Background of the Invention Field of the Invention The present invention relates to halogenated 5,6 heptenoic 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 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.

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 primarily 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.

There is a growing body of evidence that NO may be involved in the degeneration of cartilage which takes place in certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis. Accordingly, conditions in which there is an advantage in inhibiting NO production from L-arginine include arthritic conditions such as rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, septic arthritis, spondyloarthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, and pyogenic arthritis.

Other conditions which NO inhibition may be useful include chronic or inflammatory bowel disease, cardivascular ischemia, diabetes, congestive heart failure, myocarditis, atherosclerosis, migraine, glaucoma, aortic aneurysm, 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. Further neurodegenerative disorders in which NO inhibition may be useful include nerve degeneration and/or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy, and in external wounds (such as spinal cord and head injury),

hyperbaric oxygen convulsions and toxicity, dementia e. g. pre-senile dementia, and AIDS-related dementia, Sydenham's chorea, Huntington's disease, Amyotrophic Lateral Sclerosis, Korsakoff's disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, depression or other symptoms associated with Premenstrual Syndrome (PMS), anxiety and septic shock.

Nitric oxide inhibition may also play a role in the treatment of pain including somatogenic (either nociceptive or neuropathic), both acute and chronic. A nitric oxide inhibitor could be used in any situation that a common NSAID or opioid analgesic would traditionally be administered.

Still, other disorders which may be treated by inhibiting NO production include opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behavior, for example, nicotine and eating disorders. NO inhibiting agents may also be useful as antibacterial agents.

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.

Other conditions in which there is an advantage in inhibiting No production include ocular conditions such as ocular hypertension retinitis uveitis, systemic lupus erythematosis (SLE), flomerulonephritis, restenosis, inflammatory sequelae of viral infections, acute respiratory distress syndrome (ARDS), oxidant-induced lung injury, IL2 therapy such as in a cancer patient, cachexia, immunosuppression such as in transplant therapy, disorders of gastrointestinal motility, sunburn, eczema, psoriasis, and bronchitis.

Some of the NO synthase inhibitors proposed for therapeutic use 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).

More recently, NO has been identified as being a neurotransmitter in pain pathways of the spinal cord. The administration of NO synthase inhibitors in patients with cronic pain syndromes, and more specifically cronic tension-type headaches, has been shown to reduce the level of pain. (The Lancet, 353: 256-257,287-289) 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 Nos. 5,132,453 and 5,863,931 disclose compounds that inhibit nitric

oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase.

The disclosures of which are hereby incorporated by reference in their entirety as if written herein.

Brief 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. The present compounds possess useful nitric oxide synthetase inhibiting activity, and are expected to be useful in the treatment or prophylaxis of a disease or condition in which the synthesis or oversynthesis of nitric oxide forms a contributory part.

In particular, the present compounds can be used to treat diseases involving cartilage degeneration which takes place in certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis.

Accordingly, conditions in which there is an advantage in inhibiting NO production from L-arginine include arthritic conditions such as rheumatoid arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, septic arthritis, spondyloarthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, and pyogenic arthritis.

Other conditions which the present compounds may be useful include chronic or inflammatory bowel disease, cardivascular ischemia, diabetes, congestive heart failure, myocarditis, atherosclerosis, migraine, glaucoma, aortic aneurysm, 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. Further neurodegenerative disorders in which NO inhibition may be useful

include nerve degeneration and/or nerve necrosis in disorders such as hypoxia, hypoglycemia, epilepsy, and in external wounds (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia e. g. pre-senile dementia, and AIDS-related dementia, Sydenham's chorea, Huntington's disease, Amyotrophic Lateral Sclerosis, Korsakoff s disease, imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, depression or other symptoms associated with Premenstrual Syndrome (PMS), anxiety and septic shock.

The present compounds may be useful in other conditions in which nitric oxide inhibition may also play a role in the treatment, such as pain including somatogenic (either nociceptive or neuropathic), both acute and chronic. A nitric oxide inhibitor could be used in any situation that a common NSAID or opioid analgesic would traditionally be administered.

Still, other disorders which may be treated with the present compounds by inhibiting NO production include opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behavior, for example, nicotine and eating disorders. NO inhibiting agents may also be useful as antibacterial agents.

Further conditions in which the present compounds may be advantagous 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.

The present compounds may also be useful in the treatment of ocular conditions such as ocular hypertension retinitis uveitis, systemic lupus erythematosis (SLE), flomerulonephritis, restenosis, inflammatory sequelae of viral infections, acute respiratory distress syndrome (ARDS), oxidant-induced lung injury, IL2 therapy such as in a cancer patient, cachexia, immunosuppression such as in transplant therapy, disorders of gastrointestinal motility, sunburn, eczema, psoriasis, and bronchitis.

Detailed Description of the Invention Compounds of the present invention are represented by the following chemical Formula I:

and pharmaceutically acceptable salts thereof, wherein: J2J1and are independently selected from the group consisting of SR23, N(R24)R25providedthatAisR26;NHR24and J1 andJ2 can be taken together to form a group selected from the group consisting of SR28S,OR28NR24andSR28NR24providedthatAisR26;OR28S, J1canbetakentogethertofromacovalentdoublebondattachedtoJ,J2 wherein J is selected from the group consisting of O, NR22 and S provided that A is selected from other than R26; G is selected from the group consisting of O, S, CH2, CHR15, C(R15)2, NH, and NR15; A is selected from the group consisting of O, andheterocyclylwiththeS proviso that J is selected from other than O and A is selected from other than O, S and

heterocyclyl unless R8 is selected from other than the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or R is selected from other than the group consisting of hydrogen, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, formylalkyl, acylalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, CH20C (O) GR, CH20C (O) R, CH2C (=O) OR15, CH2C (=O) NHR15 CH20C (=O) RI5, hydroxyalkyl, polyhydroxyalkyl, (poly) acyloxyalkyl and alkylC (O) R wherein G is selected from O, S, CH2, CHR 15, C (ru5) 2, NH, and NR15 and R15 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclin, aryl, and heteroaryl, or R26 is present, or R27 is present, or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of rings containing one or more phosphorus atoms, rings containing one or more silicon atoms, rings larger than a 6-membered ring, or bicyclic or greater in ring number; A can be selected from the group consisting of O, N(R5) and S connected to the point of attachment of R1 orR2 by a spacer group selected from a linear moiety having a chain length of 1 to 6 atoms to form a C5 to withtheprovisothatR2isheterocyclyl selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl and C (O) R, or R is selected from other than the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or R26 is present, or R27 is present, or a heterocyclyl comprised of L, U, and V selected from the

group of rings consisting of rings containing one or more phosphorus atoms, rings containing one or more silicon atoms, rings larger than a 6-membered ring, or bicyclic or greater in ring number; A can be selected from the group consisting of O, N(R5) and S connected to the point of attachment of R1 orR2 by a spacer group selected from a linear moiety having a chain length of 1 to 6 to form C5 to C10 heterocyclyl; A can be selected from the group consisting of O, N (R) and S connected to X through 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 C5 to C10 heterocyclyl; A can be R, wherein R is 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 selected from the group consisting of N (R) OR, N(R5)SR7,N(R5)N(R7)R25,N(R5)SO2R13,N(R5)C(O)R15,N(R5)C(S)R15 , R19(R20)C=N-N(R5),R19(R20)C=N-O, natural amino acids, synthetic amino acids, N(R5)P(O)(OR13)2;N(R5)P(O)(OR13)1R6and R1 areR2 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, SO2R13, C (O) R, CH20C (O) R15, hydroxyl, sulfhydryl, OR, SR, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH2S03'M,CH2CH2S03'M,CH2P03'2M, CH2CH2PO3-22M+,CH(OR6)CF3,P(O)R30R31,P(O)(R30)2R31,C(S)R15, CH2NR C (O) R CH2NR C (S) R, CH2SC (O) RI, CH2SC (S) RI, CH20C (O) GR1 CH2NR C (O) GR, CH2NR C (S) GR15, CH20C (S) GR, CH2SC (S) oS (o) R13 OC (S) RI, SC (S) R, OC (S) GR15, SC (S) GR15, OC (O) R, SC (O) RI, OC (O) GR15, SC (O) GR, and R (R) CH with the proviso that R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, and CH2OC(O)R15 andR13areR15 independently selected from the group consisting of hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralyl, and dihydropyridyl unles J is selected from NR22 or S, or J2and are taken together to from a group selected from the group consisting of SR28S,OR28NR24OR28S, and <BR> <BR> <BR> <BR> <BR> <BR> 28 24 2<BR> <BR> SR NR, or R is selected from other than the group selected from dialkylamino, aralkyl, dihydropyridyl hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl,

cyanocycloalkyl, dicyanocycloalkyl and C (O) R wherein R15 is selected from hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl and a natural and synthetic amino acid, or R is present, or A is R, or heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those containing one or more phosphorus atoms, romgs containing one or more silicon atoms, rings larger than a 6- membered ring, or being bicyclic or greater in ring number, or R8 is selected from other than the group selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl or with the proviso that R2 is selected from the group selected from other than dialkylamino, aralkyl, dihydropyridyl hydrogen, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, and cyanocycloalkyl where R15 can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dicyanocycloalkyl, and C (O) R unless R is selected from other than the group selected from hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S (O) R, S02R, C (O) R, and CH20C (O) R wherein R15 and R are selected from the group consisting of hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralyl, and dihydropyridyl, or J is selected from NR22 or S, or J2and are taken together to from a group selected from 28 28 28 28 24 28 24 26 the group consisting of OR 0, OR S, SR S, OR NR and SR NR, or R

present, or A is R27, or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those rings containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or R8 is selected from other than the group selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl; R1 and R2can be taken together to from a substituent selected from the group consisting of R19 (R20)C=,D(C(R30)(R31))zD wherein z is 2 to 5 and D is selected from 31 30 the group consisting of oxygen, C=O, C=S, S (O) m wherein m is 0 to 2, OP (OR) R, P(O)R30,R(S)R30 and Si(R19)R20 with the proviso that only one D can be oxygen or sulfur at any whereineis1to2,kis1to2,DisD((R19)R20C)eW(C(R19)R20)kD selected from the group consisting of oxygen, C=O, C=S, S (O) m wherein m is 0 to 2, OP (OR) R, P(O)R30, P(S)R30 and Si(R19)R20 with the proviso that only one D can be oxygen or sulfur at any time, and W is selected from the group consisting of oxygen, C=O, C=S, S (O) m, S (O) m wherein m is 0 to 2, P (O) R, P (S) R, N (R), and 19 20 Si(R)R,cycloalkyl radicals, cyclolalkyenyl 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, OP (OR31)R30,P(O)R30,P(S)R30 and Si (R) R, cis-1,2-disubstituted alkyls and cis- 1,2-disubstituted alkenyls wherein said 1,2-substitutents are selected from C=O, C=S, C 32 oR31) R30 P (O) R, P (S) R, and Si (R) R and said

alkyl and alkenyl may be optionally substituted with one or more R or R substituents; R is selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, heterocyclylalkyl, alkoxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, cyanocycloalkyl, dicyanocycloalkyl, OR, SR, amino, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, S (O) R, SO2R13 P (O) R30R31,P(O)(R30)2R31,C(O)R15, C (S) R, CH20C (O) RI, CH2NR C (O) R, CH2NR C (S) RI, CH2SC (O) RI CH2SC (S) R, CH20C (O) GR, CH2NR C (O) GR, CH2NR C (S) GR CH20C (S) GR, CH2SC (S) GR, heteroaryloxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, and sulfonylalkylamino with the proviso that R is selected from other than the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, heterocyclylalkyl, alkoxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, cyanocycloalkyl, and dicyanocycloalkyl, unless J is selected from NR22 and S, or J2areand taken together to from a group selected from the group

28 28 28 28 24 28 24 26 consisting of OR 0, OR S, SR S, OR NR and SR NR, or R is present, or Aisy, or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or R8is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl; 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 C5 to C8 heterocyclyl; R can be 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 wherein said heterocyclyl radical may be optionally substituted with alkyl, hydroxy, amino, nitro, halo, cyano, haloalkyl, alkoxy, heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, haloalkylthio, alkanoyloxy, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, 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, heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, 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 with the proviso that the heterocyclyl radical is substituted with groups selected from other than allkyl, hydroxy, amino, nitro, halo, cyano, haloalky, and alkoxy unles J is selected from NR22 and S, or J2areand taken together to form a group selected from the group consisting of SR28S,OR28NR24OR28S, and SR NR, or R is present, or A is R, or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or R8is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl; R is selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaryloxyalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, halocycaralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, 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, a synthetic amino acid, and polyhydroxy compounds of carbon with the proviso that R6 is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, and dicyanocycloalkyl unles J is selected from NR22 and S, or J1 areJ2 taken together to form a group selected from the group consisting of SR28S,OR28NR24OR28S, and SR NR, or R is present, or A is R, or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or R8 is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl; R is selected from the group consisting of hydrogen, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, formylalkyl, acylalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, CH2OC (O) GR CH20C (O) R, S (O) R, So2R13 P (O) R30R31,P(O)(R30)2R31,C(O)R15,C(S)R15, CH2NR C (O) R, CH2NR C (S) R, CH2SC (O) RI, CH2SC (S) R CH2NR C (O) GR, CH2NR C (S) GR1, CH20C (S) GR, CH2SC (S) GR, amino, hydroxy, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboxamidoalkyl, dicarboxamidoalkyl, heteroaryloxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, heteroaryloxyalkyl,

alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, and sulfonylalkylamino with the proviso that R is selected from other than the group consisting of hydrogen, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, formylalkyl, acylalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, CH20C (O) GR and CH20C (O) R where G is independently selected from O, S, CH2, CHR15, C (R15) 2, NH, and NR 15 and where R15 can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, unles J is selected from NR22 and S, or J2areand taken together to from a group selected from the group consisting of OR28S, 28 28 24 28 24 26 27 SR S, OR NR and SR NR, or R is present, or A is R, or a heterocyclyl comprised of L, U, and V is selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl and cyanoalkyl; 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 C5 to C8 heterocyclyl;

R can be 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 alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, halo, haloalkyl, nitro, 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, heteroarylsulfinyl, heteroarylsulfonyl, alkyl, alkenyl, alkynyl, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, 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 with the proviso that A is selected from other than O and S unless J is selected from NR22 S, or J2and are taken together to from a group selected from the group consisting of OR 0, OR S, SR S, OR NR and SR NR, or J and J are independently selected from the group consisting of OR, SR, NHR and

N(R24)R25 whenA isR26, or a heterocyclyl comprised of L, U, and V is selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or provided that R8 is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl when N(R5);is R8R8is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, cyanoalkyl, alkylaminoalkyl, alkylthioalkyl, sulfhydrylalkyl, formyl, C (O) A-R, C (S) A- R, CH20C (O) A-R, CH2NR C (O) A-R, CH2NR C (S) A-R, CH2SC (O) A-R, CH2SC (S) A-R, CH20C (O) GR1, CH2NR C (O) GR, CH2NR C (S) GR, CH20C (S) GR, CH2SC (S) GR, and acyl with the proviso that R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl unless J is selected from NR22NR22and S, or J1 andJ2 are taken together to form a group selected from the group 28 28 28 28 24 28 24 26 consisting of OR 0, OR S, SR S, OR NR and SR NR, or R is present, or AisR, or a heterocyclyl comprised of L, U, and V is selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R13,SO2R13,C(O)R15, and R15andCH2OC(O)R15where R13 can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl,

haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralkyl, and dihydropyridyl; R13 is independently selected from the group consisting of alkyl, alkylthio, alkoxy, cycloalkoxy, amino, aralkyl, heterocyclylalkyl, dihydropyridyl, alkylamino, alkylthioalkyl, aryloxydialkylamino, hydroxyalkyl, heteroaryloxyalkyl, arylthio, alkenyl, alkynyl, aryl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, 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 compounds of carbon; R is independently selected from the group consisting of hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralkyl, aryloxy, heteroaryloxyalkyl, arylthio, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkylalkyl,

cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, 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, and polyhydroxy compounds of carbon; M is a pharmaceutically acceptable cation; X is selected from the group consisting of alkylene, alkenylene, and alkynylene groups; X can be-(CH2)pQ(CH2)r-wherein p is 1 to 3, r is 1 to 3 and Q is selected from oxygen, C=O,S(O)t, Se(O)t wherein t is 0 to 2, P(O)R21 wherein R21 is selected from hydroxyl and alkyl, and N(R12)nwhere n is 1 to 2 and R12is selected from the group consisting of hydrogen, oxy, hydroxyl and alkyl; X can be- (CH2) sT (CH2) v- wherein s is O to 2, v is 0 to 2 and T is selected from the group consisting of a 3 to 6 membered carbocyclic radical, aryl radical and a heterocyclyl radical; Y is selected from the group consisting of amino, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, alkylthio, haloalkyl, aryl heterocyclic, aralkyl, heterocyclylalkyl, alkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, cycloalkenyloxy,

cycloalkoxy,cycloalkoxy,alkylaminoalkyl, and R9where and R10 are independently selected from the group consisting of hydroxyamino, alkoxyamino, hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, alkoxy, alkylthio, alkylamino, hydroxy, thio, alkoxy, aryl, heterocyalyl, are aralyl with the proviso that only one of R9 and R10 is hydrogen and with the proviso that Y is selected from other than the group consisting of amino, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkenyl, alkylthio, haloalkyl, aryl heterocyclic, aralkyl, heterocyclylalkyl, alkylthioalkyl, and alkoxyalkyl, unles R8 is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or J is selected from NR and S, or J and J are taken together to form a group selected 28 28 28 28 24 28 24 from the group consisting of OR O, OR S, SR S, OR NR and SR NR, or R is present, or A is R, or a heterocyclyl comprised of L, U, and V selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S (O) R, SO2R C (O) R and CH2OC (O) R wherein R15 and R can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralkyl, and dihydropyridyl; R9 and R10 can be taken together to from a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a C3 to C8 heterocyclyl;

R20R19and are independently 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 with the proviso that only one of R19 and R20 is hydrogen; R19 and R20 can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms to form a group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl and C3 to C8 heterocyclyl; 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, aralkylsulfinylalkyl, and aralkylsulfonylalkyl; R24 and R25 can be taken together to form a spacer group independently selected from a linear moiety having a chain length of 4 to 7 atoms to from C5 to C8 heterocyclyl; R28 is independently selected from a group consisting of CH(R23)CH2, CH(R23)CH2CH2, CH2CH(R23)CH2, cycloalkylene, and heterocyclylene; R30 and R31 are independently selected from the group consisting of hydroxy, thiol, aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, cycloalkoxy, 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 compounds of carbon; R30 and R31 can be taken together to form a linear moiety spacer group having a chain length of 2 to 7 atoms selected to form a group consisting of C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, and C3 to C8 heterocyclyl; L, U, and V are independently selected from the group consisting of O, S, C (O), C (S), C (JH) 2 wherein JH is selected from the group consisting of OR, SR, NHR and N(R24)R25,CR29,S(O),SO2,PR30,P(O)R30,P(S)R30,C(R30)R31, C=C(R30)R31,(O)2POP(O)2,R30(O)POP(O)R30,Si(R19)R20,Si(R19)R2 0Si(R19)R20, and Si(R19)R20OSi(R19)R20 with the proviso that any one of L, U, and V must be selected from other than O,S,C(O),C(S),S(O),SO2,C(R30)R31, C=C(R30)R31 wherein R30 and independentlyselectedfromthegroupconsistingofhydrogen,is hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, halalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, and dicyanocycloalkyl unles J is selected from S,orJ1andJ2aretakentogethertofromagroupand selected from the group consisting of SR28S,OR28NR24OR28S, and

SR NR, or R is present, or A is R, or a heterocyclyl comprised of L, U, and V is selected from the group of rings consisting of those containing one or more phosphorus atoms, containing one or more silicon atoms, being larger than a 6-membered ring, or being bicyclic or greater in ring number, or R8 is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S (O) R, S02R, C (O) R and CH2OC (O) R wherein R15 and R can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural amino acid, a synthetic amino acid, dialkylamino, aralkyl, and dihydropyridyl; L, U, and V can be selected from the group consisting of DC(R30)(R31)D wherein D is selected from the group consisting of oxygen, C=O, C=S, S (O) m where m is 31) R30 P (o) R30 P (S) R, Si (RI) R, and N (R), 19 20 19 20 19 20 19 20 30 31 (R) R COC (R) R, (R) R CSC (R) R, C (O) C (R) =C (R), C(S)C(R30)=C(R31),S(O)C(R30)=C(R31),SO2C(R30)=C(R31),PR30C(R 30)=C(R31), P(O)R30C(R30)=C(R31),P(S)R30C(R30)=C(R31), and a covalent bond with the proviso that no more than any two of L, U and V are simultaneously covalent bonds and the heterocyclyl comprised of by L, U, and V is greater than a 4-membered ring; L, U, and V can be 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 R or R substituents, aryl radicals, heteroaryl

radicals, saturated heterocyclic radicals and partially saturated heterocyclic radicals 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) R, P (S) R 19 20 and Si (R) R, cis-1,2-disubstituted alkanes and cis-1,2-disubstituted alkenes wherein 19 32 said 1,2-substitutents are independently selected from C=O, C=S, C (R) R, S (O), <BR> <BR> <BR> <BR> <BR> S (0) 2, OP (OR) R, P (O) R, P (S) R, and Si (R) R and said alk 1 and alkenyl<BR> 30 31 may be optionally substituted with one or more R30 or R31 substituents; R32 is independently selected from the group consisting of aryloxy, aralkyloxy, alkoxy, alkylthio, acyloxy, aroyloxy, heteroaroyloxy, cycloalkoxy, cycloalkenyloxy, hydroxy, cycloalkylthio, cycloalkenylthio, heteroarylthio, heteroaralkylthio, heteroaryloxy, heteroaralkyloxy, arylthio, aralkylthio, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy, phosphonoalkoxy, alkoxysulfonylalkoxy, aralkoxysulfonylalkoxy, alkoxysulfonylalkoxy, sulfonylalkoxy, a natural amino acid, a synthetic amino acid, and polyhydroxy compounds of carbon.

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 than those known in the art.

It is also an advantage in that compounds of the present invention have preferred physical properties as compared 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 1 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 1 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 (1) or a pharmaceutically acceptable salt or solvate thereof (active ingredient) 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-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"alkenylene"radical denotes linear or branched radicals having from 2 to about 10 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds. Examples of such radicals are 1,1-vinylidene (CH2=C), 1,2-vinylidene (-CH=CH-), and 1,4-butadienylethylene (-CH=CH- CH=CH-).

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, trifluoroethyl, 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. Examples of"hydroxyhaloalkyl"radicals include hexafluorohydoxypropyl.

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, isopropoxy 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"and"haloalkoxyalkyl"radicals. Examples of such haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy. Examples of such haloalkoxyalkyl radicals include fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl.

The terms"alkenyloxy"and"alkenyloxyalkyl"embrace linear or branched oxy-containing radicals each having alkenyl portions of two to about ten carbon atoms, such as ethenyloxy or propenyloxy radical. The term"alkenyloxyalkyl"also embraces alkenyl radicals having one or more alkenyloxy radicals attached to the alkyl radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl radicals.

More preferred alkenyloxy radicals are"lower alkenyloxy"radicals having two to six carbon atoms. Examples of such radicals include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls. The"alkenyloxy"radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkenyloxy"radicals. Examples of such radicals include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyloxy, and fluoropropenyloxy.

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, tetrachloroethylenedioxy, 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, 1H-

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, pyridyloxy, 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"cycloalkoxy"embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy. The term"cycloalkoxyalkyl"also embraces alkyl radicals having one or more cycloalkoxy radicals attached to the alkyl radical, that is, to form monocycloalkoxyalkyl and dicycloalkoxyalkyl radicals. Examples of such radicals include cyclohexoxyethyl.

The"cycloalkoxy"radicals may be further substituted with one or more halo atoms,

such as fluoro, chloro or bromo, to provide"halocycloalkoxy"and "halocycloalkoxyalkyl"radicals.

The term"cycloalkylalkoxy"embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy.

The term"cycloalkenyloxy"embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy. The term"cycloalkenyloxyalkyl"also embraces alkyl radicals having one or more cycloalkenyloxy radicals attached to the alkyl radical, that is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl radicals. Examples of such radicals include cyclohexenyloxyethyl. The"cycloalkenyloxy"radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide"halocycloalkenyloxy"and"halocycloalkenyloxyalkyl"rad icals.

The term"cycloalkylenedioxy"radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group. Examples of "alkylenedioxy"radicals include 1,2-dioxycyclohexylene.

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"alkylthio"radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide"haloalkylthio"radicals. Examples of such radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio,

trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio.

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. Examples of such radicals include N-phenylamino and N-naphthalylamino.

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, 4-chloro-3-ethylphenoxy,

4-chloro-3-methylphenoxy, 3-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4- methylphenoxy, 3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy, 4- fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy, 4-bromo-3- fluorophenoxy, 4-fluoro-3-methylphenoxy, 5,6,7,8-tetrahydronaphthalyloxy, and 4- tert-butylphenoxy.

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. Examples of such radicals include benzyloxy, 1-phenylethoxy, 3- trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy, 3,5-difluorobenyloxy, 3- bromobenzyloxy, 4-propylbenzyloxy, 2-fluoro-3-trifluoromethylbenzyloxy, and 2- phenylethoxy.

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 atom 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"heteroarylamino"embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.

The term"heteroarylaminoalkyl"embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino.

The term"heteroaryloxy"embraces heterocyclyl radicals, as defined above, attached to an oxy group. Examples of such radicals include 2-thiophenyloxy, 2- pyrimidyloxy, 2-pyridyloxy, 3-pyridyloxy, and 4-pyridyloxy.

The term"heteroaryloxyalkyl"embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2- pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.

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, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino 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.

Said"alkyl","alkenyl","alkynyl","alkanoyl","alkylene","alken ylene", "hydroxyalkyl","haloalkyl","haloalkylene","haloalkenyl","alk oxy","alkenyloxy", "alkenyloxyalkyl","alkoxyalkyl","aryl","perhaloaryl","haloal koxy", "haloalkoxyalkyl","haloalkenyloxy","haloalkenyloxyalkyl","al kylenedioxy", "haloalkylenedioxy","heterocyclyl","heteroaryl","hydroxyhalo alkyl","alkylsulfonyl", "haloalkylsulfonyl","alkylsulfonylalkyl","haloalkylsulfonyla lkyl","alkylsulfinyl", "alkylsulfinylalkyl","haloalkylsulfinylalkyl","aralkyl","het eroaralkyl", "perhaloaralkyl","aralkylsulfonyl","aralkylsulfonylalkyl","a ralkylsulfinyl", "aralkylsulfinylalkyl","cycloalkyl","cycloalkylalkyl","cyclo alkenyl","halocycloalkyl", "halocycloalkenyl","cycloalkylsulfinyl","cycloalkylsulfinyla lkyl","cycloalkylsulfonyl", "cycloalkylsulfonylalkyl","cycloalkoxy","cycloalkoxyalkyl"," cycloalkylalkoxy", "cycloalkenyloxy","cycloalkenyloxyalkyl","cycloalkylenedioxy ","halocycloalkoxy", "halocycloalkoxyalkyl","halocycloalkenyloxy","halocycloalken yloxyalkyl","alkylthio", <BR> <BR> <BR> "haloalkylthio","alkylsulfinyl","amino","oxy","thio","alkyla mino","arylamino",<BR> <BR> <BR> <BR> <BR> "aralkylamino","arylsulfinyl","arylsulfinylalkyl","arylsulfo nyl","arylsulfonylalkyl",<BR> <BR> <BR> <BR> <BR> "heteroarylsulfinyl","heteroarylsulfinylalkyl","heteroarylsu lfonyl", "heteroarylsulfonylalkyl","heteroarylamino","heteroarylamino alkyl","heteroaryloxy", "heteroaryloxylalkyl","aryloxy","aroyl","aralkanoyl","aralko xy","aryloxyalkyl", "haloaryloxyalkyl","heteroaroyl","heteroaralkanoyl","heteroa ralkoxy", "heteroaralkoxyalkyl","arylthio","arylthioalkyl","alkoxyalky l", and"acyl"groups defined above may optionally have 1 to 3 substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino,

heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, 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, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

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.

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 (R)-,-O-,-S-,-S (O)-,-S (0) 2-,-NH-,-N (R6)-,-N=,-CH (OH)-, =C (OH)-,- CH (OR)-, =C (OR)-, 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)-,-OCH20-,-O (CH2) 20-,-NHCH2-,-OCH (R6) O-,-O (CH2CHR6) O-,- OCF20-,-O (CF2) 20-,-S-,-S (O)-,-S (0) 2-,-N (H)-,-N (H) O-,-N (R6) 0-,-N (R6 C (O)-,-C (O) NH-,-C (O) NR-,-N=,-OCH2-,-SCH2-, S (O) CH2-,-CH2C (O)-,-CH (OH)- , =C (OH)-,-CH (OR)-, =C (OR)-, S (0) 2CH2-, and-NR CH2-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 1 to 3 substituents such as perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino, N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,

aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, 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, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.

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 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 highest 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.

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 or t-butoxycarbonyl,"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) R, Cl-CH2NR C (O) R, Cl- CH2NR C (S) R, Cl-CH2SC (O) R, Cl-CH2SC (S) R, Cl-CH20C (O) GR, Cl- CH2NR C (O) GR, Cl-CH2NR C (S) GR, Cl-CH20C (S) GR, or Cl- CH2SC (S) GR,"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,"p-TsOH"represents paratoluenesulfonic acid,"TBTU"represents 2- (lH-benzotriozole-1-yl)-1, 1,3,3-tetramethyl uronium tetrafluoroborate,"TEA"represents triethylamine,"THF"represents tetrahydrofuran, and "Z"represents benzyloxycarbonyl.

Disclosed are eighty-eight synthetic processes useful in the preparation of intermediates (i. e., 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.

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 O ! ! 0 !) y ii 1. a \ reg (1) 2. aa,) H2 N maza a/R3 N (2) e p 3 R y Cl N O R 3 N y ci N 0 \R8 BocHN (5) R (6) BocHN c O O c 0 0 Z-HN A-R z-H 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 H N O y-N y IiN A-R7 (2a) (7) R8 a a H2N oh N (2b) e 1 (2b) e y OCH3 N 0 H2 A-R7 d I 8 \Rg BocHN (5 (6) BocHN c O 0 7 Z-H A-R R Boc HN (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 Ruz " Scheme 3 ? n' y HN A-R7 y H \ 2. aa0 R8 ! !. (7) H, N 1. a 2. axa R3 azur 0 R3 O 3 R y Cl N O A-R Y.AR I wR8 \ y HN A-R Z-HN (10) R (11) Z-HN c 0 0 ka Boc-8 BocHN \p,-R H-A-R R 8 Z-HN (g) 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 p Scheme 5 (13) t HN"I-A-R 7 c t H K H2N w (E-l) E b Oc Boy Boc (14) N 0 1. X. J /Boc I (14) N O y HN A-R7 R y HN R8 A-R7 HN /R Z-ho E W H ah N O HN A-R7 Zig (11) Z-HN (a) t-Butoxycarbonyl azide, H2O, dioxane, MgO (b) Pd, H2, Ethanol/Acetic Acid (c) TEA, 0-80 °C Boc p Scheme 6 ( 4) Y \ \A-R7 a R8 H K HN H b E (E-l) E b M" H Boc Boy H ! O N y HN w R8 A-R R8 N y HN R8 A-R7 H 8 H (16) HN E W H E H E K H K b Oh N H 0 y HN A-R7 R8 (17) W N H w E E H K (a) TEA, 0-80 °C (b) HC1, dioxane Scheme 7 OH 0 ! H2 CO2H H3C"Io HsC"0 H02 C NH-Boc (19) 0 H-A-R7 b CH3 C C (o)-A-R7 NH-Boc (20) c OH fH t fR7_A- (O) C NH-Boc (21) d R-A- (0) C NH-Boc (22) N-R e R7-A-(o) C NH-Boc (23) sulfhydryl,Or6orSR6)(R1=hydroxyl, (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 (R1= hydroxyl, sulfhydryl, Or6 or Sr6) (a) BH3, THF (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) HC1, 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 R1 : 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) N R3 0 O N"0 Scheme 11 YlHN XA-R7 8 0 JX. a (31) R1-HN t 1. a H H 2. aa 3 N/R j (2) y cri y C1 Z-H A-R 1. d, then 2. e \ reg c 0 0 O O Z-H A-R7 Z-HNA-R 8 boche Z-HJN r\. A-K T j. s ! RS R° H2N (29) BocHN (4) (a) R3-NH2 (aa) N-chlorosuccimide, DMF (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) H20, pH 9-10 Scheme 12/H N O Y-C==---N y HN 7 8 (2a) \. j (31) NH . \ I (2b) y OCH3 X.. J Y OCH3 / Z-H A-R R8 1. d, then 2. e R-HN (30) c j j. Z-H A-R z-HN 8A-R R8-40 Boc HN Tj BocHN (4) H2N (29) BocHN (4) (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 R 1JL A-R z a y H aa R3 / IN (2) y ci 1. d, then 2. e (32) | R8 2(32) R8 R2 _HN f c Z-H A-R 7 Z-H A-R7 BocHN(4) H2N (29) BocHN (a) R3-NH2 (aa) N-chlorosuccimide, DMF (b) HC1, 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 N ° Y EN Y HN o < R8 A-R 7y HN A-R YN \Rg (2a) (35) R2. HN f a 'H NEZ 2b (2b) y OCH3 Z-H A-R 1. d, then 2. e zig c 0 c R8 O d i R2-HN (34) "I\ g b-R 8 H2N (29) BocHN (a) HC1, methanol (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 reagent with standard conditions (d) Pd, H2, Ethanol/Acetic Acid (e) TEA, DMF Scheme 15 zH N HN A-R7 HN A-R BocHNa Y6)R8 Z BocHN A-R7 \R8 b Z (36)BocHN N'0 " ! N Or y un R8 A_R7 R8 H2 N O (40; R1) N-R1 or-R2 c e ii (41; R2) R19 R20 /H R19 R20 N 0 z N O !. x JJL ! . HNA-R). A j8 "< A R R8 Y HNA-R (39) NH R8 N (38) d N R 19 R2 0 (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 R2:or carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride or sulfinyl chloride with standard conditions. R Scheme 16 Y y HN R8 7 (7) H2N / ! f"' R ( R2 R' \R8 N (42) R3 R R 19) V A-R 7 ors R3 ß A_R7 R8 N-R1 or-R2 YHNA-R/ y HN A-R 7 R Z R3 V 1 RN/9 A-R2 7(43)NH" (44; R) R19R2 (45; R (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. R3 N 0 Scheme 17 N R3 8 Na0NaO3SCH2HN (46) y HN R8 A-R7 zig (7) H2N b \ R3 zoo N Y HN A-RR3 \R8 N/O \b/ (33) R8 A-R b W-R7 R8 _ R2 \,/ Ruz N"/"0 A-R \R8 (47)_N_R1 (a) Na03SCH20H, 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 R3 o R3 a ! ! U I \ R8 CCl3CH20C (0) H (48) | 7 ' HoN N S R3 N/H2 N S B (52) R3 Y HN \A_R7 N S R8 I 2 R HN y HNA-R 3 \R8 N CCl3CH20C (S) HN (49) -e 8s y HN \A-R (53) WR8 R3 c R2 _N_R1 N S 3 ' y un R" 7 HN (51) Rg A-R d H2N (50) (51) pS-JL H2N (50) R1 HN (a) Trichloroethyl chloroformate, Na 2CO3, H20, 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. 3 Scheme 19 g A-R OR (50) H2N y HN R8 A-R7 R3 S i JL Zig /"' (54)/R3 S R 19 R2 0 1 8 A-R7 /S _R N \ ! 1 7 N-R 1 o r-R2 \A-R c /A-R7(55) NH (56 ; R) 1 (57 ; R2) Rl9 R20 (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 O \5 R7 JL YHN<NRR7 (6; R5= H) R Boc-HN Boc-HN 3 N a 0 z N y R8 158) Boc- R3 y l BX NR7y HN NR 7 R8 (60) Boc-HN 19 b R R3 JL 1. b 2. d 1. b If /R3 O R8 (59 lR3 Y Rg 1 (59) R8 N 0 H- J R8HN NR7 R I (61) HN o 0 (a) 2 equivalents of Lithium Diisopropylamide, THF, C (0) C12 or C (S) Cl2 (b) HC1, dioxane or trifluoroacetic acid (c) 1. Lithium Diisopropylamide, THF, 2.2-haloalkanoate ester (R) (d) Na2CO3, toluene, heat R3 O Scheme 21 1 y < HN/< \ NR5R7y HN NR 5R 7 \R8 3 Boc-HN N 0 y HN R8 I (62) Boc-HN c R OR Or R N"0 NR3 < R19 b 64) N W R Boc-HN \ JL y HN R 3 R8 R20 N Boc-HI R V R R !. Ji Or R 19 19 b H 3 /R N O y HNNR R8 \R19 (a) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanal 20 (b) HCl, dioxane or trifluoroacetic acid R20 (c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone o Scheme 22 jazz H H 2. aa (1) R3 N 3 R O y C1 N/O R4_ A-R7 y N A-R7 8 4 BocHN (66) BocHN (67) ) 1. b 3 2. c 0 N R 0 N O A-R y N \A-R R8 R8 4 BocHN (5) H2N g) (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 23 N/R s I 1 OR Ru R15C1 R- b (0) 1 or 2 YHN <. AR Rcl A-R R15 Cl R (69) R is NH N s T i . 0 y HN A-R 8 (0)1 or 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 R Scheme 24 V y HNA-R \R8 (7) H2N R15 C1 R j 1 or 2 S YT \a'-R7 3 R15/\C1 R8 R (71) R15 NH I Y A-R c R8 R3 (72) R </NH / O 1 o r 2 ft R8 R3 ! R3 R8 y HN \A-R R8 . HNA-. 7 (74) F3 C NH R60/1 H (a) Na2CO3, aqueous dioxane; Acylation with carboxylic acid choride or anhydride (b) Na 2 C03, aqueous dioxane; sulfonation with sulfonyl chloride or sulfinyl chloride with standard conditions (c) trifluoroacetic acid anhydride (d) NaBH4, R6-OH, aprotic polar solvent Scheme 25 . CH20C (0) GR /CH2OC (o) GR15 N /CH OC O GR15 y N/y A-R (78) R8 OH H2N (79) 8 AJ-R R8 f O-Z Z-HN/CH2OC (O) GR N e ----y d ll H-A-R (77) R 8 5 O-Z Z-HN t/ /CH2 OC (0) GR 15 bu 2, c y Iy'OCH3 R8 (76) OH Z-HN /CH2OC (o) GR15 a y OCH2CH3 t HO-HN OCH3 Z-HN (75) (a) TEA, DMF Z-HN (b) benzyl chloroformate, Na2CO3, dioxane, water (c) NaOH, H2O (d) BOP, DIPEA, DMF (e) DMF, heat (f) Pd, H2, Ethanol Scheme2 6/CH2 oc (o) GR15 N 0 /CH20C (O) GR15 z y A-R 7 Y 8 A_R7 (83) T 4 R 4 y N \A-R R R2-HN \ reg (82) R4 f E /CH2 OC (O) GR 15 N w (E-) E E r) y /CH2 OC (O) GR 15 Yg1) R8 A-R d R4 H2N R IN (8 8 R! (80) R8 R Z-HN R /CH2OC (o) GR15 Z-HN (10) 1. b 2. c y OCH2CH3 R4_ A-R 7 (79a) | R8 (a) TEA, DMF 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 NA-R R8 A t"R' (88) i i 3 CMR NH2 N I (2) 1. c Y 2. d R3 0 N O 7 I CMR (pnZ) N X J \ N 4 A-R7 A PHTH-r R (87) CMR N-PHTH b 0 0 pnZ-IL\ 4 < A-R7 8 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. R3 O Scheme 28 ?, n* ) y N A-R7 1 A R8 A jRS R3 H NH-CMR N N Ig (2) 1. c 2 < l e p' R3 N O PHTH-N (91) 8 A-R7 1 CMR (pnZ) N H (92) R8 / (92) \ R8 / H CMR (pnZ) N b 0 8 A-R 7 H2N 8 A-R7 PTC-N PHTH-N R8 R8 pnZ- lponzpnZ-HN (89) (a) Phthalic anhydride, THF at reflux (b) LDA, THF Alkylation with a chloromethylation reagent (CMR-C1) (c) Hydrazine, methanol, reflux (d) H2O, pH 9-10 (e) Pd, H2, Ethanol Scheme 29 R3 (88) OR y N A-R7 R8 CMR NH2 /. b/N 0 T s A-R7 \ R (95) 1 N CMR NH-AA-Boc Ti<A R7 \ R8 R3 R (94) CMR NH-AA-pnZ c I c N 0 q'7 R 3 y N A-R7 / w (97) H NH-AA y N A-R 7 R8 (96) I 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 R N 0 3 N/ I (2) y N-R7 (2) Y cri y C1 pnZ-HN CMR c (101) O N R3 H2N R8 N-R7 8 1 pnZ-HN CMR (100) y HN N-R \R8 I (102) NH2 CMR b O u PHTH-HN N-R7 (99) R8 1 pnZ-HN PHTH-HN NH-R7 8 pnZ-HN(90) (a) LDA, THF Alkylation with a chloromethylation reagent (CMR-Cl) (b) Hydrazine, methanol, reflux (c) H2O, pH 9-10 (d) Pd, H2, Ethanol Scheme 31 R3 y HN A-R7 A-R 7 (6: A = O or S; R 7 = H) Boc-HN 3 N a 0 N c in / Rg 1 (103) Boc 1 y HN A R8 (105) Boc-HN R19 b N R3 0 OR N O 1. b 2 d HN \ P. R3 Y R8 1 (104) G_ J A R (106) HN I R19 Han HN R19 0 (a) 2 equivalents of Lithium Diisopropylamide, THF, C (O) C12 or C (S) Cl2 (b) HCl, dioxane or trifluoroacetic acid (c) 1. Lithium Diisopropylamide, THF, 2.2-haloalkanoate ester (R) (d) Na2CO3, toluene, heat Scheme 32 R3 O N 0 y HN JL 7 7 8 (11: A = O or S; R 7 H Z-HN R3 N a 0 N C O R8 1 (107) y y HN! Z-N A R8 I (108) Z-HN R 19 b N R 3 0 OR N 0 1. b 2. d R3 Y HN 8 (104) R8 (106) | g_ N 0 y HN A 8 HAN R (106) HN. JL If"" 0 (a) 2 equivalents of Lithium Diisopropylamide, THF, C (0) C12 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 1 y HN R8 A-R7 \R8 R3 /a Boc-HN (6: A: A = O or S; R H) H y N A (111) Boc-HN c Rl OR OR R3 b N 11-11 v 8 y HN A 20 N Boc-HN y HN A OR \R19 R y HN \ A OR R8 1 9 N 19 b H 3 N O y HN A R8 R (110) N \R19 (a) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanal R20 (b) HC1, dioxane or trifluoroacetic acid (c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone R3 ! ! Scheme 34 I y HN A-R Zig a 8 /a Z-HN (11: A 0 or S; R 7 H) RUZ y HN A 8 8/I (114) Z-HN c Rl R OR R3 N/ (113 OR Y HAN R R20 Z-HO Z-HN R J R8 R20 t Or N 0 z-HN \/ R8 I (112) N N H 3 b N Y han y han ( 10) N R19 (a) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanal R2o (b) Pd, H2, ethanol/acetic acid (c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone Scheme 35 CH J (121) HC1'H2N H A" R2 3 PHTH-N i. f 2. g 23 CH OR23 CHO 1. e Han- Oh PHTH-N (120) PHTH-N (119) ) d O d (117) CHEZ OH c BocH BocH (118) PHTH-N PHTH-N \ H PHTH-N PHTH-N 0 b O -B z -bu BocH (116) O'BocH (115) O z PTC-N PHTH-N PHTH-N lb O H Boc <BocH < O <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 HCl H2N/\ H H 23 PHTH-N Cl-or HC1'H2N H a R3 H a N PHTH-N (12 0) I (2) 3 y C1 I N C1 CH J 3 Y Y R R230 H 4 R Y14PHTH-N (124) Cl-or b PHTH-N H R3 R3 H 3 PHTH-N (122) N/v E-J Cl-J cl--J 3/ N/R R23 H2N H CH OR23 23 CL-OR H2N (123) (a) H2O, pH 9-10 (b) Hydrazine, methanol, reflux Scheme 37 CHO Boc H-R 29 Boc H c Boc PHTH-N (119) H PHTH-N (126) a R28 b \----0 b \O CH CH-R29 HC 1'H2 N HC1 *H2N HclH PHTH-N (127) PHTH-N (128) (2 or 2b) R28 R3 c N R c R3 c N (2 or 2b)/ CH-R29 HAN y H H PHTH-N (130) PHTH-N (129) R3 R28 R3 N d CH-R29 y HN- Cl CH-R2 9 Y y H H H2 H2 (132) (131) (a) BF3 etherate with HOR28OH, HOR28SH, HSR28SH, HOR28NR24H, or HSR28NR24H in an aprotic solvent or, with R23-OH,hexane,heatp-TsOH, (b) HCl, dixoane or trifluoroacetic acid (c) H20, pH 9-10 (d) Hydrazine, methanol, reflux J (139) (139) C J CJ Scheme 38 Z-HN/\ /C C (O) A-ruz /A 73 PHTH-N R230 dJ \ C_R2 3 Cl--J Z-HN Z-HN /C02CH2CH3 p PHT H-N (137) d R23 0 0 O d e CH2CH3 C--, OR23 c Z-HN Z-HN \ /CHO/"C02R" PHTH-N (135) PHTH-N A O O b CH2CH3 CH2CH3 (134)' (133) Z-HN Z-HN C02 C (CH3) 3 PHTH-N PHTH-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 R230 Scheme 39 \ \ CoR23 (139) (137) Z-HN Z-HN (0) A-R Z-HN/\ 7 PHTH-N a 23 /C (O) A-R 23 PHTH-N \ a C OR2 3 y H2 (140) 7 J H2 \ (139) C (O) A-R H2/PHTH-N 7 /C (O) A-R (2 or 2b) PHTH-N (2 or 2b) wR3 R23O y o t rE C JX COR2 3RR b J N N HC--, OR23 \R2 3 J Y HN' C (O) A-R C (O) A-R PHTH-N (142) PHTH-N (141) . R RO h r R3 J/R3 C R2 3 0 C N N/ R2 3 HC J C (O) A-R7 H2 (144) H2 (143) (a) Pd, H2, ethanol/acetic acid (b) H20, pH 9-10 (c) Hydrazine, methanol, reflux Scheme 40 R3 /NH R3 N R7_ \C N R7__ \ C (150) (149) \ Y 3HC1'H2 3HC1'H2 H e au R3 ex D (147) (148) H2 N y H H Boc-HN Boc-HN b CN CN (145) (146) PHTH- PHTH-N o </CO2CH2CH3 H a Boc-HN Boc-HN (a) 1 equivalent NaOH in ethanol, then 1 equivalent of HCl, then heat to 150 °C to decarboxylate (b) Hydrazine, methanol, reflux (c) Intermediate (2) or (2b), pH 9-10, H20 (d) -10°CHClCH2Cl2, (e) -10°CHClCH2Cl2, Scheme 41 p3 R3 | | C (154) Y 3hic1(OO-R 3HCl H2Ns \ || CN (152) (152) Y CN b C02 CH2 CH 3 /Boc-HN H2 N /CO2CH2CH3 c Boc-HN R3 a c Oc Tr a,- t CN y HN <. (145) C (O) S-R PHT H-N 3 HC 1'H 2 /CO2CH2CH3 Boc-HN (a) Hydrazine, ethanol, reflux (b) Intermediate (2) or (2b), pH 9-10, H20 (c) -10°CHClCH2Cl2, (d) -10°CHClCH2Cl2, Scheme 42 (a) H-NR5R7, toluene, reflux (b) R7-OH, CH2C12,-10 °C, HC1 (c) R7-SH, CH2C12,-10 °C, HC1 (d) 1.1 equivalent NaOH in ethanol, 2.1 equivalent of BOP,DIPEA,DMF,H-NR5R73. Scheme 43 N /\" (162) Y H R3 PHT H-HN/aQ 3) 3 N 2Cl R15 Y/3, (163) NMR N /CH2 NH2 2hic1H y (161) (161) Y R3 (CH3) 3 PHT H- N (160) cN 3 e Y N N/r YHI N PHTH-C02C (CH3) 3 I2 (164) b 3HC H24 H CON CN CN (158) (159) Z-H H2NC02C (CH3) 3 C02C (CH3) 3 PHTH- PHTH-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-CH2CH29-Bz (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 C02C (CH3) 3 a H2C Scheme 45 CH2CH20-Bz PHTHH- (170) N (171) \ /C02C (CH3) 3 R3 Y NCH2/H2 C N/4/CH2CH2O-Bz b2R PHTH- (172) (O) OH y NCH2/H2 C 14/CH2CH2O-BZ R PHTH-\ N R3 c \ (173) L 1 1 C (0)-A-R R3 NCH2/H2CC 3 /'4/CH2CH20-BZ PHTH- (174) (174) (174) X C (o)-A-R7 Y NCH2 C 14/CH2CH2OH R PHTH-N N R3 e " I l175) < C (O)-A-R Y NCH2/H2 C '4/CH2CH20H R HN (a) Intermediate (2) or (2b), pH 9-10, H 20 (b) acid (c) 1. BOP, DIPEA, DMF, 2. H-A-R 7 (d) Pd, H2, Ethanol/Acetic Acid (e) Hydrazine, methanol, reflux /R3 N Scheme 46 (178) /C (O)-A-R y NCH2/H2 C I 4 CH2 CH2-S-CMR R HN p3 \ \ in (177) \ C ( )-A-R C /R3 I 4 CH2 CH2-SH N R H2 ! \ (176) y NCH2/H2 C </X \ S (o)-A-R7 T dßCH2CH2-CN R H2N c bR3 b R3 \ (175)/ CN/ NCH2 R3 14 CH2CH2-OTs PTC- (174) X (174) (O)-A-R y NCH2 14 CH2CH20H 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 -11-r'2C02CH2CC13 XH2 C a SChPmE 48 /CMR 3 \ PHTH-g/R \ (182) N \ (183) \ C02 CH2 CC 13 Y NCH2/H2 C 14 CMR PHTH- (184) (184) /C (O) OH y NCH2/H2 C 14 CMR PHTH- c 3 N1-11 ion I (185) X (185)C (0)-A-R7 C 14 CMR R PHTH- R' R3 N d Cx C (O)-A-R 7 Y NCH2/H2 C 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 Cv N/R3 d \ R8 A (189) (190) X CO C (CH) c L/RS 14 R8 R PHTH- CHO b, | (188) C02C (CH3) 3 XH2 C 0-11 0 R8 CH PHTH- (187) C02C (CH3) 3 -r12 8 O PHTH-a CH I (167) C02C (CH3) 3 H2 Co/ H PHTH- (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 or (190) C02C (CH3) 3 YVCH2 2 3 a/'4 R' /R PHTH- (191) x 02H y TCH2 H2 R8 R PHTH-R bd (194) X-R27 Y CH2/H2 (192) 3 R4 R8 PTC- YTCH2 2 R8 . / f PHTH-N, '4/p3 L RPHTH-R c i . (195) IV7 Y CH2/--\ H2 14 R8 (193)/XH R4 H2N Y"NCH2C7 R4 H2N R8 R H2 N R8 (a) HC1 in dioxane or ethyl acetate (b) 1. BOP, DIPEA, DMF, 2. H-R 27 such as HN (R22)OR6, HN (R22) N (R24) R25, R19 (R20) C=N-N (R22) H, R19 (R20) C=N-OH (c) Hydrazine, methanol, reflux (d) 1. ClCO2Et, TEA, THF,-10 °C, 2. CH2C12, PTC, NaOH, asNH(R22)SO2R13,HN(R22)C(O)R15,such HN(R22)C(S)R15,HN(R22)P(O)(OR13)nR6 3 Scheme 51 R N (191) C02 H y NCH2 H2 C /14 R8 PHTH- R3 N (196) X C (O) HN-AA Y NCH2 H2 C d 14 R8 R4 PHT H- /R N b t (198) V c (198) C (O) O/S-AA R3 Y NCH2 H2 R8 N PHTH-N (197) R C (O) HN-AA \ I R 8 b g b c R H2N R3 c N N (199) A (O) O/S-AA Y NCH2/H C 14/R8 R H2 N (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 alkylation (c) asR8-Br,R8-OTs,R8-oxirane,such (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 R 23-SH (g) BF3 etherate with HOR 28OH, HOR28SH, HSR28SH, HSR28NR24HHOR28NR24H,or (h) H2, Pd/C, Ammonium Formate /R3 N-R22 N Scheme 53 I CH N/R N-R22 //Y ) r/tj ci d Boc-N (2 0 8b) Y / 3 Boc-N (208c)/R c N R3 N/94 e N-R22 CHO HN Oh y Boc-N (208a) H L Boc-N (208d) N | \ 3 f N 0 f N \ HO R 77! HC' /N_R22 N y \_ 7 \H Boc-N (208) H R 28 N (209)/ HAN N 0 y (132) H H2 (a) t-Butoxycarbonyl azide, H20, dioxane, MgO (b) H20, phosphoric acid (c) R22-NH2, catalytic p-TsOH, toluene, azeotropic distillation (d) N-chlorosuccinimide, DMF (e) R7-OH, toluene, reflux (f) HCl, dioxane Scheme 54 T fi \A-R (215) R8 H2N p d b Y O 0 T 4 < A-R7 \R8 Boc-HN I (292) X 9\o X PO t1 R19"" If 0 0 0 y HN A-R 7 c/3 8 (6; R OH) BocHN N > t< R8 (216) 7(216) A-R tzars R8 Boc-HN (217) R30 0 R 0 nu2 O \ 0 NH2 R3 1 130 (a) Cl-C (O) C (O)-Cl, pyridine (b) HC1, dioxane or trifluoroacetic acid (c) pyridine (d) R19C(O)R20, catalytic p-TsOH, toluene, azetropic distillation. y 0 Scheme 55 SX A-R7 N \ A-R (219) R8 O p H2 N /+ R3 0 b y 0 N44 A-R7 V (218) R8 Boc-HN R 3 0 a N O R I A-R /Boc HN c (6 ; R-OH) BocHN y 0 N \A-R (220)R Boc-HN Y O ci 1d A-R 1. d I 2. b (221) | R8 H2N OR ORO (a) R30-PCl2 where R30 is not OH, SH, or NH2, pyridine (b) HCl, dioxane or trifluoroacetic acid (c) PC13, pyridine (d) R-OH where R30 is not OH or SH, pyridine y 0 Scheme 56 N \A_R7 0 R8 ( O Si (223) /V NH2 \R19 b y 0 N \ 1 (222) R8 O Si z-HN R /\. R20 a N O A-R \ 8 (11; R = OH) c Z-HN y 0 0 (2(224 R8 O Si NH_ Z ilR20 u si NH-Z Or I 2 O Si H N /\ (225) -I/I R20 R19/R19 R R (a) R19R20SiCl2, pyridine (b) Pd, H2, methylcyclohexane (c) pyridine y o Scheme 57 O A-R / (227) R 0 H2 N R30 R/ p b b ----R 226 R Boc-HN R3 a O R30 R 1 R 30 R /Boc HN (6 ; R3 = OH) R /BocHN Boc HN BOCHE (228) 0 NA-R ors 30 R t--- 7 ) i vSX Bo- o (229) R30 R31 //<rR3 1 R8 0 nu2 R31 R31 0 R30 R (a) Cl-S (0) 2C (R30)(R31) S (0) 2-Cl, pyridine (b) HC1, dioxane or trifluoroacetic acid (c) Cl-S (O) C (R30)(R31) S (O)-Cl, pyridine y 0 Scheme 58 N \ A_R7 |/ (232) | R8 O Sv H2N Oye b/ N \A_R7 (231) R8 O S Boc-HN R c/BocHN0ouzo y HN A-R 7 \ 8 (6; R3 OH) R c Boc HN BOCHE N/\ 7 A-R 7 (233) R8 ° ' f jf 0 0 , Jk Y M Boc-HN Y O O/\0 b N \A_R7 (234) R8 : =o H2N 0 (a) SOC12, pyridine (b) HCl, dioxane or trifluoroacetic acid (c) S (0) 2Cl2, pyridine y o Scheme 59 N \ A-R (236) R8 ° P v O H2N/R30 \30 \R3 0 O N A-R7 (235) R8 Boc-HN R3 //\30 \a N- 0 0 y HN \ A-R Boc HN N < < A-R7 BOCHE y 0 N/\ 7 A-R / (237) H| R8 Boc-HN y 0 O/C1 1. d N A-R 2. b _ (238) R8 -170 H2N OR3 0 (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/N A-R7 X"' t R 0/ (240) R8 \ 30/HN 3 0 R31R3 0 1. b 2. c 'nez X (239) ) A-R7 R8 P Boc-HN/R3 a Cul R30 \ C1 R31 y HN'A-R w 8 R3 _ pH R BocHN Y N (241) A-R \ A-R Boy- Boc-HN y 30 (242) R30 R3 I c/A-R 7 R3 1A_R7 8 R NH2 R30 R30 R 30 R3 1 R31 (a) C12-P (O) C (R30)(R31) P (O)-Cl2, pyridine (b) R-OH where R30 is not OH or SH, pyridine (c) HC1, dioxane or trifluoroacetic acid (d) pyridine Y Scheine 61/ \A-R R8 R 0 OR3 0 R3 0 O Or3 0 /1. b Y 2. c N N (243) Á-R7 R8 P \ Boc-HN X/R Cl y HN A-R7 A-R w 8 R3 _H R Boc HN YOD N A/ß (245) A-R 'A-R R8 \0//Boc-HN y 30\ (246) < A-R7 R30 <K N A (246 < A-R7A-R R8 0 nu2 R30 R3 0 (a) C12-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 0 Scheme 62 N A-R7 1 (211) R8 0 H2N 0 y b N \A-R (210) R8 Boc-HN (210) R8 a NO y HN \ A-R \ 8 (6 ; R3 OH) R c BocHN A-R7 N \A-R 8 Boc-HN Y O S b NZ A-R7 (213) R8 °n H2N S (a) phosgene, pyridine (b) HCl, dioxane or trifluoroacetic acid (c) C (S) Cl2, pyridine y Scheme 63 A-R7 C R C/R R C---p. 20' (249) 20 ne2 R19 b Y O (247) Y o R 3 R19 0_ Z R3 1-9 R19 \A-R 0 (11 ; R3 R8 KOH Z-ho C lie c-HN 19 \ 24 8 R8 S'/1 Zizi P Y O A-RUZ S'R 19 0 H2 N R20 Rl9 \t</< A-R720 (250) '19 R19 (a) pyridine (b) Pd, H2, methylcyclohexane (c) pyridine Scheme 64 Y o (252) R8 0 H2 N y L N (251) A-R 7 c\ A-ruz I \R8 pnZ-HN R 3 /\ a N 0 HN A-R 7 (R 3 = OH) R (R3-OH) R pnZ-HN O (253) O N 0 0 3) 7 R31 pnZ-HN y 0 R30 (254) N A-R 7 R 8 0 nu o L ! R 31 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 (O)-OCH2CH3, heat (-ethanol) y Scheme 65 J.. N (257)"R° (257)R7 H2 N O O 1-12 Han A-R (256) R8 Boc-HN a O O O y HNA-R or 5 BocHN Boc HN C (258) N \ A_R 7 zig R30 31o Boc-HN R Ru N 7 v A-R NH2 z O R30 R (a) Cl-C (O) C (O)-Cl, pyridine (b) HCl, dioxane or trifluoroacetic acid (c) pyridine y 0 Scheme 66 > 1l A-ruz (261) IR8 H2 N R3 R31 p. p b Y O b/ (260) \R8 S Boc-HN R R31 0 Y 0 b 1 7 c/ (6) R8 /boche BocHN BOCHE (262) N |N/| À-R7 8 'IIBoc-HN O 0 R3p R31 \ (263) N A-R R8 I R8 NU2 R30 R31 (a) Cl-S (0) 2C (R30)(R31) S (0) 2-Cl, pyridine (b) HC1, dioxane or trifluoroacetic acid (c) Cl-S (O) C (R30)(R31)S(O)-Cl, pyridine Scheme 67 A-ruz / (265) R8 R3 p P p H2N 30 ? \ 30/ R or 1. b x/2- NiT X (264) \A-R7 RR8 Boc-HN R3 R 30 cri (6 ; R3 H) Cl R31 y HN R8 A-R 7 yod d BocHN (266) A-R 7 8 0 R8 //O R30/Boc-HN y R30 ß R > 4 (267 < A-R73 C) (267) R30 c 131 A_R7 ruz RP//O R 30 Ruz R30 R R (a) C12-P (O) C (R30)(R31)P(O)-Cl2, pyridine (b) R-OH where R30 is not OH or SH, pyridine (c) HC1, dioxane or trifluoroacetic acid (d) C1- (R30)P(O)C(R30)(R31)P(R30)(O)-Cl, pyridine y 0 Scheme 68!=/) N- \\/ (269) R R30O/\ O P\ H2N/ OR 1. b y 0 2. c i \ X N---" (268) R8 A-R7 z c Boc-HN R3 (6 ; R H) /BocHN Cul HN d BocHN BocHN (270) R R8 A-R 7 8 I R8 R3/O/P Boc-HN y R3p\ _ (271) 7 R8 A-R R R30/NO \ NH2 O R3 0 0 (a) Cl2-P (O)-O-P (O)-Cl2, pyridine (b) R30-OH where R30 is not OH or SH, pyridine (c) HCl, dioxane or trifluoroacetic acid (d) pyridine Scheme 69 Y o 19 N A-R 7 A/ R20 9 (273) R19 /Rl9 A_R7 Y O or A-R R!R8 R19 \ NH R19 a N/3 O (11 ; R = H) A-R7 OR Y c N \ A-R R19-si (274) R8 R20 \O Si R20 NH-Z 9\ b Y 0 \ 19 X R19-si 8 Ro SiR20 H2N (275) I 19 (a) pyridine (b) Pd, H2, methylcyclohexane (c) pyridine Scheme 70 Y o A-R7 (277) R8 t I H2N Po y 0 b Vu A-R a N 0 (276)R8 pnZ-HN R3 a N O y N A-R7 (11; R3 = H) R8 c pnZ-HN Y 0 (27 /N T A-K ; =-R7 A R8 pnZ-HN y O R30 R3 1 (279) > R31 A-R /nu2 R NU2 (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) Scheme 71 O= (Not A-R7 (281)R8 \ I H2N 0 b A-RUZ O v (280) Boc-HN R3 a y HN A-R7 H)R 6 R3-H R /Boc-HN y (282) A-R7 p IR8 Boc-HN R30 0 (283) R31 v_ w \A_R7 R 8 0 o NH2 30 \ 31R (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) C1, heat (-ethanol) Scheme 72 Y o ° A-R7 (285) Han 0 \/ NU Y b t I v (28 )R8 Boc-HN R3 Y Boc-HN . P a N O N 0 4 A-R 7 \L--NH y" HN A-R 7 (6; R3 H R8 c Boc-HN ) Boc-HN N-R R8 \ p IR8 Boc-HN 1'O R30 b (287) 31 31 N A-R7 , 1 g N < A-R7R8 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-R (289) R8 0 R1 _HN 0 Ri is an amide forming group with A-ruz 2-amino group. (288) 1 IR8 R3 a 0O O Y HN \A_R7 3 R8 (31; R OH) c HN (290) (290) A-R R8 d R1 _ RI-HN 31 0 (291) R30 R A-R 7 \ A-R -ri 31 T"' R31 ° R30 (a) Cl-C (O) C (O)-Cl, pyridine (b) pyridine (c) pyridine (d) Cl-S (0) 2C (R30)(R31) S (0) 2-Cl, pyridine Scheme 74 A-R7 N R1 _ Ri-han R is an R20 R19 R2 0 b amide forming group with \ Z b R \ 2-amino group. " (293) IR8 o o \tj J)! R1 _HN R3 O A-R w 8 (31; R3 = H) | R /R-HN (295) (295) A-R 0 R8 d Ru-ho 30 R31 R31 0 (296) \A-R R8 OU ) NH-R 0 R30 R (a) pyridine (b) pyridine (c) pyridine (d) Cl-S (0) 2C(R30)(R31) S (0) 2-C1, pyridine Scheme 75 A-R7 N (298) R8 HN R is an R20 R19 R20 amide forming group with 2-amino group. R2_HN R3 0 0 /R3 a 0 0 0 \ j \y h y HNA-R w 8 (33; R H) R2-HN (299) (299) A-R X 7 | R2_HN R30 R31 O (300) A-R 7 \ A-R NH-R2 ou _R2 R30 R (a) Cl-C (O) C (O)-Cl, pyridine (b) pyridine (c) cl-c (O) C (R30)(R31)C(O)-Cl, pyridine (d) Cl-S (0) 2C (R30)(R31) S (0) 2-Cl, pyridine y 0 Scheme 76 l ll N A-R 7 (302) R8 R2-HN R2 i s an y \ amide forming O group with 2-amino group. (301) R 3 \ a N 0 O a N/O 0 xi HN \A_R7 zig / (33; R OH) c /R2_HN /y 0 ( « A-R7 R8 d R2_HN 0 \O 1" 7 R30 Ft31 /\ 0 (304) 0 R8 S\O_R2 R31 rR ° R30 (a) pyridine (b) Cl-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-Cl, pyridine y 0 Scheme 77 N NR7 \ (306) R8 1 l9//Si/S H-Nn R R20 R19 R20 NR 0 b N NR7 1 3 0 5) J/R3 N O Y-V 0 0 a J R3 (59 ; R3-H 1 y 0 R8 /J ' (307) N NR O-R8 1 d R30 0 H \ Y-O f i y NR 0 (308) R8 I 1 0 O R30 H-r6 (a) pyridine (b) 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 o Scheme 78 x N NR7 (310) R8 0\s s H- /si 2 0 O b I R20 R19 R 0 b N NR7 H- J R3 a/ O N O Y a ° 4J R3 \ (59 ; R3-Hg 1 y 0 R8 (311) N NR7 R8 d (311) N NR R8 d 0 O H_ Y O R30 v N NR7 NR O (312) I R OO H _ O < H-< /R31 J (a) Cl-C (O) C (O)-Cl, pyridine (b) 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 79 , X N NR7 ! (314) R8 NR7 O N 0 19 b O I R20 N N'' R8 19 (313) Boc-HN 20 0 OR PRO R3 N O k (64; R3 = OH) t c Y O HN 8 N R19 R2 0 BocHN NR (315) N i R8 19 RO R2 0 OR Boc-HN O R30 R 31 0 y Ro OR 0 N N \ NR / 20 r OR O (316) R31 0 I R31 0 (316)) R8 R3 0 R20 (a) Cl-C (O) C (O)-Cl, pyridine (b) HCl, dioxane, then one equivalent water (c) Cl-C (O) C (R30)(R31) C (O)-Cl, pyridine y 0 Scheme 80 NN/< A-R7 (318) 1 R \/° H2N \ d y 0 Y 00 b N-R7 N R8 A-R7 N _R7 N N R8 1 (317)/ (319) I 0 Boc-HN-R 20 'Boc-HN 0 R3 0 R 9 \n o /R3 N O (67; R3, R4-OH) I c \ y N \ A-R Y O IR8 R4 '-BocHN A-R (320) R8 O 320) Boc-HN 1 R30 131 \//N/8 p, _R7 O (321) R 0 Q (321) \ j NH2 / o R31 (a) Cl-C (O) C (O)-Cl, pyridine (b) HC1, dioxane or trifluoroacetic acid (c) pyridine (d) p-TsOH,toluene,azeotropiccatalytic distillation. y o Scheme 81 N \A-R (323) R8 0 o' ° \/° H2N iO 130 R b N A-R I (322) I R8 o \ g Boc-HN/R3 X lu 1 30 R 130 y N R8 A-R7 R8 c 4 /BocHN O _ (67 ; R3, R4 OH) N (324) 1 ))"RS O Boc-HN Y O Pi N 7 1. d I (325)A-R 2. b \po° H2N R30o (a) R30isnotOH,SH,orNH2,pyridinewhere (b) HCl, dioxane or trifluoroacetic acid (c) PC13, pyridine (d) R30-OH where R 30 is not OH or SH, pyridine r Scheme 82 I \A-R \/0 ! (327) XS/NH2 R 19 b/R19 O N < A-R7 (326) R8 O 3 Z-ho /Sl a N/O R 120 R R OH) R I y N A-R7 R8 c 14 R8 Z-HO O N A-R7 1 8 y 0 0 (328) R R19i/NH_z Si \ 7 R 20/\ 8 \ R R20 0 (329) 0 H2N Rl9 Xi_Si 20//\ R220 (a) pyridine (b) Pd, H2, methylcyclohexane (c) pyridine y 0 Scheme 83 I \ A-R (331) 1 R8 O \suH2 N II b N N A-R7 N N A_R7 (330) 1 R8 O Boc-HN R3 N/0 O y N A-R7 8 R4 /BocHN boche 0 O/ (67; R3, R4 = OH N N A_R7 1 (332) 1 R8 0.' ! Boc-HN Y O Ils I (333) I R8 0 1 \ H2N 0 (a) SOC12, pyridine (b) HC1, dioxane or trifluoroacetic acid (c) S (0) 2C12, pyridine y 0 Scheme 84 N N A-R7 (335) R8 HAN 0 N y 0 0 N 3341 s R8 f Boc-HN \ 3 (334) 1 R8 0 Boc-HN R3 0 a\ Nu O 0 1 A_R7 \ Rg z 4 BocHN (67 ; R R OH) N w A-RUZ 1 \ o (336) | R 0 Boc-HN O S b N A_R7 (337)l (337) R 0 0 H2H2N S (a) phosgene, pyridine (b) HC1, dioxane or trifluoroacetic acid (c) C (S) Cl2, pyridine Scheme 85 z N A-R (339) IR8 8 i9 R2 0 /R" R19 R .A_R7 R19 I 8 or ex O a/ -oh) R19 R I y N A-R 7 Y OR 0 1 R8 Z-HN .. 1' (340) g R/Si \R R NH-Z 1\ b Y O /\ R20 R19 19 (341) A-R R Si IRg l \ R2 0 i 19 R19 (a) pyridine (b) Pd, H2, methylcyclohexane (c) pyridine Y Scheme 86 zozo N' (343) A-R 7 1 R8 0 PO y CMR (pnZ) N' (342). \"" -8 \p a N O R y HN A-R 8 (92; R3= OH) R CMR (pnZ) HN 0 A-R (344) \R8 N (pnZ) CMR O R 30 31 b A-R7 A-ri (345) N R8 NU-CMR 0 O 40 R31 (a) C1-C (O) C (O)-Cl, pyridine (b) Pd, H2, ethanol (c) pyridine y 0 Scheme 87 Or 1 _ (347) CMR O' Y B 0 N N-R7 (346) R8 I pnZ-HN CMR a 0 \R" N O y HN N-R 8 y o pnZ-HN NN_R7 (348) R8 / (348) R8 I b N-R7 _ (349) R8 ]/ (348) | R8 |OgR ><Ò CMR y > N-R70--cl H2N CMR 0 (a) pyridine (b) Pd, H2, ethanol (c) S (0) 2Cl2, pyridine Y R28 SChPIIIe 88 H2N O/ \0 HC N N n 0 H PO 0 /R28 Z-H (352) | \H v 0 Hc---- I (351) R28 O b H R O\ O N/\ O HC 0 y un y han d R28 (350) H Z-HN O O R28 (353) N \ _-, o H CH N-Z Ho R30 R3 s/H H2 3 H (132 ; R3-OH) 0/N'-, R2 8 (354) HC A/HoN"/ H2 N \O 0 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 88 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.

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., 1978,43,2923-2925.) The hydrochloride salts were made from 1N HCI, HCl in ethanol (EtOH), 2 N in MeOH, or 6 N HCl 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°C 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) Ethyl 6- (N-(1-oximinoethyl) amino)-2-methyl-2-(N-Boc-amino) hexanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, 2,2-dimethylmalonyl chloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated to afford ethyl 6- (4- (1,5,6,7-tetrahydro-3,6,6- 4-oxadiazepinyl))-2-methyl-2- (N-Boc-amino) hexanoate.

Ethyl 6- (4- ( 1,5,6,7-tetrahydro-3,6,6-trimethyl-5,7-dioxo-1,2,4-oxadiazep inyl))-2-methyl- 2- (N-Boc-amino) hexanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords ethyl 6- (4- (1,5,6,7-tetrahydro-3,6,6- trimethyl-5,7-dioxo-1,2,4-oxadiazepinyl))-2-methyl-2-aminohe xanoate hydrochloride.

Example 2 EX-2a) Ethyl 6- (N- (l-oximinoethyl) amino)-2- (N-Boc-amino) hexanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling to- 10 °C, dichloroethylphosphine (10.5 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 water.

The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated to afford ethyl 6- (3- (2-ethyl-1, 2-dihydro-5-methyl-1,2,3,5- oxaphosphadiazolyl))-2- (N-Boc-amino) hexanoate.

Ethyl 6- (3- (2-ethyl-1, 2-dihydro-5-methyl-1,2,3,5-oxaphosphadiazolyl))-2- (N-Boc- amino) hexanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords ethyl 6- (3- (2-ethyl-1,2-dihydro-5-methyl- 1,2,3,5-oxaphosphadiazolyl))-2-aminohexanoate hydrochloride.

Example 3 EX-3a) Ethyl S- (2- (N- ( 1-oximinoethyl) amino) ethyl)-4-thia-2- (N-Z-amino) butanoate (10 mmol) is mixed with 45 mL of anhydrous methylcyclohexane containing 22 mmol of pyridine. After cooling in an ice bath, dichlorodimethylsilane (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is cooled and filtered under an inert atmosphere to remove the pyridine hydrochloride. The solvent is concentrated in vacuo to afford ethyl S- (2- (3- (1,2- 3,5-oxasiladiazolyl)) ethyl)-4-thia-2- (N-Z-amino) butanoate.

Ethyl S- (2- (3- (1,2-dihydro-2,2,4-trimethyl-1,2,3,5-oxasiladiazolyl)) ethyl)-4-thia-2- (N-Z- amino) butanoate in methylcyclohexane 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 product ethyl S- (2- (3- (1,2-dihydro-2,2,4-trimethyl-1,2,3,5- oxasiladiazolyl)) ethyl)-4-thia-2-aminobutanoate.

Example 4 EX-4a) Ethyl 6- (N- (1-oximinoethyl) amino)-2- (N-Boc-amino) hexanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling to- 10 °C, propane-2,2-disulfonyl dichloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated to afford ethyl 6- (5- (1,2,3,4-tetrahydro-3,3,6-trimethyl- 4,5,7-oxadithiadiazepinyl))-2- (N-Boc-amino) hexanoate.

Ethyl 6- (5- (1,2,3,4-tetrahydro-3,3,6-trimethyl-2,2,4,4-tetraoxo-1,2,4,5 ,7- oxadithiadiazepinyl))-2- (N-Boc-amino) hexanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords ethyl 6- (5- (1,2,3,4-tetrahydro-3,3,6-trimethyl-2,2,4,4-tetraoxo-1,2,4,5 ,7-oxadithiadiazepinyl))-2- aminohexanoate hydrochloride.

Example 5 EX-5a) N-(Methylthiomethyl)-N-(methylsulfonyl)-6-(N-(1-oximinoethyl ) amino)-2-(N- Boc-amino) hexanamide (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling to-10 °C, thionyl chloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgSO4, and concentrated to afford N- (methylthiomethyl)- <BR> <BR> <BR> <BR> <BR> N- (methylsulfonyl)-6- (3- (4-methyl-2-oxo-1, 2-dihydro-1,2,3,5-oxathiadiazolyl))-2- (N- Boc-amino) hexanamide.

N- (Methylthiomethyl)-N- (methylsulfonyl)-6- (3- (4-methyl-2-oxo-1, 2-dihydro-1,2,3,5- oxathiadiazolyl))-2- (N-Boc-amino) hexanamide is deprotected by allowing it to stand in 2N HC1 in dioxane at 25°C for two hours. Concentrating in vacuo affords N- <BR> <BR> <BR> (methylthiomethyl)-N- (methylsulfonyl)-6- (3- (4-methyl-2-oxo-1, 2-dihydro-1,2,3,5-<BR> <BR> <BR> <BR> <BR> <BR> oxathiadiazolyl))-2-aminohexanamide hydrochloride.

Example 6 EX-6a) Ethyl S- (2- (N- (1-oximinoethyl) amino) ethyl)-4-thia-2- (N-Boc-amino) butanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine.

After cooling in an ice bath, ethyl dichlorophosphine (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated to afford ethyl S- (2- (3- (2-ethyl-1,2-dihydro-4- methyl-2-oxo-1,2,3,5-oxaphosphadiazolyl)) ethyl)-4-thia-2- (N-Boc-amino) butanoate.

Ethyl S- (2- (3- (2-ethyl-1, 2-dihydro-4-methyl-2-oxo-1,2,3,5-oxaphosphadiazolyl)) ethyl)-4- thia-2- (N-Boc-amino) butanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours.

Concentrating in vacuo affords ethyl S- (2- (3- (2-ethyl-1,2-dihydro-4-methyl-2-oxo- 1,2,3,5-oxaphosphadiazolyl)) ethyl)-4-thia-2-aminobutanoate hydrochloride.

Example 7 EX-7a) Propane-2,2-diphosphonyl tetrachloride (10.5 mmol), 45 mL of anhydrous methylcyclohexane, and pyridine (22 mmol) is cooled to-10 °C and treated with ethyl 6- (N- (l-oximinoethyl) amino)-2- (N-Boc-amino) hexanoate (10 mmol). The mixture is allowed to warm to room temperature. The reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then is concentrated in vacuum giving ethyl 6- (4- 7,2,4- oxadiphosphadiazepinyl))-2- (N-Boc-amino) hexanoate.

EX-7b) Ethyl 6- (4- (5, 7-dichloro-1,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl-1,5, 7,2,4- oxadiphosphadiazepinyl))-2- (N-Boc-amino) hexanoate is cooled to-10 °C and treated with ethanol (21 mmol) and pyridine (21 mmol). The mixture is allowed to warm to room temperature. Upon completion, 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 in vacuum. The residue is dissolved in a suitable solvent and passed through a reverse phase chromatographic column to give, after concentration, ethyl 6- (4- (5,7-diethoxy-

7,2,4-oxadiphosphadiazepinyl))-2- (N- Boc-amino) hexanoate.

Ethyl 6- (4- (5, 7-diethoxy-1,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl-1,5, 7,2,4- oxadiphosphadiazepinyl))-2- (N-Boc-amino) hexanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords ethyl 6- (4- (5, 7-diethoxy-1,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl-1,5, 7,2,4- oxadiphosphadiazepinyl))-2-aminohexanoate hydrochloride.

Example 8 EX-8a) Ethyl 6- (N- ( 1-oximinoethyl) amino)-2- (N-Boc-amino) hexanoate (10 mmol) is dissolved in 45 mL of anhydrous methylcyclohexane containing 21 mmol of pyridine.

After cooling to-10 °C, pyrophosphoryl tetrachloride (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then is concentrated in vacuum giving ethyl 6- (5- (2, 4-dichloro-1,2,3,4-tetrahydro-6- 2,4,5,7-dioxadiphosphadiazepinyl))-2- (N-Boc-amino) hexanoate.

EX-8b) Ethyl 6- (5- (2,4-dichloro-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1,3,2,4, 5,7- dioxadiphosphadiazepinyl))-2- (N-Boc-amino) hexanoate is cooled to-10 °C and treated with ethanol (21 mmol) and pyridine (21 mmol). The mixture is allowed to warm to

room temperature. Upon completion, 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 in vacuum. The residue is dissolved in a suitable solvent and passed through a reverse phase chromatographic column to give, after concentration, ethyl 6- (5- (2,4-diethoxy- 2,4,5,7-dioxadiphosphadiazepinyl))-2- (N-Boc- amino) hexanoate.

Ethyl 6- (5- (2, 4-diethoxy-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1,3,2,4,5,7 - dioxadiphosphadiazepinyl))-2- (N-Boc-amino) hexanoate is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords ethyl 6- (5- (2, 4-diethoxy-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1,3,2,4,5,7 - dioxadiphosphadiazepinyl))-2-aminohexanoate hydrochloride.

Example 9 EX-9a) N-Methylthio-N- (2-oxazolyl)-S- (2- (N- (2-fluoro-1-oximinoethyl) amino) ethyl)-2- (N-Boc-amino)-4-thiabutanamide (10 mmol) is dissolved in 45 mL of anhydrous THF containing pyridine (11 mmol). After cooling in an ice bath phosgene (10.5 mmol) is added to the mixture by a gas inlet tube 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 water. The methylene chloride

layer is separated, back washed with water, dried over MgS04, and concentrated to affordN-methylthio-N- (2-oxazolyl)-S- (2- (4- (3-fluoromethyl-1,5-dihydro-5-oxo-1,2,4- oxadiazolyl))ethyl)-2-(N-Boc-amino)-4-thiabutanamide.

N-Methylthio-N- (2-oxazolyl)-S- (2- (4- (3-fluoromethyl-1, 5-dihydro-5-oxo-1,2,4- oxadiazolyl)) ethyl)-2- (N-Boc-amino)-4-thiabutanamide is then dissolved in trifluoroacetic acid and allowed to stand at room temperature until the t-butoxycarbonyl group is removed. The reaction mixture is then concentrated in vacuo to give N- Methylthio-N- (2-oxazolyl)-S- (2- (4- (3-fluoromethyl-1, 5-dihydro-5-oxo-1,2,4- oxadiazolyl))ethyl)-2-amino-4-thiabutanamide trifluoroacetate.

Example 10 EX-10a) N-Methyl-N- (2-pyrrolyl)-3- (5- (2- (N- (1- oximinoethyl) amino) methyl) thiophenyl)-2- (N-pnZ-amino) propanamide (10 mmol) is dissolved in 45 mL of anhydrous THF and cooled to-10 °C and treated with 1,3- dichloro-1,1,3,3-tetramethyldisiloxane (10.5 mmol) and triethyl amine (TEA) (21 mmol).

After warming to room temperature and standing for 2 hours, the reaction mixture is cooled, filtered to remove crystallized triethylamine hydrochloride, and then is concentrated in vacuum giving N-methyl-N- (2-pyrrolyl)-3- (5- (2- (5- (1,2,3,4-tetrahydro-

5,7,2,4-dioxadiazadisilapinyl) methyl) thiophenyl)-2- (N-pnZ- amino) propanamide.

N-methyl-N- (2-pyrrolyl)-3- (5- (2- (5- (1,2,3,4-tetrahydro-2,2,4,4,6-pentamethyl-1,3,5,7,2,4- dioxadiazadisilapinyl) methyl) thiophenyl)-2- (N-pnZ-amino) propanamide is dissolved in anhydrous methylcyclohexane 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 pnZ- function generating the amino product N-methyl-N- (2-pyrrolyl)-3- (5- (2- (5- (1,2,3,4- 5,7,2,4-dioxadiazadisilapinyl) methyl) thiophenyl)-2- aminopropanamide.

Example 11 EX-lla) N- (5-Tetrazolyl)-6- (N- (2-fluoro-l-oximinoethyl) amino)-2- (N-TCC-amino) hex- 4-enamide (10 mmol) is treated with ethyl 3-ethoxy-2-methylbut-2-enoate (10.5 mmol) and toluene in a distillation apparatus and heated to 90°C. As the reaction progresses ethanol is distilled as it is formed. When no more ethanol distills, the toluene is removed in vacuo, and the material is purified by liquid chromatography to yield N- (5-tetrazolyl)-

6- (4- (1,5-dihydro-3-fluoromethyl-6,7-dimethyl-5-oxo-1,2,4-oxadiaz epinyl))-2- (N-TCC- amino)hex-4-enamide.

N- (5-tetrazolyl)-6- (4- ( 1,5-dihydro-3-fluoromethyl-6,7-dimethyl-5-oxo-1,2,4- oxadiazepinyl))-2- (N-TCC-amino) hex-4-enamide is dissolved in acetic acid (50 mL).

Zinc dust is added until completion of removal of the TCC-function. The reaction mixture is concentrated in vacuo and the residue neutralized with excess saturated aqueous sodium carbonate. The precipitant is removed by filtration. The aqueous solution is exhaustively extracted with methylene chloride, the extract dried over MgS04, concentrated, and purified by chromatography to afford the amino product N- (5- tetrazolyl)-6- (4- ( 1,5-dihydro-3-fluoromethyl-6,7-dimethyl-5-oxo-1,2,4-oxadiaze pinyl))-2- aminohex-4-enamide.

Example 12 EX-12a) N-Ethoxy-N-ethyl-2-(N-Boc-amino)-2-methyl-0-(2-(N-(2-fluoro- 1- oximinoethyl) amino) ethyl)-4-oxybutanamide (10 mmol) is dissolved in 45 mL of anhydrous THF containing pyridine (21 mmol). After cooling in an ice bath, 2,2- dimethylmalonyl chloride (10.5 mmol) is added 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 water. The methylene chloride

layer is separated, back washed with water, dried over MgS04, and concentrated to afford N-Ethoxy-N-ethyl-2- (N-Boc-amino)-2-methyl-O- (2- (1- (2-fluoromethyl-4,5,6- trihydro-5,5-dimethyl-4,6-dioxopyrimidinyl)) ethyl)-4-oxybutanamide.

N-Ethoxy-N-ethyl-2-(N-Boc-amino)-2-methyl-0-(2-(1-(2-fluo romethyl-4,(N-Boc-amino)-2-methyl-0-(2-(1-(2-fluoromethyl-4, 5,6-trihydro- 5,5-dimethyl-4,6-dioxopyrimidinyl)) ethyl)-4-oxybutanamide is deprotected by allowing it to stand in 2N HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords N- Ethoxy-N-ethyl-2-amino-2-methyl-O- (2- (l- (2-fluoromethyl-4,5,6-trihydro-5,5-dimethyl- 4,6-dioxopyrimidinyl)) ethyl)-4-oxybutanamide.

Example 13 EX-13a) 2- (N-Boc-amino)-6- (N- (l-iminoethyl) amino)-5-cyclopropylspiro-N-methoxy- N-methyl-hexanamide (10 mmol) dissolved in 45 mL of anhydrous THF, is cooled to-10 °C and treated with propane-2,2-disulfonyl dichloride (10.5 mmol) and pyridine (41 mmol). The mixture is allowed to warm to room temperature. 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 in vacuum. The resulting material is passed through a reverse phase chromatographic column, giving 2- (N-Boc-amino)-6- (2- (3,6,6-trimethyl-1,1,5,5-tetraoxo-1,5,2,4- dithiadiazinyl)-5-cyclopropylspiro-N-methoxy-N-methyl-hexana mide.

2- (N-Boc-amino)-6- (2- (3,6,6-trimethyl-1, 1,5,5-tetraoxo-1,5,2,4-dithiadiazinyl)-5- cyclopropylspiro-N-methoxy-N-methyl-hexanamide is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 2-amino- 6- (2- (3,6,6-trimethyl-1,1,5,5-tetraoxo-1,5,2,4-dithiadiazinyl)-5- cyclopropylspiro-N- methoxy-N-methyl-hexanamide hydrochloride.

Example 14 EX-14a) Propane-2,2-diphosphonyl tetrachloride (10.5 mmol) is dissolved in 45 mL of anhydrous methylcyclohexane and pyridine (21 mmol). The mixture is cooled to-10 °C and treated with tert-butyl 6-N-(2-fluoro-1-iminoethyl)-2-(N-Boc-amino)-5,5- dimethylhexanoate (10 mmol). The mixture is allowed to warm to room temperature.

The reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then concentrated in vacuum giving tert-butyl 6- (1- (4, 6-Dichloro-2-fluoromethyl- 4,5,6-trihydro-5,5-dimethyl-4,6-dioxo-4,6-diphosphapyrimidin yl))-2- (N-Boc-amino)-5,5- dimethylhexanoate.

EX-14b) tert-Butyl 6- (1- (4,6-dichloro-2-fluoromethyl-4,5,6-trihydro-5,5-dimethyl-4,6 - is cooled to- 10°C and treated with ethanol (21 mmol) and pyridine (21 mmol). The mixture is allowed to warm to room temperature. 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 in vacuum. The material is purified by passing it through a reverse phase chromatographic column to give tert-Butyl 6- (l- (4,6-diethoxy-2-fluoromethyl-4,5,6-trihydro-5,5-dimethyl-4,6 -dioxo-4,6- diphosphapyrimidinyl))-2- (N-Boc-amino)-5,5-dimethylhexanoate. <BR> <BR> tert-Butyl 6- (1- (4,6-diethoxy-2-fluoromethyl-4,5,6-trihydro-5,5-dimethyl-4,6 -dioxo-4,6- diphosphapyrimidinyl))-2- (N-Boc-amino)-5,5-dimethylhexanoate is deprotected by allowing it to stand in 2N HC1 and dioxane at 25°C for two hours. Concentrating in vacuo affords 6- (1- (4,6-diethoxy-2-fluoromethyl-4,5,6-trihydro-5,5-dimethyl-4,6 -dioxo- 4,6-diphosphapyrimidinyl))-2-amino-5,5-dimethylhexanoic hydrochloride.

Example 15 EX-15a) Pyrophosphoryl tetrachloride (10.5 mmol), 45 mL anhydrous methylcyclohexane and pyridine (22 mmol) is cooled to-10 °C and treated with tert-butyl 6-N- (1-iminoethyl) amino-2- (N-Boc-amino) hex-4-enoate (10 mmol). The mixture is allowed to warm to room temperature. The reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then concentrated in vacuum giving tert-butyl 6- (3- (2, 6-dichloro-1,2,6-trihydro-4-methyl-2,6-dioxo-1,2,6-oxadiphos phapyrimidinyl))-2- (N-Boc-amino) hex-4-enoate.

EX-15b) tert-Butyl 6- (3- (2,6-dichloro-1,2,6-trihydro-4-methyl-2,6-dioxo-1,2,6- oxadiphosphapyrimidinyl))-2- (N-Boc-amino) hex-4-enoate is cooled to-10 °C and treated with ethanol (21 mmol) and pyridine (21 mmol). The mixture is allowed to warm to room temperature. Upon completion the mixture is concentrated in vacuum, 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 in vacuum. The material is purified by passing it through a reverse phase chromatographic column to give tert-butyl 6- (3- (2,6-diethoxy-1,2,6-trihydro-4-methyl-2,6-dioxo-1,2,6- oxadiphosphapyrimidinyl))-2- (N-Boc-amino) hex-4-enoate. tert-Butyl 6- (3- (2, 6-diethoxy-1,2,6-trihydro-4-methyl-2,6-dioxo-1,2,6- oxadiphosphapyrimidinyl))-2- (N-Boc-amino) hex-4-enoate is deprotected by allowing it to stand in anhydrous trifluoroacetic acid until the tert-butyl groups are removed.

Concentrating in vacuo affords 6- (3- (2, 6-diethoxy-1,2,6-trihydro-4-methyl-2,6-dioxo- 1,2,6-oxadiphosphapyrimidinyl))-2-aminohex-4-enoic acid trifluoroacetate.

Example 16

1,3-Dichloro-1,1,3,3,-tetraethyldisiloxane (10.5 mmol), 45 mL anhydrous methylcyclohexane and pyridine (22 mmol) is cooled to-10 °C and treated with ethyl 6- N- (l-iminoethyl) amino-2- (N-acetamido)-2-methyl-hex-4-ynoate (10 mmol). The mixture is allowed to warm to room temperature. The reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then concentrated in vacuum giving tert-butyl giving ethyl 6- (3- (2,2,6,6-tetraethyl-1,2,6-trihydro-4-methyl-1,2,6- oxadisilapyrimidinyl))-2-acetamido-2-methyl-hex-4-ynoate.

Example 17 EX-17a) N- (5-tetrazolyl)-S- (2- (N- (l-iminoethyl) amino) ethyl)-a- (N-Boc)-2-methyl-L- cysteinamide (10 mmol) is dissolved in 45 mL of THF containing 22 mmol of pyridine.

After cooling in an ice bath, cyclopentane-1,2-dicarbonyl dichloride (10.5 mmol) is added over 20 minutes. After standing at room temperature 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 in vacuum. The material is purified by passing it through a reverse phase chromatographic column to give N- (5-tetrazolyl)-S- (2- (l- (4,5,6,7-tetrahydro-2-

ethyl)-a- (N-Boc)-2-methyl-L- cysteinamide.<BR> <BR> <P>N- (5-tetrazolyl)-S- (2- ( 1- (4,5,6,7-tetrahydro-2-methyl-4,7-dioxo-5,6-trimethylene-1,3- diazepinyl)) ethyl)-a- (N-Boc)-2-methyl-L-cysteinamide is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords N- (5-tetrazolyl)-S- (2- ( 1- (4,5,6,7-tetrahydro-2-methyl-4,7-dioxo-5,6-trimethylene-1,3- diazepinyl))ethyl)-2-methyl-L-cysteinamide hydrochloride.

Example 18 EX-18a) tert-Butyl 4- (2- (N- (l-iminoethyl) amino) ethyl) sulfonyl-2- (N-Boc- amino) butanoate (10 mmol) is dissolved in 45 mL of THF containing 22 mmol of pyridine and cooled in an ice bath. Phthaloyl chloride (10.5 mmol) is added over 20 minutes. After standing at room temperature 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 in vacuum. The material is purified by passing it through a reverse phase chromatographic column to give tert-Butyl 4- (2- (l- (5,6-benzo-4,7-dihydro-2- ethyl) sulfonyl-2- (N-Boc-amino) butanoate.

tert-Butyl 4- (2- (l- (5,6-benzo-4,7-dihydro-2-methyl-4,7-dioxo-1,3- diazepinyl) ethyl) sulfonyl-2- (N-Boc-amino) butanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 4- (2- (1- (5,6-benzo-4,7-dihydro-2-methyl-4,7-dioxo-1,3-diazepinyl) ethyl) sulfonyl-2- aminobutanoic acid hydrochloride.

Example 19 EX-19a) tert-Butyl 6-(N-(2-fluoro-1-iminoethyl) amino)-2-(N-Boc-amino)-2-methyl-L- hexanoate (10 mmol) is dissolved in 45 mL of THF containing 22 mmol of pyridine and cooled in an ice bath. 4,5-Imidazolyldicarbonyl dichloride (10.5 mmol) is added over 20 minutes. After standing at room temperature 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 in vacuum. The material is purified by passing it through a reverse phase chromatographic column to give tert-Butyl 6- (1- (2-fluoromethyl-4,7-dihydro-5,6- imidazo-4,7-dioxo-1, 3-diazepinyl))-2-(N-Boc-amino)-2-methyl-L-hexanoate.

tert-Butyl 6- (1- (2-fluoromethyl-4,7-dihydro-5,6-imidazo-4,7-dioxo-1,3-diazep inyl))-2- (N-Boc-amino)-2-methyl-L-hexanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 6- (l- (2-fluoromethyl- 4,7-dihydro-5,6-imidazo-4,7-dioxo-1, 3-diazepinyl))-2-(N-Boc-amino)-2-methyl-L- hexanoic acid dihydrochloride.

Example 20 EX-20a) tert-Butyl 6-N- (1-oximinoethyl) amino-2- (N, N-dimethylcarbamido)-2- methylthiomethyl-L-hexanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, phosgene (10.5 mmol) is added to the mixture by a gas inlet tube 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated to afford tert-Butyl 6- (4- (1,5-dihydro-3-methyl-5-oxo-1,2,4-oxadiazolyl))-2- (N, N- dimethylcarbamido)-2-methylthiomethyl-L-hexanoate. tert-Butyl 6- (4- (1, 5-dihydro-3-methyl-5-oxo-1,2,4-oxadiazolyl))-2- (N, N- dimethylcarbamido)-2-methylthiomethyl-L-hexanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating in vacuo affords 6- (4- 4-oxadiazolyl))-2-(N, N-dimethylcarbamido)-2- methylthiomethyl-L-hexanoic acid.

Example 21 EX-21a) tert-Butyl 3- (5- (2- (N- ( 1-iminoethyl) aminomethyl) thiophenyl)-2- (3- (N, N- dimethylaminomethyl) benzamido) propanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 21 mmol of pyridine. After cooling in an ice bath, cyclopentane-1,1-dicarbonyl dichloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, concentrated and purified by column chromatography to give tert-Butyl 3- (5- (2- (l- (4,5,6-trihydro-2-methyl-4,6-dioxo-5- (cyclopentanespiro) pyrimidinyl) methyl) thiophenyl)-2- (3- (N, N- dimethylaminomethyl) benzamido) propanoate. tert-Butyl 3- (5- (2- ( 1- (4,5,6-trihydro-2-methyl-4,6-dioxo-5- (cyclopentanespiro) pyrimidinyl) methyl) thiophenyl)-2- (3- (N, N-

dimethylaminomethyl) benzamido) propanoate is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours. Concentrating the solvent in vacuo affords 3- (5- (2- (1- (4,5,6-trihydro-2-methyl-4,6-dioxo-5- (cyclopentanespiro) pyrimidinyl) methyl) thiophenyl)-2- (3- (N, N- dimethylaminomethyl) benzamido) propanoic acid hydrochloride.

Example 22 EX-22a) Benzyl 6-(N-(1-iminoethyl) amino)-2-(methoxycarbonylamido)-2- methylhexanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling to-78°C, cyclopentane-1,1-disulfonyl dichloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, and concentrated to afford Benzyl 6- (2- 5,5-tetraoxo-6-cyclopentanespiro-1,5-dithiapyrimidinyl))-2- (methoxycarbonylamido)-2-methylhexanoate.

Benzyl 6- (2- ( 1,5,6-trihydro-3-methyl-1,1,5,5-tetraoxo-6-cyclopentanespiro -1,5- dithiapyrimidinyl))-2- (methoxycarbonylamido)-2-methylhexanoate is dissolved in ethanol containing 1 % acetic acid and 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 the product 6- (2- (1,5,6-trihydro-3-methyl-1,1,5,5-tetraoxo-6- cyclopentanespiro-1,5-dithiapyrimidinyl))-2- (methoxycarbonylamido)-2-methylhexanoic acid.

Example 23 EX-23a) Benzyl 6- (N-(2-fluoro-1-oximinoethyl) amino)-2-benzamidohexanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, phosgene (10.5 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 water.

The methylene chloride layer is separated, back washed with water, dried over MgS04,

and concentrated to afford benzyl 6- (4- (1,5-dihydro-3-fluoromethyl-5-oxo-1,2,4- oxadiazolyl))-2-benzamidohexanoate.

Benzyl 6- (4- ( 1,5-dihydro-3-fluoromethyl-5-oxo-1,2,4-oxadiazolyl))-2- benzamidohexanoate is dissolved in ethanol containing 1 % acetic acid and 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 the product 6- (4- (1,5-dihydro-3- fluoromethyl-5-oxo-1,2,4-oxadiazolyl))-2-benzamidohexanoic acid.

Example 24 3- (4- (N- (l-iminoethyl) amino) butyl) morpholine-2,5-dione (10 mmol) is dissolved in 45 mL of anhydrous THF containing a 22 mmol pyridine. After cooling in an ice bath, cyclopentane-1,1-dicarbonyl dichloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, concentrated and purified by chromatography to afford 3- (4- (1- (4,5,6- trihydro-2-methyl-4,6-dioxo-5-cyclopentanespiropyrimidinyl)) butyl) morpholine- 2,5, dione.

Example 25 3- (4- (N- ( 1-oximinoethyl) amino) butyl) morpholine-2,5-dione (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, oxalyl chloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, concentrated, and purified by chromatography to afford 3- (4- (4- (1,5,6-trihydro-3-methyl-5,6-dioxo-1- oxapyrimidinyl)) butyl) morpholine-2,5, dione.

Example 26 EX-26a) N- (2, 2-dimethoxycyclohexyl)-2- (N-Boc-amino)-3-methyl-6- (N- ( 1- oximinoethyl) amino) hexanamide (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, oxalyl chloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, concentrated and purified by chromatography to afford N- (2, 2-dimethoxycyclohexyl)-2- (N-Boc-amino)-3-methyl-6- (4- (1,5,6-trihydro-3-methyl-5,6-dioxo-1-oxapyrimidinyl)) hexanamide. <BR> <BR> <P>N- (2, 2-dimethoxycyclohexyl)-2- (N-Boc-amino)-3-methyl-6- (4- (1,5,6-trihydro-3-methyl- 5,6-dioxo-1-oxapyrimidinyl)) hexanamide (10 mmol) is then treated with 50 mL 2.0 M HCl in dioxane until the Boc-function is removed. After adding 10 mL water and standing at room temperature until the methoxy groups are removed, the reaction mixture is then concentrated in vacuo to give 3- (4- (4- (1,5,6-trihydro-3-methyl-5,6-dioxo-1- oxapyrimidinyl)-1-methylbutyl))-1,2,3,5,6,7,8,9-octahydroqui noxaline-2-one hydrochloride.

Example 27 EX-27a) tert-Butyl 6-(N-(1-oximinoethyl)-N-hydroxylamino)-2-(N-Boc- amino) hexanoate (10 mmol) is dissolved in 45 mL of anhydrous THF containing 11 mmol of pyridine. After cooling in an ice bath, oxalyl chloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, concentrated, and purified by chromatography to afford tert-Butyl 6- (5- (1,2,34-tetrahydro-6-methyl-2,3-dioxo-1,4,5,7-dioxadiazepiny l))-2- (N-Boc-amino) hexanoate. tert-Butyl 6- (5- ( 1,2,34-tetrahydro-6-methyl-2,3-dioxo-1,4,5,7-dioxadiazepinyl ))-2- (N- Boc-amino) hexanoate is deprotected by allowing it to stand in 2 M HCl in dioxane at 25°C for two hours. Concentrating in vacuo affords 6- (5- (1,2,34-tetrahydro-6-methyl- 2,3-dioxo-1,4,5,7-dioxadiazepinyl))-2-aminohexanoic acid hydrochloride.

Example 28 EX-28a) Phosphorus trichloride (10.5 mmol) is dissolved in 45 mL of anhydrous methylcyclohexane containing 21 mmol of pyridine. After cooling to-78°C, tert-Butyl 6- (N- (l-oximinoethyl)-N-hydroxylamino)-2- (N-Boc-amino) hexanoate (10 mmol) in methylcyclohexane is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the mixture is cooled in an ice bath and methanol (11 mmol) and pyridine (10 mmol) are added over 20 minutes. After warming to room temperature and standing for 2 hours, the mixture is cooled, and the precipitated pyridine hydrochloride removed by filtration. After concentration, the reaction mixture is purified by column chromatography to give tert-Butyl 6- (4- (1,2,3-trihydro-2-methoxy-5-methyl- 1,3,2-dioxaphosphapyrimidinyl)-2- (N-Boc-amino) hexanoate. tert-Butyl 6- (4- ( 1,2,3-trihydro-2-methoxy-5-methyl-1,3,2-dioxaphosphapyrimidi nyl)-2- (N-B oc-amino) hexanoate is deprotected by allowing it to stand in 2M HCl and dioxane at 25°C for two hours.

Concentrating in vacuo affords 6- (4- (1,2,3-trihydro-2-methoxy-5-methyl-1,3,2- dioxaphosphapyrimidinyl)-2-aminohexanoic acid hydrochloride.

Example 29 Benzyl 6- (N-(1-oximinoethyl)-N-hydroxylamino)-2-(N-Z-amino) hexanoate (10 mmol) is placed in admixture with 45 mL of anhydrous methylcyclohexane containing 21 mmol of pyridine. After cooling in an ice bath, 1,1-dichlorocyclosilolane (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the mixture is cooled, the precipitated pyridine hydrochloride is removed by filtration, and is then concentrated to give Benzyl 6- (4- (5-methyl-2-cyclosilolanespiro- 1,3,2-dioxasilapyrimidinyl))-2- (N-Z-amino) hexanoate.

Example 30 EX-30a) tert-Butyl 6-(N-(1-oximinoethyl)-N-hydroxylamino)-2-(N-Boc-amino)-2- methylthiomethylhexanoate (10 mmol) is dissolved in 45 mL of anhydrous methylcyclohexane containing 21 mmol of pyridine. After cooling to-10°C, thionyl chloride (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the mixture is cooled, the precipitated pyridine hydrochloride is removed by filtration, and is then concentrated to give tert-Butyl 6- (4- (1,2,3-trihydro-5-methyl-2-oxo-1,3,2-dioxathiapyrimidinyl))- 2- (N-Boc-amino)-2- methylthiomethylhexanoate. tert-Butyl 6- (4- ( 1,2,3-trihydro-5-methyl-2-oxo-1,3,2-dioxathiapyrimidinyl))-2 - (N-Boc- amino)-2-methylthiomethylhexanoate is deprotected by allowing it to stand in dioxane and HC1 at 25°C for two hours. Concentrating in vacuo affords 6- (4- (1,2,3-trihydro-5- methyl-2-oxo-1,3,2-dioxathiapyrimidinyl))-2-amino-2-methylth iomethylhexanoic acid hydrochloride.

Example 31 EX-31a) tert-Butyl 6-(N-(1-oximinoethyl)-N-hydroxylamino)-2-(N-Boc-amino)-2- methylthiomethylhexanoate (10 mmol) is dissolved in 45 mL of anhydrous methylcyclohexane containing 21 mmol of pyridine. After cooling to-10°C, thiophosgene (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the mixture is cooled, the precipitated pyridine hydrochloride is removed by filtration, and is then concentrated to give tert- Butyl 6- (4- (1,2,3-trihydro-5-methyl-2-thiono-1,3-dioxapyrimidinyl))-2- (N-Boc-amino)-2- methylthiomethylhexanoate. tert-Butyl 6- (4- ( 1,2,3-trihydro-5-methyl-2-thiono-1,3-dioxapyrimidinyl))-2- (N-Boc- amino)-2-methylthiomethylhexanoate is deprotected by allowing it to stand in dioxane and HC1 at 25°C for two hours. Concentrating in vacuo affords 6- (4- (1,2,3-trihydro-5- methyl-2-thiono-1,3-dioxapyrimidinyl))-2-amino-2-methylthiom ethylhexanoic acid hydrochloride.

Example 32 Benzyl 6- (N- (l-oximinoethyl)-N-hydroxylamino)-2- (N-Z-amino)-2-hexanoate (10 mmol) is dissolved in 45 mL of anhydrous methylcyclohexane containing 21 mmol of pyridine.

After cooling in an ice bath, 1,3-dichloro-1,3-dicyclosilolanespirodisiloxane (10.5 mmol) is added to the mixture over 20 minutes. After warming to room temperature and standing for 2 hours, the mixture is cooled, the precipitated pyridine hydrochloride is removed by filtration, and is then concentrated to give benzyl 6- (6- (2,4- dicyclosilolanespiro-1,2,3,4,5-pentahydro-7-methyl-1,3,5,2,4 ,6,8-trioxadisiladiazocinyl))- 2- (N-Z-amino)-hexanoate.

Example 33 EX-33a) N- (5-Tetrazolyl)-N- (methoxy)-6- (N- ( 1-oximinoethyl) amino)-2- (N-tert- butoxymethyl-N-pnZ-amino)-hexanamide (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, oxalyl chloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, concentrated, and purified by column chromatography to afford N- (5-tetrazolyl)-N- (methoxy)-6- (4- (1,5,6-trihydro-3-methyl- 5,6-dioxo-1-oxapyrimidinyl))-2-(N-tert-butoxymethyl-N-pnZ-am ino)-hexanamide.

N- (5-tetrazolyl)-N- (methoxy)-6- (4- (1,5,6-trihydro-3-methyl-5,6-dioxo-1- oxapyrimidinyl))-2- (N-tert-butoxymethyl-N-pnZ-amino)-hexanamide 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 pnZ-function generating the amino product N- (5-tetrazolyl)-N- (methoxy)-6- (4- ( 1,5,6-trihydro-3-methyl-5,6-dioxo-1- oxapyrimidinyl))-2- (N-tert-butoxymethylamino)-hexanamide.

Example 34 EX-34a) N- (Methylthiomethyl)-N- (methylsulfonyl)-6- (N- ( 1-oximinoethyl) amino)-2- (N- pnZ-amino)-hexanamide (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, phosgene (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, concentrated, and chromatographed to afford N- <BR> <BR> <BR> <BR> <BR> (Methylthiomethyl)-N- (methylsulfonyl)-6- (4- (1,5-dihydro-3-methyl-5-oxo-1,2,4-<BR> <BR> <BR> <BR> <BR> oxadiazolyl))-2- (N-pnZ-amino)-hexanamide.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>N- (Methylthiomethyl)-N- (methylsulfonyl)-6- (4- ( 1, 5-dihydro-3-methyl-5-oxo-1,2,4- oxadiazolyl))-2- (N-pnZ-amino)-hexanamide 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 pnZ-function generating the amino product N- (Methylthiomethyl)-N- (methylsulfonyl)-6- (4- ( 1, 5-dihydro-3-methyl-5-oxo-1,2,4- oxadiazolyl))-2-aminohexanamide.

Example 35 EX-35a) 5- (N- ( 1-oximinoethyl) amino)-1- (2- ( 1,3-dioxolyl)) pentanamine (10 mmol) is treated with benzyl chloroformate (10.5 mmol) and sodium carbonate in tetrahydrofuran and water to yield the Z protected product 5- (N- (1-oximinoethyl) amino)-1- (2- (1,3- dioxolyl))-1- (N-Z)-pentanamine after chromatography and concentration.

EX-35b) 5- (N- ( 1-oximinoethyl) amino)-1- (2- ( 1, 3-dioxolyl))-1- (N-Z)-pentanamine (10 mmol) is dissolved in 45 mL of anhydrous THF containing 22 mmol of pyridine. After cooling in an ice bath, oxalyl chloride (10.5 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 water. The methylene chloride layer is separated, back washed with water, dried over MgS04, concentrated, and chromatographed to afford 5- (4- (1,5,6-trihydro-3-methyl- 5,6-dioxo-1-oxapyrimidinyl))-1-(2-(1, 3-dioxolyl))-1-(N-Z)-pentanamine. <BR> <BR> <BR> <BR> <BR> <BR> <P>5- (4- ( 1,5,6-Trihydro-3-methyl-5,6-dioxo-1-oxapyrimidinyl))-1- (2- ( 1, 3-dioxolyl))-1- (N- Z)-pentanamine 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 pnZ- function generating the amino product 5- (4- (1,5,6-trihydro-3-methyl-5,6-dioxo-1- oxapyrimidinyl))-1-(2-(1,(2-(1, 3-dioxolyl)) pentanamine.

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 is measured by monitoring the conversion of L- [2, 3-3H]-arginine to L- [2, 3-3H]-citrulline. Mouse inducible NOS (miNOS) was prepared from an extract of LPS-treated mouse RAW 264.7 cells and rat brain constitutive NOS (rnNOS) was prepared from an extract of rat cerebellum. Both preparations are partially purified by DEAE-Sepharose chromatography. Enzyme (10 m L) is added to 40 m L of 50 mM Tris (pH 7.6) and the reaction initiated by the addition of 50 m L of a solution containing 50 mM Tris (pH 7.6), 2.0 mg/mL bovine serum albumin, 2.0 mM DTT, 4.0 mM CaCl2,20 mM FAD, 100 &M tetrahydrobiopterin, 2.0 mM NADPH and 60 mM L-arginine containing 0.9 m Ci 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 is terminated by addition of 300 m L cold buffer containing 10 mM EGTA, 100 mM HEPES (pH 5.5) and 1.0 mM L-citrulline. The [3H]-citrulline is separated by chromatography on Dowex 50W X-8 cation exchange resin and radioactivity quantified with a liquid scintillation counter.

Raw Cell Nitrite Assav RAW 264.7 cells are plated to confluency on a 96-well tissue culture plate grown overnight (17h) in the presence of LPS to induce NOS. A row of 3-6 wells were left untreated and served as controls for subtraction of nonspecific background. The media is

removed from each well and the cells are washed twice with Kreb-Ringers-Hepes (25 mM, pH 7.4) with 2 mg/mL glucose. The cells are then placed on ice and incubated with 50 mL of buffer containing L-arginine (30 mM) +/-inhibitors for Ih. The assay is initiated by warming the plate to 37% C in a water bath for lh. Production of nitrite by intracellular iNOS is linear with time. To terminate the cellular assay, the plate of cells is 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). All values are the average of triplicate wells and are compared to a background-subtracted induced set of cells (100% value).

In Vivo Assav Rats are treated with an intraperitoneal injection of 10 mg/kg of endotoxin (LPS) with or without oral administration of the nitric oxide synthase inhibitors. Plasma nitrites were measured 5 hours post-treatment. The results 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 be 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 usage's and conditions.