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WO1997023480A1 - Nouveaux antagonistes de recepteurs d'integrines - Google Patents

Nouveaux antagonistes de recepteurs d'integrines Download PDF

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Publication number
WO1997023480A1
WO1997023480A1 PCT/US1996/020523 US9620523W WO9723480A1 WO 1997023480 A1 WO1997023480 A1 WO 1997023480A1 US 9620523 W US9620523 W US 9620523W WO 9723480 A1 WO9723480 A1 WO 9723480A1
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Prior art keywords
alkyl
aryl
substituted
heteroaryl
ylamino
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PCT/US1996/020523
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English (en)
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Prabhakar Kondaji Jadhav
Joseph James Petraitis
Douglas Guy Batt
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The Du Pont Merck Pharmaceutical Company
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Publication date
Application filed by The Du Pont Merck Pharmaceutical Company filed Critical The Du Pont Merck Pharmaceutical Company
Priority to EP96944984A priority Critical patent/EP0939757A1/fr
Priority to JP9523845A priority patent/JP2000501105A/ja
Priority to AU13456/97A priority patent/AU1345697A/en
Publication of WO1997023480A1 publication Critical patent/WO1997023480A1/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 integrin 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 neovascularization is critical for normal physiological processes such as embryonic development and wound repair (Folkman and Shing, J.
  • angiogenesis also occurs pathologically, for example, in ocular neovascularization (leading to diabetic).
  • retinopathy retinopathy, neovascular glaucoma, retinal vein
  • 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 .
  • angiogenesis is crit ical to tumor survival .
  • tumor cells Without neovascularization, tumor cells lack the nourishment to divide and will not be able to leave the primary tumor site (Folkman and Shing, J. Biol. Chem., 1992, 267: 10931-10934).
  • the integrin ⁇ v ⁇ 3 is preferentially expressed on angiogenic blood vessels in chick and man (Brooks et al., Science, 1994, 264:569-571: Enenstein and Kramer, J. Invest.
  • integrins include but not limited to von Willebrand factor, fibronectin, and fibrin. Additionally, several members of the integrin family of adhesion receptors are expressed on the surface of endothelial, smooth muscle and on other circulating cells. Among these integrins is ⁇ v ⁇ 3 , the endothelial cell, fibroblast, and smooth muscle cell receptor for adhesive proteins including von Willebrand factor, fibrinogen (fibrin), vitronectin, thrombospondin, and osteopontin. These integrins initiate a calcium-dependent signaling pathway that can lead to endothelial cell and smooth muscle cell
  • ⁇ v ⁇ 3 integrin 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,
  • the integrin ⁇ v ⁇ 3 is a member of the ⁇ 3 integrin subfamily and has been described on platelets,
  • vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, von Willibrand factor, fibrinogen, osteopontin, bone
  • sialoprotein II and thrombospondin in a manner mediated by the RGD sequence.
  • fibrinogen receptor antagonists of the general formula shown below:
  • fibrinogen receptor antagonists of the general formula shown below:
  • the present invention provides novel nonpeptide compounds which bind to integrin 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 Ia, Ib or Ic (described below) which are useful as antagonists of the ⁇ v ⁇ 3 integrin.
  • the ⁇ v ⁇ 3 integrin is also referred to as the ⁇ v ⁇ 3
  • 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
  • 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
  • invention can be used for the treatment or prevention of restenosis.
  • the present invention also provides novel
  • rheumatoid arthritis 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 osteoarthritis, atherosclerosis,
  • metastasis metastasis, wound healing, diabetic retinopathy, ocular vasculopathies, inflammatory bowel disease and other autoimmune diseases.
  • kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula Ia, Ib or Ic, for the therapeutic inhibition of cell adhesion, the treatment of angiogenic disorders, inflammation, bone degradation, cancer metastasis, diabetic retinopathy, thrombosis,
  • the present invention provides novel compounds of Formula la, lb or Ic (described below) which bind to integrin 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 ⁇ v ⁇ 3 integrin.
  • the ⁇ v ⁇ 3 integrin is also referred to as the ⁇ v ⁇ 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
  • One aspect of the present invention comprises compounds of Formula la:
  • stereoisomeric forms thereof including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof, wherein:
  • X 1 , X 2 , X 3 , and X 4 are independently selected from
  • 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 1 -C 6 alkyl, (C 1 -C 6
  • cycloalkyl C 4 -C 11 cycloalkylalkyl, aryl,
  • heteroarylcarbonyl aryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl-, arylcarbonyl, C 1 -C 6 alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl)sulfonyl,
  • heteroarylsulfonyl heteroaryl (C 1 -C 6
  • alkyl alkyl
  • aryloxycarbonyl aryl(C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
  • R 3 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl,
  • R 4 and R 5 are independently selected from: H, C 1 -C 4
  • cycloalkylalkyl aryl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) carbonyl, (C 1 -C 6 alkoxy) carbonyl,
  • 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 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 , or NO 2 ;
  • U is selected from:
  • Q is selected from 1,2-cycloalkylene, 1,2-phenylene,
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, C 1 -C 6
  • alkyl C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl(C 0 -C 6 alkyl)-.
  • R 10 is selected from: H, C 1 -C 4 alkoxy substituted with 0- 1 R 21 , N(R 6 ) 2 , halogen, NO 2 , CN, CF 3 , CO 2 R 17 ,
  • C( O)R 17 , CONR 17 R 20 , -SO 2 R 17 , -SO 2 NR 17 R 20 , C 1 -C 6 alkyl substituted with 0-1 R 15 or 0-1 R 21 , C 3 -C 6 alkenyl 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 1 -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, NO 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 1 -C 6 alkyl)- substituted with
  • W is selected from:
  • X is -C(R 12 )(R 14 )-C(R 12 )(R 15 )-; or alternatively, W and X can be taken together to be
  • R 12 is selected from H, halogen, C 1 -C 6 alkyl, C 2 -C 6
  • R 13 is selected from H, C 1 -C 6 alkyl, C 3 -C 7
  • R 14 is selected from:
  • R 15 is selected from:
  • Y is selected from:
  • R 16 is selected from:
  • R 17 is selected from:
  • R 18 is selected from:
  • R 19 is selected from: hydroxy, C1-C 10 alkyloxy,
  • R 20 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl,
  • R 21 is selected from: COOH or NR 6 2; m is 0-4; n is 0- 4;
  • t 0 -4 ;
  • p is 0 - 2 ;
  • r 0 - 2 ; with the following provisos:
  • 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 unless U is
  • Preferred compounds of the invention as described above are compounds of the Formula Ia:
  • stereoisomeric forms thereof including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof, wherein:
  • X 1 , X 2 , X 3 , and X 4 are independently selected from
  • 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 1 -C 6 alkyl, (C 1 -C 6
  • alkyl)carbonyl (C 1 -C 6 alkoxy) carbonyl, C 1 -C 6 alkylaminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl (C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) carbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6
  • alkyl)sulfonyl heteroarylsulfonyl, heteroaryl(C 1 - C 6 alkyl)sulfonyl, aryloxycarbonyl, or aryl (C 1 -C 6 alkoxy)carbonyl, wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and nitro;
  • R 3 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl (C 1 -C 6 alkyl)-;
  • R 4 and R 5 are independently selected from: H, C 1 -C 4
  • 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 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 , or NO 2 ;
  • U is selected from:
  • Q is selected from 1,2-phenylene, 1,3-phenylene, 2,3- pyridinylene, 3,4-pyridinylene, or 2,4- pyridinylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, C 1 -C 6
  • alkyl C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl (C 0 -C 6 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 1 -C 4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C 1 -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 alkylaminosulfonyl substituted with 0-1 R 21 ;
  • X is -C(R 12 )(R 14 )-C(R 12 )(R 15 )-; alternatively, W and X can be taken together to be
  • R 12 is H or C 1 -C 6 alkyl
  • R 13 is selected from: H, C 1 -C 6 alkyl
  • R 14 is selected from:
  • heteroaryl (C 1 -C 6 alkyl)-, aryl, heteroaryl, CO 2 R 17 ,
  • R 15 is selected from:
  • Y is selected from:
  • R 16 is selected from:
  • R 17 is selected from:
  • R 18 is selected from:
  • R 19 is selected from: hydroxy, C 1 -C 10 alkyloxy,
  • R 20 selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 - C 11 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, or
  • R 21 is selected from COOH or NR 6 2 ; m is 0- 4 ;
  • n 0 - 4 ;
  • p 0-2 ;
  • q is 0- 2 ;
  • t is 0 - 4 ;
  • r is 0- 2 .
  • X 1 and X 3 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, NO 2 , CN, CF 3 , C 1 - C 4 alkoxy, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl;
  • Q is selected from 1,2-phenylene, 1,3-phenylene, 2,3- pyridinylene, 3,4-pyridinylene, or 2,4- pyridinylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 is selected from: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 - C 11 cycloalkylalkyl, aryl, aryl (C 1 -C 6 alkyl), heteroaryl, or heteroaryl (C 1 -C 6 alkyl);
  • R 10 is selected from: H, C 1 -C 4 alkoxy substituted with 0-1 R 21 , halogen, CO 2 R 17 , CONR 17 R 20 , C 1 -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 , or aryl(C 1 -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, NO 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 1 -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 -CH(R 14 )-CH(R 15 )-;
  • R 13 is H or CH 3
  • R 14 is selected from:
  • Y is -COR 19 ;
  • R 16 is selected from:
  • R 17 is selected from:
  • R 19 is selected from:
  • R 20 is H or CH 3 ;
  • R 21 is selected from COOH or NR 6 2 ; m is 0 or 1 ;
  • n 1-4 ;
  • Still further preferred compounds of the above invention are compounds of the Formula IIa or IIb:
  • X 1 and X 3 are independently selected from nitrogen or carbon, provided that at least one of X 1 and X 3 is carbon; R 1 is selected from:
  • Q is selected from 1,2-phenylere, 1,3-phenylene, 2,3- pyridinylene, 3,4-pyridinylene, or 2,4- pyridinylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl; R7 is selected from: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl,
  • R 10 is selected from: H, C 1 -C 4 alkoxy substituted with 0-1 R 21 , halogen, CO 2 R 17 , CONR 17 R 20 , C 1 -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 , or aryl(C 1 -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 ;
  • X is -CH(R 14 )-CH(R 15 )-;
  • R 13 is H or CH 3
  • R 14 is selected from:
  • R 15 is H or R 16 ;
  • Y is -COR 19 ;
  • R 16 is selected from:
  • R 17 is selected from:
  • R 19 is selected from:
  • R 20 is H or CH 3 ;
  • R 21 is selected from COOH or NR 6 2 ; m is 0 or 1;
  • n 1-4;
  • t 0 or 1.
  • enantiomeric or diasteriomeric forms thereof including enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof, selected from the group consisting of:
  • esters are also specifically preferred from the group consisting of:
  • 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, C 1 -C 6 alkyl, (C 1 -C 6
  • cycloalkyl C 4 -C 11 cycloalkylalkyl, aryl,
  • heteroarylcarbonyl aryl C 1 -C 6 alkyl, (C 1 -C 6 alkyl)carbonyl, or arylcarbonyl, C 1 -C 6
  • alkylsulfonyl arylsulfonyl, aryl(C 1 -C 6
  • R 3 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl (C 1 -C 6 alkyl)-;
  • R 4 and R 5 are independently selected from: H, C 1 -C 4
  • cycloalkylalkyl aryl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) carbonyl, (C 1 -C 6 alkoxy)carbonyl,
  • 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 -C 4 alkyl , C 1 -C 4 alkoxy, halo, cyano , amino , CF 3 , or NO 2 ;
  • U is selected from:
  • Q is selected from: 1,2-cycloalkylene, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 2,3-pyridinylene, 3,4-pyridinylene, 2,4-pyridinylene, 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 1 -C 6
  • 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 1 -C 4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C 1 -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 ;
  • W is selected from:
  • X is -C(R 12 )(R 14 )-C(R 12 )(R 15 )-; or alternatively, W and X can be taken together to be
  • R 12 is selected from: H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl,
  • R 13 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7
  • R 14 is selected from:
  • R 15 is selected from:
  • Y is selected from:
  • R 16 is selected from:
  • R 17 is selected from:
  • R 18 is selected from:
  • R 19 is selected from hydroxy, C 1 -C 10 alkyloxy,
  • R 20 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl,
  • R 21 is selected from COOH or NR 6 2 ; m is 0 - 4
  • n 0-4
  • r 0 - 2 with the following provisos:
  • t, n, m and q are chosen such that the number of atoms connecting R 1 and Y is in the range of
  • n and m are chosen such that the value of n plus m is greater than one unless U is
  • Preferred compounds of the invention as described above are compounds of the Formula lb:
  • stereoisomeric forms thereof including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof, wherein:
  • X 1 , X 2 , X 3 , and X 4 are independently selected from
  • 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 1 -C 6 alkyl, (C 1 -C 6
  • alkyl)carbonyl (C 1 -C 6 alkoxy)carbonyl, C 1 -C 6 alkylaminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl(C 1 -C 6 alkyl)carbonyl, heteroarylcarbonyl, aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl) carbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6
  • R 3 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl (C 1 -C 6 alkyl)-;
  • R 4 and R 5 are independently selected from: H, C 1 -C 4
  • 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 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 , or NO 2 ;
  • U is selected from:
  • Q is selected from 1,2-phenylene, 1,3-phenylene, 2,3- pyridinylene, 3,4-pyridinylene, or 2,4- pyridinylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, C 1 -C 6
  • alkyl C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl (C 1 -C 6 alkyl)-, or heteroaryl (C 0 -C 6 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 1 -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 ;
  • X is -C(R 12 )(R 14 )-C(R 12 )(R 15 )-; alternatively, W and X can be taken together to be ;
  • R 12 is H or C 1 -C 6 alkyl
  • R 13 is selected from: H, C 1 -C 6 alkyl
  • R 14 is selected from:
  • alkylthioalkyl)-, aryl(C 1 -C 10 alkoxyalkyl)-, C 1 -C 10 alkyl, C 1 -C 10 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, heteroaryl (C 1 -C 6 alkyl)-, aryl, heteroaryl, CO 2 R 17 , C( O)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 11 ; R 15 is selected from:
  • C 1 -C 10 alkylaminoalkyl, C 1 -C 10 dialkylaminoalkyl, C 1 -C 10 alkylcarbonyl, aryl (C 0 -C 6 alkyl)carbonyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl , C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, heteroaryl(C 1 -C 6 alkyl)-, aryl, heteroaryl, CO 2 R 17 , C( O)R 17 , CONR 17 R 20 , SO 2 R 17 , or SO 2 NR 17 R 20 , provided that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or
  • Y is selected from:
  • R 16 is selected from:
  • R 17 is selected from:
  • R 18 is selected from:
  • R 19 is selected from hydroxy, C 1 -C 10 alkyloxy,
  • C 5 -C 10 (5-alkyl-1,3-dioxa-cyclopenten-2-one- yl)methyloxy
  • C 10 -C 14 (5-aryl-1,3-dioxa-cyclopenten-
  • R 20 selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 - C 11 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, or
  • R 21 is selected from COOH or NR 6 2 ; m is 0-4 ;
  • n 0- 4 ;
  • t. is 0 - 4 ;
  • p is 0 - 2 ;
  • X 1 and X 3 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, NO 2 , CN, CF 3 , C 1 - C 4 alkoxy, C 1 -C 6 alkyl , and C 3 -C 7 cycloalkyl;
  • R 7 Q is selected from 1,2-phenylene, 1,3-phenylene, 2,3- pyridinylene, 3,4-pyridinylene, or 2,4- pyridinylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R7 is selected from: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 - C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl), heteroaryl, or heteroaryl (C 1 -C 6 alkyl);
  • R 9 is selected from: H, -SO 2 R 17 , -SO 2 NR 17 R 20 , C 1 -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 1 -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, NO 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 1 -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
  • X is -CH(R 14 )-CH(R 15 )-;
  • R 13 is H or CH 3
  • R 14 is selected from:
  • R 15 is H or R 16 ;
  • Y is -COR 19 ;
  • R 16 is selected from:
  • R 17 is selected from:
  • R 19 is selected from:
  • R 20 is H or CH 3 ;
  • R 21 is selected from COOH or NR 6 2 ; and m is 0 or 1;
  • n 1-4;
  • t 0 or 1.
  • Still further preferred compounds of the above invention are compounds of the Formula IIc or IId:
  • X 1 and X 3 are independently selected from nitrogen or carbon, provided that at least one of X 1 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, NO 2 , CN, CF 3 , C 1 - C 4 alkoxy, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl:
  • Q is selected from 1,2-phenylene, 1, 3-phenylene, 2,3- pyridinylene, 3,4-pyridinylene, or 2,4- pyridinylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R7 is selected from: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 - C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl), heteroaryl, or heteroaryl(C 1 -C 6 alkyl);
  • R 9 is selected from: H, -SO 2 R 17 , -SO 2 NR 17 R 20 , C 1 -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 1 -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 ;
  • X is -CH(R 14 )-CH(R 15 )-;
  • R 13 is H or CH 3
  • R 14 is selected from:
  • R 15 is H or R 16 ;
  • Y is -COR 19 ;
  • R 16 is selected from:
  • R 17 is selected from:
  • heteroaryl groups are optionally substituted with
  • 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 NO 2 ;
  • R 19 is selected from:
  • R 20 is H or CH 3 ;
  • R 21 is selected from COOH or NR 6 2 ; and m is 0 or 1;
  • n 1-4;
  • t 0 or 1.
  • enantiomeric or diasteriomeric forms thereof including enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof, selected from the group consisting of:
  • esters are also specifically preferred, said esters being chosen from the group consisting of:
  • 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 1 -C 6 alkyl, (C 1 -C 6
  • cycloalkyl C 4 -C 11 cycloalkylalkyl, aryl,
  • heteroarylcarbonyl aryl C 1 -C 6 alkyl, (C 1 -C 6 alkyl) carbonyl, or arylcarbonyl, C 1 -C 6
  • alkylsulfonyl alkylsulfonyl, arylsulfonyl, aryl (C 1 -C 6
  • R 3 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl,
  • R 4 and R 5 are independently selected from: H, C 1 -C 4
  • cycloalkylalkyl aryl, aryl (C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, (C 1 -C 6 alkoxy)carbonyl,
  • 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 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 , or NO 2 ;
  • U is selected from:
  • Q is selected from 1,2-cycloalkylene, 1,2-phenylene,
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R 7 and R 8 are independently selected from: H, C 1 -C 6
  • alkyl C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, or heteroaryl (C 0 -C 6 alkyl)-;
  • R 11 is selected from H, halogen, CF3, CN, NO 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 15 or 0-1 R 21 ;
  • X is -C(R 12 )(R 14 )-C(R 12 )(R 15 )-; or alternatively, W and X can be taken together to be
  • R 12 is selected from: H, halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl,
  • R 13 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7
  • R 14 is selected from:
  • R 15 is selected from:
  • Y is selected from:
  • R 16 is selected from:
  • R 17 is selected from:
  • R 18 is selected from:
  • R 19 is selected from hydroxy, C 1 -C 10 alkyloxy,
  • R 20 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl,
  • R 21 is selected from COOH or NR 6 2 ; m is 0-4;
  • n 0-4;
  • p 0-2;
  • r 0-2; with the following provisos:
  • 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 unless U 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 1 -C 6 alkyl, (C 1 -C 6
  • alkyl)carbonyl (C 1 -C 6 alkoxy) carbonyl, C 1 -C 6 alkylaminocarbonyl, C 3 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl (C 1 -C 6 alkyl) carbonyl, heteroarylcarbonyl, aryl(C 1 -C 6 alkyl)-, (C 1 -C 6 alkyl)carbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, aryl(C 1 -C 6 alkyl) sulfonyl, heteroarylsulfonyl,
  • R 3 is selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl,
  • R 4 and R 5 are independently selected from: H, C 1 -C 4
  • 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 -C 4 alkyl, C 1 -C 4 alkoxy, halo, cyano, amino, CF 3 , or NO 2 ;
  • U is selected from:
  • Q is selected from 1,2-phenylene, 1,3-phenylene, 2,3- pyridinylene, 2,4-pyridinylene, or 2,4- pyridinylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl; R 7 and R 8 are independently selected from: H, C 1 -C 6
  • 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 1 -C 4 alkoxy substituted with 0-1 R 21 , aryl substituted with 0-1 R 21 , aryl(C 1 -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 -C4 alkylsulfonyl substituted with 0-1 R 21 , or
  • X is -C(R 12 )(R 14 )-C(R 12 )(R 15 )-; alternatively, W and X can be taken together to be ;
  • R 12 is H or C 1 -C 6 alkyl;
  • R 13 is selected from: H, C 1 -C 6 alkyl
  • R 14 is selected from:
  • alkylthioalkyl)-, aryl(C ⁇ -C 10 alkoxyalkyl)-, C 1 -C 10 alkyl, C 1 -C 10 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, heteroaryl (C 1 -C 6 alkyl)-, aryl, heteroaryl, CO 2 R 17 , C( O)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 11 ;
  • R 15 is selected from:
  • Y is selected from:
  • R 16 is selected from:
  • R 17 is selected from:
  • R 18 is selected from:
  • R 19 is selected from: hydroxy, C 1 -C 10 alkyloxy,
  • R 20 selected from: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 - C 11 cycloalkylalkyl, aryl(C 1 -C 6 alkyl)-, or
  • R 21 is selected from COOH or NR 6 2 ; m is 0-4;
  • n 0-4;
  • t 0-4;
  • p 0-2;
  • r is 0-2.
  • stereoisomeric forms thereof including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof, wherein:
  • R 1 is selected from:
  • Q is selected from 1,2-phenylene, 1,3-phenylene, 2,3- pyridinylene, 3,4-pyridinylene, or 2,4- pyridinylene;
  • R 6 is selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R7 is selected from: C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl,
  • R 9 is selected from: H, -SO 2 R 17 , -SO 2 NR 17 R 20 , C 1 -C 6 alkyl substituted with 0-1 R 15 or 0-1 R 21 , C 3 -C 7
  • 0-1 R 21 or aryl(C 1 -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, NO 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 1 -C 6 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 13 is H or CH 3;
  • R 14 is selected from:
  • R 15 is H or R 16 ;
  • Y is -COR 19 ;
  • R 16 is selected from:
  • R 17 is selected from:
  • R 19 is selected from:
  • R 20 is H or CH 3 ;
  • R 21 is selected from COOH or NR 6 2 ; and m is 0 or 1 ;
  • n 1-4 ;
  • t is 0 or 1 .
  • Still further preferred compounds of the above described are compounds of the Formula IIe or IIf:
  • R 1 is selected from:
  • Q is selected from 1,2-phenylene, 1,3-phenylene, 2,3- pyridinylene, 2,4-pyridinylene, or 2,4- pyridinylene;
  • R 6 selected from: H, C 1 -C 4 alkyl, or benzyl;
  • R7 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl),
  • R 9 is selected from: H, -SO 2 R 17 , -SO 2 NR 17 R 20 , C 1 -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 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 1 -C 6 alkyl)- substituted with 0-1 R 15 or 0-2 R 11 or 0-1 R 21 ;
  • X is -CH(R 14 )-CH(R 15 )-;
  • R 13 is H or CH 3 ;
  • 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:

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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.
PCT/US1996/020523 1995-12-22 1996-12-18 Nouveaux antagonistes de recepteurs d'integrines WO1997023480A1 (fr)

Priority Applications (3)

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EP96944984A EP0939757A1 (fr) 1995-12-22 1996-12-18 Nouveaux antagonistes de recepteurs d'integrines
JP9523845A JP2000501105A (ja) 1995-12-22 1996-12-18 新規なインテグリン受容体アンタゴニスト
AU13456/97A AU1345697A (en) 1995-12-22 1996-12-18 Novel integrin receptor antagonists

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US908895P 1995-12-22 1995-12-22
US64666396A 1996-05-08 1996-05-08
US2569996P 1996-09-09 1996-09-09
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US60/025,699 1996-09-09
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US6569402B1 (en) 1998-12-18 2003-05-27 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
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US6750219B1 (en) 1999-08-05 2004-06-15 Meiji Seika Kaisha, Ltd. Ω-amino-α-hydroxycarboxylic acid derivatives having integrin ανβ3 antagonistic activity
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US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
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JP2000501105A (ja) 2000-02-02

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