EP0939757A1 - Nouveaux antagonistes de recepteurs d'integrines - Google Patents

Nouveaux antagonistes de recepteurs d'integrines

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Publication number
EP0939757A1
EP0939757A1 EP96944984A EP96944984A EP0939757A1 EP 0939757 A1 EP0939757 A1 EP 0939757A1 EP 96944984 A EP96944984 A EP 96944984A EP 96944984 A EP96944984 A EP 96944984A EP 0939757 A1 EP0939757 A1 EP 0939757A1
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Prior art keywords
alkyl
aryl
substituted
heteroaryl
propyl
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EP96944984A
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German (de)
English (en)
Inventor
Prabhakar Kondaji Jadhav
Joseph James Petraitis
Douglas Guy Batt
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Bristol Myers Squibb Pharma Co
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DuPont Merck Pharmaceutical Co
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Publication of EP0939757A1 publication Critical patent/EP0939757A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to novel heterocycles which are useful as antagonists of the ⁇ v ⁇ 3 integnn and related cell surface adhesive protein receptors, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of cell adhesion, the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
  • Angiogenesis or neovasculanzation is critical for normal physiological processes such as embryonic development and wound repair (Folkman and Shmg, J. Biol. Chem. 1992, 2£2: 10931-10934; D'Amore and Thompson, Ann. Rev. Physiol. 1987, 41:453-464).
  • angiogenesis also occurs pathologically, for example, in ocular neovasculanzation (leading to diabetic retinopathy, neovascular glaucoma, retinal vein occlusion and blindness) , in rheumatoid arthritis and in solid tumors (Folkman and Shmg, J. Biol.
  • Tumor dissemination, or metastasis involves several distinct and complementary components, including the penetration and traversing of tumor cells through basement membranes and the establishment of self- sustaining tumor foci in diverse organ systems. To this end, angiogenesis is critical to tumor survival. Without neovasculanzation, tumor cells lack the nourishment to divide and will not be able to leave the primary tumor site (Folkman and Shmg, J. Biol. Chem., 1992, 2 ⁇ Z: 10931-10934) .
  • integnn ctvfo sometimes called the vitronectin receptor
  • ⁇ *v ⁇ 3 is the most promiscuous member of the integnn family, allowing endothelial cells to interact with a wide variety of extracellular matrix components (Hynes, Cell, 1992, i ⁇ : 11-25) . These adhesive interactions are considered to be critical for angiogenesis since vascular cells must ultimately be capable of invading virtually all tissues.
  • mtegrm ctv promotes adhesive events important for angiogenesis
  • this receptor also transmits signals from the extracellular environment to the intracellular compartment (Leavesley et al., J. Cell Biol., 1993, 121:163-170, 1993) .
  • the interaction between the otv ⁇ 3 mtegrm and extracellular matrix components promotes a calcium signal required for cell motility.
  • the basement membrane zones of blood vessels express several adhesive proteins, including but not limited to von Willebrand factor, fibronectin, and fibrm. Additionally, several members of the mtegrm family of adhesion receptors are expressed on the surface of endothelial, smooth muscle and on other circulating cells. Among these lntegrms is ⁇ v ⁇ 3 , the endothelial cell, fibroblast, and smooth muscle cell receptor for adhesive proteins including von Willebrand factor, fibrinogen (fibrm), vitronectin, thrombospondin, and osteopontm. These integrins initiate a calcium-dependent signaling pathway that can lead to endothelial cell ar.d smooth muscle cell migration and, therefore, may play a fundamental role in vascular cell biology.
  • an antibody to the c_v ⁇ 3 mtegrm has been developed that inhibits the interaction of this mtegrm with agonists such as vitronectin (Brooks et al., Science, 1994, 264:569-571) .
  • Application of this antibody has been shown to disrupt ongoing angiogenesis on the chick chonoallantoic membrane (CAM) , leading to rapid regression of histologically distinct human tumor transplanted onto the CAM (Brooks et al., Cell, 1994, 21:1157-1164) .
  • CAM chick chonoallantoic membrane
  • ⁇ v ⁇ 3 mtegrm antagonists have been shown to inhibit angiogenesis and are recognized as being useful as therapeutic agents for the treatment of human diseases such as cancer, restenosis, thromoembolic disorders, rheumatoid arthritis and ocular vasculopathies (Folkman and Shmg, J. Biol. Chem., 1992, 267:10931-109341.
  • the mtegrm ⁇ v ⁇ 3 is a member of the ⁇ integnn subfamily and has been described on platelets, endothelial cells, melanoma, smooth muscle cells, and osteoclasts (Horton and Davies, J. Bone Mm. Res. 1989, 1:803-808; Davies et al . , J. Cell. Biol. 1989, 102:1817- 1826; Horton, Int. J. Exp. Pat oi., 1990, 21:741-759).
  • the vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, von Willibrand factor, fibrinogen, osteopontm, bone sialoprote II and thrombospond in a manner mediated by the RGD sequence.
  • a key event m bone resorption is the adhesion of osteoclasts to the matrix of bone.
  • Studies with monoclonal antibodies have implicated the ⁇ Xv ⁇ 3 receptor this process and suggest that a selective ctv ⁇ 3 antagonist would have utility in blocking bone resorption in diseases such as osteoporosis (Horton et al., J. Bone Miner. Res., 1993, 8:239-247; Helfnch et al., J. Bone Miner. Res., 1992, 7:335-343) .
  • PCT Patent Application Publication Number WO94/08962 published April 28, 1994 discloses fibrinogen receptor antagonists of the general formula shown below:
  • the present invention provides novel nonpeptide compounds which bind to integnn receptors thereby altering cell-matrix and cell-cell adhesion processes.
  • the compounds of the present invention are useful for the inhibition of cell adhesion and the treatment (including prevention) of angiogenic disorders, inflammation, bone degradation, cancer metastases, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis.
  • One aspect of this invention provides novel compounds of Formula la, lb or Ic (described below) which are useful as antagonists of the ctv ⁇ 3 integnn.
  • the ctv ⁇ 3 mtegrm is also referred to as the ctv ⁇ 3 receptor or the vitronectin receptor.
  • the compounds of the present invention inhibit the binding of vitronectin or other RGD-contaming ligands to ⁇ v ⁇ 3 and inhibit cell adhesion.
  • the present invention also includes pharmaceutical compositions containing such compounds, and methods of using such compounds for the inhibition of angiogenesis, and/or for the treatment of disorders mediated by angiogenesis.
  • Another aspect of the present invention comprises agents that inhibit the binding of vitronectin to the ⁇ v ⁇ 3 receptor for the treatment (including prevention) of thrombosis, which do not significantly alter hemostatic balance and do not significantly inhibit platelet aggregation and do not significantly inhibit coagulation.
  • the compounds of the current invention can be used for the treatment or prevention of restenosis.
  • the present invention also provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarth ⁇ tis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, ocular vasculopathies, inflammatory bowel disease and other autoimmune diseases.
  • diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarth ⁇ tis, atherosclerosis, metastasis, wound healing, diabetic retin
  • kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula la, ID or Ic, for the therapeutic inhibition of cell adhesion, the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis .
  • the present invention provides novel compounds of Formula la, lb or Ic (described below) which bind to integnn receptors thereby altering cell-matrix and cell-cell adhesion processes.
  • the compounds of the present invention are useful for the inhibition of cell adhesion and the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastases, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis, in a mammal.
  • One aspect of this invention provides novel compounds of Formula la, lb or Ic (described below) which are useful as antagonists of the c-vfo tegrm.
  • the ⁇ v ⁇ 3 integnn is also referred to as the ctv 3 receptor or the vitronectin receptor.
  • the compounds of the present invention inhibit the binding of vitronectin or other RGD-containing ligands to ⁇ v ⁇ 3 and inhibit cell adhesion.
  • the present invention also includes pharmaceutical compositions containing such compounds of Formula la, lb or Ic, and methods of using such compounds for the inhibition of angiogenesis, and/or for the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastases, diabetic retinopathy, thrombosis, restenosis, macular degeneration, and other conditions mediated by cell adhesion and/or cell migration and/or angiogenesis, in a mammal .
  • One aspect of the present invention comprises compounds of Formula la:
  • X 1 , X 2 , X 3 , and X 4 are independently selected from nitrogen or carbon provided that at least two of X 1 , X 2 , X 3 and X 4 are carbon;
  • R 1 is selected from:
  • a 1 and B 1 are independently -CH 2 - or -N(R 3 )-;
  • J, K, L and M are independently selected from -C(R 4 )-, -C(R 5 )- or -N-, provided that at least one of J, K, L and M is not -N-;
  • R 2 is selected from: H, Ci-C ⁇ alkyl, (Ci-C ⁇ alkyl) carbonyl, (Ci-C ⁇ alkoxy) carbonyl; (Ci-C ⁇ alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl (Ci-C ⁇ alkyl) carbonyl, heteroarylcarbonyl, aryl (Ci-C ⁇ alkyl)-, (Ci-C ⁇ alkyl) carbonyl-, arylcarbonyl, Ci-C ⁇ alkylsulfonyl, arylsulfonyl, ary iCi-Ce alkyl) sulfonyl, heteroarylsulfonyl, heteroaryl (Ci-C ⁇ alkyl) sulfonyl, aryloxycarbonyl , or
  • R 3 is selected from: H, C_-C ⁇ alkyl, C 3 -C 7 cycloalkyl,
  • R 4 and R 5 are independently selected from: H, C 1 -C 4 alkoxy, NR 2 R 3 , halogen, N0 2 , CN, CF 3 , C]-C 6 alkyl, C -C ⁇ alkenyl, C -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl (C ⁇ -C 6 alkyl)-, (Ci-C ⁇ alkyl) carbonyl, (Ci-C ⁇ alkoxy) carbonyl, arylcarbonyl, or
  • R 4 and R 5 when substituents on adjacent atoms, R 4 and R 5 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C1-C4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 , or N0 2 ;
  • U is selected from:
  • Q is selected from 1, 2-cycloalkylene, 1, 2-phenylene, 1, 3-phenylene, 1, 4-phenylene, 2, 3-pyr ⁇ d ⁇ nylene, 3 , 4-pyr ⁇ dmylene, 2 , 4-pyrldmyiene, or 3,4- pyridazinylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, C ⁇ -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C ⁇ -C6 alkyl)-, or heteroaryl (Co-C 6 alkyl)-.
  • R 11 is selected from H, halogen, CF 3 , CN, N0 2 , hydroxy, NR 2 R 3 , C 1 -C 4 alkyl substituted with 0-1 R 21 , C1-C4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C ⁇ -C 6 alkyl)- substituted with
  • W is selected from:
  • X is -C(R 12 ) (R 1 )-C(R 12 ) (R 15 ) -;
  • W and X can be taken together to be
  • R 12 is selected from H, halogen, C ⁇ -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C ⁇ alkynyl, C -C 7 cycloalkyl, C4-C10 cycloalkylalkyl, (C 1 -C 4 alkyl)carbonyl, aryl, or aryl(C ⁇ -C ⁇ alkyl) -;
  • R 13 is selected from H, C ⁇ -C 6 alkyl, C 3 -C7 cycloalkylmethyl, or aryl(C ⁇ -C 6 alkyl)-;
  • R 14 is selected from:
  • Ci-Ce alkylth ⁇ o(C ⁇ -C 6 alkyl)-, aryl(C ⁇ -C ⁇ o alkylthioalkyl) - , aryl (C 1 -C 1 0 alkoxyalkyl) -, C1-C 1 0 alkyl, C 1 -C 10 alkoxyalkyl, CI-C ⁇ hydroxyalkyl, C 2 -C ⁇ o alkenyl, C 2 -C ⁇ o alkynyl, C -C ⁇ o cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryKCi-C ⁇ alkyl)-, heteroaryl (Ci-Ce alkyl) -, aryl, heteroaryl, CO 2 R 17 , C( 0)R 17 , or CONR 17 R 20 , provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently
  • Ci-Cio alkyl, Ci-Cio alkoxyalkyl, Ci-Cio alkylammoalkyl, Ci-C o dialkylaminoalkyl, (Ci-Cio alkyl) carbonyl, aryl (Co-C ⁇ alkyl ) carbonyl , Ci-Cio alkenyl, Ci-Cio alkynyl ,C 3 -C ⁇ o cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C ⁇ -C 6 alkyl)-, heteroaryl (Ci-Ce alkyl) -, aryl, heteroaryl, C0 2 R 17 , C( 0)R 17 , C0NR 17 R 20 , S0 2 R 17 , or S0 NR 17 R 20 , provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted
  • Y is selected from: -COR 19 , - ⁇ O 3 H, -P0 3 H, tetrazolyl, -CONHNHS0 2 CF 3 ,
  • R 16 is selected from:
  • R 17 is selected from: C 1 -C 10 alkyl, C 3 -C 11 cycloalkyl, aryl(C ⁇ -C 6 alkyl ) -, (Ci-C ⁇ alkyl)aryl, heteroaryl (C ⁇ -C 6 alkyl) -, (C ⁇ -C 6 alkyl)heteroaryl, biaryl (C ⁇ -C 6 alkyl) - , heteroaryl, or aryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C 1 -C alkyl, C1-C4 alkoxy, aryl, heteroaryl, halo, cyano, ammo, CF 3 , and NO2;
  • R 1 is selected from: H,
  • R 19 is selected from: hydroxy, C1-C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, aryloxy, aryl (C ⁇ -C 6 alkoxy)-,
  • R 20 is selected from: H, C ⁇ -C 6 alkyl, C -C7 cycloalkyl,
  • R 21 is selected from: COOH or NR 6 2;
  • n 0-4;
  • r , n, and q are chosen such that the number of atoms connecting R 1 and Y s in the range of 10-14;
  • n and m are chosen such that the value of n plus m is greater than one ⁇ r.le ⁇ s " T is
  • X 1 , X 2 , X 3 , and X 4 are independently selected from nitrogen or carbon provided that at least two of X 1 , X 2 , X 3 and X 4 are carbon; R 1 is selected from:
  • a 1 and B 1 are independently -CH 2 - or -N(R 3 )-;
  • J, K, L and M are independently selected from -C(R 4 )-, -C(R 5 )- or -N-, provided that at least one of J, K, L and M is not -N-;
  • R 2 is selected from: H, C ⁇ -C 6 alkyl, (C ⁇ -C 6 alkyl)carbonyl, (Ci-C ⁇ alkoxy) carbonyl, C ⁇ -C6 alkylaminocarbonyl, C 3 -C 6 alkenyl, C 3 -C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl (Ci-C ⁇ alkyl)carbonyl, heteroarylcarbonyl, aryl (Ci-C ⁇ alkyl)-, (Ci-C ⁇ alkyl)carbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aryKCi-C ⁇ alkyl) sulfonyl, heteroarylsulfonyl, heteroaryl (Ci- C ⁇ alkyl)sulfonyl, aryloxycarbonyl, or aryl (C ⁇ -C 6 al
  • R 3 is selected from: H, Ci-C ⁇ alkyl, C 3 -C 7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl(C ⁇ -C 6 alkyl)-, or heteroaryl (C1-C0 alkyl)-,.
  • R 4 and R 5 are independently selected from: H, C 1 -C 4 alkoxy, NR 2 R 3 , halogen, N0 2 , CN, CF 3 , C ⁇ -C 6 alkyl, 3 -C ⁇ alkenyl, C3-C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl (C ⁇ -C 6 alkyl) -, C 2 -C 7 alkylcarbonyl, arylcarbonyl or
  • R 4 and R 5 when substituents on adjacent atoms, R 4 and R 5 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C 1 -C4 alkyl, C 1 -C 4 alkoxy, halo, cyano, ammo, CF 3 , or N0 2 ;
  • U is selected from: -(CH 2 ) n -,
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, Ci-C ⁇ alkyl, C 3 -C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C_-C6 alkyl)-, or heteroaryl (Co-C ⁇ alkyl)-,-
  • R 11 is selected from: H, halogen, CF 3 , CN, N0 , hydroxy, NR 2 R 3 , C 1 -C 4 alkyl substituted with 0-1 R 21 , C1-C4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C ⁇ -C 6 alkyl)- substituted with 0-1 R 21 , (C 1 -C 4 alkoxy) carbonyl substituted with 0-1 R 21 , (C 1 -C 4 alkyl) carbonyl substituted with 0-1 R 21 , C 1 -C 4 alkyl) carbonyl substituted with 0-1 R 21 , C 1 -C 4 alkylsulfonyl substituted with 0-1 R 21 , or C 1 -C4 alkylammosulfonyl substituted with 0-1 R 21 ;
  • X is -C(R 12 ) (R 14 )-C(R 12 ) (R 15 )-;
  • W and X can be taken together to be
  • R 12 is H or C ⁇ -C 6 alkyl
  • R 13 is selected from: H, Ci-Ce alkyl,
  • R 14 is selected from: H, Ci-C ⁇ alkylthioalkyl, aryl(C ⁇ -C ⁇ o alkylthioalkyl) -, aryl (C1-C 1 0 alkoxyalkyl) -, C 1 -C 10 alkyl, C ⁇ -C ⁇ o alkoxyalkyl, Ci-Ce hydroxyalkyl , C 2 -C ⁇ o alkenyl, C 2 -C ⁇ 0 alkynyl, C 3 -C 10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl(C ⁇ -C 6 alkyl)-, heteroaryl (C ⁇ -C6 alkyl)-, aryl, heteroaryl, C0 2 R 17 ,
  • R 15 is selected from:
  • R 16 C1-C10 alkyl, C 1 -C 1 0 alkoxyalkyl
  • Y is selected from:
  • R 16 is selected from:
  • R 17 is selected from:
  • R l ⁇ is selected from: H,
  • R 19 is selected from: hydroxy, C 1 -C 10 alkyloxy, C 3 -C 11 cycloalkyloxy, C ⁇ -Cio aryloxy, C 7 -C 11 aralkyloxy, C 3 -C 10 alkylcarbonyloxyalkyloxy, C 3 -C 10 alkoxycarbonyloxyalkyloxy, C 2 -C ⁇ o alkoxycarbonylalkyloxy,
  • C5-C10 (5-alkyl-l, 3-d ⁇ oxa-cyclopenten-2-one- yD ethyloxy
  • C 10 -C14 (5-aryl-l, 3-d ⁇ oxa-cyclopenten-
  • R 20 selected from: H, C ⁇ C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 - Cn cycloalkylalkyl, aryl(C ⁇ -C6 alkyl)-, or heteroaryl (C ⁇ -C6 alkyl) -•
  • R 21 is selected from COOH or NR 6 ;
  • Ila lib including stereoisomenc forms tnereof, or mixtures of stereoisomenc forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
  • Xi and X3 are independently selected from nitrogen or carbon; R 1 is selected from:
  • heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH 2 , halogen, NO2, CN, CF3, C - C4 alkoxy, Ci-C ⁇ alkyl, and C3-C7 cycloalkyl;
  • R 6 is selected from: H, C1-C4 alkyl, or benzyl
  • R7 is selected from: Ci-C ⁇ alkyl, C 3 -C 7 cycloalkyl, C4- C 1 1 cycloalkylalkyl, aryl, aryl (Ci-C ⁇ alkyl) , heteroaryl, or heteroaryl (Ci-C ⁇ alkyl) ;
  • R 10 is selected from: H, C ⁇ -C alkoxy substituted with 0-1 R 21 , halogen, C0 2 R 17 , CONR 17 R 20 , C ⁇ -C 6 alkyl substituted with 0-1 R 15 or 0-1 R 21 , C3-C 7 cycloalkyl substituted with 0-1 R 15 or 0-1 R 21 , C4-C11 cycloalkylalkyl substituted with 0-1 R 15 or 0-1 R 21 , or aryl(C ⁇ -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 ;
  • R 11 is selected from: H, halogen, CF 3 , CN, N0 2 , hydroxy, NR 2 R 3 , C 1 -C4 alkyl substituted with 0-1 R 21 , C ⁇ -C alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C ⁇ -C 6 alkyl)- substituted with 0-1 R 21 , (C1-C4 alkoxy) carbonyl substituted with 0-1 R 21 , (C1-C4 alkyl) carbonyl substituted with 0-1 R 21 , C1-C4 alkyl) carbonyl substituted with 0-1 R 21 , C1-C4 alkylsulfonyl substituted with 0-1 R 21 , or
  • X is -CH(R 1 )-CH(R 15 )-;
  • R 13 is H or CH 3
  • R 14 is selected from: H, C1-C1 0 alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C 1 -C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, ammo, CF 3 , and N0 2 ;
  • R 17 is selected from:
  • R 19 is selected from: hydroxy, C ⁇ -C ⁇ o alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy- ,
  • R 21 is selected from COOH or NR 6 ;
  • Still further preferred compounds of the above invention are compounds of the Formula Ila or lib:
  • Ila U including stereoisomeric forms thereof, or mixtures of stereoisomenc forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein: Xi and X 3 are independently selected from nitrogen or carbon, provided that at least one of X_ and X 3 is carbon;
  • R 1 is selected from:
  • heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH 2 , halogen,
  • Q s selected from 1, 2-phenylere, 1, 3- ⁇ nenyier ⁇ e, 2,3- pyridmylene, 3 , 4-py ⁇ dmyler.e, or 2,4- pynd ylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl; R7 is selected from: C ⁇ -C 6 alkyl, C 3 -C 7 cycloalkyl,
  • R 10 is selected from: H, C 1 -C 4 alkoxy substituted with 0-1 R- 1 , halogen, C0 R 17 , C0NR 17 R 20 , Ci-C ⁇ alkyl substituted with 0-1 R 15 or 0-1 R 21 , C 3 -C 7 cycloalkyl substituted with 0-1 R 15 or 0-1 R 21 , C4-C1 1 cycloalkylalkyl substituted with 0-1 R 15 or 0-1 R 21 , or aryl(C ⁇ -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R or 0-1 R 21 ;
  • R 11 is selected from: H, halogen, CF 3 , CN, N0 2 , hydroxy, NR 2 R 3 , C 1 -C 4 alkyl substituted with 0-1 R 21 , C 1 -C 4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C -C 6 alkyl)- substituted with 0-1 R 21 , (C 1 -C 4 alkoxy)carbonyl substituted with 0-1 R 21 , (C ⁇ -C 4 alkyl) carbonyl substituted with 0-1 R 21 , C 1 -C 4 alkylsulfonyl substituted with 0-1 R 21 , or C -C 4 alkyla inosulfonyl substituted with 0-1 R 21 ;W
  • X is -CH(R 1 )-CH(R 15 )-;
  • R 13 is H or CH 3
  • R 14 is selected from: H, C 1 -C 10 alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, halo, cyano, am o, CF3, and N0 2 ;
  • R 17 is selected from:
  • Ci-Cio alkyl C 3 -Cn cycloalkyl, aryl (C ⁇ -C 6 alkyl)-,
  • R 19 is selected from: hydroxy, Cj-Cio alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy- , t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy-,
  • R 21 s selected from COOH or NR 6 2 ;
  • Specifically preferred compounds of the invention as described above are compounds of Formula la, including enantiomenc or diastenomenc forms thereof, or mixtures of enantiomenc or diastenomenc forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof, selected from the group consisting of:
  • ester prodrugs of the specifically preferred compounds of Formula la said esters being chosen from the group consisting Of: methyl, ethyl, isopropyl, n-butyl, isobutyl, benzyl, methylcarbonyloxymethyl, ethylcarbonyloxymethyl, tert-butylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, tert-butyloxycarbonyloxymethyl, di ethylammoethyl, diethylaminoethyl, ⁇ icrpho11noethy1, pyrrol dir.oethyl, and tr me zh 1 mmonIoethy1.
  • Another aspect of the present invention comprises compounds of Formula lb:
  • X 1 , X 2 , X 3 , and X 4 are independently selected from nitrogen or carbon provided that at least two of X 1 , X 2 , X 3 and X 4 are carbon;
  • R 1 is selected from:
  • a 1 and B 1 are independently -CH 2 - or -N(R 3 )-;
  • J, K, L and M are independently selected from: -C(R 4 )-, -C(R 5 )- or -N-, provided that at least one of J, K, L and M is not -N-;
  • R 2 is selected from: H, Ci-C ⁇ alkyl, (Ci-C ⁇ alkyl)carbonyl, (Ci-C ⁇ alkoxy)carbonyl; (Ci-C ⁇ alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C3-C 7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, heteroaryl (C ⁇ -C 6 alkyl) carbonyl, heteroarylcarbonyl, aryl C ⁇ -C 6 alkyl, (C ⁇ -C 6 alkyl) carbonyl, or arylcarbonyl, C ⁇ -C 6 alkylsulfonyl, arylsulfonyl, aryl(C ⁇ -C 6 alkyl) sulfonyl, heteroarylsulfonyl, heteroaryl (Ci-C ⁇ alkyl) sulfonyl, aryloxycarbonyl, or aryl(C ⁇ -
  • R 3 is selected from: H, Ci-Ce alkyl, C 3 -C 7 cycloalkyl, C -C 1 cycloalkylalkyl, aryl, aryKCi-C ⁇ alkyl)-, or heteroaryl (Ci-C ⁇ alkyl)-,-
  • R 4 and R 5 are independently selected from: H, C1-C4 alkoxy, NR 2 R 3 , halogen, N0 , CN, CF 3 , Ci-C ⁇ alkyl, C3-C 6 alkenyl, C 3 -C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryl (Ci-C ⁇ alkyl)-, (C ⁇ -C 6 alkyl) carbonyl, (Ci-C ⁇ alkoxy) carbonyl, arylcarbonyl, or
  • R 4 and R 5 when substituents on adjacent atoms, R 4 and R 5 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, ammo, CF3, or N0 2 ;
  • Q is selected from: 1, 2-cycloalkylene, 1, 2-phenylene, 1, 3-phenylene, 1, 4-phenylene, 2, 3-pyridinylene, 3, 4-pyr ⁇ d ⁇ nylene, 2 , 4-py ⁇ d ⁇ r.ylene, or 3,4- pyndazmylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, Ci-C ⁇ alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl (Ci-Ce alkyl)-, or heteroaryl (Co-C ⁇ alkyl)-,.
  • R 11 is selected from H, halogen, CF 3 , CN, N0 2 , hydroxy, NR 2 R 3 , C ⁇ -C 4 alkyl substituted with 0-1 R 21 , C1-C4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryKCi-C ⁇ alkyl)- substituted with 0-1 R 21 , (C1-C4 alkoxy) carbonyl substituted with 0-1 R 21 , (C1-C4 alkyl) carbonyl substituted with 0-1 R 21 , C1-C4 alkyl) carbonyl substituted with 0-1 R 21 , C1-C4 alkylsulfonyl substituted with 0-1 R 21 , or C1-C4 alkylammosulfonyl substituted with 0-1 R 21 ;
  • W is selected from:
  • X is -C(R 12 ) (R 1 )-C(R 12 ) (R 15 )-; or
  • W and X can be taken together to be
  • R 12 is selected from: H, halogen, Ci-C ⁇ alkyl, C 2 -C ⁇ alkenyl, C 2 -C 6 alkynyl, C 3 -C7 cycloalkyl, C 4 -C 10 cycloalkylalkyl, (C 1 -C 4 alkyl) carbonyl, aryl, or aryl(C ⁇ -C 6 alkyl)-;
  • R 13 is selected from: H, C ⁇ -C 6 alkyl, C3-C7 cycloalkylmethyl, or aryl(C ⁇ -C ⁇ alkyl)-;
  • R 14 is selected from:
  • Ci-C ⁇ alkylth ⁇ o ( C ⁇ -C ⁇ alkyl ) -, aryl ( C ⁇ -C ⁇ o alkylthioalkyl)-, aryl (C 1 -C 10 alkoxyalkyl) -, C1-C10 alkyl, C 1 -C 10 alkoxyalkyl, Ci-C ⁇ hydroxyalkyl, C 2 -C ⁇ o alkenyl, C 2 -C ⁇ o alkynyl, C3-C10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryKCi-C ⁇ alkyl)-, heteroaryl (C ⁇ -C 6 alkyl) -, aryl, heteroaryl, C0 2 R 17 , C( 0)R 17 , or C0NR 17 R 20 , provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0
  • R 15 is selected from: H, R 16 , Ci-Cio alkyl, C ⁇ -C ⁇ 0 alkoxyalkyl,
  • Ci-Cio alkylam oalkyl, C ⁇ -C ⁇ o dialkylammoalkyl, (Ci-Cio alkyl) carbonyl, aryl(Co-C 6 alkyl) carbonyl, Ci-Cio alkenyl, C ⁇ -C ⁇ o alkynyl ,C 3 -C 10 cycloalkyl, C3-C10 cycloalkylalkyl, aryKCi-Ce alkyl)-, heteroaryl (C ⁇ -C 6 alkyl) -, aryl, heteroaryl, C0 2 R 17 , C( 0)R 17 , CONR 17 R 20 , S0 2 R 17 , or S0 2 NR 17 R 20 , provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-2 R 11 ;
  • Y is selected from:
  • R 17 is selected from:
  • R 18 is selected from:
  • R 19 is selected from hydroxy, C1-C10 alkyloxy
  • C5-C10 (5-alkyl-l, 3-dioxa-cyclopenten-2-one- yDmethyloxy, C1 0 -C 14 (5-aryl-l, 3-dioxa-cyclopenten- 2-one-yl)methyloxy, or (R 11 ) (R 12 )N- (C1-C10 alkoxy) -;
  • R 20 is selected from: H, Ci-C ⁇ alkyl, C3-C7 cycloalkyl,
  • R 21 is selected from COOH or NR 6 2 ;
  • n and m are chosen such that the value of n plus m is greater than one unless U is -(CH;) ⁇ Q.'CH?).,,-.
  • Preferred compounds of the invention as described above are compounds of the Formula lb:
  • X 1 , X 2 , X 3 , and X 4 are independently selected from nitrogen or carbon provided that at least two of X 1 , X 2 , X 3 and X 4 are carbon; R 1 is selected from:
  • a 1 and B 1 are independently -CH 2 - or -N(R 3 )-;
  • J, K, L and M are independently selected from -C(R 4 )-, -C(R 5 )- or -N-, provided that at least one of J, K,
  • R 2 is selected from: H, C ⁇ -C 6 alkyl, (Ci-C ⁇ alkyl)carbonyl, (Ci-C ⁇ alkoxy) carbonyl, Ci-C ⁇ alkylaminocarbonyl, C 3 -C 6 alkenyl, C 3 -C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl (Ci- ⁇ alkyl) carbonyl, heteroarylcarbonyl, aryl (Ci-C ⁇ alkyl)-, (Ci-Ce alkyl) carbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aryl(C ⁇ -C6 alkyl)sulfonyl, heteroarylsulfonyl, heteroaryl (C ⁇ -C 6 alkyl) sulfonyl, aryloxycarbonyl, aryKCi-C ⁇ alkoxy)carbony
  • R 3 is selected from: H, Ci-C ⁇ alkyl, C 3 -C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C ⁇ -Ce alkyl)-, or heteroaryl (C 1 -C6 alkyl)-,-
  • R 4 and R 5 are independently selected from: H, C 1 -C 4 alkoxy, NR 2 R 3 , halogen, N0 , CN, CF 3 , C ⁇ -C 0 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C4-C 11 cycloalkylalkyl, aryl, aryl(C ⁇ -C 6 alkyl)-, C 2 -C7 alkylcarbonyl, arylcarbonyl or
  • R 4 and R 5 when substituents on adjacent atoms, R 4 and R 5 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C1-C4 alkyl, C -C 4 alkoxy, halo, cyano, ammo, CF 3 , or N0 2 ;
  • U is selected from: -(CH 2 ) n -,
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, C ⁇ -C 6 alkyl, C3-C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl (Ci-C ⁇ alkyl ) -, or heteroaryl (Co-C ⁇ alkyl)-,-
  • R 15 or 0-1 R 21 C 4 -C 11 cycloalkylalkyl substituted with 0-1 R 15 or 0-1 R 21 , aryl substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 , or aryl(C ⁇ -C 6 alkyl) - substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 ;
  • R 11 is selected from: H, halogen, CF 3 , CN, N0 2 , hydroxy, NR 2 R 3 , C 1 -C 4 alkyl substituted with 0-1 R 21 , C1-C4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C ⁇ -C 6 alkyl)- substituted with 0-1 R 21 , (C 1 -C 4 alkoxy) carbonyl substituted with 0-1 R 21 , (C 1 -C 4 alkyl) carbonyl substituted with 0-1 R 21 , C 1 -C 4 alkyl) carbonyl substituted with 0-1 R 21 , C 1 -C 4 alkylsulfonyl substituted with 0-1 R 21 , or C 1 -C 4 alkylaminosulfonyl substituted with 0-1 R 21 ;
  • X is -C(R 12 ) (R 14 )-C(R 12 ) (R 15 )-;
  • W and X can be taken together to be
  • R 12 is H or Ci-Ce alkyl
  • R 13 is selected from: H, Ci-C ⁇ alkyl,
  • R 14 is selected from:
  • C -C 6 alkylthioalkyl, aryl(C ⁇ -C ⁇ 0 alkylthioalkyl)-, aryl(C ⁇ -C ⁇ o alkoxyalkyl)-, C 1 -C 10 alkyl, C ⁇ -C ⁇ o alkoxyalkyl, C ⁇ -C 6 hydroxyalkyl, C 2 -C ⁇ o alkenyl, C -C ⁇ o alkynyl, C 3 -C ⁇ o cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl(C ⁇ -C 6 alkyl)-, heteroaryl (C ⁇ -C6 alkyl)-, aryl, heteroaryl, C0 2 R 17 , C( 0)R 17 , or CONR 17 R 20 , provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-1 R 16 or 0-2 R
  • R 15 is selected from:
  • Y is selected from: -COR 19 , -SO 3 H,
  • R l ⁇ is selected from:
  • R 17 is selected from:
  • R 18 is selected from: H,
  • .19 is selected from hydroxy, C 1 -C 1 0 alkyloxy,
  • R20 selected from: H, C ⁇ -Ce alkyl, C 3 -C 7 cycloalkyl, C 4 - Cii cycloalkylalkyl, aryl (C -C 6 alkyl)-, or heteroaryl (C ⁇ -C6 alkyl)-,.
  • R 21 is selected from COOH or NR 6 2 ;
  • stereoisomeric forms thereof including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof, wherein:
  • Xi and X3 are independently selected from nitrogen or carbon;
  • R 1 is selected from:
  • N-( N- ⁇ / NH2 N__ ( ⁇ J ' - U -or — J .
  • the above heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH 2 , halogen, N0 2 , CN, CF3, Ci- C 4 alkoxy, Ci-C ⁇ alkyl, and C 3 -C7 cycloalkyl;
  • R ⁇ is selected from: H, C -C 4 alkyl, or benzyl;
  • R7 is selected from: C ⁇ -Ce alkyl, C 3 -C 7 cycloalkyl, C 4 - C 11 cycloalkylalkyl, aryl, aryKCi-C ⁇ alkyl) , heteroaryl, or heteroaryl (C -C 6 alkyl);
  • R 9 is selected from: H, -S0 2 R 17 , -S0 2 NR 17 R 20 , C ⁇ -C 6 alkyl substituted with 0-1 R 15 or 0-1 R 21 , C 3 -C 7 cycloalkyl substituted with 0-1 R 15 or 0-1 R 21 , C 4 -C 11 cycloalkylalkyl substituted with 0-1 R 15 or 0-1 R 21 , aryl substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 , or aryl(C ⁇ -C 6 alkyl)- substituted w th 0-1 R 15 or 0-2 R 11 or 0-1 R 21 ;
  • R 11 is selected from: H, halogen, CF , CN, N0 2 , hydroxy, NR 2 R 3 , C 1 -C 4 alkyl substituted with 0-1 R 21 , C 1 -C 4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C ⁇ -C 6 alkyl)- substituted with 0-1 R 21 , (C 1 -C 4 alkoxy)carbonyl substituted with 0-1 R 21 , (C 1 -C 4 alkyl) carbonyl substituted with 0-1 R 21 , C -C 4 alkylsulfonyl substituted with 0-1 R 21 , or
  • X is -CH(R 14 )-CH(R 15 )-;
  • R 13 is H or CH 3
  • R 14 is selected from: H, C 1 -C 10 alkyl, aryl/ or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C 1 -C 4 alkyl, C ⁇ -C 4 alkoxy, aryl, halo, cyano, amino, CF 3 , and N0 2 ;
  • R 17 is selected from:
  • R 19 is selected from: hydroxy, C1-C 1 0 alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy-,
  • R 21 is selected from COOH or NR 6 ;
  • Still further preferred compounds of the above invention are compounds of the Formula lie or lid:
  • Xx and X3 are independently selected from nitrogen or carbon, provided that at least one of Xi and X 3 is carbon;
  • R 1 is selected from:
  • heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH 2 , halogen, N0 2 , CN, CF 3 , Ci- C 4 alkoxy, C -C 6 alkyl, and C 3 -C7 cycloalkyl:
  • Q s selected from 1, 2-phenylene, 1, 3-pher ⁇ ylene, 2,3- py ⁇ dmylene, 3 , 4-pynd ⁇ r.vler.e, or 2,4- pyr ⁇ d ⁇ ny_ene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R7 is selected from: Ci-C ⁇ alkyl, C3-C 7 cycloalkyl, C 4 - C11 cycloalkylalkyl, aryl, aryl(C ⁇ -C 6 alkyl) , heteroaryl, or heteroaryl fC -C 6 alkyl);
  • R 9 is selected from: H, -S0 2 R 17 , -S0 NR 17 R 20 , ⁇ -C 6 alkyl substituted with 0-1 R 15 or 0-1 R 21 , C3-C 7 cycloalkyl substituted with 0-1 R 15 or 0-1 R 21 , C 4 -C 1 1 cycloalkylalkyl substituted with 0-1 R 15 or 0-1 R 21 , aryl substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 , or aryl(C ⁇ -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 ;
  • R 11 is selected from H, halogen, CF 3 , CN, N0 2 , hydroxy, NR 2 R 3 , C1-C4 alkyl substituted with 0-1 R 21 , C1-C4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C ⁇ -C 6 alkyl)- substituted with 0-1 R 21 , (C ⁇ -C4 alkoxy) carbonyl substituted with 0-1 R 21 , (C -C4 alkyl) carbonyl substituted with 0-1 R 21 , C -C4 alkyl) carbonyl substituted with 0-1 R 21 , C -C4 alkylsulfonyl substituted with 0-1 R 21 , or C -C 4 alkylammosulfonyl substituted with 0-1 R 21 ;W
  • X is -CH(R 1 )-CH(R 15 )-;
  • R 14 is selected from: H, C1-C10 alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, aryl, halo, cyano, amino, CF3, and N0 2 ;
  • Y is -COR 19 ;
  • R 16 is selected from:
  • R 17 is selected from:
  • Ci-Cio alkyl C3-C11 cycloalkyl, aryl(C ⁇ -C 6 alkyl)-,
  • substituents selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, aryl, heteroaryl, halo, cyano, amino, CF 3 , and N0 2 ;
  • R 19 is selected from: hydroxy, C1-C10 alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy- , t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy- ,
  • R 20 is H or CH 3 ;
  • R 21 is selected from COOH or NR 6 2 ;
  • Specifically preferred compounds of the invention as described above are compounds of Formula lb, including enantiomeric or diastenomeric forms thereof, or mixtures of enantiomeric or diastenomenc forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof, selected from the group consisting of:
  • ester prodrugs of the specifically preferred compounds of Formula lb are chosen from the group consisting Of: methyl, ethyl, isopropyl, n-butyl, isobutyl, benzyl , methylcarbonyloxymethyl , ethylcarbonyloxymethyl, tert-butylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, tert-butyloxycarbonyloxymethyl, dimethylaminoethyl, and diethylaminoethyl, morphc1inoethy1, pyrrolidir.oemyl, and tri e ⁇ hy1ammonloethy1.
  • X 1 , X 2 , X 3 , and X 4 are independently selected from nitrogen or carbon provided that at least two of X 1 , X 2 , X 3 and X 4 are carbon;
  • R 1 is selected from:
  • a 1 and B 1 are independently -CH 2 - or -N(R 3 )-;
  • J, K, L and M are independently selected from -C(R 4 )-, -C(R 5 )- or -N-, provided that at least one of J, K, L and M is not -N-;
  • R 2 is selected from: H, C ⁇ -C 6 alkyl, (C ⁇ -Ce alkyl) carbonyl, (C ⁇ -C & alkoxy) carbonyl; (C ⁇ -C ⁇ alkyl)aminocarbonyl, C 3 -C 6 alkenyl, C 3 -C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl (C ⁇ -C6 alkyl) carbonyl, heteroarylcarbonyl, aryl Ci-C ⁇ alkyl, (Ci-Ce alkyl) carbonyl, or arylcarbonyl, C ⁇ -C ⁇ alkylsulfonyl, arylsulfonyl, aryl (C
  • R 3 is selected from: H, C -C ⁇ alkyl, C 3 -C7 cycloalkyl,
  • R 4 and R 5 are independently selected from: H, C -C4 alkoxy, NR 2 R 3 , halogen, N0 2 , CN, CF 3 , C ⁇ -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 1 cycloalkylalkyl, aryl, aryl (Ci-C ⁇ alkyl)-, (C ⁇ -C ⁇ alkyl) carbonyl, (C -C 6 alkoxy) carbonyl, arylcarbonyl, or
  • R 4 and R 5 when substituents on adjacent atoms, R 4 and R 5 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C1-C4 alkyl, C -C 4 alkoxy, halo, cyano, ammo, CF3, or N0 2 ; U is selected from:
  • Q is selected from 1,2-cycloalkylene, 1,2-phenylene, 1, 3-phenylene, 1, 4-phenylene, 2, 3-pyr ⁇ dmylene, 3 , 4-pyr ⁇ dmylene, 2 , or 3,4- pyndazinylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, C ⁇ -Ce alkyl, C 3 -C 7 cycloalkyl, C 4 -C 1 cycloalkylalkyl, aryl, aryl(C ⁇ -C6 alkyl)-, or heteroaryl (C0-C6 alkyl)-,-
  • R 11 IS selected from H, halogen, CF3, CN, N0 , hydroxy, NR 2 R 3 , C -C4 alkyl substituted with 0-1 R 21 , C ⁇ -C4 alkoxy substituted with 0-1
  • W is selected from:
  • X is -C(R 12 ) (R 14 )-C(R 12 ) (R 15 )-; or
  • W and X can be taken together to be
  • R 12 is selected from: H, halogen, C ⁇ -Ce alkyl, C 2 -Ce alkenyl, C 2 -C 6 alkynyl, C3-C7 cycloalkyl, C4-C10 cycloalkylalkyl, (C1-C4 alkyl) carbonyl, aryl, or aryl(C ⁇ -C6 alkyl)-;
  • R 13 is selected from: H, C ⁇ -C 6 alkyl, C3-C7 cycloalkylmethyl, or aryl(C ⁇ -C 6 alkyl)-
  • R 14 is selected from:
  • R 15 is selected from:
  • Ci-Cio alkenyl, C ⁇ -C ⁇ o alkynyl ,C 3 -C ⁇ o cycloalkyl, C 3 -C ⁇ 0 cycloalkylalkyl, aryl (C ⁇ -C 6 alkyl) -, heteroaryl (C ⁇ -C ⁇ alkyl) -, aryl, heteroaryl, C0 2 R 17 , C( 0)R 17 , CONR 17 R 20 , S0 2 R 17 , or S0 2 NR 17 R 20 , provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 0-2 R 11 ;
  • Y is selected from: -COR 19 , -SO3H, -PO3H, tetrazolyl, -CONHNH ⁇ O2CF3,
  • R 16 is selected from:
  • R 17 is selected from:
  • R 18 is selected from: H,
  • R 19 is selected from hydroxy, C ⁇ -C ⁇ o alkyloxy, C 3 -C ⁇ cycloalkyloxy, aryloxy, aryl(C ⁇ -C6 alkoxy)-,
  • C5-C10 (5-alkyl-1, 3-d ⁇ oxa-cyclopenten-2-one- yDmethyloxy
  • C10-C14 (5-aryl-l, 3-dioxa-cyclopenten-
  • R 20 is selected from: H, C ⁇ -C 6 alkyl, C3-C7 cycloalkyl,
  • R 2 is selected from COOH or NR 6 2 ;
  • t, n, m and q are chosen such that the number of atoms connecting R 1 and Y is in the range of 10-14;
  • n and m are chosen such that the value of n plus m is greater than one __r.less is
  • X 1 , X 2 , X 3 , and X 4 are independently selected from nitrogen or carbon provided that at least two of X 1 , X 2 , X 3 and X 4 are carbon;
  • R 1 is selected from:
  • a 1 and B 1 are independently -CH 2 - or -N(R 3 )-;
  • J, K, L and M are independently selected from: -C(R 4 )-, -C(R 5 )- or -N-, provided that at least one of J, K, L and M is not -N-;
  • R 2 is selected from: H, Ci-C ⁇ alkyl, (Ci-C ⁇ alkyl)carbonyl, (C ⁇ -C ⁇ alkoxy)carbonyl, C -C ⁇ alkylaminocarbonyl, C 3 -C 6 alkenyl, C 3 -C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl(C -C ⁇ alkyl)carbonyl, heteroarylcarbonyl, aryKCi-Ce alkyl)-, (C 1 -C 6 alkyl)carbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aryl(C ⁇ -C 6 alkyl) sulfonyl, heteroarylsulfonyl, heteroaryl (C ⁇ -C6 alkyl) sulfonyl, aryloxycarbonyl, aryl(C ⁇ -C6 alkoxy)
  • R 3 is selected from: H, C ⁇ -C6 alkyl, C3-C7 cycloalkyl,
  • R 4 and R 5 are independently selected from: H, C -C 4 alkoxy, NR 2 R 3 , halogen, N0 2 , CN, CF 3 , C -C 6 alkyl, C 3 -C 6 alkenyl, C 3 -C7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C ⁇ -C6 alkyl)-, C 2 -C7 alkylcarbonyl, arylcarbonyl or
  • R 4 and R 5 when substituents on adjacent atoms, R 4 and R 5 can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or non-aromatic ring system, said carbocyclic or heterocyclic ring being optionally substituted with 0-2 groups selected from: C1-C4 alkyl, C -C 4 alkoxy, halo, cyano, amino, CF , or N0 2 ;
  • Q is selected from i , 2- her.yler.e, 1, -phenylene, 2,3- yr d ylene, 2 , 4-pyr ⁇ dmyier.e, or 2,4- py idiny e e;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, Ci-C ⁇ alkyl, C3-C7 cycloalkyl, C 4 ⁇ C cycloalkylalkyl, aryl, aryl(C ⁇ -C6 alkyl)-, or heteroaryl (C0-C6 alkyl)-,-
  • R 11 is selected from: H, halogen, CF 3 , CN, NO 2 , hydroxy, NR 2 R 3 , C 1 -C 4 alkyl substituted with 0-1 R 21 , C -C 4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C ⁇ -C 6 alkyl)- substituted with 0-1 R 21 , (C 1 -C 4 alkoxy)carbonyl substituted with 0-1 R 21 , (C1-C 4 alkyl)carbonyl substituted with 0-1 R 21 , C 1 -C4 alkylsulfonyl substituted with 0-1 R 21 , or
  • X is -C(R 12 ) (R 1 )-C(R 12 ) (R 15 )-; alternatively, W and X can be taken together to be
  • R 12 is H or C ⁇ -C 5 alkyl
  • R 13 is selected from: H, Ci-C ⁇ alkyl,
  • R 14 is selected from:
  • R 15 is selected from:
  • R 16 C 1 -C 10 alkyl, C ⁇ -C ⁇ o alkoxyalkyl,
  • R 16 is selected from:
  • R 17 is selected from:
  • R 18 is selected from: H,
  • R 19 is selected from: hydroxy, C 1 -C10 alkyloxy, C 3 -C 11 cycloalkyloxy, C 6 -C o aryloxy, C 7 -C ⁇ aralkyloxy, C 3 -C 10 alkylcarbonyloxyalkyloxy, C3-C 0 alkoxycarbonyloxyalkyloxy,
  • R 20 selected from: H, C -C6 alkyl, C3-C7 cycloalkyl, C 4 - C cycloalkylalkyl, aryl(C ⁇ -C6 alkyl)-, or heteroaryl (C1-C6 alkyl)-,.
  • R 21 is selected from COOH or NR 6 2 ;
  • R 1 is selected from:
  • heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH 2 , halogen, N0 2 , CN, CF 3 , C1-C4 alkoxy, Ci-C ⁇ alkyl, and C 3 -C7 cycloalkyl;
  • R 6 is selected from: H, C ⁇ -C alkyl, or benzyl
  • R7 is selected from: C -C6 alkyl, C 3 -C 7 cycloalkyl,
  • R 9 is selected from: H, -S0 2 R 17 , -S0 2 R 17 R 20 , Ci-C ⁇ alkyl substituted with 0-1 R 15 or 0-1 R 21 , C 3 -C7 cycloalkyl substituted witn 0-1 R 15 or 0-1 R 21 , C 4 -C 11 cycloalkylalkyl substituted with 0-1 R 15 or 0-1 R 21 , aryl substituted with 0-1 R 15 or 0-2 R 11 or
  • 0-1 R 21 or aryl(C ⁇ -C6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 ;
  • R 11 is selected from H, halogen, CF 3 , CN, N0 2 , hydroxy, NR 2 R 3 , C 1 -C 4 alkyl substituted with 0-1 R 21 , C1-C4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryKCi-Ce alkyl)- substituted with 0-1 R 21 , (C 1 -C4 alkoxy) carbonyl substituted with 0-1 R 21 , (C 1 -C 4 alkyl ) carbonyl substituted with 0-1 R 21 , C 1 -C 4 alkylsulfonyl substituted with 0-1 R 21 , or
  • X is -CH(R 14 )-CH(R 15 )-;
  • R 14 is selected from: H, C 1 -C 10 alkyl, aryl, or heteroaryl, wherein said aryl or heteroaryl groups are optionally substituted with 0-3 substituents selected from the group consisting of: C -C 4 alkyl, C -C 4 alkoxy, aryl, halo, cyano, ammo, CF 3 , and N0 2 ;
  • R 17 is selected from:
  • R 19 is selected from: hydroxy, C ⁇ -C ⁇ o alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy-,
  • R 20 is H or CH 3 ;
  • R 21 is selected from COOH or NR 6 2 ;
  • R 1 is selected from:
  • heterocycles are optionally substituted with 0-2 substituents selected from the group consisting of: NH 2 , halogen, N0 2 , CN, CF3, C -C 4 alkoxy, Ci-C ⁇ alkyl, and C 3 -C 7 cycloalkyl:
  • R 6 selected from: H, C 1 -C 4 alkyl, or benzyl
  • R7 is selected from Ci-C ⁇ alkyl, C 3 -C7 cycloalkyl, C4-C11 cycloalkylalkyl, aryl, aryKCi-C ⁇ alkyl), heteroaryl, or heteroaryl(Ci-C ⁇ alkyl);
  • R 9 is selected from: H, -S0 2 R , -S0 2 NR 17 R 20 , C ⁇ -C alkyl substituted with 0-1 R 1 - 5 or 0-1 R 21 , C 3 -C 7 cycloalkyl substituted with 0-1 R 15 or 0-1 R 21 , C4-C11 cycloalkylalkyl substituted with 0-1 R 15 or 0-1 R 21 , aryl substituted with 0-1 R 15 or 0-2 R 11 or
  • 0-1 R 21 or aryKCi-Ce alkyl)- substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 ;
  • R 11 is selected from H, halogen, CF , CN, N0 2 , hydroxy, NR 2 R 3 , C 1 -C4 alkyl substituted with 0-1 R 21 , C 1 -C 4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C ⁇ -Ce al yl)- substituted with 0-1 R 21 , (C -C 4 alkoxy) carbonyl substituted with 0-1 R 21 , (C ⁇ -C 4 alkyl) carbonyl substituted with 0-1 R 21 , C 1 -C 4 alkylsulfonyl substituted with 0-1 R 21 , or
  • X is -CH(R 1 )-CH(R 15 )-;
  • R 13 IS H or CH3;
  • R 14 is selected from:
  • R 15 IS H or R 16 ;
  • Y is -COR 19 ;
  • R 17 is selected from:
  • R 19 is selected from: hydroxy, C 1 -C 1 0 alkoxy, methylcarbonyloxymethoxy-, ethylcarbonyloxymethoxy-, t-butylcarbonyloxymethoxy-, cyclohexylcarbonyloxymethoxy-,
  • R 21 is selected from COOH or NR 6 2 ;
  • the compounds of Formula la, lb or Ic above are useful as inhibitors of cell-matrix and cell-cell adhesion processes.
  • the present invention includes novel compounds of Formula la, lb or Ic and methods for using such compounds for the prevention or treatment of diseases resulting from abnormal cell adhesion to the extracellular matrix which comprises administering to a host m need of such treatment a therapeutically effective amount of such compound of Formula la, lb or Ic.
  • the compounds of Formula la, lb or Ic above are useful as inhibitors of ctvfo.
  • the compounds of the present invention inhibit the binding of vitronectin to oivfo and inhibit cell adhesion.
  • the present invention also provides pharmaceutical compositions comprising a compound of Formula la, lb or Ic and a pharmaceutically acceptable carrier.
  • the compounds of Formula la, lb or Ic of the present invention are useful for the treatment (including prevention) of angiogenic disorders, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula la, lb or Ic described above.
  • angiogenic disorders includes conditions involving abnormal neovasculanzation, such as tumor metastasis and ocular neovasculanzation, including, for example, diabetic retinopathy, neovascular glaucoma, age-related macular degeneration, and retinal ve n occlusion.
  • the compounds of Formula la, lb or Ic of the present invention are also useful for the treatment (including prevention) of thromboembolic disorders, comprising administering to a mammal n need of such treatment a therapeutically effective amount of a compound of Formula la, lb or Ic described above.
  • thromboembolic disorders includes conditions involving platelet activation and aggregation, such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, lschemic sudden death, transient lschemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolisms, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes.
  • thrombosis unstable angina, first or recurrent myocardial infarction, lschemic sudden death, transient lschemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis
  • the compounds of Formula la, lb or Ic of the present invention may also be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, inflammation, bone degradation, restenosis, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation rejection, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, inflammatory bowel disease and other autoimmune diseases.
  • the compounds of Formula la, lb or Ic of the present invention may also be useful for wound healing.
  • the compounds of the present invention may be used for ether ex vi vo applications to prevent cellular adhesion in biological samples.
  • the compounds of the present invention can also be administered in combination with one or more additional therapeutic agents selected from: antI-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirud or argatroban; or thrombolytic or fibrmolytic agents, such as plasminogen activators, anistreplase, urokinase, or streptokinase.
  • additional therapeutic agents selected from: antI-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirud or argatroban; or thrombolytic or fibrmolytic agents, such as plasminogen activators, anistreplase,
  • the compounds of Formula la, lb or Ic of the present invention can be administered m combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect.
  • the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component.
  • a lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent.
  • Such combination therapies may be employed to achieve synergistic or additive therapeutic effects for the treatment of thromboembolic or other disorders.
  • terapéuticaally effective amount is meant an amount of a compound of Formula la, lb or Ic that when administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to prevent or ameliorate the disease condition or the progression of the disease.
  • administered in combination or “combination therapy” it is meant that the compound of Formula la, lb cr Ic and one or more additional therapeutic agents are administered concurrently to the mammal being treated.
  • each component may be administered at the same time or sequentially in any order at different points time.
  • each component may be administered separately but sufficiently closely time so as to provide the desired therapeutic effect.
  • antI-coagulant agents denotes agents that inhibit blood coagulation.
  • agents include warfarin sodium crystalline clathrate and heparin.
  • anti-platelet agents denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets.
  • agents include the various known non-steroidal anti- flammatory drugs (NSAIDS) such as aspirin, lbuprofen, naproxen, sulindac, mdomethacin, mefenamate, droxicam, diclofenac, sulf pyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof.
  • NSAIDS non-steroidal anti- flammatory drugs
  • lbuprofen naproxen
  • sulindac mdomethacin
  • mefenamate mefenamate
  • droxicam diclofenac
  • sulf pyrazone sulf pyrazone
  • piroxicam including pharmaceutically acceptable salts or prodrugs thereof.
  • suitable anti-platelet agents include ticlopid e, including pharmaceutically
  • Ticlopidme is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use.
  • Still other suitable platelet inhibitory agents include thromboxane- A2 ⁇ receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
  • thrombin inhibitors or anti-thrombm agents, as used herein, denotes inhibitors of the serine protease thrombin.
  • thromb -mediated processes such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrm formation are disrupted.
  • thrombin-mediated platelet activation that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin
  • fibrm formation include boroarginme derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof.
  • Such inhibitors include boroarginme derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof.
  • Boroargmine derivatives and boropeptides include
  • N-acetyl and peptide derivatives of boronic acid such as C-termmal ⁇ -ammoboronic acid derivatives of lys e, ormthme, argmme, homoarginine and corresponding isothiouronium analogs thereof.
  • hirudm includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.
  • Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Patent No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference.
  • Suitable boroargmine derivatives and boropeptide tnrombm inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471 651 A2, the disclosures of which are hereby incorporated herein by reference, in their entirety.
  • thrombolytics or fibr olytic agents
  • fibrinolytics agents that lyse blood clots (thrombi) .
  • agents include tissue plasminogen activator, amstreplase, urokinase, retivase or streptokinase, including pharmaceu ically acceptable salts or prodrugs thereof.
  • Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, California.
  • amstreplase refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No.
  • urokinase as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
  • the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the binding of vitronectin or fibrinogen to otv ⁇ 3 ⁇ Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving ctvfo.
  • the compounds of the present invention may also be used in diagnostic assays involving ⁇ y ⁇ s.
  • each of the two R 5a substituents on N is independently selected from the defined list of possible R 5a .
  • each of the two R 7 substituents on C is independently selected from the defined list of possible R 7 .
  • substituent when a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formula la, lb or Ic, then such substituent may be bonded via any atom m such substituent.
  • substituent when the substituent is piperaz yl, piperidinyl, or tetrazolyl, unless specified otherwise, said piperazmyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formula la, lb or Ic via any atom in such piperazmyl, piperidinyl, tetrazolyl group.
  • stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • substituted means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon conds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
  • alkylene alkenylene
  • phenylene phenylene
  • alkylene alkenylene
  • phenylene phenylene
  • alkylene alkenylene
  • phenylene phenylene
  • Halo or "halogen” as used herein refers to fluoro, chloro, bromo and lodo; and “countenon” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
  • aryl or “aromatic residue” is intended to mean phenyl or naphthyl; the term
  • arylalkyl represents an aryl group attached through an alkyl bridge.
  • carbocycle or “carbocyclic residue” is intended to mean any stable 3- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, mdanyl, adamantyl, or tetrahydronaphthyl (tetralm) .
  • heterocycle or “heterocyclic” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from tne group consisting of N, 0 and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl) , pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, mdolenyl, isoxazolmyl, isoxazolyl, qumolmyl, isoquinolmyl, benzimidazolyl, piperidinyl, 4-p ⁇ per ⁇ donyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolmyl, tetrahydrofurany
  • heteroaryl refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocyclic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, mdolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, qumolmyl, or isoquinolmyl.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound of Formula la, lb or Ic is modified by making acid or base salts of the compound of Formula la, lb or Ic.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to Formula la, lb or Ic in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of the compounds of Formula la, lb or Ic are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds .
  • Prodrugs include compounds of Formula la, lb or Ic wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy1, am o, sulfhydryl, or carboxyl group respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula la, lb or Ic, and the like.
  • Examples of representative carboxyl and ammo prodrugs are included under the definition of R 2 , R 3 , and Y.
  • the pharmaceutically acceptable salts of the compounds of Formula la, lb or Ic include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formula la, lb or Ic formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane ⁇ ulfomc, ethanedisulfonic, oxalic, lsethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succ
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula la, lb or Ic which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • the pharmaceutically acceptable salts of the acids of Formula la, lb or Ic may be prepared by reacting the acid with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dioenzyletnylenediam e, tnmethylamine, piperidme, pyrrolidine, benzylamme and the like, or a quaternary ammonium nydroxide such as tetramethylammonium hydroxide and the like.
  • a base such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium
  • an organic base such as an amine, e.g., dioenzyletnylenediam e, tnmethylamine, piperidme, pyrrolidine, benzylamme and the like, or a quaternary am
  • pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, m water or in an organic solvent, or m a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, .et-.a--c-, ethanol, isopropanol, or acetonitrile are preferred.
  • suitable salts are found in Remington ' s Pharmaceu ical Sci ences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled m the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
  • the requisite indazoles can be conveniently prepared from the commercially available nitrotoluic acids according to the example shown m Scheme 1.
  • Conversion of the acid la to a suitable ester such as the ethyl ester lb, may be carried out by one of many methods well-known to one skilled in the art of organic synthesis, for example treatment with a suitable base, such as sodium bicarbonate, in a suitable solvent, such as N,N-d ⁇ methylformam ⁇ de, followed by treatment with an alkyl halide, such as lodoethane.
  • Reduction of the nitro group of lb can be effected in a number of ways known to one skilled in the art of organic synthesis, including treatment with tm'IIi chloride m ethanol.
  • the resulting aniline derivative can be converted to the desired substituted dazole Ilia according to the method of Bartsch and Yang [J. Heterocycl . Chem. 1984,
  • Compounds of Formula la or lb wherein one or more of X 1 , X 2 , X 3 or X 4 are nitrogen may be prepared from the corresponding alkoxycaroonylmdazoles Illb in which the appropriate carbon atom or atoms have been replaced by nitrogen. These may in turn be prepared by substitution of the appropriately substituted heterocycle for the nitrotoluic acids, nitrotoluic acid esters, or am otoluic acid esters in Scheme 1 above.
  • the starting heterocycles could be obtained by following the procedures and methods in references outlined below, along with implementation of standard functional group transformations well known to one skilled in the art.
  • Functionalized pyrazines could be prepared according to procedures outlined in The Chemistry of Heterocyclic Compounds : The Pyrazines, Vol. 41 (Arnold Weissberger and Edward C. Taylor, Eds.), John Wiley and Sons (New York: 1982). Preparation of appropriately functionalized pyndazmes could be achieved using the methods described in The Chemistry of Heterocyclic Compounds : Condensed Pyridazmes Including Cinnolines and Phthalazines, Vol. 27 (Arnold Weissberger and Edward C. Taylor, Eds.), John Wiley and Sons (New York: 1973) and The Chemistry of Heterocyclic Compounds :
  • Compounds of Formula la wherein R 10 is not hydrogen may be prepared from appropriately substituted alkoxycarbonylindazoles. Some such substituted alkoxycarbonylindazoles may be prepared using the method outlined in Scheme 1. For example, methyl 4-amino-3- ethylbenzoate may be prepared as described by Witte and Boekelheide (J. Org. Chem. 1972, 22 (18) : 2849-2853) . This compound may be converted to the diazonium fluoroborate and cyclized to 3-methyl-5- methoxycarbonylmdazole using the method outlined in Scheme 1. This compound may be used as a starting material for preparation of the corresponding compounds of Formula la wherein R 10 is methyl.
  • substituted alkoxycarbonylindazoles may be prepared from unsubstituted alkoxycarbonylindazoles using the methods outlined in Scheme 2.
  • an ethoxycarbonylmdazole may be brommated by treatment with bromine m a suitable solvent, such as acetic acid, to provide the corresponding 3-bromo-ethoxycarbonyl- mdazole IIIc.
  • This compound may be coupled with a suitable reagent, alternatively followed by additional synthetic manipulations, to provide the desired 3- substituted-ethoxycarbonylmdazole.
  • Compounds IIIc, Hid, Hie and IHf may be used in the preparation of compounds of Formula la in which R 10 is phenyl, 2-phenylethynyl, or 2-phenylethyl, respectively.
  • further manipulations of the substituent may be accomplished at a later stage in the synthesis of the compound of Formula la.
  • the 2-phenylethynyl mdazoles Hie may be used in a synthetic sequence during the course of which the acetylene will be reduced, providing ultimately compounds of Formula la in which R 10 is 2-phenylethyl.
  • phrases such as “mdazoles III” and “mdazoles of Formula III” are meant to include simple mdazoles Ilia, mono- or diazaindazoles Illb, and substituted mdazoles such as but not restricted to IIIc, Hid, Hie and IHf. Substituted mono- and diazaindazoles such as but not restricted to mono- and diaza analogs of IIIc, Hid, Hie and IHf are also included.
  • Compounds of Formula la may be prepared from indazoles III as outlined in Scheme 3.
  • Alkylation of the mdazoles of Formula III with a suitably functionalized alkyl halide can oe effected in a variety of ways known to one skilled in the art. For example, using a method similar to that described by Granger et al. ( Chi . Ther. 1970, jj.: 24 ), an mdazole of Formula III is treated with a suitable base, such as potassium bis (trimethylsilyl) amide, followed by addition of the alkyl halide, for example, 3-bromopropylphthal ⁇ m ⁇ de.
  • a suitable base such as potassium bis (trimethylsilyl) amide
  • the alkylation can be carried out utilizing Mitsunobu conditions (Mitsunobu, Synthesis, 1981, 1-28) by addition of the corresponding alcohol, 3- hydroxypropylphthaliira.de, to a mixture of diethyl azodicarboxylate and triphenylphosphine in a suitable solvent, usually dry tetrahydrofuran, followed by addition of the mdazole III. Separation, if necessary, of the mixture of 1- and 2-substituted isomers by chromatography provides the desired 1-alkylated product 3a. Removal of the phthalimide may be achieved by treatment with anhydrous hydrazme to give the primary amine 3b.
  • 2-imidazolinyl- aminoalkylindazoles may be prepared by treatment of the amine 3b with a suitable reagent such as 2-methylthio- 4, 5-dihydroimidazoliurn iodide. Hydrolysis of the ester, using conventional methods known to one skilled in the art of organic synthesis, may be followed by coupling of the resulting acid to an appropriately substituted ⁇ - or ⁇ -amino ester such as a compound of Formula IV, to provide an intermediate which, after deprotection, affords compounds of Formula la wherein R 1 is 2- imidazolinylaminoalkyl. The coupling may be carried out using any of the many methods for the formation of amide bonds known to one skilled the art of organic synthesis.
  • Those methods include, but are not limited to, use of standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexyl- carbodiimide, diisopropylcarbodiiiru.de, or water-soluble carbodiimides (WSCDI) ) method, active ester (p- mtrophenyl ester, N-hydroxysuccinic imido ester) method, or by the use of one of many other known coupling reagent such as BOP-Cl.
  • Some of these methods can be enhanced by the addition of 1-hydroxybenzotr ⁇ azole to the reaction mixture.
  • Alkylation of the mdazole III may be achieved by treatment with an optionally substituted acrylonitrile in the presence of a catalytic amount of a base such as sodium ethoxide or sodium bis (tnmethylsilyl)amide, in a suitable solvent such as ethanol, to provide the intermediate it ⁇ le 4a.
  • a base such as sodium ethoxide or sodium bis (tnmethylsilyl)amide
  • a suitable solvent such as ethanol
  • Racemic ⁇ -substituted- ⁇ - am o esters may be prepared through the reaction of dialkylcuprates or alkyllithiums with 4-benzoyloxy-2- azetidinone followed by treatment with anhydrous ethanol (Scheme 5, Method 2) or by reductive animation of ⁇ -keto esters as is described in WO93/16038 (also see Rico et al., J. Org. Chem. , 1993, 5_ , 7948-51) .
  • Enantiomerically pure ⁇ -substituted- ⁇ -amino acids can be obtained through the optical resolution of the racemic mixture or can be prepared using numerous methods, including: Arndt- Eistert homologation of the corresponding ⁇ -amino acids as shown in Scheme 5, Method 3 (see Meier and Zeller, Angew. Chem. Int . Ed. Engl . , 1975 IA, 32; Rodriguez et al., Tetrahedron Let . , 1990, (31), 5153; Greenlee, J. Med. Chem.
  • N -subst t ted diaminopropiomc acid derivatives IV can be carried cut via Hoffmann rearrangement of a wide variety of asparagme derivatives as described, for example, by Waki et al . .Synthesis 1981, 266-267) or by Moore et al . (J. Med. Chem. 1976, 12.(6), 766-772).
  • They may also be prepared by manipulations, which will be familiar to one skilled in the art of organic synthesis, of the commercially available 3-ammo-2-benzyloxycarbonylam ⁇ noprop ⁇ on ⁇ c acid.
  • An example is shown m Scheme 6, Method 2.
  • This reduction may be performed using a number of methods known to one skilled in the art of organic synthesis, such as that using ammonium formate in the presence of 10% palladium on charcoal m refluxing ethanol, as described by Balicki ( Synthesis , 1989, 645-646), or by reduction with hydrogen in the presence of a catalyst such as palladium on charcoal or Raney nickel, or by treatment with triphenylphosphine.
  • the resulting 2- aminopyrid e moiety of 7b may be optionally protected, for example by treatment with di-t-butyldicarbonate in dry tetrahydrofuran in the presence of a suitable base, such as triethylamine or N,N-dimethylammopyridme, using the method of Iwanowicz ⁇ Synth . Commun . , 1993,
  • a suitable indazole III can be alkylated with an alkyl halide bearing a protected aldehyde, such as a 1,3- dioxolane, using conditions described above (see Scheme 3) to provide 8a.
  • Deprotection to the aldehyde 8b may be followed by reductive amination with a heteroarylamine such as 2- aminopyridine or a suitably protected 2-aminoimidazole, such as l-triphenylmethyl-2-aminoimidazole, in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, to provide the 1- (heteroarylaminoalkyl) indazole 8c.
  • a heteroarylamine such as 2- aminopyridine or a suitably protected 2-aminoimidazole, such as l-triphenylmethyl-2-aminoimidazole
  • a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • a route to 1- (heteroarylaminocarbonylethyl) indazoles of Formula la is outlined in Scheme 9.
  • a suitable indazole III can be alkylated by treatment with an acrylic acid ester such as tert-butyl acrylate, using a method such as that described in Scheme 4. Removal of the ester of 9a may be followed by conversion to a heteroaryl amide by treatment with a heteroaryl amme using any of a number of methods well known to one skilled in the art of organic synthesis.
  • the resulting 1- (heteroarylam ocarbonylethyl) mdazole 9b can then be elaborated to the corresponding compounds of Formula la, for example as described m Scheme 3.
  • indazole III may be alkylated by treatment with a suitable base, for example sodium hydride, followed by addition of a suitable alkylating agent such as an alkyl halide R 9 -Br or R 9 -I. Bromination of the intermediate 10a using, for example, bromine in acetic acid, provides the corresponding 3-bromo derivative 10b. (The order of these two synthetic steps may also be reversed. That is, the mdazole III may be brominated, and resulting bromoindazole may be alkylated, to provide similar products 10b.
  • a suitable base for example sodium hydride
  • a suitable alkylating agent such as an alkyl halide R 9 -Br or R 9 -I.
  • Compounds of Formula lb may alternatively be prepared from the intermediate 10b according to the method described in Scheme 11.
  • coupling of 10b under conditions similar to those described by Murakami et al. (Heterocycles, 1990, .11.(8), 1505-11) can provide a 3-allyl derivative Ila. Hydroboration as described by Brown and Subba Rao (J. Am. Chem. Soc. fi , 6428-6433) can provide the alcohol lib, which may be subjected to the Mitsunobu reaction ⁇ vide supra) with phthalimide followed by deprotection to provide an amine intermediate lie which, analogously to the method shown m Schemes 10 and 3, can be elaborated to the desired compounds of Formula lb.
  • the intermediate lib may be prepared by reduction of the aidenyde lOd shown in Scheme 10.
  • Other methods can be used for the conversion of intermediates lOd and lib to the primary amine lie which are known to those skilled in the art of organic synthesis.
  • Oxidation using silver(I) oxide as described by Campaigne and LeSuer ( Organic Syntheses , 1963, Coll. Vol. 4, 919), can provide the ⁇ es red carboxylic acid 12d.
  • Estenfication and deprotection of the ether oxygen of 12e using boron tribromide by a method analogous to that detailed by Manson and Musgrave (J. Chem. Soc. 1011 (1963)), can provide the hydroxy intermediate 12f.
  • Mitsunobu coupling, ⁇ vide supra ) followed by further transformations of 12g similar to those shown m Scheme 3, can provide compounds of Formula Ic.
  • Various compounds of Formula la, lb or Ic may be prepared from a common derivative of the corresponding compounds of Formula la, lb or Ic by functional grcup manipulations familiar to one skilled the art of organic synthesis.
  • preparation of compounds of Formula la having different sulfonamide substituents at R 16 may be achieved as outlined in Scheme 14.
  • the compound of Formula la having a benzyloxycarbonylammo group at R 16 (14a) may be hydrogenolyzed using, for example, hydrogen the presence of a catalyst such as palladium on charcoal to provide the primary amine derivative 14b.
  • a sulfonylatmg agent such as R 17 S0 C1 in the presence of an amme such as triethylamine to provide, after deprotection of the ester, the desired compound of Formula la.
  • a carboxylic acid, acid chloride or acid anhydride can provide the corresponding amide derivative
  • use of a chloroformate can provide the corresponding carbamate derivative
  • use of a sulfamoyl chloride can provide the corresponding sulfamide derivative
  • use of an lsocyanate can provide the corresponding urea derivative.
  • compounds of Formula la with different variations in R 1 may be prepared from a common precursor as outlined in Scheme 15.
  • the amine intermediate 3b may be reacted, for example, with benzyl chloroformate to provide the benzyl carbamate.
  • Hydrolysis of the ester can provide the acid intermediate 15a.
  • 15a may be reacted with, for example, a suitable beta-amino ester, followed by removal of the benzyl carbamate, for example by hydrogenolysis, to provide the amine intermediate 15b.
  • the amine may be converted to an aminoheterocyclic group.
  • the desired compound of Formula la may be obtained.
  • Mass spectra were measured using electrospray ionization (ESI) , ammonia chemical ionization (NH3-CI) , fast-atom bombardment from a glycol matrix (FAB) , or electron impact ionization (El) .
  • ESI electrospray ionization
  • NH3-CI ammonia chemical ionization
  • FAB fast-atom bombardment from a glycol matrix
  • El electron impact ionization
  • aqueous phase was extracted with additional ethyl acetate (3 x 25 mL) and the combined organic phases were washed with hydrochloric acid ( 1.0 K; 10 mL) , water (2 x 10 mL) , saturated aqueous sodium bicarbonate (10 mL) and brine v2 x 10 mL! . then were dried !MgS ⁇ 4) and concentrated under vacuum.
  • This material was combined with the crude product from another tun, starting from 10. ⁇ g of the product prepared according tc Ex m le 1 le Part .
  • Z Z . rrcl , tc provide the title product as a :r_de ⁇ ate ⁇ a- (23.0 g,' which was used m the next step without purification.
  • 6.51 is, 2H), 4.53 (t, 2H ⁇ , 4.06 (dd, IH) , 3.70 (dd, IH:, 3.50 (dd, IH) , 3.17 ⁇ z , H) , 2.59 (s, 6n) , 2. S ( ,
  • the pH of the mixture was ad -.st d to 8 witn aqueous ammcnia, ana the mixture was extracted w tn dichlcrcmethane.
  • the organic phase was concentrated to provide a solid (460 g > .
  • Th s was recrystallized from acetcn_.trile (1 CO mL; , and the rrystals were washed with et ancl, then hexar.e, and dri ⁇ u to provide 5 (231 g, 60%) as a tan solid: p 122- 124 C C; l H NMR (CDC1 3 ) 5 10.23 (bs, IH) , 8.57 (s, IH) ,
  • the solvent was removed under vacuum, and tne residue partitioned between toluene (2000 mL) and water '.1000 mL) .
  • the aqueous phase was further extracted with tol-ene (3 x 200 mLi , and the combined organic phases were washed with water 13 x 2CO mL) and brine (2 :: 200 mL) .
  • the organic phase was dried (MgS ⁇ 4) and concentrated under vacuum.
  • the pH of the residue was ad-j s si to 4, and the mixture was extracted with d ⁇ h-.cronethane and the combined organic phases were dried (Ma;_SC4, • ⁇ h mixture was filtered and the solids were washed with N,N-d ⁇ .nethylformamide to lecov r precipitated product.
  • N- ( 3-bromopropyl ) phthal ⁇ m ⁇ de (6.24 g, 23.3 mmol) dissolved in dry tetrahydrofuran (50 mL) was added. The mixture was heated at reflux for 16 h. The mixture was allowed to cool to room temperature and poured into water (200 mL) . The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum.
  • Example 1081 Part H Using the procedure of Example 1081 Part H, the product prepared according to Example 1099b Part A (100 mg, 150 ⁇ mol) was converted to the title product (90 mg, 96%) as a white solid: '-H NMR (DMSO-d ⁇ ) ⁇ 8.64 (t, IH) , 8.47 (d, IH) , 8.31 (s, IH) ,
  • A. 1- - (pyr ⁇ d ⁇ n-2-vlammo)propyl1 -5-carboxvmdazole A mixture of the product prepared according to Example 1081 Part D (1.04 g, 3.19 mmol), ethanol (16 mL) and aqueous sodium hydroxide (1.0 M; 16 ml, 16 mmol) was 0 stirred at reflux for 20 h. The mixture was allowed to cool to room temperature and aqueous hydrochloric acid (1.0 M; 16 mL, 16 mmol) was added.
  • Example 1081 Part H the product prepared according to Example 1108b Part D (60 mg, 110 ⁇ mol) was converted to the title product: : H NMR (DMSO-d 6 ) ⁇ 8.54 (m, IH) , 8.28 (s, IH) , 8.25 (s, IH) , 8.02 (d, IH) , 7.9-7.7 (m, 4H) , 6.90 (m, IH), 6.77 (m, IH) , 4.55 (t, 2H) , 4.44 (m, IH) , 3.61 ( , 2H) , 3.26 (m, 2H) , 2.16 (m, 3H) , 2.0-1.0 (m, 10H) ; High resolution mass spectrum (NH 3 -CI) calculated (M+H + ) 493.2563, found 493.2559.
  • Example 1081 Part H 3- n- T3- (N-pvr ⁇ dm-2-vTammo)nropv ⁇ mdazol-5-vl- rarbonv1ammo1-2fS)-(phenvlammocarhonvlam ⁇ no)nron ⁇ on ⁇ c acid trifluoroacetate
  • the product prepared according to Example 1110a Part A (68 mg, 104 ⁇ mol) was converted to the title product (44 mg, 68%) as a white solid after preparative reverse phase high pressure liquid cnromatcgraphy (aceton ⁇ t ⁇ le:water containing 0.05% trifluoroacetic acid, gradient from 1:9 to 9:1) : l K NMR (MeOH-d ) ⁇ 8.24 (s, IH) , 8.09 (s, IH) , 7.85-7.70 (m,
  • A. 1- (2-cvanoer.hyl) -5-ethoxvrarbonvlmdazole A mixture of the product prepared according to Example 1050e Part C (3.80 g, 20 mmol), acrylonit ⁇ le (7.9 mL, 120 mmol), sodium bis- (trimethylsilyl)amide (1.0 M in tetrahydrofuran; 1.0 mL, 1.0 mmol) and ethanol (40 mL) was heated to reflux. After 2 h, the solution was cooled to room temperature and treated with aqueous hydrochloric acid (1.0 M; 1.5 mL, 1.5 mmol) . After the mixture was partially concentrated under vacuum, a solid formed.
  • Example 1081 Part C i-r3-rN-,l-oxido)pvridin-2-vlamino1propvl1-5- e hoxvcarbonvlindazo e.
  • the product prepared according to Example 1129 Part B 566 mg, 2.0 mmol was converted to the title product (470 mg, 69%) .
  • This product is the same as the product of Example 1081 Part C.

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Abstract

Nouveaux hétérocycles comprenant de l'acide 3-[1-[3-(imidazolin-2-ylamino)propyl]indazol-5-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionique, qui sont utiles en tant qu'antagonistes des récepteurs de l'intégrine αvβ3 et de récepteurs de protéines adhésives de surface cellulaire associées, compositions pharmaceutiques contenant lesdits composés, procédés de préparation desdits composés et procédés d'utilisation desdits composés, seuls ou en combinaison avec d'autres agents thérapeutiques pour l'inhibition de l'adhésion cellulaire, le traitement des troubles angiogéniques, des inflammations, de la dégradation osseuse, des métastases cancéreuses, de la rétinopathie diabétique, de la thrombose, de la resténose, de la dégénérescence maculaire et d'autres troubles induits par l'adhésion cellulaire et/ou la migration cellulaire et/ou l'angiogenèse.
EP96944984A 1995-12-22 1996-12-18 Nouveaux antagonistes de recepteurs d'integrines Withdrawn EP0939757A1 (fr)

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