F. Borch, Organic Synthesis, 52,124 (1972)] (d) H20, pH 9-10 (e) HC1, dioxane or trifluoroacetic acid 3 Scheme 2 3/R3 y HN A-R7 OR a/|| (50) H2N R15 C1 R3 S N Y 1 or 2 \ S Y HN \A R RlsC1 R8 R3 R (69) R15 NH N s will R8 (70) R15 NH (0) ou 2 (a) Na2CO3, aqueous dioxane; Acylation with a carboxylic acid choride or anhydride (b) Na2CO3, aqueous dioxane; sulfonation with a sulfonyl chloride or sulfinyl chloride with standard conditions 3 Scheme 24 y HNA-R \ R8 HN a (7) 2N R/ b 1 or 2 (71) R Y/y HN < A-R7 *' Q/13-3 *"'- / 1 R15 1 O c Y HN R8 A_R7 (72) R1NH 0 c R 8 y ruz 1 or 2 y HN A-R R (73) F3C NH R3 / 0 y FiN \A-R 8 (74) F3C NH R 60 H (a) Na2CO3, aqueous dioxane; Acylation with carboxylic acid choride or anhydride (b) Na2CO3, aqueous dioxane; sulfonation with sulfonyl chloride or sulfinyl chloride with standard conditions (c) trifluoroacetic acid anhydride (d) aproticpolarsolventR6-OH, Scheme 25 CH2 OC (O) GR15 N 0 CH OC 0 GR15 Y.) (78) 1 RS (78) R8 OH H2 N (7 9) y 8A-R ___j O-Z Z-HN/CH20C (O) GR15 N e \ N o e 'H-A-R H-A-R y OH °~Z Z-HN t/ /CH2OC (0) GR15 bu 1. b y 8OCH3 8 (76) OH Z-HN ,,CH2 OC (0) GR15 a y OCH2CH3 HO-HN OCH3 R Z-HN (75) (a) TEA, DMF (b) benzyl chloroformate, Na2CO3, dioxane, water (c) NaOH, H20 (d) BOP, DIPEA, DMF (e) DMF, heat (f) Pd, H2, Ethanol Scheme 26CH20C (0) GR N 0 CH20C (0) GR j N" Y 8 A-R ( 3) -4 y N \A-R R R2-HN /R8 (82) R4 f f K E /CH2 OC (O) GR 15 Ka H Nl----e E W 7 /CHZOC (O) GR 25 Y' (81) R8. A'R ho N Y I 8 \ A_R7 A (8 R8 R Z-HN R /CH2 OC. ( O) GR 15 Z-HN a 1. b 1. b 2. c OCH2CH3 R4- A-R (79a) R8 (a) TEA, DMF Z-HN Z-HN (b) an aldehyde or ketone precursor to R4, catalytic p-TsOH, hexane or toluene, azeotropic distillation (c) NaCNBH3, methanol, KOH [see R. F. Borch, Organic Synthesis, 52,124 (1972)] (d) Pd, H 2, Ethanol (e) TEA, 0-80 °C (f) Acylation with R 2: carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonation reagent with standard conditions R3 Scheme 27 N o y N A-R y N A-R7 (88) I R3 CMR NH2 (2) i" 1. c Y, Cl e 2. d R3 N 0 N O I CMR (pnZ) N (86) 8 A-R7 1 7 (86) R8 PHTH-N P (87) CMR N-PHTH 0 pnZ-HE < A-R pnZ-< A-R7 R 4t a R8 PHTH-N (85) H2N (84) (a) Phthalic anhydride, THF at reflux (b) LDA, THF, then Alkylation with a chloromethylation reagent (CMR-Cl) (c) Pd, H2, Ethanol (d) H20, pH 9-10 (e) Hydrazine, methanol, reflux. 3 R Scheme 28 1 (93) N A-R j i I R8 3 H NH-CMR /R N (2) cri e 2. d Y Cl e 0 R3 N 0 PHTH-N (91) R8 I (91)R8 CMR (pnZ) N/ (92) R8 , H / H CMR (pnZ) N A-R7 7 Z- R pnZ-pnZ-HN (89) (a) Phthalic anhydride, THF at reflux (b) LDA, THF Alkylation with a chloromethylation reagent (CMR-Cl) (c) Hydrazine, methanol, reflux (d) H20, pH 9-10 (e) Pd, H2, Ethanol Scheme 29/R3 l88) H y A-R 7 R8 CMR NH2 b N/3 y a HR y N \A-R 8 (94)/ CMR CMR NH-AA-Boc y R8 A-R 3 d \ R8 3 d R3 (96) CMR NH-AA N 0 y N A-R Zips Nu-au NU-AU y N R8 A-R Ruz (96)' CMR NH-AA (a) A t-Butoxycarbonyl amino acid (Boc-AA), BOP, DIPEA, DMF (b) A 4-nitrobenzyloxycarbonyl amino acid (pnZ-AA), BOP, DIPEA, DMF (c) Pd, H2, Ethanol (d) HC1, dioxane, H20 Scheme 30 1--R N ! ! y N-R 7 1 y C1 Y Cl pnZ-HN CMR c (101) N R3 H2N R8 N-R7 /R3 H N 8 \ N_R7 1 . R pnZ-HN CMR (100) HN N-R R (102) NH2 CMR b O 0 PHTH-HN l \ N-R7 0 9) 0 pnZ-HN CMR PHTH-HN 8 ruz pnZ-HN (90) pnZ-HN (90) (a) LDA, THF Alkylation with a chloromethylation reagent (CMR-Cl) (b) Hydrazine, methanol, reflux (c) H20, pH 9-10 (d) Pd, H2, Ethanol Scheme 31 R3 1 N"0 yJX HN XA-R7 8 (6: A = 0 or S; R H) Boc-HN R3 a N 0 ZR3/Y/t N XA . O R8 1 (103) Bouc 1 y HN A Boc- R8 I (105) Boc- /pl9 b Ru OR N -1 A N/° XH-NJ\ R (104) A R y HN A 8 y HN'A R8 (106) HN JL HN C\R19 o (a) 2 equivalents of Lithium Diisopropylamide, THF, C (0) Cl2 or C (S) Cl2 (b) ortrifluoroaceticaciddioxane (c) 1. Lithium Diisopropylamide, THF, 2.2-haloalkanoate ester (R) (d) Na2CO3, toluene, heat Scheme 32 R 3 1 N"0 y HN A-R 7 \ 8 (11: A = O or S; R 7 = HX R Z-HN R3 N a 0 c N ( y HN R3 Y R$ 1 (107) Z-N y HN A Z-N R8 YHN. >r A (108) Z-HN ru b RO N 1. b 1. b 2. d y HN \ A Q Y-HN">"A N/R o R8 1 (104) H_ y HN \ A R (106) HN HN JL R19 0 (a) 2 equivalents of Lithium Diisopropylamide, THF, C (0) Cl2 or C (S) Cl2 (b) Pd, H2, ethanol/acetic acid (c) 1. Lithium Diisopropylamide, THF, 2.2-haloalkanoate ester (R) (d) Na2CO3, toluene, heat R3 N"0 Scheme 33, R3 y HN A-R7 8 3 Boc-HN (6: A = O or S; R H) R8 R8 (111) c c OR R OR R3 N/ b (109) y HN'A 20 O Boc-HN OR RUZ OR /R3 n t N N R19 H-*, R3 1 N L j R b R N 0 yHN A R8 (110) N R19 (a) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanal 20 (b) HC1, dioxane or trifluoroacetic acid R (c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone R3 Scheme 34 y)" HN A-R7 y HN \ A-R w 8 R R3 /a Z-HN (11: A = O or S; R 7 = H) R8 y HN A R8 (114) Z-HN c zR3 b y i [B ARO19 RU OR Ruz 8 y han R R2 0 Y R3 R !20 /R Z HN R19 PRO OR R8 I (112) N zR3 s /R N N N 0 y HN R 110, (110) N R19 (a) Lithium Diisopropylamide, THF, R 19 then dialkyl acetal of a bromoalkanal R20 (b) Pd, H2, ethanol/acetic acid R20 (c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone J Scheme 35 CH-J Tc/ (121) HCl H2N/\ H H R2 3 PHTH-N l. f 23 2. g CH-OR CHO l. e HC1'H2N H BocHN //H PHTH-N (120) PHTH-N (119) 0 d H c CH20H CHCH c BocHN BocH (118) han N PHTH-N PHTH-N 0 b O OH-Bz (116) 0 bock Boc a PHTH-N HO Bz-0 (a) Pd, H2, Ethanol/Acetic Acid (b) Heat up to 150 °C to decarboxylate (c) BH3 in Tetrahydrofuran (d) DMSO, DCC, H3PO4 (e) p-TsOH, R23-OH, hexane, heat (f) BF3 etherate with an R23-OH or R23-SH in an aprotic solvent (g) 1. Aqueous Na2CO3 wash, 2. thoroughly dry, then 3. HCl in dioxane \ Scheme 36 CH-j (121) R23o\ HC1-H2N/ \/" CH oR23 PHTH-N HC 1'H2 N/R3 H a N PHTH-N (12 0) I (2) 3 . 3 Y C1 -J C1 CH-J R R230 H Y/ /R3 R23/ i PHTH-N (124) CH-OR b PHTH-N R R3 PHTH-N N Cl-J . b 3 H R 23/ /R R2 30 H2N H CH-ORZ 3 H H2N (123) (a) H2O, pH 9-10 (b) Hydrazine, methanol, reflux Scheme 37 CHO Boc HI1 CH-R2 9 ira Boc PHTH-N (119) HN H PHTH-N (126) a R28 b \--\0 cl CH'" CH-R29 CH-R29 HC1 N PHTH-N (127) PHTH-N (128) (2 or 2b) 3 rus R c N (2 or 2b) H0 Cl-R c-R y han y H H PHTH-N (130) PHTH-N (129). /R3 d/R28 /R3 d N CHO N CH-R2 9 1 Y y HN H H H2 H2 (132) (131) (a) BF3 etherate with HSR28SH,HOR28SH, HOR28NR24H, oR HSR28NR24Hin an aprotic solvent or, with R23-OH,hexane,heatp-TsOH, (b) HCl, dixoane or trifluoroacetic acid (c) H2O, pH 9-10 (d) Hydrazine, methanol, reflux J (139) \ C-J J Scheme 38 Z-HN/\ 7 /2, C (O) A R PHTH-N R230 dJ \ C--, OR2 3 CHJ VX/ Z-ho Z-HN \C (O) A-R C02CH2CH3 PHTH-N (137) PHTH-N (138) A e /---OCH2CH3 "-OR Tf/v/ CH2CH3 c-, OR23 c CHO CHO \C02 R2 3 /CHO/"C02R" PHTH-N (135) PHTH-N (136) (136) j 0 CHCH OCH2CH3 CH2CH3 (134) (133) a PHTH-N C02C (CH3) 3 a PHTH-N PHT H-N Cl (a) HCl/dioxane or trifluoroacetic acid, then SOC1 2/DMF (b) 1 equivalent DIBAH/THF at-78 °C (c) p-TsOH, R23-OH, hexane, heat (d) 1.1 equivalent NaOH/alcohol, 2. HCl (1 mole), dry 3. BOP, DIPEA, DMF, 4. H-A-R7 (e) BF3 etherate with an R23-OH or R23-SH in an aprotic solvent R23 Scheme 39 (139) OR2 3 (139) (137) (139) Z-FiN \ C (0) A-R Z-HM/\ 7 PHTH-N a /C (O) A-R 23 PHTH-N R 0 a J \ JX a oR2 3 1 (140) H2 7 (139) C (O) A-R H2S/\ PHTH-N /C (o) A-R7 (2 or 2b) PHTH-N (2 or 2b)/R3 b R23o N H OR23 HCOR2 3 j Y y 7 C (O) A-R7 PHTH-N (O) A-R PHTH-N (142) PHTH-N (141) R3 R23O c HCpR23 Or Y C (O) A-R C C (O) A-R H2 (144) H2 (143) (a) Pd, H2, ethanol/acetic acid (b) H20, pH 9-10 (c) Hydrazine, methanol, reflux Scheme 40 3 R3 o j i c (150) (149) \H Y \H 3HC1'H2N HN HN CN e N R 3 CN CN N/ ?' CN CN | CN o/(C1N H H \H \H b Con CN (145) (146) PHTH-\ PHTH-N C02CH2CH3 /H a Boc-HN. Boc-HN (a) 1 equivalent NaOH in ethanol, then 1 equivalent of HC1, then heat to 150 °C to decarboxylate (b) Hydrazine, methanol, reflux (c) Intermediate (2) or (2b), pH 9-10, H20 (d) R7-SH, CH2C12,-10 °C, HC1 (e) -10°C,HClCH2Cl2, Scheme 41 (a) Hydrazine, ethanol, reflux (b) Intermediate (2) or (2b), pH 9-10, H20 (c) -10°C,HClCH2Cl2, (d) -10°C,HClCH2Cl2, Scheme 42 R3 . NH I C J! jc/ (157) II C C (0) NR5R7 3HCl H2Nz 'ruz N/ N CN ' (152) Y JTHN/S iR3 CH2 CH 3 Boc-HN Con d (155) Con (155) Y C (O) NR5R7 Boc-HN \ c R C y HN (156) Y HN /C (O) NR5R7 3HC1'H2N (a) H-NR R, toluene, reflux (b) -10°C,HClCH2Cl2, (c) -10°C,HClCH2Cl2, (d) 1.1 equivalent NaOH in ethanol, 2.1 equivalent of HC1,3. BOP, DIPEA, DMF, H-NR5R7 R3 Scheme 43 e I 2COJR15 Y H (162) Y HN . PHTH-H \Za3) 3 2R15 3 (163) N/R d 2H Cl H2 4 CCK H ll CH2NH2 y (161) 'Y HN R3 P'C02C (CH3) 3 POH-HO N/ y6o crr 3 e R N/r PHTH-C02 C (CH3) 3 22 (164) Y HN (. 3HC1 H2N CN CN (158) (159) Z-HN C02C (CH3) 3 C02C (CH3) 3 PHTH-N PHT H-N (a) Pd, H2, Ethanol/Acetic Acid (b) Intermediate (2) or (2b), pH 9-10, H20 (c) H2, Pt, Acetic acid (d) Cl-C (O) R15, triethylamine (e) 1. Hydrazine, methanol, reflux, 2. HCl, dioxane Scheme 44 (a) 1.1 equivalent LDA/THF at-78 °C, 2. bromoacetal (166) (b) 1.1 equivalent LDA/THF at-78 °C, 2. Br-CH2CH20-Bz (c) catalytic p-TsOH, H2O, 0-5 °C (d) H2N-R4, NaCNBH3, methanol, KOH [see R. F.

Borch, Organic Synthesis, 52,124 (1972) CH2 NH-R4 C02 C (CH3) 3 XH2 C a Scheme 45 -CH2CH20-Bz PHTH-/R (170) 11 \ (171) . \ C02C (CH3) 3 XN-H2C/C ( N/4 \CH2 CH2 O-Bz CHCH- (172) ) C (O) OH y NCH2 H2C 1 4/CH2 CH2 O-BZ PHTH- R3 \ \ N"\c C (l73) 8 C (O)-A-R7 Y NCH2/H2 C R3 /I 4 \CH2 CH2 O-Bz N R PHTH- (174) X C (O)-A-R7 y NCH2 H2C 4/CH2 CH2 OH R PHTH-N 3 N/R e " YNCH2 2ß (0)-A-R7 Y NCH2/H2 C '4/CH2CH20H R HN (a) Intermediate (2) or (2b), pH 9-10, H 2O (b) HC1/Acetic acid (c) 1. BOP. DIPEA, DMF, 2. H-A-R 7 (d) Pd, H2, Ethanol/Acetic Acid (e) Hydrazine, methanol, reflux R3 Scheme 46 (178). x (178)C (0)-A-R7 y NCH2/H2 C 14 CH2CH2-S-CMR 2 R3 \ N/ N"-*, CC (O)-A-R \ Z NCH2 x HC 3 Nu 14 CH2CH2-SH N HAN (176) X C (O)-A-R y NCH2/H2 C CH2 CH2-CN R N c b/R3 N ( 75.) x C (O)-A-R 7 y NCH R3/1 4/CH2CH2-OTS PHTH- (174) X C (O)-A-R y NCH2/H2 C) < 1 4 N/CH2 CH2 OH R PHTH- (a) Tosyl Chloride (TsCl), Pyridine, H20,0-5 °C (b) 1. NaCN, DMF, heat, 2. Hydrazine, methanol, reflux (c) 1. Sodium thioacetate, DMF, heat, 2. Hydrazine, methanol, reflux, 3. Hydrolysis with TsOH (d) 1. Sodium thioacetate, DMF, heat, 2. Hydrolysis with 1 equiv. NaOH, 3. CMR-Cl, 4. Hydrazine, methanol, reflux Scheme 47 (a) 1. HCl, dioxane, 2. BOP, DIPEA, DMF, 3. HOCH2CC13 (b) 1.1 equivalent LDA/THF at-78 °C, 2. CMR-Cl (c) catalytic p-TsOH, H20,0-5 °C (d) H2N-R4, NaCNBH3, methanol, KOH [see R. F.

Borch, Organic Synthesis, 52,124 (1972) CH2NH-R4 C02CH2CC13 X-H2 C/a Scheme 4 8 3 \CMR PHTH-g/R \ (182) N \ Y < NC i \ H CX 4 O2CH2CCl3(183) X C02CH2CC13 y NCH2/H2 C CMR /R3/R PHTH-N N/ (184). C (O) OH y NCH2 H2 C '4./CMR R PHTH-N \ 3 \ \ N (185) y NCH2 H2 I 4 CMR PHTH- R' d N/R3 d (186)(O)-A-R y NCH2 H2 I 4 CMR R H2N (a) Intermediate (2) or (2b), pH 9-10, H 2O (b) Zinc dust/THF (c) 1. BOP, DIPEA, DMF, 2. H-A-R 7 (d) Hydrazine, methanol, reflux Scheme 49 CH2NH-R4 C02C (CH3) 3 H2 Co/ N/R3 d \ R8 PHTH- (1$9) (190) X C02C (CH3) 3 i y NCH2/\ H2 C c 14 R8 R PHTH- CHO b C02C (CH3) 3 X--H2 C Ou R8 CH PHTH- (187) C02 C (C H3) 3 O PHTH-R \CHZ I (167) X I CO2 C (CH3) 3 X-H2 /H PHTH-N (a) 1. 1 equivalent LDA/THF at-78 °C, 2. alkylation with an asR8-Br,R8-OTs,R8-oxirane,such thiirane, or aziridine, or CMR-Cl (b) catalytic p-TsOH, H20,0-5 °C (c) H2N-R4, NaCNBH3, methanol, KOH (d) Intermediate (2) or (2b), pH 9-10, H20 Scheme 50 3 /R (190) Y C02C (CH3) 3 2 /Y/\ 8 PHT H- ) (191) 02 H Y tCH2 H2 2 4 R8 R4 PHTH-/ZR3 \d C3 d b b M (194) \ Y CH2/\ H2 C '(19 2) x (0)-R 27 R 4 R8 R CH/x\ H C PHT H- 8 4/3 PI-iTH-/R3 c c R x H2 (0)-R 27 Y (O)-R 7 4 R8 ' (193) X R H N R H2N "CH2 H2 CVC (0)-R 27 I 4 R H2 N R8 (a) HCl in dioxane or ethyl acetate (b) 1. BOP, DIPEA, DMF, 2. H-R 27 such as HN (R22)OR6, R19(R20)C=N-OHHN(R22)N(R24)R25,R19(R20)C=N-N(R22)H, (c) Hydrazine, methanol, reflux (d) 1. ClCO2Et, TEA, THF,-10 °C, 2. CH2Cl2, PTC, NaOH, H-R27 such as HN (R22)SO2R13, HN (R22) C (O) R, HN(R22)C(S)R15,HN(R22)P(O)(OR3)nR6 3 Scheme 51 R N (191) C02 H y NCH2 H2 C 14 R8 4 CHCH- R3 N (196) (196) x C (0) HN-AA Y NCH/H2 ß d 14 R8 R PHTH-3 /R N b tt If (198) V /X-,,(O) O/S-AA /R3 Y NCH2 H2C N y 14 R8 (197) R PHTH-N . C (0) HN-AA y NCH2 ß b 14 R8 b c R H2N R3 c N N (199) » (O) O/S-AA Y NCH2/H2 C 14 R8 R H2N (a) 1. BOP, DIPEA, DMF, 2. t-butyl ester of amino acid with t-butoxycarbonyl protected OH or SH group (H2N-AA) (b) Hydrazine, methanol, reflux (c) HC1 in dioxane or ethyl acetate (d) 1. BOP, DIPEA, DMF, 2. t-butyl N-t-butoxycarbonyl amino acid with unprotected OH or SH group (HO/S-AA) Scheme 52 (a) 1 equivalent LDA/THF at-78 °C (b) R26C(O)Cl acylation (c) R8-reagent such as R8-Br, R8-OTs, R8-oxirane, (d) HCl in dioxane or ethyl acetate (e) Intermediate (2) or (2b), pH 9-10, H 20 (f) BF3 etherate with an R 23-OH or R23-SH (g) BF3 etherate with HOR 28OH, HOR28SH, HSR28SH, HSR28NR24HHOR28NR24H,or (h) H2, Pd/C, Ammonium Formate 3 Nz N-R 2 2 3 Scheme 53 j en ce N/R N-R22 C/H C \ H « \ Boc N (208b) H H 3 Boc-N (208c)/R3 c N R3 R3 e N-R 22 CHO Y Boc-N (208a) HN O-R7 H y Boc-N (208a) (208a) H Boc-N (208d) R28 f N \0 R . 22 1-" R3 N-R 22 H *f y HAN Boc-N (208) Y (208) 3 R28 H2N (209) rR// N \ \ < CH- y < (132) H H2 (a) t-Butoxycarbonyl azide, H20, dioxane, MgO (b) H2O, phosphoric acid (c) R22-NH2, catalytic p-TsOH, toluene, azeotropic distillation (d) N-chlorosuccinimide, DMF (e) reflux(f)HCl,dioxanetoluene, Scheme 54 l IS A-ruz (215) R8 0 HN 0 d Y 0 0 \A-R v (214) R8 N 8 A-R 7 R8 0 Boc-HN (292) R 0 PO /R3 R 19 R2 0 O O yy HN A-R7 w 8 / (6 R3 = OH) R8 BocHN /N=9 boche A-R R8 R3 Boc-HN (217) R30 R31 O b \ A_R7 R8 O ~Xo NH2 R31 . 0 R3 0 (a) C1-C (O) C (O)-Cl, pyridine (b) HCl, dioxane or trifluoroacetic acid (c) pyridine (d) p-TsOH,toluene,azeotropiccatalytic distillation. y 0 Scheme 55k J N \ A_R7 (219) R8 . RO ° Pa H2N \R 30 b/ B N A-R7 (218) R8 O P Boc-HN \ R 'R3 0 a N O A-R w 8 R3-OH) R Boc HN BOCHE N/ A-R 7 (220) R8 Boc-HN Y O ci N/A_R7. 1. d 2. b (221) R8 2. b/ (221)"R °'P\ H2N oR3 o OR3 0 (a) R PC12 where R30 is not OH, SH, or NH2, pyridine (b) HCl, dioxane or trifluoroacetic acid (c) pyridine (d) R-OH where R30 is not OH or SH, pyridine y o Scheme 56 Or R8 ° Si-R20 (223) \ \R19 b O N A-R7 (222) R8 O Si Z-HN R R19 R a N 0 y HN A-R7 8 / (11; R = OH) OU) Z-HN y 0 NpS-0 (224) \ ri O Si NH_Z I'-'R2 0 7 R19 20 / \ (225) /Si/I \R20 Rl9//Rl9 R20 (a) pyridine (b) Pd, H2, methylcyclohexane pyridine(c)Cl-SiR19R20SiR19R20-Cl, y 0 Scheme 57 0 A-R 27) YR8 S SO H2N O O R30 R31 y x 0 b / 7 261 k A O/\ 7 ; (226)'\ A-R R8 R3 Boc-HN oui a N O R30 R31 y N HN A-R7 3 R8 / (6 ; R3 = OH) R8 c BocHN y 0 (228) / 0 N A-R7 ors s Boc-HN 0 //nR3 (229) R30 R b_ Y8 N A-R7 S\ O NH2 R3 1 zip R (a) Cl-S (0) 2C (R30)(R31) S (0) 2-Cl, pyridine (b) HCl, dioxane or trifluoroacetic acid (c) pyridine y 0 Scheme 58 N A-R 7 N \ A_R7 (232) reg O-S H2N 0 0 N/. 7 'A-R (231) R8 O S Boc-HN a 0 a N/O y HN A-R 7 W 8 (6; R3 OH) R c Boc HN y 0 N/ (233) R8 Boc-HN Y O ouzo 0 7 N/A-R7 (234) R8 0 S-p H2 N 0 (a) pyridine (b) HCl, dioxane or trifluoroacetic acid (c) S (0) 2Cl2, pyridine Y 0 Scheme 59-t) N \ A-R7 (236) R8 O H2N /+ R30 b b N/ NA-R (235) R8 Boc-HN a 3 0 a N O I y HN A-R 7 w 8 / R3-OH) R BocHN y 0 N A-R7 (237) R 8 /BocHN 0 Cl i 0 ci 1d A-R7 2. b (238) R8 O \ O H2 N oR3o (a) R30-P (O) Cl2 where R30 is not OH, SH, or NH2, pyridine (b) HCl, dioxane or trifluoroacetic acid (c) P (O) Cl3, pyridine (d) R-OH where R30 is not OH or SH, pyridine Y Scheme 60 X-R (240) Rg 40) PO R30 han R31R3 0 1. b y 1. b 2. c X (239) 1 OR/? R8 Boc-HNBoc-HN Cl/ ci ci , 3 a "yHN"T"A-R' w 8 (6 ; R OH) d boche Boche N (241) (2 R R8 \ A-R R8 O O Boc-HN y , A ß JoR30 N (242) R31 R302 R30 \ 31 Oye O P\ NH2 R30 R3 0 p NH2 R3 1 (a) pyridine (b) R-OH where R30 is not OH or SH, pyridine (c) HCl, dioxane or trifluoroacetic acid (d) pyridine y Scheme 61 \ A-R \ (244) R8 0 H2N R 300 0 O OR 1. b y 2. c cR 8 (243) \p'-R X43) 4 7 /1. Boc-HN R3 C a C1/ ci cri y HNA-R w 8 (6; R3 = OH) R BocHN Y /nez (245) \ A-R R8 0 0/P Boc-HN y \R30 N (246) c \ A-R R 8 p % O R30 \R3 0 R30 \R3 0 (a) Cl2-P (O)-O-P (O)-Cl2, pyridine (b) R-OH where R30 is not OH or SH, pyridine (c) HCl, dioxane or trifluoroacetic acid (d) pyridine y o Scheme 62 A-R7 N \ A-R V (211) R8 0 H2N 0 y b 0 'A-R (210) R8 Boc-HN 1 O a N O y HN A-R7 w 8 / (6; R3 = OH) R C BocHN y 0 N ,, A-R | !/ (212) | R8 Boc-HN Y O S b NA_R7 (213) R8 0 H2N S (a) phosgene, pyridine (b) HCl, dioxane or trifluoroacetic acid (c) C (S) Cl2, pyridine y 0 Scheme 63\ v ii N A_R7 /C \R8 R20 (249) R20 R19 ru 9 y 0 Y O (247) X or R8 A-R7 R2 0_ Z/R3 20 2 a\ y HN \ A-R N OH Y O;(11R3 = OH R Z-ho -han N \ A-R S./ (248) R° R NH-Z R20 R20 Rl9 \ R b y 0 \b / ! \s- R/\--Si-R20 H2N R20 Rl9 (250) R19 (a) pyridine (b) Pd, H2, methylcyclohexane (c) pyridine Scheme 64 Y o (252) A han R8 Han 0 0 cl\ (251) \A-R 8 pnZ-HN/R3 J JpnZ-HN \. P /4 0 N HN A-R7 (R3 OH) R8 (R3-OH) R c /pnZ-HN Y 0 (253) N A-R R8 R31 pnZ-HN y 0 R 3 0 > A (2 54 ; s tA-R 7u(254) R31 R30 R8 0 0 nu2 R31 R3 0 (a) pyridine, 1,2-cyclopentyldicarbonyl chloride as an example of a 1,2-dicarbonyl chloride or anhydride of a substituted cycloalkane, cycloalkene, aryl radical, or heterocyclyl (b) Pd, H 2, ethanol (c) CH3CH20-C (R31) =C (R30) C (0)-OCH2CH3, heat (-ethanol) y Scheme 65 S A-R7 N N _A_R7 (257) R8 H2 N Han Y b N----7 (256) R8 Boc-HN H a 0 0 1 y HN A-R 7 (6) wR8 8 BocHN C R 3 0 R3 l 0 > (2 5 9) RNboche % (258) N A-R R30 N) Boc-HN R (25 ) \ nu2 A-ruz 'R 2 O R30 R (a) Cl-C (O) C (O)-Cl, pyridine (b) HCl, dioxane or trifluoroacetic acid (c) pyridine y 0 Scheme 66 N>/ll \ A-R 8 0O (2N 30 0 H2N X A-R (260) R8 S p Boc-HN Y O b/ R- 0 R I y HN R8 CS< ; =O BOC-HN X NX OY HN/X\ w A_R(6)BocHN C BOC HN BOCHE (262) N 0 8 7 \ R8 s r4R Boc-HN O O R30 R31 (263) S I | R8 N A-R z R8 R30 R31 (a) Cl-S (0) 2C (R30)(R31) S (0) 2-Cl, pyridine (b) HC1, dioxane or trifluoroacetic acid (c) C1-S (O) C (R30)(R31)S(O)-Cl, pyridine Scheme 67 p X A-R7 (265) \R8 P R3 0O P\ ° H2N + 30 \30 R OR R31 1. b 2. c Y 2. c " (264 \A-R7 p 647 O ci p Boc-HN 3 (6 ; R H) R30 cri \ E-Boc-HN \ . P R31 y HN A-R7 w 8 R BocHN y (266) A-R7 8 \ R3 ° \/P\ Boc-HN y (267) R30 c 131 A-R7 R \ R p/O R30 NH2 R 0 Ruz 3 1 R (a) Cl2-P (O) C (R30)(R31) P (O)-Cl2, pyridine (b) R-OH where R30 is not OH or SH, pyridine (c) HCl, dioxane or trifluoroacetic acid (d) pyridine y O Scheme 68 N== 69) YR8 '\/ Q --0 OR3 0 1. b O 0 2. c \ruz /1. b /-"0 3 p, Boc-HN R d/HN < A-R7 (6 ; R ci \R$ d Boc y 0 0 (27 0) /BocHN 3 0 (271) c I 8 A_R7 OR 0 R3 0 NH2 R3 z R30 R o (a) C12-P (O)-O-P (O)-Cl2, pyridine (b) R30-OH where R30 is not OH or SH, pyridine (c) HC1, dioxane or trifluoroacetic acid (d) C1- (R30)p(O)-O-P(R30)(O)-Cl, pyridine Scheme 6 9 Y O A-R R 20 CR8 R R20 NH2 (273) 2 R b Y 0 (272) A-RUZ N A-R 7 R19 . NH-Z R3 I \N 0 (11; R-H) y liN R Y O Rg Z-HN c N \ A-R /Si/ (274) R8 R1 9 X NH-Z Ruz b Y O R 19 si 8 \R8 R20 \-Si-R20 H2N ru9 I 19 pyridine(a)Cl-CR19R20-O-CR19R20-Cl, (b) Pd, H2, methylcyclohexane (C) pyridine Scheme 70 Y o N-4 A-R7 (277)R8 H2 N ° y 0 b O \A-R 4 (275} 4 A-R7 3 pnZ-HN R 0 ho y HN A-R R8 " y HN 1< A R (11 ; R H /pnZ-HN y 0 (278) N \A_R7 8 pnZ-HN y O R30 R31 (279) 7 \N/\A-R I N < A-R7 0 nu2 R30R3 (a) pyridine, 1,2-cyclopentyldicarbonyl chloride as an example of a 1,2-dicarbonyl chloride or anhydride of a substituted cycloalkane, cycloalkene, aryl radical, or heterocyclyl (b) Pd, H 2, ethanol (c) CH3CH20-C (R31) =C (R30) C (O)-OCH2CH3, heat (-ethanol) Scheme 71 N \A-R7 (281)R8 H2 N 0 y b 8 \ 8 0) (280) IR8 Boc-HN R a a O 7 y WilV \ A-R 8 R3-H R N= jj (282) Boc-HN y (282) A-R A-. R Boc-HN soc-HN R30 0 b (283) R31 A-R7 R8 pi _ NH2 R30 R31 (a) pyridine, phthaloyl chloride as an example of a 1,2-dicarbonyl chloride or anhydride of a substituted cycloalkane, cycloalkene, aryl radical, or heterocyclyl (b) Pd, H 2, ethanol (c) Cl (O) CC (R 31) =C (R30) C (O) Cl, heat (-ethanol) Scheme 72 Y 0 \ A-R CK 0 (285) R8 \ H2N po N NH Y O Y o \b 0 A-R 7 Boc-HN R3 a N 0 \/0 \ NH y HN.A-R (6 ; R 3 H R Boc-HN y 0 (286) N \ A_R7 O I \R8 o=\) rRs \ Boc-HN O R30 0 b (287) 31 N A-R7 N A-R R8 p NH2 R30 R31 (a) pyridine, phthaloyl chloride as an example of a 1,2-dicarbonyl chloride or anhydride of a substituted cycloalkane, cycloalkene, aryl radical, or heterocyclyl (b) Pd, H 2 ethanol (c) Cl(O)CCH(R31)-CH(R30)C(O)Cl, heat (-ethanol) Scheme 73 A-ruz (289) R8 0 \ R1_HN O \ R1 i s an amide forming group with A-ruz 2-amino group. (288) I \R8 3 0 a a 0 y HN A-R7 8 (31; R OH) R1-HN (290) /N (290) A-R R8 d RL-HN w O (29 ) R30 R31 8 A-ruz R8 ouzo ° 0NH-RI Vs 0 R30 R30 (a) pyridine (b) C1-C (O)-Cl, pyridine (c) C1-C (O) C (R30) (R3!) C (0)-Cl, pyridine (d) pyridine Y Q Scheme 74 A_R7 N (294) R8A-R7 ru-han R-HN R19/i RR1 is an R20 R19 R amide forming JL) j \ group with group with (293) 8 A-R7 2-amino group. 0n\0 X 0 0 \) j J t) R1-HN R3 0 0 y HN A-R7 \ A R c RL-HN R3 _ H R HN 0 N R8 A-R d RL-HN O N \R8 d Rl _ 30 R 30R31 0 (296) \ A-R 0 R8 O s-0 NH-R O \\\ \\ R30 R3 1 (a) C1-C (O) C (O)-C1, pyridine (b) pyridine (c) Cl-C (O) C (R30)(R31) C (O)-Cl, pyridine (d) pyridine Scheme 75 X (298)R8 298) R8 R-ho R19//ll 2 R is an R20 R19 \RZ 0 amide forming group with (297) 2-amino group. (297) R8 R2 _HN R3 a O 0 0 y HN R8 A-R7 w 8 (33; R H) R2-HN y (299) N A-R 0R8 d HN 73 ou t ! ! \ A-R R8 O NH_R2 O R30 R31 (a) C1-C (O) C (O)-Cl, pyridine (b) pyridine (c) Cl-C (O) C (R30)(R31) C (0)-C1, pyridine (d) pyridine y 0 Scheme 76 N A-R 7 (302) R8 0 HN R2 is an amide forming 0 group with 2-amino group. (301) \ (301) 2 I \R8 3 y HN A-R 7 "° Jk O Y HN \A_R7 \ 8 (33 ; R3-OH) c Y/o /R2_HN O N xNX A-R7 d R8 d HN -O O R30 R31 0 (304) I. o R2R8 °sS NH-R @ DR31 R3 1 ° R30 (a) C1-C (O) C (O)-Cl, pyridine (b) C1-C (O)-Cl, pyridine (c) Cl-C (O) C (R30)(R31) C (O)-Cl, pyridine (d) Cl-S (0) 2C (R30)(R31) S (0) 2-C1, pyridine y 0 Scheme 77 N NR7 \ (306) | R \/ \Si Si H- R R20 R19 R20 Y O b Y \ (30 ) H- 1 0 0 a J R3 \ 1 R8 \ X \ 11 y KN NR7 c (59; R3 = H) \/ Y pS \/ Y ruz H- N J aSYSX H-NA Ou R8 d 31 \ H \ Y O S H- o- N. \NR7 pl (308) R8 > S So O J R30 R (a) C1-C (O) C (O)-C1, pyridine (b) pyridine (c) pyridine (d) pyridine Y 0 Scheme 78 NEZ NN">< (310) R8 /Si H_ R19 20 R 19 R 19 \R2 0 R20 0 b on NR7 \ I (309) g 1. R H- a i R3 x- \ O y? HN NR7 ,NR c (59; R OH) y 0 R H- H- (311) N NR7 % (311) N J NR N N NR7 0 (312) R30 R31 N X - V O (312) I R -O 0 (312) R\/ R30 R31 J . /p31 J (a) C1-C (O) C (O)-C1, pyridine (b) pyridine (c) Cl-C (O) C (R30)(R31) C (O)-Cl, pyridine (d) pyridine y 0 Scheme 79 Nu N N \7 (314) R8 0 R19 0 \R19 b O o R20 7 N R1 9 (313) tBoc-HN-R) >OR Ro o 0 a R3 O 1 (64 ; R OH) y Ru 9 20 BocHN NR O (315) N I\ R8 R19 RO 09 Q OR Rob O \\ -30 R Y RO OR o a N NR7 x A 0 (316) R8 N R19 4 R3 1 qz oR19 R20 (a) Cl-C (O) C (O)-Cl, pyridine (b) HC1, dioxane, then one equivalent water (c) pyridine y 0 Scheme 80 l ll NA-R7 ' (31 ) 0 H2 N d Y 0 00 b \ A-R N _R7 N N'R8 (317) (319) I 1 R8 O Boc-HN 0 0 R20 R19 O N 0 3 4 (67; R3, R4 = OH) || u y N A-R 7 N A-R y 0 1 R8 R BocHN A-R \A-R O (320) \R8 Boc-HN 30 N N A-R 7 \/° NH2 R31/R8. j NH2 0 NH2 OU R30° (a) C1-C (O) C (O)-C1, pyridine (b) HCl, dioxane or trifluoroacetic acid pyridine(c)Cl-C(O)C(R30)(R31)C(O)-Cl, (d) p-TsOH,toluene,azeotropiccatalytic distillation. Y 0 Scheme 81 NA-R 7 (323) R8 0 /+ H2N 130 b B N A-R I (322) I R$ 8 Boc-HN R3 0 R3 ° JX R 5 4 c 4 R BocHN y 3 4 (67 ; R3, R4 OH) N (324 R O O X/°Boc-HN I o Fol CI N/7 (3215) A-R 8 p H2N R 0 (a) R30-PCl2 where R30 is not OH, SH, or NH 2, pyridine (b) HC1, dioxane or trifluoroacetic acid (c) pyridine (d) R-OH where R 30 is not OH or SH, pyridine y 0 Scheme 82 / N \ A-R 7 R8 \/0 ! (327) \ X NH? si Si I R2 0 R19 y 0 N A-R7 N. \ A_R7 (3 Õ (326) ss R8 S Z-HN \/R3 Si OCH R 120 R R OH) aï C/R R8 R Z-HN O o N \ A-R 1 8 y 0 (328) I R19 \ i/NH_Z Si A-R7 1 R20 -\isi R20/Rl9 \ 2 0 R''R20 R R (a) pyridine (b) Pd, H2, methylcyclohexane (c) pyridine 1 ! Scheme 83 N A-R 7 õ (331) | | R8 0 H2N 10, Y y 0 N A-R 7 (330) IR8 0 Boc-HN/R3 N 0 0 y N/9\= A-R7 /R4R8 R4 BocHN C y 0./ (67; R3, R4 = OH / N A-R | (332) | R8 O \ Boc-HN Y 0 N A-ruz (333) R 8 C s 0 H2N (a) pyridine (b) HC1, dioxane or trifluoroacetic acid (c) pyridine 1 ! Scheme 84 S XA-R7 1 (335) 1 | R8NN 1 (335) 1 R8 0 0 y HN bu 0 b N A-R 7 (334) 1 R8 'R ) 1 \ 0- Boc-HN R 4-R O /BocHN y N N O f 14 R8 R Boc HN 0 (67 ; R3, R4 OH) N A-R 7 ) YR 8 p I (336) R8 Boc-HN Y O S N/A_R7 ° 1 (336'I R8 0 0 H2H2N s (a) phosgene, pyridine (b) HC1, dioxane or trifluoroacetic acid (c) C (S) Cl2, pyridine Scheme 85/ 3 / 1 0 /\ A-R R33 )R8 nu R19 19\ R2. 0 R O /N1 O 19 I R (338)R8 NH-Z /" 3 4 R OH R19 R y N A-R (Jo) j R8 c 4 N R Z-HN O 0 A-R7 R Si \Ft8 R8 Rl9 Si (340) t R8 Ç 0 R19 SI (341) 8 p'_R7 20 \ H2N R 20/H2N \OR./ R19 R- R19 (a) pyridine (b) Pd, H2, methylcyclohexane (c) pyridine y Scheme 86 cor-0 N I (343)A R \8 y 0 Jk N' (342) \"" R8/R3 O 0 1 y HN A-R 7 8 (92; R3 = OH) /CMR (pnZ) HN 1'O . N O 0 (344) N 8 A-R7 N (pnZ) CMR /\0 \/H 0\ \ lt==/ O Nu-cor 0 /\-3 1 NH-CMR O R30 Ruz (a) pyridine (b) Pd, H2, ethanol (c) pyridine y 0 Scheme 87 NN-R7 1 (347) R8 1 o/C ; MR o y b 0 N7 (346) R8 pnZ-HN CMR R3 O N 0 y HN N-R c \ 8 I (101 ; R3-OH) Y O pnZ-HN CMR /XgN-R7 O g<Sv PnZ IW CM ; o o N-R7(348) R8 I PnZ W Y 0 b 0 7 (349) R8 I S, p H2 N. CMR 0 (a) C (O) Cl2, pyridine (b) Pd, H2, ethanol (c) S (0) 2Cl2, pyridine y R28 Scheme 88 t noN o \ HC O Hic-' I (352) 0 H Po 0 Y/R. I Z_H O y XRXJ\ N_ N (351) b 3 R28 0 N R \ 0 1 HC--' y han 0) y HN H /R28 (350) Z-ho y 0 H R3 a R28 Nu O (353) N \--0 H CH w /\ \\ Y Hou N (132, R-OH) 0 R2 R (354) HC H2 N ou O R30 R (a) Benzyl chloroformate, Na2CO3, THF, water (b) C1-C (O) C (O)-Cl, pyridine (c) Pd, H2, ethanol (d) Cl-C (O) C (R30)(R31) C (O)-Cl, pyridine

Disclosed are 34 synthetic processes useful in the preparation of the compounds of the present invention.

The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. 3 Scheme 89 Ruz (357) Y HN ACH2 (CH2) jCH2A NH y IN A R2 N H2N H2N 3 (356) A' (356) Y HN ACH2 (CH2) jCH2A NH y zip R BocHN BocHN 1. c 2. d Z-H8 CH2 (CH2 j CH2 8 (355) Z-HN R 8T ( BocHN BocHN 1. a 2. b Z-HN OH R 8 ) BocHN (3) (a) Triethylamine, ethyl chloroformate (b) HACH2 (CH2) jCH2AH (A = O, S, NR5) (c) Pd, H2, Ethanol/Acetic Acid (d) H20, pH 9-10 with (2) or DMF, TEA with (2b) (e) HCl, dioxane or trifluoroacetic acid.

Scheme 90 (a) Triethylamine, ethyl chloroformate (b) TFA-ACH2 (CH2) jCH2AH (A = 0, S, NR5 ) (c) Pd, H2, Ethanol/Acetic Acid (d) Phthalic Anhydride, THF at reflux (e) K2C03, H20, methanol Scheme 91 PHTH-HNACH2 (CH2) jCH2A/X (361) PHTH-HN R8 R8 I (3 61) BocHN NH2NH2 BocHN CH3 OH Reflux r H2N CH2 (R84 /R pS 8 BocHN BocHN oR3. H20, pH 9-10, (2) or (363) IDMF, TEA, (2b) A IYDMI Y HN, CH2 (CH2) jCH2A tNH-Z / R BocHN BocHN R3 Pd, H2 Ethanol (364) Acetic Acid A Y HN R8 CH2 (CH2) jCH2 R8 NH2 8 R8 8 I BocHN BocHN oR3 H20, pH 9-10, (2) R3 ou rDMF', TEA, (2b) (365) I z y HN 8 CH2 (CH2) jCH2A NH y R8 8 I R BocHN BocHN HC1, dioxane or TUA-OH (366) I 1 Y HNCH2 (CH2)CH2A NH y H2N H2N R3 O Scheme 92 y HN NR5R7 5 RS (6; R = H) R Boc-HN 1. a /R 2. b 2-b 0 N 0 y HN 8 NH-R 7R3 R 8 R3 (367) N-PHTH < X /R3 d y HN N-Li+ p \ R8 ( 6 ) N-PHTH 17 y HN R8 N- (CH 2) u Q (CH 2) w-Br R 7 (369) N-pHTH R7 3 /R O p N N (370) I 1 N- (CH2) Q (CH2) W-N N Y 8 N-POH R /R3 O. R3 3 N. P 0 0"N N (371) Y Y ! j R HN I'R$ I I R8 NH2 R NH2 7 P 7) 2 R NH2 (a) HC1, dioxane (b) TEA, phthalic anhydride, THF (c) Lithium diisopropylamide, THF, (d) Br- (CH2)uQ(CH2)w-Br, THF (e) (368) in THF (f) Hydrazine, methanol, reflux Scheme 93 (a) Br- (CH2) XT (CH2) y-Br, THF (b) (368), (372) in THF, reflux (c) Hydrazine, methanol, reflux R3 Scheme 94 N 3 OR Y HN yT_ Li+ R3 (368) R8 I R a N-PHTH R (375) 1 1 y HN R8 T- (CH2) XT (CH2) y-O-THP R8 b N-PHTH R3 t I (376) y HN R8 I- (CH2) y-OH R 7 R3 N-PHTH R R3 / v (377) I 1 R8 (CH2) XT (CH2) y-O X A Y HNR8 I R8 t'7"'N-Boc N-PHTH R 1. d 2. e R3 /1 (374) V CH T CH (CH2) XT 2) y-o R8 y HN w R8 R8 I NH2 R NH2 (a) Br- (CH2) XT (CH2) y-O-THP, THF (b) Acetic Acid, reflux (c) (6; A-R7 equals OH) in THF/acetonitrile, DCC (d) Hydrazine, methanol, reflux (e) HC1, ethyl acetate R3 Scheme 95 N 0 y HNN Li+ R3 (368) | R8 | nJ N a N-PHTH or 1 y HN > 8 gN (CH2) UQ (CH2) W-O-THP 8 7 b N-PHTH R R3 z N 0 ('448) N- (CH2) uS2 (H2) "-OH 8 c N-PHTH R R3 O N N/ (449) I N- (CH) Q (CH) NH Y HN R8 | R8 N-Boc 8 N-B oc N-PHTH 1. d 3 2. e R3 2. e R3 I H N (450) I N- (CH) Q (CH) Y-"HN-P'L R y HN I'Ftg I R8 7 2 (a) Br-(CH2)uQ(CH2)W-O-THP, THF (b) Acetic Acid, reflux (c) (6; A-R7 equals OH) in THF/acetonitrile, DCC (d) Hydrazine, methanol, reflux (e) HCl, ethyl acetate 3 Scheme 96 (7) y HN A-R 8 a H2 N bu R /R3 A-R IiN A-R R y R8 y HN'A-R R8 R8 (379) R15-C- (CH2) uQ (CH2) W-C-R15 (a) moles(7),2 4 moles p-TsOH, hexane or toluene, azeotropic distillation (b) bis-dimethyl or bis-diethyl acetal/ketal of 2moles(7),R15(O)C-(CH2)uQ(CH2)w-C(O)R15, 4 moles p-TsOH, toluene, distillation of alcohol 3 Scheme 97 I (7) 4 HN 8 A-R CR 1 H2N a han Bu b 3 \ 0' HN'A R 8 R R T3 0 - II (380) II R-C- (CH2) xT (CH2) y-C-R (a) moles(7),2 4 moles p-TsOH, hexane or toluene, azeotropic distillation (b) bis-dimethyl or bis-diethyl acetal/ketal of R15 (0) C-(CH2)XT (CH2) y-C (O) R, 2 moles (7), 4 moles p-TsOH, toluene, distillation of alcohol R Scheme 9 8/R3 /R3 (7) 8 0 N H2 N ( 81) A-R R8 NH R15 O=C (CH2) XT (CH2) yC (OCH3) 2 b 3 R3 p \A-R °/\y NH N y HN A-R7 0 H2r y s \ Rs NU N R8 R8 II 15 O=C (CH2) xT (CH2) yC-R (a) Cl (O) C (CH2) XT (CH2) yC (OCH3) 2R15, TEA (b) Compound (7; 1 mole), 3 moles p-TsOH, toluene, distillation of alcohol R3 Schème 99 N 0 (460) (460) (~ A-R7 R8 Nu R 5 o=c (CH2) uQ (CH2) wC (OGH3) 2 b ( 3 R3 R A-R7 N (461) 1 HN A-R7 0 HW y b R NH N O=C (CH2) UQ (CH2) WC-R (a) Cl (O) C (CH2) uQ (CH2) wC (OCH3) 2R15, TEA (b) Compound (7; 1 mole), 3 moles p-TsOH, toluene, distillation of alcohol 3 Scheme 100 o R 3 (7) HN A-R 7 y HN 8 A-R 'R / R8 NH (383) 0 c b Nu 8 Zut O N 0 R3 ° N O NH N"0 nu (384) 0 So y HN A-R7 8 R NU NH A-R 7 (441) 0 y N R 3 O NH R8 y HN A-R7 i O (a) C (O) Cl2,2 moles TEA, 2 moles (7) (b) S (O) 2Cl2, 2 moles pyridine, 2 moles (7) (c) C1C (O) C (O) C1,2 moles TEA, 2 moles (7) OH Scheme 101 3 y HN A-R R 8 Boc-HN Y HN R7 R8 (60) Boc-HN a R19 ou /R O y N 1 j Y y UN ) \ R8 I (385) R19 Boc-HN b 0 0 y HN \ A-R 8 Boc-HN Ruz y un R8 (386) R19 H2N 0===\ z 1'JL han HN A-R 7 (a) Anhydrous toluene R 8 0.05 equivalents of NaH "2 (b) Addition of (60) H2N distillation of alcohol (R-OH) (c) HCl, dioxane N Scheme 102 0 Boc y HNA-R N O 8 (387) 7 Z-HN R= CH2CC13) y HN 8 OH R8 a N | R8 I NI O YN 7 y N A-ruz Y (388) I \R8 Z-HN (388) Z-HN CRlg R20 (CR 19 R20) j Rl9 R20 C ° Boc Boc y N 8 OH y OH y N'OH I \R8 Y \OH reg JX Z-HN (389) R O \/% Z-HN CRlg R20 (CR 19 R20) j Rl9 R20 C ° H 1. c H Nô 2. d- Nô y N'OH 8 R8 NH2 (391) y NH2 CR19 R20 (CR 19 R20 j Rlg R20 0 (a) 2 Moles (12), Cl (O) C-CR 19R20(CR19R20)jCR19R20-C(O)Cl, TEA, toluene (b) Zinc dust, acetic acid (c) Pd, H 2, Ethanol/Acetic Acid to (390) (d) (390) with HC1, dioxane Boc Scheme 103 N R (12; A = 0; 3 Z-HN R R7= CH2CC13) N 0 I (7) boy a N y HN A-R y N A-R han N'A-R R8 b Z-HN 0 (CH2) XT (CH2) y-C (O) Cl Boc 7 R3 (393) N O. _R N (393) 0 Y N A_R H Y I R8 R8 Z-HN 1. c O (CH2) xT (CH2) y 2. d 3. e R) N (396) 0 A-R7 N O \ OH \H y R8 R8 NH2 v O (CH2) xT (CH2) y 0 (a) 1 Mole (12), Cl (O) C- (CH 2) XT (CH2) y-C (O) Cl, TEA, toluene (b) 1 Mole (7), TEA, toluene (c) Zinc dust, acetic acid to (394) (d) Pd, H 2, Ethanol/Acetic Acid to (395) (e) (395) with HC1, dioxane Scheme 104 (a) 2 Moles (123), 4 Moles HC1, water Scheme 105 (a) DCC, THF/Acetonitrile (b) HC1, dioxane (c) 2 Moles HC1, water Scheme 106 (a) DCC, THF/Acetonitrile (b) HC1, dioxane Scheme 107 7 C02-Bz (191) R-A/H2C (404; (A = O, S, NH; a /pj Boc-N H R-H)) N/ (405) C02-Bz C Y NCHZ H2 C X Bouc-N R 3 PHT H- R b N C02-Bz (406) x-A\/ J !, (4 0 6, X c (o)-A H2 c 2NCH/\ H2 C X Y 2CH NH2 R4 R8 PHTH-c nu) N I (407) R4-12C 8 H 3 N y NCH2 H2 C \X 2 Rg N 4 PHTH-R Z-HN R R3 1. d N' I (40 ) C (O)-A H C C2H NH22 R I > H R4/R8 H N N R3 NH2 2 (a) 1, ClCO2Et, TEA, THF,-10 °C, 2. then (404) (b) HC1 in dioxane or ethyl acetate (c) 1.11 (A-R7 = OH), ClC02Et, TEA, THF,-10 °C, 2. add to 406 in THF (d) Hydrazine, methanol, reflux to form (408) (e) (408) with Pd, H 2, Ethanol/Acetic Acid Scheme 108 Z-Ia-OH = 410 Z-Ib-OH = 410 Z-IC-OH = 410 410Z-Id-OH= oR3 N (410) C (O)-OH Y N/ I /p8 R Z-HN CH2OH CH20-Ia-Z CH20H 1. a 1 H OH 2-Z-Ia-oH H_ OH H O~Ia~Z + H OH H OH H OH (411) (412) (413) CH2 OH CH2 OH 1. a CH2 OH 1. a 2. Z-Ib-OH CH2 0-IaX CH2 O-Ia-Z K CH2 0-Ia ~ Zc c I z H O-Ib-Z H OH H OH HOH H O-Ib-Z H OH CH2 OH CH2 OH CH20-Ib-Z b (414) b (415) b/ (416) / 2-a-H20-Ia-H 20-a-H 0-Ib-H H-OH H-OH + + HOH H O-Ib-H H OH CH2 OH CH2 OH CH2 O-Ib-H (417) (418) (419) (a) ClCO2Et, TEA, THF,-10 °C (b) Pd, H2, Ethanol/Acetic Acid Scheme 109 (see Scheme 108) (a) C1C0 2Et, TEA, THF,-10 °C (b) Pd, H 2, Ethanol/Acetic Acid Scheme 110 H2N-Ia-OBz = 462 H2N-Ib-OBz = 462 462H2N-Ic-OBz= 462H2N-Id-OBz= (a) DCC, THF/acetonitrile (b) Pd, H2, Ethanol/Acetic Acid Scheme 111 (see Scheme 110) (a) DCC, THF/acetonitrile (b) Pd, H2, Ethanol/Acetic Acid Scheme 112 R3 R" 0 N (431) (410) C (0)-OH R J<. C (CH3) 3 ' O/C, (CH3) 3 Y N / R8 4 OH R3 a R Z-HN ay 0 1 (43 ) x C (O) se oC (CH3)-3 Y)N 1 Y N, 1 4'/R8 R19 oR3 R Z-HN N R3 b 1 (462) X C (O) OBz i \ I Y N/ x c (0)-0 H R4 H2N Y nez 14/R8 R19 3 R3 N R Z-HN/ 3/N R Bz0 (O) C (434) C (O) N y !! s Ic (O)/\NA R R19 R Z-HN R \ 1 c N N/p HO (O) C (435) 1 r R 0 HO (0) C I !,/ i" R R8 R19 Y 14' R H2N (a) DCC, THF/acetonitrile (b) HC1, dioxane (c) Pd, H2, Ethanol/Acetic Acid Scheme 113 R3 14 R 8 19 R Z-HN fc'" Y N, R19 Z-HO 3 b "v ! ! (433) C (O)-p Y N/X\I. 14/\R8 ru9 (161) a R Z-HN a /0 I \ R " ''/ir"HNCH (436) C (0)-O \N Y N/X\I \HNCH2 R8 R 19 R Z_ 1. b \C02C (CH3) 3 R3 2. c PHTH-N N 3. d R3 (437) c (0) o N R I--N -HNCHo 14 R8 R19 y R HN C02H NH2 NH2 (a) DCC, THF/acetonitrile (b) HC1, dioxane (c) Hydrazine, methanol, reflux (d) Pd, H2, Ethanol/Acetic Acid 3 R3 Scheme 114 (109) y. HNA R8! 2 0 Boc-HN \ k RO Ru or .. R-' v R19 (438) 19 O R8 R2 0 (7) R Boc-HN CMR Fut3 / nu (439) R8 Y -CTs + 3 Ts CH R Boc-HN R c Ar R /R3 'f R' (440) H Y R$ -CTs + 3 TsCH R$ N-i2 R2 0 NH2 20 (a) 5% aqueous phosphoric acid (b) 4 Moles p-TsOH, hexane, azeotropic distillation (c) HC1, dioxane or trifluoroacetic acid, evaporate Scheme 115 (a) Hydrazine, methanol, reflux (b) t-Buotxycarbonyl azide, dioxane, H 20, MgO (c) DMSO, DCC, H 3 P04 (d) 1 Mole (7), 2 Moles p-TsOH, hexane, azeotropic distillation to give (445) (e) HC1, ethyl acetate Scheme 116 (a) Hydrazine, methanol, reflux (b) t-Buotxycarbonyl azide, dioxane, H 20, MgO (c) DMSO, DCC, H 3 P04 (d) 1 Mole (7), 2 Moles p-TsOH, hexane, azeotropic distillation to give (454) (e) HC1, ethyl acetate R3 N Q Scheme 117 1 (6) HA- (CH2) xT (OR2 3) 2 y HN OH \ 8 R (456; A = O, S, NR5) a Boc-HN T 08 4 A- (CH2) XT (oR23) 2 Y HAN Boc-HN b oR3 (7) N z (458) R8 A-Rt ,"E A- (CH2) xT==NH* cl y HN 0 c Boc-HN N lR HN \ A-R (45 9) R (459) 8 - (CH2) XT NH+ y han zozo H2N (a) DCC, THF/Acetonitrile (b) 3 Moles HC1, water (c) HC1, dioxane or ethyl acetate 3 Scheme 118, R3 1 (7) y HN OCH 3 a \R8 /H2N N"\0 I (477) o- (cH2) uQ (H2) W-o 0 R3 \ Y R8 Y (a) HO-(CH2)uQ (CH2) W-OH, 2 moles (7), 4.1 moles p-TsOH, toluene, distillation to remove methanol 3 Scheme 119 N--*"0 1 (7) S HN OCH3 8 R3 H2 N N O ) y HN O- (CH2) XT (CH2) y-p 0 8 R NH2 R3 22 y Ru Y (a) HO-(CH2)XT (CH2) y-OH, 2 moles (7), 4.1 moles p-TsOH, toluene, distillation to remove methanol Scheme 120 H2N-Ia-OBz = 462 H2N-Ib-OBz = 462 H2N-Ic-OBz = 462 462H2N-Id-OBz= (a) TEA, THF/acetonitrile (b) Zinc dust, acetic acid (c) ClC02Et, TEA, THF (d) Pd, H2, Acetic Acid (e) HC1, dioxane [See"Glyphosate", ACS Monograph 189, 1997, page 301 for source of (479)] Scheme 121 (a) trifluoroacetic acid (b) Z-IC-OH (410), ClCO2Et, TEA, THF added to (485) (c) Pd, H2, Acetic Acid Scheme 122 P (488) t H2 N NH2 a H (489)t/T (489) PHTH-Nv N-PHTH v b Ib (490) H PHTH-N N/\/N-PHTH ! yfb-z ! Ib-Z 1 (491) Ib-Z PHTH-N ^//N NH2 d fib-Z !/ I ta-Z Ib-z I (492) Ib-Z PHTH-N N NH e b_H fi a-H C Ib-Z i | (493) Ib-Z f a PHTH-N\/ ., N NH b-z a-Z \ H fi (494) Ib-H H2N N NH 1. f d-HIb-Z 2. e b-H Ib-Z a-H a fi (495) N NU v Ib-H Ib-H (a) Phthalic anhydride (2 moles), THF, reflux (b) Z-Ib-OH (410; 3 moles), C1C0 2Et, TEA, THF added to (489) (c) Hydrazine (1 mole), methanol, reflux (d) Z-Ia-OH (410; 1 mole), C1C0 2Et, TEA, THF added to (491) (e) Pd, H 2, Acetic Acid (f) Z-Id-OH (410; 1 mole), C1CO 2Et, TEA, THF added to (494) Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore the

following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Compounds containing multiple variations of the structural modifications illustrated in the preceding schemes or the following examples are also contemplated.

All experiments were performed under either dry nitrogen or argon. All solvents and reagents were used without further purification unless otherwise noted. The routine work-up of the reactions involved the addition of the reaction mixture to a mixture of either neutral, or acidic, or basic aqueous solutions and organic solvent. The aqueous layer was extracted n times (x) with the indicated organic solvent. The combined organic extracts were washed n times (x) with the indicated aqueous solutions, dried over anhydrous Na2S04, filtered, concentrated in vacuo, and purified as indicated. Separations by column chromatography were achieved with conditions described by Still. (Still, W.

C.; Kahn, M.; Mitra, A. Rapid Chromatograhic Technique for Preparative Separation with Moderate Resolution. J. Org. Chem., The hydrochloride salts were made from IN HC1, HC1 in ethanol (EtOH), 2 N in MeOH, or 6 N HC1 in dioxane. Thin layer chromatograms were run on 0.25 mm EM precoated plates of silica gel 60 F254.

High performance liquid chromatograms (HPLC) were obtained from C-8 or C-18 reverse phase columns which were obtained from several vendors. Analytical samples were dried in an Abderhalden apparatus at either 56°G or 78°C. 1H NMR spectra were obtained from either General Electric QE-300 or Varian VXR 400 MHz spectrometer. 13C NMR spectra were obtained from a Varian spectrometer at 125.8 MHz.

Example 1 EX-la) 6- (N-Z-amino)-2- (N-Boc-amino)-2-methylhexanoic acid (10 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (10.1 mmol) and triethyl amine (TEA) (11 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and 1,5- diaminopentane (5.0 mmol) is added. The mixture is allowed to warm to room temperature. Upon completion, the mixture is concentrated in vacuum. The resulting material is passed through a reverse phase chromatographic column, giving 1,5-bis- [6- (N- Z-amino)-2- (N-Boc-amino)-2-methylhexanamido](N-Boc-amino)-2-methylhexan amido] pentane.

EX-lb) 1,5-Bis- [6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanamido] pentane is dissolved in ethanol containing acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z- functions generating the amino product 1,5-Bis- [6-amino-2- (N-Boc-amino)-2- methylhexanamido] pentane.

EX-lc) To a 125 mL flask is added (9 mmol) of 1,5-Bis- [6-amino-2- (N-Boc-amino)-2- methylhexanamido] pentane and 70mL of DMF. To this solution is added 4.38 g of methyl acetimidate hydrochloride. Triethylamine (TEA) (0.06 mol) is added. After the addition is complete, the solution is allowed to stand at 25°C for 16 hours. The reaction mixture is filtered from triethylamine hydrochloride, and the filtrate is concentrated in vacuum. The residue is dissolved in 50% acetic acid and lyophilized. The crude product is purified by then adjusting the pH to 7.5 with 1N HC1 and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The Boc-protected product is then eluted with 10% aqueous pyridine and concentrated in vacuo to give 1,5-Bis- [6- (N- (1-iminoethyl) amino)-2- (N-Boc-amino)-2-methylhexanamido] pentane.

1,5-Bis- [6-(N-(l-iminoethyl) amino)-2-(N-Boc-amino)-2-methylhexanamido] pentane is deprotected by allowing it to stand in 2N HC1 and dioxane at 25°C for two hours.

Concentrating in vacuo affords 1,5-Bis-[6-(N-(l-iminoethyl) amino)-2-amino-2- methylhexanamido] pentane tetrahydrochloride.

Example 2 EX-2a) 6- (N-Z-amino)-2- (N-Boc-amino)-2-methylhexanoic acid (10 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (10.1 mmol) and triethyl amine (11 mmol). The mixture is allowed to warm to room temperature.

Upon completion, the mixture is again cooled in an ice bath and 4-trifluoroacetamido-1- butanamine (10.1 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield 4-trifluoroacetamido)-1-[6-(N-Z-amino)-2-(N-Boc-amino)-2- methylhexanamido] butane.

EX-2b) 4-trifluoroacetamido)-1-[(6-(N-Z-amino)-2-(N-Boc-amino)-2- methylhexanamido] butane (9.3 mmol) is dissolved in methanol/water and treated with potassium carbonate (10 mmol) in water. The mixture is stirred until the trifluoroacetyl protecting group is hydrolyzed. The product is passed through a reverse phase column to yield 4-[6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanamido]-1-butan amine.

EX-2c) 6- (N-Z-amino)-2- (N-Boc-amino)-2-methylhexanoic acid (10 mmol) is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of

time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product 6-amino-2- (N-Boc-amino)-2-methylhexanoic acid.

EX-2d) 6-amino-2- (N-Boc-amino)-2-methylhexanoic acid (9.8 mmol) is dissolved in anhydrous THF and treated with phthalic anhydride (10.3 mmol). The mixture is heated to reflux until the phthaloyl protecting group is added. The product is purified by chromatography to give 6-phthalimido-2- (N-Boc-amino)-2-methylhexanoic acid.

EX-2e) 6-phthalimido-2- (N-Boc-amino)-2-methylhexanoic acid (9 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (9.1 mmol) and triethyl amine (11 mmol).. The mixture is allowed to warm to room temperature.

Upon completion, the mixture is again cooled in an ice bath and 4- [6- (N-Z-amino)-2- (N- Boc-amino)-2-methylhexanamido]-1-butanamine from EX-2b (9.2 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water.

The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield 4- [6- phthalimido-2-(N-Boc-amino)-2-methylhexanamido]-1-[6-(N-Z-am ino)-2-(N-Boc- amino)-2-methylhexanamido] butane. <BR> <BR> <P>EX-2f) 4- [6-phthalimido-2- (N-Boc-amino)-2-methylhexanamido]-l- [6- (N-Z-amino)-2- (N-Boc-amino)-2-methylhexanamido] butane (8 mmol) is dissolved in methanol, treated with hydrazine (8.2 mmol), and heated to reflux to remove the phthaloyl protecting group.

The mixture is concentrated and purified by chromatography to give 4- [6-amino-2- (N- Boc-amino)-2-methylhexanamido]-l- [6- (N-Z-amino)-2- (N-Boc-amino)-2- methylhexanamido] butane.

EX-2g) To a 125 mL flask is added (7 mmol) 4- [6-amino-2- (N-Boc-amino)-2- methylhexanamido]-1-[6-(N-Z-amino)-2-(N-Boc-amino)-2-methylh exanamido][6-(N-Z-amino)-2-(N-Boc-amino)-2-methylhexanamido] butane and 70mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 1. 31 g of methyl acetimidate. During methyl acetimidate addition, the pH is kept at 9.5 via concomitant addition of 2.5 N NaOH. After the addition is complete, the solution is allowed to stand at 25°C for 25 minutes. The solution is then adjusted to pH = 7.5 with 1N HCI and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The protected product 4- [6- (N- (1- iminoethyl) amino)-2- (N-Boc-amino)-2-methylhexanamido]-1- [6- (N-Z-amino)-2- (N-Boc- amino)-2-methylhexanamido] butane is then eluted with 10% aqueous pyridine.

EX-2h) 4- [6- (N- (l-iminoethyl) amino)-2- (N-Boc-amino)-2-methylhexanamido]-1- [6- (N- Z-amino)-2- (N-Boc-amino)-2-methylhexanamido] butane is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product 4- [6- (N- (1-iminoethyl) amino)-2- (N-Boc-amino)-2-methylhexanamido]-1- [6- amino-2- (N-Boc-amino)-2-methylhexanamido] butane.

EX-2i) To a 125 mL flask is added (6 mmol) of 4- [6- (N- (l-iminoethyl) amino)-2- (N-Boc- amino)-2-methylhexanamido]-1- [6-amino-2- (N-Boc-amino)-2-methylhexanamido] butane and 70mL of water. This solution is adjusted to pH = 9.5 by addition of 2.5 N NaOH. To this solution is added portion wise, 1.49 g of chloroacetaldoxime which is prepared immediately prior to use. During the chloroacetaldoxime addition, the pH is kept at 9.5 via concomitant addition of 2.5 N NaOH. After the addition is complete, the solution is allowed to stand at 25°C for 25 minutes. The solution is then adjusted to pH 7.5 with IN HC1 and poured onto a Dowex 50 Cation exchange column. The column is washed with water. The Boc-protected product is then eluted with 10% aqueous pyridine.

After concentrating the product, 4-[6-(N-(l-iminoethyl) amino)-2-(N-Boc-amino)-2- methylhexanamido]-1-[6-(N-(1-oximinoethyl) amino)-2-(N-Boc-amino)-2- methylhexanamido] butane is deprotected by allowing it to stand in 2N HC1 and dioxane at 25°C for two hours. Concentrating in vacuo affords 4-[6-(N-(l-iminoethyl) amino)-2- amino-2-methylhexanamido]-1- [6- (N- (l-oximinoethyl) amino)-2-amino-2- methylhexanamido] butane tetrahydrochloride.

Example 3 EX-3a) S- (2- (N- (l-iminoethyl) amino) ethyl) cysteinamide (10 mmol) is added to anhydrous THF and treated with phthalic anhydride (10.1 mmol). The mixture is heated to reflux until the phthalimide protecting group is formed. The product is purified by chromatography to give 3- (2- (N- (l-iminoethyl) amino) ethylthio)-2- phthalimidopropanamide.

EX-3b) 3- (2-(N-(l-iminoethyl) amino) ethylthio)-2-phthalimidopropanamide (9 mmol) is thoroughly dried and dissolved in 25 ml of anhydrous THF. To the THF solution cooled to-78 °C, is added 1.1 equivalents of diisopropylamine followed by 1 equivalent of n- butyl lithium in hexane to form the lithium salt of 3- (2- (N- (1- iminoethyl) amino) ethylthio)-2-phthalimidopropanamide. Subsequently, (5 mmol) of dry 1,5-dibromo-3,3-dimethoxypentane is dissolved in anhydrous THF and is added to the solution of the lithium salt. After warming to room temperature, the reaction is heated.

Upon cooling, the reaction mixture is filtered to remove the precipitant, concentrated in vacuo and is purified by chromatography to give 1,5-bis [3-(2-(N-(l- iminoethyl) amino) ethylthio)-2-phthalimidopropanamido]-3,3-dimethoxypentane.

1,5-bis [3- (2- (N- (l-iminoethyl) amino) ethylthio)-2-phthalimidopropanamido]-3,3- dimethoxypentane (4 mmol) is added to 25 mL methanol, treated with hydrazine (8.2 mmol), and heated to reflux to remove the phthaloyl protecting groups. The solvent is removed in vacuo. The residue is slurried with 25 mL 2 M aqueous HCI for 2 hours to hydrolyze the ketal groups. The reaction mixture is filtered to remove the phthalolyl hydrazide and concentrated to give 1,5-bis [3-(2-(N-(l-iminoethyl) amino) ethylthio)-2- aminopropanamido]-pent-3-one tetrahydrochloride.

Example 4 EX-4a) The lithium salt of N-ethyl-6- (N-(l-(N-benzyloxyimino) ethyl) amino)-2- phthalimido-2-methylhexanamide (10 mmol) is prepared as in EX-3b from N-ethyl-6- (N- (1- (N-benzyloxyimino) ethyl) amino)-2-phthalimido-2-methylhexanamide is reacted in anhydrous THF at-78°C by adding to 1,3-bis (bromomethyl) benzene (5 mmol) in THF.

After warming to room temperature, the reaction mixture is allowed to warm to room temperature and heated. Upon cooling, the reaction mixture is filtered to remove the precipitant, concentrated in vacuo and purified by column chromatography to give a, a'- bis [N-ethyl-6-(N-(1-(N-benzyloxyimino) ethyl) amino)-2-phthalimido-2- methylhexanamido]-m-xylene.

EX-4b) a, a'-Bis [N-ethyl-6- (N- (1- (N-benzyloxyimino) ethyl) amino)-2-phthalimido-2- methylhexanamido]-m-xylene (5 mmol) is dissolved in methanol, treated with hydrazine (10.2 mmol), and heated to reflux to remove the phthaloyl protecting group. The mixture is concentrated and purified through by column chromatography to to give a, a'-bis [N- <BR> <BR> ethyl-6-(N-(1-(N-benzyloxyimino) ethyl) amino)-2-amino-2-methylhexanamido]-m-xylene.

a, a'-Bis [N-ethyl-6-(N-(1-(N-benzyloxyimino) ethyl) amino)-2-amino-2- methylhexanamido]-m-xylene (4 mmol) is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, the catalyst is removed by filtration, and the solvent is removed in vacuo generating the amino product a, a'-Bis [N-ethyl-6- (N- (1-oximinoethyl) amino)-2-amino-2-methylhexanamido]-m-xylene.

Example 5 EX-5a) The lithium salt of N-methyl-6- (N- (1- (N-benzyloxyimino) ethyl) amino)-2- phthalimido-2-methylhexanamide (10 mmol) is made following the procedure in EX-3b from N-methyl-6- (N- (l- (N-benzyloxyimino) ethyl) amino)-2-phthalimido-2- methylhexanamide is added in anhydrous THF at-78°C to a-bromo-a'- (2- tetrahydropyranyloxy)-m-xylene (10 mmol) in THF. After warming to room temperature, the reaction is filtered to remove the precipitant, is concentrated in vacuo and is purified by chromatography to give 3- [N-methyl-6- (N- (l- (N-benzyloxyimino) ethyl) amino)-2- phthalimido-2-methylhexanamidomethyl] benzyl 2-tetrahydropyranyloxy ether.

EX-5b) 3- [N-methyl-6- (N- (1- (N-benzyloxyimino) ethyl) amino)-2-phthalimido-2- methylhexanamidomethyl] benzyl 2-tetrahydropyranyloxy ether is dissolved in acetic acid and heated to reflux. When the THP group is completely removed, the reaction mixture is concentrated in vacuo to yield 3- [N-methyl-6- (N- (l- (N-benzyloxyimino) ethyl) amino)-2- phthalimido-2-methylhexanamidomethyl] phenylmethanol.

EX-5c) 3-[N-methyl-6-(N-(l-(N-benzyloxyimino) ethyl) amino)-2-phthalimido-2- methylhexanamidomethyl] phenylmethanol (9 mmol) and 6-(N-(1-(N- benzyloxyimino) ethyl) amino)-2- (N-Z-amino)-2-methylhexanoic acid (9 mmol) are dissolved in THF and acetonitrile and treated with 1,3-dicyclohexylcarbodiimide (9.5 mmol). The reaction is stirred until the coupling is complete, concentrated, and is purified by chromatography to give 3- [N-methyl-6- (N- (l- (N-benzyloxyimino) ethyl) amino)-2- phthalimido-2-methylhexanamidomethyl]-benzyl 6- (N- ( 1- (N- benzyloxyimino) ethyl) amino)-2- (N-Z-amino)-2-methylhexanoate.

EX-5d) 3- [N-methyl-6-(N-(l-(N-benzyloxyimino) ethyl) amino)-2-phthalimido-2- methylhexanamidomethyl]-benzyl 6- (N- (l- (N-benzyloxyimino) ethyl) amino)-2- (N-Z- amino)-2-methylhexanoate (8 mmol) is dissolved in methanol, treated with hydrazine (8.4 mmol), and heated to reflux to remove the phthaloyl protecting group. After filtering to. remove phthaloyl hydrazide and concentrating, the reaction mixture is purified by chromatography to give 3- [N-methyl-6- (N- (l- (N-benzyloxyimino) ethyl) amino)-2-amino- 2-methylhexanamidomethyl]-benzyl 6- (N- (1- (N-benzyloxyimino) ethyl) amino)-2- (N-Z- amino)-2-methylhexanoate.

3- [N-Methyl-6-(N-(1-(N-benzyloxyimino) ethyl)[N-Methyl-6-(N-(1-(N-benzyloxyimino) ethyl) amino)-2-amino-2- methylhexanamidomethyl]-benzyl 6- (N-(l-(N-benzyloxyimino) ethyl) amino)-2- (N-Z- amino)-2-methylhexanoate is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, the catalyst is removed by filtration, and the solvent is removed in vacuo. The residue is dissolved in 25 mL of 1 M HC1 in ethyl acetate and then taken to dryness to give 3-[N-methyl-6-(N-(l-oximinoethyl) amino)-2-amino-2- methylhexanamidomethyl]-benzyl 6- (N- ( 1-oximinoethyl) amino)-2-amino-2- methylhexanoate tetrahydrochloride.

Example 6 EX-6a) The lithium salt of N-methyl-6- (N- (1- (N-benzyloxyimino) ethyl) amino)-2- phthalimido-2-methylhexanamide (10 mmol) is made following the procedure in EX-3b from N-methyl-6- (N- (1- (N-benzyloxyimino) ethyl) amino)-2-phthalimido-2- methylhexanamide is added in anhydrous THF at-78°C to 2-bromoethyl 2- (2-tetrahydropyranyloxy) ethyl ether (10 mmol) in THF. After warming to room temperature, the reaction is filtered to remove the precipitant, is concentrated in yacuo and is purified through a chromatography column to give 2-[N-methyl-6-(N-(l-(N- benzyloxyimino) ethyl) amino)-2-phthalimido-2-methylhexanamido] ethyl 2- (2- tetrahydropyranyloxy) ethyl ether.

EX-6b) 2- [N-Methyl-6- (N- (I- (N-benzyloxyirnino) ethyl) amino)-2-phthalimido-2- methylhexanamido] ethyl 2- (2-tetrahydropyranyloxy) ethyl ether is dissolved in acetic acid and heated to reflux. When the THP group is completely removed the reaction mixture is concentrated in vacuo to yield 2- [2- [N-Methyl-6- (N- (l- (N-benzyloxyimino) ethyl) amino)- 2-phthalimido-2-methylhexanamido] ethoxy] ethanol.

EX-6c) 2- [2-[N-Methyl-6-(N-(l-(N-benzyloxyimino) ethyl) amino)-2-phthalimido-2- methylhexanamido] ethoxy] ethanol (9 mmol) and 6- (N- (1- (N- benzyloxyimino) ethyl) amino)-2- (N-Z-amino)-2-methylhexanoic acid (9 mmol) are dissolved in THF and acetonitrile and treated with 1,3-dicyclohexylcarbodiimide (9.5

mmol). The reaction is stirred until the coupling is complete, concentrated and is purified by chromatography to give 2- [2- [N-Methyl-6- (N- (l- (N-benzyloxyimino) ethyl) amino)-2- phthalimido-2-methylhexanamido] ethoxy] ethyl 6- (N- (l- (N-benzyloxyimino) ethyl) amino)- 2- (N-Z-amino)-2-methylhexanoate.

EX-6d) 2- [2- [N-Methyl-6- (N- (I- (N-benzyloxyimino) ethyl) amino)-2-phthalimido-2- methylhexanamido] ethoxy] ethyl 6- (N- ( 1- (N-benzyloxyimino) ethyl) amino)-2- (N-Z- amino)-2-methylhexanoate (8 mmol) is dissolved in methanol, treated with hydrazine (8.4 mmol), and heated to reflux to remove the phthaloyl protecting group. After filtering to remove phthaloyl hydrazide and concentrating, the reaction mixture is purified by chromatography to give 2- [2-[N-Methyl-6-(N-(l-(N-benzyloxyimino) ethyl) amino)-2- amino-2-methylhexanamido] ethoxy] ethyl 6- (N-(l-(N-benzyloxyimino)(N-(l-(N-benzyloxyimino) ethyl) amino)-2- (N- Z-amino)-2-methylhexanoate.

2- [2- [N-Methyl-6- (N- ( 1- (N-benzyloxyimino) ethyl) amino)-2-amino-2- methylhexanamido] ethoxy] ethyl 6- (N- ( 1- (N-benzyloxyimino) ethyl) amino)-2- (N-Z- amino)-2-methylhexanoate is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, the catalyst is removed by filtration, and the solvent is removed in vacuo. The residue is dissolved in 25 mL of 1 M HC1 in ethyl acetate and then taken to dryness to give 2- [2- [N-Methyl-6- (N- (l-oximinoethyl) amino)-2-amino-2- methylhexanamido] ethoxy] ethyl 6-(N-(l-oximinoethyl) amino)-2-amino-2- methylhexanoate tetrahydrochloride.

Example 7 N- (5-Tetrazolyl)-S- (2- (N- (l-oximinoethyl) amino) ethyl) cysteinamide (20 mmol) is added to 50 ml of toluene in 100 ml reaction flask. After adding (50 mmol) p-toluenesulfonic / acid, (10 mmol) N, N-bis (4,4-dimethoxybutyl) methylamine, and 50 mmol water, the reaction mixture is refluxed with azeotropic distillation until all alcohol and excess water is removed. After cooling, the solvent is removed in vacuo to give N, N-bis [4- [N- (3- (2- (N- (1-oximoethyl) amino) ethylthio)-1- (N-tetrazolylamidocarbonyl) propyl) imino] butyl]-N- methylamine penta-p-toluenesulfonic acid salt.

Example 8 6- (N- (l-lminoethyl) amino)-2-aminohexanoic acid (20 mmol) is added to 50 ml of toluene in 100 ml reaction flask. After adding (40 mmol) p-toluenesulfonic acid and (10 mmol) 1,3-diacetonylbenzene, the reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean-Stark trap. After cooling, the solvent and is removed in vacuo to give 1,3-bis [2- [N- (5- (N- (l- iminoethyl) amino)-l-carboxypentyl) iminopropyl] benzene tetra-p-toluenesulfonic acid salt.

Example 9 EX-9a) tert-Butyl 6- (N- (l-iminoethyl) amino)-2-aminohexanoate hydrochloride (10 mmol) and 25 mL dimethylformamide are cooled in an ice bath, 21 mmol triethylamine is added, and then the reaction mixture is treated with (10.5 mmol) 3- (2,2- dimethoxypropyl) phenylacetyl chloride. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo. Water is added, the solution is then adjusted to pH = 7.5, and then it is poured onto a Dowex 50 Cation exchange column. The column is washed with water. The product tert-butyl 6- (N- (1- iminoethyl) amino)-2- (3- (2,2-dimethoxypropyl) phenylacetamido)-hexanoate is then eluted with 10% aqueous pyridine.

EX-9b) tert-butyl 6- (N- (1-iminoethyl) amino)-2- (3- (2,2- dimethoxypropyl) phenylacetamido)-hexanoate (9 mmol) is added to 50 ml of toluene in 100 ml reaction flask. After adding 27 mmolof p-toluenesulfonic acid, 40 mmol of water, and 9 mmol of 6- (N- (l-iminoethyl) amino)-2-aminohexanoic acid, the reaction mixture is refluxed with azeotropic distillation for complete removal of methanol and excess water using a Dean-Stark trap. After cooling, the solvent and is removed in vacuo to give tert-

butyl 6- (N- ( 1-iminoethyl) amino)-2- [3- [2- (N- (5- (N- ( 1-iminoethyl) amino)-1- carboxypentyl) imino) propyl] phenylacetamido]-hexanoate tri-p-toluenesulfonic acid salt. tert-Butyl 6- (N- (1-iminoethyl) amino)-2- [3- [2- (N- (5- (N- (1-iminoethyl) amino)-1- carboxypentyl) imino) propyl] phenylacetamido]-hexanoate tri-p-toluenesulfonic acid salt is deprotected by allowing it to stand in 2N HC1 and dioxane at 25°C for two hours.

Concentrating in vacuo affords 6- (N- (l-iminoethyl) amino)-2- [3- [2- (N- (5- (N- (l- iminoethyl) amino)-1-carboxypentyl) imino) propyl] phenylacetamido]-hexanoic acid tri-p- toluenesulfonic acid salt.

Example 10 EX-lOa) tert-Butyl 6- (N- (l-iminoethyl) amino)-2-aminohexanoate dihydrochloride (10 mmol) and 25 mL dimethylformamide are cooled in an ice bath, 31 mmol triethylamine is added, and then the reaction mixture is treated with 4- (4,4-dimethoxypentylthio) butanoyl chloride (10.5 mmol). After warming to room temperature and standing for 2 hours, the

reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of 1M aqueous sodium carbonate. The methylene chloride layer is separated, the aqueous solution is extracted three times with 50 mL methylene chloride, the combined extracts are dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield tert-Butyl 6- (N- (l-iminoethyl) amino)-2- (4- (4,4- dimethoxypentylthio) butanamido)-hexanoate.

EX-lOb) tert-Butyl 6- (N- (l-iminoethyl) amino)-2- (4- (4,4- dimethoxypentylthio) butanamido)-hexanoate (9 mmol) is added to 50 ml of toluene in 100 ml reaction flask. After adding p-toluenesulfonic acid (27 mmol), 40 mmol water and 6- (N-(l-iminoethyl) amino)-2-aminohexanoic acid (9 mmol), the reaction mixture is refluxed with azeotropic distillation for complete removal of methanol and excess water using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give tert-Butyl 6- (N- (1-iminoethyl) amino)-2- [4- [4- (N- (5- (N- ( 1-iminoethyl) amino)-1- carboxypentyl) imino) pentylthio] butanamido]-hexanoate tri-p-toluenesulfonic acid salt. tert-Butyl 6- (N- (l-iminoethyl) amino)-2- [4- [4- (N- (5- (N- (l-iminoethyl) amino)-1- carboxypentyl) imino) pentylthio] butanamido]-hexanoate tri-p-toluenesulfonic acid salt is deprotected by allowing it to stand in 2N HC1 and dioxane at 25°C for two hours.

Concentrating in vacuo affords 6- (N- (l-iminoethyl) amino)-2- [4- [4- (N- (5- (N- (l- iminoethyl) amino)-l-carboxypentyl) imino) pentylthio] butanamido]-hexanoate tri-p- toluenesulfonic acid salt.

Example 11

EX-lla) tert-Butyl 6- (N- (l-iminoethyl) amino)-2-aminohexanoate dihydrochloride (10 mmol) and 50 mL methylene chloride are cooled in an ice bath, 31 mmol triethylamine is added, and then the reaction mixture is treated with (5 mmol) oxalyl chloride. After warming to room temperature and standing for 2 hours, 20 mL of 1M aqueous sodium carbonate is added. The methylene chloride layer is separated, the aqueous solution is extracted three times with 50 mL methylene chloride, the combined extracts are dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield N, N'-bis [5- (N- (l-iminoethyl) amino)-1-tert-butoxycarbonylpentyl] oxamide.

N, N'-bis [5- (N- (l-iminoethyl) amino)-1-tert-butoxycarbonylpentyl] oxamide is deprotected by allowing it to stand in 2N HCI and dioxane at 25°C for two hours. Concentrating in vacuo affords N, N'-bis [5- (N- (l-iminoethyl) amino)-l-carboxypentyl] oxamide dihydrochloride.

Example 12 EX-12a) tert-Butyl 6- (N- (1-oximinoethyl) amino)-2- (N-Boc-amino) hexanoate (10 mmol) is dissolved in 25 ml of anhydrous toluene and treated with sodium hydride (0.5 mmol) in an ice bath. Methyl N- [6- (N- (l-iminoethyl) amino)-2- (N-Boc-amino) hexanoyl] glycinate (10 mmol) is added and the reaction mixture is refluxed for complete removal of methanol using a Dean-Stark trap. After cooling, the solvent is removed in vacuo and the mixture is purified by chromatography to give tert-Butyl 6-[N-[l-[N-(2-(6-(N-(l-iminoethyl) amino)- 2- (N-Boc-amino) hexanamido) acetoxy) imino] ethyl] amino]-2-(N-Boc-amino) hexanoate. tert-Butyl 6-[N-[1-[N-(2-(6-(N-(1-iminoethyl) amino)-2-(N-Boc- amino) hexanamido) acetoxy) imino] ethyl] amino]-2- (N-Boc-amino) hexanoate is deprotected by allowing it to stand in 2N HCI and dioxane at 25°C for two hours.

Concentrating in vacuo affords 6-[N-[l-[N-(2-(6-(N-(l-iminoethyl) amino)-2- aminohexanamido) acetoxy) imino] ethyl] amino]-2-aminohexanoic acid tetrahydrochloride.

Example 13 EX-13a) 2,2,2-trichloroethyl 6- (N- (l- (N-Boc-imino) ethyl) amino)-2- (N-Z- amino) hexanoate (10 mmol) is dissolved in 25 ml of toluene containing (10.5 mmol) TEA and cooled in an ice bath. Glutaryl dichloride (5 mmol) in 25 mL toluene is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water.

The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield N, N'- bis [5- (N-Z-amino)-5- (2,2,2-trichloroethoxycarbonyl) pentyl]-N, N'-bis [ 1- (N-Boc- imino) ethyl] glutaramide.

EX-13b) N, N'-Bis [5- (N-Z-amino)-5- (2,2,2-trichloroethoxycarbonyl) pentyl]-N, N'-bis [1- (N-Boc-imino) ethyl] glutaramide is dissolved in acetic acid and treated with excess zinc dust. The reaction is stirred until the trichloroethyl protecting group is removed. The reaction is filtered and concentrated in vacuo. 100 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, dried over MgS04,

and concentrated. The resulting material is purified chromatographically to yield N, N'- bis [5- (N-Z-amino)-5-carboxypentyl]-N, N'-bis [1-(N-Boc-imino)ethyl] glutaramide.

EX-13c) N, N'-bis (5- (N-Z-amino)-5-carboxypentyl)-N, N'-bis [l- (N-Boc- imino) ethyl] glutaramide is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product. Concentration gives N, N'-bis (5- amino-5-carboxypentyl)-N, N'-bis [l- (N-Boc-imino) ethyl] glutaramide.

N, N'-bis (5-amino-5-carboxypentyl)-N, N'-bis [1-(N-Boc-imino) ethyl] glutaramide is deprotected by allowing it to stand in 2N HC1 and dioxane at 25°C for two hours.

Concentrating in vacuo affords N, N'-bis (5-amino-5-carboxypentyl)-N, N'-bis (l- iminoethyl) glutaramide tetrahydrochloride.

Example 14

EX-14a) 1,4-Phenylenediacetyl chloride (10 mmol) is dissolved in 50 ml of toluene containing (10 mmol) TEA and cooled in an ice bath. 2,2,2-Trichloroethyl 6- (N- (1- (N- Boc-imino) ethyl) amino)-2- (N-Z-amino) hexanoate (10 mmol) in toluene is added. After standing at room temperature for 2 hours, the product, 4- [N- [5- (N-Z-amino)-5- ( 2,2,2- trichloroethoxycarbonyl) pentyl]-N-(1-(N-Boc-imino) ethyl)- amidocarbonylmethyl] phenylacetyl chloride, is formed.

EX-14b) To 4- [N- [5- (N-Z-amino)-5- ( 2,2,2-trichloroethoxycarbonyl) pentyl]-N- (l- (N- Boc-imino) ethyl)-amidocarbonylmethyl] phenylacetyl chloride (10 mmol) in 50 ml of toluene containing (11 mmol) TEA and cooled in an ice bath, tert-Butyl 6- (N- (l- (N-Boc- imino) ethyl) amino)-2-aminohexanoate (10 mmol) in toluene is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated.

The resulting material is purified chromatographically to yield tert-Butyl 6- [N- (l- (N-Boc- imino) ethyl) amino]-2- [4- [N- (5- (N-Z-amino)-5- (2,2,2-trichloroethoxycarbonyl) pentyl)-N- (l-(N-Boc-imino) ethyl))-amidocarbonylmethyl] phenylacetamido] hexanoate.

EX-14c) tert-Butyl 6- [N-(l-(N-Boc-imino) ethyl) amino]-2- [4- [N- (5- (N-Z-amino)-5- (2,2,2- trichloroethoxycarbonyl) pentyl)-N-(1-(N-Boc-imino) ethyl))- amidocarbonylmethyl] phenylacetamido] hexanoate is dissolved in acetic acid and treated with excess zinc dust. The reaction is stirred until the trichloroethyl protecting group is removed. The reaction is filtered and concentrated in vacuo. 100 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield tert-Butyl 6- [N-(l-(N-Boc-imino) ethyl) amino]-2- [4- [N- (5- (N-Z-amino)-S-carboxypentyl)-N-(l-(N-Boc-imino) ethyl))-amidocarbonylmethyl]<BR> phenylacetamido]hexanoate.

EX-14d) tert-Butyl 6- [N- (l- (N-Boc-imino) ethyl) amino]-2- [4- [N- (5- (N-Z-amino)-5- carboxypentyl)-N- (1- (N-Boc-imino) ethyl))- amidocarbonylmethyl] phenylacetamido] hexanoate is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-functions generating the amino product. Concentration gives

tert-Butyl 6- [N- (I- (N-Boc-imino) ethyl) amino]-2- [4- [N- (5-amino-5-carboxypentyl)-N- (I- (N-Boc-imino) ethyl))-amidocarbonylmethyl] phenylacetamido] hexanoate. tert-Butyl 6- [N- (l- (N-Boc-imino) ethyl) amino]-2- [4- [N- (5-amino-5-carboxypentyl)-N- (I- (N-Boc-imino) ethyl))-amidocarbonylmethyl] phenylacetamido] hexanoate is deprotected by allowing it to stand in 2N HCI and dioxane at 25°C for two hours. Concentrating in vacuo affords 6- [N- (l-iminoethyl) amino]-2- [4- [N- (5-amino-5-carboxypentyl)-N- (l- iminoethyl))-amidocarbonylmethyl] phenylacetamido] hexanoic acid trihydrochloride.

Example 15 6- (N-(l-iminoethyl) amino)-2-amino-1, 1-diethoxyhexane(N-(l-iminoethyl) amino)-2-amino-1, 1-diethoxyhexane (10 mmol) is added to 30 mL 2M HC1. The reaction is stirred at room temperature until complete hydrolysis of the acetal and then the solution is taken to dryness to give 2,5-bis (4- (N- (l- iminoethyl) amino) butyl)-2,5-dihydropyrazine tetrahydrochloride.

Example 16 EX-16a) 6- (N-(l-iminoethyl) amino)-2-amino-1, 1-diethoxyhexane (10 mmol) and 6- (N- (1-iminoethyl) amino)-2- (N-Boc-amino) hexanoic acid (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) in

dry THF is added, and the mixture is allowed to warm to room temperature. The reaction is stirred until the coupling is complete, concentrated and purified by chromatography to give 6-(N-(1-iminoethyl) amino)-2- [6-[N-(1-iminoethyl) amino)-2-(N-Boc- amino] hexanamido]-1,1-diethoxyhexane.

EX-16b) 6-(N-(l-Iminoethyl) amino)-2-[6-[N-(l-iminoethyl) amino)-2-(N-Boc- amino] hexanamido]-1,1-diethoxyhexane is deprotected by allowing it to stand in 2N HC1 and dioxane at 25°C for two hours. Concentrating in vacuo affords 6- (N- (1- iminoethyl) amino)-2-[6-[N-(1-iminoethyl) amino)-2-aminohexanamido]-1,1- diethoxyhexane trihydrochloride.

6- (N- ( 1-Iminoethyl) amino)-2- [6- [N-(1-iminoethyl) amino)-2-aminohexanamido]-1,1- diethoxyhexane trihydrochloride (9 mmol) is added to water. The reaction is stirred until completion and is concentrated in vacuo to give 2,5-bis [4- (N- (l-iminoethyl) amino) butyl]- 2,3,4,5-tetrahydro-3-oxopyrazine trihydrochloride.

Example 17 EX-17a) tert-Butyl 6- (N- (l-iminoethyl) amino)-2-amino-hexanoate (10 mmol) and 6- (N- (1-iminoethyl) amino)-2- (N-Boc-amino)-2-methylhexanoic acid (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) in dry THF is added, and the mixture is allowed to warm to room temperature. The reaction is stirred until the coupling is complete, concentrated and purified by chromatography to give tert-Butyl 6-(N-(l-iminoethyl) amino)-2-[6-(N-(l- iminoethyl) amino)-2- (N-Boc-amino)-2-methylhexanamido] hexanoate.

EX-17b) tert-Butyl 6-(N-(l-iminoethyl) amino)-2-[6-(N-(l-iminoethyl) arnino)-2-(N-Boc- amino)-2-methylhexanamido] hexanoate is deprotected by allowing it to stand in 2N HCI and dioxane at 25°C for two hours. Concentrating in vacuo affords 6- (N- (1- iminoethyl) amino)-2-[6-(N-(l-iminoethyl) amino)-2-(N-Boc-amino)-2- methylhexanamido] hexanoic acid trihydrochloride.

6- (N- (l-Iminoethyl) amino)-2- [6- (N- (l-iminoethyl) amino)-2- (N-Boc-amino)-2- methylhexanamido] hexanoic acid trihydrochloride. (9 mmol) is dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (9.5 mmol) in dry THF is added and the mixture is allowed to warm to room temperature. The reaction is stirred until the coupling is complete, concentrated and purified by chromatography to give 3-methyl-3,6-bis (4- (N- (l-iminoethyl) amino) butyl)-2,5-dioxopiperazine.

(18) Example 18 EX-18a) 6- (N-(2-fluoro-1-iminoethyl) amino)-2-phthalimidohexanoic acid (10 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (10.1 mmol) and triethyl amine (TEA) (21 mmol). Upon completion, benzyl 5-amino-2- (N-Boc-amino) pentanoate hydrochloride (10 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, the aqueous layer is extracted three times with methylene chloride, the combined extracts are dried over MgS04, and concentrated. The resulting material is

purified chromatographically to yield benzyl 5-[6-(N-(2-fluoro-1-iminoethyl) amino)-2- phthalimidohexanamido]-2- (N-Boc-amino) pentanoate.

EX-18b) Benzyl 5-[6-(N-(2-fluoro-1-iminoethyl) amino)-2-phthalimidohexanamido]-2- (N-Boc-amino) pentanoate is deprotected by allowing it to stand in 2N HCI and dioxane at 25°C for two hours. Concentrating in vacuo affords benzyl 5- [6- (N- (2-fluoro-l- iminoethyl) amino)-2-phthalimidohexanamido]-2-aminopentanoate dihydrochloride.

EX-18c) 6- (N- (2-fluoro-l-iminoethyl) amino)-2- (N-Z-amino) hexanoic acid (9.1 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (9.1 mmol) and triethyl amine (27 mmol). Upon completion, benzyl 5- [6- (N- (2-fluoro-l- iminoethyl) amino)-2-phthalimidohexanamido]-2-aminopentanoate dihydrochloride (9 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 mL of methylene chloride is added along with 20 mL of water. The methylene chloride layer is separated, the aqueous layer is extracted three times with methylene chloride, the combined extracts are dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield benzyl 5- [6- (N- (2-fluoro-1-iminoethyl) amino)-2-phthalimidohexanamido]-2- [6- (N- (2-fluoro-l- iminoethyl) amino)-2- (N-Z-amino) hexanamido] pentanoate.

EX-18d) Benzyl 5- [6- (N- (2-fluoro-l-iminoethyl) amino)-2-phthalimidohexanamido]-2- [6- (N-(2-fluoro-1-iminoethyl) amino)-2-(N-Z-amino) hexanamido] pentanoate (8 mmol) is dissolved in methanol, treated with hydrazine (8.4 mmol), and heated to reflux to remove the phthaloyl protecting group. After filtering to remove phthaloyl hydrazide and concentrating, the reaction mixture is purified by chromatography to give Benzyl 5- [6- (N- (2-fluoro-1-iminoethyl) amino)-2-aminohexanamido]-2-[6-(N-(2-fluoro-1- iminoethyl) amino)-2- (N-Z-amino) hexanamido] pentanoate.

Benzyl 5- [6-(N-(2-fluoro-1-iminoethyl) amino)-2-amiriohexanamido]-2- [6-(N-(2-fluoro-1- iminoethyl) amino)-2- (N-Z-amino) hexanamido] pentanoate is dissolved in ethanol containing acetic acid, and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function generating the amino product 2,5-bis [6- (N- (2-fluoro-1-iminoethyl) amino)-2- aminohexanamido] pentanoic acid.

(19) Example 19 EX-19a) 6- (N- (2-Fluoro-l-iminoethyl) amino)-2- (N-Z-amino) hexanoic acid (10 mmol) and triethyl amine (11 mmol) are added to anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (10.1 mmol). Upon completion, erythritol (10.1 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, and the resulting material is purified chromatographically to separate isomeric products and yield 2,3,4-trihydroxybutyl 6-(N-(2-fluoro-1- iminoethyl) amino)-2- (N-Z-amino) hexanoate.

EX-19b) 6- (N- (l-iminoethyl) amino)-2- (N-Z-amino) hexanoic acid (4.1 mmol) (4 mmol) and triethyl amine (5 mmol) are added to anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (4.1 mmol). Upon completion, 2,3,4-trihydroxybutyl 6- (N-(2-fluoro-1-iminoethyl) amino)-2-(N-Z-amino) hexanoate (4.1 mmol) is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, and the resulting material is purified chromatographically to separate the three isomers and yield 2,4-dihydroxy-3-[6-(N-(l-iminoethyl) amino)-2-(N-Z- amino) hexanoyloxy] butyl 6- (N- (2-fluoro-l-iminoethyl) amino)-2- (N-Z-amino) hexanoate.

2,4-dihydroxy-3- [6-(N-(l-iminoethyl) amino)-2-(N-Z-amino) hexanoyloxy] butyl 6- (N- (2- fluoro-l-iminoethyl) amino)-2- (N-Z-amino) hexanoate (2 mmol) is mixed with tert-butanol containing 8 mmol p-toluenesulfonic acid, and a hydrogenation catalyst such as palladium on carbon and hydrogen is added. This reaction is shaken under pressure for an extended

period of time in a standard Parr hydrogenation apparatus to remove the Z-function, the catalyst is filtered, and the solvent is removed in vacuo generating the amino product 2,4- dihydroxy-3- [6- (N- ( 1-iminoethyl) amino)-2-aminohexanoyloxy] butyl 6- (N- (2-fluoro-1- iminoethyl) amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt.

(20) Example 20 EX-20a) 6- (N- (l- (N-benzyloxyimino) ethyl) amino)-2- (N-Z-amino) hexanoic acid (4.1 mmol) and triethyl amine (5 mmol) are added to anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (4.2 mmol). Upon completion, 2,4-dihydroxy-3- [6- (N- (1-iminoethyl) amino)-2-(N-Z-amino) hexanoyloxy] butyl 6-(N-(2-fluoro-1- iminoethyl) amino)-2- (N-Z-amino) hexanoate (4.1 mmol), as prepared in EX-19b), is added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo. Methylene chloride (100 mL) and 20 mL of 1M aqueous sodium bicarbonate are added. The methylene chloride layer is separated, the aqueous solution is extracted three times with 50 mL methylene chloride, the combined extracts are dried over

MgS04, and concentrated. The resulting material is purified chromatographically to separate isomers and yield 2-hydroxy-3-[6-(N-(l-iminoethyl) amino)-2-(N-Z- amino) hexanoyloxy]-4- [6- (N- (l- (N-benzyloxyimino) ethyl) amino)-2- (N-Z-amino) hexanoyloxy] butyl 6- (N- (2-fluoro-1-iminoethyl) amino)-2- (N-Z-amino) hexanoate.

EX-20b) 3- (2-(N-(l-Iminoethyl) amino) ethylthio)-2- (N-Z-amino) propanoic acid (3.1 mmol) and triethyl amine (4 mmol) are added to anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (3.2 mmol). 2-Hydroxy-3-[6-(N-(l-iminoethyl) amino)-2- (N-Z-amino) hexanoyloxy]-4- [6-(N-(1-(N-benzyloxyimino) ethyl) amino)-2-(N-Z- amino) hexanoyloxy] butyl 6-(N-(2-fluoro-1-iminoethyl) amino)-2-(N-Z-amino) hexanoate (3 mmol) is then added in anhydrous THF. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo. Methylene chloride (100 mL) and 20 mL of 1M aqueous sodium bicarbonate are added. The methylene chloride layer is separated, the aqueous solution is extracted three times with 50 mL methylene chloride, the combined extracts are dried over MgS04, and concentrated in vacuo. The resulting material is purified chromato-graphically to yield 2- [3- (2- (N- (1- iminoethyl) amino) ethylthio)-2-(N-Z-amino) propanoyloxy]-3-[6-(N-(l-iminoethyl) amino)-2- (N-Z-amino) hexanoyloxy]-4- [6- (N- ( 1- (N-benzyloxyimino) ethyl) amino)-2- (N-Z- amino) hexanoyloxy] butyl 6-(N-(2-fluoro-1-iminoethyl) amino)-2-(N-Z-amino) hexanoate.

2- [3- (2- (N- (l-Iminoethyl) amino) ethylthio)-2- (N-Z-amino) propanoyloxy]-3- [6- (N- (1- iminoethyl) amino)-2-(N-Z-amino) hexanoyloxy]-4-[6-(N-(l-(N- benzyloxyimino) ethyl) amino)-2- (N-Z-amino) hexanoyloxy] butyl 6- (N- (2-fluoro-1- iminoethyl) amino)-2- (N-Z-amino) hexanoate (2 mmol) is mixed with tert-butanol containing 16 mmol p-toluenesulfonic acid, and a hydrogenation catalyst such as palladium on carbon and hydrogen is added. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z- functions, the catalyst is filtered, and the solvent is removed in vacuo generating the amino product 2- [3- (2- (N- (l-iminoethyl) amino) ethylthio)-2-aminopropanoyloxy]-3- [6- (N- (1-iminoethyl) amino)-2-aminohexanoyloxy]-4- [6- (N- ( 1-oxyiminoethyl) amino)-2- aminohexanoyloxy] butyl 6- (N-(2-fluoro-1-iminoethyl) amino)-2-aminohexanoate octyl-p- toluenesulfonic acid salt.

Example 21 EX-21a) 1,2,3,4-butanetetracarboxylic acid (10 mmol) and benzyl 6- (N- (1- iminoethyl) amino)-2-aminohexanoate hydrochloride (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. Triethylamine (11 mmol) and 1,3- dicyclohexylcarbodiimide (10.5 mmol) in dry THF are added, and the mixture is allowed to warm to room temperature. When the coupling is complete, the mixture is concentrated, and the reaction is purified by chromatography to separate isomers and give 1- [N- [5- (N- (I-irriinoethyl) amino)-I- (benzyloxycarbonyl) pentyl] amidocarbonyl]-2,3,4- butanetricarboxylicacid.

EX-21b) 1- [N- [S- (N- (1-iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl]-2,3,4-butanetricarboxylic acid (5 mmol) and benzyl 6- (N- (2- fluoro-l-iminoethyl) amino)-2-aminohexanoate hydrochoride (5 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (5.5 mmol) and triethylamine (5 mmol) in dry THF are added, and the mixture is allowed to warm to room temperature. When the coupling is complete, the mixture is concentrated, and the reaction is purified by chromatography to separate isomers and give 1- [N- [S- (N- (1-

iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl]-4-[N- [S-(N-(2-fluoro-1- iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl]-2,3-butanedicarboxylic acid. <BR> <BR> <P>1- [N- [5- (N- (1-Iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl]-4- [N- [5- (N-(2-fluoro-1-iminoethyl) amino)-1-(benzyloxycarbonyl) pentyl] amidocarbonyl]-2,3- butanedicarboxylic acid is dissolved in tert-butanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, the catalyst is filtered, and the solvent is removed in vacuo generating the amino product 1- [N- [5- (N- (1-iminoethyl) amino)-1-carboxypentyl] amidocarbonyl]-4- [N- [5- (N- (2-fluoro-l-iminoethyl) amino)-l-carboxypentyl] amidocarbonyl]-2,3- butanedicarboxylic acid.

Example 22

EX-22a) 1- [N- [5- (N- (1-iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl]-4- [N- [5- (N- (2-fluoro-1-iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl]-2,3-butanedicarboxylic acid (10 mmol) as prepared in EX-21b and benzyl 3- (2-(N-(l-Iminoethyl) amino) ethylthio)-2- aminopropanoate hydrochloride (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) and triethylamine (11 mmol) in dry THF are added, and the mixture is allowed to warm to room temperature.

When the coupling is complete, the mixture is concentrated, and the reaction is purified by chromatography column to separate isomers and give 1- [N- [5- (N- (l-iminoethyl) amino)-l- (benzyloxycarbonyl) pentyl] amidocarbonyl]-3-[N-[2-(2-(N-(1- iminoethyl) amino) ethylthio)-l- (benzyloxycarbonyl) ethyl] amidocarbonyl]-4- [N- [5- (N- (2- fluoro-1-iminoethyl) amino)-1-(benzyloxycarbonyl) pentyl] amidocarbonyl]-2- butanecarboxylic acid.

1- [N- [5- (N- (1-iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl]-3- [N- [2- (2-(N-(1-iminoethyl) amino) ethylthio)-1-(benzyloxycarbonyl) ethyl] amidocarbonyl]-4, [N- [5- (N- (2-fluoro-l-iminoethyl) amino)-l- (benzyloxycarbonyl) pentyl] amidocarbonyl]-2- butanecarboxylic acid (4 mmol) and benzyl 6- (N- (l- (N-benzyloxyimino) ethyl) amino)-2- aminohexanoate hydrochloride (4 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (4.5 mmol) and triethylamine (5 mmol) in dry THF are added and the mixture is allowed to warm to room temperature.

When the coupling is complete, the mixture is concentrated and purified by chromatography to give l- [N- [5- (N- (l-iminoethyl) amino)-l- (benzyloxycarbonyl) pentyl] amidocarbonyl]-2- [N- [5- (N- (1- (N-benzyloxyimino) ethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl]-3- [N- [2- (2- (N- ( 1- iminoethyl) amino) ethylthio)-l- (benzyloxycarbonyl) ethyl] amidocarbonyl]-4- [N- [5- (N- (2- fluoro-1-iminoethyl) amino)-1-(benzyloxycarbonyl) pentyl] amidocarbonyl] butane. <BR> <BR> <BR> <BR> <BR> <BR> <P>1- [N- [5- (N- (1-Iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl]-2- [N- [5- (N- (1- (N-benzyloxyimino) ethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl]-3- [N- [2- (2- (N- (l-iminoethyl) amino) ethylthio)-1- (benzyloxycarbonyl) ethyl] amidocarbonyl]- 4- [N- [5- (N- (2-fluoro-1-iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl] amidocarbonyl] butane is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen.

This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the benzyl-function, the catalyst is filtered, and the

solvent is removed to give 1- [N- [5- (N- (l-iminoethyl) amino)-l- carboxypentyl] amidocarbonyl]-2- [N- [5- (N- (l-oximinoethyl) amino)-1- carboxypentyl] amidocarbonyl]-3-[N-[2-(2-(N-(l-iminoethyl)[N-[2-(2-(N-(l-im inoethyl) amino) ethylthio)-1- carboxyethyl] amidocarbonyl]-4- [N- [5- (N- (2-fluoro-1-iminoethyl) amino)-1- carboxypentyl] amidocarbonyl] butane.

(23) Example 23 EX-23a) 4- (N- (l-iminoethyl) amino)-2- (N-Z-amino) hexanoic acid (10 mmol) and tert- butyl 2-hydroxyacetate (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) in dry THF is added, and the mixture is allowed to warm to room temperature. When coupling is complete, the mixture is concentrated and purified by chromatography to give tert-butyl 2- [6- (N- (1- iminoethyl) amino)-2- (N-Z-amino) hexanoyloxy] acetate.

EX-23b) tert-Butyl 2- [6- (N- (l-iminoethyl) amino)-2- (N-Z-amino) hexanoyloxy] acetate is deprotected by allowing it to stand in 2N HC1 and dioxane at 25°C for two hours.

Concentrating in vacuo affords 2- [6- (N- (l-iminoethyl) amino)-2- (N-Z-amino) hexanoyloxy] acetic acid hydrochloride.

EX-23c) 2-[6-(N-(l-Iminoethyl) amino)-2-(N-Z-amino) hexanoyloxy] acetic acid hydrochloride (5 mmol) and benzyl 6-(N-(l-iminoethyl) amino)-2-amino-2- methylhexanoate hydrochloride (5 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (5.5 mmol) and triethylamine (11

mmol) in dry THF are added, and the mixture is allowed to warm to room temperature.

When coupling is complete, the mixture is concentrated and purified by chromatography to give N- [5- (N- (1-iminoethyl) amino)-1-methyl-1- (benzyloxycarbonyl) pentyl]-2- [6- (N- (1- iminoethyl) amino)-2- (N-Z-amino) hexanoyloxy] acetamide.

N- [5- (N- (l-irninoethyl) amino)-I-methyl-1- (benzyloxycarbonyl) pentyll-2- [6- (N- (I- iminoethyl) amino)-2- (N-Z-amino) hexanoyloxy] acetamide (3 mmol) is dissolved in tert- butanol containing 9 mmol of p-toluenesulfonic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the protecting groups, filtered to remove catalyst, and concentrated to give N- [5- (N- ( 1-iminoethyl) amino)-1-methyl-1-carboxypentyl]-2- [6- (N- ( 1-iminoethyl) amino)-2- aminohexanoyloxy] acetamide tri-p-toluenesulfonic acid salt.

Example 24 EX-24a) 2-[6-(N-(l-iminoethyl) amino)-2-(N-Z-amino) hexanoyloxy] acetic acid hydrochloride (10 mmol) and tert-butyl 6-(N-(2-fluoro-1-iminoethyl) amino)-2- aminomethyl-2-phthalimidohexanoate dihydrochloride (10 mmol) are dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) and triethylamine (32 mmol) in dry THF are added, and the mixture is allowed to warm to room temperature. When the coupling is complete, the mixture is concentrated

and purified by chromatography to give tert-butyl 6-(N-(2-fluoro-1-iminoethyl) amino)-2- [2-(6-(N-(l-iminoethyl) amino)-2-(N-Z-amino) hexanoyloxy) acetamidomethyl]-2- phthalimidohexanoate.

EX-24b) tert-Butyl 6-(N-(2-fluoro-1-iminoethyl) amino)-2-[2-(6-(N-(l- iminoethyl) amino)-2-(N-Z-amino) hexanoyloxy) acetamidomethyl]-2- phthalimidohexanoate is deprotected by allowing it to stand in 2N HC1 and dioxane at 25°C for two hours. Concentrating in vacuo affords 6-(N-(2-fluoro-1-iminoethyl) amino)- 2- [2-(6-(N-(1-iminoethyl) amino)-2-(N-Z-amino) hexanoyloxy)[2-(6-(N-(1-iminoethyl) amino)-2-(N-Z-amino) hexanoyloxy) acetamidomethyl]-2- phthalimidohexanoic acid dihydrochloride.

EX-24c) 6-(N-(2-fluoro-1-iminoethyl) amino)-2-[2-(6-(N-(1-iminoethyl) amino)-2-(N-Z- amino) hexanoyloxy) acetamidomethyl]-2-phthalimidohexanoic acid dihydrochloride (9 mmol) is dissolved in methanol and treated with hydrazine (9 mmol). The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, the reaction is concentrated and purified by chromatography to give 6- (N- (2-fluoro-1-iminoethyl) amino)- 2- [2-(6-(N-(l-iminoethyl) amino)-2-(N-Z-amino)[2-(6-(N-(l-iminoethyl) amino)-2-(N-Z-amino) hexanoyloxy) acetamidomethyl]-2- aminohexanoic acid.

6- (N- (2-fluoro-1-iminoethyl) amino)-2- [2- (6- (N- (1-iminoethyl) amino)-2- (N-Z- amino) hexanoyloxy) acetamidomethyl]-2-aminohexanoic acid (5 mmol) is dissolved in tert-butanol containing 20 mmol p-toluenesulfonic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the Z-function, filtered to remove the catalyst, and concentrated generating the amino product 6-(N-(2-fluoro-1-iminoethyl) amino)-2-[2-(6-(N-(l-iminoethyl) amino)-2- aminohexanoyloxy) acetamidomethyl]-2-aminohexanoic acid tetra-p-toluenesulfonic acid salt.

(25) Example 25 EX-25a) 2,2-diethoxy-1-propyl 6- (N- (1-iminoethyl) amino)-2- (N-Boc-amino) hexanoate (10 mmol) is treated with 5% aqueous phosphoric acid in 20 mL of water at ice bath temperature. After hydrolysis of the ketal, the pH is adjusted to pH 10 with sodium carbonate in an ice bath, and the product is rapidly extracted three times with 50 mL of methylene chloride. The solvent is dried over anhydrous MgS04,10 mmol p- toluenesulfonic acid is added, and the solvent removed to give 2-acetonyl 6- (N- (1- iminoethyl) amino)-2- (N-Boc-amino) hexanoate p-toluenesulfonic acid salt.

EX-25b) Hexane (50 mL) is added to the 2-acetonyl 6- (N- (l-iminoethyl) amino)-2- (N- Boc-amino) hexanoate p-toluenesulfonic acid salt (10 mmol). Ethyl 6- (N- (1- iminoethyl) amino)-2-aminohexanoate di-p-toluenesulfonic acid salt (10 mmol) is added.

The reaction mixture is refluxed with azeotropic distillation until complete removal of water using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give 2- [N- [6- (N- (1-iminoethyl) amino)-1-carboethoxypentyl] iminoJpropyl 6- (N- (1- iminoethyl) amino)-2- (N-Boc-amino) hexanoate tri-p-toluenesulfonic acid salt. p-Toluenesulfonic acid (10 mmol) and 2-[N-[6-(N-(l-iminoethyl) amino)-l- carboethoxypentyl] imino] propyl 6- (N-(l-iminoethyl) amino)-2-(N-Boc-amino)(N-(l-iminoethyl) amino)-2-(N-Boc-amino) hexanoate tri-p-toluenesulfonic acid salt (10 mmol) is deprotected by allowing it to stand in 2N HC1 and anhydrous dioxane at 25°C for two hours. Concentrating in vacuo affords 2- [N- [6- (N- (1-iminoethyl) amino)-1-carboethoxypentyl] imino] propyl 6- (N- ( 1-iminoethyl) amino)- 2-aminohexanoate tetra-p-toluenesulfonic acid salt.

(26) Example 26 EX-26a) N- (2- (3-Hydroxypropoxy) ethyl)-6- (N- (l-iminoethyl) amino)-2- phthalimidohexanamide (10 mmol) is dissolved in methanol and treated with hydrazine (10 mmol). The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, the reaction is concentrated and purified by chromatography to give N- (2-(3-hydroxypropoxy) ethyl)-6-(N-(1-iminoethyl) amillo)-2-aminohexanamide.

EX-26b) N- (2- (3-Hydroxypropoxy) ethyl)-6- (N- (l-iminoethyl) amino)-2- aminohexanamide (9.5 mmol) is allowed to stir with t-butoxycarbonylazide (10 mmol) and MgO (10 mmol) in dioxane/water solution. Upon completion, the magnesium salts are removed by filtration. The mixture is concentrated in vacuum and chromatographed giving N- (2- (3-hydroxypropoxy) ethyl)-6- (N- (l-iminoethyl) amino)-2- (N-Boc- amino) hexanamide.

EX-26c) N-(2-(3-hydroxypropoxy) ethyl)-6-(N-(l-iminoethyl) amino)-2-(N-Boc- amino) hexanamide (8 mmol) is dissolved in 20 mL DMSO and treated with 1,3- dicyclohexylcarbodiimide (DCC) (8 mmol) and phosphoric acid. The reaction is stirred at room temperature. Upon completion, 100 mL methylene chloride is added to the mixture, and it is washed with 10% aqueous sodium bicarbonate, water and brine. The methylene chloride layer is dried over MgS04, filtered, and solvents are removed in vacuo to give N- (2- (2-formylethoxy) ethyl)-6- (N- ( 1-iminoethyl) amino)-2- (N-Boc- amino) hexanamide.

EX-26d) N- (2- (2-Formylethoxy) ethyl)-6- (N- (l-iminoethyl) amino)-2- (N-Boc- amino) hexanamide (7 mmol) is dissolved in 25 ml of hexane and treated with p- toluenesulfonic acid (14 mmol) and ethyl 6-(N-(l-iminoethyl) amino)-2-aminohexanoate p-toluenesulfonic acid salt (7 mmol). The reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give N- [2- [2- [3- (5- (N- (l-iminoethyl) amino)- !- ethoxycarbonylpentyl) imino] propoxy] ethyl]-6-(N-(1-iminoethyl) amino)-2-(N-Boc- amino) hexanamide tri-p-toluenesulfonic acid salt.

N- [2- [2- [3- (5- (N- (l-Iminoethyl) amino)-l-ethoxycarbonylpentyl) imino] propoxy] ethyl]-6- (N- (l-iminoethyl) amino)-2- (N-Boc-amino) hexanamide tri-p-toluenesulfonic acid salt (6 mmol) is deprotected by allowing it to stand in 2N HC1 and dioxane containing 6 mmol p- toluenesulfonic acid at 25°C for two hours. Concentrating in vacuo affords N- [2- [2- [3- (5- (N- (1-Iminoethyl) amino)-1-ethoxycarbonylpentyl) imino] propoxy] ethyl]-6- (N- ( 1- iminoethyl) amino)-2-aminohexanamide tetra-p-toluenesulfonic acid salt.

(27) Example 27 EX-27a) N- [2- (4- (4-hydroxybutyl) phenyl) ethyl]-N-methyl-6- (N- ( 1-iminoethyl) amino)-2- phthalimidohexanamide (10 mmol) is dissolved in methanol and treated with hydrazine (10 mmol). The mixture is heated to reflux. After complete removal of the phthaloyl protecting group, the reaction is concentrated and passed through a chromatography column to give N- [2- (4- (4-hydroxybutyl) phenyl) ethyl]-N-methyl-6- (N- (l- iminoethyl) amino)-2-aminohexanamide.

EX-27b) N- [2- (4- (4-Hydroxybutyl) phenyl) ethyl]-N-methyl-6- (N- (1-iminoethyl) amino)-2- aminohexanamide (9.5 mmol) is allowed to stir with t-butoxycarbonylazide (10 mmol) and MgO (10 mmol) in dioxane/water solution. Upon completion, the magnesium salts are removed by filtration. The mixture is concentrated in vacuum giving, after chromatography, N- [2- (4- (4-hydroxybutyl) phenyl) ethyl]-N-methyl-6- (N- (l- iminoethyl) amino)-2- (N-Boc-amino) hexanamide.

EX-27c) N- [2- (4- (4-hydroxybutyl) phenyl) ethyl]-N-methyl-6-(N-(l-iminoethyl) amino)-2- (N-Boc-amino) hexanamide (8 mmol) is dissolved in 20 mL DMSO and treated with 1,3- dicyclohexylcarbodiimide (DCC) (8 mmol) and phosphoric acid. The reaction is stirred at room temperature. Upon completion of the oxidation, 200 mL methylene chloride is added to the mixture, and it is washed sequentially with 25 mL of brine, water and finally 10% aqueous sodium bicarbonate. The methylene chloride layer is dried over MgS04, filtered, solvents are removed in vacuo and the product is purified by column chromatography to give N- [2- (4- (3-formylpropyl) phenyl) ethyl]-N-methyl-6- (N- (l- iminoethyl) amino)-2- (N-Boc-amino) hexanamide.

EX-27d) N- [2- (4- (3-formylpropyl) phenyl) ethyl]-N-methyl-6- (N- (l-iminoethyl) amino)-2- (N-Boc-amino) hexanamide (7 mmol) is dissolved in 25 ml of hexane and treated with p- toluenesulfonic acid (7 mmol) and methyl 6- (N- (l-iminoethyl) amino)-2-aminohexanoate di-p-toluenesulfonic acid salt (7 mmol). The reaction mixture is refluxed with azeotropic distillation for complete removal of water using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give N- [2- [4- (N- (5- (N- (l-iminoethyl) amino)-l- methoxycarbonylpentyl) imino) butyl) phenyl] ethyl]-N-methyl-6- (N- (l-iminoethyl) amino)- 2- (N-Boc-amino) hexanamide tri-p-toluenesulfonic acid salt.

N- [2- [4- (N- (5- (N- (l-irriinoethyl) amino)- I- methoxycarbonylpentyl) imino) butyl) phenyl] ethyl]-N-methyl-6- (N- (l-iminoethyl) amino)- 2- (N-Boc-amino) hexanamide tri-p-toluenesulfonic acid salt (6 mmol) is deprotected by allowing it to stand in 2N HCI and dioxane containing 6 mmol p-toluenesulfonic acid at 25°C for two hours. Concentrating in vacuo gives N- [2- [4- (N- (5- (N- (1- iminoethyl) amino)-1-methoxycarbonylpentyl) imino) butyl) phenyl] ethyl]-N-methyl-6- (N- (1-iminoethyl) amino)-2-aminohexanamide tetra-p-toluenesulfonic acid salt.

(28) Example 28 EX-28a) 6- (N- (l-iminoethyl) amino)-2- (N-Boc-amino) hexanoic acid (10 mmol) and 2- (4,4-dimethoxycyclohexyl) ethanol (10 mmol) is dissolved in dry THF and acetonitrile and cooled in an ice bath. 1,3-Dicyclohexylcarbodiimide (10.5 mmol) in dry THF is added and the mixture is allowed to warm to room temperature. When the coupling is complete, the mixture is concentrated and is purified by chromatography to give 2- (4,4- dimethoxycyclohexyl) ethyl 6- (N- (l-iminoethyl) amino)-2- (N-Boc-amino) hexanoate.

EX-28b) 2- (4,4-dimethoxycyclohexyl) ethyl 6- (N- (l-iminoethyl) amino)-2- (N-Boc- amino) hexanoate (9 mmol) is stirred with p-toluenesulfonic acid (9 mmol), water (0.5 mmol), and 30 mL acetone until the ketal is hydrolyzed and transketalized. The reaction mixture is concentrated to dryness to give 2- (4-oxocyclohexyl) ethyl 6-(N-(l-iminoethyl) amino)-2- (N-Boc-amino) hexanoate p-toluenesulfonic acid salt.

EX-28c) 2- (4-oxocyclohexyl) ethyl 6- (N- (l-iminoethyl) amino)-2- (N-Boc- amino) hexanoate p-toluenesulfonic acid salt and ethyl 6- (N- (i-iminoethyl) amino)-2- aminohexanoate di-p-toluenesulfonic acid salt are slurried in a mixture of 100 mL toluene and dimethylacetamide (19: 1) and refluxed azeotropically to remove water formed in the condensation. Concentrating in vacuo affords 2- [4- [N- (5- (N- (l-iminoethyl) amino)-l- ethoxycarbonylpentyl) imino] cyclohexyl] ethyl 6-(N-(l-iminoethyl) amino)-2-(N-Boc- amino) hexanoate tri-p-toluenesulfonic acid salt.

2- [4- [N- (5- (N- (l-iminoethyl) amino)-l-ethoxycarbonylpentyl) imino] cyclohexyl] ethyl 6- (N- (l-iminoethyl) amino)-2- (N-Boc-amino) hexanoate tri-p-toluenesulfonic acid salt is deprotected by allowing it to stand in 2N HC1 and anhydrous dioxane containing one equivalent of p-toluenesulfonic acid at 25°C for two hours. Concentrating in vacuo affords 2- [4- [N- (5- (N- (l-iminoethyl) amino)-l-ethoxycarbonylpentyl) imino] cyclohexyl] ethyl 6- (N- (1-iminoethyl) amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt.

(29) Example 29 Methyl 6- (N-(l-iminoethyl) amino)-2-aminohexanoate di-p-toluenesulfonic acid salt (20 mmol) is added to 25 ml of toluene and treated with p-toluenesulfonic acid (1 mmol) and di (ethyleneglycol) (10 mmol). The reaction mixture is heated to 80 °C with distillation for removal of methanol using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give 2- [2-[6-(N-(l-iminoethyl) amino)-2-aminohexanoyloxy] ethoxy] ethyl 6- (N- (1-iminoethyl) amino)-2-aminohexanoate tetra-p-toluenesulfonic acid salt.

(30) Example 30 Methyl 6- (N-(l-iminoethyl) amino)-2-aminohexanoate di-p-toluenesulfonic acid (20 mmol) is added to 25 ml of toluene and treated p-toluenesulfonic acid (1 mmol) and 1,4- di (2-hydroxyethyl) benzene (10 mmol). The reaction mixture is heated to 80 °C with distillation for removal of methanol using a Dean-Stark trap. After cooling, the solvent is removed in vacuo to give 4-[2-[6-(N-(l-iminoethyl) amino)-2- aminohexanoyloxy] ethyl] phenethyl 6-(N-(l-iminoethyl) amino)-2-aminohexanoate tetra-p- toluenesulfonic acid salt.

(31) Example 31 EX-31a) 2,2,2-trichloroethyl mmol)(10 is dissolved in 25 ml of anhydrous THF and acetonitrile containing (42 mmol) triethylamine. After cooling in an ice bath, benzyl 6- (N- (l-iminoethyl) amino)-2- aminohexanoate dihyrochloride (20.5 mmol) is added to the mixture over 20 minutes.

After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 50 ml of methylene chloride is added along with 20 ml of 10% sodium bicarbonate. The methylene chloride layer is separated, the water is extracted with methylene chloride three times, dried over MgS04, concentrated, and chromatographed to afford 2,2,2-trichloroethyl N- [bis [N- (5- (N- (l-iminoethyl) amino)-l- (benzyloxycarbonyl) pentyl) amino] phosphinylmethyl]-N-Boc-glycinate.

EX-31b) 2,2,2-Trichloroethyl N- [bis [N- (5- (N- (l-iminoethyI) amino)- !- (benzyloxycarbonyl) pentyl) amino] phosphinylmethyl]-N-Boc-glycinate is dissolved in acetic acid (50 ml). Excess zinc dust is added until completion of removal of the trichloroethyl-function. The reaction mixture is concentrated in vacuo and the residue is neutralized with excess saturated aqueous sodium carbonate. The precipitate is removed by filtration. The residue is dissolved in 50% acetic acid and lyophilized. The crude product is purified by then adjusting the pH to 7.5 and poured onto a Dowex 50 cation exchange column. The column is washed with water. The Boc-protected product is then eluted with 10% aqueous pyridine and concentrated in vacuo to give N- [bis [N- (5- (N- (l-

iminocthyl) amino)-l-(benzyloxycarbonyl) pentyl) aniino] phosphinylmethyl]-N-Boc- glycine.

EX-31c) N- [bis [N- (S- (N- (I-Irninoethyl) amino)-l- (benzyloxycarbonyl) pentyl) amino] phosphinylmethyl]-N-Boc-glyci. ne (9 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (9.1 mmol) and triethyl amine (30 mmol). The mixture is allowed to warm. to room temperature. Upon completion, the mixture is again cooled in an ice bath and benzyl 3- (2- (N- (l-iminoethyl) amino) ethylthio)-2-aminopropanoate dihydrochloride (9.1 mmol) is added The mixture is allowed to warm to room temperature. Upon completion the mixture is concentrated in vacuum. The resulting material is purified by chromatography giving benzyl 3-[2-(N-(1-iminoethyl)amino)ethylthio]-2-[N-[bis[N-(5-(N-(1- iminoethyl)amino)-1-(benzyloxycarbonyl)pentyl)amino]phosphin ylmethyl]-N-Boc- glycinamido] propanoate.

EX-31d) Benzyl 3-[2-(N-(1-iminoethyl)amino)ethylthio]-2-[N-bis[N-(5-(N-(1- iminoethyl)amino)-1-(benzyloxycarbonyl)pentyl)amino]phosphin ylmethyl]-N-Boc- glycinamido] propanoate is dissolved in cthanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the benzyl-function generating, after filtration and removal of solvent, 3- [2- (N- (1-iminoethyl)amino)ethylthio]-2-[N-[bis[N-(5-(N-(1-iminoeth yl)amino)-1- carboxypentyl) amino] phosphinylmethyl]-N-Boc-glycinamido] propanoic acid.

3- [2' (N- (l-Iminoethyl) amino) ethylthio]-2- [N- [bis [N- (5- (N- (l-iminocthyl) amino)-1- carboxypentyl) ami. no] phosphinylmethyl.]-N-Boc-glycinamido] propanoic acid is deprotected by allowing it to stand in 2N HCI and dioxane at 25°C for two hours.

Concentrating in vacuo affords 3- [2- (N- (I-iminoethyl) amino) ethyl thi o]-2- [N- [bis [N- (5- (N-(1-iminoethyl) amino)-1- carboxypentyl) amnino] phosphinylmethyl] glycinamido] propanoic acid tetrahydrochloride.

(32) Example 32 EX-32a) Benzyl 3- [2- (N- (1-iminoethyl) amino) ethylthio]-2- [N- [bis [N- (5- (N- (l- iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl) amino] phosphinylmethyl]-N-Boc- glycinamido] propanoate as prepared in EX-31c is then dissolved in 2N HC1 and dioxane at 25°C for two hours until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give benzyl 3- [2- (N- (l-iminoethyl) amino) ethylthio]-2- [N- [bis [N- (5- (N- ( 1-iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl) amino] phosphinylmethyl] glycinamido] propanoate tetrahydrochloride.

EX-32b) 6- (N-(2-fluoro-1-iminoethyl) amino)-2-(N-Z-amino) hexanoic acid (10 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (10.1 mmol) and triethyl amine (TEA) (11 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath, and then both 42 mmol triethylamine and benzyl 3- [2-(N-(l-iminoethyl) amino) ethylthio]-2- [N- [bis [N- (5- (N- ( 1-iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl) amino] phosphinylmethyl] glycinamido] propanoate tetrahydrochloride (10.1 mmol) are added. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 100 mL of methylene chloride is added along with 20 mL of aqueous 5% sodium carbonate. The methylene chloride layer is separated, the aqueous layer is extracted twice with methylene chloride (50 mL each), dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield

benzyl 3- [2-(N-(l-iminoethyl) amino) ethylthio]-2- [N- [bis [N- (5- (N- (l-iminoethyl) amino)- l- (benzyloxycarbonyl) pentyl) amino] phosphinylmethyl]-N- [6- (N- (2-fluoro-l- iminoethyl) amino)-2- (N-Z-amino) hexanoyl] glycinamido] propanoate.

Benzyl 3- [2- (N- (l-iminoethyl) amino) ethylthio]-2- [N- [bis [N- (5- (N- (l-iminoethyl) amino)- 1- (benzyloxycarbonyl) pentyl) amino] phosphinylmethyl]-N-[6-(N-(2-fluoro-1- iminoethyl) amino)-2-(N-Z-amino)hexanoyl]glycinamido]propanoate is dissolved in ethanol and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove the protecting groups generating 3- [2- (N- (1-iminoethyl) amino) ethylthio]-2- [N- [bis [N- (5- (N- (1-iminoethyl) amino)-1- (benzyloxycarbonyl) pentyl) amino] phosphinylmethyl]-N-[6-(N-(2-fluoro-1-iminoethyl) amino)-2- (N-Z-amino) hexanoyl] glycinamido] propanoic acid.

Example 33

EX-33a) Tetraethylenepentamine (10 mmol) in THF is treated with phthalic anhydride (20.5 mmol) and heated to reflux until the protecting groups are completely reacted. The solvent is removed in vacuo, and the product is purified by chromatography to yield N- (2- phthalimidoethyl)-N'- [2- (N- (2-phthalimidoethyl) amino) ethyl]-1,2-ethanediamine.

EX-33b) 6- (N- (l-iminoethyl) amino)-2- (N-Z-amino) hexanoic acid (30 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (30.5 mmol) and triethyl amine (TEA) (33 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and is added to N- (2-phthalimidoethyl)-N'-[2-(2-phthalimidoethylamino)(2-phtha limidoethyl)-N'-[2-(2-phthalimidoethylamino) ethyl]-1,2-ethanediamine (10 mmol) cooled in an ice bath. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 100 mL of methylene chloride is added along with 20 mL of aqueous 5% sodium carbonate. The methylene chloride layer is separated, the aqueous layer is extracted twice with methylene chloride (50 mL each), dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield N, N-bis [2- [N- (2-phthalimidoethyl)-6- (N- (l- iminoethyl) amino)-2-(N-Z-amino) hexanamido] ethyl]-6-[N-(1-iminoethyl) amino]-2-[N-Z- amino] hexanamide.

EX-33c) N, N-bis [2-[N-(2-phthalimidoethyl)-6-(N-(l-iminoethyl) amino)-2-(N-Z- amino) hexanamido] ethyl]-6- [N-(l-iminoethyl) amino]-2-[N-Z-amino] hexanamide (9 mmol) is dissolved in methanol/cyclohexane (1: 1) and treated with hydrazine (9.5 mmol).

The mixture is heated to reflux. After complete removal of one phthaloyl protecting group, the reaction is filtered to removed phthaloyl hydrazide, the solvent is concentrated, and the reaction product purified by chromatography to give N- [2- [N- (2- phthalimidoethyl)-6- (N-(1-iminoethyl) amino)-2-(N-Z-amino)(N-(1-iminoethyl) amino)-2-(N-Z-amino) hexanamido] ethyl]-N- [2- [N- (2-aminoethyl)-6-(N-(1-iminoethyl) amino)-2-(N-Z-amino) hexanamido] ethyl]-6-[N-(1- iminoethyl) amino]-2-[N-Z-amino] hexanamide.

EX-33d) 3- (2- (N- (l-iminoethyl) amino) ethylthio)-2- (N-Z-amino) propanoic acid (8 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (8.5 mmol) and triethyl amine (9 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and is added to N-[2-[N-(2-phthalimidoethyl)-6-(N-(1-iminoethyl) amino)-2-(N-Z- amino) hexanamido] ethyl]-N- [2- [N- (2-aminoethyl)-6- (N- (l-iminoethyl) amino)-2- (N-Z- amino) hexanamido] ethyl]-6- [N- (1-iminoethyl) amino]-2- [N-Z-amino] hexanamide (8

mmol) cooled in an ice bath. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 100 mL of methylene chloride is added along with 20 mL of aqueous 5% sodium carbonate. The methylene chloride layer is separated, the aqueous layer is extracted twice with methylene chloride (50 mL each), dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield N-[2-[N-(2-phthalimidoethyl)-6-(N-(l-iminoethyl) amino)-2- (N-Z-amino) hexanamido] ethyl]-N- [2- [N- [2- (3- (2- (N- ( 1-iminoethyl) amino) ethylthio)-2- (N-Z-amino) propanamido) ethyl]-6-(N-(1-iminoethyl) amino)-2-(N-Z- amino) hexanamido] ethyl]-6-[N-(1-iminoethyl) amino]-2-[N-Z-amino] hexanamide.

EX-33e N- [2- [N- (2-phthalimidoethyl)-6- (N- (1-iminoethyl) amino)-2- (N-Z- amino) hexanamido] ethyl]-N- [2- [N- [2- (3- (2- (N- (l-iminoethyl) amino) ethylthio)-2- (N-Z- amino) propanamido) ethyl]-6- (N-(1-iminoethyl) amino)-2-(N-Z-amino) hexanamido] ethyl]- 6-[N-(l-iminoethyl) amino]-2-[N-Z-amino][N-(l-iminoethyl) amino]-2-[N-Z-amino] hexanamide (7 mmol) is dissolved in methanol/cyclohexane (1: 1) and treated with hydrazine (7.5 mmol). The mixture is heated to reflux. After complete removal of one phthaloyl protecting group, the reaction is filtered to removed phthaloyl hydrazide, the solvent is concentrated, and the reaction product purified by chromatography to give N- [2- [N- (2-aminoethyl)-6- (N- (l- iminoethyl) amino)-2- (N-Z-amino) hexanamido] ethyl]-N- [2- [N- [2- (3- (2- (N- (l- iminoethyl) amino) ethylthio)-2-(N-Z-amino) propanamido) ethyl]-6-(N-(l- iminoethyl) amino)-2- (N-Z-amino) hexanamido] ethyl]-6-[N-(l-iminoethyl) amino]-2-[N-Z- amino] hexanamide.

EX-33f) 6- (N-(2-fluoro-1-iminoethyl) amino)-2-(N-Z-amino) hexanoic acid (6 mmol) is dissolved in anhydrous THF, cooled in an ice bath and treated with ethyl chloroformate (6.5 mmol) and triethyl amine (TEA) (7 mmol). The mixture is allowed to warm to room temperature. Upon completion, the mixture is again cooled in an ice bath and is added to N- [2- [N- (2-aminoethyl)-6- (N- (l-iminoethyl) amino)-2- (N-Z-amino) hexanamido] ethyl]-N- [2- [N- [2- (3- (2- (N- (l-iminoethyl) amino) ethylthio)-2- (N-Z-amino) propanamido) ethyl]-6- (N-(1-iminoethyl) amino)-2-(N-Z-amino) hexanamido] ethyl]-6-[N-(1-irninoethyl) amino]-2- [N-Z-amino] hexanamide (6 mmol) cooled in an ice bath. After warming to room temperature and standing for 2 hours, the reaction mixture is concentrated in vacuo, 100 mL of methylene chloride is added along with 20 mL of aqueous 5% sodium carbonate.

The methylene chloride layer is separated, the aqueous layer is extracted twice with methylene chloride (50 mL each), dried over MgS04, and concentrated. The resulting material is purified chromatographically to yield N- [2- [N- [2- (6- (N- (2-fluoro-l-

iminoethyl) amino)-2- (N-Z-amino) hexanamido) ethyl]-6- (N- (l-iminoethyl) amino)-2- (N-Z- amino) hexanamido] ethyI]-N- [2- [N- [2- (3- (2- (N- (l-iminoethyI) amino) ethylthio)-2- (N-Z- amino) propanamido) ethyl]-6- (N- (l-iminoethyl) amino)-2- (N-Z- amino) hexanamido] ethyl]-6- [N- (l-iminoethyl) amino]-2- [N-Z-amino] hexanamide.

N- [2-[N-[2-(6-(N-(2-fluoro-1-iminoethyl) amino)-2-(N-Z-amino)[2-[N-[2-(6-(N-(2-fluoro-1-iminoethyl) amino)-2-(N-Z-amino) hexanamido) ethyl]-6- (N- (1-iminoethyl) amino)-2- (N-Z-amino) hexanamido] ethyl]-N- [2- [N- [2- (3- (2- (N- (l- iminoethyl) amino) ethylthio)-2- (N-Z-amino) propanamido) ethyl]-6-(N-(l- iminoethyl) amino)-2- (N-Z-amino) hexanamido] ethyl]-6- [N- (l-iminoethyl) amino]-2- [N-Z- amino] hexanamide is dissolved in ethanol/acetic acid and is combined with a hydrogenation catalyst such as palladium on carbon and hydrogen. This reaction is shaken under pressure for an extended period of time in a standard Parr hydrogenation apparatus to remove protecting groups, the catalyst is removed by filtration, and the solvent is removed generating the amino product N- [2- [N- [2- (6- (N- (2-fluoro-l-iminoethyl) amino)- 2-aminohexanamido) ethyl]-6- (N- (l-iminoethyl) amino)-2-aminohexanamido] ethyl]-N- [2- [N-[2-(3-(2-(N-(1-iminoethyl) amino) ethylthio)-2-aminopropanamido) ethyl]-6-(N-(1- iminoethyl) amino)-2-aminohexanamido] ethyl]-6- [N-(1-iminoethyl) amino]-2- aminohexanamide.

Biological Data The subject compounds of Formula I are expected to be found to inhibit nitric oxide synthase and posses useful pharmacological properties as demonstrated in one or more of the following assays: Citrulline Assay for Nitric Oxide Synthase NOS activity can be measured by monitoring the conversion of L- [2, 3-3H]- arginine to L- [2, 3-3H]-citrulline. Mouse inducible NOS (miNOS) can be prepared from an extract of LPS-treated mouse RAW 264.7 cells and rat brain constitutive NOS (rnNOS) can be prepared from an extract of rat cerebellum. Both preparations can be partially purified by DEAE-Sepharose chromatography. Enzyme (10 pL) can be added to 40 pL of

50 mM Tris (pH 7.6) and the reaction initiated by the addition of 50 pL of a solution containing 50 mM Tris (pH 7.6), 2.0 mg/mL bovine serum albumin, 2.0 mM DTT, 4.0 mM CaC12,20 pM FAD, 100 pM tetrahydrobiopterin, 2.0 mM NADPH and 60 pM L- arginine containing 0.9 pCi of L- [2, 3-3H]-arginine. For constitutive NOS, calmodulin is included at a final concentration of 40 nM. Following incubation at 37°C for 15 minutes, the reaction can be terminated by addition of 300 pL cold buffer containing 10 mM EGTA, 100 mM HEPES (pH 5.5) and 1.0 mM L-citrulline. The [3H]-citrulline can be separated by chromatography on Dowex 50W X-8 cation exchange resin and radioactivity quantified with a liquid scintillation counter.

Raw Cell Nitrite Assay RAW 264.7 cells can be plated to confluency on a 96-well tissue culture plate grown overnight (17 h) in the presence of LPS to induce NOS. A row of 3-6 wells can be left untreated and served as controls for subtraction of nonspecific background. The media can be removed from each well and the cells washed twice with Kreb-Ringers- Hepes (25mM, pH 7.4) with 2 mg/ml glucose. The cells are then placed on ice and incubated with 50mL of buffer containing L-arginine (30mM) +/-inhibitors for 1 h. The assay can be initiated by warming the plate to 37°C in a water bath for 1 h. Production of nitrite by intracellular iNOS will be linear with time. To terminate the cellular assay, the plate of cells can be placed on ice and the nitrite-containing buffer removed and analyzed for nitrite using a previously published fluorescent determination for nitrite. T. P. Misko et al, Analytical Biochemistry, 214,11-16 (1993).

In Vivo Assay Rats can be treated with an intraperitoneal injection of lOmg/kg of endotoxin (LPS) with or without oral administration of the nitric oxide synthase inhibitors. Plasma nitrites can be measured 5 hours post-treatment. The results can be used to show that the administration of the nitric oxide synthase inhibitor decreases the rise in plasma nitrites, a reliable indicator of the production of nitric oxide induced by endotoxin.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.