US20070249600A1 - Chemical compounds - Google Patents

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US20070249600A1
US20070249600A1 US11/763,524 US76352407A US2007249600A1 US 20070249600 A1 US20070249600 A1 US 20070249600A1 US 76352407 A US76352407 A US 76352407A US 2007249600 A1 US2007249600 A1 US 2007249600A1
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aminocarbonylamino
benzimidazol
phenoxy
phenyl
methyl
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US11/763,524
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Mui Cheung
Philip Harris
Masaichi Hasegawa
Satoru Ida
Kazuya Kano
Naohiko Nishigaki
Hideyuki Sato
James Veal
Yoshiaki Washio
Rob West
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • 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
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    • 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
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    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to benzimidazole derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments.
  • Such benzimidazole derivatives are useful in the treatment of diseases associated with inappropriate or pathological angiogenesis.
  • angiogenesis is the development of new blood vessels, generally capillaries, from pre-existing vasculature.
  • Angiogenesis is defined as involving (i) activation of endothelial cells; (ii) increased vascular permeability; (iii) subsequent dissolution of the basement membrane and extravisation of plasma components leading to formation of a provisional fibrin gel extracellular matrix; (iv) proliferation and mobilization of endothelial cells; (v) reorganization of mobilized endothelial cells to form functional capillaries; (vi) capillary loop formation; and (vii) deposition of basement membrane and recruitment of perivascular cells to newly formed vessels.
  • Normal angiogenesis is activated during tissue growth, from embryonic development through maturity, and then enters a period of relative quiescence during adulthood. Normal angiogensesis is also activated during wound healing, and at certain stages of the female reproductive cycle. Inappropriate or pathological angiogenesis has been associated with several disease states including various retinopathies; ischemic disease; atherosclerosis; chronic inflammatory disorders; and cancer. The role of angiogenesis in disease states is discussed, for instance, in Fan et al, Trends in Pharmacol Sci. 16:54-66; Shawver et al, DDT Vol. 2, No. 2 February 1997; Folkmann, 1995, Nature Medicine 1:27-31.
  • VEGF vascular endothelial growth factor
  • VAGFR vascular endothelial growth factor receptor
  • VEGF vascular endothelial growth factor
  • VEGFR(s) are protein tyrosine kinases (PTKs). PTKs catalyze the phosphorylation of specific tyrosyl residues in proteins involved in the regulation of cell growth and differentiation.
  • VEGFR-1 Flt-1
  • VEGFR-2 Flk-1 or KDR
  • VEGFR-3 Flt-4
  • VEGF vascular endothelial growth factor-1
  • Activation of VEGFR-2 by VEGF is a critical step in the signal transduction pathway that initiates tumor angiogenesis.
  • VEGF expression may be constitutive to tumor cells and can also be upregulated in response to certain stimuli.
  • VEGF vascular endothelial growth factor
  • the VEGF ligand activates VEGFR-2 by binding with its extracellular VEGF binding site. This leads to receptor dimerization of VEGFRs and autophosphorylation of tyrosine residues at the intracellular kinase domain of VEGFR-2.
  • the kinase domain operates to transfer a phosphate from ATP to the tyrosine residues, thus providing binding sites for signaling proteins downstream of VEGFR-2 leading ultimately to initiation of angiogenesis (McMahon, G., The Oncologist, Vol. 5, No. 90001, 3-10, April 2000).
  • Angiopoieten 1 (Angl), a ligand for the endothelium-specific receptor tyrosine kinase TIE-2 is a novel angiogenic factor (Davis et al, Cell, 1996, 87:1161-1169; Partanen et al, Mol. Cell. Biol, 12:1698-1707 (1992); U.S. Pat. Nos. 5,521,073; 5,879,672; 5,877,020; and 6,030,831).
  • TIE represents “tyrosine kinase containing Ig and EGF homology domains”.
  • TIE is used to identify a class of receptor tyrosine kinases, which are exclusively expressed in vascular endothelial cells and early hemopoietic cells.
  • TIE receptor kinases are characterized by the presence of an EGF-like domain and an immunoglobulin (IG) like domain, which consists of extracellular folding units, stabilized by intra-chain disulfide bonds (Partanen et al Curr. Topics Microbiol. Immunol., 1999, 237:159-172).
  • IG immunoglobulin
  • Ang1 and its receptor TIE-2 function in the later stages of vascular development, i.e., during vascular remodeling (remodeling refers to formation of a vascular lumen) and maturation (Yancopoulos et al, Cell, 1998, 93:661-664; Peters, K. G., Circ. Res., 1998, 83(3):342-3; Suri et al, Cell 87, 1171-1180 (1996)).
  • TIE-2 would be expected to serve to disrupt remodeling and maturation of new vasculature initiated by angiogenesis thereby disrupting the angiogenic process.
  • inhibition at the kinase domain binding site of VEGFR-2 would block phosphorylation of tyrosine residues and serve to disrupt initiation of angiogenesis.
  • inhibition of TIE-2 and/or VEGFR-2 should prevent tumor angiogenesis and serve to retard or eradicate tumor growth. Accordingly, a treatment for cancer or other disorder associated with inappropriate angiogenesis could be provided.
  • benzimidazole compounds which are inhibitors of TIE-2 and/or VEGFR-2 kinase activity.
  • Such benzimidazole derivatives are useful in the treatment of disorders, including cancer, associated with inappropriate angiogenesis.
  • A is aryl, heteroaryl, or heterocyclic
  • X is S, O, S(O) 2 , S(O), CH 2 , CH(OH), or C(O);
  • Z is O or S
  • p is 0 or 1;
  • q is 0 or 1
  • the dotted line bonds “---” attached to N′ and N′′ represent a single bond or a double bond wherein when q is 0 the dotted line bond “---” attached to N′ is a single bond and the dotted line bond attached to N′′ is a double bond, and when q is 1 the dotted line bond “---” attached to N′ is a double bond and the dotted line bond attached to N′′ is a single bond;
  • R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, heterocyclic, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, aralkyl, aralkoxy, aryloxy, C 1 -C 6 alkylsulfanyl, C 1 -C 6 haloalkylsulfanyl, C 1 -C 6 alkylsulfenyl, C 1 -C 6 alkylsulfonyl, —NO 2 , —NR 4 R 5 , —C(O)OR 6 , —CN, —C(O)NR 4 R 5 , —S(O) 2 NR 4 R 5 , or cyanoalkyl;
  • R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylsulfanyl, C 1 -C 6 haloalkylsulfanyl, C 1 -C 6 alkylsulfenyl, C 1 -C 6 alkylsulfonyl, oxo, hydroxy, —NO 2 , —NR 4 R 5 , —C(O)OR 6 , —CN, —C(O)NR 4 R 5 , —S(O) 2 NR 4 R 5 , or cyanoalkyl;
  • R 3 is hydrogen, C 1 -C 6 alkyl, aryl, aralkyl, aralkoxy, heteroaryl, heterocyclic, —RR 6 , —RNR 4 R 5 , —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 , —C(O)RC(O)OR 6 , —C(O)RR 6 , —C(O)RR′ R 6 , —C(O)ROR′OR′′OR 6 , —C(O)ROR′OR 6 , —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , —C(O)RNR 4 C(O)OR 6 , —C(O)ORNR 4 R 5 , —S(O) 2 R 6 , or —S(O) 2 NR 4 R 5 ; or
  • R 3 is C 1 -C 6 alkylene or C 1 -C 6 alkylene substituted with oxo, and is linked together with the nitrogen to which it is attached and to one of the benzimidazole nitrogens to form a heterocylic compound fused to the benzimidazole;
  • R, R′, and R′′ are each independently selected from C 1 -C 6 alkylene, arylene, heteroarylene, C 3 -C 7 cycloalkylene, or heterocyclylene;
  • R′′′ is C 1 -C 6 alkyl, aryl, heteroaryl, aralkyl, C 3 -C 7 cycloalkyl, or heterocyclic;
  • R 4 and R 5 are each independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkylsulfanyl, C 1 -C 6 alkylsulfenyl, C 1 -C 6 alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C 3 -C 7 cycloalkyl, —C(O)OR 6 , —C(O)NR′′′R′′′, —C(O)NR′′′H, —C(O)NH 2 , or
  • R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic, or C 3 -C 7 cycloalkyl;
  • R 7 is hydrogen, C 1 -C 6 alkyl, —S(O) 2 R 6 , —RNR 4 R 5 , —RR 6 ;
  • R 8 is hydrogen or halogen.
  • a pharmaceutical composition including a therapeutically effective amount of a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.
  • a method of treating a disorder in a mammal, said disorder being mediated by inappropriate TIE-2 activity including: administering to said mammal a therapeutically effective amount of a compound of formula (I) or a salt, solvate or a physiologically functional derivative thereof.
  • a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate TIE-2 activity.
  • a method of treating a disorder in a mammal including: administering to said mammal therapeutically effective amounts of (i) a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof and (ii) an agent to inhibit growth factor receptor function.
  • a method of treating a disorder in a mammal, said disorder being characterized by inappropriate angiogenesis including: administering to said mammal a therapeutically effective amount of a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof.
  • the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • alkyl refers to a straight or branched chain hydrocarbon having from one to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfanyl, C 1 -C 6 alkylsulfenyl, C 1 -C 6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or C 1 -C 6 perfluoroalkyl, multiple degrees of substitution being allowed.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.
  • C 1 -C 6 alkyl refers to an alkyl group as defined above containing at least 1, and at most 6, carbon atoms.
  • Examples of branched or straight chained “C 1 -C 6 alkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, and isopentyl.
  • alkylene refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.
  • C 1 -C 6 alkylene refers to an alkylene group, as defined above, which contains at least 1, and at most 6, carbon atoms respectively.
  • Examples of “C 1 -C 6 alkylene” groups useful in the present invention include, but are not limited to, methylene, ethylene, and n-propylene.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • C 1 -C 6 haloalkyl refers to an alkyl group as defined above containing at least 1, and at most 6, carbon atoms substituted with at least one halogen, halogen being as defined herein.
  • Examples of branched or straight chained “C 1 -C 6 haloalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo and iodo.
  • C 3 -C 7 cycloalkyl refers to a non-aromatic cyclic hydrocarbon ring having from three to seven carbon atoms and which optionally includes a C 1 -C 6 alkyl linker through which it may be attached.
  • the C 1 -C 6 alkyl group is as defined above.
  • Exemplary “C 3 -C 7 cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • C 3 -C 7 cycloalkylene refers to a non-aromatic alicyclic divalent hydrocarbon radical having from three to seven carbon atoms, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • cycloalkylene examples include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.
  • heterocyclic or the term “heterocyclyl” refers to a three to twelve-membered heterocyclic ring having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, SO 2 , O, or N, optionally substituted with substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfanyl, C 1 -C 6 haloalkylsulfanyl, C 1 -C 6 alkylsulfenyl, C 1 -C 6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen,
  • Such a ring may be optionally fused to one or more other “heterocyclic” ring(s) or cycloalkyl ring(s).
  • heterocyclic moieties include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
  • heterocyclylene refers to a three to twelve-membered heterocyclic ring diradical having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO 2 , O, or N, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • Such a ring may be optionally fused to one or more benzene rings or to one or more of another “heterocyclic” rings or cycloalkyl rings.
  • heterocyclylene include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, and the like.
  • aryl refers to an optionally substituted benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings to form, for example, anthracene, phenanthrene, or napthalene ring systems.
  • Exemplary optional substituents include C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfanyl, C 1 -C 6 alkylsulfenyl, C 1 -C 6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C 1 -C 6 perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed.
  • aryl include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl,
  • arylene refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl and aryl, multiple degrees of substitution being allowed.
  • substituents selected from the group which includes lower alky
  • aralkyl refers to an aryl or heteroaryl group, as defined herein, attached through a C 1 -C 6 alkyl linker, wherein C 1 -C 6 alkyl is as defined herein.
  • Examples of “aralkyl” include, but are not limited to, benzyl, phenylpropyl, 2-pyridylmethyl, 3-isoxazolylmethyl, 5-methyl, 3-isoxazolylmethyl, and 2-imidazoyl ethyl.
  • heteroaryl refers to a monocyclic five to seven membered aromatic ring, or to a fused bicyclic aromatic ring system comprising two of such monocyclic five to seven membered aromatic rings.
  • These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen heteroatoms, where N-oxides and sulfur oxides and dioxides are permissible heteroatom substitutions and may be optionally substituted with up to three members selected from a group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfanyl, C 1 -C 6 haloalkylsulfanyl, C 1 -C 6 alkylsulfenyl, C 1 -C 6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl
  • heteroaryl groups used herein include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, and substituted versions thereof.
  • heteroarylene refers to a five- to seven-membered aromatic ring diradical, or to a polycyclic heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of: lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro
  • heteroarylene used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.
  • alkoxy refers to the group R a O—, where R a is alkyl as defined above and the term “C 1 -C 6 alkoxy” refers to an alkoxy group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
  • Exemplary C 1 -C 6 alkoxy groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
  • haloalkoxy refers to the group R a O—, where R a is haloalkyl as defined above and the term “C 1 -C 6 haloalkoxy” refers to an haloalkoxy group as defined herein wherein the haloalkyl moiety contains at least 1, and at most 6, carbon atoms.
  • Exemplary C 1 -C 6 haloalkoxy groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy substituted with one or more halo groups, for instance trifluoromethoxy.
  • aralkoxy refers to the group R b R a O—, where R a is alkyl and R b is aryl as defined above.
  • aryloxy refers to the group R a O—, where R a is aryl as defined above.
  • alkylsulfanyl refers to the group R a S—, where R a is alkyl as defined above and the term “C 1 -C 6 alkylsulfanyl” refers to an alkylsulfanyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
  • haloalkylsulfanyl refers to the group R a S—, where R a is haloalkyl as defined above and the term “C 1 -C 6 haloalkylsulfanyl” refers to a haloalkylsulfanyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
  • alkylsulfenyl refers to the group R a S(O)—, where R a is alkyl as defined above and the term “C 1 -C 6 alkylsulfenyl” refers to an alkylsulfenyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
  • alkylsulfonyl refers to the group R a SO 2 —, where R a is alkyl as defined above and the term “C 1 -C 6 alkylsulfonyl”refers to an alkylsulfonyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
  • oxo refers to the group ⁇ O
  • mercapto refers to the group —SH.
  • cyano refers to the group —CN.
  • cyanoalkyl refers to the group —CNR a , wherein R a is alkyl as defined above.
  • exemplary “cyanoalkyl” groups useful in the present invention include, but are not limited to, cyanomethyl, cyanoethyl, and cyanoisopropyl.
  • aminosulfonyl refers to the group —SO 2 NH 2 .
  • carbamoyl refers to the group —C(O)NH 2 .
  • sulfanyl shall refer to the group —S—.
  • sulfenyl shall refer to the group —S(O)—.
  • sulfonyl shall refer to the group —S(O) 2 — or —SO 2 —.
  • acyl refers to the group R a C(O)—, where R a is alkyl, cycloalkyl, or heterocyclyl as defined herein.
  • aroyl refers to the group R a C(O)—, where R a is aryl as defined herein.
  • heteroaroyl refers to the group R a C(O)—, where R a is heteroaryl as defined herein.
  • alkoxycarbonyl refers to the group R a OC(O)—where R a is alkyl as defined herein.
  • acyloxy refers to the group R a C(O)O—, where R a is alkyl, cycloalkyl, or heterocyclyl as defined herein.
  • aroyloxy refers to the group R a C(O)O—, where R a is aryl as defined herein.
  • heteroaroyloxy refers to the group R a C(O)O—, where R a is heteroaryl as defined herein.
  • the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.
  • physiologically functional derivative refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof.
  • physiologically functional derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5 th Edition, Vol 1: Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or formula (II) or a salt or physiologically functional derivative thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
  • substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
  • the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formulae (I) and (II) above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that all tautomers and mixtures of tautomers of the compounds of formulae (I) or (II) are included within the scope of the compounds of formulae (I) and (II).
  • E is aryl substituted with R 1 and R 2 .
  • E is phenyl substituted with R 1 and R 2 .
  • E is unsubstituted heteroaryl, heteroaryl substituted with R 1 , or heteroaryl substituted with R 1 and R 2 .
  • E is heteroaryl substituted with R 1 or heteroaryl substituted with R 1 and R 2 .
  • E is heteroaryl substituted with R 1 , wherein R 1 is preferably C 1 -C 6 alkyl, more preferably —C(CH 3 ) 3 , i.e. tert-butyl.
  • E is selected from either unsubstituted, substituted by R 1 or substituted by R 1 and R 2 .
  • E is phenyl and R 1 and R 2 together with the phenyl ring atoms with which they are attached form a cycloalkyl, preferably cyclopentyl, or aryl, preferably phenyl fused to E.
  • the compound of formula (I) is a compound of formula (III): or salt, solvate, or physiologically functional derivative thereof.
  • the compound of formula (I) is a compound of formula (IV): wherein E is unsubstituted heteroaryl, heteroaryl substituted with R 1 , or heteroaryl substituted with R 1 and R 2 , or a salt, solvate, or physiologically functional derivative thereof.
  • R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryloxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylsulfanyl, C 1 -C 6 alkylsulfanyl, —C(O)OR 6 , halogen, —CN, or —NO 2 .
  • R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —NO 2 , or halogen.
  • R 1 is —NO 2 , —OCH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CF 3 , —F, —Cl, and —Br.
  • R 1 is C 1 -C 6 haloalkyl, preferably —CF 3 .
  • R 1 is C 1 -C 6 alkyl, preferably —C(CH 3 ) 3 .
  • R 2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl. In a preferred embodiment, R 2 is hydrogen or halogen. In a more preferred embodiment, R 2 is hydrogen, —F, —Cl, or —Br. In a most preferred embodiment, R 2 is fluorine.
  • R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryloxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylsulfanyl, C 1 -C 6 alkylsulfanyl, —C(O)OR 6 , halogen, —CN, or NO 2 and R 2 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl.
  • R 1 is C 1 -C 6 haloalkyl and R 2 is hydrogen or halogen.
  • R 1 is NO 2 , —OCH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CF 3 , —F, —Cl, and —Br and R 2 is hydrogen, —F, —Cl, or —Br.
  • R 1 is —CF 3 and R 2 is fluorine.
  • Z is S or O. In one embodiment, Z is S. In a preferred embodiment, Z is O.
  • A is aryl or heteroaryl.
  • A is phenyl, 2-pyridyl or 3-pyridyl. In a more preferred embodiment A is phenyl.
  • X is S, O, S(O) 2 , S(O), CH 2 , CH(OH), or C(O). In a preferred embodiment, X is O or C(O). In a more preferred embodiment, X is O. In another embodiment, X is S.
  • the side chain —NHC(Z)NHE of the compounds of formula (I) and formula (II) may be linked to any suitable position of the group A.
  • the linker group X linking the benzimidazole core to the group A may be linked to any suitable position of the group A.
  • the group A is linked to the side chain —NHC(Z)NHE and to the linker group X of the benzimidazole core through a ( ⁇ 1,3-) or ( ⁇ 1,4-) linkage.
  • the group A is linked through a ( ⁇ 1,4-) linkage.
  • the group A is linked through a ( ⁇ 1,3-) linkage.
  • the two dotted line bonds represented by “---”, which are attached to Q and N′ in the five-membered heterocyclic core of Formula I, may represent a single bond or a double bond.
  • the dotted line bond “---” attached to Q is a single bond and the dotted line bond attached to N′ is a double bond as illustrated following:
  • the dotted line within the 6 membered ring containing D, M, and T of Formula I, represents the appropriate aromatic bonds.
  • D is CH
  • T is CR 8
  • M is C and Q is N(R 7 ) p , wherein p is 0, q is 1, R 7 is hydrogen, methyl, or S(O) 2 R 6 or D is CH
  • T is CR 8 , wherein R 8 is hydrogen or —Br
  • M is C and Q is N(R 7 ) p , wherein p is 1, q is 0, R 7 is hydrogen, methyl, —S(O) 2 R 6 , —RNR 4 R 5 , —RR 6 or aralkyl.
  • D is CH
  • T is CR 8
  • R 8 is hydrogen
  • M is C and Q is N(R 7 ) p , wherein either p or q is 0, the other is 1 and R 7 is hydrogen.
  • D is CH, T is CR 8 , wherein R 8 is hydrogen or —Br, M is C and Q is S or O; wherein q is 0.
  • D is N
  • T is CR 8 , wherein R 8 is hydrogen or —Br, M is C and Q is N(R 7 ) p , wherein either p or q is 0, the other is 1, R 7 is hydrogen, methyl, or S(O) 2 R 6 .
  • D is CH, T is N, M is C and Q is N(R 7 ) p , wherein either p or q is 0, the other is 1, R 7 is hydrogen, methyl, or S(O) 2 R 6 .
  • D is CH
  • T is CR 8 , wherein R 8 is hydrogen or —Br, M is N and Q is CH, wherein q is 0.
  • R 3 is —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 , —C(O)RC(O)OR 6 , —C(O)ROR′OR′′OR 6 , —C(O)ROR′OR 6 , —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , —C(O)RNR 4 C(O)OR 6 , —SO 2 R 6 , or —SO 2 NR 4 R 5 ;
  • R 3 is —C(O)R 6 , —C(O)NR 4 R 5 , or —C(O)OR 6 .
  • R 3 is —C(O)OR 6 .
  • R 3 is —C(O)OR 6 and R 6 is methyl.
  • A is phenyl; X is O; Z is O; R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or NO 2 ; R 2 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and R 3 is —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 , —C(O)RC(O)OR 6 , —C(O)ROR′OR′′OR 6 , —C(O)ROR′OR 6 , —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , C(O)RNR 4 C(O)OR 6 , —SO 2 R 6 , or —SO 2 NR 4 R 5 .
  • A is phenyl; X is O; Z is O; R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; R 2 is hydrogen or halogen; and R 3 is —C(O)R 6 , —C(O)NR 4 R 5 , or —C(O)OR 6 .
  • A is phenyl; X is O; Z is O; R 1 is C 1 -C 6 haloalkyl; R 2 is halogen; and R 3 is —C(O)OR 6 .
  • A is phenyl; X is S; Z is O; R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; R 2 is hydrogen or halogen; and R 3 is —C(O)R 6 or —C(O)OR 6 .
  • A is phenyl; X is S; Z is O; R 1 is C 1 -C 6 haloalkyl; R 2 is halogen; and R 3 is —C(O)OR 6 .
  • A is pyridyl; X is O; Z is O; R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or NO 2 ; R 2 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and R 3 is —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 , —C(R)RC(O)OR 6 , —C(O)ROR′OR′′OR 6 , —C(O)ROR′OR 6 , —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , —C(O)RNR 4 C(O)OR 6 , —SO 2 R 6 , or —SO 2 NR 4 R 5 .
  • A is pyridyl; X is O; Z is O; R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; R 2 is hydrogen or halogen; and R 3 is —C(O)R 6 or —C(O)OR 6 .
  • A is pyridyl; X is O; Z is O; R 1 is C 1 -C 6 haloalkyl; R 2 is halogen; and R 3 is —C(O)OR 6 .
  • A is pyridyl; X is S; Z is O; R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or NO 2 ; R 2 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and R 3 is —C(O)R 6 , —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 , —C(R)RC(O)OR 6 , —C(O)ROR′OR′′OR 6 , —C(O)ROR′OR′′, —C(O)RNR 4 R 5 , —C(O)RNR 4 C(O)R 6 , —C(O)RNR 4 C(O)OR 6 , —SO 2 R 6 , or —SO 2 NR 4 R 5 .
  • A is pyridyl; X is S; Z is O; R 1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; R 2 is hydrogen or halogen; and R 3 is —C(O)R 6 or —C(O)OR 6 .
  • A is pyridyl; X is S; Z is O; R 1 is C 1 -C 6 haloalkyl; R 2 is halogen; and R 3 is —C(O)OR 6 .
  • the compound is a compound of formula (IV) where E is unsubstituted heteroaryl, heteroaryl substituted by R 1 , or heteroaryl substituted by R 1 and R 2 , A is phenyl; X is O; Z is O; R 1 is C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heterocyclyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkylsulfanyl; R 2 is hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; and R 3 is —C(O)R, —C(O)NR 4 R 5 , —C(O)OR 6 , —C(O)ROR 6 , —C(O)RC(O)OR 6 , —C(O)ROR′OR′′OR 6 , —C(O)ROR′OR 6 , —C(O)
  • E is heteroaryl substituted by R 1 or heteroaryl substituted by R 1 and R 2 , A is phenyl; X is O; Z is O; R 1 is C 1 -C 6 alkyl; R 2 is hydrogen or halogen; and R 3 is —C(O)R 6 , —C(O)ROR′OR 6 , or —C(O)OR 6 .
  • E is heteroaryl substituted by R 1 , A is phenyl; X is O; Z is O; R 1 is —C(CH 3 ) 3 ; and R 3 is —C(O)R 6 .
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent in the compound of formula (I).
  • Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxa
  • compositions which include therapeutically effective amounts of compounds of the formula (I) and salts, solvates and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of the formula (I) and salts, solvates and physiological functional derivatives thereof, are as described above.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I), or salts, solvates and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of formula (I), and salts, solvates and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of formula (I) and salts, solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian
  • an effective amount of a compound of formula (I) for the treatment of neoplastic growth, for example colon or breast carcinoma will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt or solvate, or physiologically functional derivative thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and the use of at least one other cancer treatment method.
  • combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and at least one other pharmaceutically active agent, preferably an anti-neoplastic agent.
  • the compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order.
  • the amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the compounds of the Formula (I) or salts, solvates, or physiologically functional derivatives thereof and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies.
  • the other anti-cancer therapy is at least one additional chemotherapeutic therapy including administration of at least one anti-neoplastic agent.
  • the administration in combination of a compound of formula (I) or salts, solvates, or physiologically functional derivatives thereof with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.
  • Anti-neoplastic agents useful in combination with the compounds and salts, solvates or physiologically functional derivatives thereof of formula I include the following:
  • cell cycle specific anti-neoplastic agents include, but are not limited to diterpenoids such as paclitaxel and its analog docetaxel; vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine; epipodophyllotoxins such as etoposide and teniposide; fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine; antimetabolites such as allopurinol, fludurabine, methotrexate, cladrabine, cytarabine, mercaptopurine and thioguanine; and camptothecins such as 9-amino camptothecin, irinotecan, CPT-11 and the various optical forms of 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin;
  • diterpenoids such as paclitaxel and its analog docetaxel
  • vinca alkaloids such as vinblast
  • cytotoxic chemotherapeutic agents including, but not limited to, alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; anti-tumour antibiotics such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dacttinomycin and mithramycin; and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; and
  • chemotherapeutic agents include, but are not limited to, anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene; progestrogens such as megestrol acetate; aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane; antiandrogens such as flutamide, nilutamide, bicalutamide, and cyproterone acetate; LHRH agonists and antagagonists such as goserelin acetate and luprolide, testosterone 5 ⁇ -dihydroreductase inhibitors such as finasteride; metalloproteinase inhibitors such as marimastat; antiprogestogens; urokinase plasminogen activator receptor function inhibitors; growth factor function inhibitors such as inhibitors of the functions of hepatocyte growth factor;
  • the compounds of formula (I) and salts, solvates and physiological functional derivatives thereof, are believed to have anticancer activity as a result of inhibition of the protein kinase TIE-2 and its effect on selected cell lines whose growth is dependent on TIE-2 protein kinase activity.
  • the present invention thus also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof, or physiologically functional derivatives thereof, for use in medical therapy, and particularly in the treatment of disorders mediated by inappropriate TIE-2 activity.
  • the inappropriate TIE-2 activity referred to herein is any TIE-2 activity that deviates from the normal TIE-2 activity expected in a particular mammalian subject.
  • Inappropriate TIE-2 activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of TIE-2 activity.
  • Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation.
  • unwanted TIE-2 activity may reside in an abnormal source, such as a malignancy. That is, the level of TIE-2 activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source.
  • the inappropriate angiogenesis referred to herein is any angiogenic activity that deviates from the normal angiogenic activity expected in a particular mammalian subject.
  • Inappropriate angiogenesis may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of angiogenic activity.
  • Such inappropriate activity may result then, for example, from overexpression or mutation of a protein kinase leading to inappropriate or uncontrolled activation.
  • unwanted angiogenic activity may reside in an abnormal source, such as a malignancy. That is, the level of angiogenic activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source.
  • the present invention is directed to methods of regulating, modulating, or inhibiting TIE-2 for the prevention and/or treatment of disorders related to unregulated TIE-2 activity.
  • the compounds of the present invention can also be used in the treatment of certain forms of cancer.
  • the compounds of the present invention can be used to provide additive or synergistic effects with certain existing cancer chemotherapies, and/or be used to restore effectiveness of certain existing cancer chemotherapies and radiation.
  • the compounds of the present invention are also useful in the treatment of one or more diseases afflicting mammals which are characterized by cellular proliferation in the area of disorders associated with neo-vascularization and/or vascular permeability including blood vessel proliferative disorders including arthritis and restenosis; fibrotic disorders including hepatic cirrhosis and atherosclerosis; mesangial cell proliferative disorders include glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection and glomerulopathies; and metabolic disorders include psoriasis, diabetes mellitus, chronic wound healing, inflammation and neurodegenerative diseases.
  • a further aspect of the invention provides a method of treatment of a mammal suffering from a disorder mediated by inappropriate TIE-2 activity, including susceptible malignancies, which includes administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof.
  • the disorder is cancer.
  • a further aspect of the invention provides a method of treatment of a mammal suffering from cancer which includes administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof.
  • a further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of a disorder characterized by inappropriate TIE-2 activity.
  • the disorder is cancer.
  • a further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of cancer and malignant tumors.
  • the mammal requiring treatment with a compound of the present invention is typically a human being.
  • therapeutically effective amounts of the compounds of formula (I) or salts, solvates or physiologically derived derivatives thereof and agents which inhibit growth factor receptor function may be administered in combination to a mammal for treatment of a disorder mediated by inappropriate TIE-2 activity, for instance in the treatment of cancer.
  • growth factor receptors include, for example, EGFR, PDGFR, erbB2, erbB4, VEGFR, and/or TIE-2.
  • Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C., Exp. Opin. Ther. Patents (2000) 10(6):803-818 and in Shawver et al DDT Vol 2, No. 2 Feb. 1997.
  • the compounds of the Formula (I) or salts, solvates, or physiologically functional derivatives thereof and the agent for inhibiting growth factor receptor function may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination.
  • the combination may be employed in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • a method of treating a disorder in a mammal, said disorder being mediated by inappropriate angiogenesis including: administering to said mammal a therapeutically effective amount of a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof.
  • the inappropriate angiogenic activity is due to at least one of inappropriate VEGFR1, VEGFR2, VEGFR3, or TIE-2 activity.
  • the inappropriate angiogenesis is due to inappropriate VEGFR2 and TIE-2 activity.
  • the method further includes administering a therapeutically effective amount of a VEGFR2 inhibitor along with the compounds of formula (I) or salts, solvates or physiologically functional derivatives thereof.
  • the disorder is cancer.
  • a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof in the preparation of a medicament for use in treating a disorder in a mammal, said disorder being characterized by inappropriate angiogenesis.
  • the inappropriate angiogenic activity is due to at least one of inappropriate VEGFR1, VEGFR2, VEGFR3 or TIE-2 activity.
  • the inappropriate angiogenesis is due to inappropriate VEGFR2 and TIE-2 activity.
  • the use further includes use of a VEGFR2 inhibitor to prepare said medicament.
  • combination of a compound of formula (I) or salts, solvates, or physiologically functional derivatives thereof with a VEGFR2 inhibitor may be employed in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the Working Examples.
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • a compound When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).
  • nitroaniline (3) is then refluxed with Na 2 S 2 O 4 to provide 4-(4-acetamidophenoxy)phenylene-1,2-diamine (4).
  • reduction of nitro group of (3) can be effected in many ways, for example by use of H 2 , Pd/C; Raney Nickel with hydrazine; SnCl 4 in HCl; etc.
  • Diamine (4) is refluxed with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in ethanol and the acetylated carbamate (5) is obtained.
  • HCl is added to deacetylate the carbamate (5) to give methyl (5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate (7).
  • carbamate (7) may be prepared by refluxing 3,4,4′-triaminodiphenylether (6) with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea and then treating with conc. HCl to give carbamate (7).
  • Carbamate (7) is then reacted with the appropriate phenyl isocyanate (8) to give the resultant benzimidazole (9) of the present invention. It is understood that R 1 and R 2 are as described above.
  • the compound (3) is reacted with 2-fluoro-5-trifluoromethylphenylisocyanate (4) to provide 5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-2-nitroaniline (5).
  • the nitroaniline (5) is hydrogenated under an H 2 atmosphere in the presence of Pd/C to give the corresponding diamine (6).
  • Diamine (6) is reacted with cyanogen bromide to give benzimidazole (7).
  • Benzimidazole (7) may be reacted with the appropriate carboxylic acid in the presence of triethylamine and HBTU (O-Benzotriazole-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) to give the corresponding benzimidazole (8).
  • Benzimidazole (7) may also be reacted with J′SO 2 Cl (J′ is methyl or p-tolyl) to give a couple of endo-sulfonated products (9, 10). J′SO 2 moiety was migrated to the exo site by heating (11). Further, benzimidazole (7) may be reacted with isocyanate J′′NCO to give diurea (12).
  • X of Formula (I) is sulfur and Z of Formula (I) is oxygen
  • the final compounds are obtained by following the same procedure except that a phenylthiol derivative of 1 is used.
  • X of Formula (I) is sulfur
  • the compound thus obtained can be oxidized with MCPBA (meta-chloroperbenzoic acid) to give compounds containing sulfonyl (—SO 2 ) or sulfenyl (—SO) as X.
  • MCPBA metal-chloroperbenzoic acid
  • 3-(3-substituted phenyl)aminocarbonylamino) phenoxy derivatives of Formula I are prepared using 3-acetamidophenol instead of 4-acetamidophenol.
  • the substituent J may be any substituent attached to C(O) within the scope of the definition of R 3 as recited herein.
  • the substituent J′′ may be any substituent R 5 as defined herein.
  • A1 and A2 refer to N and C, or C and N, respectively.
  • 5-Hydroxybenzimdazole derivative (2) with or without a protecting group L is coupled with halonitropyridine (1) in the presence of base e.g. Cs 2 CO 3 to give compound (3).
  • Subsequent hydrogenation over Pd—C provides aniline derivative (4), followed by coupling with isocyanate (and deprotection if needed) to afford urea (5).).
  • the intermediate (4) can also be provided by way of triamine (6).
  • amino-(4-methoxyphenyl)-methylpolystyrene resin was first loaded with 4-chloro-2-fluoronitrobenzene in the presence of DIEA.
  • the chlorine of compound (1) was displaced with the oxygen of the 4-aminophenol using NaH as the base to arrive at (2).
  • the free amino group of (2) was then activated with p-nitrophenyl chloroformate, the excess of which washed away before the amines were added.
  • the resin was split into 21 equal batches and twenty (20) five-membered heteroaryl amines and one substituted aniline were used to afford (3).
  • the nitro group of (3) was reduced with tin chloride to give diamine (4).
  • ⁇ L microliters
  • psi pounds per square inch
  • T r retention time
  • RP reverse phase
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • TFAA trifluoroacetic anhydride
  • THF tetrahydrofuran
  • DMSO dimethylsulfoxide
  • AcOEt ethyl acetate
  • DME (1,2-dimethoxyethane); DCM (dichloromethane);
  • DCE dichloroethane
  • DMF N,N dimethylformamide
  • DMPU N,N′-dimethylpropyleneurea
  • CDI 1,1-carbonyldiimidazole
  • IBCF isobutyl chloroformate
  • HOAc acetic acid
  • HOSu N-hydroxysuccinimide
  • HOBT 1-hydroxybenzotriazole
  • mCPBA metal-chloroperbenzoic acid
  • EDC ethylcarbodiimide
  • DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);
  • TIPS triisopropylsilyl
  • TBS t-butyldimethylsilyl
  • DMAP 4-dimethylaminopyridine
  • BSA bovine serum albumin
  • ATP adenosine triphosphate
  • HRP horseradish peroxidase
  • DMEM Dulbecco's modified Eagle medium
  • BOP bis(2-oxo-3-oxazolidinyl)phosphinic chloride
  • TBAF tetra-n-butylammonium fluoride
  • HBTU O-Benzotriazole-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid);
  • DPPA diphenylphosphoryl azide
  • EDTA ethylenediaminetetraacetic acid
  • MS mass spectra
  • MS-AX505HA a JOEL JMS-AX505HA
  • JOEL SX-102 a SCIEX-APIiii spectrometer
  • LC-MS were recorded on a micromass 2MD and Waters 2690
  • high resolution MS were obtained using a JOEL SX-102A spectrometer.
  • All mass spectra were taken under electrospray ionization (ESI), chemical ionization (CI), electron impact (EI) or by fast atom bombardment (FAB) methods.
  • ESI electrospray ionization
  • CI chemical ionization
  • EI electron impact
  • FAB fast atom bombardment
  • IR Infrared
  • Examples 2-11, 14-16, 19-21, 40-78, 81, and 86 were prepared according to the procedures described above for Example 1. Intermediates 3, 3A, and 3B, were used or other precursors as indicated.
  • the free bases obtained may be transformed into their pharmaceutically acceptable salts (e.g. HCl salts) by standard procedures known in the art.
  • Example 24 was prepared according to procedures similar to the one described above in Example 23. They can be transformed into their pharmaceutically acceptable salts (e.g. HCl salts) by standard procedures.
  • 1 H NMR (DMSO-d 6 ) ⁇ 9.18 (s, 1H), 8.88 (d, 1H), 8.63 (dd, 1H), 7.85 (d, 2H), 7.51-7.46 (m, 5H), 7.43-7.36 (m, 1H), 7.25 (d, 1H), 7.14-7.11 (m, 3H), 6.94 (d, 2H), 6.84 (dd, 1H), 2.38 (s, 3H); MS m/e 600 (M+1).
  • Examples 26-35 and 87-102 were prepared according to procedures similar to that described above. They can be transformed into their pharmaceutically acceptable salts (e.g. HCl salts) by standard procedures.
  • pharmaceutically acceptable salts e.g. HCl salts
  • Examples 37 to 39 were prepared according to procedures similar to that described for Example 36 above. They can be transformed into their pharmaceutically acceptable salts (e.g. HCl salts) by standard procedures.
  • pharmaceutically acceptable salts e.g. HCl salts
  • Example 12 The title compound was prepared following the procedure for Example 12 except that the product of Example 57 was used as a precursor.
  • Example 24 The title compound was prepared following for Example 24.
  • the products of Example 24 and 84 are separated by columnchromatography.
  • Examples 87-102 were prepared according to procedure similar to Example 25.
  • the two regioisomers were separated by successive recrystallizations from 2-butanone followed by methanol.
  • the aqueous phase was further extracted by dichloromethane twice and then combined dichloromethane solutions were dried over magnesium sulfate and concentrated to give a brown oil (0.37 g, 1.86 mmol, 0.29% yield) which was used without purification.
  • the crude oil was dissolved in acetonitrile (30 ml) and 4-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)phenylene-1,2-diamine (intermediate 6) (0.20 g, 0.47 mmol) was added. The stirred reaction was heated to reflux for 24 hours. On cooling, the reaction solution was decanted off to leave behind an insoluble dark oil residue.

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Abstract

Benzimidazole derivatives, which are useful as TIE-2 and/or VEGFR2 inhibitors are described herein. The described invention also includes methods of making such benzimidazole derivatives as well as methods of using the same in the treatment of hyperproliferative diseases.

Description

    BACKGROUND OF THE INVENTION
  • The present invention relates to benzimidazole derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions and medicaments. Such benzimidazole derivatives are useful in the treatment of diseases associated with inappropriate or pathological angiogenesis.
  • The process of angiogenesis is the development of new blood vessels, generally capillaries, from pre-existing vasculature. Angiogenesis is defined as involving (i) activation of endothelial cells; (ii) increased vascular permeability; (iii) subsequent dissolution of the basement membrane and extravisation of plasma components leading to formation of a provisional fibrin gel extracellular matrix; (iv) proliferation and mobilization of endothelial cells; (v) reorganization of mobilized endothelial cells to form functional capillaries; (vi) capillary loop formation; and (vii) deposition of basement membrane and recruitment of perivascular cells to newly formed vessels. Normal angiogenesis is activated during tissue growth, from embryonic development through maturity, and then enters a period of relative quiescence during adulthood. Normal angiogensesis is also activated during wound healing, and at certain stages of the female reproductive cycle. Inappropriate or pathological angiogenesis has been associated with several disease states including various retinopathies; ischemic disease; atherosclerosis; chronic inflammatory disorders; and cancer. The role of angiogenesis in disease states is discussed, for instance, in Fan et al, Trends in Pharmacol Sci. 16:54-66; Shawver et al, DDT Vol. 2, No. 2 February 1997; Folkmann, 1995, Nature Medicine 1:27-31.
  • In cancer the growth of solid tumors has been shown to be angiogenesis dependent. (See Folkmann, J., J. Nat'l. Cancer Inst., 1990, 82, 4-6.) Consequently, the targeting of pro-angiogenic pathways is a strategy being widely pursued in order to provide new therapeutics in these areas of great, unmet medical need. The role of tyrosine kinases involved in angiogenesis and in the vascularization of solid tumors has drawn interest. Until recently most interest in this area has focused on growth factors such as vascular endothelial growth factor (VEGF) and its receptors termed vascular endothelial growth factor receptor(s) (VEGFR). VEGF, a polypeptide, is mitogenic for endothelial cells in vitro and stimulates angiogenic responses in vivo. VEGF has also been linked to inappropriate or pathological angiogenesis (Pinedo, H. M. et al The Oncologist, Vol. 5, No. 90001, 1-2, April 2000). VEGFR(s) are protein tyrosine kinases (PTKs). PTKs catalyze the phosphorylation of specific tyrosyl residues in proteins involved in the regulation of cell growth and differentiation. (A. F. Wilks, Progress in Growth Factor Research, 1990, 2, 97-111; S. A. Courtneidge, Dev. Suppl., 1993, 57-64; J. A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R. F. Paulson, Semin. Immunol., 1995, 7(4), 267-277; A. C. Chan, Curr. Opin. Immunol., 1996, 8(3), 394-401).
  • Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1); VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involved in angiogenesis and participate in signal transduction (Mustonen, T. et al J. Cell Biol. 1995:129:895-898). Of particular interest is VEGFR-2, which is a transmembrane receptor PTK expressed primarily in endothelial cells. Activation of VEGFR-2 by VEGF is a critical step in the signal transduction pathway that initiates tumor angiogenesis. VEGF expression may be constitutive to tumor cells and can also be upregulated in response to certain stimuli. One such stimuli is hypoxia, where VEGF expression is upregulated in both tumor and associated host tissues. The VEGF ligand activates VEGFR-2 by binding with its extracellular VEGF binding site. This leads to receptor dimerization of VEGFRs and autophosphorylation of tyrosine residues at the intracellular kinase domain of VEGFR-2. The kinase domain operates to transfer a phosphate from ATP to the tyrosine residues, thus providing binding sites for signaling proteins downstream of VEGFR-2 leading ultimately to initiation of angiogenesis (McMahon, G., The Oncologist, Vol. 5, No. 90001, 3-10, April 2000).
  • Angiopoieten 1 (Angl), a ligand for the endothelium-specific receptor tyrosine kinase TIE-2 is a novel angiogenic factor (Davis et al, Cell, 1996, 87:1161-1169; Partanen et al, Mol. Cell. Biol, 12:1698-1707 (1992); U.S. Pat. Nos. 5,521,073; 5,879,672; 5,877,020; and 6,030,831). The acronym TIE represents “tyrosine kinase containing Ig and EGF homology domains”. TIE is used to identify a class of receptor tyrosine kinases, which are exclusively expressed in vascular endothelial cells and early hemopoietic cells. Typically, TIE receptor kinases are characterized by the presence of an EGF-like domain and an immunoglobulin (IG) like domain, which consists of extracellular folding units, stabilized by intra-chain disulfide bonds (Partanen et al Curr. Topics Microbiol. Immunol., 1999, 237:159-172). Unlike VEGF, which functions during the early stages of vascular development, Ang1 and its receptor TIE-2 function in the later stages of vascular development, i.e., during vascular remodeling (remodeling refers to formation of a vascular lumen) and maturation (Yancopoulos et al, Cell, 1998, 93:661-664; Peters, K. G., Circ. Res., 1998, 83(3):342-3; Suri et al, Cell 87, 1171-1180 (1996)).
  • Consequently, inhibition of TIE-2 would be expected to serve to disrupt remodeling and maturation of new vasculature initiated by angiogenesis thereby disrupting the angiogenic process. Furthermore, inhibition at the kinase domain binding site of VEGFR-2 would block phosphorylation of tyrosine residues and serve to disrupt initiation of angiogenesis. Presumably then, inhibition of TIE-2 and/or VEGFR-2 should prevent tumor angiogenesis and serve to retard or eradicate tumor growth. Accordingly, a treatment for cancer or other disorder associated with inappropriate angiogenesis could be provided.
  • The present inventors have discovered novel benzimidazole compounds, which are inhibitors of TIE-2 and/or VEGFR-2 kinase activity. Such benzimidazole derivatives are useful in the treatment of disorders, including cancer, associated with inappropriate angiogenesis.
    • BRIEF SUMMARY OF THE INVENTION
  • In one aspect of the present invention, there is provided a compound of Formula (I):
    Figure US20070249600A1-20071025-C00001
    or a salt, solvate, or physiologically functional derivative thereof:
    wherein:
    E is aryl substituted by R1 and R2, or
      • unsubstituted heteroaryl, or
      • heteroaryl substituted with R1, or
      • heteroaryl substituted by R1 and R2, or
      • R1 and R2 together with the atoms of E to which they are attached form a cycloalkyl, aryl, or heterocyclic ring fused to E;
        A is aryl, heteroaryl, or heterocyclic;
        X is S, O, S(O)2, S(O), C(H)2, C(H)(OH), or C(O);
        Z is O or S;
        p is 0 or 1;
        q is 0 or 1;
        the dotted line bonds “---” attached to Q and N′ represent a single bond or a double bond wherein when q is 0 the dotted line bond “---” attached to Q is a single bond and the dotted line bond attached to N′ is a double bond, and when q is 1 the dotted line bond “---” attached to Q is a double bond and the dotted line bond attached to N′ is a single bond; and
        the dotted line within the 6 membered ring containing D, M, and T represents appropriate aromatic bonds;
        D is CH, T is CR8, M is C and Q is N(R7)p, wherein p is 0 and q is 1; or
        D is CH, T is CR8, M is C and Q is N(R7)p, wherein p is 1 and q is 0; or
        D is CH, T is CR8, M is C and Q is S or O; wherein q is 0;
        D is N, T is CR8, M is C and Q is N(R7)p, wherein either p or q is 0 and the other is 1; or
        D is CH, T is N, M is C and Q is N(R7)p, wherein either p or q is 0 and the other is 1; or
        D is CH, T is CR8, M is N and Q is CH, wherein q is 0;
        R1 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, aralkyl, aralkoxy, aryloxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl;
        R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl;
        R3 is hydrogen, C1-C6 alkyl, aryl, aralkyl, aralkoxy, heteroaryl, heterocyclic, —RR6, —RNR4R5, —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)RR6, —C(O)RR′R6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —C(O)ORNR4R5, —S(O)2R6, or —S(O)2NR4R5; or
        R3 is C1-C6 alkylene or C1-C6 alkylene substituted with oxo, and is linked together with the nitrogen to which it is attached and to one of the benzimidazole nitrogens to form a heterocylic compound fused to the benzimidazole;
        R, R′, and R″, are each independently selected from C1-C6 alkylene, arylene, heteroarylene, C3-C7 cycloalkylene, or heterocyclylene;
        R′″ is C1-C6 alkyl, aryl, heteroaryl, aralkyl, C3-C7 cycloalkyl, or heterocyclic;
        R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C3-C7 cycloalkyl, —C(O)OR6, —C(O)NR′″R′″, —C(O)NR′″H, —C(O)NH2, or
        —S(O)2NR′″R′″;
        R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic, or C3-C7 cycloalkyl;
        R7 is hydrogen, C1-C6 alkyl, —S(O)2R6, —RNR4R5, —RR6
        R8 is hydrogen or halogen; and
        when R1 is Cl, R2 is hydrogen or Cl, R3 is —C(O)OCH3, E and A are phenyl, D is CH, T is CH, M is C, Q is N(R7)p, where R7 is H, wherein either p or q is 0 and the other is 1, and Z is O, then X is O, S(O), S(O)2, CH2, CH(OH), or C(O).
  • In a second aspect of the present invention, there is provided a compound of Formula (I):
    Figure US20070249600A1-20071025-C00002
    or a salt, solvate, or physiologically functional derivative thereof:
    wherein:
    E is unsubstituted heteroaryl, or
      • heteroaryl substituted with R1, or
      • heteroaryl substituted by R1 and R2;
        A is aryl, heteroaryl, or heterocyclic;
        X is S, O, S(O)2, S(O), CH2, CH(OH), or C(O);
        Z is O or S;
        p is 0 or 1;
        q is 0 or 1;
        the dotted line bonds “---” attached to Q and N′ represent a single bond or a double bond wherein when q is 0 the dotted line bond “---” attached to Q is a single bond and the dotted line bond attached to N′ is a double bond, and when q is 1 the dotted line bond “---” attached to Q is a double bond and the dotted line bond attached to N′ is a single bond; and
        the dotted line within the 6 membered ring containing D, M, and T represents appropriate aromatic bonds;
        D is CH, T is CR8, M is C and Q is N(R7)p, wherein p is 0 and q is 1; or
        D is CH, T is CR8, M is C and Q is N(R7)p, wherein p is 1 and q is 0; or
        D is CH, T is CR8, M is C and Q is S or O; wherein q is 0;
        D is N, T is CR8, M is C and Q is N(R7)p, wherein either p or q is 0 and the other is 1; or
        D is CH, T is N, M is C and Q is N(R7)p, wherein either p or q is 0 and the other is 1; or
        D is CH, T is CR8, M is N and Q is CH, wherein q is 0;
        R1 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, aralkyl, aralkoxy, aryloxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl;
        R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl;
        R3 is hydrogen, C1-C6 alkyl, aryl, aralkyl, aralkoxy, heteroaryl, heterocyclic, —RR6, —RNR4R5, —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)RR6, —C(O)RR′R6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —C(O)ORNR4R5, —S(O)2R6, or —S(O)2NR4R5; or
        R3 is C1-C6 alkylene or C1-C6 alkylene substituted with oxo, and is linked together with the nitrogen to which it is attached and to one of the benzimidazole nitrogens to form a heterocylic compound fused to the benzimidazole;
        R, R′, and R″, are each independently selected from C1-C6 alkylene, arylene, heteroarylene, C3-C7 cycloalkylene, or heterocyclylene;
        R′″ is C1-C6 alkyl, aryl, heteroaryl, aralkyl, C3-C7 cycloalkyl, or heterocyclic;
        R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C3-C7 cycloalkyl, —C(O)OR6, —C(O)NR′″R′″, —C(O)NR′″H, —C(O)NH2, or
        —S(O)2NR′″R′″;
        R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic, or C3-C7 cycloalkyl;
        R7 is hydrogen, C1-C6 alkyl, —S(O)2R6, —RNR4R5, —RR6; and
        R8 is hydrogen or halogen.
  • In a third aspect of the present invention, there is provided a compound of Formula (II):
    Figure US20070249600A1-20071025-C00003
    or a salt, solvate, or physiologically functional derivative thereof:
    wherein:
    A is aryl, heteroaryl, or heterocyclic;
    X is S, O, S(O)2, S(O), CH2, CH(OH), or C(O);
    Z is O or S;
    p is 0 or 1;
    q is 0 or 1;
    the dotted line bonds “---” attached to Q and N′ represent a single bond or a double bond wherein when q is 0 the dotted line bond “---” attached to Q is a single bond and the dotted line bond attached to N′ is a double bond, and when q is 1 the dotted line bond “---” attached to Q is a double bond and the dotted line bond attached to N′ is a single bond; and
    the dotted line within the 6 membered ring containing D, M, and T represents appropriate aromatic bonds;
    D is CH, T is CR8, M is C and Q is N(R7)p, wherein p is 0 and q is 1; or
    D is CH, T is CR8, M is C and Q is N(R7)p, wherein p is 1 and q is 0; or
    D is CH, T is CR8, M is C and Q is S or O; wherein q is 0;
    D is N, T is CR8, M is C and Q is N(R7)p, wherein either p or q is 0 and the other is 1; or
    D is CH, T is N, M is C and Q is N(R7)p, wherein either p or q is 0 and the other is 1; or
    D is CH, T is CR8, M is N and Q is CH, wherein q is 0;
    R1 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, aralkyl, aralkoxy, aryloxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl;
    R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl; or
    R1 and R2 together with the phenyl ring atoms to which they are attached form a cyloalkyl or aryl ring fused to the phenyl ring;
    R3 is hydrogen, C1-C6 alkyl, aryl, aralkyl, aralkoxy, heteroaryl, heterocyclic, —RR6, —RNR4R5, —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)RR6, —C(O)RR′ R6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —C(O)ORNR4R5, —S(O)2R6, or —S(O)2NR4R5; or
    R3 is C1-C6 alkylene or C1-C6 alkylene substituted with oxo, and is linked together with the nitrogen to which it is attached and to one of the benzimidazole nitrogens to form a heterocylic compound fused to the benzimidazole;
    R, R′, and R″, are each independently selected from C1-C6 alkylene, arylene, heteroarylene, C3-C7 cycloalkylene, or heterocyclylene;
    R′″ is C1-C6 alkyl, aryl, heteroaryl, aralkyl, C3-C7 cycloalkyl, or heterocyclic;
    R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C3-C7 cycloalkyl, —C(O)OR6, —C(O)NR′″R′″, —C(O)NR′″H, —C(O)NH2, or
    —S(O)2NR′″R′″;
    R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic, or C3-C7 cycloalkyl;
    R7 is hydrogen, C1-C6 alkyl, —S(O)2R6, —RNR4R5, —RR6
    R8 is hydrogen or halogen; and
    when R1 is Cl, R2 is H or Cl, R3 is —C(O)OCH3, A is phenyl, D is CH, T is CH, M is C and Q is N(R7)p, where R7 is H, wherein either p or q is 0 and the other is 1 and Z is O, then X is O, S(O), ═S(O)2, CH2, CH(OH) or C(O).
  • In a fourth aspect of the present invention, there is provided a compound of Formula (III):
    Figure US20070249600A1-20071025-C00004
    or a salt, solvate, or physiologically functional derivative thereof:
    wherein:
    A is aryl, heteroaryl, or heterocyclic;
    X is S, O, S(O)2, S(O), CH2, CH(OH), or C(O);
    Z is O or S;
    p is 0 or 1;
    q is 0 or 1, wherein either p or q is 0, and the other is 1;
    the dotted line bonds “---” attached to N′ and N″ represent a single bond or a double bond wherein when q is 0 the dotted line bond “---” attached to N′ is a single bond and the dotted line bond attached to N″ is a double bond, and when q is 1 the dotted line bond “---” attached to N′ is a double bond and the dotted line bond attached to N″ is a single bond;
    R1 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, aralkyl, aralkoxy, aryloxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl;
    R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl; or
    R1 and R2 together with the phenyl ring atoms to which they are attached form a cyloalkyl or aryl ring fused to the phenyl ring;
    R3 is hydrogen, C1-C6 alkyl, aryl, aralkyl, aralkoxy, heteroaryl, heterocyclic, —RR6, —RNR4R5, —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)RR6, —C(O)RR′R6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —C(O)ORNR4R5, —S(O)2R6, or —S(O)2NR4R5; or
    R3 is C1-C6 alkylene or C1-C6 alkylene substituted with oxo, and is linked together with the nitrogen to which it is attached and to one of the benzimidazole nitrogens to form a heterocylic compound fused to the benzimidazole;
    R, R′, and R″, are each independently selected from C1-C6 alkylene, arylene, heteroarylene, C3-C7 cycloalkylene, or heterocyclylene;
    R′″ is C1-C6 alkyl, aryl, heteroaryl, aralkyl, C3-C7 cycloalkyl, or heterocyclic;
    R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C3-C7 cycloalkyl, —C(O)OR6, —C(O)NR′″R′″; —C(O)NR′″H, —C(O)NH2, or
    —S(O)2NR′″R′″;
    R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic, or C3-C7 cycloalkyl;
    R7 is hydrogen, C1-C6 alkyl, —S(O)2R6, —RNR4R5, —RR6
    R8 is hydrogen or halogen; and
    when R1 is Cl, R2 is H or Cl, R3 is —C(O)OCH3, A is phenyl, and Z is O, then X is O, S(O), ═S(O)2, CH2, CH(OH), or C(O).
  • In a fifth aspect of the present invention, there is provided a compound of formula (IV)
    Figure US20070249600A1-20071025-C00005
    or a salt, solvate, or physiologically functional derivative thereof:
    wherein:
    E is unsubstituted heteroaryl, or
  • heteroaryl substituted with R1, or
  • heteroaryl substituted by R1 and R2;
  • A is aryl, heteroaryl, or heterocyclic;
  • X is S, O, S(O)2, S(O), CH2, CH(OH), or C(O);
  • Z is O or S;
  • p is 0 or 1;
  • q is 0 or 1;
  • the dotted line bonds “---” attached to N′ and N″ represent a single bond or a double bond wherein when q is 0 the dotted line bond “---” attached to N′ is a single bond and the dotted line bond attached to N″ is a double bond, and when q is 1 the dotted line bond “---” attached to N′ is a double bond and the dotted line bond attached to N″ is a single bond;
  • R1 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, aralkyl, aralkoxy, aryloxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl;
  • R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl;
  • R3 is hydrogen, C1-C6 alkyl, aryl, aralkyl, aralkoxy, heteroaryl, heterocyclic, —RR6, —RNR4R5, —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)RR6, —C(O)RR′ R6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —C(O)ORNR4R5, —S(O)2R6, or —S(O)2NR4R5; or
  • R3 is C1-C6 alkylene or C1-C6 alkylene substituted with oxo, and is linked together with the nitrogen to which it is attached and to one of the benzimidazole nitrogens to form a heterocylic compound fused to the benzimidazole;
  • R, R′, and R″, are each independently selected from C1-C6 alkylene, arylene, heteroarylene, C3-C7 cycloalkylene, or heterocyclylene;
  • R′″ is C1-C6 alkyl, aryl, heteroaryl, aralkyl, C3-C7 cycloalkyl, or heterocyclic;
  • R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C3-C7 cycloalkyl, —C(O)OR6, —C(O)NR′″R′″, —C(O)NR′″H, —C(O)NH2, or
  • —S(O)2NR′″R′″;
  • R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic, or C3-C7 cycloalkyl;
  • R7 is hydrogen, C1-C6 alkyl, —S(O)2R6, —RNR4R5, —RR6; and
  • R8 is hydrogen or halogen.
  • In a sixth aspect of the present invention, there is provided a pharmaceutical composition including a therapeutically effective amount of a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.
  • In a seventh aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by inappropriate TIE-2 activity, including: administering to said mammal a therapeutically effective amount of a compound of formula (I) or a salt, solvate or a physiologically functional derivative thereof.
  • In an eighth aspect of the present invention, there is provided a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof for use in therapy.
  • In a ninth aspect of the present invention, there is provided the use of a compound of formula (I), or a salt, solvate, or a physiologically functional derivative thereof in the preparation of a medicament for use in the treatment of a disorder mediated by inappropriate TIE-2 activity.
  • In a tenth aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by inappropriate TIE-2 activity, including: administering to said mammal therapeutically effective amounts of (i) a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof and (ii) an agent to inhibit growth factor receptor function.
  • In an eleventh aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being characterized by inappropriate angiogenesis, including: administering to said mammal a therapeutically effective amount of a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof.
    • DETAILED DESCRIPTION
  • As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
  • As used herein, the term “alkyl” refers to a straight or branched chain hydrocarbon having from one to twelve carbon atoms, optionally substituted with substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or C1-C6 perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.
  • As used herein, the term “C1-C6 alkyl” refers to an alkyl group as defined above containing at least 1, and at most 6, carbon atoms. Examples of branched or straight chained “C1-C6 alkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, and isopentyl.
  • As used herein, the term “alkylene” refers to a straight or branched chain divalent hydrocarbon radical having from one to ten carbon atoms, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “alkylene” as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.
  • As used herein, the term “C1-C6 alkylene” refers to an alkylene group, as defined above, which contains at least 1, and at most 6, carbon atoms respectively. Examples of “C1-C6 alkylene” groups useful in the present invention include, but are not limited to, methylene, ethylene, and n-propylene.
  • As used herein, the term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • As used herein, the term “C1-C6 haloalkyl” refers to an alkyl group as defined above containing at least 1, and at most 6, carbon atoms substituted with at least one halogen, halogen being as defined herein. Examples of branched or straight chained “C1-C6 haloalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo and iodo.
  • As used herein, the term “C3-C7 cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to seven carbon atoms and which optionally includes a C1-C6 alkyl linker through which it may be attached. The C1-C6 alkyl group is as defined above. Exemplary “C3-C7 cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • As used herein, the term “C3-C7 cycloalkylene” refers to a non-aromatic alicyclic divalent hydrocarbon radical having from three to seven carbon atoms, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, lower perfluoroalkyl, multiple degrees of substitution being allowed. Examples of “cycloalkylene” as used herein include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.
  • As used herein, the term “heterocyclic” or the term “heterocyclyl” refers to a three to twelve-membered heterocyclic ring having one or more degrees of unsaturation containing one or more heteroatomic substitutions selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen, or C1-C6 perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more other “heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” moieties include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
  • As used herein, the term “heterocyclylene” refers to a three to twelve-membered heterocyclic ring diradical having one or more degrees of unsaturation containing one or more heteroatoms selected from S, SO, SO2, O, or N, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees of substitution being allowed. Such a ring may be optionally fused to one or more benzene rings or to one or more of another “heterocyclic” rings or cycloalkyl rings. Examples of “heterocyclylene” include, but are not limited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, and the like.
  • As used herein, the term “aryl” refers to an optionally substituted benzene ring or to an optionally substituted benzene ring system fused to one or more optionally substituted benzene rings to form, for example, anthracene, phenanthrene, or napthalene ring systems. Exemplary optional substituents include C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C1-C6 perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed. Examples of “aryl” groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, as well as substituted derivatives thereof.
  • As used herein, the term “arylene” refers to a benzene ring diradical or to a benzene ring system diradical fused to one or more optionally substituted benzene rings, optionally substituted with substituents selected from the group which includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl and aryl, multiple degrees of substitution being allowed. Examples of “arylene” include, but are not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, anthracene-1,4-diyl, and the like.
  • As used herein, the term “aralkyl” refers to an aryl or heteroaryl group, as defined herein, attached through a C1-C6 alkyl linker, wherein C1-C6 alkyl is as defined herein. Examples of “aralkyl” include, but are not limited to, benzyl, phenylpropyl, 2-pyridylmethyl, 3-isoxazolylmethyl, 5-methyl, 3-isoxazolylmethyl, and 2-imidazoyl ethyl.
  • As used herein, the term “heteroaryl” refers to a monocyclic five to seven membered aromatic ring, or to a fused bicyclic aromatic ring system comprising two of such monocyclic five to seven membered aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen heteroatoms, where N-oxides and sulfur oxides and dioxides are permissible heteroatom substitutions and may be optionally substituted with up to three members selected from a group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, C1-C6 perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed. Examples of “heteroaryl” groups used herein include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, and substituted versions thereof.
  • As used herein, the term “heteroarylene” refers to a five- to seven-membered aromatic ring diradical, or to a polycyclic heterocyclic aromatic ring diradical, containing one or more nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides are permissible heteroaromatic substitutions, optionally substituted with substituents selected from the group consisting of: lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitution being allowed. For polycyclic aromatic ring system diradicals, one or more of the rings may contain one or more heteroatoms. Examples of “heteroarylene” used herein are furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.
  • As used herein, the term “alkoxy” refers to the group RaO—, where Ra is alkyl as defined above and the term “C1-C6 alkoxy” refers to an alkoxy group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms. Exemplary C1-C6 alkoxy groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
  • As used herein, the term “haloalkoxy” refers to the group RaO—, where Ra is haloalkyl as defined above and the term “C1-C6 haloalkoxy” refers to an haloalkoxy group as defined herein wherein the haloalkyl moiety contains at least 1, and at most 6, carbon atoms. Exemplary C1-C6 haloalkoxy groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy substituted with one or more halo groups, for instance trifluoromethoxy.
  • As used herein the term “aralkoxy” refers to the group RbRaO—, where Ra is alkyl and Rb is aryl as defined above.
  • As used herein the term “aryloxy” refers to the group RaO—, where Ra is aryl as defined above.
  • As used herein, the term “alkylsulfanyl” refers to the group RaS—, where Ra is alkyl as defined above and the term “C1-C6 alkylsulfanyl” refers to an alkylsulfanyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
  • As used herein, the term “haloalkylsulfanyl” refers to the group RaS—, where Ra is haloalkyl as defined above and the term “C1-C6 haloalkylsulfanyl” refers to a haloalkylsulfanyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
  • As used herein, the term “alkylsulfenyl” refers to the group RaS(O)—, where Ra is alkyl as defined above and the term “C1-C6 alkylsulfenyl” refers to an alkylsulfenyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
  • As used herein, the term “alkylsulfonyl” refers to the group RaSO2—, where Ra is alkyl as defined above and the term “C1-C6 alkylsulfonyl”refers to an alkylsulfonyl group as defined herein wherein the alkyl moiety contains at least 1, and at most 6, carbon atoms.
  • As used herein, the term “oxo” refers to the group ═O
  • As used herein, the term “mercapto” refers to the group —SH.
  • As used herein, the term “carboxy” refers to the group —COOH.
  • As used herein, the term “cyano” refers to the group —CN.
  • As used herein the term “cyanoalkyl” refers to the group —CNRa, wherein Ra is alkyl as defined above. Exemplary “cyanoalkyl” groups useful in the present invention include, but are not limited to, cyanomethyl, cyanoethyl, and cyanoisopropyl.
  • As used herein, the term “aminosulfonyl” refers to the group —SO2NH2.
  • As used herein, the term “carbamoyl” refers to the group —C(O)NH2.
  • As used herein, the term “sulfanyl” shall refer to the group —S—.
  • As used herein, the term “sulfenyl” shall refer to the group —S(O)—.
  • As used herein, the term “sulfonyl” shall refer to the group —S(O)2— or —SO2—.
  • As used herein, the term “acyl” refers to the group RaC(O)—, where Ra is alkyl, cycloalkyl, or heterocyclyl as defined herein.
  • As used herein, the term “aroyl” refers to the group RaC(O)—, where Ra is aryl as defined herein.
  • As used herein, the term “heteroaroyl” refers to the group RaC(O)—, where Ra is heteroaryl as defined herein.
  • As used herein, the term “alkoxycarbonyl” refers to the group RaOC(O)—where Ra is alkyl as defined herein.
  • As used herein, the term “acyloxy” refers to the group RaC(O)O—, where Ra is alkyl, cycloalkyl, or heterocyclyl as defined herein.
  • As used herein, the term “aroyloxy” refers to the group RaC(O)O—, where Ra is aryl as defined herein.
  • As used herein, the term “heteroaroyloxy” refers to the group RaC(O)O—, where Ra is heteroaryl as defined herein.
  • As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.
  • As used herein, the term “physiologically functional derivative” refers to any pharmaceutically acceptable derivative of a compound of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) a compound of the present invention or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles and Practice, which is incorporated herein by reference to the extent that it teaches physiologically functional derivatives.
  • As used herein, the term “solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or formula (II) or a salt or physiologically functional derivative thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
  • As used herein, the term “substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
  • Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formulae (I) and (II) above as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that all tautomers and mixtures of tautomers of the compounds of formulae (I) or (II) are included within the scope of the compounds of formulae (I) and (II).
  • It is to be understood that reference to compounds of formula (I) and formula (II) above, following herein, refers to compounds within the scope of formula (I) and formula (II) as defined above with respect to E, X, Z, A, D, M, T, Q, R1, R2, R3, R4, R5, R6, R7, or R8 unless specifically limited otherwise. It is also understood that the following embodiments, including uses and compositions, although recited with respect to formula (I) are also applicable to formulae (II), (III), and (IV).
  • In one embodiment, E is aryl substituted with R1 and R2. In a preferred embodiment, E is phenyl substituted with R1 and R2. In another embodiment, E is unsubstituted heteroaryl, heteroaryl substituted with R1, or heteroaryl substituted with R1 and R2. In a preferred embodiment, E is heteroaryl substituted with R1 or heteroaryl substituted with R1 and R2. In a more preferred embodiment, E is heteroaryl substituted with R1, wherein R1 is preferably C1-C6 alkyl, more preferably —C(CH3)3, i.e. tert-butyl. In another preferred embodiment, E is selected from
    Figure US20070249600A1-20071025-C00006
    either unsubstituted, substituted by R1 or substituted by R1 and R2.
  • It is understood that E is attached to the indicated linking group of Formula (I) through the bond of E having an unfilled valence and being indicated by “\”. The appropriate attachments are further illustrated in the working examples recited below.
  • In another embodiment, E is phenyl and R1 and R2 together with the phenyl ring atoms with which they are attached form a cycloalkyl, preferably cyclopentyl, or aryl, preferably phenyl fused to E.
  • In one embodiment, the compound of formula (I) is a compound of formula (III):
    Figure US20070249600A1-20071025-C00007
    or salt, solvate, or physiologically functional derivative thereof.
  • In one embodiment, the compound of formula (I) is a compound of formula (IV):
    Figure US20070249600A1-20071025-C00008
    wherein E is unsubstituted heteroaryl, heteroaryl substituted with R1, or heteroaryl substituted with R1 and R2, or a salt, solvate, or physiologically functional derivative thereof.
  • In one embodiment, R1 is C1-C6 alkyl, C1-C6 alkoxy, aryloxy, C1-C6 haloalkyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfanyl, —C(O)OR6, halogen, —CN, or —NO2. In a preferred embodiment, R1 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, —NO2, or halogen. In a more preferred embodiment, R1 is —NO2, —OCH3, —CH2CH3, —C(CH3)3, —CF3, —F, —Cl, and —Br. In another preferred embodiment, R1 is C1-C6 haloalkyl, preferably —CF3. In still another preferred embodiment, R1 is C1-C6 alkyl, preferably —C(CH3)3.
  • In one embodiment, R2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. In a preferred embodiment, R2 is hydrogen or halogen. In a more preferred embodiment, R2 is hydrogen, —F, —Cl, or —Br. In a most preferred embodiment, R2 is fluorine.
  • In one embodiment, R1 is C1-C6 alkyl, C1-C6 alkoxy, aryloxy, C1-C6 haloalkyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfanyl, —C(O)OR6, halogen, —CN, or NO2 and R2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. In a preferred embodiment, R1 is C1-C6 haloalkyl and R2 is hydrogen or halogen. In a more preferred embodiment, R1 is NO2, —OCH3, —CH2CH3, —C(CH3)3, —CF3, —F, —Cl, and —Br and R2 is hydrogen, —F, —Cl, or —Br. In a most preferred embodiment, R1 is —CF3 and R2 is fluorine.
  • In one embodiment Z is S or O. In one embodiment, Z is S. In a preferred embodiment, Z is O.
  • In one embodiment, A is aryl or heteroaryl. In a preferred embodiment, A is phenyl, 2-pyridyl or 3-pyridyl. In a more preferred embodiment A is phenyl.
  • In one embodiment, X is S, O, S(O)2, S(O), CH2, CH(OH), or C(O). In a preferred embodiment, X is O or C(O). In a more preferred embodiment, X is O. In another embodiment, X is S.
  • The side chain —NHC(Z)NHE of the compounds of formula (I) and formula (II) may be linked to any suitable position of the group A. Similarly, the linker group X linking the benzimidazole core to the group A may be linked to any suitable position of the group A. Preferably the group A is linked to the side chain —NHC(Z)NHE and to the linker group X of the benzimidazole core through a (−1,3-) or (−1,4-) linkage. In one preferred embodiment, the group A is linked through a (−1,4-) linkage. In another preferred embodiment, the group A is linked through a (−1,3-) linkage.
  • The two dotted line bonds represented by “---”, which are attached to Q and N′ in the five-membered heterocyclic core of Formula I, may represent a single bond or a double bond. When q is 0, the dotted line bond “---” attached to Q is a single bond and the dotted line bond attached to N′ is a double bond as illustrated following:
    Figure US20070249600A1-20071025-C00009
  • When q is 1, the dotted line bond “---” attached to Q is a double bond and the dotted line bond attached to N′ is a single bond as illustrated following:
    Figure US20070249600A1-20071025-C00010
  • The dotted line within the 6 membered ring containing D, M, and T of Formula I, represents the appropriate aromatic bonds.
  • In a preferred embodiment, D is CH, T is CR8, M is C and Q is N(R7)p, wherein p is 0, q is 1, R7 is hydrogen, methyl, or S(O)2R6 or D is CH, T is CR8, wherein R8 is hydrogen or —Br, M is C and Q is N(R7)p, wherein p is 1, q is 0, R7 is hydrogen, methyl, —S(O)2R6, —RNR4R5, —RR6 or aralkyl. In a more preferred embodiment, D is CH, T is CR8, wherein R8 is hydrogen, M is C and Q is N(R7)p, wherein either p or q is 0, the other is 1 and R7 is hydrogen.
  • In another embodiment, D is CH, T is CR8, wherein R8 is hydrogen or —Br, M is C and Q is S or O; wherein q is 0. In a further embodiment, D is N, T is CR8, wherein R8 is hydrogen or —Br, M is C and Q is N(R7)p, wherein either p or q is 0, the other is 1, R7 is hydrogen, methyl, or S(O)2R6. In an alternative embodiment, D is CH, T is N, M is C and Q is N(R7)p, wherein either p or q is 0, the other is 1, R7 is hydrogen, methyl, or S(O)2R6. In a further alternative embodiment, D is CH, T is CR8, wherein R8 is hydrogen or —Br, M is N and Q is CH, wherein q is 0.
  • In one embodiment, R3 is —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5; In a preferred embodiment, R3 is —C(O)R6, —C(O)NR4R5, or —C(O)OR6. In a more preferred embodiment, R3 is —C(O)OR6. In a most preferred embodiment, R3 is —C(O)OR6 and R6 is methyl.
  • In one embodiment, A is phenyl; X is O; Z is O; R1 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or NO2; R2 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; and R3 is —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5. In a preferred embodiment, A is phenyl; X is O; Z is O; R1 is C1-C6 alkyl or C1-C6 haloalkyl; R2 is hydrogen or halogen; and R3 is —C(O)R6, —C(O)NR4R5, or —C(O)OR6. In a more preferred embodiment, A is phenyl; X is O; Z is O; R1 is C1-C6 haloalkyl; R2 is halogen; and R3 is —C(O)OR6.
  • In one embodiment, A is phenyl; X is S; Z is O; R1 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or NO2; R2 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; and R3 is —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(R)ROR6, —C(O)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5. In a preferred embodiment, A is phenyl; X is S; Z is O; R1 is C1-C6 alkyl or C1-C6 haloalkyl; R2 is hydrogen or halogen; and R3 is —C(O)R6 or —C(O)OR6. In a more preferred embodiment, A is phenyl; X is S; Z is O; R1 is C1-C6 haloalkyl; R2 is halogen; and R3 is —C(O)OR6.
  • In one embodiment, A is pyridyl; X is O; Z is O; R1 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or NO2; R2 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; and R3 is —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(R)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5. In a preferred embodiment, A is pyridyl; X is O; Z is O; R1 is C1-C6 alkyl or C1-C6 haloalkyl; R2 is hydrogen or halogen; and R3 is —C(O)R6 or —C(O)OR6. In a more preferred embodiment, A is pyridyl; X is O; Z is O; R1 is C1-C6 haloalkyl; R2 is halogen; and R3 is —C(O)OR6.
  • In one embodiment, A is pyridyl; X is S; Z is O; R1 is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or NO2; R2 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; and R3 is —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(R)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR″, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5. In a preferred embodiment, A is pyridyl; X is S; Z is O; R1 is C1-C6 alkyl or C1-C6 haloalkyl; R2 is hydrogen or halogen; and R3 is —C(O)R6 or —C(O)OR6. In a more preferred embodiment, A is pyridyl; X is S; Z is O; R1 is C1-C6 haloalkyl; R2 is halogen; and R3 is —C(O)OR6.
  • In one embodiment, the compound is a compound of formula (IV) where E is unsubstituted heteroaryl, heteroaryl substituted by R1, or heteroaryl substituted by R1 and R2, A is phenyl; X is O; Z is O; R1 is C1-C6 alkyl, aryl, C3-C7 cycloalkyl, heterocyclyl, C1-C6 haloalkyl, or C1-C6 alkylsulfanyl; R2 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl; and R3 is —C(O)R, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5. In a preferred embodiment, E is heteroaryl substituted by R1 or heteroaryl substituted by R1 and R2, A is phenyl; X is O; Z is O; R1 is C1-C6 alkyl; R2 is hydrogen or halogen; and R3 is —C(O)R6, —C(O)ROR′OR6, or —C(O)OR6. In a more preferred embodiment, E is heteroaryl substituted by R1, A is phenyl; X is O; Z is O; R1 is —C(CH3)3; and R3 is —C(O)R6.
  • Specific examples of compounds of the present invention include the following:
    • Methyl N-(5-(4-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H -benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3,5-di(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3,5-dimethoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylsulfonyl)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate;
    • Methyl (5-(3-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Ethyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • T-butyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-t-butylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • 2-Amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;
    • (6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(methanesulfonyl)-1H-benzimidazol-2-ylamine;
    • 6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine;
    • N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)acetamide;
    • N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)cyclopentamide;
    • N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-methylpentamide;
    • N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-(N-acetylamino)acetamide;
    • N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-aminoacetamide;
    • N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-methoxyacetamide;
    • 3-(N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamoyl)propionic acid;
    • N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-(2-(methoxy)ethoxy)ethoxy)acetamide;
    • N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-(N-(t-butoxycarbony)amino)acetamide;
    • N-(5-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyl oxy)-1H-benzimidazol-2-yl)acetamide;
    • Methyl N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(5-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate; and
    • Methyl N-(5-(5-((3-ethylphenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
      or a salt, solvate, or physiologically functional derivative thereof.
  • Further specific Examples of compounds of the present invention include:
    • Methyl N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-(3-methylthiophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-(3-cyanophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-ethoxycarbonylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-carboxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl) carbamate;
    • Methyl N-(5-(4-((2-fluoro-5-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2,5-difluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((3-(phenoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((4-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((4-methoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((4-fluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-benzthiazol-2-yl)carbamate;
    • Methyl N-(4-bromo-6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)benzthiazol-2-yl)carbamate;
    • Methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-3a-aza-2-indolyl)carbamate;
    • Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-3,4-diazaindolin-2-yl)carbamate;
    • Methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-(2-(dimethylamino)ethyl)-1H-benzimidazol-2-yl)carbamate
    • Methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-(2-(4-morpholino)ethyl)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate;
    • Methyl N-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate;
    • Methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate;
    • Methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate;
    • Methyl N-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)benzthiazol-2-yl)carbamate;
    • 6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4-a,5-triazacarbazol-2-one;
    • Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylcarbonyl)-1H -benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate;
    • 2-(Dimethylamino)ethyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Benzyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • 5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(methanesulfonyl)-1H-benzimidazol-2-ylamine;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)methanesulfonamide;
    • 5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-methylbenzenesulfonamide;
    • N-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)benzthiazol-2-yl)methanesulfonamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-(4-methyl-1-piperazinomethyl)benzamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-3-(pyridine-3-yl)propionamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-5-benzimidazolecarboxamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-(pyrrol-1-yl)benzamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-(1H-imidazol-1-yl)benzamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-(dimethylamino)butylamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-3-pyridinecarboxamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-tetrahydrofurancarboxamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl) (1H-indole-3-carboxamide);
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(5-(1-pyrrolidino)tetrazol-2-yl)acetamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(1-methyl-1H-imidazol-4-yl)acetamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(1H-imidazole-4-carboxamide);
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)benzamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-thiophenecarboxamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(4-methyl-1-piperazino)acetamide;
    • N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(dimethylamino)acetamide;
    • 6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one;
    • 7-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one;
    • 2-(2-(4-Methyl-1-piperazino)ethylamino)-5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;
    • 2-(2-(Dimethylamino)ethylamino)-5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;
    • 2-(3-(4-Methyl-1-piperazino)propylamino)-5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;
    • Methyl N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-1-oxo-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
    • N-(6-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)acetamide;
    • Methyl N-(5-(5-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(5-((2,5-dichlorophenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
    • 6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-ylamine;
    • N-(6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)methanesulfonamide; and
    • Methyl N-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzoxazol-2-yl)carbamate;
      or a salt, solvate, or physiologically functional derivative thereof.
  • Additional further specific Examples of compounds of the present invention include:
    • Methyl N-(5-(3-((2-(trifluoromethoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((4-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((2-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((3-iodophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((2-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((4-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenylthio)-1H -benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((3-phenyl-1,2,4-thiadiazol-5-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((1-naphtyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • 1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;
    • 1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(4-chlorophenyl)urea;
    • 1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(4-(N,N-dimethylamino)phenyl)urea;
    • 1-(6-(4-((4-Chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)-3-(butyl)urea;
    • 1-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)-3-(butyl)urea;
    • N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)acetamide;
    • N-(5-(4-((4-tert-Butyl-thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((4-tert-Butyl thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((5-tert-Butyl1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((5-Propylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((5-Cycloproyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
    • N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
    • N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • N-(5-(4-((5-Carbamoyl-2-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
    • Methyl N-(5-(3-((2,3-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • 1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2,3-dimethylphenyl)urea;
    • Methyl N-(5-(4-((3-chlorophenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
    • Methyl N-(5-(4-((3-methoxyphenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate; and
    • Methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminothiocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate;
      or a salt, solvate, or physiologically functional derivative thereof.
  • Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen on a substituent in the compound of formula (I). Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium and valerate. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention.
  • While it is possible that, for use in therapy, therapeutically effective amounts of a compound of formula (I), as well as salts, solvates and physiological functional derivatives thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include therapeutically effective amounts of compounds of the formula (I) and salts, solvates and physiological functional derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of the formula (I) and salts, solvates and physiological functional derivatives thereof, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I), or salts, solvates and physiological functional derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • The compounds of formula (I), and salts, solvates and physiological functional derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • The compounds of formula (I) and salts, solvates and physiological functional derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • For treatments of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
  • Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
  • Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurised aerosols, nebulizers or insufflators.
  • Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian However, an effective amount of a compound of formula (I) for the treatment of neoplastic growth, for example colon or breast carcinoma, will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt or solvate, or physiologically functional derivative thereof, may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • The compounds of the present invention and their salts and solvates, and physiologically functional derivatives thereof, may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions. In particular, in anti-cancer therapy, combination with other chemotherapeutic, hormonal or antibody agents is envisaged as well as combination with surgical therapy and radiotherapy. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and the use of at least one other cancer treatment method. Preferably, combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, and at least one other pharmaceutically active agent, preferably an anti-neoplastic agent. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • The compounds of the Formula (I) or salts, solvates, or physiologically functional derivatives thereof and at least one additional cancer treatment therapy may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination with such other anti-cancer therapies. In one embodiment, the other anti-cancer therapy is at least one additional chemotherapeutic therapy including administration of at least one anti-neoplastic agent. The administration in combination of a compound of formula (I) or salts, solvates, or physiologically functional derivatives thereof with other anti-neoplastic agents may be in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one anti-neoplastic agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • Anti-neoplastic agents may induce anti-neoplastic effects in a cell-cycle specific manner, i.e., are phase specific and act at a specific phase of the cell cycle, or bind DNA and act in a non cell-cycle specific manner, i.e., are non-cell cycle specific and operate by other mechanisms.
  • Anti-neoplastic agents useful in combination with the compounds and salts, solvates or physiologically functional derivatives thereof of formula I include the following:
  • (1) cell cycle specific anti-neoplastic agents include, but are not limited to diterpenoids such as paclitaxel and its analog docetaxel; vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine; epipodophyllotoxins such as etoposide and teniposide; fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine; antimetabolites such as allopurinol, fludurabine, methotrexate, cladrabine, cytarabine, mercaptopurine and thioguanine; and camptothecins such as 9-amino camptothecin, irinotecan, CPT-11 and the various optical forms of 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin;
  • (2) cytotoxic chemotherapeutic agents including, but not limited to, alkylating agents such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; anti-tumour antibiotics such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dacttinomycin and mithramycin; and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; and
  • (3) other chemotherapeutic agents include, but are not limited to, anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene; progestrogens such as megestrol acetate; aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane; antiandrogens such as flutamide, nilutamide, bicalutamide, and cyproterone acetate; LHRH agonists and antagagonists such as goserelin acetate and luprolide, testosterone 5α-dihydroreductase inhibitors such as finasteride; metalloproteinase inhibitors such as marimastat; antiprogestogens; urokinase plasminogen activator receptor function inhibitors; growth factor function inhibitors such as inhibitors of the functions of hepatocyte growth factor; erb-B2, erb-B4, epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR, and TIE-2 (other than those VEGFR and TIE-2 inhibitors described in the present invention); and other tyrosine kinase inhibitors such as inhibitors of CDK2 and CDK4 inhibitors.
  • The compounds of formula (I) and salts, solvates and physiological functional derivatives thereof, are believed to have anticancer activity as a result of inhibition of the protein kinase TIE-2 and its effect on selected cell lines whose growth is dependent on TIE-2 protein kinase activity.
  • The present invention thus also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof, or physiologically functional derivatives thereof, for use in medical therapy, and particularly in the treatment of disorders mediated by inappropriate TIE-2 activity.
  • The inappropriate TIE-2 activity referred to herein is any TIE-2 activity that deviates from the normal TIE-2 activity expected in a particular mammalian subject. Inappropriate TIE-2 activity may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of TIE-2 activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation. Furthermore, it is also understood that unwanted TIE-2 activity may reside in an abnormal source, such as a malignancy. That is, the level of TIE-2 activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source. In a like manner, the inappropriate angiogenesis referred to herein is any angiogenic activity that deviates from the normal angiogenic activity expected in a particular mammalian subject. Inappropriate angiogenesis may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of angiogenic activity. Such inappropriate activity may result then, for example, from overexpression or mutation of a protein kinase leading to inappropriate or uncontrolled activation. Furthermore, it is also understood that unwanted angiogenic activity may reside in an abnormal source, such as a malignancy. That is, the level of angiogenic activity does not have to be abnormal to be considered inappropriate, rather the activity derives from an abnormal source.
  • The present invention is directed to methods of regulating, modulating, or inhibiting TIE-2 for the prevention and/or treatment of disorders related to unregulated TIE-2 activity. In particular, the compounds of the present invention can also be used in the treatment of certain forms of cancer. Furthermore, the compounds of the present invention can be used to provide additive or synergistic effects with certain existing cancer chemotherapies, and/or be used to restore effectiveness of certain existing cancer chemotherapies and radiation.
  • The compounds of the present invention are also useful in the treatment of one or more diseases afflicting mammals which are characterized by cellular proliferation in the area of disorders associated with neo-vascularization and/or vascular permeability including blood vessel proliferative disorders including arthritis and restenosis; fibrotic disorders including hepatic cirrhosis and atherosclerosis; mesangial cell proliferative disorders include glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection and glomerulopathies; and metabolic disorders include psoriasis, diabetes mellitus, chronic wound healing, inflammation and neurodegenerative diseases.
  • A further aspect of the invention provides a method of treatment of a mammal suffering from a disorder mediated by inappropriate TIE-2 activity, including susceptible malignancies, which includes administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or a physiologically functional derivative thereof. In a preferred embodiment, the disorder is cancer.
  • A further aspect of the invention provides a method of treatment of a mammal suffering from cancer which includes administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof.
  • A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of a disorder characterized by inappropriate TIE-2 activity. In a preferred embodiment, the disorder is cancer.
  • A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, or a physiologically functional derivative thereof, in the preparation of a medicament for the treatment of cancer and malignant tumors.
  • The mammal requiring treatment with a compound of the present invention is typically a human being.
  • In another embodiment, therapeutically effective amounts of the compounds of formula (I) or salts, solvates or physiologically derived derivatives thereof and agents which inhibit growth factor receptor function may be administered in combination to a mammal for treatment of a disorder mediated by inappropriate TIE-2 activity, for instance in the treatment of cancer. Such growth factor receptors include, for example, EGFR, PDGFR, erbB2, erbB4, VEGFR, and/or TIE-2. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C., Exp. Opin. Ther. Patents (2000) 10(6):803-818 and in Shawver et al DDT Vol 2, No. 2 Feb. 1997.
  • The compounds of the Formula (I) or salts, solvates, or physiologically functional derivatives thereof and the agent for inhibiting growth factor receptor function may be employed in combination concomitantly or sequentially in any therapeutically appropriate combination. The combination may be employed in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • In another aspect of the present invention, there is provided a method of treating a disorder in a mammal, said disorder being mediated by inappropriate angiogenesis, including: administering to said mammal a therapeutically effective amount of a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof. In one embodiment, the inappropriate angiogenic activity is due to at least one of inappropriate VEGFR1, VEGFR2, VEGFR3, or TIE-2 activity. In another embodiment, the inappropriate angiogenesis is due to inappropriate VEGFR2 and TIE-2 activity. In a further embodiment, the method further includes administering a therapeutically effective amount of a VEGFR2 inhibitor along with the compounds of formula (I) or salts, solvates or physiologically functional derivatives thereof. Preferably the disorder is cancer.
  • In another aspect of the present invention, there is provided the use of a compound of formula (I), or a salt, solvate or physiologically functional derivative thereof in the preparation of a medicament for use in treating a disorder in a mammal, said disorder being characterized by inappropriate angiogenesis. In one embodiment, the inappropriate angiogenic activity is due to at least one of inappropriate VEGFR1, VEGFR2, VEGFR3 or TIE-2 activity. In another embodiment, the inappropriate angiogenesis is due to inappropriate VEGFR2 and TIE-2 activity. In a further embodiment, the use further includes use of a VEGFR2 inhibitor to prepare said medicament.
  • The combination of a compound of formula (I) or salts, solvates, or physiologically functional derivatives thereof with a VEGFR2 inhibitor may be employed in combination in accordance with the invention by administration concomitantly in (1) a unitary pharmaceutical composition including both compounds or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the Working Examples.
  • Compounds of general formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula (I). Those skilled in the art will recognize if a stereocenter exists in compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).
  • Compounds of Formula (I), wherein R3 is —C(O)OCH3, A is phenyl, and X and Z are oxygen, D and T are CH, M is C, Q is N(R7)p, either p or q is 1, and the other is 0, can be prepared according to the synthetic sequence shown in Scheme 1 and further detailed in the Examples section following. 4-Acetamidophenol (1) in DMF is reacted with 5-chloro-2-nitroaniline (2) in the presence of 60% NaH to provide 5-(4-acetamidophenoxy)-2-nitroaniline (3). The nitroaniline (3) is then refluxed with Na2S2O4 to provide 4-(4-acetamidophenoxy)phenylene-1,2-diamine (4). (It is understood that reduction of nitro group of (3) can be effected in many ways, for example by use of H2, Pd/C; Raney Nickel with hydrazine; SnCl4 in HCl; etc.) Diamine (4) is refluxed with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in ethanol and the acetylated carbamate (5) is obtained. HCl is added to deacetylate the carbamate (5) to give methyl (5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate (7). Alternatively, carbamate (7) may be prepared by refluxing 3,4,4′-triaminodiphenylether (6) with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea and then treating with conc. HCl to give carbamate (7). Carbamate (7) is then reacted with the appropriate phenyl isocyanate (8) to give the resultant benzimidazole (9) of the present invention. It is understood that R1 and R2 are as described above. When X of Formula (I) is sulfur and Z of Formula (I) is oxygen, the final compounds are obtained by following the same procedure using a phenylthiol derivative of 1. When X of Formula (I) is sulfur, the compound thus obtained can be oxidized with MCPBA (meta-chloroperbenzoic acid) to give compounds containing sulfone (SO2) or sulfine (SO) as X. Also, when 3-(3-substitutedphenyl)aminocarbonylamino)phenoxy derivatives of Formula I are prepared, 3-acetamidophenol is utilized instead of 4-acetamidophenol.
    Figure US20070249600A1-20071025-C00011
  • Compounds of Formula (I), wherein A is phenyl, X and Z are oxygen, D and T are CH, M is C, Q is N(R7)p, either p or q is 1, and the other is 0, R1 is CF3, R2 is F, and R3 is a substituted carbonyl, can be prepared according to the synthetic sequence shown in Scheme 2 and further detailed in the Examples section following. 4-aminophenol (1) in DMF is reacted with 5-chloro-2-nitroaniline (2) in the presence of 60% NaH to give 5-(4-aminophenoxy)-2-nitroaniline (3). The compound (3) is reacted with 2-fluoro-5-trifluoromethylphenylisocyanate (4) to provide 5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-2-nitroaniline (5). The nitroaniline (5) is hydrogenated under an H2 atmosphere in the presence of Pd/C to give the corresponding diamine (6). Diamine (6) is reacted with cyanogen bromide to give benzimidazole (7). Benzimidazole (7) may be reacted with the appropriate carboxylic acid in the presence of triethylamine and HBTU (O-Benzotriazole-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) to give the corresponding benzimidazole (8). Benzimidazole (7) may also be reacted with J′SO2Cl (J′ is methyl or p-tolyl) to give a couple of endo-sulfonated products (9, 10). J′SO2 moiety was migrated to the exo site by heating (11). Further, benzimidazole (7) may be reacted with isocyanate J″NCO to give diurea (12). When X of Formula (I) is sulfur and Z of Formula (I) is oxygen, the final compounds are obtained by following the same procedure except that a phenylthiol derivative of 1 is used. When X of Formula (I) is sulfur, the compound thus obtained can be oxidized with MCPBA (meta-chloroperbenzoic acid) to give compounds containing sulfonyl (—SO2) or sulfenyl (—SO) as X. Also, as indicated above 3-(3-substituted phenyl)aminocarbonylamino) phenoxy derivatives of Formula I are prepared using 3-acetamidophenol instead of 4-acetamidophenol. The substituent J may be any substituent attached to C(O) within the scope of the definition of R3 as recited herein. The substituent J″ may be any substituent R5 as defined herein.
    Figure US20070249600A1-20071025-C00012
  • Compounds of Formula I, wherein A is pyridyl, D and T are CH, M is C, Q is N(R7)p, either p or q is 1, and the other is 0, can be prepared according to the synthetic sequence shown in Scheme 3 and further detailed in the Examples section following. The terms A1 and A2 refer to N and C, or C and N, respectively. 5-Hydroxybenzimdazole derivative (2) with or without a protecting group L is coupled with halonitropyridine (1) in the presence of base e.g. Cs2CO3 to give compound (3). Subsequent hydrogenation over Pd—C provides aniline derivative (4), followed by coupling with isocyanate (and deprotection if needed) to afford urea (5).). The intermediate (4) can also be provided by way of triamine (6).
    Figure US20070249600A1-20071025-C00013
    Figure US20070249600A1-20071025-C00014
  • Compounds of Formula I, wherein D is CH, T is C, M is C, Q is N(R7)p, R7 is CH3, p is 0 and q is 1, can be prepared according to the synthetic sequence shown in Scheme 4 and further detailed in the Examples section following. 4-(4-Nitrophenoxy)-2-nitroaniline (1) was coupled with 1-fluoro-4-nitrobenzene with NaH to give (2). Methylation, hydrogenation proceeding through (3), and subsequent cyclization with (4) afforded (5), followed by coupling with isocyanate (6) to yield urea (7).
    Figure US20070249600A1-20071025-C00015
  • Compounds of Formula I, wherein D is CH, T is CH, M is C, Q is N(R7)p (p is 1; R7 is C1-C6 alkyl, —RNR4R5 or —RR6), and q is 0, can be prepared according to the synthetic sequence shown in Scheme 5 and further detailed in the Examples section following. N-alkyl-5-chloro-2-nitroaniline (3), derived from (1) or (2), was coupled with 4-aminophenol to provide (4). Using methods similar to those shown in the previous Schemes, hydrogenation, cyclization through (5), and coupling with isocyanate afforded (6).
    Figure US20070249600A1-20071025-C00016
  • Compounds of Formula I, wherein D is CH, T is CH, M is C, Q is O, and q is 0, can be prepared according to the synthetic sequence shown in Scheme 6 and further detailed in the Examples section following. 4-Aminophenol (1) was coupled with (2) to give ether (3), which was coupled with isocyante to afford (4). Hydrogenation and cyclization with BrCN to give (5), followed by the reaction with CICOOMe gave oxazole derivative (6).
    Figure US20070249600A1-20071025-C00017
  • Compounds of Formula I, wherein D is CH, T is CH, M is C, Q is S, and q is 0, can be prepared according to the synthetic sequence shown in Scheme 7 and further detailed in the Examples section following. 4-(4-Nitrophenoxy)aniline (2), derived from (1) and 4-aminophenol, was cyclized with KSCN and Br2 in the presence of acid to provide thiazole (3). Subsequent reaction with CICO2Me or butylisocyante (BuNCO) to give (4), followed by reduction with SnCl2 to give (5) and finally coupling with isocyanate afforded (6).
    Figure US20070249600A1-20071025-C00018
  • Compounds of Formula I, wherein D is N, T is CH, M is C, Q is N(R7)p, R7 is H, either p or q is 1, and the other is 0, can be prepared according to the synthetic sequence shown in Scheme 8 and further detailed in the Examples section following. 2-Amino-6-chloro-3-nitropyridine (1) was coupled with 4-acetylaminophenol (2) with K2CO3 to provide ether (3). Using methods similar to those shown in the previous Schemes, hydrogenation and cyclization to give (4), hydrolysis to give (5), and coupling with isocyanate, were carried out to yield pyridoimidazole (6).
    Figure US20070249600A1-20071025-C00019
  • Compounds of Formula I, wherein D is N, T is CH, M is C, Q is N, q is 0, and R3 is COCH2CH2 linked together with the nitrogen at Q, can be prepared according to the synthetic sequence shown in Scheme 9 and further detailed in the Examples section following. 2,6-Dichloro-3-nitropyridine (1) was aminated to give (2) and coupled with 4-acetylaminophenol to give ether (3). After hydrogenation, and subsequent cyclization with BrCN to give (4), compound (4) was cyclized by ester hydrolysis through heating to provide (5). Using methods similar to those shown in the previous Schemes, hydrolysis to give (6) and coupling with isocyanate yielded urea (7).
    Figure US20070249600A1-20071025-C00020
  • Compounds of Formula I, wherein D is CH, T is CH, M is N, Q is CH, and q is 0, can be prepared according to the synthetic sequence shown in Scheme 10 and further detailed in the Examples section following. Ether (2), derived from 5-bromo-2-nitroaniline (1), was cyclized with ClCH2CONHCO2Me to give pyridoimidazole (3). Using methods similar to those shown in the previous Schemes, hydrolysis to give (4) and coupling with isocyanate yielded urea (5).
    Figure US20070249600A1-20071025-C00021
  • Compounds of Formula I, wherein D is CH, T is N, M is C, Q is N(R7)p, R7 is H, either p or q is 1, and the other is 0, can be prepared according to the synthetic sequence shown in Scheme 11 and further detailed in the Examples section following. A nitro moiety was added to ethyl N-(5-bromopyridine-3-yl)carbamate (1) to give (2), followed by hydrolysis to give (3). Using methods similar to those shown in the previous Schemes, coupling with phenol derivative gave (4), hydrogenation and cyclization in the presence of acid gave (5), hydrolysis gave (6), and coupling with isocyanate yielded pyridoimidazole (7).
    Figure US20070249600A1-20071025-C00022
  • Compounds of Formula I, wherein X is CO, CH2, CH(OH), D is CH, T is CH, M is C, Q is N(R7)p, R7 is H, either p or q is 1, and the other is 0, can be prepared according to the synthetic sequence shown in Scheme 12 and further detailed in the Examples section following. Friedel-Crafts condensation with the halide of (1) and acetoanilide was carried out to give ketone (2). Using methods similar to those shown in the previous Schemes, reduction with zinc and cyclization gave (3), hydrolysis, and coupling with isocyanate yielded pyridoimidazole (4). Also, reduction with NaBH4 gave carbinol (5), followed by further reduction with Et3SiH provided benzyl derivative (6).
    Figure US20070249600A1-20071025-C00023
  • J is as defined above.
  • According to Scheme 13, amino-(4-methoxyphenyl)-methylpolystyrene resin was first loaded with 4-chloro-2-fluoronitrobenzene in the presence of DIEA. The chlorine of compound (1) was displaced with the oxygen of the 4-aminophenol using NaH as the base to arrive at (2). The free amino group of (2) was then activated with p-nitrophenyl chloroformate, the excess of which washed away before the amines were added. For this step, the resin was split into 21 equal batches and twenty (20) five-membered heteroaryl amines and one substituted aniline were used to afford (3). The nitro group of (3) was reduced with tin chloride to give diamine (4). Cyclization with Fmoc-NCS resulted in the Fmoc-protected aminobenzimidazole (5). Each resin batch was split again into four even portions. They were deprotected and acylated with four different carboxylic acids. Finally, the resin was treated with 23:2:75 (v/v/v) TFA/H2O/DCM to yield 84 discrete benzimidazoles (7).
  • Certain embodiments of the present invention will now be illustrated by way of example only. The physical data given for the compounds exemplified is consistent with the assigned structure of those compounds.
    • EXAMPLES
  • As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:
  • g (grams); mg (milligrams);
  • L (liters); mL (milliliters);
  • μL (microliters); psi (pounds per square inch);
  • M (molar); mM (millimolar);
  • i. v. (intravenous); Hz (Hertz);
  • MHz (megahertz); mol (moles);
  • mmol (millimoles); rt (room temperature);
  • min (minutes); h (hours);
  • mp (melting point); TLC (thin layer chromatography);
  • Tr (retention time); RP (reverse phase);
  • MeOH (methanol); i-PrOH (isopropanol);
  • TEA (triethylamine); TFA (trifluoroacetic acid);
  • TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran);
  • DMSO (dimethylsulfoxide); AcOEt (ethyl acetate);
  • DME (1,2-dimethoxyethane); DCM (dichloromethane);
  • DCE (dichloroethane); DMF (N,N dimethylformamide);
  • DMPU (N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole);
  • IBCF (isobutyl chloroformate); HOAc (acetic acid);
  • HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole);
  • mCPBA (meta-chloroperbenzoic acid; EDC (ethylcarbodiimide
  • hydrochloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl);
  • DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl);
  • Ac (acetyl); atm (atmosphere);
  • TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl);
  • TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);
  • DMAP (4-dimethylaminopyridine); BSA (bovine serum albumin)
  • ATP (adenosine triphosphate); HRP (horseradish peroxidase);
  • DMEM (Dulbecco's modified Eagle medium);
  • HPLC (high pressure liquid chromatography);
  • BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);
  • TBAF (tetra-n-butylammonium fluoride);
  • HBTU (O-Benzotriazole-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate).
  • HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid);
  • DPPA (diphenylphosphoryl azide);
  • EtOH (Ethanol)
  • fHNO3 (fumed HNO3);
  • DIC (1,3-Diisopropylcarbodiimide);
  • EDC (1-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride;
  • DIEA (N,N-Diisopropylethylamine); and
  • EDTA (ethylenediaminetetraacetic acid).
  • All references to ether are to diethyl ether; brine refers to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C. (degrees Centigrade). All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted.
  • 1H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, a Varian Unity-400 instrument, a Brucker AVANCE-400, or a General Electric QE-300. Chemical shifts are expressed in parts per million (ppm, 6 units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).
  • Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA, JOEL SX-102, or a SCIEX-APIiii spectrometer; LC-MS were recorded on a micromass 2MD and Waters 2690; high resolution MS were obtained using a JOEL SX-102A spectrometer. All mass spectra were taken under electrospray ionization (ESI), chemical ionization (CI), electron impact (EI) or by fast atom bombardment (FAB) methods. Infrared (IR) spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1-mm NaCl cell. Most of the reactions were monitored by thin-layer chromatography on 0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (230-400 mesh, Merck).
  • A further note on characterization, when R7 is H in a compound of Formula (I) wherein Q is N(R7)p, it is not identifiable whether p or q is 1 due to the tautomerism.
  • Preparation of Intermediates
  • Intermediate 1
    • 5-(4-Acetamidophenoxy)-2-nitroaniline
  • Figure US20070249600A1-20071025-C00024
  • To a solution of 4-acetamidophenol (7.56 g, 50 mmol) in DMF (20 ml) was added 60% NaH (2.2 g) followed by 5-chloro-2-nitroaniline (9.06 g, 50 mmol). The mixture was heated to 120° C. overnight. After cooling, 800 ml of water was added and the resultant solid was collected by filtration. Desiccation in vacuo gave intermediate 1 as a brown solid (13.75 g, 96%): MS m/e 286 (M−1).
  • Intermediate 1A
    • 5-(3-Acetamidophenoxy)-2-nitroaniline
  • Figure US20070249600A1-20071025-C00025
  • 3-Acetamidophenol was utilized instead of 4-acetamidophenol, according to the same procedure for Intermediate 1 to prepare Intermediate 1A: MS m/e 286 (M−1).
  • Intermediate 2
    • 4-(4-Acetamidophenoxy)phenylene-1,2-diamine
  • Figure US20070249600A1-20071025-C00026
  • Na2S2O4 (28.2 g, 160 mmol) was added to a solution of 5-(4-Acetamidophenoxy)-2-nitroaniline (Intermediate 1) (13.7 g, 48 mmol) in EtOH (600 ml) and H2O (150 ml). The yellow mixture was refluxed with vigorous stirring until the color disappeared. After cooling, the mixture washed with brine and the product was extracted with AcOEt. The AcOEt layer was dried over MgSO4, filtered and evaporated to give intermediate 2 as a brown film (10.2 g, 83%): MS m/e 258 (M+1).
  • Intermediate 2A
    • 4-(3-Acetamidophenoxy)phenylene-1,2-diamine
  • Figure US20070249600A1-20071025-C00027
  • Intermediate 1A was treated instead of Intermediate 1 to give Intermediate 2A: MS m/e 258 (M+1).
  • Intermediate 3
    • Methyl (5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00028
    Method A:
  • A mixture of 4-(4-Acetamidophenoxy)phenylene-1,2-diamine (Intermediate 2) (750 mg, 2.9 mmol) and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (600 mg) in ETOH (13 ml) was refluxed overnight. After cooling to rt, diethyl ether was added to form a solid (830 mg), which was collected by filtration. 1N-HCl (150 ml) was poured to this acetylated version of intermediate 3 (7.7 g, 23 mmol). The mixture was heated to reflux (105° C.) for 2 h. After cooling, aq. NH3 (30%, 20 ml) was added. The precipitate thus formed was collected by filtration with suction and dried in vacuo. The solid material was then suspended in MeOH (150 ml) and heated to 70° C. for 30 min. with stirring to dissolve a minor by-product. After cooling, the undissolved material was collected by filtration and dried in vacuo to give intermediate 3 as a brown solid (6.75 g, 99%): MS m/e 299 (M+1).
  • Method B:
  • A mixture of 3,4,4′-triaminodiphenylether (12.6 g, 59 mmol) and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (26.7 g) was refluxed overnight. After cooling, Et2O was added to form a precipitate, which was then collected by filtration. The solid thus obtained (4 g) was dissolved in MeOH (20 ml) and treated with 2N-HCl (20 ml) and then with conc.HCl (3 ml). Stirring was continued overnight at rt. The mixture was evaporated to remove MeOH. The resultant material was neutralized with aq. NaOH to give intermediate 3 as an off-white solid: MS m/z 299 (M+1).
  • Intermediate 3A
    • Methyl (5-(3-aminophenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00029
  • Intermediate 3A was prepared following the Method A procedure for the preparation of Intermediate 3 using Intermediate 2A instead of Intermediate 2: MS m/z 299 (M+1).
  • Intermediate 3B
    • Methyl (5-(4-aminophenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00030
  • Intermediate 3B was prepared following the Method A procedure for the preparation of Intermediate 3 starting from 4-acetamidophenylthiol: MS m/z 315 (M+1).
  • Intermediate 3C
    • Benzyl(5-(4-(N,N′-bis(benzyloxycarbonyl)amidino)aminophenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00031
  • A mixture of 3,4,4′-triaminodiphenyl ether (5.0 g, 23.2 mmol) and 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (16.5 g, 46.0 mmol) in dry MeOH (100 ml) was refluxed overnight. The reaction mixture was cooled to room temperature and ether was added. An off white solid was generated and collected by filtration and washed with ether and dried in vacuo. 14.3 g of Intermediate 3C was obtained as off white powder. Yield 89.9% 1H NMR (DMSO-d6) δ 11.82 (br, 1H), 11.40 (br, 1H), 7.51-7.27 (m, 20H), 7.03 (s, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 5.24 (s, 4H), 5.02 (s, 2H); MS m/e 685 (M+1).
  • Intermediate 3D
    • Benzyl (5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00032
  • 14.3 g of Intermediate 3C was dissolved in 300 ml of MeOH and 300 ml of 2M HCl and stirred for 3 days at 50° C. Then MeOH was removed by evaporation and 2M of NaOH solution was added to pH 9.0. The generated solid was collected by filtration and washed with water and dried in vacuo. Yield 78.0% (7.61 g) 1H NMR (DMSO-d6) δ 7.48-7.33 (m, 8H), 7.01-6.94 (m, 3H), 6.89 (d, 2H), 6.78 (dd, 1H), 5.24 (s, 2H); MS m/e 375 (M+1).
  • Intermediate 4
    • 5-(4-Aminophenoxy)-2-nitroaniline
  • Figure US20070249600A1-20071025-C00033
  • To a solution of 4-aminophenol (5.0 g, 46 mmol) in DMF (120 ml) was slowly added 60% NaH (2.0 g, 50 mmol), followed by 5-chloro-2-nitroaniline (8.7 g). The mixture was heated to 90° C. and stirred overnight. The reaction mixture was poured onto aq. NH4Cl to form a solid, which was collected by filtration, washed with hexane and dried to give intermediate 4 as a yellow solid (12.0 g, >99%): MS m/e 244 (M−1).
  • Intermediate 5
    • 5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylaminophenoxy)-2-nitroaniline
  • Figure US20070249600A1-20071025-C00034
  • A mixture of 2-fluoro-5-(trifluoromethyl)phenylisocyanate (10.0 g, 48.8 mmol) and 5-(4-Aminophenoxy)-2-nitroaniline (Intermediate 4)(11.6 g, 47.3 mmol) in dry THF (200 ml) was stirred overnight at rt. After treatment with activated carbon, the solvent was evaporated. Purification of the crude material by column chromatography (hexane-AcOEt, 1:2) afforded intermediate 5 as a yellow solid (21.6 g, >98%): MS m/e 449 (M−1).
  • Intermediate 6
    • 4-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)phenylene-1,2-diamine
  • Figure US20070249600A1-20071025-C00035
  • Pd/C (5%, 3.0 g) was introduced to a solution of 5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-2-nitroaniline (Intermediate 5) (21.6 g, 48 mmol) in ethanol (200 ml) under Ar. The starting material was hydrogenated under a H2 atmosphere for 3 days while being stirred. The reaction mixture was then filtered through celite and evaporated to give intermediate 6 as a black film. This crude material was chromatographed through silica gel (hexane-AcOEt, 4:1-3:1-2:1-1:1-0:1) to give purified intermediate 6 (13.0 g, 64%): MS m/e 421 (M+1).
  • Intermediate 7
    • N-(5-(2-Nitro-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00036
  • To a mixture of 5-hydroxy-2-acetylaminobenzimidazole (382 mg, 2 mmol) and CS2CO3 (978 mg, 3 mmol) in DMF (20 ml) was added 5-bromo-2-nitropyridine (550 mg, 2 mmol) at room temperature. After 2 hours of stirring, the mixture was poured into water and extracted with AcOEt. The organic solvent washed with water and brine, then evaporated to obtain a crude product. It was purified with silica gel column chromatography (CHCl3-MeOH). The pure fractions were collected to provide intermediate 7, which was then used for the subsequent reduction (314 mg, 50%).
  • Intermediate 8
    • N-(5-(2-Amino-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00037
  • N-(5-(2-Nitro-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide (Intermediate 7) was hydrogenated under an H2 atmosphere with Pd—C (10%) in MeOH. After the reaction was complete, the solid was filtered off, and the filtrate was evaporated to give intermediate 8 (47 mg, 17%): 1H NMR (DMSO-d6) δ 11.56 (brs, 1H) 7.51 (d, 1H), 7.32 (d, 1H), 7.05 (dd, 1H), 6.97 (d, 1H), 6.74 (dd, 1H), 6.70 (d, 1H), 5.02 (br s, 2H), 3.74 (s, 3H), 7.08 (d, 2H), 6.84 (d, 1H), 6.61 (d, 1H), 3.75 (s, 3H); MS m/e 284 (M+1).
  • Intermediate 8A
    • 4-(4-Nitrophenoxy)-2-nitroaniline
  • Figure US20070249600A1-20071025-C00038
  • To a solution of 4-hydroxy-2-nitroaniline (3.08 g, 20.0 mmol) in DMF (30 mL) was added NaH (60% oily, 880 mg, 22.0 mmol) followed by 1-fluoro-4-nitrobenzene (2.33 mL, 22.0 mmol). The mixture was stirred at 90° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (4.56 g, 83%): MS m/e 274 (M−1).
  • Intermediate 8B
    • N-Methyl-4-(4-nitrophenoxy)-2-nitroaniline
  • Figure US20070249600A1-20071025-C00039
  • To a mixture of NaH (60% oily, 320 mg, 8.0 mmol) in DMF (30 mL) was added a solution of 4-(4-nitrophenoxy)-2-nitroaniline (Intermediate 8A—2.00 g, 7.3 mmol) in DMF (30 mL) at 0° C. followed by an excess amount of MeI (2.0 mL). The mixture was stirred at 0° C. for 1.5 hrs then at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (2.10 g, quant).): 1H NMR (CDCl3-d1) δ 3.08 (d, 3H), 6.94 (d, 1H), 7.00 (d, 2H), 7.30 (dd, 1H), 7.97 (d, 1H), 8.08 (brs, 1H), 8.22 (d, 2H).
  • Intermediate 8C
    • Methyl (1-methyl-5-(4-aminophenoxy)-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00040
  • To a mixture of N-methyl-4-(4-nitrophenoxy)-2-nitroaniline (Intermediate 8B—2.10 g, 2.27 mmol) in MeOH (100 mL) was added 5% Pd—C (catalytic amount) and stirred at room temperature under H2 atmosphere. After 7 hrs, the catalyst was removed by filtration then the solvent was evaporated off. The residual mixture was dissolved into MeOH (50 mL) and added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (3.0 g, 14.5 mmol). The mixture was refluxed overnight. The solvent was removed by evaporation and sequence purification on SiO2 column chromatography gave title compound (87.3 mg, 4%): MS m/e 313 (M+1).
  • Intermediate 8D
    • N-methyl-5-chloro-2-nitroaniline
  • Figure US20070249600A1-20071025-C00041
  • To a solution of 5-chloro-2-nitroaniline (1.73 g, 10.0 mmol) in DMF (40 mL) was added NaH (60% oily, 880 mg, 22.0 mmol) at 0° C. followed by excess amount of MeI (3.0 mL). The mixture was stirred at 0° C. for 1 hr then at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (1.86 g, quant): 1H NMR (DMSO-d6) δ 2.95 (d, 3H), 6.69 (dd, 1H), 7.03 (d, 1H), 8.08 (d, 1H), 8.28 (br, 1H).
  • Intermediate 8E
    • N-(2-(dimethylamino)ethyl)-5-chloro-2-nitroaniline
  • Figure US20070249600A1-20071025-C00042
  • To a solution of 3-fluoro-4-nitro-1-chlorobenzene (1.75 g, 10.0 mmol) in DMSO (50 mL) was added K2CO3 (2.76 g, 20.0 mmol) followed by N,N-dimethylaminoethylamine (1.21 mL, 11.0 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min. before being stirred at room temperature overnight. The mixture was poured into water then extracted with ethyl acetate. The organic layer washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (2.29 g, 94%): MS m/e 244, 246 (M+1).
  • Intermediate 8F
    • N-(2-(4-morpholino)ethyl)-5-chloro-2-nitroaniline
  • Figure US20070249600A1-20071025-C00043
  • The title compound was prepared following the procedure for Intermediate 8E using 2-(4-morpholino)ethylamine: MS m/e 286, 288 (M+1).
  • Intermediate 8G
    • 4-(3-Methylamino-4-nitrophenoxy)aniline
  • Figure US20070249600A1-20071025-C00044
  • To a mixture of NaH (60% oily, 440 mg, 11.0 mmol) in DMF (30 mL) was added a solution of 4-aminophenol (1.20 g, 11.0 mmol) in DMF (15 mL) followed by N-methyl-5-chloro-2-nitroaniline (Intermediate 8D—2.02 g, 10.0 mmol) in DMF (20 mL). The mixture was stirred at 90° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (2.44 g, 94%): MS m/e 260 (M+1).
  • Intermediate 8H
    • 4-(3-(2-(Dimethylamino)ethylamino)-4-nitrophenoxy)aniline
  • Figure US20070249600A1-20071025-C00045
  • Intermediate 8H is prepared using a procedure similar to Intermediate 8H. MS m/e 317 (M+1).
  • Intermediate 8I
    • 4-(3-(2-(4-Morpholino)ethylamino)-4-nitrophenoxy)aniline
  • Figure US20070249600A1-20071025-C00046
  • The title compound was prepared following the procedure for Intermediate 8H using Intermediate 8F. MS m/e 359 (M+1).
  • Intermediate 8J
    • Methyl (3-methyl-5-(4-aminophenoxy)-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00047
  • After hydrogenation of 4-(3-methylamino-4-nitrophenoxy)aniline (Intermediate 8G—519.2 mg, 2.0 mmol) with 5% Pd—C in MeOH (20 mL), 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.03 g, 5.0 mmol) and AcOH (2.0 mL) was added then stirred at 85° C. for 5.5 hrs. After cooling, the mixture was added 2N HClaq. (25 mL) then stirred at 65° C. for 2 hrs. The mixture was passed through celite pad to remove catalyst and the solvent was removed by evaporation. The residue was extracted with ethyl acetate. The organic layer washed with NH4OH(aq). and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (529.1 mg, 85%): MS m/e 313 (M+1).
  • Intermediate 8K
    • Methyl (3-(2-(N,N-dimethylamino)ethyl)-5-(4-aminophenoxy)-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00048
  • The title compound was prepared following the procedure for Intermediate 8J using Intermediate 8H. MS m/e 370 (M+1).
  • Intermediate 8L
    • Methyl (3-(2-(4-morpholino)ethyl)-5-(4-aminophenoxy)-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00049
  • The title compound was prepared following the procedure for Intermediate 8J using Intermediate 8I. MS m/e 412 (M+1).
  • Intermediate 9
    • Ethyl N-(5-bromopyridine-3-yl)carbamate
  • Figure US20070249600A1-20071025-C00050
  • To a solution of 5-bromonicotinic acid (20.0 g, 99.0 mmol) in ethanol (300 mL) was added DPPA (21.6 mL, 100.0 mmol) followed by triethylamine (14.3 mL, 103.0 mmol) then refluxed overnight. After cooling, a half amount of solvent was removed by evaporation. The ethanol solution was extracted with ethyl acetate. The organic layer washed with NaHCO3 (aq) and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (4.55 g, 19%): MS m/e 245, 246 (M+1).
  • Intermediate 9A
    • 5-Bromo-2-nitropyridine-3-ylamine
  • Figure US20070249600A1-20071025-C00051
  • To a mixture of concentrated H2SO4 (3.0 mL) and fHNO3 (2.1 mL), 3-bromo-5-(ethoxycarbonyl)aminopyridine (Intermediate 9—20.0 g, 99.0 mmol) was portionwise added at 0° C. After stirring at 0° C. for 5 min., the mixture was stirred at room temperature overnight. The mixture was poured into ice-water then basified with aqueous NH4OH. The mixture was extracted with ethyl acetate. The organic layer washed with aqueous NH4OH and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave 5-bromo-3-(ethoxycarbonyl)amino-2-nitropyridine (1.57 g, 54%).
  • To a solution of 5-bromo-3-(ethoxycarbonyl)amino-2-nitropyridine (1.57 g, 5.4 mmol) in ethanol (2.5 mL) was added KOH (813 mg, 14.5 mmol) in water (12.5 mL) and stirred at 90° C. for 1 hr then at room temperature for 1 hr. The mixture was added water. The formed precipitate was collected by filtration, washed with water then dried under reduced pressure to give the title compound (1.08 g, 92%): MS m/e 216, 218 (M−1).
  • Intermediate 9B
    • 3-Nitro-6-(4-acetamidophenoxy)pyridine-2-ylamine
  • Figure US20070249600A1-20071025-C00052
  • To a solution of 2-amino-6-chloro-3-nitropyridine (2.77 g, 16.0 mmol) in DMF (55 mL) was added 4-acethylaminophenol (2.67 g, 17.5 mmol) followed by K2CO3 (3.3 g, 5.0 mmol) and stirred at room temperature for 2 hrs. The solvent was removed by evaporation. To the residue, water was added to form a precipitate. The solid was collected by filtration, washed with water and ethyl acetate then dried under reduced pressure to give the title compound (4.32 g, 94%): MS m/e 289 (M+1).
  • Intermediate 9C
    • 2-Nitro-5-(4-(tert-butoxycarbonylamino)phenoxy)pyridine-3-ylamine
  • Figure US20070249600A1-20071025-C00053
  • To a solution of 5-bromo-2-nitropyridine-3-ylamine (436 mg, 2.0 mmol) in DMF (10 mL) was added Cs2CO3 (977 mg, 3.0 mmol) followed by 4-(t-butoxy carbonyl)aminophenol (459 mg, 2.2 mmol) in DMF (10 mL) at 0° C. then stirred at room temperature for 3 days. The mixture was extracted with ethyl acetate. The organic layer washed with NaHCO3 (aq) and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (624.2 mg, 90%): MS m/e 347 (M+1).
  • Intermediate 9D
    • Methyl (5-(4-aminophenoxy)-3,4-diazaindolin-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00054
  • After hydrogenation of 3-nitro-6-(4-acetamidophenoxy)pyridine-2-ylamine (2.02 g, 7.0 mmol) with 5% Pd—C in MeOH (70 mL), catalyst was removed by filtration. To the MeOH solution, 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.73 g, 8.4 mmol) was added and stirred at 75° C. After 8 days, AcOH (15 mL) was added and stirred at 80° C. overnight. Additional 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.73 g, 8.4 mmol) was added then stirred at 80° C. overnight. After cooling, the mixture was poured into NaHCO3 (aq). Formed precipitate was collected by filtration, washed with ethyl acetate then dried under reduced pressure to give methyl (5-(4-acetoamidophenoxy)-3,4-diazaindolin-2-yl)carbamate (983.0 mg, 41%). To a solution of methyl (5-(4-acetoamidophenoxy)-3,4-diazaindolin-2-yl)carbamate (102.4 mg, 0.3 mmol) in water (3 mL) was added 2N HCl (aq) (3.0 mL) then refluxed for 1 hr and stirred at room temperature for 1 hr. The mixture was extracted with ethyl acetate. The organic layer washed with NH4OH (aq), dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (33.6 mg, 37%): MS m/e 342 (M+1).
  • Intermediate 9E
    • Methyl (6-(4-aminophenoxy)-3,4-diazaindolin-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00055
  • The same procedure described in Intermediate 9D gave methyl (5-(4-(tert-butoxycarbonyl)aminophenoxy)-3,7-diazaindolin-2-yl)carbamate. To a solution of methyl (5-(4-(tert-butoxycarbonyl)aminophenoxy)-3,7-diazaindolin-2-yl)carbamate (160.8 mg, 0.4 mmol) in methanol (10 mL) was added 2N HCl (aq) (10 mL) then stirred at room temperature overnight. The solution was removed by evaporation then the residue was extracted with ethyl acetate. The organic layer washed with NaHCO3 (aq) and brine, dried over Na2SO4 then evaporated. The residual solid washed with ethyl acetate then dried under reduced pressure to give the title compound (95.3 mg, 80%): MS m/e 300 (M+1).
  • Intermediate 9F
    • Ethyl 3-(6-Chrolo-3-nitropyridine-2-ylamino)propanoate
  • Figure US20070249600A1-20071025-C00056
  • To a solution of 2,6-dichloro-3-nitropyridine (4.83 g, 25.0 mmol) in acetonitrile (100 mL) was added β-alanine hydrochloride (4.61 g, 30.0 mmol) followed by K2CO3 (10.4 g, 75.0 mmol). After stirring at room temperature for 3 days, the solvent was removed by evaporation. The residue was extracted with ethyl acetate. The organic layer washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (5.01 g, 73%): MS m/e 272, 274 (M−1).
  • Intermediate 9G
    • Ethyl 3-(6-(4-acetamidophenoxy)-3-nitropyridine-2-ylamino)propanoate
  • Figure US20070249600A1-20071025-C00057
  • To a solution of ethyl 3-(6-chrolo-3-nitropyridine-2-ylamino)propanoate (Intermediate 9F—2.72 g, 9.94 mmol) in DMF (30 mL) was added 4-acethylaminophenol (1.66 g, 11.0 mmol) followed by K2CO3 (2.1 g, 14.9 mmol) then stirred at room temperature for 1 hr. To the mixture, water was added to form precipitate. The solid was collected by filtration, washed with water and ethyl acetate then dried under reduced pressure to give the title compound (3.79 g, 98%): MS m/e 389 (M+1).
  • Intermediate 9H
    • 2-Amino-3-(2-(ethoxycarbonyl)ethyl)-5-(4-acetamidophenoxy)-3,4-diazaindolidine
  • Figure US20070249600A1-20071025-C00058
  • After hydrogenation of ethyl 3-(6-(4-acetamidophenoxy)-3-nitropyridine-2-ylamino)propanoate (Intermediate 9G—1.94 g, 5.0 mmol) with 5% Pd—C in MeOH (25 mL) and evaporation, the residue was added ethanol (65 mL) and BrCN (1.84 g, 17 mmol) and stirred at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer washed with NaHCO3 (aq) and brine, dried over Na2SO4 then evaporated. The residue washed with ethyl acetate then MeOH then dried under reduced pressure to give the title compound (800.0 mg, 42%): MS m/e 384 (M+1).
  • Intermediate 9I
    • 3,4-Dihydro-6-(4-aminophenoxy)-1,4-a,5-triazacarbazol-2-one
  • Figure US20070249600A1-20071025-C00059
  • To a solution of 2-amino-3-(2-(ethoxycarbonyl)ethyl)-5-(4-acetamidophenoxy)-3,4-diazaindolidine (Intermediate 9H—200.0 mg, 0.52 mmol) in ethanol (10 mL) was added conc.HCl (1.0 mL) and stirred at 85° C. overnight. After evaporation to remove ethanol, DMF (10 mL) was added to the mixture then heated to 120° C. for 2 hrs. After cooling, the solvent was removed by evaporation then the residue washed with MeOH. The result solid was added 2M HCl (12 mL) and stirred at room temperature overnight. The mixture was basified with NH4OH (aq). The formed precipitate was collected, washed with water then dried under reduced pressure to give the title compound (103.4 mg, 67%): MS m/e 296 (M+1).
  • Intermediate 9J
    • 5-(4-Acetamidophenoxy)pyridine-2-ylamine
  • Figure US20070249600A1-20071025-C00060
  • To a solution of 5-bromo2-nitropyridine (2.03 g, 10.0 mmol) in DMF (30 mL) was added Cs2CO3 (4.9 g, 15.0 mmol) followed by 4-acetylaminophenol (1.66 g, 11.0 mmol) in DMF (30 mL) at 0° C. then stirred at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography and recrystallization from ethyl acetate gave 5-(4-acetamidophenoxy)-2-nitropyridine (1.62 g, 59%). Hydrogenation of 5-(4-acetamidophenoxy)-2-nitropyridine (879.0 mg, 3.22 mmol) with 5% Pd—C in MeOH (80 mL) gave the title compound (575.7 mg, 74%): MS m/e 244 (M+1).
  • Intermediate 9K
    • Methyl (5-(4-aminophenoxy)azaindolizine-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00061
  • To a solution of 5-(4-acetamidophenoxy)pyridine-2-ylamine (Intermediate 9J—170.2 mg, 0.7 mmol) in DMF (2 mL) was added N-(methoxycarbonyl)chloroacetoamide (159.0 mg, 1.1 mmol). The mixture was stirred at 80° C. overnight. Additional N-(methoxy carbonyl)chloroacetoamide (159.0 mg, 1.1 mmol) was added and stirred at 80° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer washed with NaHCO3 (aq) and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave methyl (5-(4-acetoamidophenoxy)azaindolizine-2-yl)carbamate (51.7 mg, 22%). To a solution of methyl (5-(4-acetoamidophenoxy)azaindolizine-2-yl)carbamate (34.0 mg, 0.1 mmol) in water (2 mL) was added 2N HCl (aq) (2.0 mL) then refluxed for 1 hr and stirred at room temperature for 1 hr. The mixture was added NH4OH (aq). Formed precipitate was collected by filtration, washed with water then dried under reduced pressure to give the title compound (22.0 mg, 74%): MS m/e 299 (M+1).
  • Intermediate 10
    • 4-(4-Nitrophenoxy)aniline
  • Figure US20070249600A1-20071025-C00062
  • To a mixture of NaH (60% oily, 880 mg, 22.0 mmol) in DMF (40 mL) was added a solution of 4-aminophenol (2.40 g, 22.0 mmol) in DMF (30 mL) followed by 1-fluoro-4-nitrobenzene (2.12 mL, 20.0 mmol). The mixture was stirred at 90° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (4.60 g, quant): MS m/e 229 (M−1).
  • Intermediate 10A
    • 6-(4-Nitrophenoxy)benzthiazole-2-ylamine
  • Figure US20070249600A1-20071025-C00063
  • See the procedure following for Intermediate 10B.
  • Intermediate 10B
    • 4-Bromo-6-(4-nitrophenoxy)benzthiazole-2-ylamine
  • Figure US20070249600A1-20071025-C00064
  • To a solution of 4-(4-nitrophenoxy)aniline (Intermediate 10—1.15 g, 5.0 mmol) in AcOH (5 mL) was added KSCN (729 mg, 7.5 mmol). The mixture was cooled to 0° C. and added a solution of Br2 (256 μL, 5.0 mmol) in AcOH (6 mL) then stirred at room temperature overnight. The mixture was poured into H2O, basified with NH4OH (aq), then extracted with ethyl acetate. The organic layer washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave Intermediate 10A (941.5 mg, 66%): MS m/e 288 (M+1) and Intermediate 10B (223.7 mg, 12%): MS m/e 366, 368 (M+1).
  • Intermediate 10C
    • N-(6-(4-Nitrophenoxy)benzthiazole-2-yl)methanesulfonamide
  • Figure US20070249600A1-20071025-C00065
  • To a solution of Intermediate 10A (1.15 g, 4.0 mmol) in pyridine (10 ml) was added mesyl chloride (1.55 ml, 20 mmol) at 0° C. and stirred over night at 0° C.-room temperature. Then potassium carbonate (5.5 g, 40 mmol) in water (20 ml) and MeOH (20 ml) was added and stirred 4 days at 60° C. MeOH was removed by evaporated and desired compound was extracted with AcOEt x3 and organic layer washed with water and brine and dried over with MgSO4. And purified by column chromatography (AcOEt-DCM, 1:1, 3:1) and crystallized from AcOEt-Hexane. 300 mg of Intermediate 10C was obtained as yellow solid. Yield 20.5% MS m/e 366 (M+1).
  • Intermediate 10D
    • N-(6-(4-Aminophenoxy)benzthiazole-2-yl)methanesulfonamide
  • Figure US20070249600A1-20071025-C00066
  • To a solution of Intermediate 10C (100 mg, 0.27 mmol) in acetic acid (1 ml) was added Zn (54 mg, 0.81 mmol) and stirred over night at room temprature. Acetic acid was removed by evaporation and residue was dissolved in DMF and filtrated. Filtrate was purified by SPE(SCX) tube (washed with MeOH/DMF and eluted with NH3/MeOH). NH3/MeOH eluent was collected and 72 mg of Intermediate 10D was obtained. Yield 79.5% MS m/e 336 (M+1).
  • Intermediate 10E
    • Methyl (6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00067
  • To a mixture of 5-(4-nitrophenoxy)benz-3-thiazole-2-ylamine (430.5 mg, 1.5 mmol) in pyridine (6 mL) and DMF (9 mL) was dropwise added an excess amount of ClCO2Me (ca 0.8 mL) at room temperature. The mixture was added water. The formed precipitate was collected by filtration, washed with water and MeOH and dried under reduced pressure to give the title compound (503.7 mg, 97%): MS m/e 346 (M+1).
  • Intermediate 10F
    • Methyl (4-bromo-6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00068
  • The title compound was prepared following the procedure for Intermediate 10E using Intermediate 10A. MS m/e 424, 426 (M+1)
  • Intermediate 10G
    • Methyl (6-(4-aminophenoxy)benzthiazole-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00069
  • To a solution of methyl (6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate (Intermediate 10E—172.7 mg, 0.5 mmol) in DMF (5 mL) was added SnCl2 (474.0 mg, 2.5 mmol) and stirred at room temperature for 4 days. The mixture was extracted with ethyl acetate, and the organic layer washed with NaHCO3aq. and dried over Na2SO4 then evaporated to remove solvent. The residue dissolved in small amount of DMF was charged on SCX column chromatography then washed with MeOH then eluted with NH3-MeOH to give the title compound (69.2 mg, 44%): MS m/e 316 (M+1).
  • Intermediate 10H
    • Methyl (4-bromo-6-(4-aminophenoxy)benzthiazole-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00070
  • To a solution of methyl (4-bromo-6-(4-nitrophenoxy)benzthiazole-2-yl)carbamate (Intermediate 10F—65.3 mg, 0.15 mmol) in AcOH (2 mL) was added Zn powder (300 mg) and stirred at room temperature for 2 hrs. The insoluble materials were removed by filtration. The solvent was removed by evaporation. The residue was charged on SCX column chromatography then washed with MeOH then eluted with NH3-MeOH to give the title compound (39.6 mg, 65%): MS m/e 394, 396 (M+1).
  • Intermediate 11
    • 4 (3-Benzyloxy-4-nitrophenoxy)aniline
  • Figure US20070249600A1-20071025-C00071
  • To a solution of 5-fluoro-2-notrophenol (9.43 g, 60.0 mmol) in acetone (100 mL) was added K2CO3 (12.4 g, 90.0 mmol) followed by benzylbromide (8.6 mL, 72.0 mmol) and acetone (60 mL) then stirred at room temperature overnight. The mixture was extracted with ethyl acetate, and the organic layer washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave 2-benzyloxy-4-nitro-1-fluorobenzene (11.97 g, 81%).
  • To a mixture of NaH (60% oily, 440.0 mg, 11.0 mmol) in DMF (20 mL) was dropwise added 4-aminophenol (1.20 g, 11.0 mmol) in DMF (15 mL) followed by 2-benzyloxy-4-nitro-1-fluorobenzene (2.47 g, 10.0 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 10 min then at 80° C. overnight. After cooling, the mixture was extracted with ethyl acetate. The organic layer washed with water and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (3.30 g, 98%): MS m/e 337 (M+1).
  • Intermediate 11A
    • N-(4-(3-Benzyloxy-4-nitrophenoxy)phenyl) (2-fluoro-5-(trifluoromethyl)phenylamino)formamide
  • Figure US20070249600A1-20071025-C00072
  • To a mixture of 4-(3-benzyloxy-4-nitrophenoxy)aniline (Intermediate 11—1.34 g, 4.0 mmol) in THF (40 mL) was added 5-fluoro-3-trifruolomethylphenyl isocyanate (636 μL, 4.4 mmol) and stirred at room temperature overnight. The mixture was added MeOH then the solvent was removed by evaporation. The residue was purified on SiO2 column chromatography gave the title compound (2.17 g, quant): MS m/e 542 (M+1).
  • Intermediate 11B
    • 6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenyloxy)benzoxazol-2-ylamine
  • Figure US20070249600A1-20071025-C00073
  • After hydrogenation of N-(4-(3-benzyloxy-4-nitrophenoxy)phenyl) (2-fluoro-5-(trifluoromethyl)phenylamino)formamide (Intermediate 11A—542 mg, 1.0 mmol) with 5% Pd—C in MeOH (10 mL), BrCN (800 mg, 7.6 mmol) was added and stirred at room temperature for 4 days. The mixture was added NaHCO3 (aq) and stirred for 1 day. The mixture was extracted with ethyl acetate. The organic layer washed with NaHCO3 (aq) and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (237 mg, 53%): MS m/e 447 (M+1).
  • Intermediate 11C
    • 4-(4-(Acetamido)phenylcarbonyl)-1,2-dinitrobenzene
  • Figure US20070249600A1-20071025-C00074
  • A mixture of 3,4-dinitrobenzoyl chloride (4 mmol), acetoanilide (540 mg, 4 mmol), and AlCl3 (1.6 g) in CH2Cl2 was heated at 40° C. for 24 h. The slurry washed with HCl (aq) and the product was extracted with ether. It washed with K2CO3 (aq), dried, and evaporated. Purification by column-chromatography on silica-gel (hexane: AcOEt=1:3) provided 87 mg of the title compound; MS m/e 328 (M−1).
  • Intermediate 11D
    • 4-(4-Aminophenylcarbonyl)-1,2-dinitrobenzene
  • Figure US20070249600A1-20071025-C00075
  • Using the methods of Intermediate 2 and then Intermediate 3 (Method A), Intermediate 11D was prepared from Intermediate 11C; MS m/e 311 (M+1).
  • Intermediate 12
    • 4-Nitro-3-fluorophenyl tetrahydropyranyl ether
  • Figure US20070249600A1-20071025-C00076
  • To the mixture of 3-fluoro-4-nitrophenol (25 g, 0.160 mol) and 3,4-dihydro-2H-pyran (14 g, 0.167 mol)in dichloromethane (200 ml), pyridinium p-toluenesulfonate (4.0 g, 16 mol) was added portionly under ice-water bath. After overnight at room temperature, the reaction mixture was pored to Si-column chromatography. Eluting by Hexane Ethyl acetate (3:1), the desired product was obtained at 35.5 g (92%) as light yellow solid.
  • Intermediate 12A
    • 3-Benzylamino-4-nitrophenyl tetrahydropyranyl ether
  • Figure US20070249600A1-20071025-C00077
  • To the solution of Intermediate 12 (20 g, 0.083 mol) in DMSO (150 ml), benzylamine (8.9 g, 0.083 mol) and K2CO3 (23 g) were added at room temperature. NH2-TLC by eluted Hexane-AcOEt showed reaction complete. Water was added to the mixture, then, extracted by AcOEt at twice. All organic layer was evaporated. The residue is used to the next reduction. MS m/e 329 (M+1).
  • Intermediate 12B
    • 3-Benzylamino-4-nitrophenyl tetrahydropyranyl ether
  • Figure US20070249600A1-20071025-C00078
  • The product of Intermediate 12A was reduced in a usual manner to give 2-benzylaminoaniline derivative (see Intermediate 2). To the suspension of crude diamino phenylene (26.3 g, 88 mmol) derivatives in methanol (300 ml), bromocyamide (9.35 g, 1 equiv.) was added at 0° C. After 15 min, the ice-bath was removed and stirred for 1 hr at room temperature. After evaporation of the methanol solution, saturated NaHCO3 (300 ml) and AcOEt (100 ml) were added to the residue. Generated precipitates were filtered and washed with water to give a crude powder (21.68 g). MS m/e 324 (M+1).
  • Intermediate 12C
    • N-(1-Benzyl-6-hydroxy-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00079
  • To the suspension of Intermediate 12B (2 g, 6.1 mmol) in THF (5 ml), acetic anhydride (2.3 ml) was added at room temperature. After 3 hr at room temperature, THF was evaporated. Ice-water was added to the residue, then conc. HCl and methanol were added carefully at 0 C. After 30 min' stirring, the acidic solution was neutralized by NaOH and NaHCO3. The generated precipitate was collected, washed with Et2O, and dried to give the title compound. MS m/e 282 (M+1).
  • Intermediate 12D
    • 1-Benzyl-6-hydroxy-2-(tert-butoxycarbonylamino)-1H-benzimidazole
  • Figure US20070249600A1-20071025-C00080
  • 1-Benzyl-6-hydroxy-2-amino-1H-benzimidazole was treated with BOC2O in pyridine, followed by hydrolysis with NaOH (aq) to give the title compound; MS m/e 340 (M+1).
  • Intermediate 12E
    • Tert-Butyl N-(1-benzyl-6-(6-aminopyridin-3-yloxy)-1H-benzimidazol-2-yl)
  • Figure US20070249600A1-20071025-C00081
  • Coupling of Intermediate 12D with 3-bromo-6-nitropyridine and subsequent hydrogenation over Pd/C gave the title compound; MS m/e 432 (M+1).
  • Intermediate 13A
    • 1-(6-(4-Nitrophenoxy)benzthiazol-2-yl)-3-butylurea
  • Figure US20070249600A1-20071025-C00082
  • Intermediate 13A was prepared following a similar procedure for Example 1 using Intermediate 10A. MS m/e 387 (M+1)
  • Intermediate 13B
    • 1-(6-(4-Aminophenoxy)benzthiazol-2-yl)-3-butylurea
  • Figure US20070249600A1-20071025-C00083
  • Intermediate 13B was prepared following a similar procedure for Intermediate 10D using Intermediate 13A. MS m/e 357 (M+1)
    Intermediate 14A
    Figure US20070249600A1-20071025-C00084
    • Resin-Bound 5-Chloro-2-nitroaniline
  • Amino-(4-methoxyphenyl)-methylpolystyrene (loading 1.69 mmol/g, 7.00 g, 11.8 mmol) was soaked in DMSO in a peptide vessel for 30 min. The solvent was then drained. DIEA (11.3 mL, 65.1 mmol) in DMSO (88 mL) was added to the resin, followed by 4-chloro-2-fluoronitrobenzene (10.4 g, 59.2 mmol). The mixture was shaken at room temperature for 19 h, at which point it was drained. The resin washed with DMSO (3×), ETOH (3×), DMF (3×), MeOH (3×) and DCM (3×). It was then dried under vacuum overnight. A small sample (approx. 10 mg) was treated with 23:2:75 (v/v/v) TFA/H2O/DCM (0.5 mL) for ca. 1 h. The solution containing the released material was concentrated and analyzed with LC/MS. UV (254 nm): 97% @ 5.65 min. MS: m/e 171 (M−1).
  • Intermediate 14B
    • Resin-bound 5-(4-Aminophenoxy)-2-nitroanillne
  • Figure US20070249600A1-20071025-C00085
  • 4-Aminophenol (4.71 g, 43.2 mmol) was dissolved in degassed DMF (108 mL) and bubbled with Ar for 10 min in a dry, 300-mL pear-shaped flask. Sodium hydride (60% in mineral, 1.78 g, 44.5 mmol) was added. The mixture was bubbled and stirred for an additional 15 min. Resin-bound 5-chloro-2-nitroaniline 1 (4.3 g, theoretically 5.75 mmol) was added to the now dark mixture. After the evolution of gas had minimized, the flask was stoppered and shaken at room temperature for ca. 4.5 days. The mixture was filtered and the salts washed away with water. The black resin washed with H2O (3×), 1:1 DMF/H2O (3×), DMF (3×), MeOH (3×) and DCM (3×). The reaction was repeated on the same resin batch the same way. After drying in vacuo, a small sample (approx. 10 mg) was treated with 23:2:75 (v/v/v) TFA/H2O/DCM (0.5 mL) for ca. 1 h. The solution containing the released material was concentrated and analyzed with LC/MS. UV (254 nm): 90% @ 6.08 min. MS: m/e 244 (M−1).
  • Intermediate 14C (Library)
    • Resin-bound 5-(4-((Heteroaryl)aminocarbonylamino)phenoxy)-2-nitroaniline
  • Figure US20070249600A1-20071025-C00086
  • Intermediate 14B (approx. 224 mg, theoretically 0.273 mmol) was rinsed with 1:1 (v/v) THF/DCM in a 25-mL Alltech tube. p-Nitrophenyl chloroformate (551 mg, 2.73 mmol) and DIEA (476 μL, 2.73 mmol) in 1:1 (v/v) THF/DCM (5.5 mL) was added. The mixture was shaken for 18-22 h. After draining, the resin washed with 1:1 (v/v) THF/DCM (3-4×). The heteroaryl amine (2.73 mmol) and DIEA (476 μL, 2.73 mmol) in DMF (5.5 mL) were added. (Twice the equivalent of DIEA was used for the amines that were monohydrochloride salts.) The yellow mixtures were shaken for ca. 16 h. and then drained. The resin washed thoroughly with DMF (3×), 10:90 DIEA/DMF (10×), DMF (3×), 1:1 DMF/H2O (3×), MeOH (3×), DCM (3×) to wash away most of the p-nitrophenol that slowly leached away from the resin. After drying, a small sample (approx. 5 mg) was treated with 23:2:75 (v/v/v) TFA/H2O/DCM (0.5 mL) for ca. 1 h. The solution containing the released material was concentrated and analyzed with LC/MS.
  • Intermediate 14D (Library)
    • Resin-Bound 4-(4-((Heteroaryl)aminocarbonylamino)phenoxy)-1,2-phenylenediamine
  • Figure US20070249600A1-20071025-C00087
  • Intermediate 14C (theoretically 0.273 mmol) was soaked in NMP for at least 30 min in a 25-mL Alltech tube. Tin (II) chloride dihydrate (1.85 g, 8.20 mmol) in NMP (8.20 mL) was added and the mixture was shaken for ca. 5.5 days. After filtration, the resin washed with NMP (3×), 30:70 ethylene diamine/NMP (10×), NMP (3×), MeOH (3×) and DCM (3×). It was dried under vacuum and a small sample (approx. 5 mg) was treated with 23:2:75 (v/v/v) TFA/H2O/DCM (0.5 mL) for ca. 1 h. The solution containing the released material was concentrated and analyzed with LC/MS.
  • Intermediate 14E (Library)
    • 1-Resin-bound-2-(Fmoc-amino)-6-(4-((heteroaryl)aminocarbonylamino)phenoxy)-1H-benzimidazoles
  • Figure US20070249600A1-20071025-C00088
  • Intermediate 14D (theoretically 0.273 mmol) was rinsed with DMF in a 25-mL Alltech tube. DIC (1.71 mL, 10.9 mmol) was added to a solution of Fmoc-NCS (1.54 g, 5.47 mmol) in DMF (5.5 mL) and the mixture was immediately added to the resin. The Alltech tube was vortexed vigorously for ca. 6.75 days. The mixture was drained and the precipitate formed during the reaction washed away with DCM. The resin was then washed with DCM (3×), DMF (3×), 1:1 DMF/H2O (3×), MeOH (3×) and DCM (3×) and dried in vacuo. A small sample (approx. 5 mg) was treated with 23:2:75 (v/v/v) TFA/H2O/DCM (0.5 mL) for ca. 1 h. The solution containing the released material was concentrated and analyzed with LC/MS.
  • Intermediate 14F (Library)
    • 1-Resin-Bound-2-(R2-carbonylamino)-6-(4-((heteroaryl)aminocarbonylamino)phenoxy)-1H-benzimidazoles
  • Figure US20070249600A1-20071025-C00089
  • Intermediate 14E (theoretically 0.0401 mmol) was treated with 20% piperidine in DMF (1 mL) in a 6-mL Alltech tube for 30 min. The mixture was drained and the resin washed with DMF (3×). The piperidine treatment and the succeeding DMF wash were repeated for a second time.
  • Coupling Procedure A (for acetic acid and 4-dimethylaminobutyric acid hydrochloride): To a mixture of DIEA (69.9 μL, 0.400 mmol) and EDC (38.5 mg, 0.200 mmol) in DMF (0.67 mL) was added a solution of HOBt-H2O (30.7 mg, 0.200 mmol) and the acid (0.200 mmol) also dissolved in DMF (1.33 mL). (The equivalent of DIEA was doubled for the butyric acid coupling.) The acid was activated for ca. 5 min. and then added to the deprotected resin. The reaction mixture was vortexed for ca. 15 h. The solvent was removed by vacuum and the resin washed with DMF (3×), 1:1 DMF/H2O (3×), MeOH (3×) and DCM (3×).
  • Coupling Procedure B (for 2-furoic and 2-(2-methoxyethoxy)acetic acids): To a solution of the acid (0.202 mmol) in DMF (0.67 mL) was added HOBt-H2O (30.9 mg, 0.202 mmol) in DMF (0.67 mL), DIEA (70.4 μL, 0.404 mmol) and then HBTU (75.1 mg, 0.198 mmol) in DMF (0.67 mL). The reaction mixture was vortexed for ca. 20 h. After filtration, the resin was washed with DMF (3×), 1:1 DMF/H2O (3×), MeOH (3×) and DCM (3×).
  • Intermediate 15A
    • 5-Amino-2-(3,4-diaminophenoxy)pyridine
  • Figure US20070249600A1-20071025-C00090
  • 2-Nitro-4-hydroxyaniline was reacted with 2-chloro-5-nitropyridine and K2CO3 in DMF at rt, followed by hydrogenation over Pd/C in MeOH, afforded the title compound; MS m/e 217 (M+1).
  • Intermediate 15B
    • Methyl N-(5-(5-aminopyridine-2-yl)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00091
  • The title compound was obtained according to procedures for Intermediate 3C and 3D, using the product of Intermediate 15A instead of 3,4,4′-triaminodiphenylether; MS m/e 300 (M+1).
    • Example 1 Methyl N-(5-(4-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00092
  • A mixture of methyl (5-(4-aminophenoxy)-1H-benzimidazol-2-yl)carbamate (Intermediate 3) (80 mg, 0.27 mmol) and 3-chlorophenylisocyanate (49 mg, 0.32 mmol) in dry THF (2 ml) was heated to 45° C. overnight. After cooling, diethyl ether was added to form a precipitate. The solid was collected by filtration to provide the title compound (83 mg, 69%): 1H NMR (DMSO-d6) δ11.60 (brs, 2H), 9.00 (s, 1H), 8.83 (s, 1H), 7.70 (m, 1H), 7.42 (d, 2H), 7.38 (d, 1H), 7.32-7.24 (m, 2H), 7.01 (m, 2H), 6.93 (d, 2H), 6.80 (dd, 1H) 3.75 (s, 3H); MS m/e 452 (M+1).
  • Examples 2-11, 14-16, 19-21, 40-78, 81, and 86 were prepared according to the procedures described above for Example 1. Intermediates 3, 3A, and 3B, were used or other precursors as indicated. The free bases obtained may be transformed into their pharmaceutically acceptable salts (e.g. HCl salts) by standard procedures known in the art.
    • Example 2 Methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H -benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00093
  • 1H NMR (DMSO-d6) δ 11.61 (brs, 1H), 9.01 (s, 1H), 8.85 (s, 1H), 7.76 (s, 1H), 7.08-7.52 (m, 8H), 6.90 (d, 1H), 6.53 (d, 1H), 5.35 (s, 1H), 3.71 (s, 3H); MS m/e 502 (M+1).
    • Example 3 Methyl N-(5-(4-((3,5-di(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00094
  • 1H NMR (DMSO-d6) δ 11.65 (brs, 1H), 10.00 (s, 1H), 9.45 (s, 1H), 8.07 (s, 2H), 7.59 (s, 1H), 7.31-7.48 (m, 4H), 7.05-7.20 (m, 4H), 3.72 (s, 3H); MS m/e 570 (M+1).
    • Example 4 Methyl N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00095
  • 1H NMR (DMSO-d6) δ 11.61 (brs, 1H), 9.25 (s, 1H), 9.17 (s, 1H), 7.79 (s, 1H), 7.40 (d, 2H), 7.16-7.36 (m, 6H), 7.10 (d, 1H), 7.05 (d, 1H), 5.72 (s, 1H), 3.71 (s, 3H); MS m/e 513 (M+1).
    • Example 5 Methyl N-(5-(4-((3,5-dimethoxyphenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00096
  • 1H NMR (DMSO-d6) δ 11.60 (brs, 1H), 9.13 (s, 1H), 9.05 (s, 1H), 7.40 (d, 2H), 7.05-7.36 (m, 5H), 6.64 (d, 2H), 6.09 (s, 1H), 5.72 (s, 1H), 3.71 (s, 3H), 3.67 (s, 6H); MS m/e 494 (M+1).
    • Example 6 Methyl N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00097
  • 1H NMR (DMSO-d6) δ 11.24 (brs, 1H), 9.32 (s, 1H), 8.93 (dd, 1H), 8.27 (s, 1H), 7.79 (dd, 1H), 7.48-7.38 (m, 5H), 7.22 (dd, 2H), 7.12 (dd, 1H), 3.75 (s, 3H), 2.35 (s, 3H); MS m/e 493 (M+1).
    • Example 7 Methyl N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00098
  • 1H NMR (DMSO-d6) δ 11.86 (brs, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 7.46-7.34 (m, 4H), 7.29 (dd, 1H), 7.23-7.14 (m, 4H), 7.08 (dd, 1H), 6.81 (dd, 1H), 3.74 (s, 3H), 2.56 (q, 2H), 1.17 (t, 3H); MS m/e 462 (M+1).
    • Example 8 Methyl N-(5-(4-((2-fluoro-5-nitrophenyl)amino carbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00099
  • 1H NMR (DMSO-d6) δ 11.81 (brs, 1H), 9.26 (s, 1H), 9.13 (dd, 1H), 8.99 (s, 1H), 7.90 (m, 1H), 7.54 (dd, 1H), 7.46-7.38 (m, 4H), 7.21 (dd, 2H), 7.12 (dd, 1H), 3.75 (s, 3H); MS m/e 497 (M+1).
    • Example 9 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00100
  • 1H NMR (DMSO-d6) δ 11.70 (brs, 2H), 9.25 (s, 1H), 8.89 (d, 1H), 8.60 (dd, 1H), 7.53-7.36 (m, 6H), 7.22 (d, 2H), 7.12 (dd, 1H), 3.75 (s, 3H); MS m/e 520 (M+1).
    • Example 9A Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate methanesulfonic acid
  • Figure US20070249600A1-20071025-C00101
  • 1H NMR (DMSO-d6) δ 9.38 (s, 1H), 8.97 (s, 1H), 8.60 (s, 1H), 7.58-7.48 (m, 4H), 7.44-7.35 (m, 3H), 7.34 (d, 1H), 7.27 (dd, 1H), 3.85 (s, 3H), 2.34 (s, 3H); MS m/e 520 (M+1).
    • Example 9B Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H -benzimidazol-2-yl)carbamate sulfuric acid
  • Figure US20070249600A1-20071025-C00102
  • 1H NMR (DMSO-d6) δ 9.38 (s, 1H), 8.96 (s, 1H), 8.60 (s, 1H), 7.58-7.48 (m, 4H), 7.44-7.34 (m, 4H), 7.26 (dd, 1H), 3.84 (s, 3H); MS m/e 520 (M+1).
    • Example 10 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00103
  • 1H NMR (DMSO-d6) δ11.60 (brs, 2H), 9.13 (s, 1H), 8.85 (d, 1H), 8.62 (dd, 1H), 7.49 (m, 1H), 7.44 (d, 2H), 7.40-7.35 (m, 2H), 7.01 (d, 1H), 6.94 (d, 2H), 6.79 (dd, 1H) 3.74 (s, 3H); MS m/e 504 (M+1).
    • Example 11 Methyl N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00104
  • 1H NMR (DMSO-d6) δ11.60 (brs, 2H), 8.71 (s, 1H), 8.67 (s, 1H), 7.42 (d, 2H), 7.37 (d, 1H), 7.31-6.98 (m, 4H), 6.92 (d, 2H), 6.83-6.77 (m, 2H), 3.75 (s, 3H), 2.57 (q, 2H), 1.17 (t, 3H); MS m/e 446 (M+1).
    • Example 12 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylsulfonyl)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00105
  • To a solution of methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate (Product of Example 9, 100 mg, 0.19 mmol) in acetic acid (2 ml) was added mCPBA (92 mg, 0.53 mmol) in DCM (1 ml) and stirred over night. Aqueous NaHCO3 solution was added and off-white solid was generated. Solid was collected by filtration and washed with water and dried in vacuo. 80 mg of off-white compound was obtained: Yield 76.3%; 1H NMR (DMSO-d6) δ12.29 (brs, 1H), 11.60 (brs, 1H), 9.70 (s, 1H), 9.07 (d, 1H), 8.56 (dd, 1H), 7.95 (br, 1H), 7.85 (d, 2H), 7.66 (d, 2H), 7.64-7.61 (m, 1H), 7.59-7.47 (m, 2H), 7.45-7.40 (m, 1H), 3.78 (s, 3H); MS m/e 552 (M+1).
    • Example 13 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00106
  • Reduced amount of mCPBA in Example 12 also afforded the title compound.
  • 1H NMR (DMSO-d6) δ12.12 (brs, 1H), 11.49 (br, 1H), 9.46 (s, 1H), 8.96 (d, 1H), 8.58 (dd, 1H), 7.73 (s, 1H), 7.60 (s, 4H), 7.54-7.47 (m, 2H), 7.43-7.38 (m, 1H), 7.34 (dd, 1H), 3.76 (s, 3H); MS m/e 536 (M+1).
    • Example 14 Methyl (5-(3-((3-Chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate hydrochloride
  • Figure US20070249600A1-20071025-C00107
  • 1H NMR (DMSO-d6) δ 10.70 (brs, 1H), 8.82 (s, 1H), 8.79 (s, 1H), 7.64 (m, 1H), 7.40 (d, 1H), 7.23 (m, 3H), 7.11 (m, 2H), 7.07 (m, 1H), 7.00 (d, 1H), 6.82 (dd, 1H), 6.57 (d, 1H), 3.75 (s, 3H); MS m/e 452 (M+1).
    • Example 15 Methyl N-(5-(3-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00108
  • 1H NMR (DMSO-d6) δ 11.67 (brs, 2H), 9.23 (s, 1H), 8.80 (s, 1H), 8.54 (d, 1H), 7.48 (t, 1H), 7.41 (m, 2H), 7.26 (t, 1H), 7.14 (d, 1H), 7.08 (d, 2H), 6.84 (d, 1H), 6.61 (d, 1H), 3.75 (s, 3H); MS m/e 504 (M+1).
    • Example 16 Methyl N-(5-(3-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00109
  • 1H NMR (DMSO-d6) δ 11.62 (br, 2H), 8.71 (s, 1H), 8.50 (s, 1H), 7.40 (d, 1H), 7.25-7.15 (m, 5H), 7.09 (d, 2H), 6.81 (t, 2H), 6.55 (d, 1H), 3.75 (s, 3H), 2.54 (q, 2H), 1.15 (t, 3H); MS m/e 446 (M+1).
    • Example 17 Ethyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00110
  • The title compound was prepared by heating a mixture of the product of Example 10 and NaOEt in ethanol:
  • 1H NMR (DMSO-d6) δ 11.50 (brs, 2H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.49 (t, 1H), 7.43 (d, 2H), 7.37 (m, 2H), 7.01 (s, 1H), 6.93 (d, 2H), 6.79 (d, 1H), 4.21 (q, 2H), 1.27 (t, 3H); MS m/e 518 (M+1).
    • Example 18 t-Butyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00111
  • Utilizing the method described for preparing Intermediate 3, but using 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea instead of 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea afforded the title compound. 1H NMR (DMSO-d6) δ 11.80 (brs, 1H), 10.94 (brs, 1H), 9.12 (s, 1H), 8.85 (s, 1H), 8.62 (dd, 1H), 7.50 (t, 1H), 7.42 (d, 2H), 7.37 (m, 2H), 7.00 (brs, 1H), 6.91 (d, 2H), 6.76 (dd, 1H), 1.51 (s, 9H); MS m/e 546 (M+1).
    • Example 19 Methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00112
  • 1H NMR (DMSO-d6) δ 11.80 (brs, 2H), 9.04 (s, 1H), 8.78 (s, 1H), 8.01 (s, 1H), 7.57 (d, 1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.37 (d, 1H), 7.29 (d, 1H), 7.00 (s, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 486 (M+1).
    • Example 20 Methyl N-(5-(3-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00113
  • 1H NMR (DMSO-d6) δ 11.60 (brs, 2H), 8.98 (s, 1H), 8.89 (s, 1H), 7.94 (s, 1H), 7.54 (d, 1H), 7.49 (t, 1H), 7.41 (d, 1H), 7.29 (d, 1H), 7.24 (t, 1H), 7.14 (s, 1H), 7.09 (d, 2H), 6.83 (dd, 1H), 6.59 (d, 1H), 3.75 (s, 3H); MS m/e 486 (M+1).
    • Example 21 Methyl N-(5-(4-((3-t-butylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00114
  • 1H NMR (DMSO-d6) δ12.2-11.0 (brs, 2H), 8.61 (s, 1H), 8.59 (s, 1H), 7.45 (m, 3H), 7.36 (d, 1H), 7.27 (d, 1H), 7.19 (t, 1H), 6.99 (m, 2H), 6.91 (d, 2H), 6.78 (dd, 1H), 3.75 (s, 3H), 1.27 (s, 9H); MS m/e 474 (M+1).
    • Example 22 2-Amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole
  • Figure US20070249600A1-20071025-C00115
  • The title compound was prepared from intermediates 4, 5, and 6 described above. To a solution of 4-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl amino)phenoxy)phenylene-1,2-diamine (Intermediate 6) (1.5 g, 3.6 mmol) in MeOH (20 ml) was added cyanogen bromide (490 mg, 4.6 mmol). The reaction mixture was stirred for 1 h and then washed with aq. NaOH. The product was extracted with AcOEt, dried over MgSO4 and the solvent evaporated. Purification with SCX Ion exchange column chromatography (eluted first with MeOH then with aq. NH3 in MeOH) yielded the title compound (1.53 g, 96%); 1H NMR (DMSO-d6) δ 10.63 (brs, 1H), 9.08 (s, 1H), 8.83 (s, 1H), 8.62 (d, 1H), 7.49 (t, 1H), 7.40 (d, 2H), 7.38 (m, 1H), 7.05 (d, 1H), 6.89 (d, 2H), 6.74 (s, 1H), 6.55 (d, 1H), 6.15 (s, 2H); MS m/e 446 (M+1).
    • Example 23 (6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3-(methanesulfonyl)-1H-benzimidazol-2-ylamine
  • Figure US20070249600A1-20071025-C00116
  • To a mixture of 2-amino-5-4-((2-fluoro-5-trifluoromethylphenyl)aminocarbonylamino) phenoxy)-1H-benzimidazole (90 mg, 0.20 mmol) (prepared according to similar procedures as described for Intermediates 4, 5, and 6 and Example 22) and triethylamine (30 mg, 0.30 mmol) in DMF/CHCl3 (3 ml/1 ml) was added methanesulfonyl chloride (30 mg, 0.26 mmol). After stirring for 3 h at rt, the reaction mixture washed with water and extracted with CHCl3. The organic layer was dried over MgSO4 and evaporated. The crude material was purified with silica gel column chromatography (AcOEt) to give the title compound (22.0 mg, 15%): 1H NMR (DMSO-d6) δ 9.14 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.50 (t, 1H), 7.48 (d, 2H), 7.38 (m, 1H), 7.22 (d, 1H), 7.18 (s, 1H), 6.97 (d, 2H), 6.87 (s, 1H), 6.86 (d, 1H), 3.49 (s, 3H); MS m/e 524 (M+1).
    • Example 24 6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine
  • Figure US20070249600A1-20071025-C00117
  • Example 24 was prepared according to procedures similar to the one described above in Example 23. They can be transformed into their pharmaceutically acceptable salts (e.g. HCl salts) by standard procedures. 1H NMR (DMSO-d6) δ 9.18 (s, 1H), 8.88 (d, 1H), 8.63 (dd, 1H), 7.85 (d, 2H), 7.51-7.46 (m, 5H), 7.43-7.36 (m, 1H), 7.25 (d, 1H), 7.14-7.11 (m, 3H), 6.94 (d, 2H), 6.84 (dd, 1H), 2.38 (s, 3H); MS m/e 600 (M+1).
    • Example 25 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00118
  • To a mixture of 2-amino-5-4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazole (prepared according to similar procedures as described for Intermediates 4, 5, and 6 and Example 22) (72 mg, 0.165 mmol), acetic acid (15 mg, 0.24 mmol) and triethylamine (50 mg) in DMF was added HBTU (91 mg, 0.24 mmol) and HOBT (20 mg). The reaction mixture was stirred for 4 h, poured into water, washed and extracted with AcOEt. The organic layer was dried over MgSO4 and evaporated. Purification of the residue by column chromatography on silica gel (AcOEt as an eluant) afforded the title compound (28 mg, 36%): 1H NMR (DMSO-d6) δ 11.99 (brs, 1H), 11.51 (br, 1H), 9.15 (s, 1H), 8.87 (s, 1H), 8.62 (d, 1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.38 (m, 2H), 7.04 (d, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.15 (s, 3H); MS m/e 488 (M+1).
  • Examples 26-35 and 87-102 were prepared according to procedures similar to that described above. They can be transformed into their pharmaceutically acceptable salts (e.g. HCl salts) by standard procedures.
    • Example 26 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)cyclopentamide
  • Figure US20070249600A1-20071025-C00119
  • 1H NMR (DMSO-d6) δ 12.05 (brd, 1H), 11.51 (d, 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.39 (m, 2H), 6.99 (d, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.93 (quint, 1H), 1.88 (m, 2H), 1.70 (m, 4H), 1.57 (m, 2H); MS m/e 542 (M+1).
    • Example 27 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00120
  • 1H NMR (DMSO-d6) δ 12.20 (brs, 2H), 9.16 (s, 1H), 8.88 (s, 1H), 8.62 (d, 1H), 7.95 (s, 1H), 7.45 (m, 5H), 7.39 (m, 1H), 7.05 (s, 1H), 6.96 (d, 2H), 6.86 (dd, 1H), 6.70 (m, 1H); MS m/e 540 (M+1).
    • Example 28 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-methylpentamide
  • Figure US20070249600A1-20071025-C00121
  • 1H NMR (DMSO-d6) δ 12.08 (brd, 1H), 11.51 (d, 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.38 (m, 2H), 7.05 (d, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.44 (t, 2H), 1.53 (m, 2H), 0.90 (d, 6H); MS m/e 544 (M+1).
    • Example 29 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-(N-acetylamino)acetamide
  • Figure US20070249600A1-20071025-C00122
  • 1H NMR (DMSO-d6) δ 12.03 (brs, 1H), 11.58 (s, 1H), 9.14 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 8.29 (t, 1H), 7.52 (t, 1H), 7.44 (d, 2H), 7.42 (m, 1H), 7.39 (m, 1H), 7.05 (br, 1H), 6.94 (d, 2H), 6.82 (dd, 1H), 3.96 (d, 2H), 1.90 (s, 3H); MS m/e 545 (M+1).
    • Example 30 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-aminoacetamide dihydrochloride
  • Figure US20070249600A1-20071025-C00123
  • 1H NMR (DMSO-d6) δ 9.76 (s, 1H), 9.15 (d, 2H), 8.62 (d, 1H), 8.40 (br, 2H), 7.56 (d, 2H), 7.54 (d, 2H), 7.39 (m, 1H), 7.10 (s, 1H), 7.02 (m, 1H), 7.01 (d, 2H), 3.97 (m, 2H); MS m/e 503 (M+1).
    • Example 31 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-methoxyacetamide
  • Figure US20070249600A1-20071025-C00124
  • 1H NMR (DMSO-d6) δ 12.09 (brs, 1H), 11.41 (br, 1H), 9.13 (s, 1H), 8.86 (s, 1H), 8.62 (dd, 1H), 7.50 (m, 2H), 7.44 (d, 2H), 7.39 (m, 1H), 7.05 (br, 1H), 6.94 (d, 2H), 6.82 (dd, 1H), 4.14 (s, 2H), 3.39 (s, 3H); MS m/e 518 (M+1).
    • Example 32 3-(N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamoyl)propionic acid
  • Figure US20070249600A1-20071025-C00125
  • 1H NMR (DMSO-d6) δ 12.10 (brs, 1H), 11.60 (brs, 1H), 9.22 (s, 1H), 8.92 (s, 1H), 8.61 (dd, 1H), 7.60-7.40 (m, 3H), 7.44 (d, 2H), 7.05 (brs, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.67 (t, 2H), 2.55 (t, 2H); MS m/e 546 (M+1).
    • Example 33 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-(2-(methoxy)ethoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00126
  • 1H NMR (DMSO-d6) δ 12.11 (brs, 1H), 11.29 (brs, 1H), 9.15 (s, 1H), 8.86 (d, 1H), 8.61 (dd, 1H), 7.43-7.50 (m, 5H), 6.98-7.14 (brm, 1H), 6.94 (d, 2H), 6.82 (dd, 1H), 4.23 (s, 2H), 3.68-3.70 (m, 2H), 3.56-3.61 (m, 4H), 3.49-3.47 (m, 2H), 3.24 (s, 3H); MS m/e 606 (M+1).
    • Example 34 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00127
  • 1H NMR (DMSO-d6) δ 12.11 (brs, 1H), 11.28 (brs, 1H), 9.14 (s, 1H), 8.86 (d, 1H), 8.61 (dd, 1H), 7.38-7.52 (m, 5H), 6.98-7.14 (brs, 1H), 6.94 (d, 2H), 6.82 (dd, 1H), 4.22 (s, 2H), 3.68-3.71 (m, 2H), 3.51-3.54 (m, 2H), 3.30 (s, 3H); MS m/e 562 (M+1).
    • Example 35 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-(N-(t-butoxycarbony)amino)acetamide
  • Figure US20070249600A1-20071025-C00128
  • 1H NMR (DMSO-d6) δ 12.06 (d, 1H), 11.56 (brs, 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (s, 1H), 7.50 (t, 1H), 7.44 (d, 2H), 7.41 (m, 1H), 7.39 (m, 1H), 7.17 (t, 1H), 7.04 (br, 1H), 6.97 (d, 2H), 6.81 (dd, 1H), 3.82 (d, 2H), 1.40 (s, 9H); MS m/e 603 (M+1).
    • Example 36 N-(5-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyloxy)-1H-benzimidazol-2-yl)acetamide dihydrochloride
  • Figure US20070249600A1-20071025-C00129
  • The title compound was synthesized according to similar procedures as described for Intermediates 7 and 8 and for Example 1 (13.0 mg 14%): 1H NMR (DMSO-d6) δ 12.42 (brs, 1H), 10.64 (brs, 1H), 9.97 (s, 1H), 8.66 (dd, 1H), 8.11 (d, 1H), 7.68-7.61 (m, 1H), 7.60-7.48 (m, 3H), 7.47-7.41 (m, 1H), 7.17 (d, 1H), 7.04 (dd, 1H), 2.24 (s, 3H); MS m/e 489 (M+1).
  • The compounds of Examples 37 to 39 were prepared according to procedures similar to that described for Example 36 above. They can be transformed into their pharmaceutically acceptable salts (e.g. HCl salts) by standard procedures.
    • Example 37 Methyl N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00130
  • 1H NMR (DMSO-d6) δ 12.0-11.1 (brm, 2H), 9.21 (s, 1H), 8.96 (d, 1H), 8.58 (dd, 1H), 8.15 (d, 1H), 8.00 (dd, 1H), 7.52-7.48 (m, 1H), 7.41-7.38 (m, 2H), 7.11 (d, 1H), 6.94 (d, 1H), 6.82 (dd, 1H), 3.75 (s, 3H); MS m/e 505 (M+1).
    • Example 38 N-(5-(5-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00131
  • 1H NMR (DMSO-d6) δ 11.70 (brs, 2H), 9.17 (s, 1H), 8.88 (s, 1H), 8.17 (d, 1H), 7.99 (s, 1H), 7.96 (d, 1H), 7.59 (d, 1H), 7.51 (t, 1H), 7.39 (d, 1H), 7.31 (d, 1H), 7.11 (s, 1H), 6.92 (d, 1H), 6.83 (dd, 1H), 3.75 (s, 3H); MS m/e 487 (M+1).
    • Example 39 Methyl N-(5-(5-((3-ethylphenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00132
  • 1H NMR (DMSO-d6) δ 11.82 (brs, 1H), 11.30 (brs, 1H), 8.71 (d, 2H), 8.15 (d, 1H), 7.95 (d, 1H), 7.38 (d, 1H), 7.31 (s, 1H), 7.24 (d, 1H), 7.17 (t, 1H), 7.09 (brs, 1H), 6.91 (d, 1H), 6.83-6.80 (m, 2H), 3.75 (s, 3H), 2.56 (q, 2H), 1.17 (t, 3H); MS m/e 447 (M+1).
    • Example 40 Methyl N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00133
  • 1H NMR (DMSO-d6) δ 12.2-11.0 (brs, 2H), 9.11 (s, 1H), 8.93 (s, 1H), 7.84 (t, 1H), 7.42 (d, 2H), 7.37 (d, 1H), 7.31 (d, 1H), 7.22 (t, 1H), 7.13 (d, 1H), 7.00 (d, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 496 (M), 498 (M+2).
    • Example 41 Methyl N-(5-(4-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00134
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 8.96 (s, 1H), 8.73 (s, 1H), 7.98 (s, 1H), 7.55 (d, 1H), 7.46-7.42 (m, 1H), 7.43 (d, 2H), 7.37 (d, 1H), 7.29 (d, 1H), 7.00 (d, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 518 (M+1).
    • Example 42 Methyl N-(5-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00135
  • 1H NMR (DMSO-d6) δ 12.0-11.2 (brs, 2H), 9.31 (s, 1H), 8.20 (s, 1H), 7.85 (d, 1H), 7.42 (d, 2H), 7.36 (d, 1H), 6.99 (s, 1H), 6.91 (m, 3H), 6.78 (dd, 1H), 6.48 (dd, 1H), 3.82 (s, 3H), 3.74 (s, 3H), 3.68 (s, 3H). 6; MS m/e 478 (M+1).
    • Example 43 Methyl N-(5-(4-((2-chloro-5-(trifluoromethylgphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00136
  • 1H NMR (DMSO-d6) δ 12.0-11.2 (brs, 2H), 9.53 (s, 1H), 8.65 (d, 1H), 8.57 (s, 1H), 7.71 (d, 1H), 7.45 (d, 2H), 7.37 (m, 2H), 7.01 (s, 1H), 6.94 (d, 2H), 6.80 (dd, 1H), 3.75 (s, 3H); MS m/e 520 (M+1), 522 (M+3).
    • Example 44 Methyl N-(5-(4-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00137
  • 1H NMR (DMSO-d6) δ 12.0-11.2 (brs, 2H), 9.13 (s, 1H), 8.80 (s, 1H), 8.11 (d, 1H), 7.65-7.59 (m, 2H), 7.43 (d, 2H), 7.37 (d, 1H), 7.00 (d, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 520 (M+1)), 522 (M+3).
    • Example 45 Methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00138
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.50 (s, 1H), 8.42 (s, 1H), 8.33 (m, 1H), 7.49 (d, 1H), 7.43 (d, 2H), 7.38 (d, 1H), 7.08 (dd, 1H), 7.01 (d, 1H), 6.94 (d, 2H), 6.80 (dd, 1H), 3.75 (s, 3H); MS m/e 486 (M+1).
    • Example 46 Methyl N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00139
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.16 (m, 2H), 8.97 (s, 1H), 7.90 (m, 1H), 7.55 (t, 1H), 7.45 (d, 2H), 7.38 (d, 1H), 7.01 (d, 1H), 6.94 (d, 2H), 6.80 (dd, 1H), 3.75 (s, 3H); MS m/e 481 (M+1).
    • Example 47 Methyl N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00140
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.22 (s, 1H), 8.96 (d, 1H), 8.23 (s, 1H), 7.79 (dd, 1H), 7.47 (m, 1H), 7.46 (d, 2H), 7.38 (d, 1H), 7.01 (d, 1H), 6.94 (d, 2H), 6.80 (dd, 1H), 3.75 (s, 3H), 2.37 (s, 3H); MS m/e 477 (M+1).
    • Example 48 Methyl N-(5-(4-(3-methylthiophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00141
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 8.67 (s, 1H), 8.64 (s, 1H), 7.46 (t, 1H), 7.41 (d, 2H), 7.36 (d, 1H), 7.21 (t, 1H), 7.13 (d, 1H), 6.99 (d, 1H), 6.92 (d, 2H), 6.84 (d, 1H), 6.78 (dd, 1H), 3.74 (s, 3H), 2.45 (s, 3H); MS m/e 464 (M+1).
    • Example 49 Methyl N-(5-(4-(3-cyanophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00142
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.02 (s, 1H), 8.83 (s, 1H), 7.97 (s, 1H), 7.67 (d, 1H), 7.49 (t, 1H), 7.43 (d, 2H), 7.42 (t, 1H), 7.37 (d, 1H), 7.00 (d, 1H), 6.93 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 443 (M+1).
    • Example 50 Methyl N-(5-(4-((3-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00143
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.21 (s, 1H), 8.87 (s, 1H), 7.70 (s, 1H), 7.61 (d, 1H), 7.43 (d, 2H), 7.37 (d, 1H), 7.22 (d, 1H), 7.00 (d, 1H), 6.93 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 504 (M+1).
    • Example 51 Methyl N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate hydrochloride
  • Figure US20070249600A1-20071025-C00144
  • 1H NMR (DMSO-d6) δ 9.82 (s, 1H), 6.69 (s, 1H), 8.62 (d, 1H), 7.71 (d, 1H), 7.46 (d, 2H), 7.42-7.36 (m, 3H), 7.21 (d, 2H), 7.12 (dd, 1H), 3.75 (s, 3H); MS m/e 536 (M+1), 538 (M+3).
    • Example 52 Methyl N-(5-(3-((2-chloro-5-(trifluoromethylgphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate hydrochloride
  • Figure US20070249600A1-20071025-C00145
  • 1H NMR (DMSO-d6) δ 9.67 (s, 1H), 8.57 (s, 1H), 8.56 (s, 1H), 7.70 (d, 1H), 7.41 (d, 1H), 7.36 (dd, 1H), 7.27 (t, 1H), 7.18 (d, 1H), 7.09 (d, 1H), 7.03 (t, 1H), 6.84 (dd, 1H), 6.62 (dd, 1H), 3.75 (s, 3H); MS m/e 520 (M+1), 522 (M+3).
    • Example 53 Methyl N-(5-(4-((3-ethoxycarbonylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00146
  • 1H NMR (DMSO-d6) δ 12.0-11.2 (brs, 2H), 8.91 (s, 1H), 8.64 (s, 1H), 8.15 (t, 1H), 7.65 (d, 1H), 7.55 (d, 1H), 7.44-7.40 (m, 3H), 7.37 (d, 1H), 7.00 (s, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 4.31 (q, 2H), 3.74 (s, 3H), 1.32 (t, 3H); MS m/e 490 (M+1).
    • Example 54 Methyl N-(5-(4-((3-carboxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00147
  • Hydrolysis of the product of Example 53 with NaOH gave the title compound.
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 8.97 (brs, 1H), 8.77 (brs, 1H), 8.12 (s, 1H), 7.64 (d, 1H), 7.54 (d, 1H), 7.44 (d, 2H), 7.38 (m, 2H), 7.00 (d, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 462 (M+1).
    • Example 55 Methyl N-(5-(4-((2-fluoro-5-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate hydrochloride
  • Figure US20070249600A1-20071025-C00148
  • 1H NMR (DMSO-d6) δ 9.56 (s, 1H), 8.66 (s, 1H), 7.96 (d, 1H), 7.58 (d, 1H), 7.51 (d, 2H), 7.12-7.06 (m, 3H), 7.01 (d, 2H), 6.79 (m, 1H), 3.86 (s, 3H), 2.27 (s, 3H); MS m/e 450 (M+1).
    • Example 56 Methyl N-(5-(4-((2,5-difluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00149
  • 1H NMR (DMSO-d6) δ 12.0-11.0 (brs, 2H), 9.09 (s, 1H), 8.71 (s, 1H), 8.04 (m, 1H), 7.42 (d, 2H), 7.37 (d, 1H), 7.29 (m, 1H), 7.00 (d, 1H), 6.93 (d, 2H), 6.82 (m, 1H), 6.79 (dd, 1H), 3.74 (s, 3H); MS m/e 454 (M+1).
    • Example 57 Methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00150
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.60 (s, 1H), 8.46 (s, 1H), 8.30 (d, 1H), 7.49 (d, 1H), 7.45-7.39 (m, 4H), 7.21 (d, 2H), 7.13 (dd, 1H), 7.09 (dd, 1H), 3.75 (s, 3H); MS m/e 502 (M+1), 504 (M+3).
    • Example 58 Methyl N-(5-(3-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00151
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.02 (s, 1H), 8.94 (s, 1H), 7.90 (s, 1H), 7.52 (d, 1H), 7.44-7.40 (m, 2H), 7.30-7.21 (m, 2H), 7.12-7.07 (m, 3H), 6.84 (dd, 1H), 6.57 (d, 1H), 3.75 (s, 3H); MS m/e 518 (M+1).
    • Example 59 Methyl N-(5-(3-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00152
  • 1H NMR (DMSO-d6) δ 12.0-11.5 (brs, 2H), 7.78 (s, 1H), 7.41 (d, 1H), 7.30-7.00 (m, 9H), 6.83 (dd, 1H), 6.57 (dd, 1H), 3.75 (s, 3H); MS m/e 496 (M), 498 (M+2).
    • Example 60 Methyl N-(5-(3-((3-(phenoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00153
  • 1H NMR (DMSO-d6) δ 12.0-11.5 (brs, 2H), 8.94 (s, 1H), 8.91 (s, 1H), 7.39 (m, 3H), 7.30-7.21 (m, 2H), 7.19 (t, 1H), 7.11-7.00 (m, 7H), 6.83 (dd, 1H), 6.59 (d, 1H), 6.54 (d, 1H) 3.75 (s, 3H); MS m/e 510 (M+1).
    • Example 61 Methyl N-(5-(3-((4-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00154
  • 1H NMR (DMSO-d6) δ 12.0-11.2 (brs, 2H), 8.94 (s, 1H), 8.91 (s, 1H), 7.44-7.40 (m, 3H), 7.29 (d, 2H), 7.23 (t, 1H), 7.14 (t, 1H), 7.07 (s, 2H), 6.82 (dd, 1H), 6.57 (dd, 1H), 3.75 (s, 3H). 6; MS m/e 452 (M+1).
    • Example 62 Methyl N-(5-(4-((4-methoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00155
  • 1H NMR (DMSO-d6) δ 12.0-11.0 (brs, 2H), 8.53 (s, 1H), 8.42 (s, 1H), 7.40 (d, 2H), 7.36 (d, 1H), 7.34 (d, 2H), 6.99 (d, 1H), 6.90 (d, 2H), 6.86 (d, 2H), 6.78 (dd, 1H), 3.74 (s, 3H), 3.71 (s, 3H); MS m/e 448 (M+1).
    • Example 63 Methyl N-(5-(4-((4-fluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00156
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 8.66 (s, 1H), 8.61 (s, 1H), 7.46-7.40 (m, 5H), 7.36 (d, 1H), 7.11 (t, 2H), 7.00 (d, 1H), 6.91 (d, 2H), 6.78 (dd, 1H), 3.74 (s, 3H). δ; MS m/e 436 (M+1).
    • Example 64 Methyl N-(6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-benzthiazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00157
  • This example was prepared according to the procedure of Example 1 except that Intermediate 10G was used as a precursor in lieu of Intermediate 1.
  • 1H NMR (DMSO-d6) δ 12.05 (brs, 1H), 9.18 (s, 1H), 8.87 (d, 1H), 8.62 (dd, 1H), 7.66 (d, 1H), 7.60 (s, 1H), 7.50 (m, 1H), 7.47 (d, 2H), 7.38 (m, 1H), 7.07 (dd, 1H), 7.00 (d, 2H), 3.77 (s, 3H); MS m/e 521 (M+1).
    • Example 65 Methyl N-(4-bromo-6-(4-((6-fluoro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)carbamate hydrochloride
  • Figure US20070249600A1-20071025-C00158
  • This example was prepared according to the procedure of Example 1 except that Intermediate 10H was used as a precursor in lieu of Intermediate 1.
  • 1H NMR (DMSO-d6) δ 12.39 (brs, 1H), 9.27 (brs, 1H), 8.91 (d, 1H), 8.62 (dd, 1H), 7.67 (d, 1H), 7.50 (d, 2H), 7.50 (m, 1H), 7.39 (m, 1H), 7.32 (d, 1H), 7.05 (d, 2H), 3.78 (s, 3H); MS m/e 599, 601 (M+1).
    • Example 66 Methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00159
  • This example was prepared according to the procedure of Example 1 except that Intermediate 8J was used as a precursor in lieu of Intermediate 1. 1H NMR (DMSO-d6) δ 9.22 (brs, 1H), 8.92 (brs, 1H), 8.61 (d, 1H), 7.50 (m, 1H), 7.45 (d, 2H), 7.43-7.36 (m, 2H), 7.15 (d, 1H), 6.96 (d, 2H), 6.83 (dd, 1H), 3.62 (s, 3H), 3.46 (s, 3H); MS m/e 518 (M+1).
    • Example 67 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00160
  • This example was prepared according to the procedure of Example 1 except that Intermediate 8C was used as a precursor in lieu of Intermediate 1. 1H NMR (chloroform-d1) δ 8.65 (brd, 1H), 7.43 (d, 2H), 7.22 (m, 1H), 7.14 (m, 1H), 7.12 (d, 1H), 6.99-6.90 (m, 4H), 3.78 (s, 3H), 3.59 (s, 3H); MS m/e 518 (M+1).
    • Example 68 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-3a-aza-2-indolyl)carbamate
  • Figure US20070249600A1-20071025-C00161
  • This example was prepared according to the procedure of Example 1 except that Intermediate 9K was used as a precursor in lieu of Intermediate 1. 1H NMR (DMSO-d6) δ 10.28 (brs, 1H), 9.26 (s, 1H), 8.95 (s, 1H), 8.60 (dd, 1H), 8.47 (d, 1H), 7.87 (s, 1H), 7.48 (m, 1H), 7.47 (d, 2H), 7.42 (d, 1H), 7.38 (m, 1H), 7.05 (dd, 1H), 7.02 (d, 2H), 3.68 (s, 3H); MS m/e 504 (M+1).
    • Example 69 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-3,4-diazaindolin-2-yl)carbamate dihydrochloride
  • Figure US20070249600A1-20071025-C00162
  • This example was prepared according to the procedure of Example 1 except that Intermediate 9D was used as a precursor in lieu of Intermediate 1. 1H NMR (DMSO-d6) δ 9.21 (s, 1H), 8.89 (d, 1H), 8.63 (dd, 1H), 7.79 (d, 1H), 7.49 (m, 1H), 7.47 (d, 2H), 7.38 (m, 1H), 7.05 (d, 2H), 6.73 (d, 1H), 3.76 (s, 3H); MS m/e 505 (M+1).
    • Example 70 Methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-(2-(dimethylamino)ethyl)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00163
  • This example was prepared according to the procedure of Example 1 except that Intermediate 8K was used as a precursor in lieu of Intermediate 1. 1H NMR (chloroform-d1) δ 9.02 (brs, 1H), 8.59 (dd, 1H), 8.48 (brs, 1H), 7.38 (d, 2H), 7.17 (d, 1H), 7.13 (m, 1H), 7.03 (dd, 1H), 6.86 (d, 2H), 6.84 (d, 1H), 6.76 (dd, 1H), 4.06 (t, 2H), 3.79 (s, 3H), 2.70 (t, 2H), 2.32 (s, 6H); MS m/e 573 (M−1).
    • Example 71 Methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-(2-(4-morpholino)ethyl)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00164
  • This example was prepared according to the procedure of Example 1 except that Intermediate 8L was used as a precursor in lieu of Intermediate 1. 1H NMR (chloroform-d1) δ 8.66-8.59 (br, 2H), 8.15 (d, 1H), 7.38 (d, 2H), 7.19 (d, 1H), 7.18 (m, 1H), 7.07 (dd, 1H), 6.90 (d, 2H), 6.86 (d, 1H), 6.81 (dd, 1H), 4.09 (t, 2H), 3.82 (s, 3H), 3.64 (brs, 4H), 2.70 (t, 2H), 2.50 (brs, 4H); MS m/e 615 (M−1).
    • Example 72 Methyl N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate dihydrochloride
  • Figure US20070249600A1-20071025-C00165
  • This example was prepared according to the procedure of Example 1 except that Intermediate 9D was used as a precursor in lieu of Intermediate 1. 1H NMR (DMSO-d6) δ 9.60 (s, 1H), 8.65 (d, 1H), 8.61 (s, 1H), 7.80 (d, 1H), 7.72 (d, 1H), 7.48 (d, 2H), 7.37 (dd, 1H), 7.05 (d, 2H), 6.73 (d, 1H), 3.76 (s, 3H); MS m/e 521(M+1), 523 (M+3).
    • Example 73 Methyl N-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate dihydrochloride
  • Figure US20070249600A1-20071025-C00166
  • This example was prepared according to the procedure of Example 1 except that Intermediate 9E was used as a precursor in lieu of Intermediate 1. 1H NMR (DMSO-d6) δ 9.62 (s, 1H), 8.64 (d, 1H), 8.60 (s, 1H), 8.09 (d, 1H), 7.72 (d, 1H), 7.49 (d, 2H), 7.47 (d, 1H), 7.37 (dd, 1H), 7.01 (d, 2H), 3.78 (s, 3H); MS m/e 521, 523 (M+1).
    • Example 74 Methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-3,4-diaza-1H -indole-2-yl)carbamate dihydrochloride
  • Figure US20070249600A1-20071025-C00167
  • This example was prepared according to the procedure of Example 1 except that Intermediate 9D was used as a precursor in lieu of Intermediate 1. 1H NMR (DMSO-d6) δ 9.56 (s, 1H), 8.46 (s, 1H), 8.34 (d, 1H), 7.80 (d, 1H), 7.51 (d, 1H), 7.47 (d, 2H), 7.09 (dd, 1H), 7.05 (d, 2H), 6.73 (d, 1H), 3.76 (s, 3H); MS m/e 487 (M+1), 489 (M+3).
    • Example 75 Methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-3,4-diaza-1H-indole-2-yl)carbamate dihydrochloride
  • Figure US20070249600A1-20071025-C00168
  • This example was prepared according to the procedure of Example 1 except that Intermediate 9E was used as a precursor in lieu of Intermediate 1. 1H NMR (DMSO-d6) δ 9.22 (s, 1H), 8.89 (d, 1H), 8.61 (dd, 1H), 8.08 (s, 1H), 7.53-7.42 (m, 4H), 7.38 (m, 1H), 7.01 (d, 2H), 3.78 (s, 3H); MS m/e 505 (M+1).
    • Example 76 Methyl N-(6-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)benzthiazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00169
  • This example was prepared according to the procedure of Example 1 except that Intermediate 10G was used as a precursor in lieu of Intermediate 1.
  • 1H NMR (DMSO-d6) δ 12.06 (s, 1H), 9.57 (s, 1H), 8.65 (d, 1H), 8.59 (s, 1H), 7.72 (d, 1H), 7.67 (d, 1H), 7.62 (d, 1H), 7.50 (t, 1H), 7.48 (t, 1H), 7.37 (dd, 1H), 7.09 (dd, 1H), 7.02 (t, 1H), 7.00 (t, 1H), 3.77 (s, 3H). 6; MS m/e 537 (M+1), 539 (M+3).
    • Example 77 6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a,5-triazacarbazol-2-one
  • Figure US20070249600A1-20071025-C00170
  • This example was prepared according to the procedure of Example 1 except that Intermediate 9I was used as a precursor in lieu of Intermediate 3. 1H NMR (DMSO-d6) δ 9.22 (d, 1H), 8.92 (s, 1H), 8.62 (d, 1H), 7.83 (d, 1H), 7.50 (m, 1H), 7.48 (d, 2H), 7.38 (m, 1H), 7.07 (d, 2H), 6.71 (d, 1H), 4.12 (t, 2H), 2.83 (t, 2H); MS m/e 501 (M+1).
    • Example 78 Methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylcarbonyl)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00171
  • This example was prepared according to the procedure of Example 1 except that Intermediate 11D was used as a precursor in lieu of Intermediate 3.
  • 1H NMR (DMSO-d6) δ 12.5-11.2 (brs, 2H), 9.59 (s, 1H), 9.04 (s, 1H), 8.62 (d, 1H), 7.83 (brs, 1H), 7.75 (d, 2H), 7.65 (d, 2H), 7.55-7.50 (m, 3H), 7.44 (m, 1H), 3.78 (s, 3H); MS m/e 516 (M+1).
    • Example 79 Methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00172
  • The title compound was prepared following the procedure for Example 12 except that the product of Example 57 was used as a precursor.
  • 1H NMR (DMSO-d6) δ 12.4-11.3 (brs, 2H), 9.80 (s, 1H), 8.52 (s, 1H), 8.29 (d, 1H), 7.73 (s, 1H), 7.60 (s, 4H), 7.51 (m, 1H), 7.50 (d, 1H), 7.34 (dd, 1H), 7.11 (dd, 1H), 3.76 (s, 3H); MS m/e 518 (M+1).
    • Example 80 2-(Dimethylamino)ethyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00173
  • Heating of a mixture of Example 10 and NaH, 2-(dimethylamino)ethanol gave the title compound:
  • 1H NMR (DMSO-d6) δ11.62 (br, 2H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.54-7.34 (m, 5H), 7.01 (d, 1H), 6.93 (d, 2H), 6.78 (dd, 1H), 4.25 (dd, 2H), 2.54 (t, 2H), 2.20 (s, 6H); MS m/e 561 (M+1).
    • Example 81 Benzyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00174
  • Following the method for Example 1 using Intermediate 3D instead of Intermediate 3 afforded the title compound.
  • 1H NMR (DMSO-d6) δ11.73 (br, 2H), 9.17 (s, 1H), 8.87 (s, 1H), 8.62 (d, 1H), 7.53-7.33 (m, 10H), 7.01 (d, 1H), 6.93 (d, 2H), 6.79 (dd, 1H), 5.24 (s, 2H); MS m/e 580 (M+1).
    • Example 82 5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(methanesulfonyl)-1H-benzimidazol-2-ylamine
  • Figure US20070249600A1-20071025-C00175
  • To a mixture of 2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1H-benzimidazole (90 mg, 0.20 mmol) (prepared according to similar procedures as described for Intermediates 4, 5, and 6 and Example 22) and triethylamine (30 mg, 0.30 mmol) in DMF/CHCl3 (3 ml/1 ml) was added methanesulfonyl chloride (30 mg, 0.26 mmol). After stirring for 3 h at rt, the reaction mixture washed with water and extracted with CHCl3. The organic layer was dried over MgSO4 and evaporated. The crude material was purified with silica gel column chromatography (AcOEt) to give the product of Example 23 (11.0 mg, 11%) and the title compound (34 mg, 25%): 1H NMR (DMSO-d6) δ 9.14 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.51 (d, 1H), 7.47 (d, 1H), 7.46 (d, 2H), 7.38 (m, 1H), 7.02 (brs, 2H), 6.97 (d, 2H), 6.82 (d, 1H), 6.70 (dd, 1H), 3.49 (s, 3H); MS m/e 524 (M+1).
    • Example 83 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)methanesulfonamide
  • Figure US20070249600A1-20071025-C00176
  • 2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1H-benzimidazole (the product of Example 22-600 mg) and methanesulfonyl chloride (5 equiv.) in pyridine was stirred at room temperature for 2 days. The resulting mixture was treated with K2CO3 (10 equiv.) and H2O (10 mL) and MeOH (10 mL), and heated at 60 C for 7 days. The crude solid was collected by filtration. Recrystallization from hot MeOH afforded the title compound (280 mg, 40%);
  • 1H NMR (DMSO-d6) δ 11.69 (br, 2H), 9.16 (s, 1H), 8.86 (s, 1H), 8.62 (d, 1H), 7.54-7.43 (m, 3H), 7.41-7.36 (m, 1H), 7.23 (d, 1H), 6.97 (d, 2H), 6.86 (d, 1H), 6.80 (dd, 1H), 2.92 (s, 3H); MS m/e 524 (M+1).
    • Example 84 5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine
  • Figure US20070249600A1-20071025-C00177
  • The title compound was prepared following for Example 24. The products of Example 24 and 84 are separated by columnchromatography.
  • 1H NMR (DMSO-d6) δ 9.16 (s, 1H), 8.86 (s, 1H), 8.62 (d, 1H), 7.93 (d, 2H), 7.62 (d, 1H), 7.53-7.42 (m, 5H), 7.41-7.36 (m, 1H), 7.25 (br, 2H), 6.96 (d, 2H), 6.70 (d, 1H) 6.66 (dd, 1H), 2.37 (s, 3H); MS m/e 600 (M+1).
    • Example 85 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-methylbenzenesulfonamide
  • Figure US20070249600A1-20071025-C00178
  • To a mixture of Intermediate 6 (105 mg, 0.25 mmol) and N′,N″-bis-p-tolyl sulfonyl-S-methylisothiourea (100 mg, 0.25 mmol; prepared from p-toluene sulfonamide, cf. J. Org. Chem., 1998, 53, 3120-3122; Zh. Org. Khim., 1975,11, (3), 574-576) in THF (3 ml) was added acetic acid (0.5 ml) and stirred for 4 days at 90° C. Reaction mixture was treated with SPE (NH2) tube (washed with MeOH and eluted with NH3/MeOH). NH3/MeOH eluent was collected and purified by column chromatography (hexane-AcOEt, 1:1) and desired compound was obtained as off-white solid. (2.3 mg, yield 1.53%)
  • 1H NMR (DMSO-d6) δ 11.89 (br, 1H), 11.84 (br, 1H), 9.16 (s, 1H), 8.85 (s, 1H), 8.61 (d, 1H), 7.76 (d, 2H), 7.53-7.43 (m, 3H), 7.41-7.36 (m, 1H), 7.31 (d, 2H), 7.24 (d, 1H), 6.97 (d, 2H), 6.86 (d, 1H), 6.82 (dd, 1H), 2.33 (s, 3H); MS m/e 600 (M+1).
    • Example 86 N-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)benzthiazol-2-yl)methanesulfonamide
  • Figure US20070249600A1-20071025-C00179
  • A mixture of 2-fluoro-5-(trifluoromethyl)phenylisocyanate (47.4 mg, 0.23 mmol) and Intermediate 10D (72 mg, 0.21 mmol) in THF (3 ml) was stirred over night at 45° C. The reaction mixture was cooled to room temperature and ether was added and a pale brown solid was generated. The solid was collected by filtration and washed with ether and dried in vacuo. 55 mg of desired compound was obtained. (50% yield)
  • 1H NMR (DMSO-d6) δ 12.95 (br, 1H), 9.18 (s, 1H), 8.86 (s, 1H), 8.61 (d, 1H), 7.54-7.44 (m, 4H), 7.41-7.36 (m, 1H), 7.30 (d, 1H), 7.05 (dd, 1H), 6.99 (d, 2H), 2.99 (s, 3H); MS m/e 541 (M+1).
  • Examples 87-102 were prepared according to procedure similar to Example 25.
    • Example 87 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-(4-methyl-1-piperazinomethyl)benzamide
  • Figure US20070249600A1-20071025-C00180
  • 1H NMR (DMSO-d6) δ 12.20 (brs, 2H), 9.15 (s, 1H), 8.86 (d, 1H), 8.62 (dd, 1H), 8.08 (d, 2H), 7.44-7.53 (m, 4H), 7.35-7.42 (m, 1H), 7.22-7.34 (brs, 1H), 7.08 (d, 1H), 6.96 (d, 2H), 6.86 (dd, 1H), 6.64-6.76 (brs, 1H), 3.54 (s, 2H), 2.25-2.48 (brs, 4H), 2.18 (s, 4H), 1.76 (s, 3H); MS m/e 663 (M+2).
    • Example 88 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-3-(pyridine-3-yl)propionamide
  • Figure US20070249600A1-20071025-C00181
  • 1H NMR (DMSO-d6) δ 12.04 (brd, 1H), 11.57 (brd, 1H), 9.15 (s, 1H), 8.86 (d, 1H), 8.62 (dd, 1H), 8.50 (d, 1H), 8.40 (dd, 1H), 7.69 (d, 1H), 7.35-7.53 (m, 5H), 7.32 (dd, 1H), 7.03 (d, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.96 (t, 2H), 2.80 (t, 2H); MS m/e 579 (M+1).
    • Example 89 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-5-benzimidazolecarboxamide
  • Figure US20070249600A1-20071025-C00182
  • 1H NMR (DMSO-d6) δ 12.80 (brs, 1H), 12.40 (brs, 2H), 9.16 (s, 1H), 8.88 (s, 1H), 8.62 (d, 1H), 8.45 (brs, 1H), 8.39 (dd, 1H), 8.01 (d, 1H), 7.69 (brs, 1H), 7.44-7.53 (m, 4H), 7.36-7.41 (m, 1H), 7.09 (brs, 1H), 6.96 (d, 2H), 6.85 (dd, 1H); MS m/e 590 (M+1).
    • Example 90 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-(pyrrol-1-yl)benzamide
  • Figure US20070249600A1-20071025-C00183
  • 1H NMR (DMSO-d6) δ 12.26 (brs, 2H), 9.17 (s, 1H), 8.88 (s, 1H), 8.62 (d, 1H), 8.22 (d, 2H), 7.77 (d, 2H), 7.54 (t, 2H), 7.42-7.52 (m, 4H), 7.36-7.41 (m, 1H), 7.08 (brs, 1H), 6.97 (d, 2H), 6.86 (dd, 1H), 6.33 (t, 2H); MS m/e 615 (M+1).
    • Example 91 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-(1H-imidazol-1-yl)benzamide
  • Figure US20070249600A1-20071025-C00184
  • 1H NMR (DMSO-d6) δ 12.40 (brs, 2H), 9.17 (s, 1H), 8.86 (d, 1H), 8.62 (dd, 1H), 8.43 (s, 1H), 8.27 (d, 2H), 8.05 (d, 1H), 7.80-7.96 (m, 3H), 7.45-7.54 (m, 3H), 7.33-7.42 (m, 1H), 7.16 (s, 1H), 7.07 (brs, 1H), 6.98 (d, 2H), 6.88 (dd, 1H); MS m/e 616 (M+1).
    • Example 92 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-4-(dimethylamino)butylamide
  • Figure US20070249600A1-20071025-C00185
  • 1H NMR (DMSO-d6) δ12.02 (br, 1H), 11.56 (br, 1H), 9.18 (s, 1H), 8.90 (s, 1H), 8.62 (s, 1H), 7.53-7.35 (m, 5H), 7.16-6.97 (m, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 2.45 (t, 2H), 2.24 (t, 2H), 2.13 (s, 6H), 1.75 (m, 2H); MS m/e 559 (M+1).
    • Example 93 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-3-pyridinecarboxamide
  • Figure US20070249600A1-20071025-C00186
  • 1H NMR (DMSO-d6) δ12.41 (br, 2H), 9.26 (d, 1H), 9.16 (s, 1H), 8.87 (s, 1H), 8.74 (s, 1H), 8.62 (dd, 1H), 8.43 (m, 1H), 7.57-7.42 (m, 5H), 7.42-7.36 (m, 1H), 7.05 (d, 1H), 6.98 (d, 2H), 6.88 (dd, 1H); MS m/e 551 (M+1).
    • Example 94 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-tetrahydrofurancarboxamide
  • Figure US20070249600A1-20071025-C00187
  • 1H NMR (DMSO-d6) δ 12.08 (br, 1H), 11.26 (br, 1H), 9.14 (s, 1H), 8.86 (s, 1H), 8.62 (d, 1H), 7.53-7.41 (m, 4H), 7.41-7.35 (m, 1H), 7.06 (br, 1H), 6.94 (d, 2H), 6.83 (dd, 1H), 4.53 (dd, 1H), 3.99 (q, 1H), 3.83 (q, 1H), 2.28-2.18 (m, 1H), 2.04-1.83 (m, 3H); MS m/e 544 (M+1).
    • Example 95 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl) (1H-indole-3-carboxamide)
  • Figure US20070249600A1-20071025-C00188
  • 1H NMR (DMSO-d6) δ 12.25 (brs, 1H), 11.77 (s, 1H), 9.18 (s, 1H), 8.88 (d, 1H), 8.62 (dd, 1H), 7.70 (d, 1H), 7.60 (brs, 1H), 7.43-7.55 (m, 6H), 7.35-7.41 (m, 1H), 7.25 (t, 1H), 7.05-7.12 (m, 2H), 6.97 (d, 2H), 6.86 (dd, 1H); MS m/e 589 (M+1).
    • Example 96 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(5-(1-pyrrolidino)tetrazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00189
  • 1H NMR (DMSO-d6) δ 12.17 (brs, 2H), 9.14 (s, 1H), 8.85 (d, 1H), 8.61 (dd, 1H), 7.36-7.53 (m, 5H), 7.01 (d, 1H), 6.96 (d, 2H), 6.85 (dd, 1H), 5.49 (s, 2H), 3.30.3.40 (m, 4H, overlap with d6-DMSO water peak), 1.88-1.97 (m, 4H); MS m/e 625 (M+1).
    • Example 97 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(1-methyl-1H-imidazol-4-yl)acetamide
  • Figure US20070249600A1-20071025-C00190
  • 1H NMR (DMSO-d6) δ 12.10 (brs, 1H), 11.85 (brs, 1H), 9.39 (s, 1H), 9.07 (dd, 2H), 7.62-7.84 (m, 7H), 7.33 (s, 1H), 7.21 (d, 2H), 7.11 (dd, 1H), 3.99 (s, 5H); MS m/e 568 (M+1).
    • Example 98 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(1H-imidazole-4-carboxamide) dihydrochloride
  • Figure US20070249600A1-20071025-C00191
  • 1H NMR (DMSO-d6) δ 9.74 (s, 1H), 9.13 (s, 1H), 8.62 (d, 2H), 8.24 (s, 1H), 7.60 (d, 1H), 7.53 (d, 2H), 7.48 (d, 1H), 7.40 (m, 1H), 7.17 (d, 1H), 7.08 (m, 1H), 7.04 (d, 2H), 3.88 (s, 3H); MS m/e 540 (M+1).
    • Example 99 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)benzamide
  • Figure US20070249600A1-20071025-C00192
  • 1H NMR (DMSO-d6) δ 12.6-12.2 (brs, 2H), 9.15 (s, 1H), 8.87 (d, 1H), 8.62 (dd, 1H), 8.13 (d, 2H), 7.95 (s, 2H), 7.64-7.50 (m, 4H), 7.45 (d, 2H), 7.39 (brm, 1H), 6.97 (d, 2H), 6.86 (dd, 1H); MS m/e 550 (M+1).
    • Example 100 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-2-thiophenecarboxamide
  • Figure US20070249600A1-20071025-C00193
  • 1H NMR (DMSO-d6) δ 12.23 (br, 2H), 9.16 (s, 1H), 8.86 (s, 1H), 8.62 (d, 1H), 8.02 (br, 1H), 7.84 (br, 1H), 7.54-7.34 (m, 5H), 7.20 (t, 1H), 7.03 (br, 1H), 6.97 (d, 2H), 6.86 (dd, 1H); MS m/e 556 (M+1).
    • Example 101 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(4-methyl-1-piperazino)acetamide
  • Figure US20070249600A1-20071025-C00194
  • 1H NMR (DMSO-d6) δ 11.90-12.25 (brd, 1H), 10.90-11.30 (brs, 1H), 9.13 (s, 1H), 8.85 (d, 1H), 8.62 (dd, 1H), 7.33-7.53 (m, 5H), 6.97-7.18 (brd, 1H), 6.93 (d, 2H), 6.81 (dd, 1H), 3.26 (s, 2H), 2.54-2.62 (bs, 4H), 2.28-2.42 (bs, 4H), 2.16 (s, 3H); MS m/e 584 (M−1).
    • Example 102 N-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(dimethylamino)acetamide
  • Figure US20070249600A1-20071025-C00195
  • 1H NMR (DMSO-d6) δ 12.10 (brs, 1H), 9.14 (s, 1H), 8.85 (d, 1H), 8.62 (dd, 1H), 7.35-7.53 (m, 6H), 6.96 (brs, 1H), 6.95 (d, 2H), 6.85 (dd, 1H), 3.60-3.80 (brs, 2H), 2.55-2.67 (brs, 6H); MS m/e 529 (M−1).
    • Example 103
  • Figure US20070249600A1-20071025-C00196
  • Prepared as described by the coupling reaction in Example 25 using 1-piperidine propionic acid. Using these reaction conditions, elimination of piperidine followed by cyclization to the two regioisomeric products in a 1:1 ratio occurred in situ without isolation of the intermediates.
  • 1H NMR (DMSO-d6) δ 11.45 (brs, 1H), 11.42 (brs, 1H), 9.12 (s, 2H), 8.84 (d, 2H), 8.61 (dd, 2H), 7.35-7.53 (m, 10H), 7.15 (d, 1H), 7.03 (d, 1H), 6.93 (d, 2H), 6.91 (d, 2H), 6.85 (dd, 1H), 6.80 (dd, 1H), 4.25 (t, 2H), 4.21 (t, 2H), 2.89 (t, 2H), 2.86 (t, 2H); MS m/e 500 (M+1).
  • The two regioisomers were separated by successive recrystallizations from 2-butanone followed by methanol.
    • Example 103A 6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one
  • Figure US20070249600A1-20071025-C00197
  • 1H NMR (DMSO-d6) δ 9.16 (s, 1H), 8.88 (d, 1H), 8.61 (d, 1H), 7.35-7.53 (m, 5H), 7.15 (d, 1H), 6.93 (d, 2H), 6.80 (dd, 1H), 4.21 (t, 2H), 2.86 (t, 2H); MS m/e 500 (M+1).
    • Example 103B 7-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one
  • Figure US20070249600A1-20071025-C00198
  • 1H NMR (DMSO-d6) δ 11.42 (brs, 1H), 9.17 (s, 1H), 8.90 (s, 1H), 8.61 (dd, 1H), 7.35-7.53 (m, 5H), 7.03 (d, 1H), 6.91 (d, 2H), 6.84 (dd, 1H), 4.25 (t, 2H), 2.89 (t, 2H); MS m/e 500 (M+1).
    • Example 104 2-(2-(4-Methyl-1-piperazino)ethylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole
  • Figure US20070249600A1-20071025-C00199
  • To a stirred solution of N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(N-4-methyl-1-piperazino)acetamide (the product of Example 101, 150 mg, 0.26 mmol) in dry THF (10 ml) under nitrogen was added dropwise a solution of lithium aluminium hydride in THF (5 ml of a 1M solution, 5 mmol). The reaction was stirred at room temperature for 5 h and then quenched by slow dropwise addition of ethyl acetate, followed by methanol and water. The resulting white precipitate was filtered off through a celite pad and washed well with methanol. The filtered solution was evaporated to dryness and partioned between ethyl acetate and water. The aqueous phase was further extracted by ethyl acetate three times and then combined ethyl acetate solutions were dried over magnesium sulfate and concentrated to give the crude product as an oil. Purification of the crude material by column chromatography (eluting with AcOEt and incremental amounts of methanolic ammonia up to 10%) afforded the product as an oil (86 mg, 58% yield).
  • 1H NMR (DMSO-d6) δ 10.80 (brs, 1H), 9.10 (s, 1H), 8.84 (d, 1H), 8.61 (dd, 1H), 7.49 (t, 1H), 7.35-7.43 (m, 4H), 7.08 (d, 1H), 6.88 (d, 2H), 6.70 (d, 1H), 6.41 (brs, 1H), 2.25-2.45 (m, 4H), 2.15 (s, 4H), 1.76 (s, 7H); MS m/e 572 (M+1).
    • Example 105 2-(2-(Dimethylamino)ethylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole
  • Figure US20070249600A1-20071025-C00200
  • The title compound was prepared as described in Example 104 using the product of Example 102;
  • 1H NMR (DMSO-d6) δ 10.75 (brs, 1H), 9.10 (s, 1H), 8.85 (d, 1H), 8.61 (dd, 1H), 7.49 (t, 1H), 7.34-7.44 (m, 4H), 7.08 (d, 1H), 6.88 (d, 2H), 6.55 (dd, 1H), 6.43 (brs, 1H), 3.53 (t, 2H, overlap with d6-DMSO water peak), 2.44 (t, 2H), 3.19 (s, 6H); MS m/e 517 (M+1).
    • Example 106 2-(3-(4-methyl-1-piperazino)propylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole
  • Figure US20070249600A1-20071025-C00201
  • To a stirred solution of thiophosgene (1.47 g, 12.8 mmol) in acetone (10 ml) and dichloromethane (10 ml), cooled in an ice bath under nitrogen, was added dropwise a solution of 1-(3-aminopropyl)-4-methylpiperazine (1.0 g, 6.4 mmol) in acetone (5 ml) and dichloromethane (5 ml) over 10 minutes. The reaction was stirred at room temperature for 3 h and then diluted with dichloromethane (50 ml) and washed with aqueous sodium bicarbonate solution (25 ml). The aqueous phase was further extracted by dichloromethane twice and then combined dichloromethane solutions were dried over magnesium sulfate and concentrated to give a brown oil (0.37 g, 1.86 mmol, 0.29% yield) which was used without purification. The crude oil was dissolved in acetonitrile (30 ml) and 4-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)phenylene-1,2-diamine (intermediate 6) (0.20 g, 0.47 mmol) was added. The stirred reaction was heated to reflux for 24 hours. On cooling, the reaction solution was decanted off to leave behind an insoluble dark oil residue. The acetonitrile was evaporated off to give a crude oil. Purification of the crude material was achieved by two column chromatographic separations. The first eluting with dichloromethane and incremental amounts of methanolic ammonia up to 15%, and the second eluting with AcOEt and incremental amounts of methanolic ammonia up to 15%, to afford the product as an oil (79 mg, 28% yield) which solidified on standing.
  • 1H NMR (DMSO-d6) δ 10.76 (brs, 1H), 9.09 (s, 1H), 8.83 (d, 1H), 8.61 (dd, 1H), 7.49 (t, 1H), 7.35-7.43 (m, 3H), 7.07 (d, 1H), 6.88 (d, 2H), 6.76 (d, 1H), 6.63 (brs, 1H), 6.56 (brs, 1H), 2.22-2.43 (m, 10H), 2.15 (s, 4H), 1.65-1.78 (m, 3H); MS m/e 586 (M+1).
    • Example 107 Methyl N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-1-oxo-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00202
  • The title compound was prepared following the procedure for Example 12 using the compound of Example 37.
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.42 (s, 1H), 9.06 (s, 1H), 8.68 (s, 1H), 8.53 (d, 1H), 7.53 (t, 1H), 7.45 (brs, 1H), 7.39 (d, 1H), 7.30 (d, 1H), 7.11 (d, 1H), 7.02 (s, 1H), 6.80 (d, 1H), 3.75 (s, 3H); MS m/e 521 (M+1).
    • Example 108 Methyl N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate dimethanesulfonic acid
  • Figure US20070249600A1-20071025-C00203
  • The product of Example 37 was converted into the salt form.
  • 1H NMR (DMSO-d6) δ 9.31 (brs, 1H), 9.02 (d, 1H), 8.56 (dd, 1H), 8.21 (d, 1H), 8.05 (dd, 1H), 7.62 (d, 1H), 7.51 (m, 1H), 7.41 (m, 2H), 7.42 (m, 1H), 7.33 (d, 1H), 7.17 (dd, 1H), 7.08 (d, 1H), 3.89 (s, 6H); MS m/e 505 (M+1).
    • Example 109 Methyl N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate maleate
  • Figure US20070249600A1-20071025-C00204
  • The product of Example 37 was converted into the salt form.
  • 1H NMR (DMSO-d6) δ 9.21 (s, 1H), 8.95 (d, 1H), 8.57 (dd, 1H), 8.15 (d, 1H), 8.00 (dd, 1H), 7.51 (m, 1H), 7.41 (m, 2H), 7.13 (d, 1H), 6.95 (d, 1H), 6.86 (dd, 1H), 6.24 (s, 2H), 3.77 (s, 3H); MS m/e 505 (M+1).
    • Example 110 N-(6-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00205
  • Coupling of Intermediate 12C with 2-nitro-5-bromopyridine and subsequent hydrogenation gave N-(6-(2-amino-5-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)acetamide. Following the procedure for Example 1 provides the title compound.
  • 1H NMR (DMSO-d6) δ 10.62 (brs, 1H), 9.92 (s, 1H), 8.67 (dd, 1H), 8.02 (dd, 1H), 7.41-7.62 (m, 5H), 7.22-7.34 (m, 3H), 7.16 (brs, 2H), 6.91 (dd, 1H), 5.30 (s, 2H), 2.10 (s, 3H); MS m/e 579 (M+1).
  • Examples 111 and 112 are prepared according to the procedure for Example 1 using Intermediate 15B.
    • Example 111 Methyl-N-(5-(5-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00206
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.61 (s, 1H), 8.66 (s, 1H), 8.61 (d, 1H), 8.15 (d, 1H), 8.01 (dd, 1H), 7.72 (dd, 1H), 7.38 (m, 2H), 7.11 (d, 1H), 6.94 (d, 1H), 6.83 (dd, 1H), 3.76 (s, 3H); MS m/e 521 (M+1).
    • Example 112 Methyl N-(5-(5-((2,5-dichlorophenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate dihydrochloride
  • Figure US20070249600A1-20071025-C00207
  • 1H NMR (DMSO-d6) δ 10.35 (s, 1H), 8.76 (s, 1H), 8.29 (d, 1H), 8.24 (d, 1H), 8.03 (dd, 1H), 7.63 (d, 1H), 7.50 (d, 1H), 7.35 (d, 1H), 7.16 (dd, 1H), 7.11-7.07 (m, 2H), 3.88 (s, 3H); MS m/e 487 (M+1).
    • Example 113 6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-ylamine
  • Figure US20070249600A1-20071025-C00208
  • The title compound was prepared according to the procedure for Example 1 using Intermediate 12E, followed by acidic hydrolysis.
  • 1H NMR (DMSO-d6) δ 10.69 (brs, 1H), 9.87 (brs, 1H), 8.65 (dd, 1H), 7.92 (d, 1H), 7.51 (m, 2H), 7.41 (m, 2H), 7.31 (m, 2H), 7.23 (m, 1H), 7.18 (m, 1H), 7.12 (d, 1H), 6.89 (d, 1H), 6.67 (d, 1H), 6.56 (brs, 2H), 5.23 (s, 2H); MS m/e 537 (M+1).
    • Example 114 N-(6-(6-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)methanesulfonamide
  • Figure US20070249600A1-20071025-C00209
  • To the suspension of the product of Example 113 in dry THF, BOC2O (2 eq.) was added at room temperature. The solution becomes clear. After the reaction completion, the solvent was removed then Si-column chromatograpy was performed by CHCl3-MeOH (1-3%) as eluent. 5-(6-((2-fluloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-3-benzyl-1-tert-butoxycarbonyl-2-imino benzimidazolidine was obtained as amorphous in good yield.
  • The compound (100 mg) was dissolved to pyridine, and mesylchloride was dropped slowly (5-7 drops) to it at 0° C. After overnight stirring, the mixture was quenched to the ice-water and extracted with AcOEt then solvent was removed. To the obtained crude mixture. TFA (1 ml) was added. After stirring 30 min at room temperature, TFA was removed. The obtained residue was charged to the amino-column chromatography. 5-7% MeOH—CHCl3 eluent was used to get the title compound.
  • 1H NMR (DMSO-d6) δ 11.84 (brs, 1H), 10.64 (brs, 1H), 9.92 (brs, 1H), 8.66 (dd, 1H), 8.00 (brs, 1H), 7.48 (m, 4H), 7.33 (m, 5H), 7.17 (m, 1H), 5.86 (dd, 1H), 5.18 (s, 2H), 2.98 (s, 3H); MS m/e 615 (M+1).
    • Example 115 Methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzoxazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00210
  • To a mixture of 5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl amino)phenyloxy)benz-3-oxazol-2-ylamine (Intermediate 11B—67.0 mg, 0.15 mmol) in pyridine (2 mL) was dropwise added excess amount of ClCO2Me (ca 0.23 mL) at room temperature. The mixture was added water and stirred at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer washed with NaHCO3 (aq) and brine then dried over Na2SO4. After evaporation, residual solid washed with MeOH and dried under reduced pressure to give the title compound (46.1 mg, 61%):
  • 1H NMR (DMSO-d6) δ 9.17 (brs, 1H), 8.86 (d, 1H), 8.62 (dd, 1H), 7.49 (m, 2H), 7.46 (d, 2H), 7.38 (m, 1H), 7.26 (brs, 1H), 6.99 (d, 2H), 6.92 (dd, 1H), 3.70 (s, 3H); MS m/e 505 (M+1).
  • The following compounds (Example 116-132) were prepared according to the procedures described for Example 1.
    • Example 116 Methyl N-(5-(3-((2-(trifluoromethoxy)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00211
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.39 (s, 1H), 8.42 (s, 1H), 8.19 (d, 1H), 7.41 (d, 1H), 7.36 (d, 1H), 7.31 (t, 1H), 7.26 (t, 1H), 7.09 (m, 1H), 6.83 (dd, 1H), 6.60 (dd, 1H), 3.75 (t, 3H); MS m/e 502 (M+1)
    • Example 117 Methyl N-(5-(3-((4-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00212
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.17 (s, 1H), 9.04 (s, 1H), 7.58 (q, 4H), 7.41 (d, 1H), 7.24 (t, 1H), 7.15 (s, 1H), 7.08 (m, 2H), 6.83 (dd, 1H), 6.59 (dd, 1H), 3.75 (s, 3H); MS m/e 518 (M+1)
    • Example 118 Methyl N-(5-(3-((2-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00213
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.49 (s, 1H), 8.04 (s, 1H), 7.87 (d, 1H), 7.65 (d, 1H), 7.60 (t, 1H), 7.39 (d, 1H), 7.27-7.22 (m, 2H), 7.12-7.07 (m, 3H), 6.82 (dd, 1H), 6.60 (dd, 1H), 3.74 (s, 3H); MS m/e 486 (M+1)
    • Example 119 Methyl N-(5-(3-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00214
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.29 (s, 1H), 9.08 (dd, 1H), 8.94 (d, 1H), 7.90 (m, 1H), 7.53 (t, 1H), 7.42 (d, 1H), 7.27 (t, 1H), 7.14 (d, 1H), 7.09 (m, 2H), 6.84 (dd, 1H), 6.62 (dd, 1H), 3.75 (s, 3H); MS m/e 520 (M+1)
    • Example 120 Methyl N-(5-(3-((3-iodophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00215
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 8.87 (s, 1H), 8.79 (s, 1H), 7.94 (s, 1H), 7.41 (d, 1H), 7.31 (d, 2H), 7.23 (t, 1H), 7.11-7.03 (m, 4H), 6.83 (dd, 1H), 6.57 (d, 1H), 3.75 (s, 3H); MS m/e 544 (M+1)
    • Example 121 Methyl N-(5-(3-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00216
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.57 (s, 1H), 8.38 (s, 1H), 8.26 (d, 1H), 7.48 (d, 1H), 7.41 (d, 1H), 7.27 (t, 1H), 7.14 (d, 1H), 7.08 (m, 2H), 7.04 (s, 1H), 6.84 (dd, 1H), 6.62 (d, 1H), 3.75 (s, 1H); MS m/e 486 (M+1), 488 (M+3)
    • Example 122 Methyl N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00217
  • 1H NMR (DMSO-d6) 6; 12.0-11.5 (brs, 2H), 9.00 (s, 1H), 8.94 (s, 1H), 7.41-7.38 (m, 6H), 7.27 (t, 1H), 7.25 (t, 1H), 7.20 (d, 2H), 7.16-7.08 (m, 3H), 7.03 (d, 2H), 6.60 (dd, 1H), 3.73 (s, 3H), MS m/e 526 (M+1)
    • Example 123 Methyl N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00218
  • 1H NMR (DMSO-d6) 6; 12.0-11.2 (brs, 2H), 8.76 (s, 1H), 8.60 (s, 1H), 7.42-7.35 (m, 5H), 7.27 (t, 1H), 7.25 (s, 1H), 7.17-7.10 (m, 2H), 7.03 (d, 2H), 6.98 (d, 1H), 6.90 (d, 2H), 6.78 (dd, 1H), 6.60 (dd, 1H), 3.75 (s, 3H), MS m/e 510 (M+1)
    • Example 124 Methyl N-(5-(3-((2-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00219
  • 1H NMR (DMSO-d6) δ; 12.0-11.2 (brs, 2H), 9.34 (s, 1H), 8.40 (s, 1H), 7.42-7.36 (m, 3H), 7.22 (t, 1H), 7.14 (t, 1H), 7.10-7.05 (m, 4H), 7.01 (d, 2H), 6.94 (td, 1H), 6.82 (m, 2H), 6.57 (d, 1H), 3.75 (s, 3H), MS m/e 510 (M+1)
    • Example 125 Methyl N-(5-(3-((4-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00220
  • 1H NMR (DMSO-d6) δ; 12.0-11.2 (brs, 2H), 8.90 (s, 1H), 8.78 (s, 1H), 7.43-7.40 (m, 3H), 7.36 (d, 1H), 7.34 (d, 1H), 7.22 (t, 1H), 7.16 (d, 1H), 7.08 (m, 3H), 6.97-6.93 (m, 4H), 6.83 (dd, 1H), 6.55 (dd, 1H), 3.75 (s, 3H), MS m/e 510 (M+1)
    • Example 126 Methyl N-(5-(3-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00221
  • 1H NMR (DMSO-d6) δ; 12.0-11.2 (brs, 2H), 8.68 (s, 1H), 8.43 (s, 1H), 7.40 (d, 1H), 7.32 (s, 1H), 7.21 (t, 1H), 7.11 (t, 1H), 7.08 (m, 4H), 6.82 (dd, 1H), 6.55 (d, 1H), 3.75 (s, 3H), 2.79 (m, 4H), 1.98 (m, 2H), MS m/e 458 (M+1)
    • Example 127 Methyl N-(5-(4-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00222
  • 1H NMR (DMSO-d6) δ; 12.0-11.2 (brs, 2H), 8.57 (s, 1H), 8.48 (s, 1H), 7.41 (d, 2H), 7.37 (m, 2H), 7.11 (m, 2H), 6.99 (d, 1H), 6.90 (d, 2H), 6.78 (dd, 1H), 3.75 (s, 3H), 2.80 (quint, 4H), 1.99 (m, 2H), MS m/e 458 (M+1)
    • Example 128 Methyl N-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00223
  • 1H NMR (DMSO-d6) δ 11.8-11.4 (brs, 2H), 9.46 (s, 1H), 8.76 (s, 1H), 7.42 (d, 2H), 7.38 (d, 1H), 7.01 (d, 1H), 6.92 (d, 2H), 6.79 (dd, 1H), 6.48 (s, 1H), 3.74 (s, 3H), 1.29 (s, 9H); MS m/e 465 (M+1)
    • Example 129 Methyl N-(5-(3-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00224
  • 1H NMR (DMSO-d6) δ 12.0-11.2 (brs, 2H), 9.40 (s, 1H), 8.88 (s, 1H), 7.40 (d, 1H), 7.25 (t, 1H), 7.13 (t, 1H), 7.07 (m, 2H), 6.82 (dd, 1H), 6.61 (dd, 1H), 6.46 (s, 1H), 3.75 (s, 3H), 1.27 (s, 9H); MS m/e 465 (M+1)
    • Example 130 Methyl N-(5-(4-((5-tert-butylisoxazole-3-yl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00225
  • 1H NMR (DMSO-d6) δ 12.2-11.2 (brs, 2H), 9.49 (s, 1H), 8.89 (s, 1H), 7.42 (d, 2H), 7.40 (m, 2H), 7.20 (d, 2H), 7.11 (dd, 1H), 6.49 (s, 1H), 3.75 (s, 3H), 1.28 (s, 9H); MS m/e 481 (M+1)
    • Example 131 Methyl N-(5-(3-((3-phenyl-1,2,4-thiadiazol-5-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00226
  • 1H NMR (DMF-d7) δ 12.4-11.2 (brs, 2H), 9.84 (brs, 1H), 8.22-8.20 (m, 2H), 7.50 (m, 4H), 7.38 (brs, 1H), 7.36-7.34 (m, 2H), 7.22 (brs, 1H), 6.92 (dd, 1H), 6.71 (m, 1H), 3.81 (s, 1H); MS m/e 502 (M+1)
    • Example 132 Methyl N-(5-(3-((1-naphtyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00227
  • 1H NMR (DMSO-d6) δ 12.0-11.2 (brs, 2H), 9.14 (s, 1H), 8.70 (s, 1H), 8.08 (d, 1H), 7.95 (d, 1H), 7.92 (d, 1H), 7.62 (d, 1H), 7.55 (m, 2H), 7.45 (t, 1H), 7.41 (d, 1H), 7.26 (t, 1H), 7.16-7.14 (m, 2H), 7.10 (d, 1H), 6.84 (dd, 1H), 6.59 (d, 1H), 3.75 (s, 3H); MS m/e 468 (M+1)
  • The compound of Example 22 was treated with 2-fluoro-5-trifluoromethylphenyl, 4-chrolophenyl, and N,N-dimethylaminophenyl isocyanate in THF to give compounds of Example 133, 134, and 135 respectively.
    • Example 133 1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea
  • Figure US20070249600A1-20071025-C00228
  • 1H NMR (DMSO-d6) δ; 12.0-11.3 (brs, 1H), 10.7-10.1 (brs, 1H), 8.92 (s, 1H), 8.63 (s, 1H), 8.46 (d, 1H), 8.39 (d, 1H), 7.29 (m, 4H), 7.22 (d, 2H), 7.18-7.14 (m, 3H), 6.72 (d, 2H), 6.58 (dd, 1H), MS m/e 651 (M+1)
    • Example 134 1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-3-(4-chlorophenyl)urea
  • Figure US20070249600A1-20071025-C00229
  • 1H NMR (DMSO-d6) δ; 9.77 (brs, 1H), 9.14 (s, 1H), 8.86 (brs, 1H), 8.62 (d, 1H), 7.61 (d, 2H), 7.50 (m, 1H), 7.44 (d, 2H), 7.39 (m, 2H), 7.34 (d, 2H), 6.99 (d, 1H), 6.95 (d, 2H), 6.79 (dd, 1H), MS m/e 599 (M+1), 601 (M+3)
    • Example 135 1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)-3-(4-(N,N-dimethylamino)phenyl)urea
  • Figure US20070249600A1-20071025-C00230
  • 1H NMR (DMSO-d6) δ; 9.30 (brs 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.50 (t, 1H), 7.43 (d, 2H), 7.37 (brm, 2H), 7.34 (d, 2H), 7.00 (s, 1H), 6.93 (d, 2H), 6.76 (d, 1H), 6.72 (d, 2H), 2.85 (s, 6H), MS m/e 608 (M+1)
    • Example 136 1-(6-(4-((4-Chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)-3-(butyl)urea
  • Figure US20070249600A1-20071025-C00231
  • The title compound and the next compound (Example 137) were prepared according to the procedures described for Example 1, using Intermediate 13B.
  • 1H NMR (DMSO-d6) δ; 10.57 (s, 1H), 9.15 (s, 1H), 8.84 (s, 1H), 8.11 (d, 1H), 7.65-7.63 (m, 2H), 7.58 (d, 1H), 7.46 (d, 2H), 7.02 (dd, 1H), 6.98 (d, 2H), 6.72 (brs, 1H), 3.15 (q, 2H), 1.46 (quint, 2H), 1.31 (sextet, 2H), MS m/e 578 (M+1), 580 (M+3).
    • Example 137 1-(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)benzthiazol-2-yl)-3-(butyl)urea
  • Figure US20070249600A1-20071025-C00232
  • 1H NMR (DMSO-d6) δ; 10.58 (brs, 1H), 9.17 (s, 1H), 8.87 (s, 1H), 8.62 (dd, 1H), 7.59 (d, 1H), 7.54 (d, 1H), 7.52-7.47 (m, 1H), 7.47 (d, 2H), 7.39 (m, 1H), 7.03 (dd, 1H), 6.99 (d, 2H), 6.74 (brs, 1H), 3.15 (q, 2H), 1.47 (quint, 2H), 1.31 (sextet, 2H), MS m/e 562 (M+1).
    • Example 138 N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00233
  • Intermediate 14F was treated with 23:2:75 (v/v/v) TFA/H2O/DCM (1 mL) for ca. 1 h. The solution containing the released material was collected. The resin washed with DCM (3×, 1 mL each). The washings were collected and combined with the original filtrate. Evaporation of the solvent in vacuo yielded a dark sticky solid. The cleaving was repeated two more times and the materials obtained after each time were combined. The crude material was dissolved in DMSO and purified with reverse-phase preparative Gilson HPLC system to yield the desired benzimidazole.
  • 1H NMR (DMF-d7) δ 10.79 (br s, 1H), 10.40 (br s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.49 (br s, 1H), 7.15 (br s, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.87 (dd, J=8.6, 2.5 Hz, 1H), 6.62 (s, 1H), 2.38 (s, 3H), 2.24 (s, 3H); MS m/e 407 (M+1).
  • The following compounds (Example 139-180) were prepared in a combinatorial chemistry format using the same procedure as Example 138. In most cases, the benzimidazoles thus obtained were light colored after HPLC purification.
    • Example 139 N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00234
  • 1H NMR (DMF-d7) δ 12.12 (br s, 1H), 11.61 (br s, 1H), 9.58 (br s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.50 (br s, 1H), 7.39 (d, J=3.5 Hz, 1H), 7.27-7.06 (m, 2H), 7.00 (d, J=8.8 Hz, 2H), 6.88 (dd, J=8.6, 2.5 Hz, 1H), 2.25 (s, 3H); MS m/e 409 (M+1).
    • Example 140 N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00235
  • 1H NMR (DMF-d7) δ 12.12 (br s, 1H), 11.56 (br s, 1H), 9.80 (br s, 1H), 9.09 (s, 1H) 7.66 (m, 2H), 7.50 (br s, 1H), 7.19 (br s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.88 (dd, J=8.6, 2.3 Hz, 1H), 2.25 (s, 3H); MS m/e 410 (M+1).
    • Example 141 N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00236
  • 1H NMR (DMF-d7) δ 9.61 (s, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.50 (br s, 1H), 7.16 (br s, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.88 (dd, J=8.6, 2.5 Hz, 1H), 6.65 (s, 1H), 2.24 (m, 6H); MS m/e 423 (M+1).
    • Example 142 N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00237
  • 1H NMR (DMF-d7) δ 9.56 (s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.51 (br s, 1H), 7.16 (br s, 1H), 7.04 (s, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.88 (dd, J=8.5, 2.4 Hz, 1H), 2.35 (s, 3H), 2.25 (s, 3H); MS m/e 423 (M+1).
    • Example 143 N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00238
  • 1H NMR (DMF-d7) δ 12.12 (br s, 1H), 11.59 (br s, 1H), 9.70 (br s, 1H), 7.65 (m, 2H), 7.50 (br s, 1H), 7.21 (br s, 1H), 7.00 (d, J=8.8 Hz, 2H), 6.88 (dd, J=8.6, 2.3 Hz, 1H), 2.62 (s, 3H), 2.25 (s, 3H); MS m/e 424 (M+1).
    • Example 144 N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00239
  • 1H NMR (DMF-d7) δ 12.15 (br s, 1H), 11.59 (br s, 1H), 9.29 (s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.53 (br s, 1H), 7.19 (br s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 3.00 (q, J=7.6 Hz, 2H), 2.25 (s, 3H), 1.34 (t, J=7.6 Hz, 3H); MS m/e 438 (M+1).
    • Example 145 N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00240
  • 1H NMR (DMF-d7) δ 11.63 (br s, 1H), 9.28 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.53 (br d, J=8.4 Hz, 1H), 7.18 (br s, 1H), 7.01 (d, J=9.0 Hz, 2H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 2.38 (m, 1H), 2.25 (s, 3H), 1.16 (m, 2H), 0.99 (m, 2H); MS m/e 450 (M+1).
    • Example 146 N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00241
  • 1H NMR (DMF-d7) δ 12.13 (br s, 1H), 9.50 (br s, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.46 (m, 1H), 7.21-7.13 (m, 1H), 7.01 (d, J=8.9 Hz, 2H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 6.68 (s, 1H), 2.25 (s, 3H), 1.27 (s, 9H); MS m/e 465 (M+1).
    • Example 147 N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00242
  • 1H NMR (DMF-d7) δ 12.09 (br s, 1H), 11.57 (br s, 1H), 9.42 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.51 (br s, 1H), 7.17 (br s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.88 (dd, J=8.6, 2.3 Hz, 1H), 2.25 (s, 3H), 1.42 (s, 9H); MS m/e 466 (M+1).
    • Example 148 N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00243
  • 1H NMR (DMF-d7) δ 12.10 (br s, 1H), 11.58 (br s, 1H), 9.60 (br s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.50 (br s, 1H), 7.16 (br s, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.87 (dd, J=8.6, 2.3 Hz, 1H), 2.24 (m, 6H), 2.13 (s, 3H); MS m/e 437 (M+1).
    • Example 149 N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00244
  • 1H NMR (DMF-d7) δ 12.14 (br s, 1H), 11.60 (br s, 1H), 9.67 (s, 1H), 7.73 (d, J=9.1 Hz, 2H), 7.51 (br s, 1H), 7.38 (br s, 1H), 7.31-7.07 (m, 1H), 7.02 (d, J=9.1 Hz, 2H), 6.89 (dd, J=8.6, 2.3 Hz, 1H), 3.69 (m, 4H), 3.33 (m, 4H), 2.25 (s, 3H); MS m/e 478 (M+1).
    • Example 150 N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00245
  • 1H NMR (DMF-d7) δ 9.85 (s, 1H), 9.43 (s, 1H), 7.59 (d, J=8.9 Hz, 2H), 7.52 (br s, 1H), 7.17 (br s, 1H), 6.99 (d, J=9.1 Hz, 2H), 6.90 (dd, J=8.6, 2.3 Hz, 1H), 6.61 (s, 1H), 4.33 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.40 (s, 3H); MS m/e 481 (M+1).
    • Example 151 N-(5-(4-((Thiazol-2-yl)aminocarbonylamindo)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00246
  • 1H NMR (DMF-d7) δ 12.10 (br s, 1H), 11.04 (br s, 1H), 9.54 (s, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.53 (br s, 1H), 7.39 (d, J=3.5 Hz, 1H), 7.19 (br s, 1H), 7.13 (d, J=3.5 Hz), 7.02 (d, J=9.0 Hz, 2H), 6.91 (dd, J=8.6, 2.5 Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H); MS m/e 483 (M+1).
    • Example 152 N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00247
  • 1H NMR (DMF-d7) δ 12.23 (br s, 1H), 11.19 (br s, 1H), 9.45 (br s, 1H), 9.12 (s, 1H), 7.62 (d, J=9.1 Hz, 2H), 7.54 (br d, J=8.4 Hz, 1H), 7.19 (br s, 1H), 7.03 (d, J=9.1 Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 4.32 (s, 2H), 3.82 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H); MS m/e 484 (M+1).
    • Example 153 N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00248
  • 1H NMR (DMF-d7) δ 12.20 (br s, 1H), 10.95 (br s, 1H), 9.38 (s, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.53 (br d, J=8.2 Hz 1H), 7.18 (br s, 1H), 7.01 (d, J=9.0 Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 6.67 (s, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.24 (s, 3H); MS m/e 497 (M+1).
    • Example 154 N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00249
  • 1H NMR (DMF-d7) δ 9.35 (s, 1H), 7.59 (d, J=9.1, 2H), 7.53 (br d, J=8.4, 1H), 7.18 (br s, 1H), 7.04 (app d 1H), 7.01 (d, J=9.1, 2H), 6.90 (dd, J=8.4, 2.3, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.35 (app d, 3H); MS m/e 497 (M+1).
    • Example 155 N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00250
  • 1H NMR (DMF-d7) δ 12.23 (br s, 1H), 11.07 (br s, 1H), 9.32 (s, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.20 (br s, 1H), 7.02 (d, J=9.0 Hz, 2H), 6.92 (dd, J=8.5, 2.5 Hz, 1H), 4.32 (s, 2H), 3.82 (m, 2H), 3.65 (m, 2H), 3.41 (s, 3H), 2.63 (s, 3H); MS m/e 498 (M+1).
    • Example 156 N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00251
  • 1H NMR (DMF-d7) δ 12.14 (br s, 1H), 11.16 (br s, 1H), 9.38 (s, 1H), 7.62 (d, J=9.0 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.19 (br s, 1H), 7.02 (d, J=9.0 Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 4.32 (s, 2H), 3.82 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 3.00 (q, J=7.6 Hz, 2H), 1.34 (t, J=7.6 Hz, 3H); MS m/e 512 (M+1).
    • Example 157 N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00252
  • 1H NMR (DMF-d7) δ 12.13 (br s, 1H), 11.24 (br s, 1H), 9.44 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.6, 1H), 7.19 (br s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.91 (dd, J=8.6, 2.5 Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.38 (m, 1H), 1.15 (m, 2H), 1.00 (m, 2H); MS m/e 524 (M+1).
    • Example 158 N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00253
  • 1H NMR (DMF-d7) δ 9.54 (s, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.55 (br d, J=8.4 Hz, 1H), 7.20 (br s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.92 (dd, J=8.4, 2.5 Hz, 1H), 6.69 (s, 1H), 4.33 (s, 2H), 3.82 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 1.28 (s, 9H); MS m/e 539 (M+1).
    • Example 159 N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00254
  • 1H NMR (DMF-d7) δ 12.20 (br s, 1H), 11.24 (br s, 1H), 9.59 (br s, 1H), 7.65 (d, J=8.9 Hz, 2H), 7.54 (br d, J=8.4 Hz, 1H), 7.19 (br s, 1H), 7.02 (d, J=8.9 Hz, 2H), 6.91 (dd, J=8.4, 2.3 Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 1.43 (s, 9H); MS m/e 540 (M+1).
    • Example 160 N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00255
  • 1H NMR (DMF-d7) δ 9.76 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.6, 1H), 7.19 (br s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 3.25 (q, J=7.2 Hz, 2H) 1.39 (t, J=7.3 Hz, 3H); MS m/e 544 (M+1).
    • Example 161 N-(5-(4-((5-Propylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00256
  • 1H NMR (DMF-d7) δ 12.19 (br s, 1H), 7.77 (m, 2H), 7.52 (br s, 1H), 7.19 (br s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.91 (dd, J=8.6, 2.3 Hz, 1H), 4.31 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 3.20 (t, J=7.1 Hz, 2H), 1.77 (m, 2H), 1.02 (t, J=7.3 Hz, 3H); MS m/e 558 (M+1).
    • Example 162 N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00257
  • 1H NMR (DMF-d7) δ 9.57 (s, 1H), 7.60 (d, J=9.1 Hz, 2H), 7.53 (br d, J=8.3, 1H), 7.18 (br s, 1H), 7.00 (d, J=9.1 Hz, 2H), 6.90 (dd, J=8.3, 2.3 Hz, 1H), 4.32 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H); MS m/e 511 (M+1).
    • Example 163 N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00258
  • 1H NMR (DMF-d7) δ 11.22 (br s, 1H), 9.68 (s, 1H), 7.75 (d, J=9.0 Hz, 2H), 7.55 (d, J=8.7 Hz, 1H), 7.38 (br s, 1H), 7.22 (br s, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.93 (dd, J=8.7, 2.5 Hz, 1H), 4.33 (s, 2H), 3.82 (m, 2H), 3.70 (m, 4H), 3.61 (m, 2H), 3.41 (s, 3H), 3.34 (m, 4H); MS m/e 552 (M+1).
    • Example 164 N-(5-(4-((5-Methylisoxazol-3-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00259
  • 1H NMR (DMF-d7) δ 9.80 (s, 1H), 9.38 (s, 1H), 8.00 (s, 1H), 7.59 (m, 3H), 7.54 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.92 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 6.62 (s, 1H), 2.41 (s, 3H); MS m/e 459 (M+1).
    • Example 165 N-(5-(4-((Thiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00260
  • 1H NMR (DMF-d7) δ 9.56 (br s, 1H), 8.00 (s, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.58 (m, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.39 (d, J=3.5 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.13 (d, J=35 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.93 (dd, J=8.5, 2.2 Hz, 1H), 6.75 (m, 1H); MS m/e 461 (M+1).
    • Example 166 N-(5-(4-((1,3,4-Thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00261
  • 1H NMR (DMF-d7) δ 11.95 (br s, 1H), 9.56 (br s, 1H), 9.12 (s, 1H), 8.00 (s, 1H), 7.65 (d, J=8.9 Hz, 2H), 7.59 (m, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 6.75 (m, 1H); MS m/e 462 (M+1).
    • Example 167 N-(5-(4-((4-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00262
  • 1H NMR (DMF-d7) δ 9.41 (s, 1H), 8.00 (s, 1H), 7.61 (d, =9.0 Hz, 2H), 7.58 (m, 1H), 7.54 (d, =8.7 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.92 (dd, =8.7, 2.4 Hz, 1H), 6.75 (m, 1H), 6.67 (s, 1H), 2.24 (s, 3H); MS m/e 475 (M+1).
    • Example 168 N-(5-(4-((5-Methylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00263
  • 1H NMR (DMF-d7) δ 9.48 (s, 1H), 8.00 (s, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.58 (d, J=3.8 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.03 (m, 3H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 2.35 (s, 3H); MS m/e 475 (M+1).
    • Example 169 N-(5-(4-((5-Methyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00264
  • 1H NMR (DMF-d7) δ 11.99 (br s, 1H), 9.45 (br s, 1H), 8.00 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.59 (br d, J=3.3 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 2.62 (s, 3H); MS m/e 476 (M+1).
    • Example 170 N-(5-(4-((5-Ethyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00265
  • 1H NMR (DMF-d7) δ 11.93 (br s, 1H), 9.37 (br s, 1H), 8.00 (s, 1H), 7.63 (d, J=9.1 Hz, 2H), 7.59 (br d, J=3.3 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 3.00 (q, J=7.5 Hz, 2H), 1.33 (t, J=7.5 Hz, 3H); MS m/e 490 (M+1).
    • Example 171 N-(5-(4-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00266
  • 1H NMR (DMF-d7) δ 11.92 (br s, 1H), 9.42 (br s, 1H), 8.00 (s, 1H), 7.62 (d, J=9.1 Hz, 2H), 7.59 (br d, J=3.3 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 2.38 (m, 1H), 1.15 (m, 2H), 0.99 (m, 2H); MS m/e 502 (M+1).
    • Example 172 N-(5-(4-((4-tert-Butylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00267
  • 1H NMR (DMF-d7) δ 10.60 (br s, 1H), 9.41 (br s, 1H), 8.00 (s, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.58 (br d, J=3.5 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 6.69 (s, 1H), 1.27 (s, 9H); MS m/e 517 (M+1).
    • Example 173 N-(5-(4-((5-tert-Butyl-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00268
  • 1H NMR (DMF-d7) δ 11.96 (br s, 1H), 9.39 (br s, 1H), 8.00 (s, 1H), 7.64 (d, J=9.1 Hz, 2H), 7.59 (m, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.93 (dd, J=8.5, 2.3 Hz, 1H), 6.75 (m, 1H), 1.43 (s, 9H); MS m/e 518 (M+1).
    • Example 174 N-(5-(4-((5-Ethylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00269
  • 1H NMR (DMF-d7) δ 12.20 (br s, 1H), 8.00 (s, 1H), 7.75 (m, 2H), 7.58 (br s, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 3.25 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H); MS m/e 522 (M+1).
    • Example 175 N-(5-(4-((4,5-Dimethylthiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00270
  • 1H NMR (DMF-d7) δ 9.37 (br s, 1H), 8.00 (s, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.58 (m, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 6.75 (m, 1H), 2.24 (s, 3H), 2.14 (s, 3H); MS m/e 489 (M+1).
    • Example 176 N-(5-(4-((5-Morpholino-1,3,4-triazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00271
  • 1H NMR (DMF-d7) δ 9.69 (s, 1H), 8.00 (s, 1H), 7.76 (d, J=8.9 Hz, 2H), 7.60 (br d, J=3.3 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.38 (br s, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 6.94 (dd, J=8.6, 2.4 Hz, 1H), 6.75 (m, 1H), 3.70 (m, 4H), 3.33 (m, 4H); MS m/e 530 (M+1).
    • Example 177 N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)acetamide
  • Figure US20070249600A1-20071025-C00272
  • 1H NMR (DMF-d7) δ 12.11 (br s, 1H), 11.57 (br s, 1H), 10.58 (br s, 1H), 7.74 (m, 2H), 7.52 (br s, 1H), 7.30-7.07 (m, 1H), 7.00 (d, J=9.1 Hz, 2H), 6.88 (dd, J=8.6, 2.5 Hz, 1H), 2.95-2.72 (m, 3H), 2.24 (s, 3H); MS m/e 456 (M+1).
    • Example 178 N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl) (2-(methoxy)ethoxy)acetamide
  • Figure US20070249600A1-20071025-C00273
  • 1H NMR (DMF-d7) δ 12.20 (br s, 1H), 7.77 (m, 2H), 7.52 (br s, 1H), 7.18 (br s, 1H), 7.01 (d, J=9.1 Hz, 2H), 6.91 (dd, J=8.6, 2.5 Hz, 1H), 4.31 (s, 2H), 3.81 (m, 2H), 3.61 (m, 2H), 3.41 (s, 3H), 2.95-2.72 (m, 3H); MS m/e 530 (M+1).
    • Example 179 N-(5-(4-((5-Methylthio-1,3,4-thiadiazol-2-yl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00274
  • 1H NMR (DMF-d7) δ 12.12 (br s, 1H), 9.91 (br s, 1H), 8.00 (s, 1H), 7.69 (m, 2H), 7.58 (m, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.93 (dd, J=8.6, 2.3 Hz, 1H), 6.75 (m, 1H), 2.95-2.72 (m, 3H); MS m/e 508 (M+1).
    • Example 180 N-(5-(4-((5-Carbamoyl-2-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide
  • Figure US20070249600A1-20071025-C00275
  • This compound was prepared according to procedure for Example 1381 by way of Intermediate 14F, although left-hand ring is not heteroarylic.
  • 1H NMR (DMF-d7) δ 12.26 (br s, 1H), 9.23 (s, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.00 (s, 1H), 7.61-7.58 (m, 4H), 7.53 (d, J=8.6 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.23 (br s, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.92 (dd, J=8.6, 2.3 Hz, 1H), 6.74 (m, 1H), 2.34 (s, 3H); MS m/e 511 (M+1).
  • Examples 181-182 were prepared according to the procedures described for Example 1 using intermediate 3A.
    • Example 181 Methyl N-(5-(3-((2,3-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00276
  • 1H NMR (DMSO-d6) δ 12.0-11.2 (brs, 2H), 9.53 (s, 1H), 8.40 (s, 1H), 8.10 (dd, 1H), 7.41 (d, 1H), 7.30-7.24 (m, 3H), 7.13-7.07 (m, 3H), 6.83 (dd, 1H), 6.62 (dd, 1H), 3.75 (s, 3H); MS m/e 486 (M+1), 488 (M+3).
    • Example 182 Methyl N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00277
  • 1H NMR (DMSO-d6) δ 12.0-11.2 (brs, 2H), 8.98 (s, 1H), 7.86 (s, 1H), 7.48 (d, 1H), 7.40 (d, 1H), 7.22 (t, 1H), 7.10 (d, 1H), 7.07 (m, 2H), 7.00 (t, 1H), 6.88 (d, 1H), 6.82 (dd, 1H), 3.75 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H); MS m/e 446 (M+1)
    • Example 183 1-(5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2,3-dimethylphenyl)urea
  • Figure US20070249600A1-20071025-C00278
  • The compound of Example 22 was treated with 2,3-dimethylphenylisocyanate in THF to give the title compound.
  • 1H NMR (DMSO-d6) δ; 11.5 (brs, 1H), 10.4 (brs, 1H), 9.6 (brs, 1H), 9.13 (s, 1H), 8.85 (s, 1H), 8.62 (d, 1H), 7.68 (d, 1H), 7.50 (t, 1H), 7.44 (d, 2H), 7.38 (m, 2H), 7.08 (t, 1H), 7.02 (brs, 1H), 6.94 (d, 2H), 6.94 (d, 1H), 6.79 (dd, 1H), 2.28 (s, 3H), 2.22 (s, 3H), MS m/e 593 (M+1)
  • The following compounds (Example 184-186) are synthesized according to the similar procedure for Example 1 using corresponding isothiocyanate in lieu of isocyanate.
    • Example 184 Methyl N-(5-(4-((3-chlorophenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00279
  • 1H NMR (DMSO-d6) δ; 12.0-11.2 (brs, 2H), 9.89 (s, 1H), 9.85 (s, 1H), 7.70 (t, 1H), 7.42-7.32 (m, 5H), 7.16 (d, 1H), 7.06 (d, 1H), 6.92 (d, 2H), 6.81 (dd, 1H), 3.75 (s, 3H); MS m/e 468 (M+1), 470 (M+3).
    • Example 185 Methyl N-(5-(4-((3-methoxyphenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00280
  • 1H NMR (DMSO-d6) δ; 12.0-11.2 (brs, 2H), 9.73 (s, 1H), 9.71 (s, 1H), 7.40 (m, 1H), 7.39 (d, 2H), 7.22 (t, 1H), 7.18 (s, 1H), 7.05 (s, 1H), 7.01 (d, 1H), 6.91 (d, 2H), 6.80 (dd, 1H), 6.70 (dd, 1H), 3.75 (s, 3H), 3.74 (s, 3H); MS m/e 464 (M+1).
    • Example 186 Methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminothiocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate
  • Figure US20070249600A1-20071025-C00281
  • 1H NMR (DMSO-d6) δ; 12.0-11.2 (brs, 2H), 9.95 (s, 1H), 9.92 (s, 1H), 7.95 (s, 1H), 7.75 (d, 1H), 7.55 (t, 1H), 7.44 (d, 1H), 7.39 (m, 1H), 7.38 (d, 2H), 7.06 (s, 1H), 6.93 (d, 2H), 6.81 (dd, 1H), 3.75 (s, 3H); MS m/e 502 (M+1).
    • Biological Data
  • TIE-2 Enzyme Assay (TIE2-E)
  • The TIE-2 enzyme assay used the LANCE method (Wallac) and GST-TIE2, baculovirus expressed recombinant constructs of the intracellular domains of human TIE2 (amino acids 762-1104, GenBank Accession # L06139) tagged by GST). The method measured the ability of the purified enzymes to catalyse the transfer of the γ-phosphate from ATP onto tyrosine residues in a biotinylated synthetic peptide, D1-15 (biotin-C6-LEARLVAYEGWVAGKKKamide). This peptide phosphorylation was detected using the following procedure: for enzyme preactivation, GST-TIE2 was incubated for 30 mins at room temperature with 2 mM ATP, 5 mM MgCl2 and 12.5 mM DTT in 22.5 mM HEPES buffer (pH7.4). Preactivated GST-TIE2 was incubated for 30 mins at room temperature in 96 well plates with 1 μM D1-15 peptide, 80 uM ATP, 10 mM MgCl2, 0.1 mg/ml BSA and the test compound (diluted from a 10 mM stock in DMSO, final DMSO concentration was 2.4%) in 1 mM HEPES (pH7.4). The reaction was stopped by the addition of EDTA (final concentration 45 mM). Streptavidin linked-APC (allophycocyanin, Molecular Probe) and Europium-labeled anti-phosphorylated tyrosine antibody (Wallac) were then added at the final concentration of 17 μg/well and 2.1 μg/well, respectively. The APC signal was measured using an ARVO multilabel counter. (Wallac Berthold Japan). The percent inhibition of activity was calculated relative to blank control wells. The concentration of test compound that inhibits 50% of activity (IC50) was interpolated using nonlinear regression (Levernberg-Marquardt) and the equation, y=Vmax (1−x/(K+x))+Y2, where “K” was equal to the IC50. The IC50 values were converted to pIC50 values, i.e., −log IC50 in Molar concentration. The results are represented in Table 1 below.
  • TIE-2 Autophosphorylation Assay (TIE2-C)
  • The TIE-2 autophosphorylation assay used an ELISA method and a TIE2 intracellular domain/c-fms extracellular domain (TIE2/c-fms) chimeric protein expressing mouse 3T3 cells. This assay measured the autophosphorylation level of TIE2 protein expressed in cells. The cells were cultured in high glucose DMEM (Sigma) containing 10% serum at 37° C. in a humidified 10% CO2, 90% air incubator. The test compound (diluted from a 10 mM stock in DMSO, final DMSO concentration was 0.1%) was incubated with TIE2/c-fms expressing cells for 1 hr in serum free DMEM in 96 well plates followed by the activation of TIE2/c-fms receptor using c-fms ligand, MCSF (macrophage colony stimulating factor). The culture media was removed by aspiration and the cells incubated for at least 30 mins on ice with lysis buffer containing 137 mM NaCl, 2 mM EDTA, 10% glycerol, 0.09 ml sodium ortho vanadate and complete protease inhibitor cocktail (Roche) in 20 mM Tris-HCl (pH8.0). The cell extracts were transferred into Rat anti-c-fms antibody coated 96 well plates and incubated for 12 hrs at 4° C. The extracts were removed by aspiration and the plate was incubated with biotinylated anti-phosphotyrosine antibody, PT66 (Sigma) and then with HRP (Horseradish Peroxidase)-labeled streptavidin (PIERCE). The optical density at 450 nm derived from HRP catalyzed TMB was measured with an ARVO multilabel counter. (Wallac Berthold Japan). The percent inhibition of activity was calculated relative to blank control wells. The concentration of test compound that inhibits 50% of activity (IC50) was interpolated using nonlinear regression (Levernberg-Marquardt) and the equation, y=Vmax (1−x/(K+x))+Y2, where “K” was equal to the IC50. The IC50 values were converted to pIC50 values, i.e., −log IC50 in Molar concentration. The results are represented in Table 1 below.
  • Tie2 Fluorescence Polarization Kinase Activity Assay: (TIE2-FP)
  • Activation of Recombinant Tie2 Activation:
  • Recombinant GST-Tie2 was activated by incubating the enzyme in 20 mM Tris-HCl, pH 7.5, 12 mM MgCl2, 100 mM NaCl, 20 μM sodium vanidate, 1 mM DTT and 300 μM ATP at room temperature for 2 hours. The activation mixture was then passed through a NAP-25 desalting column (Pharmacia Biotech cat. no. 17-0852-02) to remove the free ATP. The activated enzyme was stored as aliquots at −80° C. in 20 mM Tris-HCl, pH 7.5 and 100 mM NaCl.
  • Assay Conditions:
  • The final assay conditions were 50 mM HEPES, pH 7.5, 5% DMSO (when screening compounds), 200 μM ATP, 5 mM MgCl2, 1 mM DTT, 50 μM sodium vanidate, 1 nM activated enzyme, and 200 μM peptide. IC50's of compounds were measured under subsaturating ATP (200 μM) and varing concentrations of activated Tie2 and peptide substrate (RFWKYEFWR-OH; MW 1873 Da, TFA salt). Panvera Anti-phosphotyrosine antibody (Cat#P2840) and PTK Green Tracer (Cat#P2842) were used to detect the phosphorylated peptide. Polarization was measured on a TECAN Polarion in 138-second cycles for 30 minutes at room temperature. IC50's were then determined from the % polarization using normal calculation methods. Results are indicated below.
  • VEGF-R2 Enzyme Assay (VEGF-E)
  • The VEGF enzyme assay used the LANCE method (Wallac) and GST-VEGFR2, baculovirus expressed recombinant constructs of the intracellular domains of human TIE2 tagged by GST. The method measured the ability of the purified enzymes to catalyse the transfer of the γ-phosphate from ATP onto tyrosine residues in a biotinylated synthetic peptide, (biotin-aminohexyl-EEEEYFELVAKKKK-NH2). This peptide phosphorylation was detected using the following procedure: GST-VEGFR2 was incubated for 40-60 mins at room temperature with 75 μM ATP, 5 mM MgCl2, 0.1 mM DTT, 0.1 mg/mL BSA and the test compound (diluted from a 10 mM stock in DMSO for desired concentration) in 100 mM HEPES buffer. The reaction was stopped by the addition of EDTA (final concentration 50 mM). Streptavidin linked-APC (allophycocyanin, Molecular Probe) and Europium-labeled anti-phosphorylated tyrosine antibody (Wallac) were then added at the final concentration of 15 nM and 1 nM, respectively. The APC signal was measured using an ARVO multilabel counter (Wallac Berthold, Japan). The percent inhibition of activity was calculated relative to blank control wells. The concentration of test compound that inhibits 50% of activity (IC50) was interpolated using nonlinear regression (Levernberg-Marquardt) and the equation, y=Vmax(1−x/(K+ x))+Y2, where “K” was equal to the IC50. The IC50 values were converted to pIC50 values, i.e., −log IC50 in Molar concentration. The results are represented in Table 1 below.
  • VEGF-Driven Cellular Proliferation Assay: BrdU Incorporation Assay (VEGF-C)
  • Human umbilical cord endothelial cells (HUVEC, Clonetics, CC2519) were passaged in Type I collagen-coated 100-mm petridishes in EGM-MV medium (Clonetics, CC3125) at 37° C. in a humidified 5% CO2, 95% air incubator. (HUVEC passaged more than 6 times in vitro were discarded and not subjected to assaying.) The cells were harvested using trypsin/EDTA, counted using a haemocytometer and plated at 5000 cells/well in a Type I-collagen coated 96-well plate (Becton Dickinson, 354407) in M199 medium (Gibco BRL, 12340-030) containing 5% FBS (Hyclone, A 1115-L) and gentamicin (at 50 μg/ml, Gibco BRL). After incubation overnight at 37° C., the media were replaced with 100 ul of M199 serum-free medium containing compounds at various concentrations with 0.6% DMSO and gentamicin. The compounds were diluted in serum-free M199 medium from 10 mM stock solutions prepared in 100% DMSO. After a 30 min incubation at 37° C., the cells were fed with 100 μl of serum-free M199 medium containing gentamicin, 0.2% culture-grade bovine serum albumin (BSA, Sigma A1993) and 20 ng/ml of VEGF (R&D systems, 293-VE) or 0.6 ng/ml of basic FGF (R&D systems, 233-FB), and cultured at 37° C. for another 24 h. The cells were pulsed with bromodeoxyuridine (BrdU at 10 μM in serum-free M199) at 37° C. for an additional 24 h. The incorporation of BrdU into the proliferating HUVEC were analyzed using BrdU Cell Proliferation ELISA (Roche Molecular Biochemicals, 1647229) according to the manufacturer's protocols. The optical density at 450 nm was measured with a multilabel counter (ARVO SX, Wallac). The percent inhibition of cell growth was calculated relative to blank control wells. The concentration of test compound that inhibits 50% of cell growth (IC50) was interpolated using nonlinear regression (Levernberg-Marquardt) and the equation, y=Vmax (1−x/(K+x))+Y2, where “K” was equal to the IC50. The IC50 values were converted to pIC50 values, i.e., −log IC50 in Molar concentration. The results are represented in Table 1 below.
  • Test compounds are employed in free or salt form.
    TABLE I
    Ex. No TIE2-E TIE2-C VEGF-E VEGF-C
     1 +++ ++ +++ −
     2 +++ +++ +++ +
     3 ++ +++ −
     4 +++ + ++ −
     5 ++ +++ + −
     6 +++ + −
     7 +++ − −
     8 +++ +++ −
     9 +++ +++ +++ −
     10 +++ +++ +++ +++
     11 +++ ++ +++ −
     12 ++ +++ + −
     13 +++ ++ ++ −
     14 ++ ++ +++ ++
     15 +++ +++ +++ ++
     16 +++ +++ +++
     17 +++ +++ +++ +++
     18 +++ +++ +++ +++
     19 +++ +++ +++ −
     20 +++ ++ +++
     21 +++ +++ −
     22 +++ + +++ +
     23 +++ +++ ++
     24 +++ ++ +++ −
     25 +++ +++ +++ +++
     26 +++ ++ +++ ++
     27 +++ +++ +++ ++
     28 +++ +++ +++ ++
     29 +++ +++ +++ ++
     30 +++ +++ +++ ++
     31 +++ +++ +++ +++
     32 +++ ++ +
     33 +++ +++ +++ +++
     34 +++ +++ +++ −
     35 +++ ++ +++ +
     36 +++ +++ −
     37 +++ +++ +++ −
     38 +++ +++ +++ −
     39 ++ ++ ++
     40 +++ +++ +++ −
     41 +++ +++ +++ −
     42 +++ +++ +++ ++
     43 +++ +++ +++ +
     44 +++ ++ +++ −
     45 +++ +++ +++ −
     46 +++ +++ +++ −
     47 +++ +++ +++ −
     48 +++ +++ +++ −
     49 ++ ++ +++ −
     50 +++ +++ +++ ++
     51 +++ +++ +++ −
     52 +++ ++ +++
     55 +++ +++ +++ −
     56 ++ +++ +++ −
     57 +++ ++
     58 +++
     59 +++
     60 +++
     61 +++
     62 + +++
     63 − +++
     64 +++ +++ +++ +++
     65 +++ +++ +++ −
     68 +++ +++ +++ +++
     69 +++ +++ +++ ++
     70 +++ ++ +++ +
     71 +++ ++ +++ +
     72 +++ +++ +++ +
     73 ++ ++ +++
     74 +++ +++ +++ −
     75 ++ +++ +++ −
     76 +++ +++ −
     77 +++ +++ +++ ++
     78 +++
     79 ++ ++
     80 +++ +++ +++ +++
     81 +++ +++ +++ −
     87 +++ +++ +++ ++
     88 +++ +++ +++ +++
     89 +++ +++ +++ ++
     90 +++ + +++
     91 +++ +++ +++ −
     92 +++ +++ +++ +++
     93 +++ +++ +++ +
     94 +++ +++ +++ +
     95 +++ ++ +++
     96 +++ +++ +++ ++
     97 +++ +++ +++ +++
     98 +++ +++ +++ ++
     99 +++ ++ +++
    100 +++ +++ +++
    101 +++ +++ +++ +++
    102 +++ +++ +++ +++
    103 +++ +++ +++ +
    104 ++ ++ +++
    105 ++ + +++
    106 ++ ++ +++
    107 +++ ++ ++
    110 +++ ++ ++
    111 +++ +++ +++ −
    112 ++ ++ ++
    113 +++
    115 +++ +++ +++ +++
    116 +++
    117 +++
    118 ++
    119 +++
    120 +++
    121 ++
    123 ++
    124 +++
    125 +++
    127 +++
    128 +++
    129 +++
    130 +++
    133 +++
    134 +++
    136 +++
    137 +++
    146* ++ +++
    151* + ++
    152* + +
    153* + ++
    155* + ++
    156* ++ +++
    158* ++ +++
    159* +++ +++
    163 +
    184 + + +++
    185 ++ +
    186 + ++ +++

    + = pIC50 of 5.0-6.0;

    ++ = pIC50 of 6.0-7.0;

    +++ = pIC50 of >7.0;

    − = a negative or inconclusive result;

    blank = not tested

    *Tie-2 activities run utilizing Tie2-FP assay described above.

Claims (57)

1. A compound of Formula (I):
Figure US20070249600A1-20071025-C00282
or a salt or solvate thereof:
wherein:
E is aryl substituted by R1 and R2, or R1 and R2 together with the atoms of E to which they are attached form a cycloalkyl, aryl, or heterocyclic ring fused to E;
A is aryl, heteroaryl, or heterocyclic;
X is S, O, S(O)2, S(O), C(H)2, C(H)(OH), or C(O);
Z is O or S;
p is 0 or 1;
q is 0 or 1;
the dotted line bonds “---” attached to Q and N′ represent a single bond or a double bond wherein when q is 0 the dotted line bond “---” attached to Q is a single bond and the dotted line bond attached to N′ is a double bond, and when q is 1 the dotted line bond “---” attached to Q is a double bond and the dotted line bond attached to N′ is a single bond; and
the dotted line within the 6 membered ring containing D, M, and T represents appropriate aromatic bonds;
D is CH, T is CR8, M is C and Q is N(R7)p, wherein p is 0 and q is 1; or
D is CH, T is CR8, M is C and Q is N(R7)p, wherein p is 1 and q is 0; or
R1 is C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, aralkyl, aralkoxy, aryloxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl;
R2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, heterocyclic, aralkyl, aralkoxy, aryloxy, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylsulfanyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, oxo, hydroxy, —NO2, —NR4R5, —C(O)OR6, —CN, —C(O)NR4R5, —S(O)2NR4R5, or cyanoalkyl;
R3 is hydrogen, C1-C6 alkyl, aryl, aralkyl, aralkoxy, heteroaryl, heterocyclic, —RR6, —RNR4R5, —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)RR6, —C(O)RR′R6, —C(O)ROR′OR″O R6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —C(O)ORNR4R5, —S(O)2R6, or —S(O)2NR4R5; or
R3 is C1-C6 alkylene or C1-C6 alkylene substituted with oxo, and is linked together with the nitrogen to which it is attached and to one of the benzimidazole nitrogens to form a heterocylic compound fused to the benzimidazole;
R, R′, and R″, are each independently selected from C1-C6 alkylene, arylene, heteroarylene, C3-C7 cycloalkylene, or heterocyclylene;
R′″ is C1-C6 alkyl, aryl, heteroaryl, aralkyl, C3-C7 cycloalkyl, or heterocyclic;
R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkylsulfanyl, C1-C6alkylsulfenyl, C1-C6alkylsulfonyl, aryl, heteroaryl, aralkyl, heterocyclic, C3-C7 cycloalkyl, —C(O)OR6, —C(O)NR′″R′″, —C(O)NR′″H, —C(O)NH2, or
—S(O)2NR′″R′″;
R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, aralkyl, heterocyclic, or C3-C7 cycloalkyl;
R7 is hydrogen, C1-C6 alkyl, —S(O)2R6, —RNR4R5—RR6, or aralkyl; and
R8 is hydrogen or halogen; and
when R1 is Cl, R2 is hydrogen or Cl, R3 is —C(O)OCH3, E and A are phenyl, D is CH, T is CH, M is C, Q is N(R7)p, where R7 is H, wherein either p or q is 0 and the other is 1, and Z is O, then X is O, S(O), S(O)2, CH2, CH(OH), or C(O).
2. A compound as claimed in claim 1, wherein the compound is a compound of formula (III):
Figure US20070249600A1-20071025-C00283
or salt or solvate thereof.
3. A compound as claimed in claim 1, wherein E is aryl substituted with R1 and R2.
4. A compound as claimed in claim 1, wherein E is phenyl substituted with R1 and R2.
5. A compound as claimed in claim 1, wherein E is phenyl and R1 and R2 together with the phenyl ring atoms with which they are attached form a cycloalkyl ring fused to E.
6. A compound as claimed in claim 10, wherein the cycloalkyl ring is cyclopentyl.
7. A compound as claimed in claim 1, wherein E is phenyl and R1 and R2 together with the phenyl ring atoms with which they are attached form an aryl ring fused to E.
8. A compound as claimed in claim 7, wherein the aryl ring is phenyl.
9. A compound as claimed in claim 1, wherein A is phenyl, 2-pyridyl or 3-pyridyl.
10. A compound as claimed in claim 1, wherein A is phenyl.
11. A compound as claimed in claim 1, wherein the group A is linked to the side chain —NHC(Z)NHE and to the linker group X of the benzimidazole core through a (−1,3-) or a (−1,4-) linkage.
12. A compound as claimed in claim 1, wherein A is a phenyl group linked through a (−1,4-) or (−1,3-) linkage.
13. A compound as claimed in claim 1, wherein X is C(O) or O.
14. A compound as claimed in claim 1, wherein X is O.
15. A compound as claimed in claim 1, wherein X is S.
16. A compound as claimed in claim 1, wherein Z is O.
17. A compound as claimed in claim 1, wherein Z is S.
18. A compound as claimed in claim 1, wherein R1 is C1-C6 alkyl, aryloxy, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfanyl, —C(O)OR6, halogen, —CN, or —NO2.
19. A compound as claimed in claim 1, wherein R1 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy, halogen, or —NO2.
20. A compound as claimed in claim 1, wherein R1 is C1-C6 haloalkyl.
21. A compound as claimed in claim 1, wherein R1 is —CF3.
22. A compound as claimed in claim 1, wherein R1 is C1-C6 alkyl.
23. A compound as claimed in claim 1, wherein R1 is —C(CH3)3.
24. A compound as claimed in claim 1, wherein R2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl.
25. A compound as claimed in claim 1, wherein R2 is hydrogen or halogen.
26. A compound as claimed in claim 1, wherein R2 is halogen.
27. A compound as claimed in claim 1, wherein R2 is fluorine.
28. A compound as claimed in claim 1, wherein R1 is C1-C6 alkyl, C1-C6 alkoxy, aryloxy, C1-C6 haloalkyl, C1-C6 haloalkylsulfanyl, C1-C6 alkylsulfanyl, C(O)OR6, halogen, —CN, or —NO2 and R2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl.
29. A compound as claimed in claim 1, wherein R1 is C1-C6 haloalkyl and R2 is hydrogen or halogen.
30. A compound as claimed in claim 1, wherein R1 is —CF3 and R2 is fluorine.
31. A compound as claimed in claim 1, wherein D is CH, T is CR8, M is C and Q is N(R7)p, wherein p is 0, q is 1, R7 is hydrogen, methyl, or S(O)2R6.
32. A compound as claimed in claim 1, wherein D is CH, T is CR8, wherein R8 is hydrogen or —Br, M is C and Q is N(R7)p, wherein p is 1, q is 0, R7 is hydrogen, methyl, —S(O)2R6, —RNR4R5, —RR6 or aralkyl.
33. A compound as claimed in claim 1, wherein D is CH, T is CR8, wherein R8 is hydrogen, M is C and Q is N(R7)p, wherein either p or q is 0, the other is 1 and R7 is hydrogen.
34. A compound as claimed in claim 1, wherein D is CH, T is CR8, wherein R8 is hydrogen or —Br, M is C and Q is S or O; wherein q is 0.
35. A compound as claimed in claim 1, wherein R3 is —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5.
36. A compound as claimed in claim 1, wherein R3 is —C(O)R6, —C(O)NR4R5, or —C(O)OR6.
37. A compound as claimed in claim 1, wherein R3 is —C(O)OR6.
38. A compound as claimed in claim 1, wherein R3 is —C(O)OR6 and R6 is methyl.
39. A compound as claimed in claim 1, wherein A is phenyl; X is O; Z is O; R1 is C1-C6alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or —NO2; R2 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; and R3 is —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6—C(O)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5.
40. A compound as claimed in claim 1, wherein A is phenyl; X is O; Z is 0; R1 is C1-C6 alkyl, or C1-C6 haloalkyl; R2 is hydrogen or halogen; and R3 is —C(O)R6, —C(O)NR4R5, or —C(O)OR6.
41. A compound as claimed in claim 1, wherein A is phenyl; X is O; Z is O; R1 is C1-C6 haloalkyl; R2 is halogen; and R3 is —C(O)OR6.
42. A compound as claimed in claim 1, wherein A is phenyl; X is S; Z is O; R1 is C1-C6alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or —NO2; R2 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; and R3 is —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6—C(O)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5.
43. A compound as claimed in claim 1, wherein A is phenyl; X is S; Z is O; R1 is C1-C6 alkyl, or C1-C6 haloalkyl; R2 is hydrogen or halogen; and R3 is —C(O)R6, or —C(O)OR6.
44. A compound as claimed in claim 1, wherein A is phenyl; X is S; Z is O; R1 is C1-C6 haloalkyl; R2 is halogen; and R3 is —C(O)OR6.
45. A compound as claimed in claim 1, wherein A is pyridyl; X is O; Z is O; R1 is C1-C6alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or —NO2; R2 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; and R3 is —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5.
46. A compound as claimed in claim 1, wherein A is pyridyl; X is O; Z is O; R1 is C1-C6 alkyl, or C1-C6 haloalkyl; R2 is hydrogen or halogen; and R3 is —C(O)R6, or —C(O)OR6.
47. A compound as claimed in claim 1, wherein A is pyridyl; X is O; Z is O; R1 is C1-C6 haloalkyl; R2 is halogen; and R3 is —C(O)OR6.
48. A compound as claimed in claim 1, wherein A is pyridyl; X is S; Z is O; R1 is C1-6alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or —NO2; R2 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 alkoxy; and R3 is —C(O)R6, —C(O)NR4R5, —C(O)OR6, —C(O)ROR6, —C(O)RC(O)OR6, —C(O)ROR′OR″OR6, —C(O)ROR′OR6, —C(O)RNR4R5, —C(O)RNR4C(O)R6, —C(O)RNR4C(O)OR6, —SO2R6, or —SO2NR4R5.
49. A compound as claimed in claim 1, wherein A is pyridyl; X is S; Z is O; R1 is C1-C6 alkyl, or C1-C6 haloalkyl; R2 is hydrogen or halogen; and R3 is —C(O)R6, or —C(O)OR6.
50. A compound as claimed in claim 1, wherein A is pyridyl; X is S; Z is O; R1 is C1-C6 haloalkyl; R2 is halogen; and R3 is —C(O)OR6.
51. A compound as claimed in claim 1, selected from the group consisting of:
methyl N-(5-(4-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3,5-di(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H -benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3,5-dimethoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylsulfonyl)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate;
methyl (5-(3-((3-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((3-ethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
ethyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
t-butyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-t-butylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;
(6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(methanesulfonyl)-1H-benzimidazol-2-ylamine;
6-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)cyclopentamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-methylpentamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-(N-acetylamino)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-aminoacetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-methoxyacetamide;
3-(N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamoyl)propionic acid;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(2-(methoxy)ethoxy)ethoxy)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-(methoxy)ethoxy)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-(N-(t-butoxycarbony)amino)acetamide;
N-(5-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyloxy)-1H -benzimidazol-2-yl)acetamide;
methyl N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(5-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)acetamide; and
methyl N-(5-(5-((3-ethylphenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
or a salt or solvate thereof.
52. A compound as claimed in claim 1, selected from the group consisting of:
methyl N-(5-(4-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((4-chloro-3-trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-fluoro-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-methyl-5-nitrophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-(3-methylthiophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-(3-cyanophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H -benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenylthio)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-ethoxycarbonylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-carboxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-fluoro-5-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2,5-difluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((3-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((3-bromophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((3-(phenoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((4-chlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((4-methoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((4-fluorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-methyl-1H-benzimidazol-2-yl)carbamate;
methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-(2-(dimethylamino)ethyl)-1H-benzimidazol-2-yl)carbamate;
methyl N-(6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino) phenoxy)-1-(2-(4-morpholino)ethyl)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenylcarbonyl)-1H -benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenylsulfinyl)-1H-benzimidazol-2-yl)carbamate;
2-(dimethylamino)ethyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
benzyl N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(methanesulfonyl)-1H-benzimidazol-2-ylamine;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)methanesulfonamide;
5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1-(4-(methyl)phenylsulfonyl)-1H-benzimidazol-2-ylamine;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-methylbenzenesulfonamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(4-methyl-1-piperazinomethyl)benzamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(pyridine-3-yl)propionamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-5-benzimidazolecarboxamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(pyrrol-1-yl)benzamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(1H-imidazol-1-yl)benzamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-4-(dimethylamino)butylamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-pyridinecarboxamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-tetrahydrofurancarboxamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1H-indole-3-carboxamide);
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(5-(1-pyrrolidino)tetrazol-2-yl)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1-methyl-1H-imidazol-4-yl)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(1H-imidazole-4-carboxamide);
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)benzamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-2-thiophenecarboxamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(4-methyl-1-piperazino)acetamide;
N-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(dimethylamino)acetamide;
6-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one;
7-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-3,4-dihydro-1,4a-diazacarbazol-2-one;
2-(2-(4-methyl-1-piperazino)ethylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;
2-(2-(dimethylamino)ethylamino)-5-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;
2-(3-(4-methyl-1-piperazino)propylamino)-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole;
methyl N-(5-(5-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-1-oxo-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
N-(6-(2-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-5-pyridyloxy)-3-benzyl-1H-benzimidazol-2-yl)acetamide;
methyl N-(5-(5-((2-chloro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(5-((2,5-dichlorophenyl)aminocarbonylamino)-2-pyridyloxy)-1H-benzimidazol-2-yl)carbamate;
6-(6-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-ylamine; and
N-(6-(6-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-3-pyridyloxy)-1-benzyl-1H-benzimidazol-2-yl)methanesulfonamide;
or a salt or solvate thereof.
53. A compound as claimed in claim 1, selected from the group consisting of:
methyl N-(5-(3-((2-(trifluoromethoxy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((4-(trifluoromethylthio)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((2-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((4-chloro-3-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((3-iodophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((2,5-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenylthio)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((2-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((4-phenoxyphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((5-indanyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((1-naphtyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
1-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea;
1-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(4-chlorophenyl)urea;
1-(5-(4-((2-fluoro-5-(trifluoromethy)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(4-(N,N-dimethylamino)phenyl)urea;
N-(5-(4-((5-carbamoyl-2-methylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)(2-furyl)formamide;
methyl N-(5-(3-((2,3-dichlorophenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(3-((2,3-dimethylphenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
1-(5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)-3-(2,3-dimethylphenyl)urea;
methyl N-(5-(4-((3-chlorophenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
methyl N-(5-(4-((3-methoxyphenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate; and
methyl N-(5-(4-((3-(trifluoromethyl)phenyl)aminothiocarbonylamino)phenoxy)-1H-benzimidazol-2-yl)carbamate;
or a salt or solvate thereof.
54. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in claim 1, or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.
55. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in claim 51, or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.
56. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in claim 52, or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.
57. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound as claimed in claim 53, or a salt or solvate thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients.
US11/763,524 2000-11-29 2007-06-15 Chemical compounds Abandoned US20070249600A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010126922A1 (en) * 2009-04-30 2010-11-04 Glaxosmithkline Llc Benzimidazolecarboxamides as inhibitors of fak
US20110237620A1 (en) * 2008-12-01 2011-09-29 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
EP2671891A2 (en) 2008-06-27 2013-12-11 Amgen Inc. Ang-2 inhibition to treat multiple sclerosis

Families Citing this family (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2377847T3 (en) 1999-01-13 2012-04-02 Bayer Healthcare Llc Diphenyl ureas substituted with omega-carboxy aryl as kinase inhibitors p38
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
KR100600550B1 (en) 2000-10-20 2006-07-13 에자이 가부시키가이샤 Nitrogenous aromatic ring compounds
PT2305255E (en) † 2001-12-03 2012-09-04 Bayer Healthcare Llc Aryl urea compounds in combination with other cytostatic or cytotoxic agents for treating human cancers
SI1478358T1 (en) 2002-02-11 2013-09-30 Bayer Healthcare Llc Sorafenib tosylate for the treatment of diseases characterized by abnormal angiogenesis
US8299108B2 (en) 2002-03-29 2012-10-30 Novartis Ag Substituted benzazoles and methods of their use as inhibitors of raf kinase
CA2480638C (en) 2002-03-29 2013-02-12 Chiron Corporation Substituted benzazoles and use thereof as raf kinase inhibitors
ATE323702T1 (en) 2002-08-06 2006-05-15 Astrazeneca Ab CONDENSED PYRIDINES AND PYRIMIDINES WITH TIE2 (TEK) ACTIVITY
NZ538617A (en) * 2002-08-30 2005-12-23 Eisai Co Ltd Azaarene derivatives
US7365209B2 (en) 2003-02-11 2008-04-29 Pharmacopeia, Inc. Nitrogen heterocycle biaryls for osteoporosis and other diseases
US7531553B2 (en) * 2003-03-21 2009-05-12 Amgen Inc. Heterocyclic compounds and methods of use
JP2006521345A (en) * 2003-03-28 2006-09-21 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー Positive allosteric modulator of nicotinic acetylcholine receptor
ES2423800T3 (en) 2003-03-28 2013-09-24 Novartis Vaccines And Diagnostics, Inc. Use of organic compounds for immunopotentiation
DK1626714T3 (en) 2003-05-20 2007-10-15 Bayer Pharmaceuticals Corp Dirarylurine drugs for diseases mediated by PDGFR
US6887798B2 (en) 2003-05-30 2005-05-03 International Business Machines Corporation STI stress modification by nitrogen plasma treatment for improving performance in small width devices
ATE538787T1 (en) 2003-07-11 2012-01-15 Merck Patent Gmbh BENZIMIDAZOLE DERIVATIVES AS RAF-KINASE INHIBITORS
RS52625B (en) 2003-07-23 2013-06-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
DE10334663A1 (en) * 2003-07-30 2005-03-10 Merck Patent Gmbh urea derivatives
DE10337942A1 (en) * 2003-08-18 2005-03-17 Merck Patent Gmbh aminobenzimidazole derivatives
DE10342503A1 (en) * 2003-09-12 2005-04-14 Merck Patent Gmbh Benzyl-Benzimidazolylderivate
DE10344223A1 (en) * 2003-09-24 2005-04-21 Merck Patent Gmbh New 2-anilino-1,3-benzoxazole derivatives, are inhibitors of kinases, especially tyrosine- or Raf-kinases, useful e.g. for treating solid tumors, angiogenesis, diabetic retinopathy, inflammation or psoriasis
US7423150B2 (en) 2003-10-16 2008-09-09 Novartis Ag Substituted benzazoles and methods of their use as inhibitors of Raf kinase
DE10349587A1 (en) * 2003-10-24 2005-05-25 Merck Patent Gmbh Benzimidazolylderivate
CN101337930B (en) 2003-11-11 2010-09-08 卫材R&D管理有限公司 Urea derivative preparation process
DE10352979A1 (en) * 2003-11-13 2005-06-09 Merck Patent Gmbh Pyridopyrimidinone
JP2007512255A (en) * 2003-11-13 2007-05-17 アンビット バイオサイエンシス コーポレーション Urea derivatives as kinase regulators
TW200530236A (en) 2004-02-23 2005-09-16 Chugai Pharmaceutical Co Ltd Heteroaryl phenylurea
WO2005082862A2 (en) * 2004-02-26 2005-09-09 Merck Patent Gmbh Benzimidazolyl derivatives as kinase inhibitors
US7459562B2 (en) 2004-04-23 2008-12-02 Bristol-Myers Squibb Company Monocyclic heterocycles as kinase inhibitors
TW200538453A (en) 2004-04-26 2005-12-01 Bristol Myers Squibb Co Bicyclic heterocycles as kinase inhibitors
EP1751139B1 (en) 2004-04-30 2011-07-27 Bayer HealthCare LLC Substituted pyrazolyl urea derivatives useful in the treatment of cancer
US7173031B2 (en) 2004-06-28 2007-02-06 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
US7439246B2 (en) 2004-06-28 2008-10-21 Bristol-Myers Squibb Company Fused heterocyclic kinase inhibitors
US7432373B2 (en) 2004-06-28 2008-10-07 Bristol-Meyers Squibb Company Processes and intermediates useful for preparing fused heterocyclic kinase inhibitors
US20090181092A1 (en) * 2004-07-16 2009-07-16 Spinal Restoration, Inc. Methods for Treating Joints and Discs with a Carrier Matrix and Cells
ATE428421T1 (en) 2004-09-17 2009-05-15 Eisai R&D Man Co Ltd MEDICAL COMPOSITION WITH IMPROVED STABILITY AND REDUCED GELING PROPERTIES
JP4789180B2 (en) * 2004-09-28 2011-10-12 第一三共株式会社 Method for producing 6-substituted-1-methyl-1-H-benzimidazole derivative and production intermediate thereof
WO2006035685A1 (en) * 2004-09-28 2006-04-06 Sankyo Company, Limited Intermediate of 6-substituted-1-methyl-1-h-benzimidazole derivative and method for producing same
JP5065034B2 (en) * 2004-10-13 2012-10-31 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング N, N'-diphenylurea derivatives suitable as kinase inhibitors
EP1799669A1 (en) 2004-10-13 2007-06-27 Merck Patent GmbH Heterocyclic substituted bisarylurea derivatives as kinase inhibitors
GB0423554D0 (en) * 2004-10-22 2004-11-24 Cancer Rec Tech Ltd Therapeutic compounds
DE102004054216A1 (en) 2004-11-10 2006-05-11 Merck Patent Gmbh Substituted 4-amino-pyridopyrimidinones
EP1674466A1 (en) * 2004-12-27 2006-06-28 4Sc Ag 2,5- and 2,6-disubstituted benzazole analogues useful as protein kinase inhibitors
US7576090B2 (en) 2004-12-27 2009-08-18 4Sc Ag Benzazole analogues and uses thereof
WO2007015578A1 (en) 2005-08-02 2007-02-08 Eisai R & D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US7202513B1 (en) 2005-09-29 2007-04-10 International Business Machines Corporation Stress engineering using dual pad nitride with selective SOI device architecture
US8986650B2 (en) 2005-10-07 2015-03-24 Guerbet Complex folate-NOTA-Ga68
US8926945B2 (en) 2005-10-07 2015-01-06 Guerbet Compounds comprising a biological target recognizing part, coupled to a signal part capable of complexing gallium
US7553854B2 (en) 2006-04-19 2009-06-30 Novartis Vaccines And Diagnostics, Inc. 6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling
US7951819B2 (en) 2006-04-26 2011-05-31 Cancer Research Technology Limited Imidazo[4, 5-B]pyridin-2-one and oxazolo[4, 5-B] pyridin-2-one compounds and analogs thereof as cancer therapeutic compounds
CN101490046A (en) 2006-05-09 2009-07-22 辉瑞产品公司 Cycloalkylamino acid derivatives and pharmaceutical compositions thereof
CN101443009A (en) 2006-05-18 2009-05-27 卫材R&D管理有限公司 Antitumor agent for thyroid cancer
KR101472600B1 (en) 2006-08-28 2014-12-15 에자이 알앤드디 매니지먼트 가부시키가이샤 Antitumor agent for undifferentiated gastric cancer
EP2066642A1 (en) * 2006-09-25 2009-06-10 Arete Therapeutics, INC. Soluble epoxide hydrolase inhibitors
CA2664364A1 (en) * 2006-09-28 2008-04-03 Arete Therapeutics, Inc. Soluble epoxide hydrolase inhibitors
WO2008093855A1 (en) 2007-01-29 2008-08-07 Eisai R & D Management Co., Ltd. Composition for treatment of undifferentiated-type of gastric cancer
CA2689514C (en) * 2007-06-05 2015-09-29 Takeda Pharmaceutical Company Limited Heterobicyclic compounds as kinase inhibitors
US8431608B2 (en) 2007-08-17 2013-04-30 Icagen Inc. Heterocycles as potassium channel modulators
WO2009026254A1 (en) * 2007-08-17 2009-02-26 Icagen, Inc. Heterocycles as potassium channel modulators
US8324395B2 (en) 2007-08-23 2012-12-04 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
JP5350247B2 (en) * 2007-08-29 2013-11-27 武田薬品工業株式会社 Heterocyclic compounds and uses thereof
CA2704000C (en) 2007-11-09 2016-12-13 Eisai R&D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
NZ586418A (en) 2007-12-19 2012-09-28 Cancer Rec Tech Ltd Pyrido[2,3-b]pyrazine-8-substituted compounds and their use
JPWO2009128520A1 (en) 2008-04-18 2011-08-04 塩野義製薬株式会社 Heterocyclic compounds having PI3K inhibitory activity
GB0807609D0 (en) * 2008-04-25 2008-06-04 Cancer Rec Tech Ltd Therapeutic compounds and their use
WO2009136663A1 (en) * 2008-05-08 2009-11-12 Takeda Pharmaceutical Company Limited Fused heterocyclic derivatives and use thereof
JO3101B1 (en) * 2008-12-02 2017-09-20 Takeda Pharmaceuticals Co Benzothiazole derivatives as anticancer agents
FR2942227B1 (en) 2009-02-13 2011-04-15 Guerbet Sa USE OF BUFFERS FOR RADIONUCLEID COMPLEXATION
WO2011092469A1 (en) 2010-02-01 2011-08-04 Cancer Research Technology Limited 1-(5-tert-butyl-2-phenyl-2h-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy
CN102762101B (en) 2010-02-18 2014-09-17 高点制药有限责任公司 Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
US8759535B2 (en) 2010-02-18 2014-06-24 High Point Pharmaceuticals, Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
KR101677790B1 (en) 2010-06-25 2016-11-18 에자이 알앤드디 매니지먼트 가부시키가이샤 Antitumor agent using compounds having kinase inhibitory effect in combination
WO2012031196A1 (en) 2010-09-03 2012-03-08 Forma Therapeutics, Inc. 4- { [ ( pyridin- 3 - yl -methyl) aminocarbonyl] amino} benzene - sulfone derivatives as nampt inhibitors for therapy of diseases such as cancer
FR2968999B1 (en) 2010-12-20 2013-01-04 Guerbet Sa CHELATE NANOEMULSION FOR MRI
RU2580609C2 (en) 2011-04-18 2016-04-10 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Anticancer therapeutic agent
EP3444363B1 (en) 2011-06-03 2020-11-25 Eisai R&D Management Co., Ltd. Biomarkers for prediciting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
FR2980364B1 (en) 2011-09-26 2018-08-31 Guerbet NANOEMULSIONS AND THEIR USE AS CONTRAST AGENTS
KR20150098605A (en) 2012-12-21 2015-08-28 에자이 알앤드디 매니지먼트 가부시키가이샤 Amorphous form of quinoline derivative, and method for producing same
FR3001154B1 (en) 2013-01-23 2015-06-26 Guerbet Sa MAGNETO-EMULSION VECTORIZED
US9242969B2 (en) 2013-03-14 2016-01-26 Novartis Ag Biaryl amide compounds as kinase inhibitors
SG11201509278XA (en) 2013-05-14 2015-12-30 Eisai R&D Man Co Ltd Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
CA2913417A1 (en) * 2013-05-30 2014-12-11 Kala Pharmaceuticals, Inc. Substituted n-(5-(2-aminoimidaz0[1,2-b]pyridazin-6-yloxy) derivatives a nd pharmaceutical compositions thereof useful for the treatment of diseases associated with abnormal angiogenesis and/or aberrant signaling of a growth factor
GB201320732D0 (en) 2013-11-25 2014-01-08 Cancer Rec Tech Ltd Methods of chemical synthesis
GB201320729D0 (en) 2013-11-25 2014-01-08 Cancer Rec Tech Ltd Therapeutic compounds and their use
SI3524595T1 (en) 2014-08-28 2022-10-28 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
UY36294A (en) 2014-09-12 2016-04-29 Novartis Ag COMPOUNDS AND COMPOSITIONS AS QUINASA INHIBITORS
WO2016089648A1 (en) 2014-12-01 2016-06-09 Vtv Therapeutics Llc Bach 1 inhibitors in combination with nrf2 activators and pharmaceutical compositions thereof
WO2016136745A1 (en) 2015-02-25 2016-09-01 エーザイ・アール・アンド・ディー・マネジメント株式会社 Method for suppressing bitterness of quinoline derivative
KR102662228B1 (en) 2015-03-04 2024-05-02 머크 샤프 앤드 돔 코포레이션 Combination of PD-1 antagonists and VEGFR/FGFR/RET tyrosine kinase inhibitors to treat cancer
CA2988707C (en) 2015-06-16 2023-10-10 Eisai R&D Management Co., Ltd. Combination of cbp/catenin inhibitor and immune checkpoint inhibitor for treating cancer
US11028055B2 (en) 2015-11-30 2021-06-08 Children's Medical Center Corporation Compounds for treating proliferative diseases
CN109715163B (en) 2016-09-19 2022-11-22 诺华股份有限公司 Therapeutic combination comprising a RAF inhibitor and an ERK inhibitor
JP7309614B2 (en) 2017-05-02 2023-07-18 ノバルティス アーゲー combination therapy
CN107954939B (en) * 2017-12-07 2019-09-17 福建医科大学 N under a kind of microwave radiation, the method for the thio formyl chloride derivatives catalysis synthesizing benzimidazole derivative of N- dimethylamino
WO2020201773A1 (en) * 2019-04-05 2020-10-08 Storm Therapeutics Ltd Mettl3 inhibitory compounds
EP4146639A1 (en) 2020-05-06 2023-03-15 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors
EP4267574A1 (en) 2020-12-23 2023-11-01 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors
TW202334139A (en) 2021-11-09 2023-09-01 美商雅捷可斯治療公司 6-heteroaryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors
TW202346485A (en) 2022-03-28 2023-12-01 瑞士商杭斯曼高級材料公司 Disperse azo dyes based on 2-hydroxynaphthalene-3-carboxylic acid
CN115724837B (en) * 2022-10-26 2024-07-23 中国人民解放军海军军医大学 Benzothiazole derivative for inhibiting programmed cell necrosis and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5477860A (en) * 1992-11-05 1995-12-26 Synectics Medical, Inc. Catheter for measuring respiration and respiratory effort
US5624947A (en) * 1992-12-21 1997-04-29 Merck, Sharp & Dohme Ltd. Phenyl derivatives useful as tachykinin antagonists
US5877020A (en) * 1994-09-22 1999-03-02 Helsinki University Licensing, Ltd. Promoter for the receptor tyrosine kinase, Tie
US6030831A (en) * 1997-09-19 2000-02-29 Genetech, Inc. Tie ligand homologues

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU4651893A (en) 1992-06-26 1994-01-24 Immunex Corporation Novel tyrosine kinase
JP4344960B2 (en) 1997-05-23 2009-10-14 バイエル、コーポレイション Inhibition of p38 kinase activity by arylureas
WO1998052559A1 (en) 1997-05-23 1998-11-26 Bayer Corporation Raf kinase inhibitors
RU2212407C2 (en) * 1997-11-10 2003-09-20 Бристол-Маерс Сквибб Компани Benzothiazole inhibitors of protein tyrosine kinases
SK286564B6 (en) 1997-12-22 2009-01-07 Bayer Corporation Substituted aryl ureas as raf kinase inhibitors and pharmaceutical composition containing thereof
UA71904C2 (en) 1997-12-22 2005-01-17 Compounds and methods of treating by inhibiting raf kinase using heterocyclic substituted urea derivatives
JP4403482B2 (en) 1997-12-22 2010-01-27 バイエル コーポレイション Intermediates for the synthesis of substituted heterocyclic ureas and methods for their preparation
AU762077B2 (en) 1997-12-22 2003-06-19 Bayer Healthcare Llc Inhibition of p38 kinase activity using aryl and heteroaryl substituted heterocyclic ureas
DK1042305T3 (en) 1997-12-22 2005-09-19 Bayer Pharmaceuticals Corp Inhibition of p38 kinase using symmetric and asymmetric diphenylureas
ES2155045T3 (en) 1997-12-22 2007-02-01 Bayer Pharmaceuticals Corp. INHIBITION OF THE QUINASA RAF USING HETEROCICLIC UREAS REPLACED WITH ARILO AND HETEROARILO.
GB9900752D0 (en) 1999-01-15 1999-03-03 Angiogene Pharm Ltd Benzimidazole vascular damaging agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5477860A (en) * 1992-11-05 1995-12-26 Synectics Medical, Inc. Catheter for measuring respiration and respiratory effort
US5624947A (en) * 1992-12-21 1997-04-29 Merck, Sharp & Dohme Ltd. Phenyl derivatives useful as tachykinin antagonists
US5877020A (en) * 1994-09-22 1999-03-02 Helsinki University Licensing, Ltd. Promoter for the receptor tyrosine kinase, Tie
US6030831A (en) * 1997-09-19 2000-02-29 Genetech, Inc. Tie ligand homologues

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2671891A2 (en) 2008-06-27 2013-12-11 Amgen Inc. Ang-2 inhibition to treat multiple sclerosis
US20110237620A1 (en) * 2008-12-01 2011-09-29 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8697874B2 (en) 2008-12-01 2014-04-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
WO2010126922A1 (en) * 2009-04-30 2010-11-04 Glaxosmithkline Llc Benzimidazolecarboxamides as inhibitors of fak

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