WO2005021531A1 - N-substituted benzimidazolyl c-kit inhibitors - Google Patents

N-substituted benzimidazolyl c-kit inhibitors Download PDF

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Publication number
WO2005021531A1
WO2005021531A1 PCT/US2004/026482 US2004026482W WO2005021531A1 WO 2005021531 A1 WO2005021531 A1 WO 2005021531A1 US 2004026482 W US2004026482 W US 2004026482W WO 2005021531 A1 WO2005021531 A1 WO 2005021531A1
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WO
WIPO (PCT)
Prior art keywords
benzimidazole
phenyl
carboxamide
pyridin
ylmethyl
Prior art date
Application number
PCT/US2004/026482
Other languages
French (fr)
Inventor
Joshua Bolger
Arlindo L. Castelhano
Andrew Philip Crew
Han-Qing Dong
Ayako Honda
Radoslaw Laufer
An-Hu Li
Kristen Mulvihill
Li Qui
Smith Colin Peter Sambrook
Yingchuan Sun
Graham Michael Wynne
Tao Zhang
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Osi Pharmaceuticals, Inc.
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Filing date
Publication date
Priority to BRPI0413746-9A priority Critical patent/BRPI0413746A/en
Priority to AP2006003549A priority patent/AP2006003549A0/en
Priority to CA002535896A priority patent/CA2535896A1/en
Priority to UAA200602942A priority patent/UA82395C2/en
Priority to EP04781204A priority patent/EP1664021A1/en
Priority to JP2006523955A priority patent/JP4769720B2/en
Application filed by Osi Pharmaceuticals, Inc. filed Critical Osi Pharmaceuticals, Inc.
Priority to MXPA06002018A priority patent/MXPA06002018A/en
Priority to AU2004268949A priority patent/AU2004268949A1/en
Publication of WO2005021531A1 publication Critical patent/WO2005021531A1/en
Priority to IL173614A priority patent/IL173614A0/en
Priority to NO20060664A priority patent/NO20060664L/en
Priority to IS8319A priority patent/IS8319A/en

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    • 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
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00—Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/622—Forming processes; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/626—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B
    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
    • C04B35/632—Organic additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention is directed to N-substituted benzimidazolyl compounds, h particular, the present invention is directed to N-substituted benzimidazolyl compounds that are inhibitors of the c-Kit proto-oncogene (also known as KIT, CD-I 17, stem cell factor receptor, mast cell growth factor receptor).
  • the present invention is also directed to (Nl -substituted) benzimidazolyl compounds that are inhibitors of c-Kit.
  • the c-Kit proto-oncogene is believed to be important in embryogenesis, melanogenesis, hematopoiesis, and the pathogenesis of mastocytosis, gastrointestinal tumors, and other solid tumors, as well as certain leukemias, including AML. Accordingly, it would be desirable to develop novel compounds that are inhibitors of the c-Kit receptor.
  • cancer utilize compounds that inhibit DNA synthesis. Such compounds' mechanism of operation is to be toxic to cells, particularly to rapidly dividing tumor cells. Thus, their broad toxicity can be a problem to the subject patient.
  • anti-cancer agents that act other than by the inhibition of DNA synthesis have been explored to try to enhance the selectivity of the anti-cancer action and thereby reduce adverse side-effects.
  • a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene which, on ⁇ activation, leads to the formation of malignant tumor cells).
  • oncogenes encode proteins that are aberrant protein-tyrosine kinases capable of causing cell transformation.
  • the overexpression of a normal proto-oncogenic tyrosine kinase can also result in proliferative disorders, sometimes resulting in a , malignant phenotype.
  • co-expression of a receptor tyrosine kinase and its cognate ligand within the same cell type may also lead to malignant transformation.
  • Receptor tyrosine kinases are large enzymes which span the cell membrane and possess i) an extracellular binding domain for growth factors such as KIT ligand (also known as stem cell factor (SCF), Steel factor (SLF) or mast cell growth factor (MGF)), ii) a transmembrane domain, and iii) an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins.
  • KIT ligand also known as stem cell factor (SCF), Steel factor (SLF) or mast cell growth factor (MGF)
  • SCF stem cell factor
  • SSF Steel factor
  • MMF mast cell growth factor
  • Binding of KIT ligand to KIT tyrosine kinase results in receptor homodimerization, the activation of KIT tyrosine kinase activity, and the subsequent phosphorylation of a variety of protein substrates, many of which are effectors of intracellular signal transduction, These events can lead to enhanced cell proliferation or promote enhanced cell survival. With some receptor kinases, receptor heterodimerization can also occur. [6] It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, head and neck cancers, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial, lung or pancreatic cancer.
  • KIT kinase expression has been documented in a wide variety of human malignancies such as mastocytosis/ mast cell leukemia, gastrointestinal stromal tumors (GIST), small cell lung carcinoma (SCLC), sinonasal natural killer/T-cell lymphoma, testicular cancer (seminoma), thyroid carcinoma, malignant melanoma, ovarian carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia (AML), breast carcinoma, pediatric T-cell acute lymphoblastic leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma, and prostate carcinoma.
  • GIST gastrointestinal stromal tumors
  • SCLC small cell lung carcinoma
  • sinonasal natural killer/T-cell lymphoma testicular cancer
  • thyroid carcinoma malignant melanoma
  • ovarian carcinoma adenoid cystic carcinoma
  • AML acute myelogenous leukemia
  • KIT The kinase activity of KIT has been implicated in the pathophysiology of several of these - and additional tumors - including breast carcinoma, SCLC, GIST, germ cell tumors, mast cell leukemia, neuroblastoma, AML, melanoma and ovarian carcinoma.
  • Several mechanisms of KIT activation in tumor cells have been reported, including activating mutations, autocrine and paracrine activation of the receptor kinase by its ligand, loss of pro,tein-tyrosine phosphatase activity, and cross activation by other kinases.
  • the transforming mechanisms initiated by the activating mutations are thought to include dimer formation and increased intrinsic activity of the kinase domain, both of which result in constitutive ligand-independent kinase activation, and possibly altered substrate specificity. More than thirty activating mutations of the Kit protein have been associated with highly malignant tumors in humans.
  • GleevecTM also known as imatinib mesylate, or STI571
  • STI571 2- phenylpyrimidine tyrosine kinase inhibitor that inhibits the kinase activity of the BCR- ABL fusion gene product
  • GleevecTM in addition to inhibiting BCR- ABL kinase, also inhibits the KIT kinase and PDGF receptor kinase, although it is not effective against all mutant isoforms of the KIT kinase.
  • Kit ligand-stimulated growth of MO7e human leukemia cells is inhibited by GleevecTM, which also induces apoptosis under these conditions.
  • GM-CSF stimulated growth of MO7e human leukemia cells is not affected by GleevecTM.
  • GleevecTM in recent clinical studies using GleevecTM to treat patients with GIST, a disease in which KIT kinase is involved in transformation of the cells, many of the patients showed marked improvement.
  • KIT kinase inhibitors can treat tumors whose growth is dependent on KIT kinase activity.
  • Other kinase inhibitors show even greater kinase selectivity.
  • the 4-anilinoquinazoline compound TarcevaTM inhibits only EGF receptor kinase with high potency, although it can inhibit the signal transduction of other receptor kinases, probably by virtue of the fact that these receptors heterodimerize with EGF receptor.
  • WO 01/57020 describes indole and benzimidazole inhibitors of factor Xa.
  • International Patent Publication No. WO 00/15222 describes fused pyridine inhibitors of cGMP phosphodiesterase.
  • International Patent Publication No. WO 01/12600 describes inhibitors of Factor Xa.
  • International Patent Publication No. WO 97/12613 describes method for treating and preventing inflammation and atherosclerosis.
  • U.S. Patent No. 6,316,474 describes 2-benzyl and 2-heteroaryl benzimidazole NMDA/NR2b antagonists.
  • U.S. Patent No. 6,479,508 describes viral polymerase inhibitors.
  • 6,444,617 describes fused-heterocycle dicarboxylic acid diamide derivatives or salts thereof, herbicide and usage thereof.
  • U.S. Patent Nos. 6,087,380, 6,414,008, and 6,469,039 describe disubstituted bicyclic heterocycles.
  • U.S. Patent No. 5,118,688 describes tetrahydropyridonquinolone derivatives.
  • U.S. Patent No. 4,975,435 describes certain lH-pyrrolo[3,4-b]quinolin-l- one-9-amino-2,3-dihydro derivatives useful for treating anxiety.
  • U.S. Patent No. 6,548,524 describes ortho-sulfonamido bicyclic heteroaryl hydroxamic acids.
  • U.S. Patent No. 6,348,474 describes sulfonamide compounds.
  • U.S. Patent Nos. 5,972,980 and 6,001,866 describe method for treating and preventing inflammation and atherosclerosis.
  • U.S. Patent No. 5,814,651 describes catechol diethers as selective PDEIV inhibitors.
  • U.S. Patent No. 6,329,383 describes 2- amino-5-pyrimidine acetic acid compounds.
  • U.S. Patent No. 5,688,809 describes 5- heteroarylindole derivatives.
  • European Patent Application No. EP 0 846 689 describes benzimidazole compounds.
  • International Patent Publication No. WO 00/59888 describes N-benzimidazolylmethyl- and N-indolylmethyl-benzamides and their use as CRF modulators.
  • WO 02/069965 describes benzimidazole derivatives as therapeutic agents.
  • International Patent Publication No. WO 02/30886 describes heterocyclic angiogenesis inhibitors.
  • U.S. Patent No. 6,162,804 describes tyrosine kinase inhibitors.
  • U.S. Patent No. 6,465,484 describes angiogenesis inhibitors.
  • International Patent Publication No. WO 00/12089 describes novel angiogenesis inhibitors.
  • German Patent Publication No. DE 2244908 describes selectively permeable polymeric membranes.
  • European Patent Application No. EP 0 706 795 describes catechol diether compounds as inhibitors of TNF release.
  • International Patent Publication No. WO 02/076960 describes transition metal mediated process.
  • International Patent Publication No. WO 02/059118 describes process for N- (oxyalkylation) of carboxamides.
  • International Patent Publication No. WO 02/04425 describes viral polymerase inhibitors.
  • International Patent Publication No. WO 02/083143 describes CXCR3 antagonists.
  • International Patent Publication No. WO 01/57019 describes indolone and benzimidazolone inhibitors of factor Xa.
  • EP 1 085 372 describes photographic material having improved color reproduction.
  • International Patent Publication No. WO 01/14342 describes aminocarbonyl-substituted benzimidazole derivatives.
  • International Patent Publication No. WO 00/76501 describes IL-8 receptor antagonists.
  • Kit inhibition in order to treat oncology.
  • compounds may be active in other kinases such as, for example, GIST, FLT3, Hematopoietic R-PTKs, PDGFR-beta or KDR to add efficacy in mast cell leukemias, small cell lung cancer (SCLC), mastocytosis, leukemias, myelodysplastic disorders, or angiogenic dependent diseases.
  • SCLC small cell lung cancer
  • mastocytosis leukemias
  • myelodysplastic disorders myelodysplastic disorders
  • angiogenic dependent diseases SUMMARY OF THE INVENTION
  • Rl 1, R12, R13 and R14 is -NR 3 COR 31 , -NR 3 CONR 3 R 31 , -
  • X is a cyclyl or heterocyclyl group, optionally substituted with 1-4 halogen, -NR32R33, -NR 3 2COR 33 , -NR 32 CO2R 33 , -NR 32 SO 2 R 33 , -OR 32 , -SR 32 , - SO2R32, -SO 2 NR 32 R33, -CO2R32, -CO2H, -CONR32R33, -C 0-8 alkyl, -C 2-8 alkenyl, -C 2- 8 alkynyl, -CN, CF 3 , OCF 3 , NO 2
  • R a and R b are each independently Co -8 alkyl or C 3-8 cycloalkyl
  • R a and Rb taken together with the C to which they are attached form a saturated or partially unsaturated 3-10 membered ring optionally containing 0-4 N, O, S,
  • Re is C 0-8 alkyl
  • m is 0, 1, 2, 3, 4 or 5; provided that when m is 0 or 1, no N, O or S atoms are adjacent to each other in the N-X-Y-Z linking bridge;
  • n is 1, 2, 3, 4 or 5; provided that, when n is 1, no N, O or S atoms are adjacent to each other in the N-X-Y-Z linking bridge;
  • Z is a cyclyl or heterocycyl group, optionally substituted with 1-5 independent halogen, -NR 34 R 35 , -NR 34 COR 35 , -NR 34 C(O)OR 35 , ANR 34 SO 2 R 35 , -OR 3 ,
  • Z further can be C 0-8 alkyl-O-Cc -8 alkyl, Co -8 alkyl-O-C(O)-Co -8 alkyl, or Co-salkyl-C(O)-O-C 0 . 8 alkyl;
  • R 3 , R 31 , R 32 , R3 3 , R 34 and R 35 are independently Co -8 alkyl substituted with heterocyclyl, or OH substituents; CF 3 , CHF 2 , -Co -8 alkyl-O-C 0-8 alkyl, -C 0-8 alkyl-N(Co-
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -NR 3 COR 31 , -NR 3 CONR 3 R 3 ⁇ , -NR 3 SO 2 R 31 , -CO 2 R 3 , -CO 2 H, -C 0 . 8 alkylNR 3 R 31 or -CONR 3 R 31 ; and the other variables are as described above for Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -NR 3 COR 31 , -NR 3 CONR 3 R 3 ⁇ , -NR 3 SO 2 R 31 , -CO 2 R 3 , -CO 2 H, -C 0 . 8 alkylNR 3 R 31 or -CONR 3 R 31 ; and the other variables are as described above for Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -NR 3 COR 31 , -NR 3 CONR 3
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; and the other variables are as described above for Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; and the other variables are as described above for Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; and the other variables are as described above for Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; and the other variables are as described above for Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; and the other variables are as described above for Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; and the other variables are as
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; X is cyclyl; and the other variables are as described above for Formula (I).
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 3! ; X is heterocyclyl; and the other variables are as described above for Formula (I).
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR3R31; X is cyclyl; Y is absent; and the other variables are as described above for Formula (I).
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; X is cyclyl; Y is
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; X is cyclyl; Y is
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; X is cyclyl; Y is
  • the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR 3 R 31 ; X is cyclyl; Y is
  • alkyl as well as other groups having the prefix “alk” such as, for example, alkoxy, alkanyl, alkenyl, alkynyl, and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert- butyl, pentyl, hexyl, heptyl and the like. "Alkenyl”, “alkynyl” and other like terms include carbon chains having at least one unsaturated carbon-carbon bond.
  • C 0- alkyl is used to mean an alkyl having 0-4 carbons - that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration.
  • An alkyl having no carbon is hydrogen when the alkyl is a terminal group.
  • An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.
  • fused ring systems can include one ring that is partially or fully unsaturated, such as a benzene ring, to form fused ring systems, such as benzofused carbocycles.
  • Cycloalkyl includes such fused ring systems as spirofused ring systems.
  • cycloalkyl and carbocyclic rings include C 3- 8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and decahydronaphthalene, adamantane, indanyl, 1,2,3,4-tetrahydronaphthalene and the like.
  • halogen includes fluorine, chlorine, bromine, and iodine atoms.
  • aryl is well known to chemists.
  • the preferred aryl groups are phenyl and naphthyl.
  • heteroaryl is well known to chemists.
  • the term includes 5- or 6- membered heteroaryl rings containing 1-4 heteroatoms chosen from oxygen, sulfur, and nitrogen in which oxygen and sulfur are not next to each other.
  • heteroaryl rings are furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • hetaryl includes hetaryl rings with fused carbocyclic ring systems that are partially or fully unsaturated, such as a benzene ring, to form a benzofused hetaryl.
  • benzimidazole benzoxazole, benzothiazole, benzofuran, quinoline, isoquinoline, quinoxaline, and the like.
  • heterocyclic ring Unless otherwise stated, the terms “heterocyclic ring”, “heterocycle”,
  • the terms include 4-8-membered saturated rings containing one or two heteroatoms chosen from oxygen, sulfur, and nitrogen.
  • heterocyclic rings examples include azetidine, oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, thietane, thiazolidine, oxazohdine, oxazetidine, pyrazolidine, isoxazolidine, isothiazohdine, tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiocane, azetidine, pyrrolidine, piperidine, azepane, azocane, [l,3]dioxane, oxazolidine, piperazine, homopiperazine, morpholine, thiomorpholine, and the like.
  • heterocyclic rings include the oxidized forms of the sulfur-containing rings.
  • tetrahydrothiophene- 1 -oxide, tetrahydrothiophene- 1 , 1 -dioxide, thiomorpholine- 1 -oxide, thiomorpholine- 1 , 1 -dioxide, tetrahydrothiopyran-1 -oxide, tetrahydrothiopyran- 1,1 -dioxide, thiazolidine- 1 -oxide, and thiazolidine- 1,1 -dioxide are also considered to be heterocyclic rings.
  • heterocyclic also includes fused ring systems, including het-het fused systems, and can include a carbocyclic ring that is partially or fully unsaturated, such as a benzene ring, to form benzofused heterocycles.
  • fused ring systems including het-het fused systems
  • carbocyclic ring that is partially or fully unsaturated, such as a benzene ring, to form benzofused heterocycles.
  • benzene ring such as 1,4-dihydro-l,4-benzodioxine, tetrahydroquinoline, tetrahydroisoquinoline and the like.
  • Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above Formula I is shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • the invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula I in combination with a pharmaceutically acceptable carrier.
  • the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of Formula I as described above (or a pharmaceutically acceptable salt or N-oxide thereof).
  • the invention encompasses a pharmaceutical composition for the treatment of disease by the inhibition of the c-Kit kinase, which may be a wild-type or mutant form of the protein, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above (or a pharmaceutically acceptable salt or N- oxide thereof).
  • the compounds and compositions of the present invention are effective for treating mammals such as, for example, humans.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethyl
  • the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • compositions of the present invention comprise a compound represented by formula I (or a pharmaceutically acceptable salt or N-oxide thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds represented by Formula I, or pharmaceutically acceptable salts or N-oxides thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration. E.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in- water emulsion, or as a water-in-oil liquid emulsion.
  • the compound represented by Formula I, or a pharmaceutically acceptable salt or N-oxide thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy.
  • such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients, hi general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt or N-oxide of Formula I.
  • the compounds of Formula I, or pharmaceutically acceptable salts or N-oxides thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical compositions of this invention include a pharmaceutically acceptable liposomal formulation containing a compound of Formula I or a pharmaceutically acceptable salt or N-oxide thereof.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • any convenient pharmaceutical media may be employed.
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be 1 prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent or other such excipient.
  • excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer time.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be used.
  • the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, hi soft gelatin capsules, the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg.
  • Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions, hi all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt or N- oxide thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal a ⁇ ir ⁇ nistration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient
  • dosage levels on the order of from about O.Olmg/kg to about
  • 750mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 75g per patient per day.
  • breast cancer, head and neck cancers, and gastrointestinal cancer such as colon, rectal or stomach cancer may be effectively treated by the administration of from about 0.01 to 500mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 50g per patient per day.
  • leukemia, ovarian, bronchial, lung, and pancreatic cancer may be effectively treated by the administration of from about 0.01 to 500mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 50g per patient per day.
  • GIST small cell lung carcinoma
  • SCLC small cell lung carcinoma
  • colon cancer sinonasal natural killer/T-cell lymphoma
  • testicular cancer saliva
  • thyroid carcinoma malignant melanoma
  • ovarian carcinoma adenoid cystic carcinoma
  • AML acute myelogenous leukemia
  • breast carcinoma pediatric T-cell acute lymphoblastic leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma, and prostate carcinoma
  • AML acute myelogenous leukemia
  • pediatric T-cell acute lymphoblastic leukemia angiosarcoma
  • anaplastic large cell lymphoma endometrial carcinoma
  • prostate carcinoma may be effectively treated by the administration of from about 0.01 to 500mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 50g per patient per day.
  • the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the compounds of the present invention, or pharmaceutically acceptable salts or N-oxides thereof can also be effectively administered in conjunction with other cancer therapeutic compounds.
  • cytotoxic agents and angiogenesis inhibiting agents can be advantageous co-agents with the compounds of the present invention.
  • the present invention includes compositions comprising the compounds represented by Formula I, or a pharmaceutically acceptable salt or N-oxide thereof, and a cytotoxic agent or an angiogenesis-inhibiting agent.
  • the amounts of each can be therapeutically effective alone - in which case the additive effects can overcome cancers resistant to treatment by monotherapy.
  • the amounts of any can also be subtherapeutic - to minimize adverse effects, particularly in sensitive patients.
  • the treatment of cancer depends on the type of cancer. For example, lung cancer is treated differently as a first line therapy than are colon cancer or breast cancer treated. Even within lung cancer, for example, first line therapy is different from second line therapy, which in turn is different from third line therapy. Newly diagnosed patients might be treated with cisplatinum containing regimens. Were that to fail, they move onto a second line therapy such as a taxane.
  • the compounds of the present invention can be beneficially co-administered in conjunction or combination with other such cancer therapeutic compounds.
  • Such other compounds include, for example, a variety of cytotoxic agents (alkylators, D ⁇ A topoisomerase inhibitors, antimetabolites, tubulin binders); inhibitors of angiogenesis; and different other forms of therapies including kinase inhibitors such as Tarceva, monoclonal antibodies, and cancer vaccines.
  • compositions of the present invention include a compound according to Formula I, or a pharmaceutically acceptable salt or N-oxide thereof, and an anti-neoplastic, anti-tumor, anti-angiogenic, or chemofherapeutic agent.
  • the compounds of the present invention can also be effectively administered in conjunction with other therapeutic compounds, aside from cancer therapy.
  • therapeutic agents effective to ameliorate adverse side-effects can be advantageous co-agents with the compounds of the present invention.
  • the ability of compounds to inhibit the tyrosine kinase activity of c-Kit was determined in a cell-based ELISA assay using the H526 cell line (ATCC # CRL- 5811), which was originally derived from a human small cell lung cancer.
  • the assay determines the ability of compounds to block ligand-stimulated tyrosine phosphorylation of the wild-type c-Kit receptor protein that is endogenously expressed in H526 cells.
  • Cells are pre-incubated with compounds at various concentrations prior to addition of stem cell factor (SCF), the ligand for the c-Kit receptor tyrosine kinase.
  • SCF stem cell factor
  • Cell lysates are then prepared and the c-Kit protein is captured onto a c-Kit antibody- coated 96-well ELISA plate.
  • the phosphotyrosine content of the receptor protein is then monitored by quantitation of the degree of binding of an antibody that recognizes only the phosphorylated tyrosine residues within the captured protein.
  • the antibody used has a reporter enzyme (e.g. horseradish peroxidase, HRP) covalently attached, such that binding of antibody to phosphorylated c-Kit can be determined quantitatively by incubation with an appropriate HRP substrate.
  • HRP horseradish peroxidase
  • Cell lysis buffer 150 mM NaCl 10% Glycerol 1% Triton X- 100 0.5 mM EDTA 1 ⁇ g/mL leupeptin 1 ⁇ g/mL aprotinin 1 mM Sodium orthovanadate
  • Anti c-Kit antibody 0.5/xg/mL anti c-Kit Ab-3 (Lab Vision, catalog #MS289P1 ) in 50mM Sodium bicarbonate, pH 9.
  • ELISA Assay plates 100 0.5 mM EDTA 1 ⁇ g/mL leupeptin 1 ⁇ g/mL aprotinin 1 mM Sodium orthovanadate
  • Anti c-Kit antibody 0.5/xg/mL anti c-Kit Ab-3 (Lab Vision, catalog #MS289P1 ) in 50mM Sodium bicarbonate, pH 9.
  • ELISA Assay plates 100 0.5 mM EDTA 1 ⁇ g/mL leupeptin 1 ⁇ g/mL
  • ELISA assay plates are prepared by addition of 1 OO ⁇ L of anti c-Kit antibody to each well of a 96-well Microlite-2 plate (Dynex, catalog # 7417), followed by incubation at 37°C for 2h. The wells are then washed twice with 300 ⁇ L wash buffer. Plate wash buffer:
  • Compound dilutions were prepared from lOmM DMSO stocks by dilution in cell assay medium, the final concentration of DMSO in the assay being 0.1%.
  • 50 ⁇ L of the test compound was added (compounds are assayed at concentrations between 0.1 nM and 100 ⁇ M); to positive and negative control wells, 50 L cell assay medium containing 0.1% DMSO was added. The cells were then incubated with compound at 37°C for 3h. SCF (R&D Systems, catalog #255-SC-010) was then added in order to stimulate the Kit receptor and induce its tyrosine phosphorylation.
  • lO ⁇ L of a 1.6 g/mL solution of SCF in cell assay medium was added to all wells apart from the negative control wells, and the cells were incubated for an additional 15min at 37°C.
  • the plate was centrifuged at lOOOrpm for 5min, the medium removed by aspiration, and the cell pellet lysed by the addition of 120 L ice-cold cell lysis buffer per well.
  • the plate was kept on ice for 20min and lOO ⁇ L of the cell lysates from each well were then transferred to the wells of an ELISA assay plate and incubated at 4°C for 16h.
  • the EXAMPLES of this invention reduced the level of SCF-induced tyrosine phosphorylation of Kit in intact H526 cells as determined in the above assay with IC 50 values between 15 ⁇ M and O.lnM.
  • Reduction of III to give the phenylenediamines (IV) may be achieved using for example, hydrogen in the presence of a suitable transition metal catalyst (palladium, platinum, ruthenium, nickel), iron, zinc or tin under acidic conditions, with sodium hydrosulphite or with tin( ⁇ )chloride dihydrate.
  • Cychsation of IV to the benzimidazoles (V) may be achieved by reaction with a corresponding carboxylic acid, acid halide, acid anhydride or an orthoformate (e.g. (MeO) 3 CH)) and an acid such as formic acid.
  • conversion to the benzimidazoles V may be achieved in one pot.
  • N-arylbenzimidazoles may also be accomplished via the process outlined, whereby N1H benzimidazoles (VIII) may be arylated under Pd(0) mediated conditions as disclosed in J Amer. Chem. Soc, (2000), 122, 7600. Separation of the resulting regioisomers may be achieved by a number of means known to those skilled in the art including, but not limited to, chromatographic means or through crystallisation from a suitable solvent.
  • Benzimidazoles may be produced from the cychsation of the anilides (VII) with acids such as, but not limited to, acetic, p-toluenesulphonic, hydrochloric, sulphuric or phosphoric acid.
  • the anilides (VII) can be prepared by reaction of o- phenylenediamines with acid halides or anhydrides or with carboxylic acids in the presence of appropriate coupling reagents known to those skilled in the art such as, but not limited to, EDC, DCC, HOAt, HOBt, HATU, TBTU, or GDI including solid supported versions of these solution phase reagents.
  • R3 H
  • compounds such as VII may be prepared by formylation of VI with alkyl formates (e.g. methyl formate). In the processes described, conversion of VI into VII may also lead to the partial or complete conversion to VIII.
  • Functionalities Rl and R2 may be included into the target molecules through appropriate choice of starting materials, e.g. of type I, II, VI and IX. Where the final functionality is not available directly through this process, or where such functionality may be compromised during the subsequent chemistry to build the final molecule, alternative functionalities may be used and subsequently transformed into the final desired functionality by methods, and at points in the sequence, readily determined by one skilled in the art.
  • a non-exhaustive list of such transformations includes the conversions: OMe ⁇ OH (BBr 3 ), NH 2 ⁇ C1 (NaNO 2 , CuCl), Br ⁇ CN (Pd 2 (dba) 3 , Zn(CN) 2 , DPPF), Me ⁇ CO 2 H (KMnO 4 ), CO 2 H ⁇ CO 2 Me (MeOH, H 2 SO 4 ), OH ⁇ OAlkyl (Alkyl halide, base), CO 2 H ⁇ CONR'R" (EDC, HOAt, DIPEA, HNR'R"), Br ⁇ CO 2 Me (Pd 2 (dba) 3 , DPPF, CO(g), MeOH), Br->CO 2 H ( 4 BuLi, CO 2 ), Ar-H ⁇ Ar-Br (NBS), CN ⁇ CO 2 H (cone. H 2 SO ), Br ⁇ NR'R" (Pd 2 (dba) 3, DPPF, HNR'R”).
  • Amino derivatives of the type XXI may be prepared as in Scheme 5 whereby the appropriate bromobenzimidazole (XX) is formed under the conditions employed for Scheme 4 and is subjected to Pd(0) mediated amination conditions to introduce, in this case, a substituted benzylamino group.
  • EDC ethyl dimethylaminopropylcarbodiimide hydrochloride
  • HOAt 1-hydroxyazabenzotriazole
  • HOBt 1-hydroxybenzotriazole
  • CDI 1,1 '-carbonyldiimidazole
  • TBTU O-benzotriazole-N,N,N',N'- tetramethyluronium tetrafluoroborate
  • HATU azabenzotriazolyl-N,N,N',N',- tetramethyluronium hexafluorophosphate
  • DIPEA diisopropylethylamine
  • TEA triethylamine
  • DMF N,N-dimethylformamide
  • NMP N-methylpyrrolidinone
  • DCM dichloromethane
  • DMAP 4-dimethylaminopyridine
  • TFA trifluoroacetic acid
  • Boc hutoxycarbonyl
  • Fmoc fluoroacetic acid
  • reaction mixture was then concentrated in vacuo and purified by reverse- phase preparative ⁇ PLC to give N-pyridin-3-ylmethyl-l-(4- ⁇ 3-[3-(trifluoromethoxy) phenoxyjpropoxy ⁇ phenyl)- lH-benzimidazole-5-carboxamide.
  • N-Pyridin-3-ylmethyl-l-(4- ⁇ [4-(trifluoromethoxy)benzyl]oxy ⁇ phenyl)- lH-benzimidazole-5-carboxamide (EXAMPLE 35, 31mg, 0.060mmol) was dissolved in DCM (3mL) and treated with -chloroperoxybenzoic acid (18mg, 0.72mmol) and the mixture stirred at rt for 4h. After this time the mixture was concentrated in vacuo and the crude product purified by preparative ⁇ PLC to give the title compound. !
  • the resin was filtered and washed with DMF (3xlmL), CH 2 C1 2 (3xlmL), DMF (3xlmL), and THF (3xlmL).
  • the resin was resuspended in DMF (ImL) and then DIEA (lO ⁇ L, 0.058mmol) and 2-pyrrolidin-l- ylethanamine (7mg, 0.058mmol) were added. After shaking for 48h, the reaction was filtered and the resin washed with CH2CI2. The filtrate was concentrated in vacuo.
  • EXAMPLE G75 [305] N-(2-Morpholin-4ylethyl)-l-(4- ⁇ [4-(trifluoromethyl)benzyl]oxy ⁇ phenyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 525 [M ⁇ 4" ].
  • EXAMPLE G76 [306] N-(l-Tefrahy ⁇ o-2H-pyran-4-ylme yl)-l-(4- ⁇ [4-(trifluoromethyl) benzyl]oxy ⁇ phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 510 [M ⁇ 4" ].
  • reaction mixture was shaken at rt overnight in a capped vial and then filtered through a plug of cotton wool.
  • the resin was washed with MeOH and the combined filtrate and MeOH washings were concentrated under reduced pressure and purified by silica gel chromatography eluting with 5 % MeOH in DCM to yield l- ⁇ 3-[(4- chlorobenzyl)amino]phenyl ⁇ -N-pyridin-3 -ylmethyl- lH-benzimidazole-5-carboxamide.
  • reaction mixture was concentrated in vacuo and the crude reaction mixture was purified by silica gel chromatography (1:1 ethyl acetate/hexanes to 1:9 methanol/ethyl acetate) to obtain a mixture of l-[4-(2- hy(hoxyethoxy)phenyl]-N-(pyridin-3-ylmethyl)-lH-benzimidazole-5-carboxamide and l- ⁇ 4-[2-(2-hydroxyethoxy)ethoxy]phenyl ⁇ -N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide dialkylated byproduct as a viscous brown solid.
  • the mixture was carried onto the next step without further purification.
  • the crude product was purified by Jones column chromatography (100% hexanes to 50% ethyl acetate/hexanes) to give 2-(pyridin-2-yloxy)ethanol as a dark brown oil containing 15% w/w of 18-crown-6 ether.
  • Methylamine hydrochloride (27mg, 0.40mmol) and NN -diisopropylethylamine (52mg, 0.40mmol, 70 ⁇ L) were added and the reaction was allowed to stir at rt. After 18h, the reaction mixture was concentrated in vacuo, diluted with C ⁇ 2 C1 2 (2mL), and washed with distilled water (ImL). The aqueous phase was back extracted with CH 2 CI2 (2mL x 5) and the combined organic extracts were concentrated in vacuo.
  • EXAMPLE ⁇ 4 [354] N-(2-M ⁇ holin-4-ylethyl)-l- ⁇ 4-[2-(pyridin-2-yloxy)ethoxy]phenyl ⁇ -lH- benzimidazole-5-carboxamide; MS(ES+): m/z 488 [M ⁇ 4" ].
  • EXAMPLE N5 [355] l- ⁇ 4-[2-(Pyridin-2-yloxy)ethoxy]phenyl ⁇ -N-(l-tetrahydro-2H-pyran-4- ylmethyl)-lH-benzimidazole-5-carboxamide; MS(ES+): m/z 473 [M ⁇ 4" ].
  • the resin was resuspended in DMF (ImL) and 2-aminoethanol (15mg, 0.24mmol) and DIEA (31mg, 0.24mmol) were added. The reaction mixture was allowed to shake overnight. The reaction mixture was then filtered, and washed with CH 2 C1 2 (3x3mL), DMF (3x3mL), and THF (3x3mL). The filtrate and the washes were combined and concentrated in vacuo.
  • the crude product was purified by using the Waters mass-directed HPLC purification system to yield N-(2 -hydroxyethyl)- 1 - ⁇ 4-[2-(pyridin-2-yloxy)ethoxy]phenyl ⁇ -lH-benzimidazole- 5-carboxamide as a yellowish white powder.
  • the reaction was heated to 80°C under ⁇ 2 atmosphere upon which methyl 3- ⁇ [(4-methylphenyl)sulfonyl]oxy ⁇ cyclobutanecarboxylate was added drop-wise. After heating at 80°C for 48h, the reaction was cooled to rt, concentrated in vacuo, and purified using silica gel chromatography (5% methanokC ⁇ zCk). To remove residual 7-toluenesulfonic acid and 18-crown-6, the foamy white solid was washed with ethyl acetate.

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Abstract

Compounds represented by Formula (I): or a pharmaceutically acceptable salt or N-oxide thereof, are useful in the treatment of cancer.

Description

N-SUBSTITUTED BENZIMIDAZOLYL C-KIT INHIBITORS
BACKGROUND OF THE INVENTION
[1] The present invention is directed to N-substituted benzimidazolyl compounds, h particular, the present invention is directed to N-substituted benzimidazolyl compounds that are inhibitors of the c-Kit proto-oncogene (also known as KIT, CD-I 17, stem cell factor receptor, mast cell growth factor receptor). The present invention is also directed to (Nl -substituted) benzimidazolyl compounds that are inhibitors of c-Kit.
[2] The c-Kit proto-oncogene is believed to be important in embryogenesis, melanogenesis, hematopoiesis, and the pathogenesis of mastocytosis, gastrointestinal tumors, and other solid tumors, as well as certain leukemias, including AML. Accordingly, it would be desirable to develop novel compounds that are inhibitors of the c-Kit receptor.
[3] Many of the current treatment regimes for hyperproliferative disorders
(cancer) utilize compounds that inhibit DNA synthesis. Such compounds' mechanism of operation is to be toxic to cells, particularly to rapidly dividing tumor cells. Thus, their broad toxicity can be a problem to the subject patient. However, other approaches to anti-cancer agents that act other than by the inhibition of DNA synthesis have been explored to try to enhance the selectivity of the anti-cancer action and thereby reduce adverse side-effects.
[4] It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene which, on ■ activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant protein-tyrosine kinases capable of causing cell transformation. By a different route, the overexpression of a normal proto-oncogenic tyrosine kinase can also result in proliferative disorders, sometimes resulting in a , malignant phenotype. Alternatively, co-expression of a receptor tyrosine kinase and its cognate ligand within the same cell type may also lead to malignant transformation. [5] Receptor tyrosine kinases are large enzymes which span the cell membrane and possess i) an extracellular binding domain for growth factors such as KIT ligand (also known as stem cell factor (SCF), Steel factor (SLF) or mast cell growth factor (MGF)), ii) a transmembrane domain, and iii) an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins. Binding of KIT ligand to KIT tyrosine kinase results in receptor homodimerization, the activation of KIT tyrosine kinase activity, and the subsequent phosphorylation of a variety of protein substrates, many of which are effectors of intracellular signal transduction, These events can lead to enhanced cell proliferation or promote enhanced cell survival. With some receptor kinases, receptor heterodimerization can also occur. [6] It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, head and neck cancers, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial, lung or pancreatic cancer. KIT kinase expression has been documented in a wide variety of human malignancies such as mastocytosis/ mast cell leukemia, gastrointestinal stromal tumors (GIST), small cell lung carcinoma (SCLC), sinonasal natural killer/T-cell lymphoma, testicular cancer (seminoma), thyroid carcinoma, malignant melanoma, ovarian carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia (AML), breast carcinoma, pediatric T-cell acute lymphoblastic leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma, and prostate carcinoma. The kinase activity of KIT has been implicated in the pathophysiology of several of these - and additional tumors - including breast carcinoma, SCLC, GIST, germ cell tumors, mast cell leukemia, neuroblastoma, AML, melanoma and ovarian carcinoma. [7] Several mechanisms of KIT activation in tumor cells have been reported, including activating mutations, autocrine and paracrine activation of the receptor kinase by its ligand, loss of pro,tein-tyrosine phosphatase activity, and cross activation by other kinases. The transforming mechanisms initiated by the activating mutations are thought to include dimer formation and increased intrinsic activity of the kinase domain, both of which result in constitutive ligand-independent kinase activation, and possibly altered substrate specificity. More than thirty activating mutations of the Kit protein have been associated with highly malignant tumors in humans.
[8] Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, Gleevec™ (also known as imatinib mesylate, or STI571), a 2- phenylpyrimidine tyrosine kinase inhibitor that inhibits the kinase activity of the BCR- ABL fusion gene product, was recently approved by the U.S. Food and Drug Administration for the treatment of CML. Gleevec™, in addition to inhibiting BCR- ABL kinase, also inhibits the KIT kinase and PDGF receptor kinase, although it is not effective against all mutant isoforms of the KIT kinase. Kit ligand-stimulated growth of MO7e human leukemia cells is inhibited by Gleevec™, which also induces apoptosis under these conditions. By contrast, GM-CSF stimulated growth of MO7e human leukemia cells is not affected by Gleevec™. Further, in recent clinical studies using Gleevec™ to treat patients with GIST, a disease in which KIT kinase is involved in transformation of the cells, many of the patients showed marked improvement. [9] These studies demonstrate how KIT kinase inhibitors can treat tumors whose growth is dependent on KIT kinase activity. Other kinase inhibitors show even greater kinase selectivity. For example, the 4-anilinoquinazoline compound Tarceva™ inhibits only EGF receptor kinase with high potency, although it can inhibit the signal transduction of other receptor kinases, probably by virtue of the fact that these receptors heterodimerize with EGF receptor.
[10] Although anti-cancer compounds such as those described above make a significant contribution to the art, there is a continuing need for improved anti-cancer pharmaceuticals, and it would be desirable to develop new compounds with better selectivity or potency, or with reduced toxicity or side effects. [11] U.S. Patent Nos. 5,990,146 and 6,218,388 describe benzimidazoles for inhibiting protein tyrosine kinase mediated cellular proliferation. U.S. Patent No. 6,348,032 describes method of inhibiting neoplastic cells with benzimidazole derivatives. International Patent Publication No. WO 01/21634 describes benzimidazole derivatives and combinatorial libraries thereof. International Patent Publication No. WO 01/57020 describes indole and benzimidazole inhibitors of factor Xa. International Patent Publication No. WO 00/15222 describes fused pyridine inhibitors of cGMP phosphodiesterase. International Patent Publication No. WO 01/12600 describes inhibitors of Factor Xa. International Patent Publication No. WO 97/12613 describes method for treating and preventing inflammation and atherosclerosis. [12] U.S. Patent No. 6,316,474 describes 2-benzyl and 2-heteroaryl benzimidazole NMDA/NR2b antagonists. U.S. Patent No. 6,479,508 describes viral polymerase inhibitors. U.S. Patent No. 6,444,617 describes fused-heterocycle dicarboxylic acid diamide derivatives or salts thereof, herbicide and usage thereof. U.S. Patent Nos. 6,087,380, 6,414,008, and 6,469,039 describe disubstituted bicyclic heterocycles. U.S. Patent No. 5,118,688 describes tetrahydropyridonquinolone derivatives. U.S. Patent No. 4,975,435 describes certain lH-pyrrolo[3,4-b]quinolin-l- one-9-amino-2,3-dihydro derivatives useful for treating anxiety. U.S. Patent No. 6,548,524 describes ortho-sulfonamido bicyclic heteroaryl hydroxamic acids. U.S. Patent No. 6,348,474 describes sulfonamide compounds.
[13] U.S. Patent Nos. 5,972,980 and 6,001,866 describe method for treating and preventing inflammation and atherosclerosis. U.S. Patent No. 5,814,651 describes catechol diethers as selective PDEIV inhibitors. U.S. Patent No. 6,329,383 describes 2- amino-5-pyrimidine acetic acid compounds. U.S. Patent No. 5,688,809 describes 5- heteroarylindole derivatives. European Patent Application No. EP 0 846 689 describes benzimidazole compounds. International Patent Publication No. WO 00/59888 describes N-benzimidazolylmethyl- and N-indolylmethyl-benzamides and their use as CRF modulators. International Patent Publication No. WO 02/069965 describes benzimidazole derivatives as therapeutic agents. International Patent Publication No. WO 02/30886 describes heterocyclic angiogenesis inhibitors. U.S. Patent No. 6,162,804 describes tyrosine kinase inhibitors. U.S. Patent No. 6,465,484 describes angiogenesis inhibitors. International Patent Publication No. WO 00/12089 describes novel angiogenesis inhibitors.
[14] German Patent Publication No. DE 2244908 describes selectively permeable polymeric membranes. European Patent Application No. EP 0 706 795 describes catechol diether compounds as inhibitors of TNF release. International Patent Publication No. WO 02/076960 describes transition metal mediated process. International Patent Publication No. WO 02/059118 describes process for N- (oxyalkylation) of carboxamides. International Patent Publication No. WO 02/04425 describes viral polymerase inhibitors. International Patent Publication No. WO 02/083143 describes CXCR3 antagonists. International Patent Publication No. WO 01/57019 describes indolone and benzimidazolone inhibitors of factor Xa. European Patent Application No. EP 1 085 372 describes photographic material having improved color reproduction. International Patent Publication No. WO 01/14342 describes aminocarbonyl-substituted benzimidazole derivatives. International Patent Publication No. WO 00/76501 describes IL-8 receptor antagonists.
[15] Thus, it is desirable to develop compounds that exhibit Kit inhibition in order to treat oncology. Further, such compounds may be active in other kinases such as, for example, GIST, FLT3, Hematopoietic R-PTKs, PDGFR-beta or KDR to add efficacy in mast cell leukemias, small cell lung cancer (SCLC), mastocytosis, leukemias, myelodysplastic disorders, or angiogenic dependent diseases. SUMMARY OF THE INVENTION
[16] Compounds represented by Formula (I):
Figure imgf000007_0001
(D or a pharmaceutically acceptable salt or N-oxide thereof, are useful in the treatment of tumors.
DETAILED DESCRIPTION OF THE INVENTION
[17] The present invention is directed to a compound represented by Formula
(I):
Figure imgf000007_0002
(I) or a pharmaceutically acceptable salt or N-oxide thereof, wherein:
[18] one of Rl 1, R12, R13 and R14 is -NR3COR31, -NR3CONR3R31, -
NR3SO2R31, -CO2R3, -CO2H, -C0-8alkylNR3R31 or-CONR3R31; the others each independently F, CI, C0-3alkyl, C0-8alkoxy, or -N(Co-8alkyl)(Co-8alkyl); [19] X is a cyclyl or heterocyclyl group, optionally substituted with 1-4 halogen, -NR32R33, -NR32COR33, -NR32CO2R33, -NR32SO2R33, -OR32, -SR32, - SO2R32, -SO2NR32R33, -CO2R32, -CO2H, -CONR32R33, -C0-8alkyl, -C2-8alkenyl, -C2- 8alkynyl, -CN, CF3, OCF3, NO2, oxo, cyclyl or heterocyclyl substituents; [20] Y is absent or
Figure imgf000008_0001
[21] wherein the point of attachment to X can be from either the left or the right as shown;
[22] Ra and Rb are each independently Co-8alkyl or C3-8cycloalkyl;
[23] or Ra and Rb taken together with the C to which they are attached form a saturated or partially unsaturated 3-10 membered ring optionally containing 0-4 N, O, S,
SO, or SO2 at the ring nodes, provided that no N, O or S atoms are placed adjacent to each other at ring nodes;
[24] Re is C0-8alkyl;
[25] or Re, taken with either Ra or R , form a 3-7 membered saturated or partially unsaturated ring;
[26] m is 0, 1, 2, 3, 4 or 5; provided that when m is 0 or 1, no N, O or S atoms are adjacent to each other in the N-X-Y-Z linking bridge;
[27] n is 1, 2, 3, 4 or 5; provided that, when n is 1, no N, O or S atoms are adjacent to each other in the N-X-Y-Z linking bridge;
[28] Z is a cyclyl or heterocycyl group, optionally substituted with 1-5 independent halogen, -NR34R35, -NR34COR35, -NR34C(O)OR35, ANR34SO2R35, -OR3 ,
-SR3 , -SO2R34, -SO2NR34R35, -C(O)OR34, -CO2H, -CONR34R35, C0-8alkyl, C2-
8alkenyl, C2-8alkynyl, -OC0-8alkyl, -SC0-8alkyl, -Sθ2Co-8alkyl,-Sθ2N(C0-8alkyl)(C0- salkyl), -C(O)OCo-8alkyl, CN, CF3, NO2, oxo, cyclyl or heterocyclyl substituents; or, when Y is present, Z further can be C0-8alkyl-O-Cc-8alkyl, Co-8alkyl-O-C(O)-Co-8alkyl, or Co-salkyl-C(O)-O-C0.8alkyl;
[29] provided that when Y is -OCH2-, Z must be substituted with 1-5 -
NR3 R35, -NR34COR35, -NR34C(O)OR35, -NR34SO2R35, -OR34, -SR34, -SO2R34, - SO2NR34R35, -C02R34, -C02H, -CONR34R355 C0-8alkyl, C2-8alkenyl, C2-8alkynyl, CF3,
NO2, oxo, cyclyl or heterocyclyl substituents;
[30] provided that when Y is NHCH , Z must be substituted with 1-5 halogen,
-NR34R35, -NR34COR35, -NR34C(O)OR35, -NR34SO2R35, -OR34, -SR34, -SO2R34,
-SO2NR34R35, -CO2R34, -CO2H, -CONR34R35, C0-8alkyl, C2-8alkenyl, C2-8alkynyl, CF3,
NO2, oxo, cyclyl or heterocyclyl substituents;
[31] provided that when Y is absent, X and Z cannot contain N;
[32] R3, R31, R32, R33, R34 and R35 are independently Co-8alkyl substituted with heterocyclyl, or OH substituents; CF3, CHF2, -Co-8alkyl-O-C0-8alkyl, -C0-8alkyl-N(Co-
8alkyl)(C0-8alkyl), -C0-8alkyl-S(O)o-2-Co-8alkyl or -C0-8alkyl-S(O)2N(C0-8alkyl)(C0- salkyl).
[33] In one aspect, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -NR3COR31, -NR3CONR3R3ι, -NR3SO2R31, -CO2R3, -CO2H, -C0. 8alkylNR3R31 or -CONR3R31; and the other variables are as described above for Formula
(I). 1
[34] In another aspect, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR3R31; and the other variables are as described above for Formula
(I).
[35] In an embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR3R31; X is cyclyl; and the other variables are as described above for Formula (I).
[36] In another embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR3R3!; X is heterocyclyl; and the other variables are as described above for Formula (I).
[37] In still another embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR3R31; X is cyclyl; Y is absent; and the other variables are as described above for Formula (I). [38] In yet another embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR3R31; X is cyclyl; Y is
Figure imgf000010_0001
and the other variables are as described above for Formula (I). [39] In yet another embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR3R31; X is cyclyl; Y is
Figure imgf000010_0002
and the other variables are as described above for Formula (I). [40] In yet another embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR3R31; X is cyclyl; Y is
Figure imgf000010_0003
and the other variables are as described above for Formula (I). ). [41] In yet another embodiment, the present invention is directed to a compound represented by Formula (I), or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR3R31; X is cyclyl; Y is
Figure imgf000010_0004
and the other variables are as described above for Formula (I). [42] As used herein, unless stated otherwise, "alkyl" as well as other groups having the prefix "alk" such as, for example, alkoxy, alkanyl, alkenyl, alkynyl, and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert- butyl, pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other like terms include carbon chains having at least one unsaturated carbon-carbon bond. [43] As used herein, "C0- alkyl" is used to mean an alkyl having 0-4 carbons - that is, 0, 1, 2, 3, or 4 carbons in a straight or branched configuration. An alkyl having no carbon is hydrogen when the alkyl is a terminal group. An alkyl having no carbon is a direct bond when the alkyl is a bridging (connecting) group.
[44] The terms "cycloalkyl", "carbocyclic ring", cyclic", or "cyclyl" mean 3-
10 membered mono or polycyclic aromatic, partially aromatic or non-aromatic ring carbocycles containing no heteroatoms, and include mono-, bi-, and tricyclic saturated carbocycles, as well as fused and bridged systems. Such fused ring systems can include one ring that is partially or fully unsaturated, such as a benzene ring, to form fused ring systems, such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl and carbocyclic rings include C3- 8cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and decahydronaphthalene, adamantane, indanyl, 1,2,3,4-tetrahydronaphthalene and the like. [45] The term "halogen" includes fluorine, chlorine, bromine, and iodine atoms.
[46] The term "carbamoyl" unless specifically described otherwise means -
C(O)-NH- or -NH-C(O)-.
[47] The term "aryl" is well known to chemists. The preferred aryl groups are phenyl and naphthyl.
[48] The term "hetaryl" is well known to chemists. The term includes 5- or 6- membered heteroaryl rings containing 1-4 heteroatoms chosen from oxygen, sulfur, and nitrogen in which oxygen and sulfur are not next to each other. Examples of such heteroaryl rings are furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. The term "hetaryl" includes hetaryl rings with fused carbocyclic ring systems that are partially or fully unsaturated, such as a benzene ring, to form a benzofused hetaryl. For example, benzimidazole, benzoxazole, benzothiazole, benzofuran, quinoline, isoquinoline, quinoxaline, and the like.
[49] Unless otherwise stated, the terms "heterocyclic ring", "heterocycle",
"heterocyclic", and "heterocyclyl" are equivalent, and is defined as for cyclic but also contains one or more atoms chosen independently from N, O, and S (and the N and S oxides), provided such derivatives exhibit appropriate and stable valencies and excludes moieties containing O-O, S(O)n-S(O)n, S(O)n-O bonds where n=0-2. The terms include 4-8-membered saturated rings containing one or two heteroatoms chosen from oxygen, sulfur, and nitrogen. Examples of heterocyclic rings include azetidine, oxetane, tetrahydrofuran, tetrahydropyran, oxepane, oxocane, thietane, thiazolidine, oxazohdine, oxazetidine, pyrazolidine, isoxazolidine, isothiazohdine, tetrahydrothiophene, tetrahydrothiopyran, thiepane, thiocane, azetidine, pyrrolidine, piperidine, azepane, azocane, [l,3]dioxane, oxazolidine, piperazine, homopiperazine, morpholine, thiomorpholine, and the like. Other examples of heterocyclic rings include the oxidized forms of the sulfur-containing rings. Thus, tetrahydrothiophene- 1 -oxide, tetrahydrothiophene- 1 , 1 -dioxide, thiomorpholine- 1 -oxide, thiomorpholine- 1 , 1 -dioxide, tetrahydrothiopyran-1 -oxide, tetrahydrothiopyran- 1,1 -dioxide, thiazolidine- 1 -oxide, and thiazolidine- 1,1 -dioxide are also considered to be heterocyclic rings. The term "heterocyclic" also includes fused ring systems, including het-het fused systems, and can include a carbocyclic ring that is partially or fully unsaturated, such as a benzene ring, to form benzofused heterocycles. For example, 3,4,-dihydro-l,4-benzodioxine, tetrahydroquinoline, tetrahydroisoquinoline and the like.
[50] Compounds described herein may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. [51] The invention also encompasses a pharmaceutical composition that is comprised of a compound of Formula I in combination with a pharmaceutically acceptable carrier.
[52] Preferably, the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of Formula I as described above (or a pharmaceutically acceptable salt or N-oxide thereof). [53] Moreover, within this preferred embodiment, the invention encompasses a pharmaceutical composition for the treatment of disease by the inhibition of the c-Kit kinase, which may be a wild-type or mutant form of the protein, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above (or a pharmaceutically acceptable salt or N- oxide thereof).
[54] The compounds and compositions of the present invention are effective for treating mammals such as, for example, humans.
[55] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
[56] When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrochloric, maleic, phosphoric, sulfuric, methanesulfonic, and tartaric acids. [57] The pharmaceutical compositions of the present invention comprise a compound represented by formula I (or a pharmaceutically acceptable salt or N-oxide thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
[58] In practice, the compounds represented by Formula I, or pharmaceutically acceptable salts or N-oxides thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. E.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in- water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or a pharmaceutically acceptable salt or N-oxide thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients, hi general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
[59] Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt or N-oxide of Formula I. The compounds of Formula I, or pharmaceutically acceptable salts or N-oxides thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds. [60] The pharmaceutical compositions of this invention include a pharmaceutically acceptable liposomal formulation containing a compound of Formula I or a pharmaceutically acceptable salt or N-oxide thereof.
[61] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
[62] In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
[63] A tablet containing the composition of this invention may be1 prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent or other such excipient. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used.
[64] In hard gelatin capsules, the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, hi soft gelatin capsules, the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
[65] For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or lOOOmg. [66] Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. [67] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions, hi all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
[68] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt or N- oxide thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
[69] Pharmaceutical compositions of this invention can be in a form suitable for rectal aαirήnistration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
[70] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts or N-oxides thereof, may also be prepared in powder or liquid concentrate form.
[71] Generally, dosage levels on the order of from about O.Olmg/kg to about
750mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 75g per patient per day. For example, breast cancer, head and neck cancers, and gastrointestinal cancer such as colon, rectal or stomach cancer may be effectively treated by the administration of from about 0.01 to 500mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 50g per patient per day.
[72] Similarly, leukemia, ovarian, bronchial, lung, and pancreatic cancer may be effectively treated by the administration of from about 0.01 to 500mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 50g per patient per day.
[73] Mastocytosis/ mast cell leukemia, gastrointestinal stromal tumors
(GIST), small cell lung carcinoma (SCLC), colon cancer, sinonasal natural killer/T-cell lymphoma, testicular cancer (seminoma), thyroid carcinoma, malignant melanoma, ovarian carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia (AML), breast carcinoma, pediatric T-cell acute lymphoblastic leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma, and prostate carcinoma may be effectively treated by the administration of from about 0.01 to 500mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 50g per patient per day.
[74] It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. [75] The compounds of the present invention, or pharmaceutically acceptable salts or N-oxides thereof, can also be effectively administered in conjunction with other cancer therapeutic compounds. For example, cytotoxic agents and angiogenesis inhibiting agents can be advantageous co-agents with the compounds of the present invention. Accordingly, the present invention includes compositions comprising the compounds represented by Formula I, or a pharmaceutically acceptable salt or N-oxide thereof, and a cytotoxic agent or an angiogenesis-inhibiting agent. The amounts of each can be therapeutically effective alone - in which case the additive effects can overcome cancers resistant to treatment by monotherapy. The amounts of any can also be subtherapeutic - to minimize adverse effects, particularly in sensitive patients. [76] It is understood that the treatment of cancer depends on the type of cancer. For example, lung cancer is treated differently as a first line therapy than are colon cancer or breast cancer treated. Even within lung cancer, for example, first line therapy is different from second line therapy, which in turn is different from third line therapy. Newly diagnosed patients might be treated with cisplatinum containing regimens. Were that to fail, they move onto a second line therapy such as a taxane. Finally, if that failed, they might get a tyrosine kinase EGFR inhibitor as a third line therapy. Further, The regulatory approval process differs from country to country. Accordingly, the accepted treatment regimens can differ from country to country. Nevertheless, the compounds of the present invention, or pharmaceutically acceptable salts or N-oxides thereof, can be beneficially co-administered in conjunction or combination with other such cancer therapeutic compounds. Such other compounds include, for example, a variety of cytotoxic agents (alkylators, DΝA topoisomerase inhibitors, antimetabolites, tubulin binders); inhibitors of angiogenesis; and different other forms of therapies including kinase inhibitors such as Tarceva, monoclonal antibodies, and cancer vaccines. Other such compounds that can be beneficially co- administered with the compounds of the present invention include doxorubicin, O 2005/021531 vincristine, cisplatm, carboplatm, gemcitabine, and the taxanes. Thus, the compositions of the present invention include a compound according to Formula I, or a pharmaceutically acceptable salt or N-oxide thereof, and an anti-neoplastic, anti-tumor, anti-angiogenic, or chemofherapeutic agent.
[77] The compounds of the present invention, or pharmaceutically acceptable salts or N-oxides thereof, can also be effectively administered in conjunction with other therapeutic compounds, aside from cancer therapy. For example, therapeutic agents effective to ameliorate adverse side-effects can be advantageous co-agents with the compounds of the present invention.
I. Assay for inhibition of c-Kit in intact cells
[78] The ability of compounds to inhibit the tyrosine kinase activity of c-Kit was determined in a cell-based ELISA assay using the H526 cell line (ATCC # CRL- 5811), which was originally derived from a human small cell lung cancer. The assay determines the ability of compounds to block ligand-stimulated tyrosine phosphorylation of the wild-type c-Kit receptor protein that is endogenously expressed in H526 cells. Cells are pre-incubated with compounds at various concentrations prior to addition of stem cell factor (SCF), the ligand for the c-Kit receptor tyrosine kinase. Cell lysates are then prepared and the c-Kit protein is captured onto a c-Kit antibody- coated 96-well ELISA plate. The phosphotyrosine content of the receptor protein is then monitored by quantitation of the degree of binding of an antibody that recognizes only the phosphorylated tyrosine residues within the captured protein. The antibody used has a reporter enzyme (e.g. horseradish peroxidase, HRP) covalently attached, such that binding of antibody to phosphorylated c-Kit can be determined quantitatively by incubation with an appropriate HRP substrate. [79] The stock reagents used are as follows:
Cell lysis buffer:
Figure imgf000019_0001
150 mM NaCl 10% Glycerol 1% Triton X- 100 0.5 mM EDTA 1 μg/mL leupeptin 1 μg/mL aprotinin 1 mM Sodium orthovanadate Anti c-Kit antibody: 0.5/xg/mL anti c-Kit Ab-3 (Lab Vision, catalog #MS289P1 ) in 50mM Sodium bicarbonate, pH 9. ELISA Assay plates:
[80] ELISA assay plates are prepared by addition of 1 OOμL of anti c-Kit antibody to each well of a 96-well Microlite-2 plate (Dynex, catalog # 7417), followed by incubation at 37°C for 2h. The wells are then washed twice with 300μL wash buffer. Plate wash buffer:
[81] PBS containing 0.5% Tween-20 (PBST)
Cell assay medium: [82] RPMI with 0.1% BSA pY20-HRP:
[83] 25ng/mL ρY20-HRP (Calbiochem, catalog # 525320) in PBS, containing
0.5% Tween-20, 5% BSA, 1 mM Sodium orthovanadate HRP substrate:
[84] Chemoluminescent detection reagent (Pierce, catalog # 37075)
Assay protocol:
[85] Cultures of H526 cells, growing in RPMI with 10% fetal calf serum, were collected by centrifugation, washed twice with PBS, and suspended in cell assay medium. Cells were then distributed into a V-bottom 96-well plate at 7.5 x 104 cells per well in lOOμL cell assay medium.
[86] Compound dilutions were prepared from lOmM DMSO stocks by dilution in cell assay medium, the final concentration of DMSO in the assay being 0.1%. To compound incubation wells, 50μL of the test compound was added (compounds are assayed at concentrations between 0.1 nM and 100μM); to positive and negative control wells, 50 L cell assay medium containing 0.1% DMSO was added. The cells were then incubated with compound at 37°C for 3h. SCF (R&D Systems, catalog #255-SC-010) was then added in order to stimulate the Kit receptor and induce its tyrosine phosphorylation. Then, lOμL of a 1.6 g/mL solution of SCF in cell assay medium was added to all wells apart from the negative control wells, and the cells were incubated for an additional 15min at 37°C. Following the addition of ice-cold PBS, the plate was centrifuged at lOOOrpm for 5min, the medium removed by aspiration, and the cell pellet lysed by the addition of 120 L ice-cold cell lysis buffer per well. The plate was kept on ice for 20min and lOOμL of the cell lysates from each well were then transferred to the wells of an ELISA assay plate and incubated at 4°C for 16h.
[87] Following incubation of the cell lysates in the ELISA plate, the wells were washed 4 times with 300 L wash buffer, then lOOμL of the phosphotyrosine detection antibody ρY20-HRP was added to each well and the plate incubated at rt for
2h. The wells were then washed 4 times with 300μL wash buffer. Then, 50μL of the chemiluminescent HRP substrate was added to each well for luminometric quantitation of the amount of antiphosphotyrosine-HRP conjugate bound to the plate.
[88] Comparison of the assay signals obtained in the presence of compound with those of the positive and negative controls (cells incubated in the presence or absence of SCF, with no compound added), allows the degree of inhibition of c-Kit receptor tyrosine phosphorylation to be determined over a range of compound concentrations. These inhibition values were fitted to a sigmoidal dose-response inhibition curve to determine the IC50 values (i.e. the concentration of compound that inhibits SCF-induced tyrosine phosphorylation of the c-Kit protein by 50%).
[89] The EXAMPLES of this invention reduced the level of SCF-induced tyrosine phosphorylation of Kit in intact H526 cells as determined in the above assay with IC50 values between 15μM and O.lnM.
EXPERIMENTAL
[90] The EXAMPLES of the present invention were prepared according to the following procedures by the methods illustrated in the following schemes.
Appropriate solvents, temperatures, pressures and other reaction conditions may be readily selected by one of ordinary skill in the art. Similarly, suitable starting materials may be commercially obtained or readily prepared by one skilled in the art.
Scheme 1
Figure imgf000022_0001
rv v
[91] hi Scheme 1, diarylamines (III) may be produced from the condensation of nitrobenzenes (I, X = F, OMS, OTs) with substituted anilines (II). Coupling of the anilines (II) may also be achieved where X = I, Br, CI, OTf by utilisation of Pd(0) mediated Buchwald-Hartwig-type conditions (such as those described in J Organic Chem., (1996), 61(21), 7240) or with Cu(I) catalysts and base (e.g. K2CO3). Reduction of III to give the phenylenediamines (IV) may be achieved using for example, hydrogen in the presence of a suitable transition metal catalyst (palladium, platinum, ruthenium, nickel), iron, zinc or tin under acidic conditions, with sodium hydrosulphite or with tin(π)chloride dihydrate. Cychsation of IV to the benzimidazoles (V) may be achieved by reaction with a corresponding carboxylic acid, acid halide, acid anhydride or an orthoformate (e.g. (MeO)3CH)) and an acid such as formic
Figure imgf000022_0002
acid. Under certain conditions used to reduce III e.g. iron powder in formic acid, conversion to the benzimidazoles V may be achieved in one pot. Also, by inclusion of trimethyl orthoformate into a hydrogenation mixture with III, allows the direct conversion to V. [92] Scheme 2 below shows that formation of N-arylbenzimidazoles (V) may also be accomplished via the process outlined, whereby N1H benzimidazoles (VIII) may be arylated under Pd(0) mediated conditions as disclosed in J Amer. Chem. Soc, (2000), 122, 7600. Separation of the resulting regioisomers may be achieved by a number of means known to those skilled in the art including, but not limited to, chromatographic means or through crystallisation from a suitable solvent. Benzimidazoles (VTII) may be produced from the cychsation of the anilides (VII) with acids such as, but not limited to, acetic, p-toluenesulphonic, hydrochloric, sulphuric or phosphoric acid. In turn the anilides (VII) can be prepared by reaction of o- phenylenediamines with acid halides or anhydrides or with carboxylic acids in the presence of appropriate coupling reagents known to those skilled in the art such as, but not limited to, EDC, DCC, HOAt, HOBt, HATU, TBTU, or GDI including solid supported versions of these solution phase reagents. Where R3 = H, compounds such as VII may be prepared by formylation of VI with alkyl formates (e.g. methyl formate). In the processes described, conversion of VI into VII may also lead to the partial or complete conversion to VIII.
Scheme 2
Figure imgf000023_0001
VII
Figure imgf000023_0002
V
[93] Functionalities Rl and R2, may be included into the target molecules through appropriate choice of starting materials, e.g. of type I, II, VI and IX. Where the final functionality is not available directly through this process, or where such functionality may be compromised during the subsequent chemistry to build the final molecule, alternative functionalities may be used and subsequently transformed into the final desired functionality by methods, and at points in the sequence, readily determined by one skilled in the art.
[94] For example, a non-exhaustive list of such transformations includes the conversions: OMe→OH (BBr3), NH2→C1 (NaNO2, CuCl), Br→CN (Pd2(dba)3, Zn(CN)2, DPPF), Me→CO2H (KMnO4), CO2H→CO2Me (MeOH, H2SO4), OH→OAlkyl (Alkyl halide, base), CO2H→CONR'R" (EDC, HOAt, DIPEA, HNR'R"), Br→CO2Me (Pd2(dba)3, DPPF, CO(g), MeOH), Br->CO2H (4BuLi, CO2), Ar-H→Ar-Br (NBS), CN→CO2H (cone. H2SO ), Br→NR'R" (Pd2(dba)3, DPPF, HNR'R").
[95] Representative examples of the incorporation of such functionality into target molecules are shown below in Schemes 3-5. Scheme 3
Figure imgf000024_0001
[96] Condensation of 3-benzyloxyaniline with 4-fluoro-3-nitrobenzoic acid occurs through heating in ethanol to give X which may be reduced via catalytic hydrogenation over 10%Pd/C in ethanol to give the phenylenediamine (XI). Cychsation of XI to the benzimidazole (XII) is achieved by heating with an excess of trimethylorthoformate. 1 , 1 '-Carbonyldiimidazole mediated coupling with 3- pyridylmethylamine gives amide XIII which may be alkylated with 3-(2- chloroethyl)indole in the presence of sodium hydride.
Scheme 4
Figure imgf000024_0002
[97] In Scheme 4 the aniline X is reduced and cyclised in one-pot using trimethylorthoformate in the presence of the iron and formic acid reducing mixture. The acid XII in this instance is coupled with 3-aminomethylpyridine utilising EDC and HOBt to give amide XV which is alkylated with l-bromo-2-chloroethane and sodium hydride. The resulting haloalkyl derivative XVI is used to alkylate 2-pyridol, again using sodium hydride as base, to give the target molecule XVII. Scheme 5
Figure imgf000025_0001
[98] ( Amino derivatives of the type XXI may be prepared as in Scheme 5 whereby the appropriate bromobenzimidazole (XX) is formed under the conditions employed for Scheme 4 and is subjected to Pd(0) mediated amination conditions to introduce, in this case, a substituted benzylamino group. [99] Definitions: EDC = ethyl dimethylaminopropylcarbodiimide hydrochloride, HOAt = 1-hydroxyazabenzotriazole, HOBt = 1-hydroxybenzotriazole, CDI = 1,1 '-carbonyldiimidazole, TBTU = O-benzotriazole-N,N,N',N'- tetramethyluronium tetrafluoroborate, HATU = azabenzotriazolyl-N,N,N',N',- tetramethyluronium hexafluorophosphate, DIPEA = diisopropylethylamine, TEA = triethylamine, DMF = N,N-dimethylformamide, NMP = N-methylpyrrolidinone, DCM = dichloromethane, DMAP = 4-dimethylaminopyridine, TFA = trifluoroacetic acid, Boc = hutoxycarbonyl, Fmoc = fluorenylmethyloxycarbonyl, DMSO = dimethylsulphoxide, OMs = OSO2Me, OTs = OSO2-(4-Me)Ph, OTf = OSO2CF3, DPPF = , Pd2(dba)3, NBS = N-bromosuccimimide, HC1 (aq) = aqueous hydrochloric acid, DMA = N,N- dimethylacetamide, MeOH = methanol, EtOH = ethanol, EtOAc = ethyl acetate, DCM = dichloromethane, THF = tetrahydrofuran, HO Ac = acetic acid, DMF = N,N- dimethylformamide, HPLC = high performance liquid chromatography,
General procedures for the preparation of N-substituted benzimidazoles: [100] a) 3-FluoiO-2-nitrobenzoic acid (21.6mmol) and an aniline (43.2mmol) in 15mL of ethanol were stirred at reflux under argon for 5h resulting in the formation of an orange precipitate. After 12h the heterogeneous reaction mixture was poured into 50mL of IN HCl(aq) and diluted with lOOmL of water. The solution was stirred for 20min then the precipitate filtered to yield the 4-anilino-3-nitrobenzoic Acid: e.g. 4-{[3- (benzyloxy)phenyl]amino} -3-nitrobenzoic acid.
[101] b) A solution of the 4-anilino-3-nitrobenzoic acid (20. lmmol) in THF
(lOOmL) was charged with 10% Pd/C (500mg) and the reaction flask evacuated and subsequently charged with H2 (g) three times. The mixture was stirred vigorously for 12h after which time it was filtered through diatomaceous earth and the filtrate concentrated in vacuo to give the desired 3-amino-4-anilinobenzoic acid: e.g. 3-amino- 4-[(3-hydroxyphenyl)amino]benzoic acid.
[102] c) A solution of 3-amino-4-anilinobenzoic acid (20. lmmol) in formic acid (40mL) was charged with trimethylorthoformate (2.4mL, 22.0mmol) and heated at reflux for 3h after which time the mixture was allowed to cool to rt and stirred for 12h. The reaction mixture was then poured into 150mL of H2O and stirred for 20min yielding a precipitate which was isolated by filtration to give the l-aryl-lH-benzimidazole-5- carboxylic acid: e.g. l-(3-hydroxyphenyl)-lH-benzimidazole-5-carboxylic acid. [103] d) A solution of the l-aryl-lH-benzimidazole-5-carboxylic acid
(0.39mmol) in DMF (5mL) was treated with GDI (95mg, 0.58mmol) and stirred for 15min resulting in the formation of a white precipitate. A primary or secondary amine (0.78mmol) was then added and the mixture was stirred overnight prior to being poured into 75mL Η2O and any solid subsequently formed, isolated by filtration to give the 1- aryl-N-(substituted)-lH-benzimidazole-5-carboxamide. Where the desired product did not precipitate from the reaction solution or during the work up, it was isolated by addition of water, extraction into organic solvent (typically EtOAc), drying and concentration of the extracts, and the residue then purified by preparative ΗPLC or by normal phase chromatography over silica gel. [104] e) Alternatively:
[105] A solution of l-aryl-lH-benzimidazole-5-carboxylic acid (0.78mmol) in
DMF (4mL) was treated with EDC (227mg, 1.18mmol) and DMAP (9mg, 0.07mmol) and the mixture stirred for lOmin prior to the addition of a primary or secondary amine (1.68mmol). The mixture was stirred overnight after which time product was isolated by filtration and the cake washed with methanol (3 x 5mL) to give the desired 1-aryl-N-
(substimted)-lH-benzimidazole-5-carboxamide.
[106] Again, where the desired product did not precipitate from the reaction solution or during the work up, it was isolated by addition of water, extraction into organic solvent (typically EtOAc), drying and concentration of the extracts, and the residue then purified by preparative ΗPLC or by normal phase chromatography over silica gel.
[1] General procedure for the alkylation of N-(hydroxyphenyl) benzimidazole derivatives:
[107] f) A mixture of l-(3-hydroxyphenyl)-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide (prepared as described above, 75mg, 0.22mmol) and potassium carbonate (33mg, 0.24mmol) in acetonitrile (4mL), DMF (ImL), and distilled water (0.5mL), was treated with an alkyl bromide (0.22mmol) and the reaction mixture heated at 60°C under Ν2 for 16h. The reaction mixture was then concentrated in vacuo and the residue subjected to reverse-phase preparative ΗPLC purification to give the 1-
(3-alkyloxyphenyl)-N-pyridin-3-yhnethyl-lH-benzimidazole-5-carboxamide.
[108] The following compounds were prepared according to the procedures described above utilizing an appropriately substituted phenol and alkylating agent in place of l-(3-hydroxyphenyl)-N-pyridin-3-ylmethyl-lH-benzimidazole-5-carboxamide and the 'alkyl' bromide, respectively.
EXAMPLE 1 [109] 1- {3-[2-(Phenylthio)ethoxy]ρhenyl}-N-ρyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; (DMSO-d6, 400 MHz): d 3.41 (t, 2H, J= 6.4 Hz), 4.29 (t, 2H, J= 6.4 Hz), 4.54 (d, 2H, J= 6.0 Hz), 7.06 (dd, IH, J= 8.2, 2.4 Hz), 7.18-7.34 (m, 5H), 7.37 (dd, 2H, J= 8.0, 4.8 Hz), 7.42 (d, IH, J= 8.0 Hz), 7.53 (dd, IH, J= 8.0, 8.0 Hz), 7.67 (d, IH, J= 8.4 Hz), 7.76 (d, IH, J= 7.6 Hz), 7.91 (dd, IH, J= 8.8, 1.6 Hz), 8.36 (s, IH), 8.46 (d, IH, J= 3.6 Hz), 8.58 (s, IH), 8.66 (s, IH), 9.15 (t, IH, J= 6.0); MS (ES+): m/z 481 [MH+]
EXAMPLE 2 [110] 1 - [3 -(3 -phenylpropoxy)phenyl] -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 463 [MΗ+] EXAMPLE 3
[111] l-[3-(3-phenoxypropoxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 479 [MET4"]
EXAMPLE 4 [112] 1 - {3-[(4-Cyanobenzyl)oxy]phenyl} -N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 460 [MΗ+]
EXAMPLE 5 [113] Ethyl 5-[(3- {5-[(pyridin-3-ylmethylamino)carbonyl]- IH-benzimidazol- 1 - yl}phenoxy)methyl]-2-furoate. MS (ES+): m/z 497 [MΗ+]
EXAMPLE 6
[114] N-Pyridin-3-ylmethyl- 1 -(3- {[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 519 [MΗ4"]
EXAMPLE 7 [115] 3-(3-{5-[(Pyridin-3-ylmethylamino)carbonyl]-lH-benzimidazol-l- yl}ρhenoxy)pentyl acetate. MS (ES+): m/z 473 [MET4"]
EXAMPLE 8 [116] l-[3-(2-Νaphthylmethoxy)ρhenyl]-N-ρyridin-3-ylmethyl-lH- benzimidazole-5-carbQxamide. MS (ES+): m/z 485 [MΗ+]
EXAMPLE 9
[117] N-Pyridin-3-ylmethyl- 1 -(3- {[4-(trifluoromethyl)benzyl]oxy} phenyl)- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 503 [MΗ+]
EXAMPLE 10
[118] Ethyl 4-{3-[5-(pyridin-3-ylmethylaminocarbonyl)-lH-benzimidazol-l- yl]ρhenoxy}hexanoate. MS (ES+): m/z 487 [MΗ*]
EXAMPLE 11 [119] 1 -[3-(2-Moφholin-4-ylethoxy)phenyl]-N-ρyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 458 [MΗ+]
EXAMPLE 12 [120] l-{4-[(4-Fluorobenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 452 [MET4"]
EXAMPLE 13
[121] l-{4-[2-(Phenylthio)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 481 [MΗ+]
EXAMPLE 14
[122] Methyl 4-[(4-{5-[(pyridin-3-ylmethylamino)carbonyl]-lH-benzimidazol- l-yl}phenoxy)methyl]benzoate. MS (ES+): m/z 493 [MΗ+]
EXAMPLE 15
[123] Ethyl 5-[(4- {5-[(pyridin-3-ylmethylamino)carbonyl]- IH-benzimidazol- 1 - yl}ρhenoxy)methyl]-2-furoate. MS (ES+): m/z 497 [MΗ+]
EXAMPLE 16
[124] 1 - {3-[(4-Methylbenzyl)oxy]phenyl} -N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 449 [MΗ+]
EXAMPLE 17 [125] l-{3-[(4-Νitrobenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 480 [MET4"]
EXAMPLE 18
[126] l-{4-[(4-Methylbenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 449 [MΗ+]
EXAMPLE 19
[127] l-[3-(3-phenoxypropoxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 479 [MΗ+] EXAMPLE 20 [128] 5-(4- {5-[(pyridin-3-ylmethylamino)carbonyl]- IH-benzimidazol- 1 - yl}phenoxy)pentyl acetate. MS (ES+): m/z 473 [MΗ4"]
EXAMPLE 21
[129] Methyl 4-[(3- {5-[(pyridin-3-ylmethylamino)carbonyl]- lH-benzimidazol- l-yl}phenoxy)methyl]benzoate. MS (ES+): m/z 493 [MΗ+]
EXAMPLE 22
[130] l-[4-(2-Phenylethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-
5-carboxamide. MS (ES+): m/z 449 [MΗ+]
EXAMPLE 23
[131] Ethyl 4-{4-[5-(pyridin-3-ylmethylaminocarbonyl)-lH-benzimidazol-l- yl]ρhenoxy}hexanoate. MS (ES+): m/z 487 [MΗ4]
EXAMPLE 24
[132] 1 - {4-[(4-Trifluoromethylbenzyl)oxy]phenyl} -N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 503 [MΗ+]
EXAMPLE 25 [133] l-[4-(2-naphthylmethoxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 485 [MΗ+]
EXAMPLE 26 [134] l-[4-(l, -biphenyl-2-ylmethoxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 511 [MΗ+]
EXAMPLE 27 [135] l-{4-[(4-Νitrobenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 480 [MET4"]
EXAMPLE 28 [136] 1 -[4-(Cyclohexylmethyloxy)phenyl]-N-ρyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 441 [MΗ+]
EXAMPLE 29 [137] l-[4-(l-Phenethylethoxy)ρhenyl]-N-ρyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 449 [MΗ+]
EXAMPLE 30
[138] l-[3-(l-Phenethylethoxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 449 [MΗ+]
EXAMPLE 31
[139] l-[3-(2-Phenylethoxy)phenyl]-N-pyridin-3-yhnethyl-lH-benzimidazole-
5-carboxamide. MS (ES+): m/z 449 [MΗ+]
EXAMPLE 32 [140] 1 -[4-(l , 1 '-Biphenyl-4-ylmethoxy)phenyl]-N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 511 [MΗ+]
EXAMPLE 33 [141] l-[4-(lH-rndol-3-ylmethoxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 488 [MET4]
EXAMPLE 34
[142] 1 -[4-(2-Morpholin-4-ylethoxy)phenyl]-N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 458 [MΗ4]
EXAMPLE 35 [143] N-Pyridin-3-ylmethyl- 1 -(4- {[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 519 [MΗ+]
EXAMPLE 36
[144] l-[4-(2-Phenoxyethoxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 465 [MΗ+] EXAMPLE 37 [145] l-[3-(2-Phenoxyethoxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 465 [MΗ+]
EXAMPLE 38
[146] l-[3-(lH-Indol-3-ylmethoxy)phenyl]-N-ρyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 488 [MET4"]
EXAMPLE 39
[147] 1 - {4-[3-(4-Fluorophenoxy)propoxy]phenyl} -N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 497 [MΗ+]
EXAMPLE 40
[148] 1 - {3-[3-(4-Fluorophenoxy)propoxy]phenyl} -N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 497 [MΗ+]
EXAMPLE 41
[149] 1 - {4-[2-(4-Fluorophenoxy)ethoxy]phenyl} -N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 544 [MΗ4]
EXAMPLE 42
[150] 1 -[3-(2-Methoxyethoxy)phenyl]-N-pyridin-3-yhnethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 403 [MET4]
EXAMPLE 43 [151] l-{4-[2-(2-Methoxyethoxy)ethoxy]phenyl}-N-pyridin-3-yhnethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 447 [MΗ+]
EXAMPLE 44
[152] 1 -[4-(2-Methoxyethoxy)phenyl]-N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 403 [MET4"]
EXAMPLE 45 [153] l-{3-[2-(2-Methoxyethoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 447 [MET4]
EXAMPLE 46 [154] l-[4-(2-Ethoxyethoxy)phenyl]-N-pyridin-3-yhnethyl-lH-benzimidazole-
5-carboxamide. MS (ES+): m/z 417 [MΗ4]
EXAMPLE 47 [155] l-[3-(2-Ethoxyethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-
5-carboxamide. MS (ES+): m/z 417 [MΗ+]
EXAMPLE 48
[156] l-{3-[2-(4-Bromophenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 543 [Br^MET4"], 545 [Br81MΗ+]
EXAMPLE 49
[157] l-{4-[2-(4-Bromophenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 543 [Br79MΗ+], 545 [Br81MH+]
EXAMPLE 50
[158] 1 - {4-[2-Methylthiazol-4-ylmethyl)oxy]phenyl} -N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 456 [MΗ+]
EXAMPLE 51
[159] 1 - {3 - [(2-Methylthiazol-4-ylmethyl)oxy]phenyl} -N-pyridin-3 -ylmethyl- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 456 [MΗ4"]
EXAMPLE 52 [160] l-{3-[(Quinolin-2-ylmethyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 486 [MΗ4]
EXAMPLE 53 [161] l-{4-[(Quinolin-2-ylmethyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 486 [MΗ+] EXAMPLE 54 [162] l-{3-[2-(4-Chlorophenoxy)ethoxy]phenyl}-N-pyridin-3-yιmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 499 [MET4]
EXAMPLE 55
[163] N-Pyridin-3 -ylmethyl- 1 -(4- {3 -[3 -(trifluoromethoxy)ρhenoxy] propoxy}phenyl)-lH-benzimidazole-5-carboxamide. [164] ', l-[4-(2-Chloropropoxy)phenyl]-N-pyridin-3-yhnethyl-lH- benzimidazole-5-carboxamide (prepared as described above using l-(4-hydroxyphenyl)- N-pyridin-3-ylmethyl-lH-benzimidazole-5-carboxamide as phenol and l-bromo-3- chloropropane as alkylating agent) (100 mg, 0.24 mmol), 3-trifluoromethoxyphenol (42mg, 31μL 0.24mmol) and potassium carbonate (36 mg, 0.26 mmol) were suspended in acetonitrile (2 mL), DMF (1 mL), and water (0.5 mL) and the mixture stirred at 60 °C for 18h. The reaction mixture was then concentrated in vacuo and purified by reverse- phase preparative ΗPLC to give N-pyridin-3-ylmethyl-l-(4-{3-[3-(trifluoromethoxy) phenoxyjpropoxy} phenyl)- lH-benzimidazole-5-carboxamide. 1H ΝMR (CDC13, 400 MHz): δ 8.66 (d, J= 2.0 Hz, IH), 8.56 (dd, J= 4.8, 1.2 Hz, IH), 8.34 (d, J= 1.6 Hz, IH), 8.05 (s, IH), 7.90 (dd, J= 8.4, 1.6 Hz, IH), 7.78 (ddd, J= 8.0, 2.0, 2.0 Hz, IH), 7.48 (d, J= 8.0 Hz, IH), 7.43-7.37 (m, 2H), 7.34-7.28 (m, 2H), 7.20-7.08 (m, 3H), 6.90- 6.78 (m, 3H), 4.75 (d, J= 5.6 Hz, 2H), 4.27 (t, J= 6.0 Hz, 2H), 4.22 (t, J= 6.0 Hz, 2H), 2.35 (quin, J= 6.0 Hz, 2H); MS (ES+): m/z 563 [MH+]
[165] The following compounds were prepared according to procedures analogous to those described above.
EXAMPLE 56
[166] l-{4-[3-(3-Methoxyphenoxy}propoxy]phenyl}-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 509 [MΗ+]
EXAMPLE 57 [167] l-{4-[3-(3-Chlorophenoxy)propoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 513 [MΗ+], 515 [MH4] EXAMPLE 5 [168] l-{4-[3-(4-Cyanophenoxy)propoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 504 [MET4"]
EXAMPLE 59 [169] l-{4-[3-(4-Methoxyphenoxy)propoxy]phenyl}-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 509 [MΗ+]
EXAMPLE 60
[170] 1 - {4- [3 -(3 -Methylphenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 493 [MΗ4]
EXAMPLE 61
[171] l-{4-[3-(3-Ethynylphenoxy)propoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 503 [MET4]
EXAMPLE 62
[172] l-{3-[3-(4-Methylphenoxy)propoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 493 [MET4"]
EXAMPLE 63
[173] l-{3-[3-(4-Cyanophenoxy)propoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 504 [MΗ+]
EXAMPLE 64
[174] l-(3-{3-[3-(Trifluoromethoxy)phenoxy]propoxy}phenyl)-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 563 [MΗ+]
EXAMPLE 65
[175] 1 - {3 - [3 -(3 -Chlorophenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 513 [MET4]
EXAMPLE 66 [176] l-{3-[3-(4-Chlorophenoxy)propoxy]phenyl}-N-pyridin-3-yhnethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 513 [MΗ4], 515 [MH4"]
EXAMPLE 67 [177] l-{3-[3-(4-Bromophenoxy)propoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 557 [MΗ4], 559 [MH4"]
EXAMPLE 68
[178] l-(3-{3-[4-(Trifluoromethoxy)phenoxy]propoxy}phenyl)-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 563 [MΗ1"]
EXAMPLE 69
[179] 1 - {3 -[3 -(3 ,4-Dichlorophenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 547 [MΗ+], 548 [MH*]
EXAMPLE 70 [180] 1 - {3-[3-(4-Imidazol- 1 -ylphenoxy)propoxy]phenyl} -N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 545 [MET4"]
EXAMPLE 71 [181] l-(3-{3-[4-(^H-l,2,4-Triazol-4-yl)phenoxy]propoxy}phenyl)-N-pyridin-
3 -ylmethyl- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 546 [MET4"]
EXAMPLE 72 [182] l-(3-{3-[4-(Trifluoromethyl)phenoxy]propoxy}phenyl)-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 550 [MET4"]
EXAMPLE 73 [183] Methyl 4-(3-{3-[5-(N-pyridin-3-ylmethyl)aminocarbonyl]-lH- benzimidazol-l-ylphenoxy}propoxy)benzoate. MS (ES+): m/z 537 [MΗ4]
EXAMPLE 74 [184] l-{4-[3-(4-Bromophenoxy)propoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 557 [Br79MΗ+], 559 [Br81MH+] EXAMPLE 75 [185] l-{3-[2-(4-Methylphenoxy)ethoxy]ρhenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide.
[186] 1 -(3-Ηydroxyphenyl)-N-pyridin-3 -ylmethyl- lH-benzimidazole-5- carboxamide (5.0g, 14.5mmol), tetrabutylammonium iodide (536mg, 1.5mmol) and sodium hydroxide (9.8g, 41.7mmol) were dissolved in anhydrous ethanol and heated to reflux for 15min. 2-Chloroethyl tosylate (581mg, 41.67mmol, 7.6mL) was then added and the mixture allowed to stir at 80°C for 18h. After this time, the reaction mixture was concentrated in vacuo and the crude product purified by chromatography over silica gel eluting with 50% ethyl acetate/hexanes to 10% methanol in ethyl acetate to give 1- [3-(2-chloroethoxy)phenyl]-N-pyridin-3-yhnethyl-lH-benzimidazole-5-carboxamide. [187] This material was reacted with 4-methylphenol using the previously described procedures to give the title compound. !Η ΝMR (CDC13, 400 MHz): δ 1.19 (s, 3H), 4.35 (dd, 2H, J = 5.6, 2.8 Hz), 4.39 (dd, 2H, J = 5.2, 3.2 Hz), 4.74 (d, 2H, J = 5.6 Hz), 6.64 (dd, IH, J = 7.2, 7.2 Hz), 6.85 (ddd, 2H, J = 9.6, 3.2, 3.2 Hz), 7.07-7.13 (m, 4H), 7.30 (dd, IH, J = 7.6, 4.8 Hz), 7.51 (dd, IH, J = 7.6, 7.6 Hz), 7.61 (d, IH, J = 8.8 Hz), 7.77 (dd, IH, J = 6.4, 1.6 Hz), 7.88 (dd, IH, J - 8.8, 2.0 Hz), 8.17 (s, IH), 8.27 (s, IH), 8.56 (dd, IH, J = 4.8, 1.6 Hz), 8.66 (d, IH, J = 2.0 Hz); MS (ES+): m/z 479 [MH+] [188] The following compounds were prepared according to the previously described procedures, substituting the l-(3-hydroxyphenyl)-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide for l-(4-hydroxyphenyl)-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide where applicable, and 4-methylphenol for the appropriately substituted phenol.
EXAMPLE 76 [189] l-{4-[2-(3-Chloroρhenoxy)ethoxy]ρhenyl}-N-ρyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 499 [MΗ4], 501 [MH4"]
EXAMPLE 77 [190] l-{4-[2-(3-Ethynylphenoxy)ethoxy]phenyl}-N-ρyridin-3-yhnethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 499 [MET4"]
EXAMPLE 78 [191] l-{4-[2-(3-Bromophenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 543 [Br79MΗ+], 545 [Br81MH+]
EXAMPLE 79 [192] l-{4-[2-(4-Cyanophenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 490 [MET"]
EXAMPLE 80
[193] l-{4-[2-(4-Chlorophenoxy)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 499 [C135MΗ+], 501 [C137MH+]
EXAMPLE 81
[194] 1 - {4-[2-(4-Methoxyphenoxy)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 495 [MΗ4]
EXAMPLE 82 [195] 1 - {4- [2-(3 -Methylphenoxy)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 479 [MET4"]
EXAMPLE 83 [196] N-Pyridin-3-ylmethyl-l-(4-{2-[(3-trifluoromethoxy)phenoxy]ethoxy} phenyl)- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 549 [MΗ+]
EXAMPLE 84
[197] l-{4-[2-(4-Methylphenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 479 [MΗ+]
EXAMPLE 85 [198] l-{4-[2-(3-Methoxyphenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 495 [MH4]
EXAMPLE 86
[199] l-{3-[2-(3-Chlorophenoxy)ethoxy]phenyl}-N-pyridin-3-yhnethyl-lH- benzimidazole-5-carboxamide. MS (ES+); m/z 499 [C135MΗ+], 501 [Cl^MH4] EXAMPLE FI [200] l-[4-(Pyridin-3-ylmethoxy)phenyl]- N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide.
[201] A mixture of l-(4-hydroxyphenyl)-N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide (75mg, 0.22mmol), PS-triphenylphosphine resin (327mg, 0.33mmol), and 3-pyridinecarbinol (35mg, 32μL, 0.33mmol) in anhydrous DMF (or TΗF) (2mL) under Ν2, was treated dropwise with DIAD (Diisopropyl azodicarboxylate) (66mg, 0.33mmol, 64μL). The mixture was heated at 40°C and stirred vigorously for 18h under nitrogen, after which time it was concentrated in vacuo and the residue purified by reverse-phase preparative ΗPLC to give the title compound as an opaque glassy solid. 1H NMR (CDC13, 400 MHz): δ 8.74 (dd, J= 2.4, 0.4 Hz, IH), 8.67-8.62 (m, 2H), 8.53 (dd, J= 4.8, 1.6 Hz, IH), 8.37 (d, J= 1.2 Hz, IH), 8.03 (s, IH), 7.92 (dd, J= 8.8, 1.6 Hz, IH), 7.84 (ddd, J= 8.0, 2.4, 1.6 Hz, IH), 7.77 (ddd, J= 8.4, 1.6, 1.6 Hz, IH), 7.59 (dd, J= 8.4, 0.4 Hz, IH), 7.45-7.35 (m, 4H), 7.32-7.26 (m, 2H), 7.20-7.13 (m, 2H), 5.18 (s, 2H), 4.74 (d, J= 6.0 Hz, 2H); MS (ES+): m/z 436 (100) [MH4], 437 (30) [MH+2].
[202] The following compounds were prepared according to the previously described procedures, replacing the l-(4-hydroxyphenyl)-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide and 3-pyridinecarbinol, for the appropriately substituted phenol and primary alcohol respectively.
EXAMPLE F2 [203] l-[3-(l,l,-biphenyl-2-ylmethoxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 511 [MET4]
EXAMPLE F3
[204] l-{3-[(3,4-Dimethoxybenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 495 [MΗ+]
EXAMPLE F4
[205] l-[3-(Cyclobutylmethoxy)phenyl]-N-ρyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 413 [MET4] EXAMPLE F5 [206] l-{3-[(4-Methoxybenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 465 [MΗ4]
EXAMPLE F6
[207] l-{3-[(2-Methoxybenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 465 [MET4]
EXAMPLE F7 [208] 1 - {3-[(4-Benzyloxy-3-methoxybenzyl)oxy]phenyl} -N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 571 [MΗ+]
EXAMPLE F8 [209] 1 - {3-[(4- {t-Butyl}benzyl)oxy]phenyl} -N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 491 [MΗ+]
EXAMPLE F9
[210] l-{3-[(4-Phenylbutyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzirnidazole-5-carboxamide. MS (ES+): m/z 477 [MET4"]
EXAMPLE F10
[211] 1 -[3-(Pyridin-4-ylmethoxy)phenyl]-N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 436 [MΗ4]
EXAMPLE Fll
[212] 1 - [3 -(3 -Pyridin-4-ylpropoxy)phenyl] -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 464 [MΗ+]
EXAMPLE F12
[213] l-[3-(Pyridin-3-ylmethoxy)ρhenyl]-N-ρyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 436 [MΗ+]
EXAMPLE F13 [214] l-[4-(Pyridin-4-ylmethoxy)phenyl]-N-p}ridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 436 [MΗ+]
EXAMPLE F14
[215] l-[4-(3-Pyridin-4-ylρroρoxy)phenyl]-N-ρyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 464 [MΗ+]
EXAMPLE F15
[216] 1 - {4-[2-(4-Methylthiazol-5-yl)ethoxy]ρhenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 470 [MΗ4"]
EXAMPLE F16
[217] l-[3-(Furan-3-ylmethyl)oxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 425 [MET4"]
EXAMPLE F17
[218] N-pyridin-3-ylmethyl-l-{4-[(2-Thiophen-2-ylethyl)oxy]phenyl}-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 455 [MΗ+]
EXAMPLE F18
[219] N-pyridin-3-ylmethyl-l-{3-[(2-Thioρhen-2-ylethyl)oxy]ρhenyl}-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 455 [MET4"]
EXAMPLE F19
[220] N-pyridin-3-ylmethyl- 1 - {4-[(2-Thioρhen-3 -ylethyl)oxy]ρhenyl} - 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 455 [MET4"]
EXAMPLE F20
[221] l-(3-{[l-(4-Chlorophenyl)cyclopropyl]methoxy}phenyl)-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 509 [C135MΗ+], 511 [C137MH+]
EXAMPLE F21 [222] l-(4-{[l-(4-Chlorophenyl)cyclopropyl]methoxy}phenyl)-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 509 [C135MΗ ], 511 [C137MH+]
EXAMPLE F22 [223] N-pyridin-3-yhnethyl-l-{3-[(2-Thiophen-3-ylethyl)oxy]phenyl}-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 455 [MET4"]
EXAMPLE Gl
[224] N-(2-morpholin-4-ylethyl)- 1 -(4- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 541 [MET4"] [225] a) A 0.02M methanolic solution of l-(4-hydroxyphenyl)-lΗ- benzimidazole-5-carboxylic acid, (4.5g, 17.7mmol) was treated with 12M HC1 (15mL, 177mmol) and the resulting mixture allowed heated at reflux (90°C) for 2d. Upon completion of reaction, the mixture was concentrated in vacuo to afford methyl l-(4- hydroxyphenyl)-lH-benzimidazole-5-carboxylate which was used without further purification. 1H ΝMR (DMSO-cfo 400 MHz) δ 3.89 (s, 3H), 7.01 (d, 2H, J= 8.8 Hz), 7.47 (d, 2H, J = 8.8 Hz), 7.59 (d, IH, J= 8.4 Hz), 7.94 (dd, IH, J= 8.4 Hz, 1.2 Hz), 8.34 (d, IH, .7=1.2 Hz), 8.34 (s, IH), 10.02 (s, IH); MS (ES+): m/z 269 (MH4"). [226] b) A 0.2M DMF solution of methyl l-(4-hydroxyphenyl)-lH- benzimidazole-5-carboxylate (3.0g, 9.8mmol) with KOtBu (2.2g, 19.6mmol) was stirred at rt for 20min. prior to treatment with Νal (9.8mmol, 1.47g)
Figure imgf000042_0001
benzylbromide (1.88mL, 11.2mmol). The mixture was heated at 60°C for 24h. after which the mixture was concentrated in vacuo, and the residue purified by chromatography over silica gel eluting with 1:1 EtOAc:Ηexane to afford methyl l-(4- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5-carboxylate. 1H ΝMR (OMSO-d6, 400 MHz) δ 3.89 (s, 3H), 5.26 (s, 2H), 7.26-7.29 (m, 2H), 7.43 (d, 2H, J= 7.6 Hz), 7.61-7.65 (m, 5H), 7.86 (dd, IH, J= 8.8 Hz, 1.6 Hz), 8.35 (d, IH, J= 1.2 Hz), 8.65 (s, IH); MS (ES+): m/z 443 (MH+).
[227] c) A 0.5M THF solution of methyl l-(4-{[4-(trifluoromethoxy)benzyl] oxy} phenyl)- lH-benzimidazole-5-carboxylate (3.7g, 8.4mmol) was treated with 10M ΝaOΗ (8.4mL, 84mmol) and enough methanol to make the mixture homogeneous. The reaction mixture was then heated at 70°C for 24h, after which it was concentrated in vacuo, taken up in water and acidified to pH 4 with 2M HCl(aq). The resulting precipitate was filtered and washed with water to afford l-(4-{[4-(trifluoromethoxy) benzyl]oxy}phenyl)-lH-benzimidazole-5-carboxylic acid. 1H NMR (BMS>0-d6, 400 MHz) δ 5.26 (s, 2H), 7.26-7.29 (m, 2H), 7.43 (d, 2H, J= 8.0 Hz), 7.58 (d, IH, J= 8.0 Hz), 7.63-7.66 (m, 4H), 7.94 (dd, IH, J= 8.8 Hz, 1.6 Hz), 8.33 (d, IH, J = 0.8 Hz), 8.62 (s, IH); MS (ES+): m/z 429 (MH+).
[228] d) A 0.3 M THF solution of l-(4- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5-carboxylic acid (lOOmg, 0.23mmol) and CDI (76mg, 0.46mmol) was stirred at 60°C for 4h, after which the mixture was treated with a primary or secondary amine (0.35mmol) and heating continued for a further 16h. After this time, the mixture was concentrated in vacuo and the resulting residue purified by chromatography over silica gel. Recrystallization of the eluted product afforded [229] The following compounds were prepared according to the procedures described above for EXAMPLE Gl utilizing the appropriate alkyl halides and amines.
EXAMPLE G2
[230] N-(3-Dimethylaminopropyl)- 1 -(4- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 513 [MET4"]
EXAMPLE G3
[231] N-(2-Dimethylaminoethyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 499 [MΗ4]
EXAMPLE G4
[232] N-(3-Methoxypropyl)- 1 -(4- {[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 500 [MET]
EXAMPLE G5
[233] N-(2-Methoxyethyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy}ρhenyl)-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 486 [MΗ+]
EXAMPLE G6
[234] N-(2-Piperidin-l-ylethyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 539 [MET4"] EXAMPLE G7 [235] 2-(4- {[1 -(4- {[4-(trifluoromethoxy)benzyl]oxy}phenyl)- 1H- benzimidazol-5-yl]carbonyl}piperazin-l-yl)ethanol. MS (ES+): m/z 541 [MET4"]
EXAMPLE G8
[236] N-[3-(4-Methylpiperazin-l-yl)propyl]-l-(4-{[4-(trifluoromethoxy) benzyl]oxy}phenyl)-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 568 [MET4]
EXAMPLE G9
[237] N-(3-Morρholin-4-ylρropyl)-l-(4-{[4-(trifluoromethoxy) benzyl]oxy}phenyl)-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 555 [MΗ4"]
EXAMPLE G10
[238] l-{4-[2-(4-Fluorophenoxy)ethoxy]phenyl}-N-[3-(4-methylpiperazin-l- yl)propyl]-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 532 [MΗ+]
EXAMPLE Gil
[239] 1 - {4-[2-(4-Fluorophenoxy)ethoxy]phenyl} -N-(2-morpholin-4-ylethyl)- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 505 [MΗ+]
EXAMPLE G12
[240] 1 - {4-[2-(4-Fluorophenoxy)ethoxy]phenyl} -N-[2-(Ν,Ν- dimethylamino)ethyl]-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 463 [MET4]
EXAMPLE G13 [241] l-{4-[2-(4-Fluorophenoxy)ethoxy]phenyl}-N-[3-(N,N- dimethylamino)propyl]-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 477 [MΗ+]
EXAMPLE G14
[242] l-{4-[2-(4-Fluorophenoxy)ethoxy]phenyl}-N-(3-methoxypropyl)-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 464 [MΗ+]
EXAMPLE G15 [243] 1 - {4-[2-(4-Fluorophenoxy)ethoxy]phenyl} -N-(2-methoxyethyl)- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 450 [MFf4"]
EXAMPLE G16 [244] 2- { 1 -[(1 - {4-[2-(4-Fluorophenoxy)ethoxy]phenyl} - lH-benzimidazol-5- yl)carbonyl]piperidin-4-yl}ethanol. MS (ES+): m/z 504 [MΗ4"]
EXAMPLE G17
[245] 1 - {4-[2-(4-Fluorophenoxy)ethoxy]ρhenyl} -N-(2-piperidin- 1 -ylethyl)- 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 503 [MET4"]
EXAMPLE G18
[246] 1 - {4-[2-(4-Fluorophenoxy)ethoxy]phenyl} -N-(3-morpholin-4-ylpropyl)- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 519 [MΗ+]
EXAMPLE G19
[247] 1 - {4-[2-(4-Fluorophenoxy)ethoxy]phenyl} -N-ethyl- lH-benzimidazole-5- carboxamide. MS (ES+): m/z 420 [MFf4"]
EXAMPLE G20
[248] 2- { 1 -[(1 - {4-[2-(4-Fluorophenoxy)ethoxy]phenyl} -lH-benzimidazol-5- yl)carbonyl]ρiρerazin-4-yl}ethanol. MS (ES+): m/z 505 [MΗ4]
EXAMPLE G21
[249] N-[(l -oxidopyridin-3-yl)methyl]- 1 -(4- {[4-(trifluoromethoxy) benzyl]oxy}phenyl)-lH-benzimidazole-5-carboxamide.
[250] N-Pyridin-3-ylmethyl-l-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide (EXAMPLE 35, 31mg, 0.060mmol) was dissolved in DCM (3mL) and treated with -chloroperoxybenzoic acid (18mg, 0.72mmol) and the mixture stirred at rt for 4h. After this time the mixture was concentrated in vacuo and the crude product purified by preparative ΗPLC to give the title compound. !Η ΝMR (CD3OD, 400 MHz): δ 4.63 (s, 2H), 5.21 (s, 2H), 7.24 (d, 2H, J= 9.1 Hz), 7.31 (d, 2H, J= 8.4 Hz), 7.51-7.60 (m, 6H), 7.66 (d, IH, J= 8.0 Hz), 7.90 (dd, IH, J= 8.8, 1.6 Hz), 8.25 (d, IH, J= 6.0 Hz), 8.31 (s, IH), 8.38 (s, IH), 8.46 (s, IH). MS (ES+); m/z 535 (100) [MH+], 536 (25) [MH+2].
EXAMPLE G22
[251] N-(2-Pyrrolidin-l-ylethyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide
[252] l-(4-{[4-(Trifluoromethyl)benzyl]oxy}phenyl)-lH-benzimidazole-5- carboxylic acid (25mg, 0.058mmol), PS-TFP (37mg, 0.053mmol), and DMAP (4mg, 0.032mmol) were added to a 24mL scintillation vial. CΗ2CI2 (ImL) and DMF (0.25mL) were added and the vial was shaken for 5min. DIC (33mg, 0.263mmol) was then added and the vial was shaken for 3h. The resin was filtered and washed with DMF (3xlmL), CH2C12 (3xlmL), DMF (3xlmL), and THF (3xlmL). The resin was resuspended in DMF (ImL) and then DIEA (lOμL, 0.058mmol) and 2-pyrrolidin-l- ylethanamine (7mg, 0.058mmol) were added. After shaking for 48h, the reaction was filtered and the resin washed with CH2CI2. The filtrate was concentrated in vacuo. The resultant crude white solid was purified using the Waters mass-directed HPLC purification system to give N-(2-pyrrolidin-l-ylethyl)-l-(4-{[4-(trifluoromethoxy) benzyl]oxy} phenyl)- lH-benzimidazole-5-carboxamide as an off-white solid. MS (ES+): w/z 526 (100) [MΗ+].
EXAMPLE G23
[253] N-Isopropyl- 1 -(4- {[4-(difluoromethoxy)benzyl]oxy} phenyl)- 1H- benzimidazole-5-carboxamide; MS (ES+): m/z 452 [MET4].
EXAMPLE G24
[254] N-(l-Tetrahydro-2H-pyran-4-ylmethyl)-l-(4-{[4-(difluoromethoxy) benzyl]oxy}phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 508 [MET4"].
EXAMPLE G25
[255] N-Isopropyl-l-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 454 [MΗ4"].
EXAMPLE G26 [256] N-[3-(Dimethylamino)propyl]-l-{4-[2-(4-fluorophenoxy)ethoxy] phenyl} -lH-benzimidazole-5-carboxamide; MS (ES+): m/z 477 [MET4"].
EXAMPLE G27 [257] (4-{[l-([2-(4-Fluorophenoxy)ethoxy]phenyl)-lΗ-benzimidazol-5- yl]carbonyl}piperazin-l-yl)ethanol; MS (ES+): m/z 505.1 [MET4"].
EXAMPLE G28
[258] N-Ethyl-l-{4-[2-(4-fluorophenoxy)ethoxy]phenyl}-lH-benzimidazole-5- carboxamide; MS (ES+): m/z 420 [MΗ4].
EXAMPLE G29
[259] N-(2-Pyrrolidin-l-ylethyl)-l-(4-{[4-(trifluoromethyl)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 509 [MH4].
EXAMPLE G30
[260] N-(2-Hydroxyethyl)-l-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 456 [MΗ4].
EXAMPLE G31
[261] N-[3-(Dimethylamino)propyl]-l-(4-{[4-(trifluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 499 [MΗ4"].
EXAMPLE G32
[262] 1 - {4-[3-(4-Fluorophenoxy)propoxy]phenyl} -N-(3-methoxypropyl)- 1H- benzimidazole-5-carboxamide; MS (ES+): m/z 478 [MΗ4].
EXAMPLE G33
[263] l-{4-[3-(4-Fluorophenoxy)propoxy]phenyl}-N-(2-methoxyethyl)-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 464 [MΗ4"].
EXAMPLE G34
[264] 1 - {4-[3-(4-Fluorophenoxy)propoxy]phenyl} -N-(3-morpholin-4- ylpropyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 533 [MΗ4]. EXAMPLE G35 [265] l-{4-[3-(4-Fluorophenoxy)propoxy]phenyl}-N-(2-morpholin-4-ylethyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 519 [MΗ4].
EXAMPLE G36
[266] N-[2-(Dimethylamino)ethyl]- 1 - {4-[3-(4-fluorophenoxy)propoxy] phenyl} -lH-benzimidazole-5-carboxamide; MS (ES+): m/z 477 [MΗ4"].
EXAMPLE G37
[267] N-(2-Methoxyethyl)- 1 -(3- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- 1H- benzimidazole-5-carboxamide; MS (ES+): m/z 486 [MΗ+].
EXAMPLE G38
[268] . N-[2-(Dimethylamino)ethyl]- 1 -(3- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 499 [MΗ4"].
EXAMPLE G39
[269] N-(2-Mθ holin-4-ylethyl)-l-(3-{[4-(trifluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 541 [MΗ4"].
EXAMPLE G40
[270] N-[3-(4-Methylpiperazin-l-yl)propyl]-l-(3-{[4-(trifluoromethoxy) benzyl]oxy}phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 568 [MΗ4].
EXAMPLE G41
[271] N-Methyl-1 -(3- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- 1H- benzimidazole-5-carboxamide; MS (ES+) m/z 442 [MΗ+]. 1H ΝMR (DMSO-cfe 400 MHz): δ 2.82 (d, J= 4.5 Hz, 3H), 5.28 (s, 2H), 7.17 (dd, J= 8.4, 2.3 Hz, IH), 7.29 (d, J = 7.8 Hz, IH), 7.37 (t, J= 1.1 Hz, IH), 7.43 (s, IH), 7.45 (s, IH), 7.60 (m, 4H), 7.85 (dd, J= 8.6, 1.5 Hz, IH), 8.29 (d, J= 1.4 Hz, IH), 8.51 (brs, IH), 8.67 (s, IH).
EXAMPLE G42 [272] N-(l-Tefrahydro-2H-pyran-4-ylmethyl)-l-(4-{[4-(trifluoromethoxy) benzyl]oxy}phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 516 [MΗ4].
EXAMPLE G43 [273] N-[2-(lH-hnidazol-2-yl)ethyl]-l-(4-{[4-(trifluoromethoxy)benzyl] oxy}phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 522 [MΗ4"].
EXAMPLE G44
[274] N-(2-Ηydroxyethyl)- 1 -(4- {[4-(trifluoromethoxy)benzyl]oxy}phenyl)- 1H- benzimidazole-5-carboxamide; MS (ES+): m/z 472 [MΗ4"].
EXAMPLE G45
[275] N-(3-Ηydroxypropyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 486 [MΗ4"].
EXAMPLE G46
[276] l-{4-[3-(4-Fluorophenoxy)propoxy]phenyl}-N-(2-hydroxyethyl)-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 450 [MΗ4"].
EXAMPLE G47
[277] l-{4-[3-(4-Fluorophenoxy)propoxy]phenyl}-N-(2-piperidin-l-ylethyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 517 [MΗ4].
EXAMPLE G48
[278] N-(3-Morpholin-4-ylpropyl)-l -(3- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 555 [MΗ4"].
EXAMPLE G49
[279] N- [3 -(Dimethylamino)propyl] - 1 -(3 - { [4-(trifluoromethoxy)benzyl] oxy} phenyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 513 [MΗ4].
EXAMPLE G50
[280] N-(3-Methoxypropyl)-l-(3-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 500 [MΗ4]. EXAMPLE G51 [281] 5-(Morpholin-4-ylcarbonyl)-l-(3-{[4-(trifluoromethoxy)benzyl]oxy} ρhenyl)-lH-benzimidazole; MS (ES+): m/z 498 [MΗ4"].
EXAMPLE G52
[282] (4-{[l-(3-{[4-(Trifluoromethoxy)benzyl]oxy}phenyl)-lH-benzimidazol-
5-yl]carbonyl}piperazin-l-yl)ethanol; MS (ES+): m/z 541 [MΗ4].
EXAMPLE G53
[283] (l-{[l-(3-{[4-(Trifluoromethoxy)benzyl]oxy}phenyl)-lH-benzimidazol-
5-yl]carbonyl}piperidin-4-yl)ethanol; MS (ES+): m/z 540 [MΗ4].
EXAMPLE G54
[284] N-(2-Piperidin- 1 -ylethyl)- 1 -(3- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 539 [MΗ4"].
EXAMPLE G55
[285] 5-[4-(2-Methoxyethyl)piperazin-l-ylcarbonyl]-l-[3-(4-trifluoromethoxy- benzyloxy)-phenyl]-lH-benzimidazole; MS (ES+): m/z 555 [MΗ4"].
EXAMPLE G56
[286] N-Ethyl-l-(3-{[4-(trifluoromethoxy)benzyl]oxy}ρhenyl)-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 456 [MET4"].
EXAMPLE G57 [287] l-{3-[3-(4-Fluorophenoxy)propoxy]phenyl}-N-[3-(4-methylpiperazin-l- yl)propyl]-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 532 [MΗ4"].
EXAMPLE G58
[288] 1 - {3-[3-(4-Fluorophenoxy)propoxy]phenyl} -N-(3-morpholin-4ylpropyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 519 [MΗ4"].
EXAMPLE G59 [289] N-[2-(Dimethylamino)ethyl]-l-{3-[2-(4-fluorophenoxy)ethoxy]phenyl}- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 463 [MΗ+].
EXAMPLE G60 [290] N-[3-(Dimethylamino)propyl]- 1 - {3-[2-(4-fluorophenoxy)ethoxy]phenyl}
-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 477 [MΗ4"].
EXAMPLE G61
[291] l-{3-[2-(4-Fluoroρhenoxy)ethoxy]phenyl}-N-(2-methoxyethyl)-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 450 [MΗ4].
EXAMPLE G62
[292] 1 - {3 -[2-(4-Fluorophenoxy)ethoxy]phenyl} -N-tetrahydro-2H-pyran-4-yl- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 476 [MΗ4"].
EXAMPLE G63
[293] l-{3-[2-(4-Fluorophenoxy)ethoxy]phenyl}-N-(l-tetrahydro-2H-pyran-4- ylmethyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 490 [MΗ4"].
EXAMPLE G64
[294] N-Tetrahydro-2H-pyran-4-yl- 1 -(4- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 513 [MΗ4].
EXAMPLE G65
[295] N-Cyclobutyl- 1 -(4- { [4-(trifluoromethoxy)benzyl] oxy} phenyl)- 1H- benzimidazole-5-carboxamide; MS (ES+): m/z 482 [MET4"].
EXAMPLE G66
[296] N-Isopropyl- 1 -[4-( {4-[(trifluoromethyl)thio]benzyl} oxy)phenyl]- 1H- benzimidazole-5-carboxamide; MS (ES+): m/z 486 (100) [MΗ4].
EXAMPLE G67
[297] N-(2-Morpholin-4ylethyl)-l-[4-({4-[(trifluoromethyl)thio]benzyl}oxy) ρhenyl]-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 558 (100) [MΗ4]. EXAMPLE G68 [298] N-Methyl-l-[4-({4-[(trifluoromethyl)thio]benzyl}oxy)phenyl]-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 458 (100) [MΗ4"].
EXAMPLE G69
[299] N-(2-Pyrrolidin- 1 -ylethyl)- 1 -[4-( {4-[(trifluoromethyl)thio]benzyl} oxy)phenyl]-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 542 (100) [MΗ4"].
EXAMPLE G70
[300] N-(2-Ηydroxyethyl)-l-[4-({4-[(trifluoromethyl)thio]benzyl}oxy)phenyl]- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 488 (100) [MΗ4"].
EXAMPLE G71
[301] N-(l-Tetrahydro-2H-ρyran-4-ylmethyl)-l-[4-({4-[(trifluoromethyl)thio] benzyl} oxy)phenyl]-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 528 (100) [MΗ4"].
EXAMPLE G72 [302] N-(2-Methoxyethyl)-l-(4-{[4-(trifluoromethyl)benzyl]oxy}ρhenyl)-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 470 [MΗ4"].
EXAMPLE G73
[303] 1 -(4- {[4-(Trifluoromethyl)benzyl]oxy} phenyl)- lH-benzimidazole-5- carboxamide; MS (ES+): m/z 412 [MΗ4"].
EXAMPLE G74
[304] N-Methyl-l-(4-{[4-(trifluoromethyl)benzyl]oxy}ρhenyl)-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 426[MΗ4].
EXAMPLE G75 [305] N-(2-Morpholin-4ylethyl)-l-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 525 [MΗ4"]. EXAMPLE G76 [306] N-(l-Tefrahyώo-2H-pyran-4-ylme yl)-l-(4-{[4-(trifluoromethyl) benzyl]oxy}phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 510 [MΗ4"].
EXAMPLE G77 [307] N-Ethyl-l-[4-({4-[(trifluoromethyl)thio]benzyl}oxy)phenyl]-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 559 (100) [MΗ4].
EXAMPLE G78
[308] l-[4-({4-[(Trifluoromethyl)thio]benzyl}oxy)phenyl]-lH-benzimidazole-
5-carboxamide; MS (ES+): m/z 444 (100) [MΗ4"].
EXAMPLE G79
[309] 1 -(4- {[4-(Difluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5- carboxamide; MS (ES+): m/z 410 [MΗ4"].
EXAMPLE G80
[310] N-Methyl- 1 -(4- { [4-(difluoromethoxy)benzyl] oxy} phenyl)- 1H- benzimidazole-5-carboxamide; MS (ES+): m/z 424 [MΗ4"].
EXAMPLE G81
[311] N-(2-Morpholin-4ylethyl)-l-(4-{[4-(difluoromethoxy)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 523 [MΗ4].
EXAMPLE G82
[312] N-(2-Pyrrolidin-l-ylethyl)-l-(4-{[4-(difluoromethoxy)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 507 [MΗ4"].
EXAMPLE G83
[313] N-(2-Methoxyethyl)-l-(4-{[4-(difluoromethoxy)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 468 [MET4].
EXAMPLES Ηl & Η2 [314] N-Pyridin-3-ylmethyl- 1 - {4-[3-(pyridin-2-yloxy)propoxy]phenyl} - 1H- benzimidazole-5-carboxamide and l-{4-[3-(2-oxopyridin-l(2H)-yl)propoxy]phenyl}-N- pyridin-3-ylmethyl-lH-benzimidazole-5-carboxamide [315] l-[4-(3-Chloropropoxy)phenyl]-N-pyridin-3-yhnethyl-lH- benzimidazole-5-carboxamide (185mg, 0.44mmol), 2-pyridinol (42mg, 0.44mmol), cesium carbonate (156mg, 0.48mmol) and sodium iodide (72mg, 0.48mmol) were dissolved in DMF (4mL) and the mixture heated at 80°C under Ν2 for 16h. After this time the reaction mixture was concentrated in vacuo and subjected to reverse-phase preparative ΗPLC purification to afford isolation of N-pyridin-3-yhnethyl-l-{4-[3- (pyridin-2-yloxy)propoxy]phenyl}-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 480 [MΗ4] and l-{4-[3-(2-Oxopyridin-l(2H)-yl)propoxy]phenyl}-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 480 [MΗ4"] [316] The following examples were prepared according to the procedure described above for EXAMPLES Ηl & Η2 utilizing the appropriate alkyl halide and pyridinol in place of l-[4-(3-Chloropropoxy)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide and 2-pyridinol, respectively.
EXAMPLE Η3
[317] N-Pyridin-3 -ylmethyl- 1 - {3 -[3 -(pyridin-2-yloxy)propoxy]phenyl} - 1 H- benzimidazole-5-carboxamide. MS (ES+): m/z 480 [MΗ4]
EXAMPLES Η4 & H5
[318] N-Pyridin-3-ylmethyl- 1 - {4-[2-(ρyridin-2-yloxy)ethoxy]ρhenyl} - 1H- benzimidazole-5-carboxamide. MS (ES+): m/z 466 [MΗ4"] and l-{4-[2-(2-Oxopyridin- l(2H)-yl)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 466 [MΗ+]
EXAMPLE H6
[319] Ν-Pyridin-3-ylmethyl-l-{4-[2-(ρyridin-3-yloxy)ethoxy]ρhenyl}-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 466 [MH4]
EXAMPLE H7
[320] N-Pyridin-3-ylmethyl-l-{3-[3-(pyridin-3-yloxy)propoxy]phenyl}-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 480 [MΗ4] EXAMPLE H8 [321] l-{4-[2-(4-Oxopyridin-l(4H)-yl)ethoxy]phenyl}-N-pyridin-3-yhnethyl- lH-benzimidazole-5-carboxamide. MS (ES+): m/z 466 [MΗ4"]
EXAMPLE Η9
[322] l-(4-{2-[2-Oxo-5-(trifluoromethyl)pyridin-l(2H)-yl]ethoxy}phenyl)-N- pyridin-3-ylmethyl-lH-benzimidazole-5-carboxamide. MS (ES+): m/z 534 [MΗ4]
EXAMPLES Η10 & Ηll
[323] N-Pyridin-3 -ylmethyl- 1 - {4-[2-(5-chloropyridin-2-yloxy)ethoxy]phenyl} - lH-benzimidazole-5-carboxamide; MS (ES+): m/z 500 [MΗ4] and l-{4-[2-(5-Chloro-2- oxopyridin-l(2H)-yl)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide. MS (ES+): m/z 500 [MΗ4]
EXAMPLE Η12
[324] 5-(2-{4-[5-(Pyridin-3-ylmethylaminocarbonyl)-lH-benzimidazol-l- yl]phenoxy}ethoxy)nicotinic acid
[325] An aqueous solution of sodium hydroxide (0.107mmol, 43 μL, lOOmg/mL) was added to methyl 5-(2-{4-[5-(pyridin-3-ylmethylaminocarbonyl)- IH- benzimidazol- l-yl]phenoxy}ethoxy)nicotinate (prepared according to the procedure described above utilising methyl 5-hydroxynicotinate in place of 3-hydroxypyridine, 37mg, 0.07mmol) in methanol and the mixture heated at reflux for 18h. The mixture was then concentrated in vacuo and purified by preparative ΗPLC to yield the title compound. 1H ΝMR (d6-DMSO, 400 MHz): δ 9.15 (t, J= 6.0 Hz, IH), 8.64 (s, IH), 8.60-8.50 (m, 2H), 8.40-8.39 (m, 2H), 8.38 (d, J= 1.6 Hz, IH), 8.35 (s, IH), 7.87 (dd, J = 8.4, 1.6 Hz, IH), 7.78 (s, IH), 7.73 (d, J= 7.6 Hz, IH), 7.59 (dd, J= 12.4, 8.8 Hz, 3H), 7.35 (dd, J= 7.6, 5.2 Hz, IH), 7.23 (d, J= 8.8 Hz, 2H), 4.51 (d, J= 6.0 Hz, 2H), 4.50-4.4 (m, 4H); MS (ES+): m/z 510 [MH4], 511 [MH+2].
COMPOUND H13
[326] N-Pyridin-3-ylmethyl-l-{4-[2-(3-chloro-5-trifluoromethylρyridin-2- yloxy)ethoxy]phenyl}-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 568 [MET4"], 570 [MΗ+2]. This compound displayed results greater than lOμM in the assay above. EXAMPLE II [327] 1- {3-[(4-Chlorobenzyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide
[328] a) A mixture of 4-fluoro-3-nitrobenzoic acid (5) (10.2g, 54.9mmol), N-
(3-aminophenyl)acetamide (9.2 lg, 66.6mmol) andEt3Ν (1.4mL, 10. lmmol) in anhydrous EtOΗ (160mL) was heated at reflux under N2 overnight. The reaction mixture was then cooled and filtered, and the orange solid collected by filtration. It was then washed with 2 M ΗCl(aq), and dried in vacuo to give 4-{[3- (acetylamino)phenyl]amino}-3-nitrobenzoic acid. 1H NMR (400 MHz, DMSO- 6): δ
2.03 (s, 3H), 7.02 (d, J= 7.9 Hz, IH), 7.13 (d, J= 9.0 Hz, IH), 7.37 (t, J= 8.0 Hz, IH), 7.42 (d, J= 8.0 Hz, IH), 7.68 (s, IH), 7.93 (dd, J= 9.0, 1.9 Hz, IH), 8.62 (s, IH), 9.76 (s, IH), 10.08 (s, IH), 13.02 (br, IH); MS (ES+): m/z 316 [MH4"]
[329] b) A suspension of 4- { [3 -(acetylamino)phenyl] amino } -3 -nitrobenzoic acid (1.27g, 4.04mmol), Fe (1.77g, 31.6mmol, powder) inHCO2H (30mL) and HC(OMe) (20mL) was stirred under N2 at rt for 18h. After this time, the reaction mixture was filtered through Celite, the cake washed with EtOH and the filtrate concentrated in vacuo. The resultant crude material was purified by column chromatography over silica gel eluting with 10 % MeOH in DCM to afford l-[3- (acetylamino)phenyl]-lH-benzimidazole-5-carboxylic acid. 1H NMR (400 MHz, DMSO-rfβ): 8 2.07 (s, 3H), 7.36 (d, J = 8.4 Hz, IH), 7.56 (t, J = 8.0 Hz, IH), 7.63 (d, J = 8.4 Hz, IH), 7.69 (d, J= 8.8 Hz, IH), 7.96 (d, J= 8.8 Hz, IH), 8.02 (s, IH), 8.34 (s, IH), 8.71 (s, IH), 10.3 (s, IH); MS (ES+): m/z 196 [MH4]
[330] c) DIPEA (0.75mL, 4.3 lmmol) was added at rt to a mixture of l-[3-
(acetylamino)phenyl]-lH-benzimidazole-5-carboxylic acid (0.83g, 2.8mmol), EDC (0.8 lg, 4.22mmol), ΗOBt (0.57g, 4.22mmol) in anhydrous DMA (lOmL). The reaction mixture was stirred for 30min prior to the dropwise addition of 3-aminomethylpyridine (0.57mL, 5.62mmol). After stirring for a further 25h, the solvent was removed in vacuo and the crude material purified by column chromatography over silica gel eluting with 5-15 % MeOΗ in DCM. The product was further purified by recrystallisation from acetone to afford l-[3-(acetylamino)phenyl]-N-(pyridin-3-yhnethyl)-lH-benzimidazole- 5-carboxamide. 1H ΝMR (400 MHz, OMSO-d6): δ 1.09 (3H, s), 4.54 (d, J = 6.0 Hz, 2H), 7.35-7.4 (m, 2H), 7.56 (t, J = 8.0 Hz, IH), 7.62 (d, J = 7.6 Hz, IH), 7.70 (d, J =
8.4 Hz, IH), 7.76 (d, J = 8.4 Hz, IH), 7.92 (dd, J = 8.4 Hz, 1.2 Hz, IH), 8.04 (t, J = 2.0 Hz, IH), 8.38 (d, J= 1.2 Hz, IH), 8.46 (dd, J= 4.8 Hz, 1.6 Hz, IH), 8.58 (IH, J= 1.6 Hz, IH), 8.68 (s, IH), 9.21 (t, J= 5.6 Hz, IH), 10.33 (s, IH); MS (ES+): m/z 386 [MH4"]
[331] d) A solution of l-[3-(acetylamino)phenyl]-N-(pyridin-3-yhnethyl)-lH- benzimidazole-5-carboxamide (0.47g) in 2M ΗCl(aq) (5mL) was heated at reflux until complete consumption of the starting material as judged by LC-MS (approximately 40min). The crude reaction mixture was concentrated in vacuo and the residue dried in vacuo to afford l-(3-aminophenyl)-N-(pyridin-3 -ylmethyl)- lH-benzimidazole-5- carboxamide that was used without further purification. 1Η-ΝMR (DMSO-d6, 400 MHz): δ 3.5-5.5 (br), 4.72 (d, J = 5.2 Hz, 2H), 7.24 (d, J = 7.6 Hz, IH), 7.39 (d, J = 7.6 Hz, IH), 7.44 (s, IH), 7.56 (t, J= 8.4 Hz, IH), 7.82 (d, J= 8.4 Hz,lH), 8.10-8.50 (m, 2H), 8.47 (s, IH), 8.59 (d, J= 8.0 Hz, IH), 8.85 (IH, J= 5.6 Hz, IH), 8.96 (s, IH), 9.25 (s, IH), 9.64 (t, J = 5.6 Hz, IH). MS (ES+): m/z 344 [MH4] [332] e) A mixture of l-(3-aminophenyl)-N-(pyridin-3-yhnethyl)-lH- benzimidazole-5-carboxamide (l.Oeq) and 4-chlorobenzaldehyde (l.Oeq) in MeOΗ:ΗOAc (10:1 v/v, 0.017M) was stirred for 15min at rt prior to the addition of (polystyrylmethyl)trimethylammonium cyanoborohydride (3.5-5.0mmol/g, 2.5eq). The reaction mixture was shaken at rt overnight in a capped vial and then filtered through a plug of cotton wool. The resin was washed with MeOH and the combined filtrate and MeOH washings were concentrated under reduced pressure and purified by silica gel chromatography eluting with 5 % MeOH in DCM to yield l-{3-[(4- chlorobenzyl)amino]phenyl} -N-pyridin-3 -ylmethyl- lH-benzimidazole-5-carboxamide. 1H-ΝMR (CD3OD, 400 MHz): δ 4.38 (s, 2H), 4.89 (s, 2H), 6.68 (s, IH), 6.76 (dd, J = 2.0 Hz, 7.0 Hz, 2H), 7.20-7.45 (m, 7H), 7.81 (dd, J = 8.4 Hz, 1.6 Hz, IH), 7.89 (d, J = 6.0 Hz, IH), 8.26 (d, J= 1.2 Hz, IH), 8.42 (s, IH), 8.45 (d, J= 4 Hz, IH), 8.60 (s, IH). MS (ES+): m/z 469 [MH4"]
[333] The following compounds were prepared according to the procedures described above for EXAMPLE II, utilising the appropriate aldehydes in place of 4- chlorobenzaldehyde.
EXAMPLE 12
[334] l-{3-[(4-Bromobenzyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 513 [MΗ4] EXAMPLE 13 [335] l-{3-[(3-Methoxybenzyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 464 [MΗ4"]
EXAMPLE 14
[336] l-{3-[(Pyridin-4-ylmethyl)aπnho]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide. MS (ES+): m/z 435 [MET4"]
EXAMPLE 15
[337] l-{3-[(Pyridin-3-ylmethyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide.
[338] A solution of l-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-lH- benzimidazole-5-carboxamide (prepared in Steps (a)-(d) of the procedure used for the synthesis of EXAMPLE II, 70.2mg, 0.205mmol) and nicotinaldehyde (20μL, 0.21mmol) in DCM (ImL) under Ν2 was treated with TFA (ImL) and after 5min was heated at reflux for 2h. The cooled reaction mixture was then treated with Et3SiΗ (70μL, 0.44mmol) and the mixture re-heated to reflux for 19h. After this time the solvents and excess reagents were removed by concentration in vacuo and the crude residue purified by column chromatography over silica gel eluting with 0.7-15% MeOH/DCM to provide the title compound; MS (ES+): m/z 435 [MH4]
EXAMPLE Ml
[339] l-{4-[2-(Pyrazin-2-yloxy)ethoxy]phenyl}-N-(pyridin-3-ylmethyl)-lH- benzimidazole-5-carboxamide
HetAr-X
Figure imgf000058_0001
[340] a) 1 -(3-Hydroxyphenyl)-N-pyridin-3-ylmethyl- lH-benzimidazole-5- carboxamide (EXAMPLE B25, 2g, 5.81mmol), potassium carbonate (4.41g, 31.94mmol) and sodium iodide (1.92g, 12.77mmol) were dissolved in DMF (lOOmL). 2-Bromoethanol (3.63g, 17.42mmol) was added drop-wise and the reaction was heated at 80°C under N2 atmosphere for 16h. The reaction mixture was concentrated in vacuo and the crude reaction mixture was purified by silica gel chromatography (1:1 ethyl acetate/hexanes to 1:9 methanol/ethyl acetate) to obtain a mixture of l-[4-(2- hy(hoxyethoxy)phenyl]-N-(pyridin-3-ylmethyl)-lH-benzimidazole-5-carboxamide and l-{4-[2-(2-hydroxyethoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide dialkylated byproduct as a viscous brown solid. The mixture was carried onto the next step without further purification. MS(ES+): m/z 389.27 (100) [MΗ4]. [341] b) l-[4-(2-Ηydroxyethoxy)phenyl]-N-(pyridin-3-ylmethyl)-lH- benzimidazole-5-carboxamide (lOOmg, 0.26mmol) and sodium hydride (6mg, 0.26mmol) were dissolved in anhydrous DMF (2mL) under Ν2 atmosphere. The reaction mixture was heated to 60°C until hydrogen gas evolution ceased. 2- Chloropyrazine (35mg, 0.3 lmmol, 28μL) was then added drop-wise and the reaction was heated to 100°C. After 18 h, the reaction mixture was concentrated in vacuo and purified by mass-directed purification to provide l-{4-[2-(Pyrazin-2- yloxy)ethoxy]phenyl}-N-(pyridin-3-ylmethyl)-lH-benzimidazole-5-carboxamide (OSIP484814AA) as a white powder. 1H ΝMR (d6-OMSO, 400 MHz): δ 9.17 (brt, J= 6.0 Hz, IH), 8.60 (s, IH), 8.58 (d, J- 1.6 Hz, IH), 8.47 (dd, J= 5.2, 1.2 Hz, IH), 8.40 (d, J= 0.8 Hz, IH), 8.37 (d, J= 1.2 Hz, IH), 8.26 (s, 2H), 7.90 (dd, J= 8.6, 1.8Hz, IH), 7.76 (ddd, J= 8.2, 1.8 Hz, IH), 7.65-7.55 (m, 3H), 7.37 (ddd, J = 8.0, 4.8, 0.8 Hz, IH), 7.24 (ddd, J = 9.2, 2.2, 2.2 Hz, 2H), 4.69 (m, 2H), 4.54 (d, J= 4.4 Hz, 2H), 4.47 (m, 2H). MS(ES+): m/z 467 (100) [MH4"].
[342] The following compound was prepared according to the procedure described above for EXAMPLE Ml utilizing 2-chloropyrimidine in place of 2- chloropyrazine.
EXAMPLE M2 [343] l-{4-[2-(Pyrimidin-2-yloxy)ethoxy]phenyl}-N-(pyridin-3-ylmethyl)-lH- benzimidazole-5-carboxamide; MS(ES+): m/z 467 [MΗ ].
EXAMPLE Νl [344] N-Methyl-l-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-lH-benzimidazole-
5-carboxamide
Figure imgf000060_0001
[345] a) Ethylene glycol (30. lg, 484mmol), 2-chloropyridine (lO.Og,
88mmol), powdered potassium hydroxide (9.9g, 176.13mmol), and 18-crown-6 ether (9.3g, 35mmol) were dissolved in anhydrous toluene (500mL) under a N2 atmosphere. The reaction mixture was stirred vigorously and heated to reflux. After 48h, the reaction reached 50% conversion. The reaction mixture was concentrated in vacuo to approximately lOOmL volume then diluted with water (lOOmL). After stirring for 0.5h, the organic layer was separated and the aqueous layer was extracted with CH2C12. The organic extracts were combined, dried over anhydrous Na2SO , and concentrated in vacuo. The crude product was purified by Jones column chromatography (100% hexanes to 50% ethyl acetate/hexanes) to give 2-(pyridin-2-yloxy)ethanol as a dark brown oil containing 15% w/w of 18-crown-6 ether. 1H NMR -DMSO, 400 MHz): δ 8.14 (ddd, J= 5.0, 2.0, 1.2 Hz, IH), 7.68 (ddd, J= 9.4, 7.2, 2.4 Hz, IH), 6.95 (ddd, J= 8.0, 4.8, 1.2 Hz, IH), 6.80 (ddd, J= 8.4, 1.0, 1.0 Hz, IH), 4.83 (t, J= 5.6 Hz, IH), 4.26 (t, J= 5.2 Hz, 2H), 3.70 (dt, J= 10.4, 5.2 Hz, 2H).
[346] b) To a suspension of sodium hydride (21.6mg, 0.90mmol) in anhydrous
DMF (0.5mL), 2-(pyridin-2-yloxy)-ethanol (lOOmg, 0.72mmol) in DMF (1.5mL) was added drop-wise under a N2 atmosphere. Once hydrogen gas evolution ceased, 4- nitrofluorobenzene (102mg, 0.72mmol, 76μL) was added drop-wise to the yellow suspension. The resultant red-orange solution was allowed to stir at rt for 18h. Upon completion, distilled water (2mL) was added and the bright yellow solid precipitate was filtered, washed with distilled water, and dried in vacuo to give 2-[2-(4- nitrophenoxy)ethoxy]pyridine as a pale yellow solid. 1H NMR (</>DMSO, 400 MHz): δ 8.21 (ddd, J= 5.6, 3.6, 3.6 Hz, 2H), 7.72 (ddd, J= 9.2, 7.2, 2.0 Hz, IH), 7.21 (ddd, J= 5.6, 3.6, 3.6 Hz, IH), 7.01 (ddd, J= 7.0, 4.8, 0.8 Hz, IH), 6.86 (ddd, J= 8.4, 0.8, 0.8 Hz, IH), 4.62 (m, 2H), 4.49 (m, 2H). MS(ES+): m/z 261 [MH4"]. [347] c) 2-[2-(4-Nitrophenoxy)ethoxy]pyridine (1 OOmg, 0.38mmol) and tin (II) chloride dihydrate (433mg, 1.92mmol) were dissolved in ethanol (1.5mL) and refluxed under nitrogen for 18h. The reaction mixture was basified to pH 12 with 3M aqueous sodium hydroxide solution. The reaction mixture was stirred for lh and then filtered through Celite. The reaction mixture was concentrated in vacuo and the aqueous layer was separated and extracted with CH2CI2 (5x). The combined organic extracts were concentrated in vacuo to give 4-[2-(pyridin-2-yloxy)ethoxy]aniline as a purple glassy solid. 1H NMR -DMSO, 400 MHz): δ 8.16 (ddd, J= 5.2, 2.0, 0.8 Hz, IH), 7.71 (ddd, J= 9.2, 7.2, 2.0 Hz, IH), 6.99 (ddd, J= 7.2, 5.2, 1.0 Hz, IH), 6.85 (ddd, J= 8.4, 0.8, 0.8 Hz, IH), 6.68 (ddd, J= 5.6, 3.6, 3.6 Hz, 2H), 6.50 (ddd, J= 5.6, 3.6, 3.6 Hz, 2H), 4.62 (brs, 2H), 4.50 (m, 2H), 4.15 (m, 2H).
[348] d) 4-[2-(Pyridin-2-yloxy)ethoxy]aniline (4.50g, 19.50mmol) and 4- fluoro-3-nitrobenzoic acid (3.60g, 19.50mmol) were dissolved in ethanol (lOOmL) and refluxed under nitrogen for 18h. The reaction mixture was filtered and washed with cold ethanol (x2) to give 3-nitro-4-({4-[2-(pyridin-2-yloxy)ethoxy]phenyl}amino) benzoic acid as a reddish orange solid. !H NMR (< -DMSO, 400 MHz): δ 9.77 (brs, IH), 8.64 (d, J= 2.4 Hz, IH), 8.18 (ddd, J= 5.2, 2.0, 0.8 Hz, IH), 7.88 (dd, J= 9.6, 2.0 Hz, IH), 7.73 (ddd, J= 8.8, 6.8, 2.0 Hz, IH), 7.29 (ddd, J= 6.4, 3.2, 3.2 Hz, IH), 7.08 (ddd, J= 5.6, 3.2, 3.2 Hz, IH), 7.01 (ddd, J= 7.4, 5.2, 1.2 Hz, IH), 6.97 (d, J= 9.2 Hz, IH), 6.87 (ddd, J= 8.4, 0.8, 0.8 Hz, IH), 4.60 (m, 2H), 4.37 (m, 2H), 4.15 (m, 2H). MS(ES+): m/z 396.45 (100) [MH4].
[349] e) 3-Nitro-4-({4-[2-(pyridin-2-yloxy)ethoxy]phenyl}amino)benzoic acid
(6.00g, 15.20mmol), iron powder (8.49g, 152.00mmol), and formic acid (68mL) were dissolved in dry trimethyl orthoformate (175mL). The reaction was allowed to stir at rt. After 18h, the reaction mixture was diluted with CH2CI2 and filtered through Celite to give a bright orange solid. The crude mixture was recrystallized from methanol to give l-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-lH-benzimidazole-5-carboxylic acid as a yellow-tan powder. 1H NMR -DMSO, 400 MHz): δ 8.61 (d, J= 2.4 Hz, IH), 8.32 (d, J= 1.6 Hz, IH), 8.19 (ddd, J= 5.2, 1.6, 0.8 Hz, IH), 7.93 (dd, J= 8.8, 1.6 Hz, IH), 7.73 (ddd, J= 8.8, 6.8, 1.8, Hz, IH), 7.61 (ddd, J= 4.8, 2.8, 2.8 Hz, 2H), 7.58 (s, IH), 7.24 (ddd, J= 5.2, 3.2, 3.2 Hz, 2H), 7.01 (ddd, J= 6.8, 5.2, 1.2 Hz, IH), 6.88 (dd, J= 8.4, .4.0 Hz, IH), 4.64 (t, J= 4.2 Hz, 2H), 4.43 (t, J= 4.6 Hz, 2H). MS(ES+): m/z 376.47 (10) [MH4]. [350] £) l-{4-[2-(Pyridin-2-yloxy)ethoxy]phenyl}-lH-benzimidazole-5- carboxylic acid (lOOmg, 0.266mmol) and 1,1' -carbonyldiimidazole (86mg, 0.53mmol) were dissolved in dry TΗF (2mL) under a N2 atmosphere. The reaction mixture was heated at 60°C for lh and then cooled to rt. Methylamine hydrochloride (27mg, 0.40mmol) and NN -diisopropylethylamine (52mg, 0.40mmol, 70μL) were added and the reaction was allowed to stir at rt. After 18h, the reaction mixture was concentrated in vacuo, diluted with CΗ2C12 (2mL), and washed with distilled water (ImL). The aqueous phase was back extracted with CH2CI2 (2mL x 5) and the combined organic extracts were concentrated in vacuo. The resulting yellow solid was purified using the Waters mass-directed HPLC purification system to give N-methyl-l-{4-[2-(pyridin-2- yloxy)ethoxy]phenyl}-lH-benzimidazole-5-carboxamide as a white powder. 1H ΝMR -DMSO, 400 MHz): δ 8.57 (s, IH), 8.49 (brq, J= 4.4 Hz, IH), 8.28 (d, J= 1.2 Hz, IH), 8.19 (ddd, J= 5.2, 2.0, 0.8 Hz, IH), 7.85 (dd, J= 8.6, 1.4 Hz, IH), 7.74 (ddd, j = 8.8, 6.8, 2.0 Hz, IH), 7.61 (ddd, J- 5.2, 3.2, 3.2 Hz, 2H), 7.55 (d, J= 9.2 Hz, IH), 7.23 (ddd, J= 5.8, 3.6, 3.6 Hz, 2H), 7.01 (ddd, J= 7.2, 5.2, 1.2 Hz, IH), 6.88 (ddd, J= 8.4, 0.8, 0.8 Hz, IH), 4.63 (m, 2H), 4.43 (m, 2H), 2.82 (d, J= 4.8 Hz, 3H). MS(ES+): m/z 389 [MH4"].
[351] The following compounds were prepared according to the procedures described above for EXAMPLE Νl utilizing the appropriate amines in place of methylamine hydrochloride.
EXAMPLE Ν2 [352] N-Ethyl- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - lH-benzimidazole-5- carboxamide; MS(ES+): m/z 403 [MΗ4].
EXAMPLE Ν3 [353] N-(2-Methoxyethyl)- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]ρhenyl} - 1H- benzimidazole-5-carboxamide; MS(ES+): m/z 433 [MΗ4].
EXAMPLE Ν4 [354] N-(2-Mθ holin-4-ylethyl)-l-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-lH- benzimidazole-5-carboxamide; MS(ES+): m/z 488 [MΗ4"]. EXAMPLE N5 [355] l-{4-[2-(Pyridin-2-yloxy)ethoxy]phenyl}-N-(l-tetrahydro-2H-pyran-4- ylmethyl)-lH-benzimidazole-5-carboxamide; MS(ES+): m/z 473 [MΗ4"].
EXAMPLE Ν6
[356] 1 - {4-[2-(Pyridin-2-yloxy)ethoxy]phenyl} -N-tetrahydro-2H-pyran-4-yl- lH-benzimidazole-5-carboxamide; MS(ES+): m/z 459 [MΗ4"].
EXAMPLE Ν7 [357] N-Cyclobutyl- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide; MS(ES+): m/z 430 [MΗ4].
EXAMPLE Ν8 [358] N-(2-Ηydroxyethyl)-l-{4-[2-(pyridin-2-yloxy)ethoxy]ρhenyl}-lH- benzimidazole-5-carboxamide
[359] To a 20mL Bohdan MiniBlock 12-position glass reaction tube, l-{4-[2-
(pyridin-2-yloxy)ethoxy]phenyl}-lH-benzimidazole-5-carboxylic acid (100mg, 0.27mmol), PS- ΗOBt (ΗL; 269mg, 0.24mmol), DMAP (18mg, 0.15mmol), CΗ2C12 (lmL),and DMF (0.25mL) were added. The reaction mixture was shaken for 5min. 1,3-Diisopropylcarbodiimide (138mg, 1.09mmol) was added to the reaction mixture and shaken for 4h. The solution was filtered and the resin was washed with CH2CI2 (3x3mL), DMF (3x3mL), and THF (3x3mL). The resin was resuspended in DMF (ImL) and 2-aminoethanol (15mg, 0.24mmol) and DIEA (31mg, 0.24mmol) were added. The reaction mixture was allowed to shake overnight. The reaction mixture was then filtered, and washed with CH2C12 (3x3mL), DMF (3x3mL), and THF (3x3mL). The filtrate and the washes were combined and concentrated in vacuo. The crude product was purified by using the Waters mass-directed HPLC purification system to yield N-(2 -hydroxyethyl)- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} -lH-benzimidazole- 5-carboxamide as a yellowish white powder. 1H ΝMR (d6-DMSO, 400 MHz): δ 8.57 (s, IH), 8.49 (t, J= 4.4 Hz, IH), 8.32 (d, J= 1.2 Hz, IH), 8.19 (ddd, J= 5.2, 2.0, 0.8 Hz, IH), 7.85 (dd, J= 8.4, 1.6 Hz, IH), 7.74 (ddd, J = 9.2, 7.2, 2.0 Hz, IH), 7.61 (ddd, J= 5.6, 3.6, 3.6 Hz, 2H), 7.56 (d, J= 8.0 Hz, IH), 7.23 (ddd, J= 6.0, 3.6, 3.6 Hz, 2H), 7.01 (ddd, J= 7.2, 5.2, 0.8 Hz, IH), 6.88 (ddd, J= 8.4, 0.8, 0.8 Hz, IH), 4.63 (m, 2H), 4.43
(m, 2H), 2.82 (d, J= 4.8 Hz, 3H). MS(ES+): m/z 419 (60) [MH4"].
[360] The following compounds were prepared according to the procedures described above for EXAMPLE N8 utilizing the appropriate amines in place of 2- aminoethanol.
EXAMPLE N9 [361] l-{4-[2-(Pyridin-2-yloxy)ethoxy]phenyl}-N-(2-pyrrolidin-l-ylethyl)-lH- benzimidazole-5-carboxamide; MS(ES+): m/z 472 [MΗ4"].
EXAMPLE Ν10
[362] tert-Butyl-4- {[(1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} -1H- benzimidazol-5-yl)carbonyl]amino}ethyl)piperazine-l-carboxylate; MS(ES+): m/z 587 [MΗ4"].
EXAMPLE Nil
[363] N-Isopropyl- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide; MS(ES+): m/z 417 [MΗ4].
EXAMPLE Ν12 [364] l-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-lH-benzimidazole-5- carboxamide; MS(ES+): m/z 375 [MΗ+].
[365] The following compounds were prepared according to the procedures described above for EXAMPLE N8 utilizing the appropriate diols and amines in place of ethylene glycol and 2-aminoethanol, respectively.
EXAMPLE N13 [366] 1 - {4-[ 1 -Methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} -N-(2-morpholin-4- ylethyl)- lH-benzimidazole-5-carboxamide and N-(2-Morpholin-4-ylethyl)- 1 - {4-[2- (pyridin-2-yloxy)propoxy]phenyl}-lH-benzimidazole-5-carboxamide (1:1 mix of regioisomers); MS(ES+): m/z 503 [MΗ4].
EXAMPLE Ν14 [367] N-(2-Morpholin-4-ylethyl)- 1 - {4-[ 1 -methyl-2-(pyridin-2- yloxy)propoxy]phenyl}-lH-benzimidazole-5-carboxamide; MS(ES+): m/z 517 [MΗ4].
EXAMPLE Ν15
[368] 1 - {4-[ 1 -Methyl-2-(pyridin-2-yloxy)ethoxy]ρhenyl} - lH-benzimidazole-5- carboxamide and 1 - {4-[2-(pyridin-2-yloxy)propoxy]phenyl} - lH-benzimidazole-5- carboxamide (1:1 mix of regioisomers); MS(ES+): m/z 389 [MET4"].
EXAMPLE N16
[369] N-Isopropyl- 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide and N-Isopropyl-1- {4-[2-(pyridin-2- yloxy)propoxy]phenyl}-lH-benzimidazole-5-carboxamide (1:1 mix of regioisomers); MS(ES+): m/z 431 [MΗ4"].
EXAMPLE Ν17
[370] N-(2-Ηydroxyethyl)- 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} - lH-benzimidazole-5-carboxamide and N-(2-Ηydroxyethyl)- 1 - {4-[2-(pyridin-2- yloxy)propoxy]phenyl}-lH-benzimidazole-5-carboxamide (1:1 mix of regioisomers); MS(ES+): m/z 533 [MΗ4].
EXAMPLE Ν18
[371] 1- {4-[ 1 -Methyl-2-(pyridin-2-yloxy)ethoxy]ρhenyl} -N-(2-pyrrolidin- 1 - ylethyl)- lH-benzimidazole-5-carboxamide and l-{4-[2-(Pyridin-2- yloxy)propoxy]phenyl} -N-(2-Pyrrolidin- 1 -ylethyl)- lH-benzimidazole-5-carboxamide (1:1 mix of regioisomers); MS(ES+): m/z 487 [MΗ4"].
EXAMPLE Ν19
[372] 1 - {4-[ 1 -Methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} -N-(l -tetrahydro-2H- pyran-4-yhnethyl)-lH-benzimidazole-5-carboxamide and l-{4-[2-(Pyridin-2- yloxy)propoxy]phenyl}-N-(l-tetrahydro-2H-pyran-4-ylmethyl)-lH-benzimidazole-5- carboxamide (1:1 mix of regioisomers); MS(ES+): m/z 474 [MΗ4"].
EXAMPLE Ν20 [373] 1 - {4-[ l-Methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} -N-[3-
(methyltMo)propyl]-lH-benzimidazole-5-carboxamide andN-[3-(Methylthio)propyl]-l- {4-[2-(pyridin-2-yloxy)propoxy]phenyl}-lH-benzimidazole-5-carboxamide (1:1 mix of regioisomers); MS(ES+): m/z 478 [MΗ4"].
EXAMPLE Ν21 [374] 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)propoxy]phenyl} - lH-benzimidazole-
5-carboxamide; MS(ES+): m/z 403 [MET4"].
EXAMPLE N22 [375] N-Isopropyl- 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)propoxy]phenyl} - 1H- benzimidazole-5-carboxamide; MS(ES+): m/z 446 [MΗ4"].
EXAMPLE Ν23 [376] N-(2-Ηydroxyethyl)-l - {4-[ 1 -methyl-2-(pyridin-2- yloxy)propoxy]phenyl}-lH-benzimidazole-5-carboxamide; MS(ES+): m/z 447 [MΗ4"].
EXAMPLE Ν24 [377] 1 - {4-[ 1 -Methyl-2-(pyridin-2-yloxy)propoxy]phenyl} -N-(2-pyrrolidin- 1 - ylethyl)-lH-benzimidazole-5-carboxamide; MS(ES+): m/z 501 [MΗ4"].
EXAMPLE Ν25 [378] 1 - {4-[ 1 -Methyl-2-(pyridin-2-yloxy)propoxy]phenyl} -N-(l -tetrahydro-
2H-pyran-4-yhnethyl)-lH-benzimidazole-5-carboxamide; MS(ES+): m/z 488 [MΗ4].
EXAMPLE Ν26
[379] 1 - {4-[l -Methyl-2-(ρyridin-2-yloxy)propoxy]phenyl} -N-[3-
(methylthio)propyl]-lH-benzimidazole-5-carboxamide; MS(ES+): m/z 492 [MΗ+].
EXAMPLE Ν27 [380] N-Methyl- 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide andN-Methyl-l-{4-[2-(pyridin-2-yloxy)propoxy] phenyl} -lH-benzimidazole-5-carboxamide (1:1 mix of regioisomers); MS(ES+): m/z 403 [MΗ4"]. EXAMPLE N28 [381] N-Methyl-l-{4-[l-Methyl-2-(pyridin-2-yloxy)propoxy]phenyl}-lH- benzimidazole-5-carboxamide; MS(ES+): m/z 417 [MET4"].
EXAMPLE Ql
[382] 1 -(4- {[3-(2-Pyridyloxymethyl)cyclobutyl]oxy}phenyl)-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide
Figure imgf000067_0001
[383] a) Methyl 3-hydroxycyclobutanecarboxylate (671mg, 5.16mmol) was dissolved in CΗ2CI2 (20mL). Pyridine (0.63mL, 7.73mmol) was then added followed by 7-toluenesulfonic anhydride (1.85g, 5.67mmol) and the reaction was stirred at rt for 14h. The reaction was concentrated in vacuo, dissolved in ether, and washed with H2O, 2M HC1, 2M NaHCO , brine, and dried over MgSO . The solution was then filtered, and concentrated in vacuo to give methyl 3-{[(4-methylphenyl)sulfonyl]oxy} cyclobutanecarboxylate as a colorless oil, which was taken on crude. l-(4- Hydroxyphenyl)-N-(pyridin-3-ylmethyl)-lH-benzimidazole-5-carboxamide (0.88g, 2.56mmol), 18-crown-6 (1.36g, 5.13mmol), andK2CO3 (0.71g, 5.13mmol) were dissolved in DMF (26mL) in a 50mL round bottom flask. The reaction was heated to 80°C under Ν2 atmosphere upon which methyl 3-{[(4-methylphenyl)sulfonyl]oxy} cyclobutanecarboxylate was added drop-wise. After heating at 80°C for 48h, the reaction was cooled to rt, concentrated in vacuo, and purified using silica gel chromatography (5% methanokCΗzCk). To remove residual 7-toluenesulfonic acid and 18-crown-6, the foamy white solid was washed with ethyl acetate. The combined organic washes were then washed with water and dried over MgSO , filtered, and concenfrated in vacuo to provide methyl 3-(4-{5-[(pyridin-3-ylmethylamino)carbonyl]- lH-benzimidazol-l-yl}phenoxy)cyclobutanecarboxylate as an off-white foamy solid (3:1 trans is isomers). MS (ES+): m/z 457 (100) [MΗ4"]. [384] b) Methyl 3-(4- {5-[(ρyridin-3-ylmethylamino)carbonyl]- IH- benzimidazol- l-yl}phenoxy)cyclobutanecarboxylate (150mg, 0.33mmol) and sodium borohydride (25mg, 0.66mmol) were dissolved in TΗF (3mL), put under a N2 atmosphere, and heated to 60°C. Methanol (13μL, 0.33mmol) was then added and the reaction was stirred at 60°C for 48h. The reaction was cooled to rt and concentrated in vacuo. Methanol (2mL) was then added followed by sodium hydroxide (3M, 5mL) and the methanol was removed in vacuo. The resultant aqueous solution was extracted with ethyl acetate (3x), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was purified using the Waters mass-directed HPLC purification system to provide 1 -(4- { [3 -(hydroxymethyl)cyclobutyl] oxy} phenyl)-N-pyridin-3 -ylmethyl- 1 H- benzimidazole-5-carboxamide as a white solid. MS (ES+): m/z 429 (90) [MH4"]. [385] c) l-(4-{[3-(Hydroxymethyl)cyclobutyl]oxy}phenyl)-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide (33mg, 0.08mmol) was dissolved in DMF and put under Ν2 atmosphere. Sodium hydride (2mg, 0.08mmol) was added and the reaction was heated to 60°C. 2-Fluoropyridine was then added and the reaction was then heated to 80°C for 14h. The reaction was cooled to rt and concentrated in vacuo. The crude solid was purified using the Waters mass-directed ΗPLC purification system to provide l-(4-{[3-(2-pyridyloxymethyl)cyclobutyl]oxy}phenyl)-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide as an off-white solid. MS (ES+): m/z 507 (10) [MΗ4].
EXAMPLE PI
[386] 1 - {4-[(3-Phenoxypropyl)amino]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide
Figure imgf000068_0001
[387] A flask containing l-(4-bromophenyl)-N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide (EXAMPLE C2, lOOmg, 0.25mmol) and 3- phenoxypropylamine hydrochloride (54mg, 0.29mmol) was evacuated and refilled with Ν2 (2x). To this was added BTNAP (112mg, 0.18mmol), Pd2dba3 (55mg, 0.06mmol) and t-BuONa (68mg, 0.7 lmmol) in one portion as a mixture, with minimum exposure to air. The flask was again evacuated and refilled with N2 (3x). Degassed, anhydrous dioxane (2mL) was added via syringe and the solution was stirred under N2 for lOmin at rt and then at 80°C for 18h. Later, the reaction was cooled to rt, filtered through Celite (using MeOH and CH2CI2 to rinse the Celite), concentrated under reduced pressure and purified using the Waters mass-directed HPLC purification system to provide l-{4-[(3- phenoxypropyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole-5-carboxamide as a white solid. MS (ES+): m/z 478 (100) [MΗ4].
[388] The following compounds were prepared according to the procedure described above for EXAMPLE PI utilizing the appropriate amines in place of 3- phenoxypropylamine and either l-(3-bromophenyl)-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide or 1 -(4-bromophenyl)-N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide.
EXAMPLE P2
[389] 1 - {4-[4-(4-Fluorophenyl)piperidin- 1 -yl]phenyl} -N-pyridin-3 -ylmethyl- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 506 (100) [MΗ4"].
EXAMPLE P3
[390] 1 - {4-[4-(4-Fluorophenyl)piperazin-l -yfjphenyl} -N-pyridin-3 -yhnethyl- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 507 (100) [MΗ4].
EXAMPLE P4
[391] 1 - {3-[4-(4-Fluorophenyl)piperidin- 1 -yl]phenyl} -N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 506 (100) [MΗ+].
EXAMPLE P5
[392] N-Pyridin-3-ylmethyl-l-{3-[(2-thien-3-ylethyl)amino]phenyl}-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 454 (100) [MΗ4"].
EXAMPLE P6
[393] l-[3-(Cyclohexylmethylamino)phenyl]-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 440 (100) [MΗ4].
EXAMPLE P7
[394] l-{4-[(2-Phenoxyethyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 464 (100) [MΗ4"]. EXAMPLE P8 [395] l-(3-{[l-(4-Chlorophenyl)ethyl]amino}phenyl)-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 482 (100) [MΗ4"].
EXAMPLE P9
[396] l-(3-{[3-(lH-lmidazol-l-yl)propyl]amino}ρhenyl)-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 452 [MΗ4"].
EXAMPLE P10
[397] N-Pyridin-3-ylmethyl-l-[3-(4-pyrimidin-2-ylpiperazin-l-yl)phenyl]-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 491 [MΗ4].
EXAMPLE Pll
[398] l-(3-[l,4']Bipiperidinyl-l'-yl-phenyl)-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 495 [MΗ4"].
EXAMPLE P12
[399] 1 - {3-[Benzyl(methyl)amino]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; MS (ES+): m/z 44 [MΗ4"].
EXAMPLE P13
[400] N-Isopropyl- 1 -(4- {[4-(trifluoromethoxy)benzyl]amino}phenyl)- 1H- benzimidazole-5-carboxamide; MS (ES+): m/z 469 (100) [MΗ4].
EXAMPLE P14
[401] N-Methyl-l-(4-{[4-(trifluoromethoxy)benzyl]amino}phenyl)-lH- benzimidazole-5-carboxamide; MS (ES+): m/z 441 (100) [MΗ4"].
EXAMPLE P15
[402] N-(2-Morpholin-4-ylethyl)-l-(4-{[4-(trifluoromethoxy)benzyl] amino}phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 540 (100) [MΗ4"].
EXAMPLE P16 [403] N-Tetrahydro-2H-pyran-4-yl- 1 -(4- {[4-(trifluoromethoxy)benzyl] amino}phenyl)-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 511 (100) [MΗ+].
EXAMPLE P17 [404] N-Pyridin-3-ylmethyl-l-(3-{[4-(trifluoromethoxy)benzyl]amino}phenyl)- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 518 (100) [MΗ4].
EXAMPLE P18
[405] 1 - {3-[(4-Trifluoromethylphenyl)amino]phenyl} -N-pyridin-3 -ylmethyl- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 489 (100) [MΗ4"].
EXAMPLE Ql
[406] 1 -(3- {[(4-Methylphenyl)sulfonyl]amino}phenyl)-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide
Figure imgf000071_0001
[407] a) A mixture of 4-fluoro-3-nitrobenzoic acid (10.2g, 54.9mmol), N-(3- aminophenyl)-acetamide (9.21g, 66.6mmol), and Et3Ν (1.4mL, 10. lmmol.) in anhydrous EtOΗ (160mL) was heated at reflux under N2 atmosphere. After 16h, the reaction mixture was cooled and the resultant precipitate filtered. The orange solid was washed with 2 M aq ΗC1 and dried to yield 4-{[3-(acetylamino)phenyl]amino}-3- nitrobenzoic acid. 1H NMR (400 MHz, OMSO-d6): δ 2.03 (s, 3H), 7.02 (d, J = 7.9 Hz, IH), 7.13 (d, J = 9.0 Hz, IH), 7.37 (t, J = 8.0 Hz, IH), 7.42 (d, J = 8.0 Hz, IH), 7.68 (s, IH), 7.93 (dd, J= 9.0, 1.9 Hz, IH), 8.62 (s, IH), 9.76 (s, IH), 10.08 (s, IH), 13.02 (brs, IH). MS (ES+): m/z 316 [MH4].
[408] b) A suspension of 4-{[3-(acetylamino)phenyl]amino}-3-nitrobenzoic acid
(1.27g, 4.04mmol) and iron powder (1.77g, 31.6mmol) in HCO2H (30mL) and HC(OMe)3 (20mL) was stirred at rt under N2 atmosphere. After 18h, the reaction mixture was filtered through Celite and the Celite pad was washed with EtOH. The solvent was removed in vacuo. The resultant crude material was purified by silica gel chromatography (10% MeOH in CH2CI2) to afford l-[3-(acetylamino)phenyl]-lH- benzimidazole-5-carboxylic acid as a light yellow solid. 1H NMR (400 MHz, DMSO- d6): δ 2.07 (s, 3H), 7.36 (d, J= 8.4 Hz, IH), 7.56 (t, J= 8.0 Hz, IH), 7.63 (d, J= 8.4 Hz, IH), 7.69 (d, J = 8.8 Hz, IH), 7.96 (d, J= 8.8 Hz, IH), 8.02 (s, IH), 8.34 (s, IH), 8.71 (s, IH), 10.3 (s, IH). MS (ES+): rø/z 296 [MH4"].
[409] c) To a stirred mixture of l-[3-(acetylamino)phenyl]-lH-benzimidazole-
5-carboxylic acid (0.83g, 2.8mmol), EDCI (0.81g, 4.22mmol), ΗOBt (0.57g, 4.22mmol) in anhydrous DMA (lOmL) was added DIPEA (0.75mL, 4.3 lmmol) at rt. The reaction mixture was stirred for 0.5h and then (3-aminomethyl)pyridine (0.57mL, 5.62mmol) was added drop-wise. Stirring was continued for an additional 25h. The solvent was evaporated in vacuo and the crude material was purified by silica gel chromatography (5%-15 % MeOΗ in CΗ2C12) and then recrystallized from acetone to afford l-[3- (acetylammo)phenyl]-N-( yridin-3-ylmethyl)-lH-benzirnidazole-5-carboxarnide as a light yellow solid. 1H ΝMR (400 MHz, DMSO-tf6): δ 2.09 (3H, s), 4.54 (d, J = 6.0 Hz, 2H), 7.35-7.40 (m, 2H), 7.56 (t, J = 8.0 Hz, IH), 7.62 (d, J = 7.6 Hz, IH), 7.70 (d, J = 8.4 Hz, IH), 7.76 (d, J = 8.4 Hz, IH), 7.92 (dd, J = 8.4 Hz,1.2 Hz, IH), 8.04 (t, J = 2.0 Hz, IH), 8.38 (d, J= 1.2 Hz, IH), 8.46 (dd, J = 4.8 Hz, 1.6 Hz, IH), 8.58 (IH, J= 1.6 Hz, IH), 8.68 (s, IH), 9.21 (t, J= 5.6 Hz, IH), 10.33 (s, IH). MS (ES+): m/z 386 [MH4"]. [410] d) An aqueous HC1 (2M, 5mL) solution of l-[3-(acetylamino)phenyl]-N-
(pyridin-3 -ylmethyl)- lH-benzimidazole-5-carboxamide (0.47g) was heated at reflux. After 40min, the crude reaction mixture was evaporated under reduced pressure at rt and dried in vacuo to afford l-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-lH-benzimidazole-5- carboxamide dihydrochloride as a purple solid. 1H-ΝMR (DMSO-d6, 400 MHz): δ 4.00 (brs, 2H), 4.72 (d, J = 5.2 Hz, 2H), 7.24 (d, J = 7.6 Hz, IH), 7.39 (d, J = 7.6 Hz, IH), 7.44 (s, IH), 7.56 (t, J= 8.4 Hz, IH), 7.82 (d, J= 8.4 Hz,lH), 8.10-8.50 (m, 2H), 8.47 (s, IH), 8.59 (d, J = 8.0 Hz, IH), 8.85 (IH, J = 5.6 Hz, IH), 8.96 (s, IH), 9.25 (s, IH), 9.64 (t, J = 5.6 Hz, IH). MS (ES+): m/z 344 [MH4"]. [411] e) A mixture of l-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-lH- benzimidazole-5-carboxamide dihydrochloride (47mg, 0.14mmol) and TsCl (27mg, 0.14mmol) was dissolved in anhydrous TΗF (3mL) at 0°C and treated with Et3Ν (95 μL, 0.68mmol). The reaction mixture was stirred for 72h and then filtered. The solid residue was washed with TΗF and the combined washings and filtrate were concentrated in vacuo. The resultant residue was purified by silica gel chromatography (0-7% MeOΗ in CΗ2C12). Further purification was achieved by triruration with MeOH to afford l-(3-{[(4-methylphenyl)sulfonyl]amino}phenyl)-N-pyridin-3-y lmethyl-lH- benzimidazole-5-carboxamide as a white solid. 1H-NMR (DMSQ-d6, 400 MHz): δ
2.35 (s, 3H), 4.54 (d, J= 5.6 Hz, 2H), 7.20 (d, J= 8.0 Hz, IH), 7.32-7.44 (m, 4H), 7.50
(t, J= 7.6 Hz, IH), 7.68-7.81 (m, 3H), 7.89 (d, J= 8.8 Hz, IH), 8.36 (s, IH), 8.47 (brs,
IH), 8.61 (s, IH), 9.19 (brs, IH). MS (ES+): m/z 498 [MH4].
[412] The following compounds were prepared according to the procedure described above for EXAMPLE Ql utilizing the appropriate sulfonyl chlorides in place ofTsCl.
EXAMPLE Q2
[413] l-(3-{[(4-Chlorophenyl)sulfonyl]amino}phenyl)-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 518 (100) [M], 519 (30) [MΗ4].
EXAMPLE O3
[414] N-Pyridin-3 -ylmethyl- 1 - {3-[(thien-2-ylsulfonyl)amino]phenyl} - 1H- benzimidazole-5-carboxamide
[415] l-(3-Aminophenyl)-N-(pyridin-3-ylmethyl)-lH-benzimidazole-5- carboxamide dihydrochloride (60mg, 0.17mmol) was dissolved in 2mL pyridine at 0°C and 2-thiophenesulphonyl chloride (31mg, 0.17mmol) was added in one portion to the mixture, and the reaction was stirred room temperature. After 16h, the reaction mixture was concentrated in vacuo. The residue was purified using the Waters mass-directed ΗPLC purification system to yield N-pyridin-3 -ylmethyl- 1- {3-[(thien-2- ylsulfonyl)amino]phenyl}-lH-benzimidazole-5-carboxamide as a white solid. 1H ΝMR (400 MHz, CD3OD): δ 8.60 (s, 1 H), 8.48 (d, J= 12.0 Hz, 2 H), 8.30 (s, 1 H), 7.90 (t, J = 8.0 Hz, 2 H), 7.69 (d, J= 4.0 Hz, 1 H), 7.55 (dd, J= 1.2 Hz, 4.0 Hz, 1 H), 7.48-7.43 (m, 3 H), 7.37 (t, J= 2.0 Hz, 1 H), 7.21 (t, J= 8.0 Hz, 1 H), 7.09 (t, J= 8.0 Hz, 1 H), 4.67 (d, J= 5.4 Hz, 2H). MS (ES+): m/z 490 [MH4"].
[41 ] The following compounds were prepared according to the procedure described above for EXAMPLE Q3 utilizing the appropriate sulfonyl chlorides in place of thiophenesulphonyl chloride.
EXAMPLE O4
[417] N-Pyridin-3 -ylmethyl- 1 - [3 -( { [4-(trifluoromethoxy)phenyl] sulfonyl} amino)phenyl]-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 490 [MΗ4]. COMPOUND OS [418] l-(3-{[(3-Chlorophenyl)sulfonyl]amino}phenyl)-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide; MS (ES+): m/z 519 [MΗ4"]. This compound displayed results greater than 10/ M in the assay above.
EXAMPLE O6
[419] l-(3-{[(2,4-Difluorophenyl)sulfonyl]amino}phenyl)-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 520 [MΗ4].
EXAMPLE O7
[420] l-(3-{[(3,4-Dichlorophenyl)sulfonyl]amino}phenyl)-N-pyridin-3- ylmethyl-lH-benzimidazole-5-carboxamide; MS (ES+): m/z 553 [MΗ4].

Claims

WHAT IS CLAIMED IS:
1. A compound represented by Formula (I):
Figure imgf000075_0001
(I) or a pharmaceutically acceptable salt or N-oxide thereof, wherein: one of Rl 1, R12, R13 and R14 is -NR3COR31, -NR3CONR3R31, -NR3SO2R31, - CO2R3, -CO2H, -C0-8alkylNR3R31 or-CONR3R31; the others each independently F, CI, C0-3alkyl, C0-8alkoxy, or -N(Co,8alkyl)(Co-8alkyl); X is a cyclyl or heterocyclyl group, optionally substituted with 1-4 halogen, -NR32R33, -NR32COR33, -NR32CO2R33, -NR32SO2R33, -OR32, -SR32, -SO2R32, -SO2NR32R33, -CO2R3 , -CO2H, -CONR32R33, -C0-8alkyl, -C2-8alkenyl, -C2-8alkynyl, - CN, CF3, OCF3, NO2, oxo, cyclyl or heterocyclyl substituents; Y is absent or
Figure imgf000075_0002
wherein the point of attachment to X can be from either the left or the right as shown; Ra and R are each independently Co-salkyl or C3-8cycloalkyl; or Ra and R taken together with the C to which they are attached form a saturated or partially unsaturated 3-10 membered ring optionally containing 0-4 N, O, S, SO, or SO2 at the ring nodes, provided that no N, O or S atoms are placed adjacent to each other at ring nodes; Re is Co-8alkyl; or Re, taken with either Ra or Rb, form a 3-7 membered saturated or partially unsaturated ring; m is 0, 1, 2, 3, 4 or 5; provided that when m is 0 or 1, no N, O or S atoms are adjacent to each other in the N-X-Y-Z linking bridge; n is 1, 2, 3, 4 or 5; provided that, when n is 1, no N, O or S atoms are adjacent to each other in the N-X-Y-Z linking bridge; Z is a cyclyl or heterocycyl group, optionally substituted with 1-5 independent halogen, -NR34R35, -NR34COR35, -NR34C(O)OR35, -NR34SO2R35, -OR34, -SR34, -SO2R34, -SO2NR34R35, -C(O)OR34, -CO2H, -CONR34R35, C0-8alkyl, C2-8alkenyl, C2- 8alkynyl, -OC0-8alkyl, -SC0-8alkyl, -SO2Co-8alkyl,-SO2N(Co-8alkyl)(Co-8alkyl), -C(O)OCo-8alkyl, CN, CF3, NO2, oxo, cyclyl or heterocyclyl substituents; or, when Y is present, Z further can be Co-8alkyl-O-Co-8alkyl, C0-8alkyl-O-C(O)-Co-8alkyl, or Co-8alkyl- C(O)-O-C0-8alkyl; provided that when Y is -OCH2-, Z must be substituted with 1-5 -NR 4R35, -NR34COR35, -NR34C(O)OR35, -NR34SO2R35, -OR34, -SR34, -SO2R3 , -SO2NR34R35, - CO2R34, -CO2H, -CONR34R35, C0-8alkyl, C2-8alkenyl, C2-8alkynyl, CF3, NO2, oxo, cyclyl or heterocyclyl substituents; provided that when Y is NHCH2, Z must be substituted with 1-5 halogen, -NR34R35, -NR34COR35, -NR34C(O)OR35, -NR34SO2R35, -OR34, -SR34, -SO2R34, -SO2NR34R35, -CO2R34, -CO2H, -CONR34R35, C0-8alkyl, C^salkenyl, C2-8alkynyl, CF3, NO2, oxo, cyclyl or heterocyclyl substituents; provided that when Y is absent, X and Z cannot contain N; R3, R31, R32, R33, R34 and R35 are independently Co-8alkyl substituted with heterocyclyl, or OH substituents; CF3, CHF2, -C0-8alkyl-O-C0-8alkyl, -C0-8alkyl-N(C0-8alkyl)(C0- 8alkyl), -Co-8alkyl-S(O)0-2-C0-8alkyl or -C0-8alkyl-S(O)2N(C0-8alkyl)(Co-8alkyl).
2. The compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -NR3COR31, -NR3CONR3R31, -NR3SO2R31, -CO2R3, -CO2H, -Co. 8alkylNR3R3ι or -CONR3R3ι.
3. The compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, wherein R12 is -CONR3R31.
4. The compound according to claim 3, or a pharmaceutically acceptable salt or N-oxide thereof, wherein X is cyclyl.
5. The compound according to claim 4, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Y is absent.
6. The compound according to claim 4, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Y is
Figure imgf000077_0001
7. The compound according to claim 4, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Y is
Figure imgf000077_0002
8. The compound according to claim 4, or a pharmaceutically acceptable salt or
N-oxide thereof, wherein Y is
Figure imgf000077_0003
9. The compound according to claim 4, or a pharmaceutically acceptable salt or N-oxide thereof, wherein Y is
Figure imgf000077_0004
10. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable carrier.
11. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof; and an anti-neoplastic, anti-tumor, anti-angiogenic, or chemotherapeutic agent.
12. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, and a cytotoxic cancer therapeutic agent.
13. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt or N-oxide thereof, and an angiogenesis inhibiting cancer therapeutic agent.
14. A compound consisting of 1 - {3-[2-(phenylthio)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- lH-benzimidazole-5- carboxamide; l-{4-[2-(phenylthio)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; or a pharmaceutically acceptable salt, or N-oxide, thereof.
15. A compound consisting of l-[3-(3-phenylpropoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; 1 - {3-[(4-cyanobenzyl)oxy]phenyl} -N-pyridin-3 -ylmethyl- lH-benzimidazole-5- carboxamide; ethyl 5-[(3- {5-[(pyridin-3-ylmethylamino)carbonyl]- IH-benzimidazol- 1 - yl} phenoxyhnethyl] -2-fiιroate; 3-(3-{5-[(pyridin-3-ylmethylamino)carbonyl]-lH-benzimidazol-l- yl}phenoxy)pentyl acetate; 1 - [3 -(2-naphthylmethoxy)phenyl] -N-pyridin-3 -ylmethyl- lH-benzimidazole-5 - carboxamide; N-pyridm-3-ylmethyl-l-(3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; ethyl 4-{3-[5-(pyridin-3-ylmethylaminocarbonyl)-lH-benzimidazol-l- yl]phenoxy}hexanoate; l-[3-(2-morpholin-4-ylethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole- 5-carboxamide; l-{4-[(4-fluorobenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; methyl 4-[(4-{5-[(pyridin-3-ylmethylamino)carbonyl]-lH-benzimidazol-l- yl}phenoxy)methyl]benzoate; ethyl 5-[(4-{5-[(pyridin-3-ylmethylamino)carbonyl]-lH-benzimidazol-l- yl } phenoxy)methyl] -2-furoate; l-{3-[(4-methylbenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-{3-[(4-nitrobenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-{4-[(4-methylbenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; methyl 4-[(3-{5-[(pyridin-3-ylmethylamino)carbonyl]-lH-benzimidazol-l- yl}phenoxy)methyl]benzoate; 1 - {4-[(4-trifluoromethylbenzyl)oxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; l-[4-(2-naphthylmethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-{4-[(4-nitrobenzyl)oxy]phenyl}-N-ρyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-[4-(cyclohexylmethyloxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-[4-(l-phenethylethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; 1 -[3-(l -phenethylethoxy)phenyl] -N-pyridin-3 -ylmethyl- lH-benzimidazole-5- carboxamide; 1 - [3 -(2-phenylethoxy)phenyl] -N-pyridin-3 -ylmethyl- lH-benzimidazole-5 - carboxamide; l-[4-(2-moφholin-4-ylethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole- 5-carboxamide; N-pyridin-3 -ylmethyl- 1 -(3 - { [4-(trifluoromethoxy)benzyl] oxy} phenyl)- 1H- benzimidazole-5-carboxamide; N-pyridin-3-ylmethyl-l-(4-{[4-(trifluoromethoxy)benzyl]oxy} phenyl)- 1H- benzimidazole-5-carboxamide; l-[4-(2-phenoxyethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-[3-(2-phenoxyethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-[3-(lH-indol-3-ylmethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole- 5-carboxamide; 1 - {4-[3-(4-fluorophenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {3-[3-(4-fluorophenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; l-{4-[2-(2-methoxyethoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-[4-(2-methoxyethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-{3-[(2-methylthiazol-4-ylmethyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-{4-[(quinolin-2-ylmethyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-{3-[2-(4-chlorophenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-[4-(pyridin-3-ylmethoxy)phenyl]- N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; 1 - [3 -( 1 , 1 '-biphenyl-2-ylmethoxy)phenyl] -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {3-[(3,4-dimethoxybenzyl)oxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; l-[3-(cyclobutylmemoxy)phenyl]-N-pyridm-3-ylmethyl-lH-benzinιidazole-5- carboxamide; l-{3-[(4-methoxybenzyl)oxy]phenyl}-N-pyridin-3-yhnethyl-lH-benzimidazole- 5-carboxamide; l-{3-[(2-methoxybenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole- 5-carboxamide; l-{3-[(4-benzyloxy-3-methoxybenzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-{3-[(4-{t-butyl}berιzyl)oxy]phenyl}-N-pyridin-3-ylmethyl-lH-berιzimidazole- 5-carboxamide; 1 - {3-[(4-phenylbutyl)oxy]phenyl} -N-pyridin-3 -ylmethyl- lH-benzimidazole-5- carboxamide; l-[3-φyridin-4-ylmethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-[3-(3-pyridin-4-ylpropoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole- 5-carboxamide; l-[3-(pyridin-3-ylmethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-[4-(pyridin-4-ylmethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-[4-(3-pyridin-4-ylpropoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole- 5-carboxamide; 1 - [4-(2-(4-methylthiazol-5 -yl) ethoxy)phenyl] -N-pyridin-3 -ylmethyl- 1 H- benzimidazole-5-carboxamide; l-[3-(furan-3-ylmethyl)oxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; N-pyridin-3 -ylmethyl- 1 - {4-[(2-thiophen-2-ylethyl)oxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 - {3-[(2-thiophen-2-ylethyl)oxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 - {4-[(2-thiophen-3 -ylethyl)oxy]phenyl} - 1H- benzimidazole-5-carboxamide; l-(3-{[l-(4-chlorophenyl)cyclopropyl]methoxy}phenyl)-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide; l-(4-{[l-(4-chlorophenyl)cyclopropyl]methoxy}phenyl)-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 - {3-[(2-thiophen-3-ylethyl)oxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-(2-morpholin-4-ylethyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; N-(3 -dimethylaminopropyl)- 1 -(4- { [4-(trifluoromethoxy)benzyl] oxy} phenyl)- lH-benzimidazole-5-carboxamide; N-(2-dimethylaminoethyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; N-(3-methoxypropyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; N-(2-methoxyethyl)- 1 -(4- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- 1H- benzimidazole-5-carboxamide; N-(2-piperidin-l -ylethyl)- 1 -(4- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- 1H- benzimidazole-5-carboxamide; 2-(4-{[l-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH-benzimidazol-5- yl]carbonyl}piperazin-l-yl)ethanol; N-[3-(4-methylpiperazin-l-yl)propyl]-l-(4-{[4-(trifluoromethoxy)benzyl] oxy}phenyl)-lH-benzimidazole-5-carboxamide; N-(3-morpholin-4-ylpropyl)- 1 -(4- {[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide; N- [( 1 -oxidopyridin-3 -yl)methyl] - 1 -(4- { [4-(trifluoromethoxy)benzyl] oxy} phenyl)-lH-benzimidazole-5-carboxamide; l-{4-[3-(2-oxopyridin-l(2H)-yl)propoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-{4-[2-(4-oxopyridin-l(4H)-yl)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-(4-{2-[2-oxo-5-(trifluoromethyl)pyridin-l(2H)-yl]ethoxy}phenyl)-N-pyridin- 3-ylmethyl-lH-benzimidazole-5-carboxamide; 1 - {4-[2-(5-chloro-2-oxopyridin- 1 (2H)-yl)ethoxy]phenyl} -N-pyridin-3 -yhnethyl- lH-benzimidazole-5-carboxamide; or a pharmaceutically acceptable salt, or N-oxide, thereof.
16. A compound consisting of l-[3-(3-phenoxypropoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-[4-(2-phenylethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; 1 - {4-[2-(4-fluorophenoxy)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; l-[3-(2-methoxyethoxy)phenyl]-N-pyridin-3-yhnethyl-lH-benzimidazole-5- carboxamide; l-[4-(2-ethoxyethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; l-[3-(2-ethoxyethoxy)phenyl]-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; 1 - {3 -[2-(4-bromophenoxy)ethoxy]phenyl} -N-pyridin-3-ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {4-[2-(4-bromophenoxy)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {4-[2-methylthiazol-4-ylmethyl)oxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {3-[(quinolin-2-ylmethyl)oxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 -(4- {3 - [3 -(trifluoromethoxy)phenoxy]propoxy } phenyl)- lH-benzimidazole-5-carboxamide; 1 - {4-[3-(3-methoxyphenoxy}propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {4-[3-(3-chlorophenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {4-[3 -(4-cyanophenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {4-[3-(4-methoxyphenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; l-{4-[3-(3 -methylphenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; l-{4-[3-(3-ethynylphenoxy)propoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-{3-[3-(4-methylphenoxy)propoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-{3-[3-(4-cyanophenoxy)ρropoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-(3-{3-[3-(trifluoromethoxy)phenoxy]ρropoxy}phenyl)-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide; 1 - {3 - [3 -(3 -chlorophenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {3-[3-(4-chlorophenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {3 -[3 -(4-bromophenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1 H- benzimidazole-5-carboxamide; 1 -(3 - {3 -[4-(trifluoromethoxy)phenoxy]propoxy} phenyij-N-pyridin-3 -ylmethyl- lH-benzimidazole-5-carboxamide; l-{3-[3-(3 ,4-dichlorophenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5 -carboxamide; 1- {3-[3-(4-imidazol- 1 -ylphenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 -(3 - {3 - [4-(4H- 1 ,2,4-triazol-4-yl)phenoxy]propoxy} phenyl)-N-pyridin-3 - ylmethyl-lH-benzimidazole-5-carboxamide; 1 -(3 - {3 - [4-(trifluoromethyl)phenoxy]propoxy } phenyl)-N-pyridin-3 -ylmethyl- lH-benzimidazole-5-carboxamide; methyl 4-(3- {3-[5-(N-pyridin-3-ylmethyl)aminocarbonyl]- IH-benzimidazol- 1 - ylphenoxy}propoxy)benzoate; 1 - {4-[3 -(4-bromoρhenoxy)propoxy]phenyl} -N-pyridin-3 -ylmethyl- 1 H- benzimidazole-5-carboxamide; l-{3-[2-(4-methylphenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; 1 - {4-[2-(3 -chlorophenoxy)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {4-[2-(3-ethynylphenoxy)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; l-{4-[2-(3-bromophenoxy)ethoxy]ρhenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-{4-[2-(4-cyanophenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-{4-[2-(4-chlorophenoxy)ethoxy]phenyl}-N-pyridin-3-yhnethyl-lH- benzimidazole-5-carboxamide; l-{4-[2-(4-methoxyphenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-{4-[2-(3-methylphenoxy)ethoxy]phenyl}-N-pyrid ι-3-ylmethyl-lH- benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 -(4- {2- [(3 -trifluoromethoxy)phenoxy] ethoxy} phenyl)- lH-benzimidazole-5-carboxamide; 1 - {4-[2-(4-methylphenoxy)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; l-{4-[2-(3-methoxyphenoxy)ethoxy]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; 1 - {3-[2-(3-chlorophenoxy)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; 1 - {4- [2-(4-fluorophenoxy)ethoxy]phenyl} -N- [3 -(4-methylpiperazin- 1 - yl)propyl]-lH-benzimidazole-5-carboxamide; l-{4-[2-(4-fluorophenoxy)ethoxy]phenyl}-N-(2-morpholin-4-ylethyl)-lH- benzimidazole-5-carboxamide; l-{4-[2-(4-fluorophenoxy)ethoxy]phenyl}-N-[2-(Ν,Ν-dimethylamino)ethyl]-lH- benzimidazole-5-carboxamide; 1 - {4-[2-(4-fluorophenoxy)ethoxy]phenyl} -N-[3-(N,N-dimethylamino)propyl]- lH-benzimidazole-5-carboxamide; 1 - {4-[2-(4-fluorophenoxy)ethoxy]phenyl} -N-(3-methoxypropyl)- 1H- benzimidazole-5-carboxamide; 1 - {4-[2-(4-fluorophenoxy)ethoxy]phenyl} -N-(2-methoxyethyl)- 1H- benzimidazole-5-carboxamide; 2- { 1 -[(1 - {4-[2-(4-fluorophenoxy)ethoxy]phenyl} - lH-benzimidazol-5- yl)carbonyl]piperidin-4-yl}ethanol; 1 - {4-[2-(4-fluorophenoxy)ethoxy]phenyl} -N-(2-piperidin- 1 -ylethyl)- 1H- benzimidazole-5-carboxamide; l-{4-[2-(4-fluoroρhenoxy)ethoxy]ρhenyl}-N-(3-moφholin-4-ylpropyl)-lH- benzimidazole-5-carboxamide; 1 - {4-[2-(4-fluorophenoxy)ethoxy]phenyl} -N-ethyl- lH-benzimidazole-5- carboxamide 2- { 1 -[(1 - {4-[2-(4-fluorophenoxy)ethoxy]phenyl} - lH-benzimidazol-5- yl)carbonyl]piperazin-4-yl}ethanol; N-pyridin-3-ylmethyl- 1 - {4-[3-(pyridin-2-yloxy)propoxy]phenyl}- 1H- benzimidazole-5-carboxamide; N-pyridin-3-ylmethyl- 1 - {3-[3-(pyridin-2-yloxy)propoxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide; 1 - {4-[2-(2-oxopyridin- 1 (2H)-yl)ethoxy]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 - {4-[2-(pyridin-3-yloxy)ethoxy]phenyl}- 1H- benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 - {3 - [3 -(pyridin-3 -yloxy)propoxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 - {4-[2-(5-chloropyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide; 5-(2- {4-[5-(pyridin-3 -ylmethylaminocarbonyl)- IH-benzimidazol- 1 - yl]phenoxy}ethoxy)nicotinic acid; or a pharmaceutically acceptable salt, or N-oxide, thereof.
17. A compound consisting of l-{3-[(4-bromobenzyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole- 5-carboxamide; 1 - {3-[(3-methoxybenzyl)amino]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5 -carboxamide; i-{3-[(pyridin-4-ylmethyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5 -carboxamide; l-{3-[(pyridin-3-ylmethyl)amino]ρhenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; or a pharmaceutically acceptable salt, or N-oxide, thereof.
18. A compound consisting of N-[3-(dimethylamino)propyl]-l-{4-[2-(4-fluorophenoxy)ethoxy]phenyl}-lH- benzimidazole-5-carboxamide; (4-{[l-([2-(4-fluorophenoxy)ethoxy]phenyl)-lΗ-benzimidazol-5-yl]carbonyl} piperazin- 1 -yl)ethanol; N-ethyl- 1 - {4-[2-(4-fluorophenoxy)ethoxy]phenyl} - lH-benzimidazole-5- carboxamide; N-[3 -(dimethylamino)propyl] - 1 -(4- { [4-(trifluoromethoxy)benzyl] oxy} phenyl)- lH-benzimidazole-5-carboxamide; l-{4-[3-(4-fluorophenoxy)propoxy]phenyl}-N-(3-methoxypropyl)-lH- benzirnidazole-5-carboxamide; l-{4-[3-(4-fluorophenoxy)propoxy]phenyl}-N-(2-methoxyethyl)-lH- benzimidazole-5-carboxamide; l-{4-[3-(4-fluorophenoxy)propoxy]ρhenyl}-N-(3-moφholin-4-ylpropyl)-lH- benzimidazole-5-carboxamide; l-{4-[3-(4-fluorophenoxy)propoxy]phenyl}-N-(2-moφholin-4-ylethyl)-lH- benzimidazole-5-carboxamide; N-[2-(dimethylamino)ethyl]-l-{4-[3-(4-fluorophenoxy)proρoxy]phenyl}-lH- benzimidazole-5-carboxamide; N-(2-methoxyethyl)-l-(3-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; N-[2-(dimethylamino)ethyl]- 1 -(3- {[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide; N-(2-moφholin-4-ylethyl)-l-(3-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; N-[3-(4-methylpiperazin-l-yl)propyl]-l-(3-{[4-(trifluoromethoxy)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide; N-methyl-l-(3-{[4-(trifluoromethoxy)benzyl]oxy}ρhenyl)-lH-benzimidazole-5- carboxamide; N-(l-tefrahydro-2H-pyran-4-ylmethyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide; N-[2-(lH-imidazol-2-yl)ethyl]-l-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide; N-(2-hydroxyethyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; N-(3-hydroxypropyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; 1 - {4-[3-(4-fluorophenoxy)propoxy]phenyl} -N-(2-hydroxyethyl)- 1H- benzimidazole-5-carboxamide; 1 - {4-[3-(4-fluorophenoxy)propoxy]phenyl} -N-(2-piperidin- 1 -ylethyl)- 1H- benzimidazole-5-carboxamide; N-(3-moφholin-4-ylpropyl)- 1 -(3- {[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide; N- [3 -(dimethylamino)propyl] - 1 -(3 - { [4-(trifluoromethoxy)benzyl] oxy} phenyl)- lH-benzimidazole-5-carboxamide; N-(3-methoxypropyl)-l-(3-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; 5-(moφholin-4-ylcarbonyl)-l-(3-{[4-(trifluoromethoxy)benzyl]oxy}ρhenyl)-lH- benzimidazole; (4- {[ 1 -(3- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazol-5- yl]carbonyl}piperazin- 1 -yl)ethanol; (1 - {[ 1 -(3- {[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH-benzimidazol-5- yl]carbonyl}piperidin-4-yl)ethanol; N-(2-piperidin-l-ylethyl)-l-(3-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; 5- [4-(2-methoxyethyl)piperazin- 1 -ylcarbonyl] - 1 - [3 -(4-trifluoromethoxy- benzyloxy)-phenyl] - lH-benzimidazole; N-ethyl- 1 -(3- {[4-(trifluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5- carboxamide; l-{3-[3-(4-fluorophenoxy)propoxy]phenyl}-N-[3-(4-methylpiρerazin-l- yl)propyl]-lH-benzimidazole-5-carboxamide; l-{3-[3-(4-fluorophenoxy)propoxy]phenyl}-N-(3-moφholin-4ylpropyl)-lH- benzimidazole-5-carboxamide; N-[2-(dimethylamino)ethyl]-l-{3-[2-(4-fluoroρhenoxy)ethoxy]phenyl}-lH- benzimidazole-5-carboxamide; N-[3-(dimethylamino)propyl]-l-{3-[2-(4-fluorophenoxy)ethoxy]phenyl}-lH- benzimidazole-5-carboxamide; l-{3-[2-(4-fluorophenoxy)ethoxy]phenyl}-N-(2-methoxyethyl)-lH- benzimidazole-5-carboxamide; l-{3-[2-(4-fluorophenoxy)ethoxy]phenyl}-N-tetrahydro-2H-ρyran-4-yl-lH- benzimidazole-5-carboxamide; 1 - {3-[2-(4-fluorophenoxy)ethoxy]phenyl} -N-(l -tetrahydro-2H-pyran-4- ylmethyl)-lH-benzimidazole-5-carboxamide; N-tetrahydro-2H-pyran-4-yl- 1 -(4- {[4-(trifluoromethoxy)benzyl]oxy}phenyl)- lH-benzimidazole-5-carboxamide; N-isopropyl-l-[4-({4-[(trifluoromethyl)thio]benzyl}oxy)phenyl]-lH- benzimidazole-5-carboxamide; N-(2-moφholin-4ylethyl)-l-[4-({4-[(trifluoromethyl)thio]benzyl}oxy)phenyl]- lH-benzimidazole-5-carboxamide; N-methyl- 1-[4-( {4-[(trifluoromethyl)thio]benzyl} oxy)phenyl]- 1H- benzimidazole-5-carboxamide; N-(2-pyrrolidin- 1-ylethyl)- 1 - [4-( {4- [(trifluoromethyl)thio]benzyl} oxy)phenyl] - lH-benzimidazole-5-carboxamide; N-(2-hydroxyethyl)- 1 -[4-( {4-[(trifluoromethyl)thio]benzyl} oxy)phenyl]- 1H- benzimidazole-5-carboxamide; N-(l-tetrahydro-2H-pyran-4-ylmethyl)-l-[4-({4-[(trifluoromethyl)thio]benzyl} oxy)phenyl]-lH-benzimidazole-5-carboxamide; N-(2-methoxyethyl)-l-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-lH- benzimidazole-5-carboxamide; l-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-lH-benzimidazole-5- carboxamide; N-methyl-l-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-lH-benzimidazole-5- carboxamide; N-(2-moφholin-4ylethyl)-l-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-lH- benzimidazole-5 -carboxamide; N-(l-tefrahydro-2H-pyran-4-ylmethyl)-l-(4-{[4-(trifluoromethyl)benzyl]oxy} phenyl)-lH-benzimidazole-5-carboxamide; N-ethyl-l-[4-({4-[(trifluoromethyl)thio]benzyl}oxy)phenyl]-lH-benzimidazole- 5 -carboxamide; l-[4-({4-[(trifluoromethyl)thio]benzyl}oxy)phenyl]-lH-benzimidazole-5- carboxamide; l-(4-{[4-(difluoromethoxy)benzyl]oxy} phenyl)- lH-benzimidazole-5- carboxamide; N-methyl-l-(4-{[4-(difluoromethoxy)benzyl]oxy}phenyl)-lH-benzimidazole-5- carboxamide; N-(2-moφholin-4ylethyl)- 1 -(4- { [4-(difluoromethoxy)benzyl] oxy}phenyl)- 1H- benzimidazole-5-carboxamide; N-(2-pyrrolidin-l -ylethyl)- 1 -(4- {[4-(difluoromethoxy)benzyl]oxy} phenyl)- 1H- benzimidazole-5-carboxamide; N-(2-methoxyethyl)- 1 -(4- { [4-(difluoromethoxy)benzyl] oxy} phenyl)- 1H- benzimidazole-5-carboxamide; N-isopropyl-l-(4-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-lH-benzimidazole-5- carboxamide; N-(2-pyrrolidin- 1 -ylethyl)- 1 -(4- { [4-(trifluoromethyl)benzyl]oxy} phenyl)- 1H- benzimidazole-5-carboxamide; N-(2-hydroxyethyl)- 1 -(4- { [4-(trifluoromethyl)benzyl] oxy} phenyl)- 1H- benzimidazole-5-carboxamide; N-isopropyl-l-(4-{[4-(difluoromethoxy)benzyl]oxy}phenyl)-lH-benzimidazole- 5-carboxamide; N-( 1 -tetrahydro-2H-pyran-4-ylmethyl)- 1 -(4- { [4-(difluoromethoxy)benzyl] oxy} phenyl)-lH-benzimidazole-5-carboxamide; N-(2-pyrrolidin-l-ylethyl)-l-(4-{[4-(trifluoromethoxy)benzyl]oxy} phenyl)- 1H- benzimidazole-5-carboxamide; 1 - {4-[2-(pyrazin-2-yloxy)ethoxy]phenyl} -N-φyridin-3-ylmethyl)- 1H- benzimidazole-5-carboxamide; 1 - {4-[2-(pyrimidin-2-yloxy)ethoxy]phenyl} -N-(pyridin-3-ylmethyl)- 1H- benzimidazole-5-carboxamide; N-methyl-l-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-lH-benzimidazole-5- carboxamide; N-ethyl- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - lH-benzimidazole-5- carboxamide; N-(2-methoxyethyl)- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-(2-moφholin-4-ylethyl)- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide; l-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-N-(l-tetrahydro-2H-pyran-4- ylmethyl)-lH-benzimidazole-5-carboxamide; 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} -N-tetrahydro-2H-pyran-4-yl- 1H- benzimidazole-5-carboxamide; N-cyclobutyl- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - lH-benzimidazole-5- carboxamide; N-(2-hydroxyethyl)- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide; 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} -N-(2-pyrrolidin- 1 -ylethyl)- 1H- benzimidazole-5-carboxamide; tert-butyl-4- { [(1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - lH-benzimidazol-5- yl)carbonyl] amino } ethyl)piperazine- 1 -carboxylate; N-isopropyl- 1 - {4-[2-(pyridin-2-yloxy)ethoxy]phenyl} - lH-benzimidazole-5- carboxamide; l-{4-[2-(pyridin-2-yloxy)ethoxy]phenyl}-lH-benzimidazole-5-carboxamide; 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} -N-(2-moφholin-4-ylethyl)- lH-benzimidazole-5-carboxamide; N-(2-moφholin-4-ylethyl)- 1 - {4-[2-(pyridin-2-yloxy)propoxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-(2-moφholin-4-ylethyl)- 1 - {4- [ 1 -methyl-2-(pyridin-2-yloxy)propoxy]phenyl} - lH-benzimidazole-5-carboxamide; 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} - lH-benzimidazole-5- carboxamide; 1 - {4-[2-(pyridin-2-yloxy)propoxy]phenyl} - lH-benzimidazole-5-carboxamide; N-isopropyl- 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-isopropyl-l-{4-[2-(pyridin-2-yloxy)propoxy]phenyl}-lH-benzimidazole-5- carboxamide; N-(2-hydroxyethyl)- 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-(2-hydroxyethyl)- 1 - {4-[2-(pyridin-2-yloxy)propoxy]phenyl} - 1H- benzimidazole-5-carboxamide; 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} -N-(2-pyrrolidin- 1 -ylethyl)- lH-benzimidazole-5 -carboxamide; l-{4-[2-(pyridin-2-yloxy)ρropoxy]phenyl}-N-(2-Pyrrolidin-l-ylethyl)-lH- benzimidazole-5-carboxamide; l-{4-[l-methyl-2-(pyridin-2-yloxy)ethoxy]phenyl}-N-(l-tetrahydro-2H-pyran-4- ylmethyl)-lH-benzimidazole-5-carboxamide; l-{4-[2-(pyridin-2-yloxy)propoxy]phenyl}-N-(l-tetrahydro-2H-pyran-4- ylmethyl)-lH-benzimidazole-5-carboxamide; 1 - {4- [ 1 -methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} -N- [3 -(methylthio)propyl] - lH-benzimidazole-5-carboxamide; N-[3-(methylthio)propyl]-l-{4-[2-(pyridin-2-yloxy)propoxy]phenyl}-lH- benzimidazole-5-carboxamide; l-{4-[l-methyl-2-(pyridin-2-yloxy)propoxy]phenyl}-lH-benzimidazole-5- carboxamide; N-isopropyl- 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)propoxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-(2-hydroxyethyl)- 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)propoxy]phenyl} - 1H- benzimidazole-5-carboxamide; 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)propoxy]phenyl} -N-(2-pyrrolidin- 1 -ylethyl)- lH-benzimidazole-5-carboxamide; 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)propoxy]phenyl} -N-( 1 -tetrahydro-2H-pyran- 4-ylmethyl)-lH-benzimidazole-5-carboxamide; 1 - {4- [ 1 -methyl-2-(pyridin-2-yloxy)propoxy]phenyl } -N- [3 -(methylthio)propyl] - lH-benzimidazole-5-carboxamide; N-methyl- 1 - {4-[ 1 -methyl-2-(pyridin-2-yloxy)ethoxy]phenyl} - 1H- benzimidazole-5-carboxamide; N-methyl- 1 - {4-[2-(pyridin-2-yloxy)propoxy]phenyl} - lH-benzimidazole-5- carboxamide; N-methyl- 1 - {4-[ 1 -Methyl-2-(pyridin-2-yloxy)propoxy]phenyl} - 1H- benzimidazole-5-carboxamide; l-(4-{[3-(2-pyridyloxymethyl)cyclobutyl]oxy}phenyl)-N-pyridin-3-ylmethyl- lH-benzimidazole-5-carboxamide; l-{4-[(3-phenoxypropyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; 1 - {4-[4-(4-fluorophenyl)piperidin- 1 -yl]phenyl} -N-pyridin-3-yhnethyl-lH- benzimidazole-5-carboxamide; l-{4-[4-(4-fluorophenyl)piperazin-l-yl]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; 1 - {3-[4-(4-fluorophenyl)piperidin-l -yl]phenyl} -N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; N-pyridin-3-ylmethyl-l-{3-[(2-thien-3-ylethyl)amino]phenyl}-lH- benzimidazole-5-carboxamide; 1 - [3 -(cyclohexylmethylamino)phenyl] -N-pyridin-3 -ylmethyl- lH-benzimidazole- 5-carboxamide; 1 - {4-[(2-phenoxyethyl)amino]phenyl} -N-pyridin-3 -ylmethyl- lH-benzimidazole- 5-carboxamide; 1 -(3 - { [ 1 -(4-chlorophenyl)ethyl] amino }phenyl)-N-ρyridin-3 -ylmethyl- 1 H- benzimidazole-5-carboxamide; 1 -(3 - { [3 -( lH-imidazol- 1 -yl)propyl] amino }phenyl)-N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 -[3-(4-pyrimidin-2-ylpiperazin- 1 -yl)phenyl]- 1H- benzimidazole-5-carboxamide; 1 -(3-[ 1 ,4']bipiperidinyl- 1 '-yl-phenyl)-N-pyridin-3 -ylmethyl- lH-benzimidazole- 5 -carboxamide; l-{3-[benzyl(methyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH-benzimidazole-5- carboxamide; N-isopropyl- 1 -(4- {[4-(trifluoromethoxy)benzyl]amino}phenyl)-lH- benzimidazole-5-carboxamide; N-methyl-l-(4-{[4-(trifluoromethoxy)benzyl]amino}phenyl)-lH-benzimidazole- 5 -carboxamide; N-(2-moφholin-4-ylethyl)-l-(4-{[4-(trifluoromethoxy)benzyl]amino}phenyl)- lH-benzimidazole-5-carboxamide; N-tetrahydro-2H-pyran-4-yl- 1 -(4- {[4-(trifluoromethoxy)benzyl] amino }phenyl)- lH-benzimidazole-5-carboxamide; N-pyridin-3-ylmethyl-l-(3-{[4-(trifluoromethoxy)benzyl]amino}phenyl)-lH- benzimidazole-5-carboxamide; l-{3-[(4-trifluoromethylphenyl)amino]phenyl}-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-(3-{[(4-methylphenyl)sulfonyl]amino}phenyl)-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; l-(3-{[(4-chlorophenyl)sulfonyl]ammo}phenyl)-N-pyridin-3-ylmethyl-lH- benzimidazole-5-carboxamide; N-pyridin-3-ylmethyl-l - {3-[(thien-2-ylsulfonyl)amino]phenyl}-lH- benzimidazole-5-carboxamide; N-pyridin-3 -ylmethyl- 1 -[3-( { [4-(trifluoromethoxy)phenyl] sulfonyl} amino) phenyl]-lH-benzimidazole-5-carboxamide; l-(3-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)-N-pyridin-3-ylmethyl-lH- benzimidazole-5 -carboxamide; 1 -(3 - { [(3 ,4-dichlorophenyl)sulfonyl] amino }phenyl)-N-pyridin-3 -ylmethyl- 1H- benzimidazole-5-carboxamide; or a pharmaceutically acceptable salt, or N-oxide, thereof.
19. A method of treatment of hypeφroliferative disorder comprising a step of administering an effective amount of the compound according to claim 1.
20. The method of claim 19, further comprising the step of administering an anti-neoplastic, anti-tumor, anti-angiogenic, or chemotherapeutic agent.
21. The method of claim 19 wherein the hypeφroliferative disorder is breast cancer, head cancer, or neck cancer.
22. The method of claim 19 wherein the hypeφroliferative disorder is gastrointestinal cancer.
23. The method of claim 19 wherein the hypeφroliferative disorder is leukemia.
24. The method of claim 19 wherein the hypeφroliferative disorder is ovarian, bronchial, lung, or pancreatic cancer.
25. The method of claim 19 wherein the hypeφroliferative disorder is small cell lung or colon cancer.
26. The method of claim 19 wherein the hypeφroliferative disorder is sinonasal natural killer/T-cell lymphoma, testicular cancer (seminoma), thyroid carcinoma, malignant melanoma, ovarian carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia (AML), breast carcinoma, pediatric T-cell acute lymphoblastic leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial carcinoma, or prostate carcinoma.
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