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WO2000063195A1 - Novel heterocyclic amino carbonyl derivatives useful as nitric oxide synthase inhibitors - Google Patents

Novel heterocyclic amino carbonyl derivatives useful as nitric oxide synthase inhibitors Download PDF

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Publication number
WO2000063195A1
WO2000063195A1 PCT/US2000/008735 US0008735W WO0063195A1 WO 2000063195 A1 WO2000063195 A1 WO 2000063195A1 US 0008735 W US0008735 W US 0008735W WO 0063195 A1 WO0063195 A1 WO 0063195A1
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group
heterocyclyl
alkyl
aryl
haloalkyl
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PCT/US2000/008735
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French (fr)
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WO2000063195A8 (en
Inventor
R. Keith Webber
Melvin L. Rueppel
Donald W. Hansen, Jr.
E. Ann Hallinan
Timothy J. Hagen
Barnett S. Pitzele
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G.D. Searle & Co.
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Priority to AU43290/00A priority Critical patent/AU4329000A/en
Publication of WO2000063195A1 publication Critical patent/WO2000063195A1/en
Publication of WO2000063195A8 publication Critical patent/WO2000063195A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C07D273/02—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having two nitrogen atoms and only one oxygen atom
    • C07D273/06—Seven-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/06—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
    • C07F9/65844—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a five-membered ring which may be condensed with another ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6587—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having two phosphorus atoms as ring hetero atoms in the same ring

Definitions

  • 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.
  • endothelium-derived relaxing factor a labile humoral factor termed endothelium-derived relaxing factor (EDRF).
  • NO nitric oxide
  • EDRF endothelium-derived relaxing factor
  • 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.
  • a constitutive, Ca-H-/calmodulin dependent enzyme located in the endothelium, that releases NO in response to receptor or physical stimulation.
  • a constitutive, Ca++/calmodulin dependent enzyme located primarily in the brain, that releases NO response to receptor or physical stimulation.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • Nitric oxide inhibition may also play a role in the treatment of pain including somatogenic (either nociceptive or neuropathic), both acute and chronic.
  • somatogenic either nociceptive or neuropathic
  • a nitric oxide inhibitor could be used in any situation that a common NS AID or opioid analgesic would traditionally be administered.
  • NO inhibiting agents may also be useful as antibacterial agents.
  • 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.
  • 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.
  • SLE systemic lupus erythematosis
  • ARDS acute respiratory distress syndrome
  • IL2 therapy such as in a cancer patient
  • cachexia such as in transplant therapy
  • 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.
  • 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.
  • 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).
  • NO has been identified as being a neurotransmitter in pain pathways of the spinal cord.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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, e
  • J and J are independently selected from the group consisting of OR , SR ,
  • NHR and N(R )R provided that A is R ;
  • J and J can be taken together to form a group selected from the group consisting of
  • OR S OR S, SR S, OR NR and SR NR provided that A is R ;
  • J and J can be taken together to form a covalent double bond attached to J
  • J is selected from the group consisting of O, NR and S provided that A is
  • G is selected from the group consisting of O, S, CH2, CHR , C(R )2, NH, and
  • 5 A is selected from the group consisting of O, N(R ), S and heterocyclyl with the proviso that J is selected from other than O and A is selected from other than O, S and heterocyclyl unless R is selected from other than the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl,
  • 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, CH OC(O)GR 15 , CH2
  • heterocyclic, aryl, and heteroaryl or R is present, or R 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;
  • 5 A can be selected from the group consisting of O, N(R ) and S connected to the
  • R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl,
  • R is selected from other than the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl,
  • R 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(R ) and S connected to the
  • 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 CIO 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
  • 27 27 5 7 A can be R , wherein R is selected from the group consisting of N(R )OR ,
  • N(R 5 )SR 7 N(R 5 )N(R ? )R 25 , N(R 5 )SO 2 R 13 , N(R 5 )C(O)R 15 , N(R 5 )C(S)R 15 ,
  • R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl,
  • R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl,
  • 13 13 15 dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R , SO2R , C(O)R , and
  • Rl5 and R are 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, and dihydropyridyl
  • J is selected from NR or S, or J and J are taken together to form a group
  • 28 28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and
  • 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, 15 ⁇ ⁇ cyanocycloalkyl, dicyanocycloalkyl and C(O)R wherein R 1D is selected from hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloal
  • 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- g membered ring, or being bicyclic or greater in ring number, or R is selected from other than the group selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl or
  • R 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 R 1 ⁇ 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
  • 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,
  • Ri 5 and R 1 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, aralkyl, and dihydropyridyl, or J
  • 22 1 2 is selected from NR or S, or J and J are taken together to form a group selected from
  • OR O OR S, SR S, OR NR and SR NR , or R is 27 present, or A is R , 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
  • R is selected from other than the group selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
  • R and R can be taken together to form a substituent selected from the group
  • 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-
  • C(R )R , S(O), S(O)2, OP(OR )R , P(O)R , P(S)R , and Si(R )R and said 30 31 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, carboalkoxycyanoalkyl, carboalkoxycyan
  • CH2OC(S)GR , CH2SC(S)GR heteroaryloxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, heteroaryloxyalkyl, alkenyloxy alkyl, alkylthioalkyl, arylthioalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkyl
  • 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
  • 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 g number, or R 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 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
  • 28 28 28 28 28 28 24 group selected 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
  • Q being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
  • 6 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, cyclo
  • 28 28 28 28 28 24 selected 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
  • R 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, dicarboalkoxycycloalkyl,
  • 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, CH2OC(O)GR and CH2OC(O)R where G
  • R 5 can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural
  • J 22 1 2 amino acid, a synthetic amino acid, a synthetic amino acid, unless J is selected from NR and S, or J and J are
  • 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
  • R 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; 7 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, thi
  • 28 28 28 28 28 28 28 24 28 24 ⁇ 2 consisting of OR O, OR S, SR S, OR NR and SR NR , or J and J are
  • R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl,
  • R 7 CH 2 OC(O)A-R 7 , CH 2 NR 19 C(O)A-R ? , CH NR 19 C(S)A-R 7 , CH 2 SC(O)A-R 7 ,
  • R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl unless J is selected from
  • 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 R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl,
  • 13 13 15 dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R , SO2R , C(O)R , and
  • R!5 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;
  • R 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, cycloal
  • 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,
  • 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
  • X can be -(CH2) S T(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, 9 10 9 10 cycloalkoxy, alkylaminoalkyl, and NR R where R and R are independently selected from the group consisting of hydroxyamino, alkoxyamino, hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, alkoxy, alkylthio, alkylamino, hydroxy, thio, alkoxy, aryl,
  • R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or J
  • 22 l 2 is selected from NR and S, or J and J are taken together to form a group selected
  • 28 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,
  • R 5 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;
  • R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a C3 to C8 heterocyclyl; 19 20
  • R and R 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, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl
  • R and R 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;
  • R and R 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, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, halocycloalkyl, halocycloalkenyl, hal
  • R and R 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, haloalkenyl
  • R and R 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 form C5 to C8 heterocyclyl;
  • R is independently selected from a group consisting of CH(R )CH2,
  • R and R 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, cycloalkenyl, cycl
  • R and R 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),
  • R and R is independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, and dicyanocycloalkyl
  • 28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and 28 24 26 27
  • 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 g being bicyclic or greater in ring number, or R 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, cyanocycloalky
  • Ri 5 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 cycloalkyl radicals, cycloalkenyl radicals wherein said cycloalkyl radicals and cycloalkenyl radicals may be
  • R or R substituents 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
  • R 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • alkenyl radicals examples include propylenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2-methylbuten-l-yl, 3- methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-l-yl, hepten-1-yl, and octen-1-yl, and the like.
  • 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.
  • alkynyl radicals examples include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn- 1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals and the like.
  • hydro 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
  • carbon radical denotes a carbon atom without any covalent bonds and capable of forming four covalent bonds.
  • cyano radical denotes a carbon radical having three of four covalent bonds shared by a nitrogen atom.
  • 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.
  • 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.
  • dicarbonylalkyl radicals examples include oxalyl, malonyl, and succinyl.
  • 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.
  • 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.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • 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.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • hydroxy haloalkyl embraces radicals wherein any one or more of the haloalkyl carbon atoms is substituted with hydroxy as defined above.
  • hydroxyhaloalkyl radicals include hexafluorohydoxypropyl.
  • 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.
  • haloalkylene radicals include difluoromethylene, tetrafluoroethylene, tetrachloroethylene, alkyl substituted monofluoromethylene, and aryl substituted trifluoromethylene.
  • 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.
  • 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.
  • 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.
  • haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
  • haloalkoxyalkyl radicals include fluoromethoxy methyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxy ethyl, and trifluoroethoxymethyl.
  • 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.
  • 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.
  • radicals examples 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.
  • haloalkenyloxy examples include trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyloxy, and fluoropropenyloxy.
  • haloalkoxyalkyl also embraces alkyl radicals having one or more haloalkoxy radicals attached to the alkyl radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl radicals.
  • haloalkenyloxy also embraces oxygen radicals having one or more haloalkenyloxy radicals attached to the oxygen radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy radicals.
  • haloalkenyloxyalkyl also embraces alkyl radicals having one or more haloalkenyloxy radicals attached to the alkyl radical, that is, to form monohaloalkenyloxy alkyl and dihaloalkenyloxy alkyl radicals.
  • alkylenedioxy denotes alkylene radicals having at least two oxygens bonded to a single alkylene group.
  • alkylenedioxy examples include methylenedioxy, ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted methylenedioxy.
  • haloalkylenedioxy denotes haloalkylene radicals having at least two oxy groups bonded to a single haloalkyl group.
  • haloalkylenedioxy radicals include difluoromethylenedioxy, tetrafluoroethylenedioxy, tetrachloroethylenedioxy, alkylsubstituted monofluoromethylenedioxy, and arylsubstituted monofluoromethylenedioxy.
  • 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.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • 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.
  • heterocyclyl embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • 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
  • heteroaryl radicals examples include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,
  • 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
  • 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.
  • fused bicyclic radicals examples 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.
  • 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
  • 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.
  • alkylsulfinyl 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.
  • 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.
  • heteroarylkyl embraces heteroaryl-substituted alkyl radicals wherein the heteroaralkyl radical may be additionally substituted with three or more substituents as defined above for aralkyl radicals.
  • perhaloaralkyl embraces aryl-substituted alkyl radicals wherein the aralkyl radical is substituted with three or more halo radicals as defined above.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 poly halocycloalkenyl radicals.
  • cycloalkoxy embraces cycloalkyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexoxy and cyclopentoxy.
  • 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 cyclohexoxy ethyl.
  • cycloalkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkoxy” and "halocycloalkoxyalkyl” radicals.
  • cycloalkylalkoxy embraces cycloalkyl radicals attached to an alkoxy radical. Examples of such radicals includes cyclohexylmethoxy and cyclopentylmethoxy.
  • cycloalkenyloxy embraces cycloalkenyl radicals attached to an oxy radical. Examples of such radicals includes cyclohexenyloxy and cyclopentenyloxy.
  • 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 cyclohexenyloxy ethyl.
  • cycloalkenyloxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkenyloxy” and "halocycloalkenyloxyalkyl” radicals.
  • cycloalkylenedioxy radicals denotes cycloalkylene radicals having at least two oxygens bonded to a single cycloalkylene group.
  • alkylenedioxy radicals include 1,2-dioxycyclohexylene.
  • 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.
  • 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.
  • 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 (CH 3 -S-).
  • the "alkylthio" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkylthio" radicals.
  • radicals include fluoromethylthio, chloromethylthio, trifluoromethylthio, difluoromethylthio, trifluoroethylthio, fluoroethylthio, tetrafluoroethylthio, pentafluoroethylthio, and fluoropropylthio .
  • alkylamino denotes "monoalkylamino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical.
  • 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.
  • Aralkylamino embraces aralkyl radicals attached to an amino radical, where aralkyl is defined as above.
  • aralkylamino denotes "monoaralkylamino” and “diaralkylamino” containing one or two aralkyl radicals, respectively, attached to an amino radical.
  • aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.
  • arylsulfinylalkyl denotes arylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
  • 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.
  • heteroarylsulfinylalkyl denotes heteroarylsulfinyl radicals attached to a linear or branched alkyl radical, of one to ten carbon atoms.
  • 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.
  • aryloxy embraces aryl radicals, as defined above, attached to an oxygen atom.
  • 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.
  • aroyl embraces aryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include benzoyl and toluoyl.
  • aralkanoyl embraces aralkyl radicals, as defined herein, attached to an carbonyl radical as defined above. Examples of such radicals include, for example, phenylacetyl.
  • 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.
  • aryloxyalkyl embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxy methyl.
  • haloaryloxy alkyl embraces aryloxyalkyl radicals, as defined above, wherein one to five halo radicals are attached to an aryloxy group.
  • heteroaryloxy embraces heteroaryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include pyridyloxy and furyloxy.
  • heteroaroyl embraces heteroaryl radicals, as defined above, attached to an carbonyl radical as defined above. Examples of such radicals include furoyl and nicotinyl.
  • 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.
  • 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.
  • heteroaryloxyalkyl embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridyloxy methyl .
  • haloheteroaryloxyalkyl embraces heteroaryloxyalkyl radicals, as defined above, wherein one to four halo radicals are attached to an heteroaryloxy group.
  • heteroarylamino embraces heterocyclyl radicals, as defined above, attached to an amino group. Examples of such radicals include pyridylamino.
  • heteroarylaminoalkyl embraces heteroarylamino radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyridylmethylamino.
  • 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.
  • heteroaryloxyalkyl embraces heteroaryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include 2- pyridyloxymethyl, 3-pyridyloxyethyl, and 4-pyridyloxymethyl.
  • arylthio embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio.
  • arylthioalkyl embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl.
  • alkylthioalkyl embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl.
  • alkoxyalkyl embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl.
  • carbonyl denotes a carbon radical having two of the four covalent bonds shared with an oxygen atom.
  • carboxy embraces a hydroxyl radical, as defined above, attached to one of two unshared bonds in a carbonyl group.
  • carboxamide embraces amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group.
  • carboxyalkyl embraces carboxamide radicals, as defined above, attached to an alkyl group.
  • carboxy radical as defined above, attached to an alkyl group.
  • carbboalkoxy 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.
  • 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.
  • 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.
  • acyl are formyl, acetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
  • 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 heptafluorobutyry 1.
  • phosphono embraces a pentavalent phosphorus attached with two covalent bonds to an oxygen radical.
  • dialkoxyphosphono denotes two alkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds.
  • diaralkoxyphosphono denotes two aralkoxy radicals, as defined above, attached to a phosphono radical with two covalent bonds.
  • dialkoxyphosphonoalkyl denotes dialkoxyphosphono radicals, as defined above, attached to an alkyl radical.
  • diaralkoxyphosphonoalkyl denotes diaralkoxyphosphono radicals, as defined above, attached to an alkyl radical.
  • heterooaralkoxy alkyl 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,
  • 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
  • Multi-valent chains may consist of a straight chain of
  • 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)-, -OCH 2 O-, -O(CH 2 )2O-, -NHCH 2 -, -OCH(R 6 )O-, -O(CH 2 CHR 6 )O-, -
  • 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,
  • prodrug refers to a compound that is made more active in vivo.
  • treatment of a patient is intended to include prophylaxis.
  • 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.
  • 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.
  • R -reagent such as R -Br, R -OTs, R -oxirane, thiirane, or aziridine, or CMR-Cl
  • R -reagent such as R ,8 -Br, R ,8 -OTs, R -oxirane
  • EX-la Ethyl 6-(N-(l-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.
  • Ethyl 6-(4-( 1 ,5,6,7-tetrahydro-3,6,6-trimethyl-5,7-dioxo- 1 ,2,4-oxadiazepinyl))-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-(l,5,6,7-tetrahydro-3,6,6- trimethyl-5,7-dioxo- 1 ,2,4-oxadiazepinyl))-2-methyl-2-aminohexanoate hydrochloride.
  • 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.
  • Ethyl 6-(3-(2-ethyl-l,2-dihydro-5-methyl-l,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-l,2-dihydro-5-methyl- l,2,3,5-oxaphosphadiazolyl))-2-aminohexanoate hydrochloride.
  • EX-3a Ethyl S-(2-(N-(l-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.
  • 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.
  • 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-(l,2-dihydro-2,2,4-trimethyl- 1,2,3,5- oxasiladiazolyl))ethyl)-4-thia-2-aminobutanoate.
  • EX-4a Ethyl 6-(N-(l-oxirninoethyl)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 MgSO4, and concentrated to afford ethyl 6-(5-(l,2,3,4-tetrahydro-3,3,6-trimethyl-
  • Ethyl 6-(5-(l,2,3,4-tetrahydro-3,3,6-trimethyl-2,2,4,4-tetraoxo-l,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- (l,2,3,4-tetrahydro-3,3,6-trimethyl-2,2,4,4-tetraoxo-l,2,4,5,7-oxadithiadiazepinyl))-2- aminohexanoate hydrochloride.
  • 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)-
  • N-(Methylthiomethyl)-N-(methylsulfonyl)-6-(3-(4-methyl-2-oxo-l,2-dihydro-l,2,3,5- oxathiadiazolyl))-2-(N-Boc-amino)hexanamide is deprotected by allowing it to stand in 2N HCl in dioxane at 25 °C for two hours.
  • 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.
  • Ethyl S-(2-(3-(2-ethyl-l,2-dihydro-4-methyl-2-oxo-l,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.
  • reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then is concentrated in vacuum giving ethyl 6-(4- (5,7-dichloro-l,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl-l,5,7,2,4- oxadiphosphadiazepinyl))-2-(N-Boc-amino)hexanoate.
  • EX-7b) Ethyl 6-(4-(5,7-dichloro-l,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl-l,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.
  • 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.
  • EX-8a Ethyl 6-(N-(l-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.
  • reaction mixture 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-l,2,3,4-tetrahydro-6- methyl-2,4-dioxo-l, 3,2,4,5 ,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.
  • Ethyl 6-(5-(2,4-diethoxy-l,2,3,4-tetrahydro-6-methyl-2,4-dioxo-l,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.
  • N-Methylthio-N-(2-oxazolyl)-S-(2-(4-(3-fluoromethyl-l,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.
  • N-methyl-N-(2-pyrrolyl)-3-(5-(2-(5-(l,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.
  • 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.
  • aqueous solution is exhaustively extracted with methylene chloride, the extract dried over MgSO4, 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-oxadiazepinyl))-2- aminohex-4-enamide .
  • N-Ethoxy-N-ethyl-2-(N-Boc-amino)-2-methyl-O-(2-(l-(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.
  • reaction mixture is cooled, filtered to remove crystallized pyridine hydrochloride, and then concentrated in vacuum giving tert-butyl 6-(l-(4,6-Dichloro-2-fluoromethyl- 4,5,6-trihydro-5,5-dimethyl-4,6-dioxo-4,6-diphosphapyrimidinyl))-2-(N-Boc-amino)-5,5- dimethylhexanoate .
  • the methylene chloride layer is separated, back washed with water, dried over MgSO4, 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.
  • 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 is deprotected by allowing it to stand in 2N HCl and dioxane at 25°C for two hours.
  • 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-oxadiphosphapyrimidinyl))-2- (N-Boc-amino)hex-4-enoate.
  • 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-l,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.
  • Example 16 l,3-Dichloro-l,l,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.
  • 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-l,2,6-trihydro-4-methyl- 1,2,6- oxadisilapyrimidinyl))-2-acetamido-2-methyl-hex-4-ynoate.
  • the methylene chloride layer is separated, back washed with water, dried over MgSO4, 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- methyl-4,7-dioxo-5 ,6-trimethylene- 1 ,3-diazepinyl))ethyl)-a-(N-Boc)-2-methyl-L- cysteinamide.
  • N-(5-tetrazolyl)-S-(2-(l-(4,5,6,7-tetrahydro-2-methyl-4,7-dioxo-5,6-trimethylene-l,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.
  • 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- methyl-4,7-dioxo-l,3-diazepinyl)ethyl)sulfonyl-2-(N-Boc-amino)butanoate.
  • the material is purified by passing it through a reverse phase chromatographic column to give tert-Butyl 6-(l-(2-fluoromethyl-4,7-dihyd ⁇ o-5,6- imidazo-4,7-dioxo-l,3-diazepinyl))-2-(N-Boc-amino)-2-methyl-L-hexanoate.
  • 6-(4-(l, 5-dihydro-3-methyl-5-oxo-l,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- ( 1 ,5-dihydro-3-methyl-5-oxo- 1 ,2,4-oxadiazolyl))-2-(N,N-dimethylcarbamido)-2- methylthiomethyl-L-hexanoic acid.
  • 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.
  • Benzyl 6-(2-( 1 ,5,6-trihydro-3-methyl- 1 , 1 ,5,5-tetraoxo-6-cyclopentanespiro-l ,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-l,5-dithiapyrimidinyl))-2-(methoxycarbonylamido)-2-methylhexanoic acid.
  • 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-(l,5-dihydro-3- fluoromethyl-5-oxo- 1 ,2,4-oxadiazolyl))-2-benzamidohexanoic acid.
  • a hydrogenation catalyst such as palladium on carbon and hydrogen
  • 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-(l,2,34-tetrahydro-6-methyl- 2,3-dioxo- 1 ,4,5,7-dioxadiazepinyl))-2-aminohexanoic acid hydrochloride.
  • 6-(4-( 1 ,2,3-trihydro-2-methoxy-5-methyl- 1 ,3,2-dioxaphosphapyrimidinyl)-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-(l,2,3-trihydro-2-methoxy-5-methyl- 1,3,2- dioxaphosphapyrimidinyl)-2-aminohexanoic acid hydrochloride.
  • Benzyl 6-(N-(l-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.
  • 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 HCl at 25°C for two hours. Concentrating in vacuo affords 6-(4-(l,2,3-trihydro-5- methyl-2-oxo- 1 ,3,2-dioxathiapyrimidinyl))-2-amino-2-methylthiomethylhexanoic acid hydrochloride.
  • 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 HCl at 25°C for two hours. Concentrating in vacuo affords 6-(4-(l,2,3-trihydro-5- methyl-2-thiono- 1 ,3-dioxapyrimidinyl))-2-amino-2-methylthiomethylhexanoic acid hydrochloride.
  • 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, l,3-dichloro-l,3-dicyclosilolanespirodisiloxane (10.5 mmol) is added to the mixture over 20 minutes.
  • N-(5-tetrazolyl)-N-(methoxy)-6-(4-(l,5,6-trihydro-3-methyl-5,6-dioxo-l- 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.
  • 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 MgSO4, concentrated, and chromatographed to afford N-
  • 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.
  • 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-(l-oximinoethyl)amino)-l-(2-(l,3- dioxolyl))-l-(N-Z)-pentanamine after chromatography and concentration.
  • EX-35b 5-(N-( 1 -oximinoethyl)amino)- l-(2-(l ,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.
  • 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-(l,5,6-trihydro-3-methyl-5,6-dioxo-l- oxapyrimidinyl))-l-(2-(l,3-dioxolyl))pentanamine.
  • 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:
  • NOS activity is measured by monitoring the conversion of L-[2,3- H]-arginine to
  • Mouse inducible NOS 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 CaCl 2 , 20 mM FAD, 100 &M tetrahydrobiopterin, 2.0 mM NADPH and 60 mM L-arginine containing 0.9 m Ci of L-[2,3--1H]-arginine.
  • 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,
  • 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 lh.
  • 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.
  • 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).
  • 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.

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Abstract

The current invention discloses novel heterocyclic amino carbonyl derivatives useful as nitric oxide synthase inhibitors

Description

NOVEL HETEROCYCLIC AMINO CARBONYL DERIVATIVES
USEFUL AS NITRIC OXIDE SYNTHASE INHIBITORS
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 nitro vasodilators. 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-H-/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 NS AID 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, WO94/12165, WO94/14780, WO93/13055, 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:
Figure imgf000009_0001
and pharmaceutically acceptable salts thereof, wherein:
1 2 23 23
J and J are independently selected from the group consisting of OR , SR ,
24 24 25 26
NHR and N(R )R provided that A is R ;
1 2
J and J can be taken together to form a group selected from the group consisting
28 28 28 28 24 28 24 26 of OR O, OR S, SR S, OR NR and SR NR provided that A is R ;
1 2
J and J can be taken together to form a covalent double bond attached to J,
22 wherein J is selected from the group consisting of O, NR and S provided that A is
26 selected from other than R ;
G is selected from the group consisting of O, S, CH2, CHR , C(R )2, NH, and
NR1 ;
5 A is selected from the group consisting of O, N(R ), S and heterocyclyl with the proviso that J is selected from other than O and A is selected from other than O, S and heterocyclyl unless R is selected from other than the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl,
7 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, CH OC(O)GR15, CH2OC(O)R15, CH2C(=O)OR15> CH2C(=O)NHRl5'
Figure imgf000010_0001
(poly)acyloxyalkyl and alkylC(O)R wherein G is selected from O, S, CH2, CHR!5, C(R15)2, NH, and NR15 and R15 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
26 27 heterocyclic, aryl, and heteroaryl, or R is present, or R 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;
5 A can be selected from the group consisting of O, N(R ) and S connected to the
1 2 point of attachment of R or R by a spacer group selected from a linear moiety having a
2 chain length of 1 to 6 atoms to form a C5 to CIO heterocyclyl with the proviso that R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl,
15 8 cyanocycloalkyl, dicyanocycloalkyl and C(O)R , or R is selected from other than the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl,
26 cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or R is
27 present, or R 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(R ) and S connected to the
1 2 points of attachment of R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 to form C5 to CIO 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 CIO heterocyclyl;
26 26
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;
27 27 5 7 A can be R , wherein R is selected from the group consisting of N(R )OR ,
N(R5)SR7, N(R5)N(R?)R25, N(R5)SO2R13, N(R5)C(O)R15, N(R5)C(S)R15,
19 20 5 19 20
R (R )C=N-N(R ), R (R )C=N-O, natural amino acids, synthetic amino acids,
N(R5)P(O)(OR13)ιR6 and N(R5)P(O)(OR13)2;
1 2
R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl,
S(O)R13, SO R13, C(O)R15, CH2OC(O)R15, hydroxyl, sulfhydryl, OR6, SR6, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxy cyanocycloalkyl, carboalkoxy cycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH2SO3 " M+, CH2CH2SO3" M+, CH2PO "2 2M+,
-2 + 6 30 31 30 31 15
CH2CH2PO3 2M , CH(OR )CF3, P(O)R R , P(O)(R )2 R , C(S)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH SC(O)R15, CH SC(S)R15,
CH OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15, CH2OC(S)GR15,
CH2SC(S)GR15, OSO2R13, OS(O)R13, OC(S)R15, SC(S)R15, OC(S)GR15,
15 15 15 15 15 19 20
SC(S)GR , OC(O)R , SC(O)R , OC(O)GR , 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,
13 13 15 dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R , SO2R , C(O)R , and
15 13 CH2OC(O)R wherin Rl5 and R are 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, and dihydropyridyl
22 l 2 unless J is selected from NR or S, or J and J are taken together to form a group
28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and
28 24 2
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, 15 ι ς cyanocycloalkyl, dicyanocycloalkyl and C(O)R wherein R1D 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
26 27 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- g membered ring, or being bicyclic or greater in ring number, or R is selected from other than the group selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl or
2 with the proviso that R 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 R1^ 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)R13, SO2R13, C(O)R15, and CH2OC(O)R1 wherein Ri5 and R1 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, aralkyl, and dihydropyridyl, or J
22 1 2 is selected from NR or S, or J and J are taken together to form a group selected from
28 28 28 28 24 28 24 26 the group consisting of OR O, OR S, SR S, OR NR and SR NR , or R is 27 present, or A is R , 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
8 greater in ring number, or R is selected from other than the group selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
1 2
R and R can be taken together to form a substituent selected from the group
19 20 30 31 consisting of R (R )C=, D(C(R )(R ))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 ,
30 30 19 20 P(O)R , P(S)R and Si(R )R with the proviso that only one D can be oxygen or
19 20 19 20 sulfur at any time, D((R )R C)eW(C(R )R ) wherein e is 1 to 2, k is 1 to 2, D is
selected from the group consisting of oxygen, C=O, C=S, S(O)m wherein m is 0 to 2,
31 30 30 30 19 20
OP(OR )R , P(O)R , P(S)R and Si(R )R 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,
30 30 19 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, cycloalkenyl radicals wherein said cycloalkyl radicals
30 31 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-
19 32 substitutents are independently selected from C=O, C=S, C(R )R , S(O), S(O)2,
31 30 30 30 19 20
OP(OR )R , P(O)R , P(S)R 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,
19 32 31 30 30 30 19 20
C(R )R , S(O), S(O)2, OP(OR )R , P(O)R , P(S)R , and Si(R )R and said 30 31 alkyl and alkenyl may be optionally substituted with one or more R or R substituents;
5 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, carboalkoxy cycloalkyl, dicarboalkoxycycloalkyl,
13 13 30 31 30 31 15 formylalkyl, acylalkyl, S(O)R , SO2R , P(O)R R , P(O)(R )2 R , C(O)R ,
15 15 19 15 19 15 15
C(S)R , CH2OC(O)R , CH NR C(O)R , CH NR C(S)R , CH SC(O)R ,
CH2SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15,
15 15
CH2OC(S)GR , CH2SC(S)GR , heteroaryloxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, heteroaryloxyalkyl, alkenyloxy alkyl, alkylthioalkyl, arylthioalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, phosphonoalkyl, dialkoxyphosphonoalkylamino, diaralkoxyphosphonoalkylamino, phosphonoalkylamino, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylammo,
5 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
22 1 2 from NR and S, or J and J are taken together to form a group selected from the group 28 28 28 28 24 28 24 26 consisting of OR O, OR S, SR S, OR NR and SR NR , or R is present, or
27 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 g number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
5 1 2
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;
5 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 alkyl, hydroxy, amino, nitro, halo, cyano, haloalkyl, and
22 l 2 alkoxy unless J is selected from NR and S, or J and J are taken together to form a
28 28 28 28 24 group selected from the group consisting of OR O, OR S, SR S, OR NR and
28 24 26 27
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
Q being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
6 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, alkoxysulfonylalkylammo, aralkoxysulfonylalkylamino, sulfonylalkylamino, a natural amino acid, a synthetic amino acid, and polyhydroxy compounds of carbon with the proviso that R^ is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, and dicyanocycloalkyl
22 l 2 unless J is selected from NR and S, or J and J are taken together to form a group
28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and
28 24 26 27
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
8 being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
7 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,
15 alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, CH2OC(O)GR ,
15 13 13 30 31 30 31 15 15
CH2OC(O)R , S(O)R , SO2R , P(O)R R , P(O)(R )2 R , C(O)R , C(S)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH2SC(S)R15,
CH2NR19C(O)GR15, CH2NR19C(S)GR15, CH2OC(S)GR15, CH2SC(S)GR15, 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, alkoxysulfonylalkylammo, aralkoxysulfonylalkylamino, and
7 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, CH2OC(O)GR and CH2OC(O)R where G is independently selected
from O, S, CH2, CHRI5, C(R 5)2, NH, and NR15 and where R 5 can represent hydrogen, alkylamino, hydroxyalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, alkylthio, alkoxy, amino, cyanocycloalkyl, dicyanocycloalkyl, a natural
22 1 2 amino acid, a synthetic amino acid, unless J is selected from NR and S, or J and J are
28 28 taken together to form a group selected from the group consisting of OR O, OR S,
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
8 larger than a 6-membered ring, or being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl and cyanoalkyl;
7 1 2
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; 7 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, hydroxy haloalkyl, 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
22 1 2
NR S, or J and J are taken together to form a group selected from the group
28 28 28 28 24 28 24 ι 2 consisting of OR O, OR S, SR S, OR NR and SR NR , or J and J are
23 23 24 independently selected from the group consisting of OR , SR , NHR and 24 25 26
N(R )R when 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 o bicyclic or greater in ring number, or provided that R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl,
5 heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl when A is N(R );
8 R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl,
7 cyanoalkyl, alkylaminoalkyl, alkylthioalkyl, sulfhydrylalkyl, formyl, C(O)A-R , C(S)A-
R7, CH2OC(O)A-R7, CH2NR19C(O)A-R?, CH NR19C(S)A-R7, CH2SC(O)A-R7,
CH2SC(S)A-R7, CH OC(O)GR15, CH NR19C(O)GR15, CH NR19C(S)GR15,
15 15 8
CH2OC(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
22 l 2 NR and S, or J and J are taken together to form a group selected from the group
28 28 28 28 24 28 24 26 consisting of OR O, OR S, SR S, OR NR and SR NR , or R is present, or
27 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 R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl,
13 13 15 dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R , SO2R , C(O)R , and
15 13
CH2OC(O)R where R!5 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;
13 R 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;
15 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
21 21 oxygen, C=O, S(O)t, Se(O)t wherein t is 0 to 2, P(O)R wherein R is selected from
12 12 hydroxyl and alkyl, and N(R )n where n is 1 to 2 and R is 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, 9 10 9 10 cycloalkoxy, alkylaminoalkyl, and NR R where R and R are independently selected from the group consisting of hydroxyamino, alkoxyamino, hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, alkoxy, alkylthio, alkylamino, hydroxy, thio, alkoxy, aryl,
9 10 heterocyclyl, and aralkyl with the proviso that only one of R and R 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
8 heterocyclic, aralkyl, heterocyclylalkyl, alkylthioalkyl, and alkoxyalkyl, unless R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or J
22 l 2 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
26 27
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,
13 13 cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R , SO2R ,
15 15 13
C(O)R and CH2OC(O)R wherein R 5 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;
9 10
R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a C3 to C8 heterocyclyl; 19 20
R and R 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
19 20 diaralkoxyphosphonoalkyl with the proviso that only one of R and R is hydrogen;
19 20
R and R 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;
22 23
R and R 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;
24 25
R and R 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;
24 25
R and R 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 form C5 to C8 heterocyclyl;
28 23
R is independently selected from a group consisting of CH(R )CH2,
23 23
CH(R )CH2CH2, CH2CH(R )CH2, cycloalkylene, and heterocyclylene;
30 31
R and R 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;
30 31
R and R 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),
23 23 24 C(S), C(JH)2 wherein JH is selected from the group consisting of OR , SR , NHR ,
24 25 29 30 30 30 30 31 and N(R )R , CR , S(O), SO2, PR , P(O)R , P(S)R , C(R )R ,
30 31 30 30 19 20 19 20 19 20
C=C(R )R , (O)2POP(O)2, R (O)POP(O)R , Si(R )R , Si(R )R Si(R )R ,
19 20 19 20 and Si(R )R OSi(R )R with the proviso that any one of L, U, and V must be
30 31 30 31 selected from other than O, S, C(O), C(S), S(O), SO2, C(R )R , and C=C(R )R
30 31 wherein R and R is independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, and dicyanocycloalkyl
22 l 2 unless J is selected from NR and S, or J and J are taken together to form a group
28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and 28 24 26 27
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 g being bicyclic or greater in ring number, or R 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,
13 13 15 15 13
S(O)R , SO2R , C(O)R and CH2OC(O)R wherein Ri5 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;
30 31 L, U, and V can be selected from the group consisting of DC(R )(R )D
wherein D is selected from the group consisting of oxygen, C=O, C=S, S(O)m where m is
31 30 30 30 19 20 30
0 to 2, OP(OR )R , P(O)R , P(S)R , Si(R )R , and N(R ),
(R1 V 1 V° (RV CSQR1 20, C(0)C(R3VC(R31),
30 31 30 31 30 31 30 30 31
C(S)C(R )=C(R ), S(O)C(R )=C(R ), SO C(R )=C(R ), PR C(R )=C(R ),
30 30 31 30 30 31
P(O)R C(R )=C(R ), P(S)R C(R )=C(R ), 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
30 31 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
19 32 31 30 30 30 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),
31 30 30 30 19 20
S(O)2, OP(OR )R , P(O)R , P(S)R , and Si(R )R and said alkyl and alkenyl
30 31 may be optionally substituted with one or more R or R substituents;
32 R 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-l-yl, 3- methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-l-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-l-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-l-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
( — CH — > , 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 "hydroxy haloalkyl" 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 fluoromethoxy methyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxy ethyl, 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 monohaloalkenyloxy alkyl and dihaloalkenyloxy alkyl 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-l,2,4-triazolyl, 1H- 1,2,3-triazolyl, 2H-l,2,3-triazolyl, etc.] tetrazolyl [e.g. lH-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 poly halocycloalkenyl 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 cyclohexoxy ethyl.
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 cyclohexenyloxy ethyl. The "cycloalkenyloxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "halocycloalkenyloxy" and "halocycloalkenyloxyalkyl" radicals.
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 phenoxy methyl.
The term "haloaryloxy alkyl" 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 pyridyloxy methyl .
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 heptafluorobutyry 1.
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", "alkenylene", "hydroxyalkyl", "haloalkyl", "haloalkylene", "haloalkenyl", "alkoxy", "alkenyloxy", "alkenyloxyalkyl", "alkoxyalkyl", "aryl", "perhaloaryl", "haloalkoxy", "haloalkoxyalkyl", "haloalkenyloxy", "haloalkenyloxyalkyl", "alkylenedioxy",
"haloalkylenedioxy", "heterocyclyl", "heteroaryl", "hydroxyhaloalkyl", "alkylsulfonyl", "haloalkylsulfonyl", "alkylsulfonylalkyl", "haloalkylsulfonylalkyl", "alkylsulfinyl", "alkylsulfinylalkyl", "haloalkylsulfinylalkyl", "aralkyl", "heteroaralkyl", "perhaloaralkyl", "aralkylsulfonyl", "aralkylsulfonylalkyl", "aralkylsulfinyl", "aralkylsulfinylalkyl", "cycloalkyl", "cycloalkylalkyl", "cycloalkenyl", "halocycloalkyl", "halocycloalkenyl", "cycloalkylsulfinyl", "cycloalkylsulfinylalkyl", "cycloalkylsulfonyl", "cycloalkylsulfonylalkyl", "cycloalkoxy", "cycloalkoxyalkyl", "cycloalkylalkoxy", "cycloalkenyloxy", "cycloalkenyloxyalkyl", "cycloalkylenedioxy", "halocycloalkoxy", "halocycloalkoxyalkyl", "halocycloalkenyloxy", "halocycloalkenyloxyalkyl", "alkylthio", "haloalkylthio", "alkylsulfinyl", "amino", "oxy", "thio", "alkylamino", "arylamino", "aralkylamino", "arylsulfinyl", "arylsulfinylalkyl", "arylsulfonyl", "arylsulfonylalkyl", "heteroarylsulfinyl", "heteroarylsulfinylalkyl", "heteroarylsulfonyl", "heteroarylsulfonylalkyl", "heteroarylamino", "heteroarylaminoalkyl", "heteroaryloxy", "heteroaryloxylalkyl", "aryloxy", "aroyl", "aralkanoyl", "aralkoxy", "aryloxyalkyl", "haloaryloxy alkyl", "heteroaroyl", "heteroaralkanoyl", "heteroaralkoxy",
"heteroaralkoxy alkyl", "arylthio", "arylthioalkyl", "alkoxyalkyl", 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, heteroaralkoxy alkyl, 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, alkenyloxy alky, 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(R6)-, -O-, -S-, -S(O)-, -S(O)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)-, -OCH2O-, -O(CH2)2O-, -NHCH2-, -OCH(R6)O-, -O(CH2CHR6)O-, -
OCF2O-, -O(CF2)2O-, -S-, -S(O)-, -S(O)2-, -N(H)-, -N(H)O-, -N(R6)O-, -N(R6)-, -
C(O)-, -C(O)NH-, -C(O)NR6-, -N=, -OCH2-, -SCH -, S(O)CH2-, -CH C(O)-, -CH(OH)-
, =C(OH)-, -CH(OR )-, =C(OR )-, S(O)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, heteroaralkoxy alkyl, 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-C1" represents a chloromethylation or
15 19 15 bromomethylation reagent such as Cl-CH2OC(O)R , CI-CH2NR C(O)R , Cl-
CH2NR19C(S)R15, Cl-CH2SC(O)R15, C1-CH2SC(S)R15, Cl-CH2OC(O)GR15, CI-
19 15 19 15 15
CH2NR C(O)GR , C1-CH2NR C(S)GR , Cl-CH2OC(S)GR , or Cl-
CH2SC(S)GR , "DCC" represents 1 ,3-dicyclohexylcarbodiimide, "DIB AH" represents diisobutylaluminum hydride, "DIPEA" represents diisopropylethylamine, "DMF" represents dimethylformamide, "DMSO" represents dimethylsulf oxide, "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-l-yl)-l,l,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.
Figure imgf000052_0001
BocH (4) BocHN (3)
(a) R -NH2 (aa) N-chlorosuccimide, DMF
(b) BOP, DIPEA, DMF
(c) Pd, H2, Ethanol/Acetic Acid
(d) H20, pH 9-10
(e) HCl, dioxane or trifluoroacetic acid. Scheme 2
Figure imgf000053_0001
(a) HCl, Methanol
(b) BOP, DIPEA, DMF
(c) Pd, H2, Ethanol/Acetic Acid
(d) TEA, DMF
(e) HCl, dioxane or trifluoroacetic acid
Figure imgf000054_0001
Z-HN (9)
(a) R3 -NH2 (aa) N-chlorosuccimide, DMF
(b) BOP, DIPEA, DMF
(c) HCl, dioxane or trifluoroacetic acid
(d) H20, pH 9-10 (e) Pd, H2 , Ethanol/Acetic Acid
Scheme 4
Figure imgf000055_0001
(a) HCl, Methanol
(b) BOP, DIPEA, DMF
(c) HCl, dioxane or trifluoroacetic acid
(d) TEA, DMF
(e) Pd, H2, Ethanol/Acetic Acid
Figure imgf000056_0001
(a) t-Butoxycarbonyl azide, H2O, dioxane, MgO
(b) Pd, H2, Ethanol/Acetic Acid
(c) TEA, 0-80 °C
Figure imgf000057_0001
(a) TEA, 0-80 °C
(b) HCl, dioxane
Figure imgf000058_0001
(R = hydroxyl, sulfhydryl, OR D or SR D )
(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) R -NH , ethanol, sodium carbonate Scheme 8
Figure imgf000059_0001
(R1= hydroxyl, sulfhydryl, OR6 or SR6 ) (a) BH3 , THF
(b) Acylation with R : a carboxylic acid choπde or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions
(c) HCl, dioxane or trifluoroacetic acid
(d) H20, pH 9-10 with (2) or TEA, DMF with (2b) Scheme 9
Figure imgf000060_0001
(a) 1. t-butoxycarbonylazide, H 20, 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
Figure imgf000061_0001
(R = hydroxyl, sulfhydryl, OR0 or SRD ) (a) BH3 , THF
(b) Acylation with R : a carboxylic acid choπde or anhydride, a chloroformate, an isocyanate, a sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating reagent with standard conditions
(c) HCl, dioxane or trifluoroacetic acid
(d) H 0, pH 9-10 with (2) or TEA, DMF with (2b)
Figure imgf000062_0001
(a) R -NH2 (aa) N-chlorosuccimide , DMF
(b) HCl , dioxane or trifluoroacetic acid
1 . . .
(c) Acylation with R : a carboxylic acid choπde 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) H 0, pH 9-10
Figure imgf000063_0001
(a) HCl, Methanol
(b) HCl, 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
Figure imgf000064_0001
BocHN (4)
H2N (29:
(a) R -NH2 (aa) N-chlorosuccimide, DMF
(b) HCl, dioxane or trifluoroacetic acid
(c) Acylation with R : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, sulfinyl chloride, or phosphating or phosphonating eagent with standard conditions
(d) Pd, H , Ethanol/Acetic Acid
(e) H20, pH 9-10
Figure imgf000065_0001
(a) HCl, methanol
(b) HCl, dioxane or trifluoroacetic acid
2
(c) Acylation with R : 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
Figure imgf000066_0001
(a) Benzyl chloroformate, Na 2Cθ3 THF, Water
(b) HCl, dioxane or trifluoroacetic acid
(c) catalytic p-TsOH, hexane or toluene, azeotropic distillation (d) Pd, H 2 , Ethanol/Acetic Acid (e) Acylation with R 1 or R2 : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride or sulfinyl chloride with standard conditions.
Figure imgf000067_0001
(a) catalytic p-TsOH, hexane or toluene, azeotropic distillation
(b) Pd, H2, Ethanol/Acetic Acid
(c) Acylation with R 1or R2 : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride or sulfinyl chloride with standard conditions .
Figure imgf000068_0001
(a) Naθ3SCH2OH, 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. aCNBH3 , methanol, KOH [see R. F. Borch, Organic Synthesis, 52, 124 (1972)
Figure imgf000069_0001
(a) Trichloroethyl chloroformate, Na 2C03' H 2 0' 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 2 03' H 2°
(d) Acylation w th R : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, or sulfinyl chloride with standard conditions
(e) Acylation with R 2 with (d) -conditions .
Figure imgf000070_0001
(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 R 1or R2 : carboxylic acid choride or anhydride, chloroformate, isocyanate, sulfonyl chloride, or sulfinyl chloride with standard conditions
Figure imgf000071_0001
(a) 2 equivalents of Lithium Diisopropylamide, THF, C(0)C12 or C(S)C12
(b) HCl, dioxane or trifluoroacetic acid
(c) 1. Lithium Diisopropylamide, THF, 2. 2-haloalkanoate ester (R)
(d) a2Cθ3, toluene, heat
Figure imgf000072_0001
(b) HCl, dioxane or trifluoroacetic acid
(c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone
Figure imgf000073_0001
(a) R -NH2 (aa) N-chlorosuccimide, DMF
(b) an aldehyde or ketone precursor toR , catalytic p-TsOH, hexane or toluene, azeotropic distillation
(c) NaCNBKj , methanol, KOH [see R. F. Borch, Organic Synthesis, 52, 124 (1972)]
(d) H 0, pH 9-10
(e) HCl, dioxane or trifluoroacetic acid
Figure imgf000074_0001
(a) Na2Cθ3, aqueous dioxane; Acylation with a carboxylic acid choride or anhydride
(b) Na2C03, aqueous dioxane; sulfonation with a sulfonyl chloride or sulfinyl chloride with standard conditions
Figure imgf000075_0001
(a) Na2Cθ3, aqueous dioxane; Acylation with carboxylic acid choride or anhydride
(b) a C03, aqueous dioxane; sulfonation with sulfonyl chloride or sulfinyl chloride with standard conditions
(c) trifluoroacetic acid anhydride
(d) NaBH 4 , R -OH, aprotic polar solvent
Figure imgf000076_0001
Z-HN {75)
(a) TEA, DMF
(b) benzyl chlorof ormate, Na Cθ3, dioxane, water
(c) NaOH, H20
(d) BOP, DIPEA, DMF
(e) DMF, heat
(f) Pd, H2, Ethanol
Figure imgf000077_0001
(b) an aldehyde or ketone precursor to R , catalytic p-TsOH, hexane or toluene, azeotropic distillation
(c) NaCNBH 3 , 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
Figure imgf000078_0001
(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.
Figure imgf000079_0001
(a) Phthalic anhydride, THF at reflux
(b) LDA, THF Alkylation with a chloromethylation reagent (CMR-Cl)
(c) Hydrazine, methanol, reflux
(d) H20, pH 9-10
(e) Pd, H2, Ethanol
Figure imgf000080_0001
(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) HCl, dioxane, H20
Figure imgf000081_0001
(a) LDA, THF Alkylation with a chloromethylation reagent (CMR-Cl)
(b) Hydrazine, methanol, reflux
(c) H20, pH 9-10
(d) Pd, H2, Ethanol
Figure imgf000082_0001
(a) 2 equivalents of Lithium Diisopropylamide, THF, C(0)C12 or C(S)C12
(b) HCl, dioxane or trifluoroacetic acid
(c) 1. Lithium Diisopropylamide, THF, 2. 2-haloalkanoate ester (R)
(d) a C03, toluene, heat
Figure imgf000083_0001
(a) 2 equivalents of Lithium Diisopropylamide, THF, C(0)C12 or C(S)C12
(b) Pd, H2, ethanol/acetic acid
(c) 1. Lithium Diisopropylamide, THF, 2. 2-haloalkanoate ester (R)
(d) Na2C03 , toluene, heat
Figure imgf000084_0001
(b) HC , oxane or tr fluoroacet c ac d
(c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone
Figure imgf000085_0001
( P , H , et ano acet c ac d
(c) Lithium Diisopropylamide, THF, then dialkyl acetal of a bromoalkanone
Figure imgf000086_0001
(a) Pd, H2, Ethanol/Acetic Acid
(b) Heat up to 150 °C to decarboxylate
(c) BH3 in Tetrahydrofuran (d) DMSO, DCC, H 3 PO4
(e) p-TsOH, R -OH, hexane, heat
(f) BF3 etherate with an R23-OH or R23 -SH in an aprotic solvent
(g) 1. Aqueous Na2Cθ3 wash, 2. thoroughly dry, then 3. HCl in dioxane
Figure imgf000087_0001
(a) H20, pH 9-10
(b) Hydrazine, methanol, reflux
Figure imgf000088_0001
(a) BF3 etherate with
Figure imgf000088_0003
H0R ,2,8oSH,
Figure imgf000088_0002
HOR28NR24H, or HSR28NR H in an aprotic solvent or, with HOR28OH, p-TsOH, R23-OH, hexane, heat
(b) HCl, dixoane or trifluoroacetic acid
(c) H2O, pH 9-10 (d) Hydrazine, methanol, reflux
Figure imgf000089_0001
(a) HCl/dioxane or trifluoroacetic acid, then SOCl 2/DMF
(b) 1 equivalent DIBAH/THF at -78 °C
(c) p-TsOH, R23-0H, hexane, heat
(d) 1. 1 equivalent NaOH/alcohol, 2. HCl (1 mole), dry 3. BOP, DIPEA, DMF, 4. H-A-R 7
(e) BF3 etherate with an R23-OH or R23 -SH in an aprotic solvent
Figure imgf000090_0001
(a) Pd, H2 , ethanol/acetic acid
(b) H20, pH 9-10
(c) Hydrazine, methanol, reflux Scheme 40
Figure imgf000091_0001
(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, H 0
(d) R7-SH, CH2C12, -10 °C, HCl
(e) R7-OH, CH Cl2, -10 °C, HCl Scheme 41
(a) Hydrazine, ethanol, reflux
(b) Intermediate (2) or (2b) , pH 9-10, H20
(c) R7-SH, CH2C12, -10 °C, HCl
(d) R7-OH, CH2C12, -10 °C, HCl
Scheme 42
Figure imgf000093_0001
(a) H-NR ,5„ R7 , toluene, reflux
(b) R7-OH, CH2C12. -10 °C, HCl
(c) R7-SH, CH2C12- -10 °C, HCl
(d) 1. 1 equivalent NaOH in ethanol, 2. 1 equivalent of HCl, 3. BOP, DIPEA, DMF, H-NR5R7 3
Figure imgf000094_0001
(a) Pd, H2, Ethanol/Acetic Acid
(b) intermediate (2) or (2b), pH 9-10, H20
(c) H2 , Pt, Acetic acid
(d) C1-C(0)R15, triethylamine
(e) 1. Hydrazine, methanol, reflux, 2. HCl, dioxane Scheme 44
Figure imgf000095_0001
(a) 1. 1 equivalent LDA/THF at -78 °C, 2. bromoacetal (166)
(b) 1. 1 equivalent LDA/THF at -78 °C, 2. Br-CH2CH20-Bz
(c) catalytic p-TsOH, H 0, 0-5 °C
(d) H N-R4 , NaCNBH3, methanol, KOH [see R. F Borch, Organic Synthesis, 52, 124 (1972)
Figure imgf000096_0001
(a) Intermediate (2) or (2b) , pH 9-10, H 20
(b) HCl/Acetic acid
(c) 1. BOP, DIPEA, DMF, 2. H-A-R 7
(d) Pd, H2, Ethanol/Acetic Acid
(e) Hydrazine, methanol, reflux
Figure imgf000097_0001
(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
Figure imgf000098_0001
(a) 1. HCl, dioxane, 2. BOP, DIPEA, DMF, 3. HOCH2CCl
(b) 1. 1 equivalent LDA/THF at -78 °C, 2. CMR-Cl
(c) catalytic p-TsOH, H20, 0-5 °C
(d) H2N-R , NaCNBH3, methanol, KOH [see R. F. Borch, Organic Synthesis, 52, 124 (1972)
Figure imgf000099_0001
(a) Intermediate (2) or (2b) , pH 9-10, H 0
(b) Zinc dust/THF
(c) 1. BOP, DIPEA, DMF, 2. H-A-R 7
(d) Hydrazine, methanol, reflux
Figure imgf000100_0001
(a) 1. 1 equivalent LDA/THF at -78 °C, 2. alkylation
Q 8 8 8 with an R -reagent such as R -Br, R -OTs, R -oxirane, thiirane, or aziridine, or CMR-Cl
(b) catalytic p-TsOH, H 0, 0-5 °C
(c) H N-R4 , NaCNBH3, methanol, KOH
(d) Intermediate (2) or (2b) , pH 9-10, H20
Figure imgf000101_0001
(a) HCl in dioxane or ethyl acetate
(b) 1. BOP, DIPEA, DMF, 2. H-R 27 such as HN(R 22 OR
HN(R22 )N(R24)R25 , R19 (R20 )C=N-N(R22 )H, R19 (R20 ) C=N-OH (c) Hydrazine, methanol, reflux
(d) 1. ClC02Et, TEA, THF, -10 °C, 2. CH2C12, PTC, NaOH, H-R27such as HN (R 22 ) S02R13 , HN(R22 ) C (O) R 15
HN(R22 )C(S)R15 HN(R22 )P(0) (OR 13
)nR'
Figure imgf000102_0001
(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) HCl 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
Figure imgf000103_0001
(a) 1 equivalent LDA/THF at -78 °C (b) R26C(0)C1 acylation
(c) R -reagent such as R ,8 -Br, R ,8 -OTs, R -oxirane,
(d) HCl in dioxane or ethyl acetate
(e) Intermediate (2) or (2b), pH 9-10, H 20
(f) BF3 etherate with an R 23 -OH or R23-SH
(g) BF3 etherate with HOR 280H, HOR28SH, HSR28SH, HOR28NR24H, or HSR28NR H
(h) H2 , Pd/C, Ammonium Formate
Figure imgf000104_0001
(a) t-Butoxycarbonyl azide, H2O, dioxane, MgO
(b) H2O, phosphoric acid
(c) R -NH2 , catalytic p-TsOH, toluene, azeotropic distillation (d) N-chlorosuccinimide, DMF
7 (e) R -OH, toluene, reflux (f) HCl, dioxane
Figure imgf000105_0001
(b) HCl, dioxane or trifluoroacetic acid
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) R C(0)R , catalytic p-TsOH, toluene, azeotropic distillation.
Figure imgf000106_0001
(a) R30-PC1 where R30 is not OH, SH, or NH 2 , pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) PCI3 , pyridine
(d) R30-OH where R30 is not OH or SH, pyridine
Figure imgf000107_0001
(a) R19R20SiCl2, pyridine
(b) Pd, H2, methylcyclohexane
(c) Cl-SiR19R20SiR19R20-Cl, pyridine
Figure imgf000108_0001
(a) C1-S(0)2C(R30 ) (R31)S(0)2-C1, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) C1-S(0)C(R30) (R31)S(0)-C1, pyridine
Figure imgf000109_0001
(a) SOCI2 pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) S(0)2C12/ pyridine
Figure imgf000110_0001
(a) R ,30 -P(0)C1 where R ,30 is not OH, SH, or NH2 , pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) P(0)Cl3, pyridine
(d) R30-OH where R30 is not OH or SH, pyridine
Figure imgf000111_0001
(a) C12-P(0)C(R30 ) (R31 )P(0)-C12, pyridine
(b) R30-OH where R30 is not OH or SH, pyridine
(c) HCl, dioxane or trifluoroacetic acid
(d) Cl-(R30)P(O)C(R30) (R31)P(R30) (O)-Cl, pyridine
Figure imgf000112_0001
(a) Cl2-P(0)-0-P(0)-Cl2 , pyridine
(b) R30-OH where R30 is not OH or SH, pyridine
(c) HCl, dioxane or trifluoroacetic acid
(d) Cl-(R30)P(O)-O-P(R30 ) (O)-Cl, pyridine
Figure imgf000113_0001
(a) phosgene, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) C(S)C12, pyridine
Figure imgf000114_0001
(a) Cl-CR19R20-O-CR19R20-Cl, pyridine
(b) Pd, H2 , methyl cyclohexane
(c) Cl-SiR19R20-O-SiR19R20-Cl, pyridine
Figure imgf000115_0001
(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(R3° )C(0)-OCH 2CH3, heat ( -ethanol)
Figure imgf000116_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
Figure imgf000117_0001
(a) C1-S(0)2C(R3° ) (R31)S(0)2-C1, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) C1-S(0)C(R30) (R31)S(0)-C1, pyridine
Figure imgf000118_0001
(a) C12-P(0)C(R30 ) (R31 )P(0)-C12, pyridine
(b) R30-OH where R30 is not OH or SH, pyridine
(c) HCl, dioxane or trifluoroacetic acid
(d) Cl-(R30)P(O)C(R30) (R31)P(R30) (O)-Cl, pyridine
Figure imgf000119_0001
(a) Cl -P(0)-0-P(0)-Cl2 , pyridine
(b) R30-OH where R30 is not OH or SH, pyridine
(c) HCl, dioxane or trifluoroacetic acid
(d) Cl-(R30)P(O)-O-P(R30 ) (O)-Cl, pyridine
Figure imgf000120_0001
(a) Cl-CR19R20-O-CR19R20-Cl, pyridine
(b) Pd, H2, methylcyclohexane
(c) Cl-SiR19R20-O-SiR19R20-Cl, pyridine
Figure imgf000121_0001
(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 , ethanol (c) CH3CH 0-C(R31)=C(R30 )C(0) -OCH2CH3, heat ( -ethanol)
Figure imgf000122_0001
(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) C1(0)CC(R 31)=C(R30)C(O)Cl, heat (-ethanol)
Figure imgf000123_0001
(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) C1(0)CCH(R 31 )-CH(R30 )C(0)C1, heat (-ethanol)
Figure imgf000124_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) C1-C(0)-C1, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) C1-S(0)2C(R30 ) (R31 )S(0)2-C1, pyridine
Figure imgf000125_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) Cl-SiR19R20SiR19R20-Cl, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) Cl-S(O) 2C(R30 ) (R31 )S(0) 2-C1, pyridine
Figure imgf000126_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) Cl-SiR19R20SiR19R20-Cl, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) Cl-S(O) 2C(R30 ) (R31 )S(0)2-C1, pyridine
Figure imgf000127_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) C1-C(0)-C1, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) C1-S(0)2C(R30 ) (R31)S(0)2-C1, pyridine
Figure imgf000128_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) Cl-SiR19R20SiR19R20-Cl, pyridine
(c) C1-C(0)C(R30) (R31)C(0) -Cl, pyridine
(d) Cl-S(O) 2C(R30 ) (R31 )S(0) 2-Cl, pyridine
Figure imgf000129_0001
(b) Cl-SiR19R20SiR19R20-Cl, pyridine
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) Cl-S(O) 2C(R30 ) (R31 )S(0)2-C1, pyridine
Figure imgf000130_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) HCl, dioxane, then one equivalent water
(c) Cl-C(0)C(R3°) (R31)C(0)-C1, pyridine
Figure imgf000131_0001
(b) HCl, dioxane or trifluoroacetic acid
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
(d) R C(0)R , catalytic p-TsOH, toluene, azeotropic distillation.
Figure imgf000132_0001
(a) R30-PC12 where R30 is not OH, SH, or NH , pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) PCI 3 , pyridine
(d) R30-OH where R 30 is not OH or SH, pyridine
Figure imgf000133_0001
(a) R19R20SiCl2, pyridine
(b) Pd, H2, methylcyclohexane
(c) Cl-SiR19R20SiR19R20-Cl, pyridine
Figure imgf000134_0001
(b) HCl, dioxane or trifluoroacetic acid
(c) S(0)2C12 pyridine
Figure imgf000135_0001
(a) phosgene, pyridine
(b) HCl, dioxane or trifluoroacetic acid
(c) C(S)C12, pyridine
Figure imgf000136_0001
(a) Cl-CR19R20-O-CR19R20-Cl, pyridine
(b) Pd, H , methylcyclohexane
(c) Cl-SiR19R20-O-SiR19R20-Cl, pyridine
Figure imgf000137_0001
(a) C1-C(0)C(0)-C1, pyridine
(b) Pd, H2, ethanol
(c) C1-C(0)C(R30) (R31)C(0)-C1, pyridine
Figure imgf000138_0001
(a) C (0) Cl2 , pyridine
(b) Pd, H2, ethanol
(c) S(0)2C12, pyridine
Figure imgf000139_0001
(a) Benzyl chloroformate, Na2C03, THF, water
(b) C1-C(0)C(0)-C1, pyridine
(c) Pd, H2, ethanol
(d) C1-C(0)C(R30) (R31)C(0)-C1, 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 Na2SO4, 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 IN HCl, 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. ^C NMR spectra were obtained from a Varian spectrometer at 125.8 MHz.
Figure imgf000141_0001
(1)
Example 1
EX-la) Ethyl 6-(N-(l-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 MgSO and concentrated to afford ethyl 6-(4-(l,5,6,7-tetrahydro-3,6,6- trimethyl-5,7-dioxo-l,2,4-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-oxadiazepinyl))-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-(l,5,6,7-tetrahydro-3,6,6- trimethyl-5,7-dioxo- 1 ,2,4-oxadiazepinyl))-2-methyl-2-aminohexanoate hydrochloride.
Figure imgf000142_0001
(2)
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 MgSO4, and concentrated to afford ethyl 6-(3-(2-ethyl-l,2-dihydro-5-methyl- 1,2,3,5- oxaphosphadiazolyl))-2-(N-Boc-amino)hexanoate.
Ethyl 6-(3-(2-ethyl-l,2-dihydro-5-methyl-l,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-l,2-dihydro-5-methyl- l,2,3,5-oxaphosphadiazolyl))-2-aminohexanoate hydrochloride.
Figure imgf000143_0001
(3)
Example 3
EX-3a) Ethyl S-(2-(N-(l-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-(l,2- dihydro-2,2,4-trimethyl-l,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-(l,2-dihydro-2,2,4-trimethyl- 1,2,3,5- oxasiladiazolyl))ethyl)-4-thia-2-aminobutanoate.
Figure imgf000144_0001
(4)
Example 4
EX-4a) Ethyl 6-(N-(l-oxirninoethyl)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 MgSO4, and concentrated to afford ethyl 6-(5-(l,2,3,4-tetrahydro-3,3,6-trimethyl-
2,2,4 ,4-tetraoxo-l,2,4,5,7-oxadithiadiazepinyl))-2-(N-Boc-amino)hexanoate.
Ethyl 6-(5-(l,2,3,4-tetrahydro-3,3,6-trimethyl-2,2,4,4-tetraoxo-l,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- (l,2,3,4-tetrahydro-3,3,6-trimethyl-2,2,4,4-tetraoxo-l,2,4,5,7-oxadithiadiazepinyl))-2- aminohexanoate hydrochloride.
Figure imgf000145_0001
(5)
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)-
N-(methylsulfonyl)-6-(3-(4-methyl-2-oxo-l,2-dihydro-l,2,3,5-oxathiadiazolyl))-2-(N- B oc-amino)hexanamide .
N-(Methylthiomethyl)-N-(methylsulfonyl)-6-(3-(4-methyl-2-oxo-l,2-dihydro-l,2,3,5- oxathiadiazolyl))-2-(N-Boc-amino)hexanamide is deprotected by allowing it to stand in 2N HCl in dioxane at 25 °C for two hours. Concentrating in vacuo affords N- (methylthiomethyl)-N-(methylsulfonyl)-6-(3-(4-methyl-2-oxo-l,2-dihydro-l,2,3,5- oxathiadiazolyl))-2-aminohexanamide hydrochloride.
Figure imgf000146_0001
(6)
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 MgSO4, and concentrated to afford ethyl S-(2-(3-(2-ethyl-l,2-dihydro-4- methyl-2-oxo-l,2,3,5-oxaphosphadiazolyl))ethyl)-4-thia-2-(N-Boc-amino)butanoate.
Ethyl S-(2-(3-(2-ethyl-l,2-dihydro-4-methyl-2-oxo-l,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-l,2-dihydro-4-methyl-2-oxo- 1 ,2,3,5-oxaphosphadiazolyl))ethyl)-4-thia-2-aminobutanoate hydrochloride.
Figure imgf000147_0001
(7)
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- (5,7-dichloro-l,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl-l,5,7,2,4- oxadiphosphadiazepinyl))-2-(N-Boc-amino)hexanoate.
EX-7b) Ethyl 6-(4-(5,7-dichloro-l,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl-l,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 MgSO4, 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- 1 ,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl- 1 ,5,7,2,4-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.
Figure imgf000148_0001
(8)
Example 8
EX-8a) Ethyl 6-(N-(l-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-l,2,3,4-tetrahydro-6- methyl-2,4-dioxo-l, 3,2,4,5 ,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 MgSO4, 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-
1 ,2,3,4-tetrahydro-6-methyl-2,4-dioxo- 1 ,3,2,4,5,7-dioxadiphosphadiazepinyl))-2-(N-Boc- amino)hexanoate.
Ethyl 6-(5-(2,4-diethoxy-l,2,3,4-tetrahydro-6-methyl-2,4-dioxo-l,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.
Figure imgf000149_0001
(9)
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 MgSO4, and concentrated to afford 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.
N-Methylthio-N-(2-oxazolyl)-S-(2-(4-(3-fluoromethyl-l,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.
Figure imgf000150_0001
(10)
Example 10
EX-10a) N-Methyl-N-(2-pyrrolyl)-3-(5-(2-(N-(l- 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-l,l,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-(l,2,3,4-tetrahydro- 2,2,4 ,4,6-pentamethyl-l, 3,5 ,7,2,4-dioxadiazadisilapinyl)methyl)thiophenyl)-2-(N-pnZ- amino)propanamide .
N-methyl-N-(2-pyrrolyl)-3-(5-(2-(5-(l,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-(l,2,3,4- tetrahydro-2,2,4,4,6-pentamethyl-l,3,5,7,2,4-dioxadiazadisilapinyl)methyl)thiophenyl)-2- aminopropanamide .
Figure imgf000151_0001
(11)
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-(l,5-dihydro-3-fluoromethyl-6,7-dimethyl-5-oxo-l,2,4-oxadiazepinyl))-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 MgSO4, 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-oxadiazepinyl))-2- aminohex-4-enamide .
Figure imgf000152_0001
(12)
Example 12
EX- 12a) N-Ethoxy-N-ethyl-2-(N-Boc-amino)-2-methyl-O-(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 MgSO4, and concentrated to afford N-Ethoxy-N-ethyl-2-(N-Boc-amino)-2-methyl-O-(2-(l-(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-O-(2-(l-(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.
Figure imgf000153_0001
(13)
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 MgSO4, 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-l,l,5,5-tetraoxo-l,5,2,4- dithiadiazinyl)-5-cyclopropylspiro-N-methoxy-N-methyl-hexanamide. 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-l , 1 ,5,5-tetraoxo- 1 ,5,2,4-dithiadiazinyl)-5-cyclopropylspiro-N- methoxy-N-methyl-hexanamide hydrochloride.
Figure imgf000154_0001
(14)
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-l-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-(l-(4,6-Dichloro-2-fluoromethyl- 4,5,6-trihydro-5,5-dimethyl-4,6-dioxo-4,6-diphosphapyrimidinyl))-2-(N-Boc-amino)-5,5- dimethylhexanoate .
EX-14b) tert-Butyl 6-(l-(4,6-dichloro-2-fluoromethyl-4,5,6-trihydro-5,5-dimethyl-4,6- dioxo-4,6-diphosphapyrimidinyl))-2-(N-Boc-amino)-5,5-dimethylhexanoate 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 MgSO4, 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.
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 is deprotected by allowing it to stand in 2N HCl 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.
Figure imgf000155_0001
(15)
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-(l-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-oxadiphosphapyrimidinyl))-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 MgSO4, 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-l,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-l,2,6-trihydro-4-methyl-2,6-dioxo- l,2,6-oxadiphosphapyrimidinyl))-2-aminohex-4-enoic acid trifluoroacetate.
Figure imgf000156_0001
(16)
Example 16 l,3-Dichloro-l,l,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-l,2,6-trihydro-4-methyl- 1,2,6- oxadisilapyrimidinyl))-2-acetamido-2-methyl-hex-4-ynoate.
Figure imgf000157_0001
(17)
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-l,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 MgSO4, 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- methyl-4,7-dioxo-5 ,6-trimethylene- 1 ,3-diazepinyl))ethyl)-a-(N-Boc)-2-methyl-L- cysteinamide.
N-(5-tetrazolyl)-S-(2-(l-(4,5,6,7-tetrahydro-2-methyl-4,7-dioxo-5,6-trimethylene-l,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-(l-(4,5,6,7-tetrahydro-2-methyl-4,7-dioxo-5,6-trimethylene-l,3- diazepinyl))ethyl)-2-methyl-L-cysteinamide hydrochloride.
Figure imgf000158_0001
(18)
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 MgSO4, 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- methyl-4,7-dioxo-l,3-diazepinyl)ethyl)sulfonyl-2-(N-Boc-amino)butanoate. tert-Butyl 4-(2-(l-(5,6-benzo-4,7-dihydro-2-methyl-4,7-dioxo-l,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.
Figure imgf000159_0001
(19)
Example 19
EX-19a) tert-Butyl 6-(N-(2-fluoro-l-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 MgSO4, and concentrated in vacuum. The material is purified by passing it through a reverse phase chromatographic column to give tert-Butyl 6-(l-(2-fluoromethyl-4,7-dihydτo-5,6- imidazo-4,7-dioxo-l,3-diazepinyl))-2-(N-Boc-amino)-2-methyl-L-hexanoate. tert-Butyl 6-(l-(2-fluoromethyl-4,7-dihydro-5,6-imidazo-4,7-dioxo-l,3-diazepinyl))-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-l,3-diazepinyl))-2-(N-Boc-amino)-2-methyl-L- hexanoic acid dihydrochloride.
Figure imgf000160_0001
(20)
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 MgSO4, 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-(l, 5-dihydro-3-methyl-5-oxo-l,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- ( 1 ,5-dihydro-3-methyl-5-oxo- 1 ,2,4-oxadiazolyl))-2-(N,N-dimethylcarbamido)-2- methylthiomethyl-L-hexanoic acid.
Figure imgf000161_0001
(21)
Example 21
EX-21a) tert-Butyl 3-(5-(2-(N-(l-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-l,l-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 MgSO4, 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.
Figure imgf000162_0001
(22)
Example 22
EX-22a) Benzyl 6-(N-(l-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-l,l-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 MgSO4, and concentrated to afford Benzyl 6-(2- (1 ,5,6-trihydro-3-methyl- 1 , 1 ,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-l ,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-l,5-dithiapyrimidinyl))-2-(methoxycarbonylamido)-2-methylhexanoic acid.
Figure imgf000163_0001
(23)
Example 23
EX-23a) Benzyl 6-(N-(2-fluoro-l-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 MgSO4, and concentrated to afford benzyl 6-(4-(l,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-(l,5-dihydro-3- fluoromethyl-5-oxo- 1 ,2,4-oxadiazolyl))-2-benzamidohexanoic acid.
Figure imgf000164_0001
(24)
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-l,l-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 MgSO4, concentrated and purified by chromatography to afford 3-(4-(l-(4,5,6- trihydro-2-methyl-4,6-dioxo-5-cyclopentanespiropyrimidinyl)) butyl)morpholine- 2,5,dione.
Figure imgf000165_0001
(25)
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 MgSO4, concentrated, and purified by chromatography to afford 3-(4-(4-(l,5,6-trihydro-3-methyl-5,6-dioxo-l- oxapyrimidinyl))butyl)morpholine-2,5,dione.
Figure imgf000166_0001
(26)
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 MgSO4, 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.
N-(2,2-dimethoxycyclohexyl)-2-(N-Boc-amino)-3-methyl-6-(4-(l,5,6-trihydro-3-methyl- 5,6-dioxo-l-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-(l,5,6-trihydro-3-methyl-5,6-dioxo-l- oxapyrimidinyl)-l-methylbutyl))- 1,2,3,5,6,7, 8,9-octahydroquinoxaline-2-one hydrochloride.
Figure imgf000167_0001
(27)
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 MgSO4, concentrated, and purified by chromatography to afford tert-Butyl 6-(5-( 1 ,2,34-tetrahydro-6-methyl-2,3-dioxo- 1 ,4,5,7-dioxadiazepinyl))-2- (N-B oc-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-(l,2,34-tetrahydro-6-methyl- 2,3-dioxo- 1 ,4,5,7-dioxadiazepinyl))-2-aminohexanoic acid hydrochloride.
Figure imgf000168_0001
(28)
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-arnino)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-(l,2,3-trihydro-2-methoxy-5-methyl- l,3,2-dioxaphosphapyrimidinyl)-2-(N-Boc-amino)hexanoate.
tert-Butyl 6-(4-( 1 ,2,3-trihydro-2-methoxy-5-methyl- 1 ,3,2-dioxaphosphapyrimidinyl)-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-(l,2,3-trihydro-2-methoxy-5-methyl- 1,3,2- dioxaphosphapyrimidinyl)-2-aminohexanoic acid hydrochloride.
Figure imgf000169_0001
(29)
Example 29
Benzyl 6-(N-(l-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.
Figure imgf000170_0001
(30)
Example 30
EX-30a) tert-Butyl 6-(N-( l-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- (l,2,3-trihydro-5-methyl-2-oxo-l,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 HCl at 25°C for two hours. Concentrating in vacuo affords 6-(4-(l,2,3-trihydro-5- methyl-2-oxo- 1 ,3,2-dioxathiapyrimidinyl))-2-amino-2-methylthiomethylhexanoic acid hydrochloride.
Figure imgf000171_0001
(31)
Example 31
EX-31a) tert-Butyl 6-(N-( l-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-(l,2,3-trihydro-5-methyl-2-thiono-l,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 HCl at 25°C for two hours. Concentrating in vacuo affords 6-(4-(l,2,3-trihydro-5- methyl-2-thiono- 1 ,3-dioxapyrimidinyl))-2-amino-2-methylthiomethylhexanoic acid hydrochloride.
Figure imgf000172_0001
(32)
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, l,3-dichloro-l,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.
Figure imgf000173_0001
(33)
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 MgSO4, concentrated, and purified by column chromatography to afford N-(5-tetrazolyl)-N-(methoxy)-6-(4-(l,5,6-trihydro-3-methyl- 5,6-dioxo-l-oxapyri--ddinyl))-2-(N-tert-butoxymethyl-N-pnZ-aι no)-hexanamide.
N-(5-tetrazolyl)-N-(methoxy)-6-(4-(l,5,6-trihydro-3-methyl-5,6-dioxo-l- 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-l- oxapyriι dinyl))-2-(N-tert-butoxymethylamino)-hexanamide.
Figure imgf000174_0001
(34)
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 MgSO4, concentrated, and chromatographed to afford N-
(Methylthiomethyl)-N-(methylsulfonyl)-6-(4-( 1 ,5-dihydro-3-methyl-5-oxo- 1 ,2,4- oxadiazolyl))-2-(N-pnZ-amino)-hexanamide.
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-aminohexan amide.
Figure imgf000175_0001
(35)
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-(l-oximinoethyl)amino)-l-(2-(l,3- dioxolyl))-l-(N-Z)-pentanamine after chromatography and concentration.
EX-35b) 5-(N-( 1 -oximinoethyl)amino)- l-(2-(l ,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 MgSU4, concentrated, and chromatographed to afford 5-(4-(l,5,6-trihydro-3-methyl- 5,6-dioxo-l-oxapyrimidinyl))-l-(2-(l,3-dioxolyl))-l-(N-Z)-pentanamine.
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-(l,5,6-trihydro-3-methyl-5,6-dioxo-l- oxapyrimidinyl))-l-(2-(l,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- H]-arginine to
L-[2,3- H]-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--1H]-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 Assay
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 lh. 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 Assay
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.

Claims

We Claim:
1. The compound of Formula I
Figure imgf000178_0001
and pharmaceutically acceptable salts thereof, wherein:
J
Figure imgf000178_0002
, SR ,
24 24 25 26
NHR and N(R )R provided that A is R ;
1 2 J and J can be taken together to form a group selected from the group
28 28 28 28 24 28 24 consisting of OR O, OR S, SR S, OR NR and SR NR provided that A is
R26;
1 2
J and J can be taken together to form J, wherein J is connected to the carbon of
1 2
J and J by a covalent double bond and wherein J is independently selected from the
22 26 group consisting of O, NR and S provided that A is selected from other than R ; 15 15
G is selected from the group consisting of O, S, CH2, CHR , C(R )2, NH, and
15
NR
5 A is selected from the group consisting of O, N(R ), S and heterocyclyl with the proviso that J is selected from other than O and A is selected from other than O, S and heterocyclyl unless R is selected from other than the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl,
7 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, CH2OC(O)GR15, CH2OC(O)R15, CH2C(=O)OR15> CH2C(=O)NHR15>
CH2OC(=O)R1^' hydroxyalkyl, polyhydroxyalkyl, (poly)acyloxyalkyl and alkylC(O)R wherein G is selected from O, S, CH2, CHR15, C(R15)2, NH, and NR15 and R15 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
26 27 heterocyclic, aryl, and heteroaryl, or R is present, or R 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;
5 A can be selected from the group consisting of O, N(R ) and S connected to the
1 2 point of attachment of R or R by a spacer group selected from a linear moiety having a
2 chain length of 1 to 6 atoms to form a C5 to CIO heterocyclyl with the proviso that R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl,
15 8 cyanocycloalkyl, dicyanocycloalkyl and C(O)R , or R is selected from other than the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl,
26 cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or R is
27 present, or R 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;
5 A can be selected from the group consisting of O, N(R ) and S connected to the
1 2 points of attachment of R and R by a spacer group selected from a linear moiety having a chain length of 1 to 6 to form C5 to CIO 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 CIO heterocyclyl;
26 26
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; 27 27 5 7
A can be R , wherein R is selected from the group consisting of N(R )OR ,
N(R5)SR?, N(R5)N(R7)R25, N(R5)SO2R13, N(R5)C(O)R15, N(R5)C(S)R15,
19 20 5 19 20
R (R )C=N-N(R ), R (R )C=N-O, natural ammo acids, synthetic amino acids,
N(R5)P(O)(OR13)ιR6 and N(R5)P(O)(OR13)2;
1 2 R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl,
S(O)R13, SO R13, C(O)R15, CH2OC(O)R15, hydroxyl, sulfhydryl, OR6, SR6, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH2SO3" M+, CH2CH2SO3" M+, CH2PO3"2 2M+,
-2 + 6 30 31 30 31 15
CH2CH2PO3 2M , CH(OR )CF3, P(O)R R , P(O)(R )2 R , C(S)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH2SC(S)R15,
CH OC(O)GR15, CH NR19C(O)GR15, CH2NR19C(S)GR15, CH2OC(S)GR15,
CH SC(S)GR15, OSO R13, OS(O)R13, OC(S)R15, SC(S)R15, OC(S)GR15,
15 15 15 15 15 19 20
SC(S)GR , OC(O)R , SC(O)R , OC(O)GR , 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,
13 13 15 dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R , SO2R , C(O)R , and
15 13
CH2OC(O)R wherin R^5 and R are 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, and dihydropyridyl
22 l 2 unless J is selected from NR or S, or J and J are taken together to form a group
28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and
28 24 2 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,
15 ι ς cyanocycloalkyl, dicyanocycloalkyl and C(O)R wherein R1D 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
26 27 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-
8 membered ring, or being bicyclic or greater in ring number, or R is selected from other than the group selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl or
2 with the proviso that R 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 Rl5 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, 13 13 15 15 13
S(O)R , SO2R , C(O)R , and CH2OC(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, aralkyl, and dihydropyridyl, or J
22 l 2 is selected from NR or S, or J and I are taken together to form a group selected from
28 28 28 28 24 28 24 26 the group consisting of OR O, OR S, SR S, OR NR and SR NR , or R is
27 present, or A is R , 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 g greater in ring number, or R is selected from other than the group selected from hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
1 2
R and R can be taken together to form a substituent selected from the group
19 20 30 1 consisting of R (R )C=, D(C(R )(R ))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 ,
30 30 19 20
P(O)R , P(S)R and Si(R )R with the proviso that only one D can be oxygen or
19 20 19 20 sulfur at any time, D((R )R C)eW(C(R )R )kD wherein e is 1 to 2, k is 1 to 2, D is
selected from the group consisting of oxygen, C=O, C=S, S(O)m wherein m is 0 to 2,
31 30 30 30 19 20 OP(OR )R , P(O)R , P(S)R and Si(R )R 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,
30 30 19
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, cycloalkenyl radicals wherein said cycloalkyl radicals 30 31 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-
19 32 substitutents are independently selected from C=O, C=S, C(R )R , S(O), S(O)2,
31 30 30 30 19 20 OP(OR )R , P(O)R , P(S)R 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,
19 32 31 30 30 30 19 20
C(R )R , S(O), S(O)2, OP(OR )R , P(O)R , P(S)R , and Si(R )R and said
30 31 alkyl and alkenyl may be optionally substituted with one or more R or R substituents;
5 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,
6 6 haloalkenyl, halocycloalkyl, cyanocycloalkyl, dicyanocycloalkyl, OR , SR , amino, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl,
13 13 30 31 30 31 15 formylalkyl, acylalkyl, S(O)R , SO2R , P(O)R R , P(O)(R )2 R , C(O)R ,
C(S)R15, CH2OC(O)R15, CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15,
CH2SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15,
15 15 CH2OC(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,
5 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
22 1 2 from NR and S, or J and J are taken together to form a group selected from the group
28 28 28 28 24 28 24 26 consisting of OR O, OR S, SR S, OR NR and SR NR , or R is present, or
27 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
8 number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
5 1 2
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;
5 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 alkyl, hydroxy, amino, nitro, halo, cyano, haloalkyl, and
22 l 2 alkoxy unless J is selected from NR and S, or J and J are taken together to form a
28 28 28 28 24 group selected from the group consisting of OR O, OR S, SR S, OR NR and
28 24 26 27 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
8 being bicyclic or greater in ring number, or R 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, 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 R" is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, and dicyanocycloalkyl
22 1 2 unless J is selected from NR and S, or J and J are taken together to form a group
28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and
28 24 26 27
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
8 being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl;
7 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, 15 alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, CH2OC(O)GR ,
15 13 13 30 31 30 31 15 15
CH OC(O)R , S(O)R , SO2R , P(O)R R , P(O)(R )2 R , C(O)R , C(S)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH SC(S)R15,
19 15 19 15 15 15
CH2NR C(O)GR , CH2NR C(S)GR , CH2OC(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
7 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, CH2OC(O)GR and CH2OC(O)R where G is independently selected
from O, S, CH2, CHR15, C(R15)2, NH, and NR15 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
22 l 2 amino acid, a synthetic amino acid, unless J is selected from NR and S, or I and I are
28 28 taken together to form a group selected from the group consisting of OR O, OR S, 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 g larger than a 6-membered ring, or being bicyclic or greater in ring number, or R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl and cyanoalkyl;
7 1 2
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;
7 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
22 1 2
NR S, or J and I are taken together to form a group selected from the group
28 28 28 28 24 28 24 i 9 consisting of OR O, OR S, SR S, OR NR and SR NR , or J and J are
23 23 24 independently selected from the group consisting of OR , SR , NHR and
24 25 26 N(R )R when 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
8 bicyclic or greater in ring number, or provided that R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl,
5 heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl when A is N(R );
R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl,
7 cyanoalkyl, alkylaminoalkyl, alkylthioalkyl, sulfhydrylalkyl, formyl, C(O)A-R , C(S)A-
7 7 19 7 19 7 7
R , CH2OC(O)A-R , CH2NR C(O)A-R , CH2NR C(S)A-R , CH2SC(O)A-R ,
CH2SC(S)A-R7, CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15,
15 15 8
CH2OC(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
22 l 2
NR and S, or J and J are taken together to form a group selected from the group 28 28 28 28 24 28 24 26 consisting of OR O, OR S, SR S, OR NR and SR NR , or R is present, or
27 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 R is selected from other than hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl,
13 13 15 dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R , SO2R , C(O)R , and
15 13
CH2OC(O)R where 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;
13 R 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;
15 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
21 21 oxygen, C=O, S(O)t, Se(O)t wherein t is 0 to 2, P(O)R wherein R is selected from
12 12 hydroxyl and alkyl, and N(R )n where n is 1 to 2 and R is 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,
9 10 9 10 cycloalkoxy, alkylaminoalkyl, and NR R where R and R are independently selected from the group consisting of hydroxyamino, alkoxyamino, hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, alkoxy, alkylthio, alkylamino, hydroxy, thio, alkoxy, aryl,
9 10 heterocyclyl, and aralkyl with the proviso that only one of R and R 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 g heterocyclic, aralkyl, heterocyclylalkyl, alkylthioalkyl, and alkoxyalkyl, unless R is selected from other than hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl, and cyanoalkyl, or J
22 1 2 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
26 27
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,
13 13 cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl, S(O)R , SO2R ,
15 15 ι ς 13
C(O)R and CH2OC(O)R wherein Rι:> 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;
9 10
R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a C3 to C8 heterocyclyl;
19 20
R and R 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
19 20 diaralkoxyphosphonoalkyl with the proviso that only one of R and R is hydrogen; 19 20
R and R 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;
22 23
R and R 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;
24 25
R and R 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;
24 25 R and R 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 form C5 to C8 heterocyclyl; 28 23
R is independently selected from a group consisting of CH(R )CH2,
23 23
CH(R )CH2CH2, CH2CH(R )CH2, cycloalkylene, and heterocyclylene;
30 31
R and R 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;
30 31
R and R 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),
23 23 24
C(S), C(JH)2 wherein JJ-J is selected from the group consisting of OR , SR , NHR , 24 25 30 30 30 30 31 30 31 and N(R )R , S(O), SO2, PR , P(O)R , P(S)R , C(R )R , C=C(R )R ,
30 30 19 20 19 20 19 20
(O)2POP(O) , R (O)POP(O)R , Si(R )R , Si(R )R Si(R )R , and
19 20 19 20
Si(R )R OSi(R )R with the proviso that any one of L, U, and V must be selected
30 31 30 31 from other than O, S, C(O), C(S), S(O), SO2, C(R )R , and C=C(R )R wherein
30 31 R and R is independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, and dicyanocycloalkyl
22 1 2 unless J is selected from NR and S, or J and J are taken together to form a group
28 28 28 28 24 selected from the group consisting of OR O, OR S, SR S, OR NR and
28 24 26 27 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
8 being bicyclic or greater in ring number, or R 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,
13 13 15 15 13
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;
30 31 L, U, and V can be selected from the group consisting of DC(R )(R )D
wherein D is selected from the group consisting of oxygen, C=O, C=S, S(O)m where m is 31 30 30 30 19 20 30
0 to 2, OP(OR )R , P(O)R , P(S)R , Si(R )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 ),
30 31 30 31 30 31 30 30 31
C(S)C(R )=C(R ), S(O)C(R )=C(R ), SO2C(R )=C(R ), PR C(R )=C(R ),
30 30 31 30 30 31
P(O)R C(R )=C(R ), P(S)R C(R )=C(R ), 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
30 31 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
19 32 31 30 30 30 selected from C=O, C=S, C(R )R , S(O), S(O) , 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),
31 30 30 30 19 20 S(O)2, OP(OR )R , P(O)R , P(S)R , and Si(R )R and said alkyl and alkenyl
30 31 may be optionally substituted with one or more R or R substituents;
32 R 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.
2. A compound of Formula II
Figure imgf000199_0001
π
and pharmaceutically acceptable salts thereof, wherein:
22 J is selected from the group consisting of O, NR and S;
A is selected from the group consisting of O, N(R ), S and heterocyclyl;
5 A can be selected from the group consisting of O, N(R ) and S connected to the
1 2 point of attachment of R or R by a spacer group selected from a linear moiety having a chain length of 1 to 6 atoms to form a C5 to CIO heterocyclyl
5 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 CIO heterocyclyl; 5 7 5 7
A can be is selected from the group consisting of N(R )OR , N(R )SR ,
5 7 25 5 13 5 15 5 15 19 20 5
N(R )N(R )R , N(R )SO R , N(R )C(O)R , N(R )C(S)R , R (R )C=N-N(R ),
R (R )C=N-O, natural amino acids, synthetic amino acids, N(R )P(O)(OR )ιR and
N(R5)P(O)(OR13)2;
1 2 R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, haloalkyl, haloalkenyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl, dicyanocycloalkyl,
S(O)R13, SO2R13, C(O)R15, CH2OC(O)R15, hydroxyl, sulfhydryl, OR6, SR6, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH2SO3" M+, CH2CH2SO3" M+, CH2PO3"2 2M+,
CH2CH2PO3 "2 2M+, CH(OR6)CF3, P(O)R3°R31, P(O)(R3°)2
Figure imgf000200_0001
C(S)R15,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH SC(S)R15,
CH2OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15, CH2OC(S)GR15,
CH2SC(S)GR15, OSO2R13, OS(O)R13, OC(S)R15, SC(S)R15, OC(S)GR15,
SC(S)GR15, OC(O)R15, SC(O)R15, OC(O)GR15, SC(O)GR15, and R19(R2°)CH
1 2
R and R can be taken together to form a substituent selected from the group
19 20 30 31 consisting of R (R )C=, D(C(R )(R ))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 ,
30 30 19 20
P(O)R , P(S)R and Si(R )R ; 5 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,
13 13 30 31 30 31 15 formylalkyl, acylalkyl, S(O)R , SO2R , P(O)R R , P(O)(R )2 R , C(O)R ,
C(S)R15, CH OC(O)R15, CH NR19C(O)R15, CH NR19C(S)R15, CH SC(O)R15,
CH2SC(S)R15, CH2OC(O)GR15, CH2NR19C(O)GR15, CH NR19C(S)GR15,
CH2OC(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;
5 1 2 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;
5 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;
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;
7 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 ,
15 13 13 30 31 30 31 15 15
CH OC(O)R , S(O)R , SO2R , P(O)R R , P(O)(R ) R , C(O)R , C(S)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH SC(O)R15, CH2SC(S)R15,
CH2NR19C(O)GR15, CH2NR19C(S)GR15, CH2OC(S)GR15, CH2SC(S)GR15, 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;
7 1 2
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; 7 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;
8 R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, heterocyclyl, aryl, heterocyclylalkyl, aralkyl,
7 cyanoalkyl, alkylaminoalkyl, alkylthioalkyl, sulfhydrylalkyl, formyl, C(O)A-R , C(S)A- R7, CH2OC(O)A-R7, CH2NR19C(O)A-R?, CH2NR19C(S)A-R?, CH2SC(O)A-R7,
7 15 19 15 19 15
CH2SC(S)A-R , CH2OC(O)GR , CH2NR C(O)GR , CH2NR C(S)GR ,
CH2OC(S)GR15, CH SC(S)GR15, and acyl;
13 R is 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;
15 R is 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;
X can be -(CH2)nQ(CH2)r- wherein p is 1 to 3, r is 1 to 3 and Q is selected from
21 the group consisting of oxygen, C=O, S(O)t, and Se(O)t wherein t is 0 to 2, P(O)R
21 12 wherein R is selected from hydroxyl and alkyl, and N(R )n wherein n is 1 to 2 and
12 R is 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, 9 10 9 10 cycloalkoxy, alkylaminoalkyl, and NR R wherein R and R are independently selected from the group consisting of hydroxyamino, alkoxyamino, hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, alkoxy, alkylthio, alkylamino, hydroxy, thio, alkoxy, aryl, heterocyclyl, and aralkyl;
9 Λ 10 R and R can be taken together to form a spacer group selected from a linear moiety having a chain length of 2 to 7 atoms to form a C3 to C8 heterocyclyl;
19 20
R and R 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 ;
19 20
R and R 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; 23 R is 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;
24 25
R and R 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;
24 25
R and R 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 form C5 to C8 heterocyclyl;
30 31
R and R 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;
30 31
R and R 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),
23 23 24 C(S), C(JH)2 wherein JH is selected from the group consisting of OR , SR , NHR ,
24 25 30 30 30 30 31 30 31 and N(R )R , S(O), SO2, PR , P(O)R , P(S)R , C(R )R , C=C(R )R ,
30 30 19 20 19 20 19 20
(O) POP(O)2, R (O)POP(O)R , Si(R )R , Si(R )R Si(R )R , and
19 20 19 20
Si(R )R OSi(R )R with the proviso that the 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; L, U, and V can be independently selected from the group consisting of
30 31 DC(R )(R )D wherein D is selected from the group consisting of oxygen, C=O, C=S,
31 30 30 30 19 20 30
S(O)m where m is 0 to 2, OP(OR )R , P(O)R , P(S)R , Si(R )R , and N(R ),
(R19,R20COC(R19)R20 (R19)R2°CSC(R19)R20 C(0)C(R3°)=C(R31),
30 31 30 31 30 31 30 30 31 C(S)C(R )=C(R ), S(O)C(R )=C(R ), SO2C(R )=C(R ), PR C(R )=C(R ),
30 30 31 30 30 31
P(O)R C(R )=C(R ), P(S)R C(R )=C(R ), 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 independently selected from the group consisting of cycloalkyl radicals, cycloalkenyl radicals wherein said cycloalkyl radicals and cycloalkenyl radicals
30 31 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
19 32 31 30 independently selected from C=O, C=S, C(R )R , S(O), S(O)2, OP(OR )R ,
30 30 19 20 P(O)R , P(S)R and Si(R )R , cis- 1, 2-disubstituted alkanes and cis- 1,2- disubstituted alkenes wherein said 1,2-substitutents are independently selected from
19 32 31 30 30 30
C=O, C=S, C(R )R , S(O), S(O)2, OP(OR )R , P(O)R , P(S)R , and
19 20 Si(R )R and said alkyl and alkenyl may be optionally substituted with one or more
R or R substituents;
32 R 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.
3. The compound as recited in claim 2 and pharmaceutically acceptable salts, wherein:
22 J is selected from the group consisting of O, NR and S;
5 A is selected from the group consisting of O, N(R ), S and heterocyclyl;
5 7 5 7
A can be is selected from the group consisting of N(R )OR , N(R )SR ,
5 7 25 5 13 5 15 5 15 19 20 5
N(R )N(R )R , N(R )SO2R , N(R )C(O)R , N(R )C(S)R , R (R )C=N-N(R ),
R (R )C=N-O, natural amino acids, synthetic amino acids, N(R )P(O)(OR )]R and
N(R5)P(O)(OR13)2;
1 2
R and R are independently selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, cyanoalkyl, dicyanoalkyl, cyanocycloalkyl,
13 13 15 15 dicyanocycloalkyl, S(O)R , SO2R , C(O)R , CH2OC(O)R , hydroxyl, sulfhydryl,
OR , SR , carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl, acylalkyl, CH SO3 " M+, CH2CH2SO3" M+, CH PO3 "2 2M+,
.2 + 6 30 31 30 31 15
CH2CH2PO3 2M , CH(OR )CF , P(O)R R , P(O)(R )2 R , C(S)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH2SC(S)R15,
CH2OC(O)GR15, CH2NR1 C(O)GR , CH2NR1 C(S)GR , CH2OC(S)GR , CH2SC(S)GR15, OSO2R13, OS(O)R13, OC(S)R15, SC(S)R15, OC(S)GR15,
SC(S)GR15, OC(O)R15, SC(O)R15, OC(O)GR15, SC(O)GR15, and R19(R2°)CH
1 2
R and R can be taken together to form a substituent selected from the group
19 20 30 31 consisting of R (R )C=, D(C(R )(R ))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 ,
30 30 19 20
P(O)R , P(S)R and Si(R )R ;
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,
6 6 haloalkenyl, halocycloalkyl, cyanocycloalkyl, dicyanocycloalkyl, OR , SR , amino, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl,
13 13 30 31 30 31 15 formylalkyl, acylalkyl, S(O)R , SO2R , P(O)R R , P(O)(R )2 R , C(O)R ,
C(S)R15, CH2OC(O)R15, CH2NR19C(O)R15, CH2NR19C(S)R15, CH SC(O)R15,
CH2SC(S)R15, CH OC(O)GR15, CH2NR19C(O)GR15, CH2NR19C(S)GR15,
CH2OC(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;
5 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;
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;
7 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,
15 alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, CH2OC(O)GR ,
15 13 13 30 31 30 31 15 15
CH2OC(O)R , S(O)R , SO R , P(O)R R , P(O)(R )2 R , C(O)R , C(S)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH2SC(S)R15,
19 15 19 15 15 15
CH2NR C(O)GR , CH2NR C(S)GR , CH2OC(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;
7 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; o
R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, alkylthioalkyl, sulfhydrylalkyl;
13 R is 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 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;
X can be -(CH2)nQ(CH2)r- wherein p is 1 to 3, r is 1 to 3 and Q is selected from
21 the group consisting of oxygen, C=O, S(O)t, and Se(O)t wherein t is 0 to 2, P(O)R
21 12 wherein R is selected from hydroxyl and alkyl, and N(R )n wherein n is 1 to 2 and
12 R is 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, heterocyclylalkyl, alkylthioalkyl, alkoxyalkyl, alkenyloxyalkyl, cycloalkenyloxy, 9 10 9 10 cycloalkoxy, alkylaminoalkyl, and NR R wherein R and R are independently selected from the group consisting of hydroxyamino, alkoxyamino, hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, alkoxy, alkylthio, alkylamino, hydroxy, thio, alkoxy, aryl, heterocyclyl, and aralkyl;
19 20 R and R 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 ;
23 R is 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;
24 25
R and R 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;
30 31 R and R 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;
L, U, and V are independently selected from the group consisting of O, S, C(O),
23 23 24
C(S), C(JH)2 wherein JH is selected from the group consisting of OR , SR , NHR ,
24 25 30 30 30 30 31 30 31 and N(R )R , S(O), SO2, PR , P(O)R , P(S)R , C(R )R , C=C(R )R ,
30 30 19 20 19 20 19 20
(O)2POP(O)2, R (O)POP(O)R , Si(R )R , Si(R )R Si(R )R , and
19 20 19 20
Si(R )R OSi(R )R with the proviso that the 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;
L, U, and V can be independently selected from the group consisting of
30 31 DC(R )(R )D wherein D is selected from the group consisting of oxygen, C=O, C=S,
31 30 30 30 19 20 30
S(O)m where m is 0 to 2, OP(OR )R , P(O)R , P(S)R , Si(R )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 ),
30 31 30 31 30 31 30 30 31
C(S)C(R )=C(R ), S(O)C(R )=C(R ), SO2C(R )=C(R ), PR C(R )=C(R ),
30 30 31 30 30 31
P(O)R C(R )=C(R ), P(S)R C(R )=C(R ), 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.
4. The compound as recited in Claim 3 and pharmaceutically acceptable salts, wherein: J is selected from the group consisting of O and S;
5 A is selected from the group consisting of O, N(R ), S and heterocyclyl;
5 7 5 7
A can be is selected from the group consisting of N(R )OR , N(R )SR ,
N(R5)N(R?)R25, N(R5)SO2R13, N(R5)C(O)R15, N(R5)C(S)R15, natural amino acids,
synthetic amino acids, N(R )P(O)(OR )]R and N(R )P(O)(OR )2;
1 2
R and R are independently selected from the group consisting of hydrogen,
hydroxyalkyl, aminoalkyl, alkyl, C(O)R , CH2OC(O)R , hydroxyl, sulfhydryl, OR ,
SR
Figure imgf000221_0001
,
OC(O)R15, SC(O)R15, OC(O)GR15, SC(O)GR15;
5 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,
6 6 haloalkenyl, halocycloalkyl, cyanocycloalkyl, dicyanocycloalkyl, OR , SR , ammo, carboxamidoalkyl, dicarboxamidoalkyl, cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl, carboalkoxycycloalkyl, dicarboalkoxycycloalkyl,
13 13 30 31 30 31 15 formylalkyl, acylalkyl, S(O)R , SO2R , P(O)R R , P(O)(R )2 R , C(O)R ,
C(S)R15, CH2OC(O)R15, CH2NR19C(O)R15, CH2NR19C(S)R15, CH SC(O)R15,
15 15 19 15 19 15
CH SC(S)R , CH2OC(O)GR , CH2NR C(O)GR , CH NR C(S)GR ,
CH2OC(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;
5 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;
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;
7 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 ,
15 13 13 30 31 30 31 15 15
CH2OC(O)R , S(O)R , SO2R , P(O)R R , P(O)(R )2 R , C(O)R , C(S)R ,
19 15 19 15 15 15 CH NR C(O)R , CH2NR C(S)R , CH2SC(O)R , CH SC(S)R ,
CH2NR19C(O)GR15, CH2NR19C(S)GR15, CH2OC(S)GR15, CH2SC(S)GR15, 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;
7 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;
8 R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl, alkoxyalkyl, aminoalkyl, sulfhydrylalkyl;
13 R is 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;
15 R is 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;
X can be -(CH2)pQ(CH2)r- wherein p is 1 to 3, r is 1 to 3 and Q is selected from
the group consisting of oxygen, C=O, S(O)t, and Se(O)t wherein t is 0 to 2;
X can be -(CH2)sT(CH2)γ- 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, alkylthio, haloalkyl, alkylthioalkyl, alkoxyalkyl, alkylaminoalkyl, and
9 10 9 10 NR R wherein R and R are independently selected from the group consisting of hydroxyamino, alkoxyamino, hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, alkoxy, alkylthio, alkylamino, hydroxy, thio, alkoxy, aryl, heterocyclyl, and aralkyl;
19 R is 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;
30 31 R and R 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;
L, U, and V are independently selected from the group consisting of O, S, C(O),
C(S), with the proviso that the 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.
5. The compound as recited in Claim 4 and pharmaceutically acceptable salts, wherein:
J is selected from the group consisting of O and S;
5 A is selected from the group consisting of O, N(R ), S and heterocyclyl;
1 2
R and R are independently selected from the group consisting of hydrogen,
15 15 6 hydroxyalkyl, aminoalkyl, alkyl, C(O)R , CH2OC(O)R , hydroxyl, sulfhydryl, OR ,
6 13 13 15 15 15 15
SR , OSO2R , OS(O)R , OC(S)R , SC(S)R , OC(S)GR , SC(S)GR ,
OC(O)R15, SC(O)R15, OC(O)GR15, SC(O)GR15;
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,
13 13 30 31 30 31 15 formylalkyl, acylalkyl, S(O)R , SO2R , P(O)R R , P(O)(R )2 R , C(O)R ,
15 15 19 15 19 15 15
C(S)R , CH2OC(O)R , CH2NR C(O)R , CH2NR C(S)R , CH2SC(O)R ,
CH2SC(S)R15, CH2OC(O)GR15, CH NR19C(O)GR15, CH2NR19C(S)GR15,
15 15
CH2OC(S)GR , CH2SC(S)GR , alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl, sulfonylalkyl, alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkylamino, aralkoxysulfonylalkylamino, and sulfonylalkylamino ;
5 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, guanidino, amidino, and acylamino;
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;
7 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,
15 alkoxyalkyl, hydroxyalkyl, haloalkyl, haloalkenyl, halocycloalkyl, CH2OC(O)GR ,
15 13 13 30 31 30 31 15 15
CH2OC(O)R , S(O)R , SO2R , P(O)R R , P(O)(R )2 R , C(O)R , C(S)R ,
CH2NR19C(O)R15, CH2NR19C(S)R15, CH2SC(O)R15, CH2SC(S)R15,
CH NR19C(O)GR15, CH NR19C(S)GR15, CH2OC(S)GR15, CH2SC(S)GR15, amino, hydroxy, carboxamidocycloalkyl, dicarboxamidocycloalkyl, carboxamidoalkyl, dicarboxamidoalkyl, heteroaryloxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxyalkyl, carboalkoxyalkyl;
7 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, guanidino, amidino, and acylamino;
R is selected from the group consisting of hydrogen, hydroxyalkyl, haloalkyl, alkyl; 13 R is 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;
15 R is 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;
M is a pharmaceutically acceptable cation;
X is selected from the group consisting of alkylene, alkenylene, and alkynylene; X can be -(CH2)pQ(CH2)r- wherein p is 1 to 3, r is 1 to 3 and Q is selected from
the group consisting of oxygen, S(O)t, wherein t is 0 to 2;
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 and a heterocyclyl radical;
9 10 Y is selected from the group consisting of alkyl, alkylthio, haloalkyl, and NR R
9 10 wherein R and R are independently selected from the group consisting of hydroxyamino, alkoxyamino, hydrogen, alkyl, alkenyl, alkynyl, nitro, amino, alkoxy, alkylthio, alkylamino, hydroxy, thio, alkoxy, aryl, heterocyclyl, and aralkyl;
19 R is 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; 30 31
R and R 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;
L, U, and V are independently selected from the group consisting of O, S, C(O), C(S), with the proviso that the 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.
6. The compound as recited in Claim 5 and pharmaceutically acceptable salts, wherein:
J is selected from the group consisting of O;
A is selected from the group consisting of O, N(R ) and S;
1 2
R and R are independently selected from the group consisting of hydrogen,
hydroxyalkyl, hydroxyl, sulfhydryl, OR , SR ; 5 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, OR ,
6 SR , and amino;
5 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, guanidino, amidino, and acylamino;
R is selected from the group consisting of hydrogen, hydroxyalkyl, aminoalkyl, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, and haloalkyl; 7 R is selected from the group consisting of hydrogen, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, and hydroxy;
7 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, guanidino, amidino, and acylamino;
R is selected from the group consisting of hydrogen, hydroxyalkyl, alkyl;
M is a pharmaceutically acceptable cation;
X is selected from the group consisting of alkylene, alkenylene, and alkynylene;
X can be -(CH2)pQ(CH2)r- wherein p is 1 to 3, r is 1 to 3 and Q is selected from
the group consisting of oxygen, S(O)t, wherein t is 0 to 2;
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 and a heterocyclyl radical;
Y is selected from the group consisting of alkyl, alkylthio, and haloalkyl;
L, U, and V are independently selected from the group consisting of O, S, C(O),
C(S), with the proviso that the 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.
7. A compound as recited in Claim 4 wherein:
R is 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.
8. The compound and pharmaceutically acceptable salts of Claim 2 wherein the compound is selected from the group consisting of ethyl 6-(4-(l,5,6,7-tetrahydro-3,6,6- trimethyl-5,7-dioxo-l,2,4-oxadiazepinyl))-2-methyl-2-(N-t-butoxycarbonyl- amino)hexanoate, ethyl 6-(4-( 1 ,5,6,7-tetrahydro-3,6,6-trimethyl-5,7-dioxo- 1 ,2,4- oxadiazepinyl))-2-methyl-2-aminohexanoate, ethyl 6-(3-(2-ethyl- 1 ,2-dihydro-5-methyl- l,2,3,5-oxaphosphadiazolyl))-2-(N-t-butoxycarbonyl-amino)hexanoate, ethyl 6-(3-(2- ethyl- 1 ,2-dihydro-5-methyl- 1 ,2,3,5-oxaphosphadiazolyl))-2-aminohexanoate, ethyl S-(2- (3-( 1 ,2-dihydro-2,2,4-trimethyl- 1 ,2,3 ,5-oxasiladiazolyl))ethyl)-4-thia-2-(N- benzyloxycarbonyl-amino)butanoate, ethyl S-(2-(3-(l,2-dihydro-2,2,4-trimethyl-l,2,3,5- oxasiladiazolyl))ethyl)-4-thia-2-aminobutanoate, ethyl 6-(5-( 1 ,2,3,4-tetrahydro-3,3,6- trimethyl-2,2,4,4-tetraoxo-l,2,4,5,7-oxadithiadiazepinyl))-2-(N-t-butoxycarbonyl- 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-aminohexanoate, N-(methylthiomethyl)-N- (methylsulfonyl)-6-(3-(4-methyl-2-oxo- 1 ,2-dihydro- 1 ,2,3,5-oxathiadiazolyl))-2-(N-t- butoxycarbonyl-amino)hexanamide, N-(methylthiomethyl)-N-(methylsulfonyl)-6-(3-(4- methyl-2-oxo- 1 ,2-dihydro- 1 ,2,3,5-oxathiadiazolyl))-2-aminohexanamide, ethyl S-(2-(3- (2-ethyl- 1 ,2-dihydro-4-methyl-2-oxo- 1 ,2,3,5-oxaphosphadiazolyl))ethyl)-4-thia-2-(N-t- butoxycarbonyl-amino)butanoate, ethyl S-(2-(3-(2-ethyl- 1 ,2-dihydro-4-methyl-2-oxo- 1 ,2,3,5-oxaphosphadiazolyl))ethyl)-4-thia-2-aminobutanoate, 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-t- butoxycarbonyl-amino)hexanoate, ethyl 6-(4-(5,7-diethoxy- 1 ,5,6,7-tetrahydro-5,7-dioxo- 3,6,6-trimethyl-l,5,7,2,4-oxadiphosphadiazepinyl))-2-(N-t-butoxycarbonyl- amino)hexanoate, ethyl 6-(4-(5,7-diethoxy- 1 ,5,6,7-tetrahydro-5,7-dioxo-3,6,6-trimethyl- l,5,7,2,4-oxadiphosphadiazepinyl))-2-aminohexanoate, 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-t- butoxycarbonyl-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-t-butoxycarbonyl- amino)hexanoate, ethyl 6-(5-(2,4-diethoxy- 1 ,2,3,4-tetrahydro-6-methyl-2,4-dioxo- l,3,2,4,5,7-dioxadiphosphadiazepinyl))-2-aminohexanoate, N-methylthio-N-(2-oxazolyl)- S-(2-(4-(3-fluoromethyl-l,5-dihydro-5-oxo-l,2,4-oxadiazolyl))ethyl)-2-(N-t- butoxycarbonyl-amino)-4-thiabutanamide, N-Methylthio-N-(2-oxazolyl)-S-(2-(4-(3- fluoromethyl- 1 ,5-dihydro-5-oxo- 1 ,2,4-oxadiazolyl))ethyl)-2-amino-4-thiabutanamide, N- methyl-N-(2-pyrrolyl)-3-(5-(2-(5-(l,2,3,4-tetrahydro-2,2,4,4,6-pentamethyl- 1,3,5,7,2,4- dioxadiazadisilapinyl)methyl)thiophenyl)-2-(N-paranitrobenzyloxycarbonyl- amino)propanamide, N-methyl-N-(2-pyrrolyl)-3-(5-(2-(5-( 1 ,2,3,4-tetrahydro-2,2,4,4,6- pentamethyl-l,3,5,7,2,4-dioxadiazadisilapinyl)methyl)thiophenyl)-2-aminopropanamide, N-(5-tetrazolyl)-6-(4-( 1 ,5-dihydro-3-fluoromethyl-6,7-dimethyl-5-oxo- 1 ,2,4- oxadiazepinyl))-2-(N-2,2,2-trichloroethoxycarbonyl-amino)hex-4-enamide, N-(5- tetrazolyl)-6-(4-( 1 ,5-dihydro-3-fluoromethyl-6,7-dimethyl-5-oxo- 1 ,2,4-oxadiazepinyl))-2- aminohex-4-enamide, N-Ethoxy-N-ethyl-2-(N-t-butoxycarbonyl-amino)-2-methyl-O-(2- (l-(2-fluoromethyl-4,5,6-trihydro-5,5-dimethyl-4,6-dioxopyrimidinyl))ethyl)-4- oxybutanamide, N-Ethoxy-N-ethyl-2-amino-2-methyl-O-(2-( 1 -(2-fluoromethyl-4,5,6- trihydro-5,5-dimethyl-4,6-dioxopyrimidinyl))ethyl)-4-oxybutanamide, 2-(N-t- butoxycarbonyl-amino)-6-(2-(3,6,6-trimethyl- 1 , 1 ,5,5-tetraoxo- 1 ,5,2,4-dithiadiazinyl)-5- cyclopropylspiro-N-methoxy-N-methyl-hexanamide, 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, tert-butyl 6-(l-(4,6-Dichloro-2-fluoromethyl-4,5,6-trihydro-5,5-dimethyl- 4,6-dioxo-4,6-diphosphapyrimidinyl))-2-(N-t-butoxycarbonyl-amino)-5,5- dimethylhexanoate, tert-Butyl 6-(l-(4,6-diethoxy-2-fluoromethyl-4,5,6-trihydro-5,5- dimethyl-4,6-dioxo-4,6-diphosphapyrimidinyl))-2-(N-t-butoxycarbonyl-amino)-5,5- dimethylhexanoate, 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 acid, tert-butyl 6-(3- (2,6-dichloro- 1 ,2,6-trihydro-4-methyl-2,6-dioxo- 1 ,2,6-oxadiphosphapyrimidinyl))-2-(N-t- butoxycarbonyl-amino)hex-4-enoate, tert-butyl 6-(3-(2,6-diethoxy- 1 ,2,6-trihydro-4- methyl-2,6-dioxo-l,2,6-oxadiphosphapyrimidinyl))-2-(N-t-butoxycarbonyl-amino)hex-4- enoate, 6-(3-(2,6-diethoxy- 1 ,2,6-trihydro-4-methyl-2,6-dioxo- 1 ,2,6- oxadiphosphapyrimidinyl))-2-aminohex-4-enoic acid, ethyl 6-(3-(2,2,6,6-tetraethyl-l,2,6- trihydro-4-methyl- 1 ,2,6-oxadisilapyrimidinyl))-2-acetamido-2-methyl-hex-4-ynoate, N-
(5-tetrazolyl)-S-(2-(l-(4,5,6,7-tetrahydro-2-methyl-4,7-dioxo-5,6-trimethylene-l,3- diazepinyl))ethyl)-a-(N-t-butoxycarbonyl)-2-methyl-L-cysteinamide, N-(5-tetrazolyl)-S- (2-(l -(4,5,6,7 -tetrahydro-2-methyl-4,7-dioxo-5,6-trimethylene-l,3-diazepinyl))ethyl)-2- methyl-L-cysteinamide, tert-Butyl 4-(2-( 1 -(5,6-benzo-4,7-dihydro-2-methyl-4,7-dioxo- l,3-diazepinyl)ethyl)sulfonyl-2-(N-t-butoxycarbonyl-amino)butanoate, 4-(2-(l-(5,6- benzo-4,7-dihydro-2-methyl-4,7-dioxo-l,3-diazepinyl)ethyl)sulfonyl-2-aminobutanoic acid, tert-Butyl 6-(l-(2-fluoromethyl-4,7-dihydro-5,6-imidazo-4,7-dioxo- 1 ,3- diazepinyl))-2-(N-t-butoxycarbonyl-amino)-2-methyl-L-hexanoate, 6-(l-(2-fluoromethyl- 4,7-dihydro-5,6-imidazo-4,7-dioxo-l,3-diazepinyl))-2-(N-t-butoxycarbonyl-amino)-2- methyl-L-hexanoic acid, tert-Butyl 6-(4-(l,5-dihydro-3-methyl-5-oxo- 1,2,4- oxadiazolyl))-2-(N,N-dimethylcarbamido)-2-methylthiomethyl-L-hexanoate, 6-(4-( 1 ,5- dihydro-3-methyl-5-oxo-l,2,4-oxadiazolyl))-2-(N,N-dimethylcarbamido)-2- methylthiomethyl-L-hexanoic acid, 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, 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, Benzyl 6-(2-(l,5,6-trihydro-3-methyl- 1 , 1 ,5,5-tetraoxo-6-cyclopentanespiro- 1 ,5-dithiapyrimidinyl))-2-(methoxycarbonylamido)- 2-methylhexanoate, 6-(2-( 1 ,5,6-trihydro-3-methyl- 1 , 1 ,5,5-tetraoxo-6-cyclopentanespiro- l,5-dithiapyrimidinyl))-2-(methoxycarbonylamido)-2-methylhexanoic acid, benzyl 6-(4- (1 ,5-dihydro-3-fluoromethyl-5-oxo- 1 ,2,4-oxadiazolyl))-2-benzamidohexanoate, 6-(4-
( 1 ,5-dihydro-3-fluoromethyl-5-oxo- 1 ,2,4-oxadiazolyl))-2-benzamidohexanoic acid, 3-(4- (l-(4,5,6-trihydro-2-methyl-4,6-dioxo-5-cyclopentanespiropyrimidinyl)) butyl)mo holine-2,5,dione, 3-(4-(4-(l,5,6-trihydro-3-methyl-5,6-dioxo-l- oxapyrimidinyl))butyl)morpholine-2,5,dione, N-(2,2-dimethoxycyclohexyl)-2-(N-t- butoxycarbonyl-amino)-3-methyl-6-(4-(l,5,6-trihydro-3-methyl-5,6-dioxo-l- oxapyrimidinyl))hexanamide, 3-(4-(4-( 1 ,5 ,6-trihydro-3-methyl-5 ,6-dioxo- 1 - oxapyrimidinyl)-l-methylbutyl))-l,2,3,5,6,7,8,9-octahydroquinoxaline-2-one, tert-Butyl 6-(5-(l,2,34-tetrahydro-6-methyl-2,3-dioxo-l,4,5,7-dioxadiazepinyl))-2-(N-t- butoxycarbonyl-amino)hexanoate, 6-(5-( 1 ,2,34-tetrahydro-6-methyl-2,3-dioxo- 1 ,4,5,7- dioxadiazepinyl))-2-aminohexanoic acid, tert-Butyl 6-(4-(l,2,3-trihydro-2-methoxy-5- methyl- 1 ,3,2-dioxaphosphapyrimidinyl)-2-(N-t-butoxycarbonyl-amino)hexanoate, 6-(4- ( 1 ,2,3-trihydro-2-methoxy-5-methyl- 1 ,3,2-dioxaphosphapyrimidinyl)-2-aminohexanoic acid, Benzyl 6-(4-(5-methyl-2-cyclosilolanespiro- 1 ,3,2-dioxasilapyrimidinyl))-2-(N- benzyloxycarbonyl-amino)hexanoate, tert-Butyl 6-(4-( 1 ,2,3-trihydro-5-methyl-2-oxo- l,3,2-dioxathiapyrimidinyl))-2-(N-t-butoxycarbonyl-amino)-2- methylthiomethylhexanoate, 6-(4-(l,2,3-trihydro-5-methyl-2-oxo-l,3,2- dioxathiapyrimidinyl))-2-amino-2-methylthiomethylhexanoic acid, tert-Butyl 6-(4-( 1,2,3- trihydro-5-methyl-2-thiono-l,3-dioxapyrimidinyl))-2-(N-t-butoxycarbonyl-amino)-2- methylthiomethylhexanoate, 6-(4-( 1 ,2,3-trihydro-5-methyl-2-thiono- 1,3- dioxapyrimidinyl))-2-amino-2-methylthiomethylhexanoic acid, benzyl 6-(6-(2,4- dicyclosilolanespiro-l,2,3,4,5-pentahydro-7-methyl-l,3,5,2,4,6,8-trioxadisiladiazocinyl))- 2-(N-benzyloxycarbonyl-amino)-hexanoate, N-(5-tetrazolyl)-N-(methoxy)-6-(4-( 1 ,5,6- trihydro-3-methyl-5,6-dioxo-l-oxapyrimidinyl))-2-(N-tert-butoxymethyl-N- paranitrobenzyloxycarbonyl-amino)-hexanamide, N-(5-tetrazolyl)-N-(methoxy)-6-(4- ( 1 ,5 ,6-trihydro-3-methyl-5 ,6-dioxo- 1 -oxapyrimidinyl))-2-(N-tert-butoxymethylamino)- hexanamide, N-(Methylthiomethyl)-N-(methylsulfonyl)-6-(4-( 1 ,5-dihydro-3-methyl-5- oxo- 1 ,2,4-oxadiazolyl))-2-(N- paranitrobenzyloxycarbonyl-amino)-hexanamide, N- (Methylthiomethyl)-N-(methylsulfonyl)-6-(4-( 1 ,5-dihydro-3-methyl-5-oxo- 1 ,2,4- oxadiazolyl))-2-aminohexanamide, 5-(N-( 1 -oximinoethyl)amino)- 1 -(2-( 1 ,3-dioxolyl))- 1 - (N-benzyloxycarbonyl)-pentanamine, 5-(4-( 1 ,5,6-trihydro-3-methyl-5,6-dioxo- 1 - oxapyrimidinyl))- 1 -(2-( 1 ,3-dioxolyl))- 1 -(N-benzyloxycarbonyl)-pentanamine, and 5-(4- ( 1 ,5,6-trihydro-3-methyl-5,6-dioxo- 1 -oxapyrimidinyl))- 1 -(2-( 1 ,3-dioxolyl))pentanamine.
9. A method of inhibiting nitric oxide synthesis in a subject in need of such inhibition by administering a therapeutically effective amount of the compound found in Claim 1 and pharmaceutically acceptable salts thereof.
10. A method of inhibiting nitric oxide synthesis in a subject in need of such
inhibition by administering a therapeutically effective amount of the compound found in Claims 2, 3, 4, 5, 6, 7 or 8 and pharmaceutically acceptable salts thereof.
11. A method of selectively inhibiting nitric oxide synthesis produced by inducible NO synthase over nitric oxide porduced by the constitutive forms of NO synthase in a subject in need of such selective inhibition by administering a therapeutically effective amount of a compound of Claim 1.
12. A method of selectively inhibiting nitric oxide synthesis produced by inducible
NO synthase over nitric oxide porduced by the constitutive forms of NO synthase in a subject in need of such selective inhibition by administering a therapeutically effective amount of a compound of Claims 2, 3, 4, 5, 6, 7 or 8.
13. A method of lowering nitric oxide levels in a subject in need of such by
administering a therapeutically effective amount of a compound Claim 1.
14. A method of lowering nitric oxide levels in a subject in need of such by administering a therapeutically effective amount of a compound Claims 2, 3, 4, 5, 6, 7 or 8.
15. A pharmaceutical composition comprising the compound of Claim 1 together
with one or more pharmaceutcally acceptable carriers.
16. A pharmaceutical composition comprising the compound of Claims 2, 3, 4, 5, 6, 7 or 8 together with one or more pharmaceutcally acceptable carriers.
PCT/US2000/008735 1999-04-19 2000-04-17 Novel heterocyclic amino carbonyl derivatives useful as nitric oxide synthase inhibitors WO2000063195A1 (en)

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