WO2006044509A2 - Methods of treating vascular injuries - Google Patents

Methods of treating vascular injuries Download PDF

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Publication number
WO2006044509A2
WO2006044509A2 PCT/US2005/036770 US2005036770W WO2006044509A2 WO 2006044509 A2 WO2006044509 A2 WO 2006044509A2 US 2005036770 W US2005036770 W US 2005036770W WO 2006044509 A2 WO2006044509 A2 WO 2006044509A2
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Prior art keywords
pyridin
methyl
imidazol
benzo
dioxol
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PCT/US2005/036770
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French (fr)
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WO2006044509A3 (en
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Leona E. Ling
Kai Fu
Alan Gill
Philip J. Gotwals
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Biogen Idec Ma Inc.
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Priority to JP2007536868A priority Critical patent/JP2008516962A/en
Priority to CA002584248A priority patent/CA2584248A1/en
Priority to AU2005295734A priority patent/AU2005295734A1/en
Priority to EP05813747A priority patent/EP1804801A2/en
Publication of WO2006044509A2 publication Critical patent/WO2006044509A2/en
Publication of WO2006044509A3 publication Critical patent/WO2006044509A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • TGF/3 Transforming Growth Factor /3 is a member of a large family of dimeric polypeptide growth factors that includes, for example, activins, inhibins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and mullerian inhibiting substance (MIS).
  • BMPs bone morphogenetic proteins
  • GDFs growth and differentiation factors
  • MIS mullerian inhibiting substance
  • TGF/3 exists in three isoforms (TGF 1 Sl, TGF
  • Each TGF/3 isoform is synthesized as a precursor protein that is cleaved intracellularly into a C-terminal region (latency associated peptide (LAP)) and an N-terminal region known as mature or active TGFjS.
  • LAP latency associated peptide
  • TGFjS N-terminal region
  • LAP is typically non-covalently associated with mature TGFjS prior to secretion from the cell.
  • the LAP-TGFjS complex cannot bind to the TGF/3 receptors and is not biologically active.
  • TGF/3 is generally released (and activated) from the complex by a variety of mechanisms including, for example, interaction with thrombospondin-1 or plasmin.
  • TGF 1 S binds at high affinity to the type II receptor (TGFjSRII), a constitutively active serine/threonine kinase.
  • TGFjSRII type II receptor
  • the ligand-bound type II receptor phosphorylates the TGF/3 type I receptor (AIk 5) in a glycine/serine rich domain, which allows the type I receptor to recruit and phosphorylate downstream signaling molecules, Smad2 or Smad3.
  • TGFjSRII type II receptor
  • AIk5 TGF/3 type I receptor
  • Phosphorylated Smad2 or Smad3 can then complex with Smad4, and the entire hetero-Smad complex translocates to the nucleus and regulates transcription of various TGF/3-responsive genes. See, e.g., Massague, J. Ann. Rev. Biochem. Med. 67: 773 (1998).
  • Activins are also members of the TGF/3 superfamily, which are distinct from TGF/3 in that they are homo- or heterodimers of activin /3a or /3b. Activins signal in a manner similar to TGF/3, that is, by binding to a constitutive serine-threonine receptor kinase, activin type II receptor (ActRIIB), and activating a type I serine-threonine receptor, AIk 4, to phosphorylate Smad2 or Smad3. The consequent formation of a hetero-Smad complex with Smad4 also results in the activin-induced regulation of gene transcription.
  • ActRIIB activin type II receptor
  • AIk 4 type I serine-threonine receptor
  • TGF 1 S and related factors such as activin regulate a large array of cellular processes, e.g., cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, inflammatory cell recruitment, immunosuppression, wound healing, and extracellular matrix production.
  • cellular processes e.g., cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, inflammatory cell recruitment, immunosuppression, wound healing, and extracellular matrix production.
  • TGF 1 S signaling pathway underlies many human disorders (e.g., excess deposition of extracellular matrix, an abnormally high level of inflammatory responses, fibrotic disorders, and progressive cancers). See, e.g. Blobe G.C., Schiemann W.P., Lodish H.F. N. Eng. J. Med. 342: 1350-8 (2000).
  • activin signaling and overexpression of activin is linked to pathological disorders that involve extracellular matrix accumulation and fibrosis (see, e.g., Matsuse, T. et al., Am. J. Respir.
  • TGF/3 and activin can act synergistically to induce extracellular matrix production (see, e.g., Sugiyama, M. et al., Gastroenterology 114: 550-558, (1998)). It is therefore desirable to develop modulators (e.g., antagonists) to members of the TGF ' ⁇ family to prevent and/or treat disorders involving this signaling pathway.
  • modulators e.g., antagonists
  • the compounds of formulae I, II, III, IV, V, and VI, described herein unexpectedly exhibit systemic bioavailability and are useful in combating restenosis (e.g., coronary restenosis, peripheral restenosis, and carotid restenosis), vascular diseases (e.g., intimal thickening, vascular remodeling, or organ transplant-related vascular disease), and hypertension (e.g., primary or secondary, systolic hypertension, pulmonary hypertension or hypertension-induced vascular remodeling) when administered to a subject (e.g., a patient).
  • restenosis e.g., coronary restenosis, peripheral restenosis, and carotid restenosis
  • vascular diseases e.g., intimal thickening, vascular remodeling, or organ transplant-related vascular disease
  • hypertension e.g., primary or secondary, systolic hypertension, pulmonary hypertension or hypertension-induced vascular remodeling
  • Methods of inhibiting intimal thickening or vascular remodeling include administering to a subject (e.g., a human patient) in need thereof an inhibitor of TGF ⁇ type I receptor or Alk4.
  • a subject e.g., a human patient
  • an inhibitor of TGF ⁇ type I receptor or Alk4 Embodiments of these aspects may include one or more of the following.
  • the inhibitor is a compound of formula I, II, III, IV, V, or VI.
  • the inhibitor is administered locally.
  • the inhibitor is administered via an implantable device such as a delivery pump or a stent.
  • the invention features an implantable device, such as a delivery pump or stent, including an inhibitor of TGF ⁇ type I receptor or Alk4.
  • the inhibitor can be a compound of formula I, II, III, IV, V, or VI.
  • an "alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms.
  • An alkyl group can be straight or branched. Examples of an alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and 2-ethylhexyl.
  • An alkyl group can be optionally substituted with one or more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl- alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylammo, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl,
  • an "alkenyl” group refers to an aliphatic carbon group that contains 2- 8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
  • An alkenyl group can be optionally substituted with one or more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl- alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylammo, het ' er ⁇ aralkylcarbonylamino, urea, thiourea, s
  • an "alkynyl” group refers to an aliphatic carbon group that contains 2- 8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond.
  • An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, proparg;yl and butynyl.
  • An alkynyl group can be optionally substituted with one or more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl
  • an “amino” group refers to -NR X R Y wherein each of R x and R ⁇ is independently hydrogen, hydroxyl, alkyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl.
  • R x is independently hydrogen, hydroxyl, alkyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl.
  • an "aryl” group refers to phenyl, naphthyl, or a benzofused group having 2 to 3 rings.
  • a benzofused group includes phenyl fused with one or two C 4-8 carbocyclic moieties, e.g., 1,2,3,4-tetrahydronaphthyl, indanyl, or fluorenyl.
  • An aryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyL, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloal
  • an "aralkyl” group refers to an alkyl group (e.g., a Ci -4 alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” are as defined above. An example of an aralkyl group is benzyl.
  • a "cycloalkyl” group refers to an aliphatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms.
  • Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro- naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, and bicyclo[3.2.3]nonyl.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bond.
  • cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl.
  • a cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkyl
  • heterocycloalkyl refers to a 3- to 10-membered (e.g., 4- to 8-membered) saturated ring structure, in which one or more of the ring atoms is a heteroatom, e.g., N, O, or S.
  • heterocycloalkyl group examples include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, dioxolanyl, oxazolidinyl, isooxazolidinyl, morpholinyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[b]thiophenyl, 2-oxa- bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa- tricyclo[3.3.1.0 3>7 ]nonyl.
  • heterocycloalkenyl group refers to a 3- to 10- membered (e.g., 4- to 8-membered) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom, e.g., N, O, or S.
  • a heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloallcyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamin.o, arylcarbonylamino, aral
  • a "heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring structure having 5 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom, e.g., N, O, or S, and wherein one ore more rings of the bicyclic or tricyclic ring structure is aromatic.
  • heteroaryl examples include pyridyl, furyl., pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, and benzo[l,3]dioxole.
  • a tieteroaryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cyclo alkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl;, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalk ⁇ alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycl
  • heteroaryl group refers to an alkyl group (e.g., a C 1-4 alkyl group) th.at is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” are as defined above.
  • cyclic moiety includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocyclo alkenyl, aryl, or heteroaryl, each of which has Been defined previously.
  • a “carbamoyl” group refers to a group having the structure
  • R x and R ⁇ have been defined above and R z is alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl.
  • a "carboxy” group and a “sulfo” group refer to -COOH and -SO 3 H, respectively.
  • alkoxy refers to an alkyl-O- group wherein “alkyl” has been defined previously.
  • a "sulfoxy" group refers to -O-SO-R X or -SO-O-R* 1 , wherein R x has been defined above.
  • halogen or halo group refers to fluorine, chlorine, bromine or iodine.
  • a "sulfamoyl” group refers to the structure -SO 2 -NR X R Y or -NR X - SO 2 -R 2 wherein R x , R ⁇ , and R z have been defined above.
  • sulfamide refers to the structure -NR X -S(O) 2 -NR Y R Z wherein R x , R ⁇ , and R z have been defined above.
  • urea refers to the structure -NR X -CO-NR ⁇ R Z and a "thiourea” group refers to the structure -NR X -CS-NR Y R Z .
  • R x , R ⁇ , and R z have been defined above.
  • an effective amount is defined as the amount which is required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient.
  • the interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al, Cancer Chemother. Rep., 50: 219 (1966).
  • Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970).
  • a. "patient” refers to a mammal, including a human.
  • An antagonist is a molecule that binds to the receptor without activating the receptor. It competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor and, thus inhibits the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.
  • Figure 1 is an illustration of a delivery device.
  • the inhibitors described herein are effective at treating, preventing, or reducing intimal thickening, vascular remodeling, restenosis (e.g., coronary, peripheral, carotid restenosis), vascular diseases, (e.g., organ transplant-related, cardiac, and renal), and hypertension (e.g., primary and secondary, systolic, pulmonary, and hypertension-induced vascular remodeling resulting in target organ damage).
  • restenosis e.g., coronary, peripheral, carotid restenosis
  • vascular diseases e.g., organ transplant-related, cardiac, and renal
  • hypertension e.g., primary and secondary, systolic, pulmonary, and hypertension-induced vascular remodeling resulting in target organ damage.
  • TGF ⁇ and activin pathway plays a critical role in the progression of fibrotic diseases.
  • TGF ⁇ RT TGF ⁇ type I receptor
  • Alk4 activin type I receptor
  • TGF ⁇ RI kinase activity is required for TGF ⁇ signaling as is Alk4 for activin signaling.
  • Kinases have proven to be useful targets for development of small molecule drugs. There is a good structural understanding of the TGF ⁇ RI kinase domain allowing the use of structure-based drug discovery and design to aid in the development of inhibitors.
  • T 1 GrFPi or activin-mediated pathological changes in vascular flow and tone are often the cause of morbidity and mortality in a number of diseases (see, e.g., Gibbons G.H. and Dzau V.J. NEng. J. Med 330: 1431-1438 (1994)).
  • the initial response of the vasculature to injury is an infiltration of adventitial inflammatory cells and induction of activated myofibroblasts or smooth muscle cells (referred to as myofibroblasts from hereon).
  • TGF ⁇ is initially produced by infiltrating inflammatory cells and activates myofibroblasts or smooth muscle cells. These activated myofibroblasts can also secrete TGF ⁇ as well as respond to it.
  • TGF ⁇ vascular remodeling processes, intimal thickening and vascular contraction, restrict blood flow to the tissues supported by the effected vasculature and result in tissue damage.
  • Activin is also produced in response to injury and shows very similar actions in inducing activated myofibroblasts or activated smooth muscle cells intimal thickening and vascular remodeling.
  • Stent placement physically prevents remodeling, but hyperplasia and extracellular matrix deposition by activated myofibroblasts proliferating at the luminal side of the stent results in mtimal thickening within the stented vessel resulting in the eventual impairment of blood flow.
  • the treatment of arterial stenotic diseases by surgical grafts also can elicit restenosis in the grafted vessel.
  • vein grafts undergo intimal thickening and vascular remodeling through a similar mechanism involving TGF ⁇ -induced intimal thickening and vascular remodeling.
  • the injury is either due to the overdistention of the thin- walled vein graft placed into an arterial vascular context or due to anastamotic or ischemic injury during the transplantation of the graft.
  • Elevated TGF ⁇ is implicated in chronic allograft vasculopathy both in animals and humans.
  • Vascular injury, intimal thickening and vascular remodeling is a characteristic pathology in chronic allograft failure.
  • the fibrotic response in chronic allograft failure initiates in the vasculature of the donor organ.
  • Chronic allograft vasculopathy in allografted hearts often manifests within 5 years of transplantation and is the main cause of death in Long term survivors of cardiac transplant.
  • Elevation of TGF ⁇ can be induced by ischemic, immune and inflammatory responses to the allograft organ.
  • Animal models of acute and chronic renal allograft rejection identify the elevation of TGF ⁇ as a significant contributor to graft failure and rejection (see, e.g., Nagano, H. et al., 1997, Transplantation, 63: 1101; Paul, LC. et al., 1996, Am. J. Kidney Dis., 28: 441; and Shihab, FS. et al., 1996, Kidney M., 50: 1904).
  • Rodent models of chronic allograft nephropathy show elevation of TGF ⁇ mRNA and immunostaining.
  • TGF ⁇ immunostaining is strongly positive in interstitial inflammatory andfibrotic cells, but also in blood vessels and glomeruli.
  • the loss of renal function 1 year post renal allograft correlates with TGF ⁇ staining in the grafted kidney. See, e.g., Cuhaci, B. et al., 1999, Transplantation, 68: 785).
  • Graft biopsies show also that renal dysfunction correlates with chronic vascular remodeling, i.e., vasculopathy, and the degree of TGF ⁇ expression correlates significantly with chronic vasculopathy (see, e.g., Viticiany, O. et al., 2003, Physiol Res. 52: 353).
  • TGF ⁇ is implicated in chronic allograft rejection in both renal and lung transplants due to the clear TGF ⁇ -related fibrotic pathology of this condition as well as the ability of immune suppressants, esp cyclosporin A, to induce TGF ⁇ (Jain, S. et al., 2000 Transplantation, 69: 1759).
  • TGF ⁇ blockade improved renal function while decreasing collagen deposition, renal TGF ⁇ expression as well as vascular afferent arteriole remodeling in a cyclosporine A-induced renal failure model using an anti-TGF ⁇ monoclonal antibody (Islam, M. et al., 2001 Kidney Int., 59: 498; Khanna, A.K. et al., 1997 Transplantation, 67: 882).
  • These data are strongly indicative of a causal role for TGF ⁇ in the development and progression of chonic allograft vasculopathy and chronic allograft failure.
  • Hypertension is a major cause of morbidity and mortality in the U.S. population affecting approximately 1 in 3 individuals.
  • the effect of hypertension on target organs include increased incidence of cardiac failure, myocardial infarction, stroke, renal failure, aneurysm and microvascular hemorrhage.
  • Hypertension-induced damage to the vasculature results in vascular remodeling and intimal thickening which are a major causative factor in many ofthese morbidities (Weber, W.T. 2000 Curr. Opin. Cardiol. 15:264-72).
  • Animal experiments suggest that TGF ⁇ is elevated upon induction of hypertension and anti-XGF ⁇ monoclonal antibody blockade of this pathway decreases blood pressure and renal pathology in hypertensive rats (Xu, C.
  • plasma TGF ⁇ is elevated in hypertensive individuals compared to normotensive controls and plasma TGF ⁇ is also higher in hypertensive individuals with manifest target organ disease compared to hypertensive individuals without apparent target organ damage (Derhaschnig, U. et al., 2002 Am. Jf. Hypertens., 15:207; Suthanthiran, M. 2000 PrOc. Natl. Acad. ScL U.S.A., 97:3479).
  • TGF ⁇ -producing genotypes of TGF ⁇ are a risk factor for development of hypertension (Lijnen, PJ. 2003 Am. J. Hypertens., 16:604; Suthanthiran, M. 2000 Proc. Natl. Acad. ScL U.S.A., 97:3479).
  • the inhibition of the TGF ⁇ pathway may provide a effective therapeutic approach for hypertension or hypertension-induced organ damage.
  • Pulmonary hypertension is also a sequalae of mixied connective tissue disease, chronic obstructive pulmonary disease (COPD) and lupus erythematosis (Fagan, K. A., Badesch, D.B., 2002, Prog. Cardiovasc. Dis., 45:225-34; and Presberg, K.W., Dincer, H.E., 2003, Curr. Opin. PuIm. Med., 9:131-8).
  • COPD chronic obstructive pulmonary disease
  • diabetic patients have significantly higher rates of restenosis, vein graft stenosis, peripheral artery disease, chronic allograft nephropathy and chronic allograft vasculopathy (Reginelli, J.P., Bhatt, D. L., 2002, J. Invasive Cardiol., 14 Suppl E:2E-10E; Eisen. H., Ross, H., 2004, J. Heart Lung Transplant., 23:S207- 13; Valentine, H., 2004, J. Heart Lung Transplant., 23:S187-93).
  • blockade of TGF ⁇ is of particular utility in diabetic patients at risk for hypertension-related organ failure, diabetic nephropathy, restenosis or vein graft stenosis in coronary or peripheral arteries, and chronic failure of allograft organ transplants (Endemann, D.H. et al., 2004, Hypertension, 43(2):399- 404; Ziyadeh, FJ., Am. Soc. Nephrol, 2004 15 Suppl l:S55-7; and Jerums, G. et al., 2003, Arch. Bi ⁇ chem. Biophys., 419:55-62).
  • TGF ⁇ RI and Alk4 antagonists are effective at treating, preventing, or reducing intimal thickening, vascular remodeling, restenosis (e.g., coronary, peripheral, and carotid restenosis), vascular diseases, (e.g., organ transplant-related, cardiac, and renal), and hypertension (e.g., systolic, pulmonary, and hypertension-induced vascular remodeling resulting in target organ damage).
  • vascular remodeling e.g., coronary, peripheral, and carotid restenosis
  • vascular diseases e.g., organ transplant-related, cardiac, and renal
  • hypertension e.g., systolic, pulmonary, and hypertension-induced vascular remodeling resulting in target organ damage.
  • Changes in vascular remodeling and intimal thickening may be qualified by measuring the intimal versus medial vascular thickness.
  • TGFjS and activin inhibitory activity of compounds can be assessed by methods described below.
  • the antagonists have the structure shown in formula I:
  • R 1"1 can be aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • Each R 1"8 can be alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, svilfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, lieterocycloal
  • Xi -J can be cycloalkyl or heterocycloalkyl.
  • Yn can be a bond, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O) P -O-, -O-S(O) P -, -C(O)-N(R 1"13 )-, -N(R 1 ⁇ )-C(O)-, -O- C(O)-N(R 1"13 )-, -N(R ⁇ )-C(O)-O-, -0-S(O) P -N(R 1" ")-, -N(R 1 ⁇ )-S(O) P -O-, -N(R 1 ⁇ )-C(O)-N(R 1" c )-, -N(R 1 ⁇ )-S(O) P -N(R 1"0 )-, -C(O)-N(
  • R 1"2 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkcenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl.
  • Each of A 1"1 and A 1"2 can be O, S, N, or NR 1"13 , provided that at least one of A 1"1 and A 1"2 can be N.
  • m can be O, 1, 2, or 3.
  • the 2- pyridyl ring can be unsubstituted or substituted with 1 to 3 R 1" * 1 groups. Note that when m > 2, two adjacent R ⁇ a groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety.
  • the 2-pyridyl ring can fuse with a cyclic moiety to form a moiety, e.g., 7H-[2]pyrindiiiyl, 6,7-dihydro-5H-[l]pyrindinyl, 5,6,7,8-tetrahydro- quinolinyl, 5,7-dihydro-furo[3,4-b]pyridinyl, or 3,4-dihydro-lH-thiopyrano[4,3-c]pyridinyl, that can be optionally substituted with one or more substituents such as alkyl (including substituted alkyl such as carboxyalkyl, hydroxyalkyl, and haloalkyl (e.g., trifluoromethyl)), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aroyl, heteroaroyl, amino,
  • Methanesulfonic acid 4-[4-toenzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct- 1-ylmethyl ester;
  • Butane- 1 -sulfonic acid ⁇ 4-[4-benzo[ l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexylmethyl ⁇ -amide;
  • the antagonists have the structure shown below in formula II:
  • each OfXn -1 , Xn -2 , Xn -3 , and Xn -4 can be independently CR ⁇ "x or N, provided that only two of X ⁇ -i, Xn -2 , Xn -3 , and Xn -4 can be N simultaneously.
  • Each OfYn -1 and Y 11-2 can be independently CR ⁇ "y or N, provided that at least one OfYn -1 and Yn -2 must be N.
  • the ring having Y n-1 and Yn -2 ring atoms can be a pyrimidinyl or pyridyl.
  • Each R 11'1 can be independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl,
  • Each R 11"2 can be independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -NH(cycloalkyl), -
  • R ⁇ "x and R ⁇ "y can be independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloal
  • two adjacent R 11"1 groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety. That is, tlie 2- pyridyl ring can fuse with a 4- to 8-membered cyclic moiety to form a moiety such as 7H- [l]py ⁇ indinyl, 6,7-dihydro-5H-[l]pyrindinyl, 5,6,7,8-tetrahydro-quinolinyl, 5,7-dihydro- furo[3,4-b]pyridinyl, or 3,4-dihydro-lH-thiopyrano[4,3-c]pyridinyl.
  • the fused ring moiety can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl; see the defmitoix of "alkyl” below), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, eye Io alkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino, heterocycloalkyl- alkylcarbonylamino,
  • n _ ⁇ 2 two adjacent R 11"2 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety, thereby forming a ring fused with the pyridyl or pyrimidinyl group.
  • the 4- to 8-membered cyclic moiety formed by two adjacent R 11"2 groups can be optionally substituted with substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl; see the defmiton of "alkyl” below), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylarnino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloal
  • the antagonists have the structure shown in formula III:
  • each OfXm -1 , Xm -2 , X ⁇ i- 3 , and Xm -4 can be independently CR or N, provided that only two of X ⁇ i -i, Xm-2, X 111 - 3 , and Xm -4 can be N simultaneously.
  • ⁇ and Ym -2 can be independently CR. m ⁇ y or N, provided that at least one of Y ⁇ n and Y m-2 must be N.
  • Each of R 111"1 can be independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxiy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocyclo alkyl, heterocycl
  • Each of R 111"2 can be independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH 2 , -NH(alkyl), -N(alkyl) 2 , -NH(cycloalkyl), -N(alkyl)(cyclocalkyl), - NH(heterocycloalkyl), -NH(heteroaryl), -NH-alkyl-hetero cycloalkyl, -NH-alkyl- heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy,
  • R m"x and R rII"y can be independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino ., nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarbonyl, aroyl, aralkylcarbonyl, heterocyeloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkyl sulfonylamino, cycloalkylcarbon
  • the antagonists have the structure shown in formula IV:
  • Each R IV"a can be independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl
  • R ⁇ '1 can be a bond, alkylene, alkenylene, alkynylene, or -(CH 2 ) rl -O-(CH 2 ) r2 -, wherein each of rl and r2 is independently 2 or 3.
  • R ⁇ "2 can be cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, or a bond.
  • R 1 ⁇ 3 can be -C(O)-, -C(O)O-, -OC(O)-, -C(O)-N(R 1 ⁇ )-, -N(R 1 ⁇ )-C(O)-, -0-C(O)- N(R 1 ⁇ )-, -N(R 1 ⁇ )-C(O)-O-, -0-S(O) P -N(R ⁇ 13 )-, -N(R 1 ⁇ )- S(O) P -O-, -N(R 1 ⁇ )-C(O)- N(R 1 ⁇ 0 )-, -N(R IV - b )-S(0) p -N(R IV - b )-, -C(O)-N(R 1 ⁇ )-S(OV, -S(O) P -N(R ⁇ )-C(O)-, -S(0) p - N(R ⁇ )-, -C
  • K W' ⁇ can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
  • R ⁇ '5 can be hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulfinyl, amino, alkenyl, alkynyl, cycloalkyl, cycloalko:xy, cycloalkylsulf ⁇ nyl, heterocycloalkyl, heterocycloalkoxy, heterocycloalkylsulf ⁇ n ⁇ l, aryl, aryloxy, arylsulfinyl, heteroaryl, heteroaryloxy, or heteroarylsulfinyl.
  • Ring A can be an aromatic ring containing 0-4 hetero ring atoms
  • ring B can be a 5- to 7- membered aromatic or nonaromatic ring containing 0-4 hetero ring atoms, provided that at least one of ring A and ring B contains one or more hetero rmg atoms.
  • Ring A' can be an aromatic ring containing 0-4 hetero ring atoms
  • ring B' can be a 5- to 7-membered saturated or unsaturated ring containing 0-4 hetero ring atoms, provided that at least one of ring A' and ring B' contains one or more hetero ring atoms.
  • Each X 1 can be independently N or C.
  • R w'h and R IV" ' can be independently alkyl, alkenyl, alkynyL, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonyl-amino, alkylsulfonylamino, arylsulfonylamirLO, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamo>4, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkyl
  • R 17"6 is 2-naphthyridinyl, 4-quinolinyl, imidazo[l,2- a] ⁇ yridyl, or benzimidazolyl
  • -R ⁇ "1 -R IV"2 -R IV"3 -R IV'4 is not H, unsubstituted alkyl, -CH 2 -C(O)-N(H)-alkyl, -CH 2 -C(O)-N(alkyl) 2 , or benzyl.
  • WO 04/072033 which is incorpoarated in its entrity by reference, describes synthetic methods for producing inhibitors of formula IV.
  • compounds of formula IV include, but are not limited to,
  • the antagonists have the structure shown in formula V.
  • R v ⁇ ! can be heteroaryl
  • Each R v"a can be alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cya.no, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycl
  • Xv can be cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a bond.
  • Yv can be a bond, -CCO)-, -C(O)-O-, -0-C(O)-, -S(O) P -O-, -O-S(O) P -, -C(O)-N(IT 13 )-, -N(R v"b )-C(O)-, -O-C(O)-N(R v - b )-, -N(R v'b )-C(O)-O-, -C(O)-N(R v"b )-O-, -O-N(R v - b )-C(O)-, -O-S(O)p-N(R v"b )-, -N(R v"b )-S(O)p-N(R v"b )-, -N(R v"b )-S(O)p-N(R v"b )-
  • R v ⁇ h and R v"c independently, can be hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, rieterocyclo alkyl, heteroaryl, or heteroaralkyl.
  • p can be 1 or 2
  • q can be 1-4.
  • R v"2 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (Tieterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl.
  • Each of A v"! and A v"2 can be N or NR v"b . It is to be understood that when A v ⁇ ' is NR v"b , A v ⁇ 2 is N, and vice versa.
  • the variable, m can be 0, 1, 2, or 3.
  • the pyrimidinyl ring can be unsubstituted or substituted with 1-3 R v"a groixps. Note that when m ⁇ 2, two adjacent R v"a groups can. optionally together to form a 4- to 8-membered optionally substituted cyclic moiety.
  • the pyrimidinyl ring can fuse with a cyclic moiety to form a moiety, that can be optionally substituted with one or more sub> stituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoronx ethyl), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylthio, sulfoxy, sulfamoyl, oxo, or carbamoyl.
  • alkyl including carboxyalkyl, hydroxyalkyl, and haloal
  • R v ⁇ 2 is hydrogen or alkyl
  • m is 1, 2, or 3
  • at least one R v"a is substituted at the 2-p;yrimidinyl position (i.e., the position of the pyrimidinyl ring that is between the two nitrogen ring atoms).
  • the metrxoxy-methyl- amide can be prepared by reacting a corresponding acid chloride (i.e., R ⁇ -CO-G) with N, O-dimethylhydroxylamine hydrochloride.
  • R ⁇ -CO-G N, O-dimethylhydroxylamine hydrochloride.
  • the R v"1 -(6-methylpyrimidinyl)-ke “ tone (III) can then be treated with sodium nitrite in acetic acid to afford an ⁇ -keto-oxime (IV), "which can undergo a further reaction with an appropriate substituted (and optionally protected) aldehyde (VI) in the presence of ammonium acetate to yield a compound of formula V.
  • the above-described compounds of formula V can be prepared according to Scheme V-Ib below. Specifically, l,l-dimethoxy-propan-2-one can first react with dimethoxymethyl-dimethyl-amine at an elevated temperature to produce the intermediate 4-dimethylamino-l,l-dimethoxy-but-3-en-2-one, which can then react an R v"a - substituted amidine to form an R v"a -substituted pyrimidine-2-carbaldehyde (Ha).
  • This carbaldehyde (Ha) can then react with aniline and diphenyl phosphite to form a resulting N,P- acetal, which can further couple with an R ⁇ -substituted aldehyde to produced an (R v" '- methyl)-pyrimidinyl-ketone (Ilia). See, e.g., Journet et al., Tetrahedron Lett. 39:1717-1720 (1998).
  • the above-described compounds of formula V can be prepared according to Scheme V-Ic below. Specifically, an (Ilia) (described above) can be oxidized to form a pyrimidinyl-diketone (FVb), which can undergo reaction with an appropriate substituted (and optionally protected) aldehyde (VI) to yield a compound of formula V (V) as described above.
  • an (Ilia) (described above) can be oxidized to form a pyrimidinyl-diketone (FVb), which can undergo reaction with an appropriate substituted (and optionally protected) aldehyde (VI) to yield a compound of formula V (V) as described above.
  • a compound of formula V can be prepared by reacting intermediate (IV) or (IVa) with an aldehyde (VII) to yield a further intermediate (VIII), which can then react with compound (IX) to yield a compound of formula V.
  • VIII aldehyde
  • moieties Y' and Y" are precursors of moiety Yv. See Scheme V-2 below, hi addition, desired substitutions at R v"a can be obtained by selecting, for example, the appropriate compound (Ha) intermediate.
  • moiety Xv in compound (VII) is a nitrogen-containing heterocycloalkyl (e.g., piperidine).
  • the nitrogen ring atom can be protected by a nitrogen protecting group (e.g., Cbz, Boc, or FMOC) before coupling to compound (IV) or (IVa) and deprotected afterwards (see first step of Scheme 3) to yield compound (Villa).
  • This compound can further react with various compounds (IX) to produce a compound of formula V. See second steps of Scheme V-3 below. It should be noted that compound (VIII) or compound (Villa) can be a compound of formula V as well.
  • Examples of compounds of formula V include, but are not limited to,
  • the antagonists have the structure shown in formula VI:
  • each R VI"a can be alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, -NH 2 , -NH(unsubstituted alkyl), -N(unsubstituted alkyl) 2 , nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarboixyloxy, urea, thiourea,
  • R VM can be a bond, alkylene, alkenylene, alkynylene, or -(CH 2 )ri-O-(CH 2 ) r2 -, wherein- each of rl and r2, independently, is 2 or 3.
  • R y ⁇ can be cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, arylene, heteroaryleae, or a bond.
  • R VM can be -C(O)-, -C(O)-O-, -O-C(O)-, -S(O) P -O-, -O-S(O) P -, -C(O)-N(R VI'b )-, -N(R VI"b )-C(O)-, -O-C(O)-N(R VI"b )-, -N(R VI'b )-C(O)-O-, -C(0)-N(R VI"b )-0-, -O-N(R VI" b )-C(O)-, -O-S(O)p-N(R VI"b )-, -N(R VW > S(O) P -O-, -S(O) p -N(R VI - b )-O-, -O-N(R VW >S(O) P -, -N(R VI - -O
  • R Vhb and R VI"C independently, can be hydrogen, hydroxy, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl.
  • p can be 1 or 2 and q can be 1-4.
  • R VM can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocyclo alkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
  • R VI"5 can be hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulflnyl, amino, alkenyl, alkynyl, cycloalkoxy, cycloalkylsulfmyl, heterocycloalkoxy, heterocycloalkylsulfinyl, aryloxy, arylsulfinyl, heteroaryloxy, or heteroarylsulfmyl.
  • R VI"6 can be a 5- to 6-membered monocyclic heterocyclyl or a 8- to 11-membered bicyclic heteroaryl, and optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl,
  • m can be 0-3, and when m ⁇ 2, two adjacent R a groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety.
  • the intermediate (III) can be further substituted at the 4-position of the pyrazole core ring with a good leaving group such as halo (e.g., iodo or bromo) t>y reacting with a halogenation reagent (e.g., bromination reagent such as Br 2 or iodination reagent such as N-iodosuccinimide) to form a 2-(4-halo-pyrazol-3-yl)-pyrimidine (IV).
  • halo e.g., iodo or bromo
  • a good leaving group such as halo (e.g., iodo or bromo) t>y reacting with a halogenation reagent (e.g., bromination reagent such as Br 2 or iodination reagent such as N-iodosuccinimide) to form a 2-(4-halo-pyrazol-3-yl)-pyrim
  • the iodo substituent can be converted into a boronic acid substituent (see compound (V) below), which can react with a R VI"6 -halide (VI) C ⁇ g-, an aryl halide or a heteroaryl halide) via Suzuki coupling reaction to form a compound of formula VI.
  • R VI"6 -halide (VI) C ⁇ g-, an aryl halide or a heteroaryl halide) via Suzuki coupling reaction to form a compound of formula VI.
  • Other substitution reactions can also be employed to produce a wide range of compounds of formula VI (see, e.g., via a reaction between the protected iodinated compound. (Wa) and phthalic anhydride to form a di-keto intermediate (VII), which can undergo a cyclization reaction with an R g -substituted hydrazine to form a compound (VI); for reference, see J. Med.
  • a compound of formula VI can be prepared according to Scheme VI-3 shown below.
  • a dirnethoxymethyl-substituted pyrimidine of formula (IEa) can be prepared by reacting dimethylformamide dimethylacetal with l,l-dimethoxy-propan-2-one to form 4-dimethylamino-l,l-dirnethoxy-but-3-en-2-one as an intermediate, which can further react with an R VI"a -substituted acetamidine (i.e., R VI"a -C(NH)-NH 2 ) to produce a compound of formula (Ha).
  • R VI"a -substituted acetamidine i.e., R VI"a -C(NH)-NH 2
  • the compound of formula (Ha) can then be deprotected in an acidic medium (e.g., aqueous HBr) and react with aniline and diphenylphosphite to form a compound of formula (lib), which can then react with an R VI"6 -substituted aldehyde to form a compound of formula (lie). Further reaction of a compound of formula (lie) with N,N-dimethylformamide dimettiylacetal (DMFDMA), followed by hydrazine hydrate, yields a compound of formula VI.
  • DMFDMA N,N-dimethylformamide dimettiylacetal
  • a compound of formula VI can also be prepared via a phenylacetyl pyrimidine compound (IX) as shown in Scheme VI-5 below. Specifically, a pyrimidine- carboxyaldehyde compound (VIII) is converted to the N 5 P acetal intermediate with aniline and diphenylphosphite. This acetal intermediate is then coupled to an aldehyde substituted with R VI"6 in basic condition (e.g., Cs 2 CO 3 ) to afford an enamine intermediate, which is hydrolyzed to a ketone intermediate (DC).
  • DC ketone intermediate
  • Cyclizing the ketone intermediate (IX) with N 5 N- dimethylformamide dimethyl acetal and hydrazine affords the pyrazole ring of the desired compound of formula VI.
  • the pyrazole ring of a compound of formula VI can also be formed by cyclizing the ketone intermediate (IX) with an R VI"5 -substituted carboxylic acid hydrazide (X).
  • R VI"5 -substituted carboxylic acid hydrazide (X) For reference, see, e.g., Chemistry of Heterocyclic compounds 35(11): 1319- 1324 (2000).
  • a compound of formula VI wherein the 1 -position of the pyrazole core ring is unsubstituted can undergo a conjugate addition reaction as shown in reaction (B) below.
  • the electrophile or acceptor in the addition reaction generally contains a double bond connecting to an electron-withdrawing group or a double bond conjugating to groups such as carbonyl, cyano, or r ⁇ itro.
  • the -R VI"1 -R VI"2 -R VI"3 -R VI"4 giOup can be further transformed into other functionalities as shown in Scheme VI-8 below.
  • a compound of formula VI wherein the -R VM - R VI ⁇ 2 -R VI"3 -R VI"4 group is cyanoalkyl can be reduced to aminoallcyl, which can be further converted to other functionalities such as heteroaralkyl, heterocycloalkylalkyl, and carboxylic acid.
  • Substituents at the pyrimidinyl ring can also be converted into other functionalities.
  • R VI"a is bromo
  • a compound of formula VI wherein R VI"a is bromo can be converted into other functionalities such as alkyl, alkenyl, cycloalkyl and the like, by known methods.
  • R VI"6 substituents of the R VI"6 moiety can be further converted into other functionalities as well.
  • A-S will be obvious to a skilled person in the art, some starting materials and intermediates may need to be protected before undergoing synthetic steps as described above.
  • suitable protecting groups see, e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York (1981).
  • Examples of compounds of formula VI include, but are not limited to,
  • an effective amount is the amount which is required to confer a therapeutic effect on the treated subject, e.g. a patient.
  • an effective amount can range from about 1 mg/kg to about 150 mg/kg (e.g., from about 1 mg/kg to about 100 mg/kg).
  • Effective doses will also vary, as recognized by those skilled in the art, dependent on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents and/or radiation therapy.
  • the compounds of formulae I, II, III, IV, V, and VI can be administered by any method that permits the delivery of the compounds to combat vascular injuries.
  • the compounds of formulae I, II, III, IV, V, and VI can be admininistered via pills, tablets, capsules, aerosols, suppositories, liquid formulations for ingestion or injection or for use as eye or ear drops, dietary supplements, and topical preparations.
  • a pharmaceutically acceptable composition includes the aqueous solution of the compound of formula I, II, III, IV, V, or VI, in an isotonic saline, 5% glucose or another well-known pharmaceutically acceptable excipient.
  • Solubilizing agents such as cyclodextrins, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compounds.
  • the compositions can be administered orally, intranasally, transdermally, intradermally, vaginally, intraaurally, intraocularly, buccally, rectally, transmucosally, or via inhalation, or intravenous administration.
  • the compositions may be delivered intravenously via a ballon catheter.
  • compositions can be administered to an animal (e.g., a mammal such as a human, non-human primate, horse, dog, cow, pig, sheep, goat, cat, mouse, rat, guinea pig, rabbit, hamster, gerbil, ferret, lizard, reptile, or bird).
  • an animal e.g., a mammal such as a human, non-human primate, horse, dog, cow, pig, sheep, goat, cat, mouse, rat, guinea pig, rabbit, hamster, gerbil, ferret, lizard, reptile, or bird.
  • the compounds of formulae I, U, III, IV, V, and VI also can be delivered by implantation (e.g., surgically) with an implantable device.
  • implantable devices include, but are not limited to, stents, delivery pumps, vascular filters, and implantable control release compositions. Any implantable device can be used to deliver the compound provided that 1) the device, compound and any pharmaceutical composition including the compound are biocompatible, and 2) that the device can deliver or release an effective amount of the compound to confer a therapeutic effect on the treated patient within, a short or over an extended period of time.
  • stents Delivery of therapeutic agents via stents, delivery pumps (e.g., mini-osmotic pumps), and other implantable devices is known in the art. See for example, "Recent Developments in Coated Stents” by Hofrna et al., published in Current Interventional Cardiology Reports 2001, 3:28-36, the entire contents of which, including references cited therein, are incorporated herein. Other descriptions of implantable devices, such as stents, can " be found, e.g., in U.S. Patent Nos.
  • a delivery device such as stent 10, includes a compound 20 of formula I, II, III, IV, V, or VI.
  • the compound, as a therapeutic agent may be incorporated into or onto the stent using methodologies known in the art.
  • a stent can include interlocked meshed cables. Each cable can include metal wires for structural support and polyermic wires for delivering the therapeutic agent.
  • the polymeric wire can be dosed by immersing the polymer in a solution of the therapeutic agent.
  • the therapeutic agent can be embedded in the polymeric wire during the formation of the wire from polymeric precursor solutions.
  • stents or implatable devices can be coated with polymeric coatings that include the therapeutic agent. The polymeric coating can be designed to control the release rate of the therapeutic agent.
  • Controlled release of therapeutic agents can utilize various technologies.
  • Devices having a monolithic layer or coating incorporating a heterogeneous solution and/or dispersion of an active agent in a polymeric substance (e.g., a polyester), where the diffusion of the agent is irate ⁇ m ⁇ t ⁇ ngj as ' the agent diffuses through the polymer to the polymer- fluid interface and is released into the surrounding fluid, hi some devices, a soluble substance is also dissolved or dispersed in, or chemically bonded to, the polymeric material, such that additional pores or channels are left after the material dissolves.
  • a matrix device is generally diffusion limited as well, but with the channels or other internal geometry of the device also playing a role in releasing the agent to the fluid. The channels can be pre-existing or left behind by released agent or other soluble substances.
  • Erodible or degradable devices typically have the active agent physically immobilized in the polymer.
  • the active agent can be dissolved and/or dispersed throughout the polymeric material.
  • the polymeric material is often hydrolytically degraded over time through hydrolysis of labile bonds, allowing the polymer to erode into the fluid and releasing the active agent into the fluid.
  • Hydrophilic polymers have a generally faster rate of erosion relative to hydrophobic polymers. Hydrophobic polymers are believed to have almost purely surface diffusion of active agent, having erosion from the surface inwards. Hydrophilic polymers are believed to allow water to penetrate the surface of the polymer, allowing hydrolysis of labile bonds beneath the surface, which can lead to homogeneous or bulk erosion of polymer.
  • the implantable device coating can include a blend of polymers each having a different release rate of the therapeutic agent.
  • the coating can include a polylactic acid/polyethylene oxide (PLA-PEO) copolymer and a polylactic acid/polycaprolactone (PLA-PCL) copolymer.
  • the polylactic acid/polyethylene oxide (PLA- PEO) copolymer can exhibit a higher release rate of therapeutic agent relative to the polylactic acid/polycaprolactone (PLA-PCL) copolymer.
  • the relative amounts and dosage rates of therapeutic agent delivered over time can be controlled by changing the relative amounts of the faster releasing polymers relative to the slower releasing polymers.
  • the proportion of faster releasing polymer can be increased relative to the slower releasing polymer. If most of the dosage is desired to be released over a. long time period, most of the polymer can be the slower releasing polymer.
  • the stent can " be coated by spraying the stent with a solution or dispersion of polymer, active agent, and solvent. The solvent can be evaporated, leaving a coating of polymer and active agent. The active agent can be dissolved and/or dispersed in the polymer. In some embodiments., the co ⁇ polymers can be extruded over the stent body.
  • compounds of formula I can be administered in conjunction with one or more other agents that inhibit the TGF/3 signaling pathway or treat the corresponding pathological disorders (e.g., fibrosis or progressive cancers) by way of a different mechanism of action.
  • agents include angiotensin converting enzyme inhibitors, nonsteroid, steroid anti-inflammatory agents, and chemotherapeutics or radiation, as well as agents that antagonize ligand binding or activation of the TGFjS receptors, e.g., anti-TGF/3, anti-TGF/3 receptor antibodies, or antagonists of the TGF/? type II receptors.
  • Example 1 Balloon Catheter Injury of the Rat Carotid Artery
  • Sprague Dawley rats 400g, 3 to 4 months old were anesthetized by i.p. injection with 10 mg/kg xylazine (XyIa- Ject, Phoenix Pharmaceuticals) and 80 mg/kg ketamine (Ketaset, Fort Dodge).
  • the left carotid artery and the aorta were denuded with a 2F balloon catheter (Edwards Life Sciences) according to the procedure described in Clowes et al., Lab Invest. 49: 327-333 (1983).
  • the animals were sacrificed under anesthesia 14 days post-balloon injury.
  • Exsanguination and then perfusion fixation was carried out under physiological pressure with 0.9% sodium chloride, injection USP (310 mOsmol/L, pH 5.6 (4.5-7.0)) and (10% neutral buffered formalin).
  • the injured carotid artery was excised, post-fixed and embedded for histological and morphometic analysis. Sections (5 ⁇ m) were cut from the proximal, middle and distal segments of the denuded vessel and analyzed using image analysis software.
  • the circumference of the lumen and the lengths of the internal elastic lamina (IEL) and the external elastic lamina (EEL) were determined by tracing along the luminal surface the perimeter of the neointima (IEL) and the perimeter of the tunica media (EEL), respectively.
  • the lumen (area within the lumen), medial (area between the IEL and EEL) and intimal (area between the lumen and the IEL) areas were also determined using morphometric analysis.
  • Statistical analysis used ANOVA to determine statistically significant differences between the means of treatment groups (p ⁇ 0.05). Multiple comparisons between groups were then performed using the Dunnet's Multiple Comparisons test. The Student t test was used to compare the means between 2 groups, and differences were considered significant if P ⁇ 0.05. All data are shown as mean + SEM.
  • the serine-threonine kinase activity of TGF/? type I receptor was measured as th.e autophosphorylation activity of the cytoplasr ⁇ ic domain of the receptor containing an IST- terminal poly histidine, TEV cleavage site-tag, e.g., His-TGF/3RI.
  • the His-tagged receptor cytoplasmic kinase domains were purified from infected insect cell cultures using the Gibco- BRL FastBac HTb baculovirus expression system.
  • Compounds of formulae I, II, III, IV, V, and VI typically exhibited low IC 50 values of less than 10 ⁇ M; some exhibited IC 50 values of less than 1 ⁇ M; and some even exhibited IC 5O values of less than 50 nM.
  • Example 3 Cell-Free Assay for Evaluating Inhibition of Activin Type I Receptor Kinase Activity
  • Inhibition of the Activin type I receptor (AIk 4) kinase autophosphorylation activity by compounds of formulae I, II, III, IV, V, and VI, can be determined in a similar manner to that described above in Example 2 except that a similarly His-tagged form of AIk 4 (His- AIk 4) is used in place of the HiS-TGF 1 SRI.
  • AIk 4 Activin type I receptor
  • Control wells containing either DMSO without any test compound or controL compound in DMSO were used.
  • His-TGF ⁇ Type I receptor in the same assay buffer Hepes, NaCl 2 , MgCl 2 , MnCl 2 , DTT, and 30% Brij ® added fresh
  • PE nickel coated FlashPlate
  • the control wells contained only buffer (i.e., no His-TGF/3 Type I receptor).
  • the premixed solution of tritiated 4-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinoline and the test compound was then added to the wells.
  • the wells were aspirated after an hour at room temperature and radioactivity in wells (emitted from the tritiated compound) was measured using TopCount (PerkinElmer Lifesciences, Inc., Boston MA).
  • Biological activity of the compounds of formulae I, II, III, IV, V, and VI was determined by measuring their ability to inhibit TGF ⁇ -induced PAI-Luciferase reporter activity in HepG2 cells.
  • HepG2 cells were stably transfected with the PAI-luciferase reporter grown in DMEM medium containing 10% FBS, penicillin (100 U/ml), streptomycin (100 ⁇ g/ml), L-glutamine (2 mM), sodium pyruvate (1 mM), and non-essential amino acids (Ix).
  • the transfected cells were then plated at a concentration of 2.5 x 10 4 cells/well in 96-well plates and starved for 3-6 hours in media with 0.5% FBS at 37 0 C in a 5% CO 2 incubator.
  • the cells were then stimulated with 2.5 ng/ml TGF/3 ligand in the starvation media containing 1 % DMSO either in the presence or absence of a test compound of formula I, II, III, IV, V, or VI and incubated as described above for 24 hours.
  • the media was washed out the following day and the luciferase reporter activity was detected using the LucLite Luciferase Reporter Gene Assay kit (Packard, Cat. No. 6016911) as recommended.
  • the plates were read on a Wallac Microbeta plate reader, the reading of which was used to determine the IC 50 values of the test compounds for inhibiting TGF ⁇ -induced PAI-Luciferase reporter activity in HepG2 cells.
  • Compounds of formulae I, II, III, IV, V, and VI typically exhibited IC 50 values of less 10 uM.
  • Cytotoxicity was determined using the same cell culture conditions as described above. Specifically, cell viability was determined after overnight incubation with the CytoLite cell viability kit (Packard, cat. no. 6016901). Compounds of formula I, II, III, IV, V, and VI typically exhibited LD 25 values greater than 10 /xM.
  • Fibroblasts are derived from the skin of adult transgenic mice expressing Green Fluorescent Protein (GFP) under the control of the collagen IAl promoter (see Krempen, K. et al., Gene Exp. 8: 151-163 (1999)).
  • GFP Green Fluorescent Protein
  • Cells are immortalized with a temperature sensitive large T antigen that is in an active stage at 33 0 C, and then expanded at 33°C before being transferred to 37°C at which temperature the large T antigen becomes inactive (see, e.g., Xu, S. et al., Exp. Cell Res., 220: 407-414 (1995)). Over the course of about 4 days and one split, the cells cease proliferating. The cells are then frozen in aliquots sufficient for a single 96- well plate.
  • Cells are thawed, plated in complete DMEM (contains non-essential amino acids, ImM sodium pyruvate and 2mM L-glutamine) with 10 % fetal calf serum, and then incubated for overnight at 37°C, 5% CO 2 .
  • the cells are trypsinized in the following day and transferred into 96-well format with 30,000 cells per well in 50 ⁇ complete DMEM containing 2 % fetal calf serum, but without phenol red.
  • the cells are incubated at 37°C for 3 to 4 h-ours to allow them to adhere to the plate.
  • Solutions containing a test compound of formula I, II, III, IV, V, or VI are then added to wells with no TGFjS (in triplicates), as well as wells with 1 ng/ml TGF/3 (in triplicates).
  • DMSO is also added to all of the wells at a final concentration of 0.1%.
  • GFP fluorescence emission at 530 ran following excitation at 485 urn is measured 48 hours after the addition of solutions containing a test compound on a CytoFluor microplate reader (PerSeptive Biosystems). The data are expressed as the ratio of TGF ⁇ -induced to non-induced for each test sample.

Abstract

The present invention relates to use of compounds and implantable devices including those compounds in treating, preventing, or reducing intimal thickening, vascular remodeling, restenosis (e.g., coronary, peripheral, carotid restenosis), vascular diseases, (e.g., organ transplant-related, cardiac, lung and renal), and hypertension (e.g., primary and secondary hypertension, systolic hypertension, pulmonary hypertension, and hypertension-induced vascular remodeling resulting in target organ damage).

Description

METHODS OF TREATING VASCULAR INJURIES BACKGROUND OF THE INVENTION
[001] TGF/3 (Transforming Growth Factor /3) is a member of a large family of dimeric polypeptide growth factors that includes, for example, activins, inhibins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and mullerian inhibiting substance (MIS). TGF/3 exists in three isoforms (TGF1Sl, TGF|82, and TGF03) and is present in most cells, along with its receptors. Each isoform is expressed in both a tissue-specific and developmentally regulated fashion. Each TGF/3 isoform is synthesized as a precursor protein that is cleaved intracellularly into a C-terminal region (latency associated peptide (LAP)) and an N-terminal region known as mature or active TGFjS. LAP is typically non-covalently associated with mature TGFjS prior to secretion from the cell. The LAP-TGFjS complex cannot bind to the TGF/3 receptors and is not biologically active. TGF/3 is generally released (and activated) from the complex by a variety of mechanisms including, for example, interaction with thrombospondin-1 or plasmin.
[002] Following activation, TGF1S binds at high affinity to the type II receptor (TGFjSRII), a constitutively active serine/threonine kinase. The ligand-bound type II receptor phosphorylates the TGF/3 type I receptor (AIk 5) in a glycine/serine rich domain, which allows the type I receptor to recruit and phosphorylate downstream signaling molecules, Smad2 or Smad3. See, e.g., Huse, M. et al., MoI. Cell. 8: 671-682 (2001). Phosphorylated Smad2 or Smad3 can then complex with Smad4, and the entire hetero-Smad complex translocates to the nucleus and regulates transcription of various TGF/3-responsive genes. See, e.g., Massague, J. Ann. Rev. Biochem. Med. 67: 773 (1998).
[003] Activins are also members of the TGF/3 superfamily, which are distinct from TGF/3 in that they are homo- or heterodimers of activin /3a or /3b. Activins signal in a manner similar to TGF/3, that is, by binding to a constitutive serine-threonine receptor kinase, activin type II receptor (ActRIIB), and activating a type I serine-threonine receptor, AIk 4, to phosphorylate Smad2 or Smad3. The consequent formation of a hetero-Smad complex with Smad4 also results in the activin-induced regulation of gene transcription.
[004] Indeed, TGF1S and related factors such as activin regulate a large array of cellular processes, e.g., cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, inflammatory cell recruitment, immunosuppression, wound healing, and extracellular matrix production. See, e.g., Massague, J. Ann. Rev .Cell. Biol. 6: 594-641 (1990); Roberts, A. B. and Sporn M. B. Peptide Growth Factors and Their Receptors, 95: 419-472 Berlin: Springer- Verlag (1990); Roberts, A. B. and Sporn M. B. Growth Factors 8:1-9 (1993); and Alexandrow, M. G., Moses, H. L. Cancer Res. 55: 1452- 1457 (1995). Hyperactivity of TGF1S signaling pathway underlies many human disorders (e.g., excess deposition of extracellular matrix, an abnormally high level of inflammatory responses, fibrotic disorders, and progressive cancers). See, e.g. Blobe G.C., Schiemann W.P., Lodish H.F. N. Eng. J. Med. 342: 1350-8 (2000). Similarly, activin signaling and overexpression of activin is linked to pathological disorders that involve extracellular matrix accumulation and fibrosis (see, e.g., Matsuse, T. et al., Am. J. Respir. Cell MoI. Biol. 13: 17- 24 (1995); Inoue, S. et al., Biochem. Biophys. Res. Comm. 205: 441-448 (1994); Matsuse, T. et al, Am. J. Pathol. 148: 707-713 (1996); De Bleser et al., Hepatology 26: 905-912 (1997); Pawlowski, J.E., et al., J. CHn. Invest. 100: 639-648 (1997); Sugiyama, M. et al., Gastroenterology 114: 550-558 (1998); Munz, B. et al., EMBO J. 18: 5205-5215 (1999)), inflammatory responses (see, e.g., Rosendahl, A. et al., Am. J. Repir. Cell MoI. Biol. 25: 60- 68 (2001)), cachexia or wasting (see Matzuk, M. M. et al., Proc. Nat. Acad. Sd. USA 91 : 8817-8821 (1994); Coerver, K.A. et si, MoL Endocrinol. 10: 534-543 (1996); Cipriano, S.C. et al. Endocrinology 141: 2319-27 (2000)), diseases of or pathological responses in the central nervous system (see Logan, A. et al. Eur. J. Neurosci. 11: 2367-2374 (1999); Logan, A. et al. Exp. Neurol. 159: 504-510 (1999); Masliah, E. et al., Neurochem. Int. 39: 393-400 (2001); De Groot, C. J. A. et al, J. Neuropathol. Exp. Neurol. 58: 174-187 (1999), John, G. R. et al, Nat Med. 8: 1115-21 (2002)) and hypertension (see Dalily, A. J. et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 283: R757-67 (2002)). Studies have shown that TGF/3 and activin can act synergistically to induce extracellular matrix production (see, e.g., Sugiyama, M. et al., Gastroenterology 114: 550-558, (1998)). It is therefore desirable to develop modulators (e.g., antagonists) to members of the TGF 'β family to prevent and/or treat disorders involving this signaling pathway.
SUMMARY OF THE INVENTION
[005] Ih general, the compounds of formulae I, II, III, IV, V, and VI, described herein, unexpectedly exhibit systemic bioavailability and are useful in combating restenosis (e.g., coronary restenosis, peripheral restenosis, and carotid restenosis), vascular diseases (e.g., intimal thickening, vascular remodeling, or organ transplant-related vascular disease), and hypertension (e.g., primary or secondary, systolic hypertension, pulmonary hypertension or hypertension-induced vascular remodeling) when administered to a subject (e.g., a patient). [006J""" Methods of inhibiting intimal thickening or vascular remodeling include administering to a subject (e.g., a human patient) in need thereof an inhibitor of TGFβ type I receptor or Alk4. Embodiments of these aspects may include one or more of the following. The inhibitor is a compound of formula I, II, III, IV, V, or VI. The inhibitor is administered locally. The inhibitor is administered via an implantable device such as a delivery pump or a stent.
[007] In another aspect, the invention features an implantable device, such as a delivery pump or stent, including an inhibitor of TGFβ type I receptor or Alk4. The inhibitor can be a compound of formula I, II, III, IV, V, or VI.
Definitions;
[008] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. An alkyl group can be straight or branched. Examples of an alkyl group include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and 2-ethylhexyl. An alkyl group can be optionally substituted with one or more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl- alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylammo, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy.
[009] As used herein, an "alkenyl" group refers to an aliphatic carbon group that contains 2- 8 (e.g., 2-6 or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can be optionally substituted with one or more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl- alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylammo, het'erόaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy.
[010] As used herein, an "alkynyl" group refers to an aliphatic carbon group that contains 2- 8 (e.g., 2-6 or 2-4) carbon atoms and has at least one triple bond. An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, proparg;yl and butynyl. An alkynyl group can be optionally substituted with one or more substituents such as alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, or alkylcarbonyloxy.
[011] As used herein, an "amino" group refers to -NRXRY wherein each of Rx and Rγ is independently hydrogen, hydroxyl, alkyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NRX- wherein Rx has the same meaning as defined above.
[012] As used herein, an "aryl" group refers to phenyl, naphthyl, or a benzofused group having 2 to 3 rings. For example, a benzofused group includes phenyl fused with one or two C4-8 carbocyclic moieties, e.g., 1,2,3,4-tetrahydronaphthyl, indanyl, or fluorenyl. An aryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyL, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. [0Ϊ3] Xs' used "Herein, an "aralkyl" group refers to an alkyl group (e.g., a Ci-4 alkyl group) that is substituted with an aryl group. Both "alkyl" and "aryl" are as defined above. An example of an aralkyl group is benzyl.
[014] As used herein, a "cycloalkyl" group refers to an aliphatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro- naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, and bicyclo[3.2.3]nonyl. A "cycloalkenyl" group, as used herein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bond. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl. A cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocyclo alkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[015] As used herein, a "heterocycloalkyl" group refers to a 3- to 10-membered (e.g., 4- to 8-membered) saturated ring structure, in which one or more of the ring atoms is a heteroatom, e.g., N, O, or S. Examples of a heterocycloalkyl group include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, dioxolanyl, oxazolidinyl, isooxazolidinyl, morpholinyl, octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl, octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl, octahydro-benzo[b]thiophenyl, 2-oxa- bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa- tricyclo[3.3.1.03>7]nonyl. A "heterocycloalkenyl" group, as used herein, refers to a 3- to 10- membered (e.g., 4- to 8-membered) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom, e.g., N, O, or S. A heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloallcyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamin.o, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, rnercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[016] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic, or tricyclic ring structure having 5 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom, e.g., N, O, or S, and wherein one ore more rings of the bicyclic or tricyclic ring structure is aromatic. Some examples of heteroaryl are pyridyl, furyl., pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, and benzo[l,3]dioxole. A tieteroaryl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cyclo alkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl;, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalk^alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalky^carbonylamino, (heterocycloalkytyalkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl. A. "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a C1-4 alkyl group) th.at is substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" are as defined above.
[017] As used herein, "cyclic moiety" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocyclo alkenyl, aryl, or heteroaryl, each of which has Been defined previously.
[018] As used herein, an "acyl" group refers to a formyl group or alkyl-C(=O)- where "alkyl" has been defined previously. Acetyl and pivaloyl are examples of acyl groups. [019] As' used herein, a "carbamoyl" group refers to a group having the structure
-O-CO-NRXRY or -NRX-CO-O-RZ wherein Rx and Rγ have been defined above and Rz is alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, or heteroaralkyl.
[020] As used herein, a "carboxy" group and a "sulfo" group refer to -COOH and -SO3H, respectively.
[021] As used herein, an "alkoxy" group refers to an alkyl-O- group wherein "alkyl" has been defined previously.
[022] As used herein, a "sulfoxy" group refers to -O-SO-RX or -SO-O-R*1, wherein Rx has been defined above.
[023] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.
[024] As used herein, a "sulfamoyl" group refers to the structure -SO2-NRXRY or -NRX- SO2-R2 wherein Rx, Rγ, and Rz have been defined above.
[025] As used herein, a "sulfamide" group refers to the structure -NRX-S(O)2-NRYRZ wherein Rx, Rγ, and Rz have been defined above.
[026] As used herein, a "urea" group refers to the structure -NRX-CO-NR^RZ and a "thiourea" group refers to the structure -NRX-CS-NRYRZ. Rx, Rγ, and Rz have been defined above.
[027] As used herein, an effective amount is defined as the amount which is required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al, Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, a. "patient" refers to a mammal, including a human.
[028] An antagonist is a molecule that binds to the receptor without activating the receptor. It competes with the endogenous ligand(s) or substrate(s) for binding site(s) on the receptor and, thus inhibits the ability of the receptor to transduce an intracellular signal in response to endogenous ligand binding.
[029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
[030] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[031] Figure 1 is an illustration of a delivery device.
DETAILED DESCRIPTION OF THE INVENTION
[032] The inhibitors described herein are effective at treating, preventing, or reducing intimal thickening, vascular remodeling, restenosis (e.g., coronary, peripheral, carotid restenosis), vascular diseases, (e.g., organ transplant-related, cardiac, and renal), and hypertension (e.g., primary and secondary, systolic, pulmonary, and hypertension-induced vascular remodeling resulting in target organ damage).
[033] Without wishing to be bound by any p articular theory, one possible explanation for the efficacy of the compounds described herein may be their inhibitory effect on the TGFβ and activin pathways.
[034] The pathological activation of the TGFβ and activin pathway plays a critical role in the progression of fibrotic diseases. The critical serine-threonine kinase in the TGFβ type I receptor (TGFβRT) and the activin type I receptor (Alk4) are attractive targets for blockade of the TGFb pathway for several important reasons. TGFβRI kinase activity is required for TGFβ signaling as is Alk4 for activin signaling. Kinases have proven to be useful targets for development of small molecule drugs. There is a good structural understanding of the TGFβRI kinase domain allowing the use of structure-based drug discovery and design to aid in the development of inhibitors. [03*5] T1GrFPi or activin-mediated pathological changes in vascular flow and tone are often the cause of morbidity and mortality in a number of diseases (see, e.g., Gibbons G.H. and Dzau V.J. NEng. J. Med 330: 1431-1438 (1994)). Typically, the initial response of the vasculature to injury is an infiltration of adventitial inflammatory cells and induction of activated myofibroblasts or smooth muscle cells (referred to as myofibroblasts from hereon). TGFβ is initially produced by infiltrating inflammatory cells and activates myofibroblasts or smooth muscle cells. These activated myofibroblasts can also secrete TGFβ as well as respond to it. Within the first few days following injury, myofibroblasts secreting TGFβ migrate from the various layers of the vascular wall towards the lumen where they undergo proliferation and extracellular matrix secretion resulting in intimal thickening. Additionally, TGFβ induces activated myofibroblasts to contract which results in lumenal narrowing. These vascular remodeling processes, intimal thickening and vascular contraction, restrict blood flow to the tissues supported by the effected vasculature and result in tissue damage. Activin is also produced in response to injury and shows very similar actions in inducing activated myofibroblasts or activated smooth muscle cells intimal thickening and vascular remodeling. See, for example, Pawlowski et al., Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo, published in 1997 in J. Clin. Invest. 100: 639-648; Woodruff TK, Regulation of cellular and system function by activin, published in 1998 in Biochem Pharmacol. 55:953-963; Molloy et al., Novel cardiovascular actions of the activins, published in 1999 in J Endocrinol. 161(2): 179-85.; and Harada K et al., Immunoreactive activin A levels in normal subjects and patients with various diseases, published in 1996 in J Clin Endocrinol Metab. 81(6):2125-30.
[036] In coronary, peripheral or carotid artery disease, balloon angioplasty or stent placement is used to increase lumen size and blood flow. However, the physical damage created by stretching the vessel wall causes injury to the vessel wall tissue. TGFβ elevation following injury induces myofibroblasts in 2-5 days and frequently results in restenosis within 6 months of balloon angioplasty or within a few years of stent placement in human patients. Following balloon angioplasty, both intimal thickening and vascular remodeling due to myofibroblast contraction, cause narrowing of the lumen and decreased blood flow. Stent placement physically prevents remodeling, but hyperplasia and extracellular matrix deposition by activated myofibroblasts proliferating at the luminal side of the stent results in mtimal thickening within the stented vessel resulting in the eventual impairment of blood flow.
[037] The treatment of arterial stenotic diseases by surgical grafts, e.g. coronary bypass or other bypass surgery, also can elicit restenosis in the grafted vessel. In particular, vein grafts undergo intimal thickening and vascular remodeling through a similar mechanism involving TGFβ-induced intimal thickening and vascular remodeling. In this case, the injury is either due to the overdistention of the thin- walled vein graft placed into an arterial vascular context or due to anastamotic or ischemic injury during the transplantation of the graft.
[038] The loss of patency in arteriovenous or synthetic bridge graft fistulas is another vascular remodeling response involving increased TGFβ production. See, e.g., IkegayalST. et al., J. Am. Soc. Nephrol, 11 :928-35 (2000); Heine G.H. et al., Kidney Int., 64:1101-7 (2O03). Loss of fistula patency causes complications for renal dialysis or other treatments requiring chronic access to the circulatory system (Ascher E., Ann. Vase. Surg., 15:89-97 (2001)). Blockade of TGFβ by TGFβRI inhibitors will be beneficial for preventing restenosis and extending arteriovenous fistula patency.
[039] Elevated TGFβ is implicated in chronic allograft vasculopathy both in animals and humans. Vascular injury, intimal thickening and vascular remodeling is a characteristic pathology in chronic allograft failure. The fibrotic response in chronic allograft failure initiates in the vasculature of the donor organ. Chronic allograft vasculopathy in allografted hearts often manifests within 5 years of transplantation and is the main cause of death in Long term survivors of cardiac transplant. Early detection of cardiac allograft vasculopathy measured as mtimal thickening by intravascular ultrasound, as well as the elevation of pla-sma TGFβ, has been suggested as a prognostic marker for late cardiac allograft failure (see, e.g., Mehra MR et al., 2004, Am. J. Transplant., 4:1184). Cardiac biopsies of grafted hearts also suggest that graft tissue expression of TGFβ correlates significantly to vasculopathy and Che number of rejection episodes (see, e.g., Aziz, T. et al., 2000, J. Thorac. Cardiovasc. Surg., 119: 700). Finally, patients with high-producing TGFβl genotypes are more susceptible to earlier onset cardiac-transplant coronary vasculopathy (see, e.g., Densem, CG et al., 200O5, J. Heart Lung Transplant, 19:551; Aziz, T. et al., 2000, J. Thorac. Cardiovasc. Surg., 119: 7€0; and Holweg, CT, 2001, Transplantation, 71 :1463).
[040] Elevation of TGFβ can be induced by ischemic, immune and inflammatory responses to the allograft organ. Animal models of acute and chronic renal allograft rejection identify the elevation of TGFβ as a significant contributor to graft failure and rejection (see, e.g., Nagano, H. et al., 1997, Transplantation, 63: 1101; Paul, LC. et al., 1996, Am. J. Kidney Dis., 28: 441; and Shihab, FS. et al., 1996, Kidney M., 50: 1904). Rodent models of chronic allograft nephropathy (CAN) show elevation of TGFβ mRNA and immunostaining. In renal allografts TGFβ immunostaining is strongly positive in interstitial inflammatory andfibrotic cells, but also in blood vessels and glomeruli. In humans, the loss of renal function 1 year post renal allograft correlates with TGFβ staining in the grafted kidney. See, e.g., Cuhaci, B. et al., 1999, Transplantation, 68: 785). Graft biopsies show also that renal dysfunction correlates with chronic vascular remodeling, i.e., vasculopathy, and the degree of TGFβ expression correlates significantly with chronic vasculopathy (see, e.g., Viklicky, O. et al., 2003, Physiol Res. 52: 353).
[041] The use of immunosuppressive agents such as cyclosporine A in organ transplantation has not prevented vasculopathy and chronic allograft nephropathy suggesting non-immune mechanisms are involved in allograft failure. In fact, cyclosporinA and other immunosuppressants have been shown to induce TGFβ expression and may contribute to vasculopathy (see, e.g., Moien-Afshari, F. et al., 2003, Pharmacol. Ther., 100: 141; and Jain, S. et al., 2000, Transplantation, 69: 1759).
[042] TGFβ is implicated in chronic allograft rejection in both renal and lung transplants due to the clear TGFβ-related fibrotic pathology of this condition as well as the ability of immune suppressants, esp cyclosporin A, to induce TGFβ (Jain, S. et al., 2000 Transplantation, 69: 1759). TGFβ blockade improved renal function while decreasing collagen deposition, renal TGFβ expression as well as vascular afferent arteriole remodeling in a cyclosporine A-induced renal failure model using an anti-TGFβ monoclonal antibody (Islam, M. et al., 2001 Kidney Int., 59: 498; Khanna, A.K. et al., 1997 Transplantation, 67: 882). These data are strongly indicative of a causal role for TGFβ in the development and progression of chonic allograft vasculopathy and chronic allograft failure.
[043] Hypertension is a major cause of morbidity and mortality in the U.S. population affecting approximately 1 in 3 individuals. The effect of hypertension on target organs include increased incidence of cardiac failure, myocardial infarction, stroke, renal failure, aneurysm and microvascular hemorrhage. Hypertension-induced damage to the vasculature results in vascular remodeling and intimal thickening which are a major causative factor in many ofthese morbidities (Weber, W.T. 2000 Curr. Opin. Cardiol. 15:264-72). Animal experiments suggest that TGFβ is elevated upon induction of hypertension and anti-XGFβ monoclonal antibody blockade of this pathway decreases blood pressure and renal pathology in hypertensive rats (Xu, C. et al., 2001 J. Vase. Surg., 33:570; Dahly, AJ. et al, 20O2 Am. J. Physiol. Regul. Integr. Comp. Physiol, 283:R757). hi humans, plasma TGFβ is elevated in hypertensive individuals compared to normotensive controls and plasma TGFβ is also higher in hypertensive individuals with manifest target organ disease compared to hypertensive individuals without apparent target organ damage (Derhaschnig, U. et al., 2002 Am. Jf. Hypertens., 15:207; Suthanthiran, M. 2000 PrOc. Natl. Acad. ScL U.S.A., 97:3479). There is also evidence suggesting that high TGFβ-producing genotypes of TGFβ are a risk factor for development of hypertension (Lijnen, PJ. 2003 Am. J. Hypertens., 16:604; Suthanthiran, M. 2000 Proc. Natl. Acad. ScL U.S.A., 97:3479). Thus the inhibition of the TGFβ pathway may provide a effective therapeutic approach for hypertension or hypertension-induced organ damage.
[044] The vascular injury response in the pulmonary vasculature results in pulmonary hypertension which can lead to overload of the right heart and cardiac failure (Runo, J.R., Loyd, J.E., 2003 Lancet 361(9368):1533-44; Sitbon, O. et al., 2002 Prog. Cardiovasc Dis., 45: 115-28; Jeffery, T.K., Morrell, N. W. 2002 Cardiovasc. Dis., 45:173-202). Prevention of pulmonary vascular remodeling by TGFβRI inhibitors can be of practical utility in diseases such as primary or secondary pulmonary hypertension (Sitbon, O. et al., 2002, Prog. Cardiovasc. Dis., 45: 115-28; Humbert, M. et al., J. Am. Coll. Cardiol, 2004 43:13S -24S). Inhibition of the progression of vascular remodeling over time will prevent the progression of pulmonary pathology in these life threatening diseases. Secondary pulmonary hypertension occurs often as a manifestation of scleroderma and is one of the primary causes of morbidity and mortality in scleroderma patients (Denton, CP. , Black, CM. 2003, Rheum. Dis. CHn. Norih. Am., 29:335-49). Pulmonary hypertension is also a sequalae of mixied connective tissue disease, chronic obstructive pulmonary disease (COPD) and lupus erythematosis (Fagan, K. A., Badesch, D.B., 2002, Prog. Cardiovasc. Dis., 45:225-34; and Presberg, K.W., Dincer, H.E., 2003, Curr. Opin. PuIm. Med., 9:131-8).
[045] Many of the diseases described above involving vascular remodeling are particularly severe in diabetic patients (Reginelli, J.P., Bhatt, D. L., 2002, J. Invasive Cardiol., 14 Suppl E:2E-10E). Elevated glucose in diabetes can itself induce TGFβ which leads to the increased vascular remodeling and intimal thickening response to vascular injury (Ziyadeh, FJ., Am. Soc. Nephrol, 2004, 15 Suppl 1 :S55-7). In particular, diabetic patients have significantly higher rates of restenosis, vein graft stenosis, peripheral artery disease, chronic allograft nephropathy and chronic allograft vasculopathy (Reginelli, J.P., Bhatt, D. L., 2002, J. Invasive Cardiol., 14 Suppl E:2E-10E; Eisen. H., Ross, H., 2004, J. Heart Lung Transplant., 23:S207- 13; Valentine, H., 2004, J. Heart Lung Transplant., 23:S187-93). Thus, blockade of TGFβ is of particular utility in diabetic patients at risk for hypertension-related organ failure, diabetic nephropathy, restenosis or vein graft stenosis in coronary or peripheral arteries, and chronic failure of allograft organ transplants (Endemann, D.H. et al., 2004, Hypertension, 43(2):399- 404; Ziyadeh, FJ., Am. Soc. Nephrol, 2004 15 Suppl l:S55-7; and Jerums, G. et al., 2003, Arch. Biσchem. Biophys., 419:55-62).
[046] Surprisingly, TGFβRI and Alk4 antagonists are effective at treating, preventing, or reducing intimal thickening, vascular remodeling, restenosis (e.g., coronary, peripheral, and carotid restenosis), vascular diseases, (e.g., organ transplant-related, cardiac, and renal), and hypertension (e.g., systolic, pulmonary, and hypertension-induced vascular remodeling resulting in target organ damage). Changes in vascular remodeling and intimal thickening may be qualified by measuring the intimal versus medial vascular thickness.
TGFβRI and AIk 4 Inhibitors
[047] The TGFjS and activin inhibitory activity of compounds can be assessed by methods described below.
[048] Examples of these antagonists are shown below in formulae I, II, III, IV, V, and VI.
[049] In one embodiment, the antagonists have the structure shown in formula I:
Figure imgf000014_0001
[050] In formula I, R1"1 can be aryl, heteroaryl, aralkyl, or heteroaralkyl. Each R1"8, independently, can be alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, svilfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, lieterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl. Xi-J can be cycloalkyl or heterocycloalkyl. Yn can be a bond, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(O)-N(R1"13)-, -N(R1^)-C(O)-, -O- C(O)-N(R1"13)-, -N(R^)-C(O)-O-, -0-S(O)P-N(R1"")-, -N(R1^)-S(O)P-O-, -N(R1^)-C(O)-N(R1" c)-, -N(R1^)-S(O)P-N(R1"0)-, -C(O)-N(R1^)-S(O)P-, -S(O)P-N(R1^)-C(O)-, -C(O)-N(R1'13)- S(O)P-N(R!"C)-, -C(O)-O-S(O)P-N(R1"13)-, -N(RI-b)-S(0)p-N(RI"c)-C(0)-, -N(R1^)-S(O)P-O- C(O)-, -S(O)P-N(R1"13)-, -N(R1^)-S(O)P-, -N(R1"13)-, -S(0)p-, -0-, -S-, or -(C(R1^)(R1" c))q-, wherein each of R1"13 and R1"0 is independently hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl. p can be 1 or 2, and q can be 1-4. R1"2 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkcenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl. Each of A1"1 and A1"2, independently, can be O, S, N, or NR1"13, provided that at least one of A1"1 and A1"2 can be N. m can be O, 1, 2, or 3. In other words, the 2- pyridyl ring can be unsubstituted or substituted with 1 to 3 R1"*1 groups. Note that when m > 2, two adjacent Rμa groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety. That is, the 2-pyridyl ring can fuse with a cyclic moiety to form a moiety, e.g., 7H-[2]pyrindiiiyl, 6,7-dihydro-5H-[l]pyrindinyl, 5,6,7,8-tetrahydro- quinolinyl, 5,7-dihydro-furo[3,4-b]pyridinyl, or 3,4-dihydro-lH-thiopyrano[4,3-c]pyridinyl, that can be optionally substituted with one or more substituents such as alkyl (including substituted alkyl such as carboxyalkyl, hydroxyalkyl, and haloalkyl (e.g., trifluoromethyl)), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylthio, sulfoxy, sulfamoyl, oxo, or carbamoyl.
[051] Compounds of formula I and methods for producing the same are known in the art. For instance, WO 03/087304, which, is incorpoarated in its entrity by reference, describes synthetic methods for producing inhibitors of formula I. Examples of compounds of formula I include, but are not limited to,
1) 4-(4-Benzo[l ,3]dioxol-5-yl-5-(6-rnethyl-pyridin-2-yl)-lH-imidazol-2-yl)-piperidine-l - carboxylic acid benzyl ester; 2) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid benzyl ester;
3) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imi<lazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
4) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-pyrrolidine-l- carboxylic acid benzyl ester;
5) 2-(5-Benzo[ 1 ,3]dioxol-5-yl-2-piperidm-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine;
6) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid benzyl ester;
7) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
8) 3-[4-Benzo[ 1 ,3]dioxol-5-yl~5-(6-methyl-pyridin-2-yl)- lH-imid.azol-2-yl]-pyrrolidine- 1 - carboxylic acid benzyl ester;
9) 2-(5-Benzo[ 1 ,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine; 10) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl]-6-metliyl-pyridine;
11) 2-[5-B enzo[ 1 ,3]dioxol-5-yl-2-(l -phenylmethanesulfonyl-piperidin-4-yl)-3H-irnidazol-4- yl]-pyridine;
12) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-metlianesulfonyl-piperidin-'4-yl)-3H-imidazol-4-yl]- pyridine;
13) 2-[5-B enzo[ 1 ,3]dioxol-5-yl-2-(l -methanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
14) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 2-chloro-benzyl ester;
15) 4-(4-B enzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl) -piperidine- 1 -carboxylic acid 2,4-dichloro-benzylamide;
16) l-[4-(4-Benzo[l,3]dioxol-5-yl-5-ρyridin-2-yl-lH-imidazol-2-yl)-piperidin-l-yl]- ethanone;
17) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-furan-2-yl-methyl-ρiperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
18) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-cyclohexyl}- carbamic acid benzyl ester;
19) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl] cyclohexylamine; 20) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexyl}-C-phenyl-methanesulfonamide;
21) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
22) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
23) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester;
24) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-ethyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
25) 2-(5-Benzo[l,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine;
26) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-nitro-benzyl ester;
27) 4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid 4,5-dimetlioxy-2-nitro-benzyl ester;
28) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 3-fluoro-benzylamide;
29) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l -carboxylic acid 4-fluoro-benzylamide;
30) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid benzylamide;
31) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(toluene-4-sulfonyl)-piρeridin-4-yl]-3H-imidazol-4-yl} - pyridine;
32) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-methyl-benzylamide;
33) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridm-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-methoxy-benzylamide;
34) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 2-chloro-benzylamide;
35) 4-[4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidine- 1 -sulfonyl]- benzoic acid;
36) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid amide;
37) 4-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- benzonitrile; 38) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(4-chloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
S^ Z-IS-Benzotl^Jdioxol-S-yl-l-tl-CS^-dichloro-benzenesulfonyO-piperidin^-y^-SH- imidazol-4-yl} -pyridine;
40) {5-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- naphthalen- 1 -yl} -dimethyl-amine;
41) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-4-yl-methyl)-piperidin-4-yl)]-3H-imidazol-4- yl} -pyridine;
42) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
43) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-methoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
44) 1 - {4-[4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine- 1 - sulfonyl]-phenyl}-ethanone;
45) 2- {5-Benzo[l,3]dioxol-5-yl-2-[l-(4-methyl-benzyl)-piperidin-4-yl] -3H-imidazol-4-yl}- pyridine;
46) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(3-fluoro-5-trifluoromethyl-ben2;yl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
47) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-cyclohexylmethyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
48) 2-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-l-ylmethyl]- cyclopropanecarboxylic acid ethyl ester;
49) 2-[4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidin- 1 -ylmethyl]- pyrrolidine-1-carboxylic acid tert-butyl ester;
50) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-piperidin-4- yl]-3H-imidazol-4-yl} -pyridine;
51) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-ethanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
52) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(butane- 1 -sulfonyl)-piperidin-4-yl]-3H-imidazol-4-yl} - pyridine;
53) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
54) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethenesulfonyl)-piperidin-4-yl]-3H-imidazol-
4-yl} -pyridine; 55) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-l-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
56) l-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l- sulfonylmethyl]-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one;
57) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[ 1 -(4-chloro-phenylmethanesulfonyl)-piperidin-4-yl] -3H- imidazol-4-yl} -pyridine;
58) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-dichloro-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -pyridine;
59) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-fluoro-phenylmethanesulfonyl)-piperidin-4-yl]— 3H- imidazol-4-yl} -pyridine;
60) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,4-dichloro-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -pyridine;
61) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-3H-imidazol- 4-yl} -pyridine;
62) 2-[5-Benzo[ 1 ,3]dioxol-5-yl-2-(l -p-tolylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -pyridine;
63) 3-(4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine— 1- carboxylic acid benzyl ester;
64) 3-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxyLic acid benzyl ester;
65) 4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
66) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-2-yl-methanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
67) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-naphthalen-l-yl-ethanesulfonyl)-piperidin-4-yl] -3H- imidazol-4-yl} -pyridine;
68) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-3-yl)-3H-imidazol-4- yl] -pyridine;
69) 3-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl] - piperidine-1-carboxylic acid benzyl ester;
70) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-4-yl-methanesulfonyl)-piρeridin-4-yl]-3H:- imidazol-4-yl} -pyridine;
71) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-3-yl-methanesulfonyl)-piperidin-4-yl]-3H:- imidazol-4-yl} -pyridine; 72) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3-trifluoromethyl-phenylmethanesulfonyl)-piperidin-4- yl]-3H-imidazol-4-yl} -pyridine;
73) 3-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridiii-2-yl)-lH-imidazol-2-yl]- pyrrolidine- 1-carboxylic acid benzyl ester;
74) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(4-trifluoromethyl-phenylmethanesulfonyl)-piperidin-4- yl]-3H-imidazol-4-yl} -pyridine;
75) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-bis-trifluoromethyl-phenylmethanesulfonyl)- piperidin-4-yl]-3H-imidazol-4-yl}-pyridine;
76) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(biphenyl-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
77) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-difluoro-phenylmethιanesulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl} -pyridine;
78) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(pyridin-2-yl-methanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
79) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
80) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(biphenyl-4-ylmethanesiLlfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
81) 4-[5-Benzo[ 1 ,3]dioxol-5-yl-l -methyl-4-(6-methyl-pyridin-2-yl)- lH-imidazol-2-yl]- piperidine- 1-carboxylic acid benzyl ester;
82) 4-[4-Benzo[l,3]dioxol-5-yl-l-methyl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine- 1-carboxylic acid benzyl ester;
83) {4-[4-Benzo[ 1 ,3]dioxol-5-yl- 1 -hydroxy-5-(6-methyl-pyridin-2-yl)- 1 H-imidazol-2-yl]- cyclohexyl}-carbamic acid benzyl ester;
84) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3-phenoxy-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl}-6-methyl-pyridine;
85) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-ethanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
86) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(propane- 1 -sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
87) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(butane-l-sulfonyl)-piperidin-4-yl]-3H-imidazol-4-yl}- 6-methyl-pyridine;
88) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-3-ylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine; 89) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-4-ylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
90) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(3,5-difluoro-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -6-methyl-pyridine;
91) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3-trifluoromethyl-phenylmethaaesulfonyl)-piperidin-4- yl]-3H-imidazol-4-yl} -6-methyl-pyridine;
92) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(thiophene-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl } -6-methyl-pyridine;
93) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(butane-l-sulfonyl)-piperidin-3-yl]-3H-imidazol-4-yl}- 6-methyl-pyridine;
94) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-3-yl)-3H-imidazol-4- yl]-6-methyl-pyridine;
95) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(l-methyl-lH-imidazole-4-sulfoiα.yl)-piperidin-4-yl]- 3H-imidazol-4-yl}-6-methyl-pyridine;
96) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(5-methyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
97) 4-[5-Benzo[l,3]dioxol-5-yl-l-hydroxy-4-(6-methyl-pyridin-2-yl)-l H-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
98) Butane- 1 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl] -cyclohexyl} -amide;
99) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexyl}-C-pyridin-2-yl-methanesulfonamide;
100) Thioρhene-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-meth.yl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexyl}-amide;
101) 1 -Methyl- lH-imidazole-4-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl- pyridin-2-yl)-lH-imidazol-2-yl]-cyclohexyl}-amide;
102) 4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-ρyridin-2-yl)- lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
103) 4-[4-Benzo [ 1 ,3] dioxol-5-yl- 1 -hydroxy-5 -(6-methyl-pyridin-2-yl)- 1 H-imidazol-2-yl] - bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
104) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-bromo-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
105) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(thiophene-3-sulfonyl)-piperidia-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine; 106) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(5-methyl-2-trifluoromethyl-furan-3-sulfonyl)- piperidin-4-yl]-3H-imidazol-4-yl}-6-methyl-pyridine;
107) 4-[2-(l-phenylmethanesulfonyl-piperidin-4-yl)-5-(6-methyl-pyridin-2-yl)-lH-imidazol-
4-yl]-pyridin-2-yl- fluoride;
108) 4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-trifluoromethyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
109) 4-[5-Benzo[l ,3]dioxol-5-yl-4-(6-bromo-pyridin-2-yl)-l-hydroxy-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
110) 2-[5-Benzo[l ,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -6 -bromo-pyridϊne;
111) {4-[4-Benzo[ l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct- 1 -yl} -methanol;
112) 4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
113) 4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-2H-imidazol-2-yl]-piperidine-l- sulfonic acid dimethylamide;
114) l-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin- 1 -yl} -3-phenyl-propan- 1 -one;
115) 2-{5-Benzo[l ,3]dioxol-5-yl-2-[l-(propane-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
116) 4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] octane- 1 -carbonitrile;
117) 4-[4-Benzo[l:(3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l -ylamine;
118) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct- 1 -yl} -C-phenyl-methanesulfonamide;
119) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] oct- 1 -yl } -methanesulfonamide;
120) N-{4-[4-Berizo[l33]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-C-pyridin-2-yl-methanesulfonamide; 121) 2-{5-Benzo[l53]dioxol-5-yl-2-[4-(lH-tetrazol-5-yl)-bicyclo[2.2.2]oct-l-yl]-3H- imidazol-4-yl} -6-m.ethyl-pyridine;
122) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetamide; 123) Thiophene-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
124) l-Methyl-lH-imidazole-4-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl- pyridin-2-yl)-lH-imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
125) Thiophene-3 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
126) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(2-phenyl-ethenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
127) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridiixe;
128) Methanesulfonic acid 4-[4-toenzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct- 1-ylmethyl ester;
129) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetonitrile;
130) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl} -acetic acid;
13I) N- {4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)- 1 H-imidazo 1-2-yl]- bicycloP^^Joct-l-ylmethylj-rriethanesulfonainide;
132) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(biphenyl-4-sulfonyl)-piperidin-4-yl] -3H-imidazol-4- yl } -6-methyl-pyridine;
133) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
134) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
135) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-ylmethyl}-C-phenyl-methanesulfonamide;
136) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct- 1 -ylmethyl} -C-pyridin-2-yl-methanesulfonamide;
137) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid benzylamide;
138) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (pyridin-2-ylmethyl)-amide;
139) 4-[4-Benzo[l,3]dioxol"5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid 3-chloro-4-fluoro-benzylamide; 140) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lE[-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (furan-2-ylmethyl)-anαide;
141) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfonyl-ρyrrolidin-3-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
142) 2- {5-B enzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(butane-l-sulfonyl)-pyrτolidin-3-yl]-3H-imidazol-4- yl} -6-methyl-pyridine ;
143) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(I -methyl- lH-imidazole-4-sulfonyl)-pyrrolidin-3-yl]- 3H-imidazol-4-yl}-6-methyl-pyrϊdine;
144) 2-[5-Betizo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-pyrrolidin-3-yl)-3H-imidazol- 4-yl] -6-metb.yl-pyridine;
145) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-benzenesulfonyl)-ρyrrolidin-3-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
146) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl } -6-methyl-pyridine;
147) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-naphthalen-2-yl-etha.nesulfonyl)-ρiperidin-4-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
148) l-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-
1 -sulfonylmethyl} -7,7-dimethyl-bicyclo[2.2.1 ]heptan-2-one;
149) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
150) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lE[-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methylamide;
151) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH:-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid ethylamide;
152) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lHI-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid butylamide;
153) 4-[4-Beπzo[ 133]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)- lH-imidazol-2-yl]- bicyclo[2.2.2] octane- 1-carboxylic acid isopropylamide;
154) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2] octane- 1 -carboxylic acid (3-imidazol- 1 -yl-propyl)-amide;
155) 2-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-
1 -sulfonylmethyl} -phenylamine;
156) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2] octane- 1 -carboxylic acid (1 -methyl-5-methylsulfanyl-lH-[ 1 ,2,4]triazol-3-yl)- amide; l57) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid cyclohexylamide; 158) {4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2]oct- 1 -yl} -pyrrolidin- 1 -yl-methanone;
159) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-cart>oxylic acid dimethylamide; 160) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid diethylamide;
161) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid dipropylamide;
162) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (5,7-difluoro-benzothiazol-2-yl)-amide; 163) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid benzothiazol-2-ylamide; 164) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (lH-benzoimidazol-2-yl)-amide; 165) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-amicie; 166) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (pyridin-4-ylmetliyl)-amide;
167) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin-l- yl} -(3-chloro-phenyl)-methanone;
168) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin-l- yl}-(4-fluoro-phenyl)-methanone;
169) {4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)- lH-imidazol-2-yl]-piperidin- 1 - yl}-(4-methoxy-phenyl)-methanone;
170) 4-[5-Benzo[ 1 ,3]dioxol-5-yl-4-(6-cyclopropyl-pyridin-2-yl)- lH-imidazol-2-yO- bicyclo [2.2.2] octane- 1 -carb oxylic acid;
171) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide; 172) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
173) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-carbamic acid benzyl ester; 174) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydrazide;
175) N- {4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl} -acetamide;
176) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-methanesulfonamide;
177) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethylJ-C-phenyl-methanesulfbnamide;
178) Butane- 1 -sulfonic acid {4-[4-benzo[ l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexylmethyl}-amide;
179) Propane-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexylmethyl}-amide;
180) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-C-pyridin-2-yl-methanesulfonamide;
181) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-C-pyridin-4-yl-methanesulfonamide;
182) (4-Methoxy-benzyl)- {4-[5-(6-methyl-pyridin-2-yl)-2-(l -phenylmethanesulfonyl- piperidin-4-yl)-lH-imidazol-4-yl]-pyridin-2-yl}-amine;
183) 4-[5-(6-Metb.yl-ρyridin-2-yl)-4-[l,2,4]triazolo[l,5-a]pyridm-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
184) 4-[5-(6-Methyl-pyridin-2-yl)-4-[l ,2,4]triazolo[l ,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
185) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5- [ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl- lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
186) 4-[4-(6-Methyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydxoxyamide;
187) 4-[4-(6-Methyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
188) 4-[4-(6-Cycloρroρyl-pyridin-2-yl)-5- [ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl- lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
189) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-rnethyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;
190) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-mettiyl-pyridm-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol; 191) 4-[4-(6-Cyclopropyl-ρyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH:-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
192) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl-l H-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
193) N-{4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2]oct- 1 -yl} -sulfamide;
194) Sulfamic acid 4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl ester;
195) {4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cycloh.exyl}- carbamic acid benzyl ester;
196) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonyl}-methanesulfonamide;
197) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonyl}-benzenesulfonamide;
198) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)- IH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
199) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
200) N-{4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl}- acetamide;
201) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo|[2.2.2]octane-
1-carboxylic acid methyl ester;
202) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-
1-carboxylic acid;
203) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-
1-carboxylic acid hydroxyamide;
204) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-
1-carboxylic acid amide;
205) N- {4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl- lH-imidazol-2-yl]-cyclohexyl} - methanesulfonamide;
206) 2,2,2-Trifluoro-N-{4-[4-(6-methyl-ρyridm-2-yl)-5-quinoxalin-6-yl-lH-imi(iazol-2-yl]- cyclohexyl} -acetamide;
207) 4-[4-(5-Fluoro-6-methyl-ρyridin-2-yl)-5-[ 1 ,2,4]triazolo[l ,5-a]pyridin-6-yl- 1 H-imidazol-
2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester; 2US) {4-L2-Ll-(Butane-l-sulfonyl)-piperidin-4-yl]-5-(6-methyl-pyridin-2-yl)-lH-imidazol-4- yl]-pyridin-2-yl}-(4-methoxy-benzyl)-amine;
209) 4-[2-[ 1 -(Butane- 1 -sulfonyl)-ρiρeridin-4-yl]-5-(6-methyl-pyridin-2-yl)- lH-imidazol-4- yl] -pyridin-2-ylamine;
210) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl]-6-ethyl-pyridine;
211) 4-[5-(3-Methyl-4-oxo-3J4-dihydro-quinazolin-6-yl)-4-(6-methyl-ρyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
212) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
213) N- {4-[5-(6-Methyl-pyridin-2-yl)-4-quinoxalin-6-yl- lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanesulfonamide; and
214) N-{4-[5-(6-Methyl-pyridin-2-yl)-4-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetamide.
[052] In another embodiment, the antagonists have the structure shown below in formula II:
Figure imgf000028_0001
[053] In formula II, each OfXn-1, Xn-2, Xn-3, and Xn-4 can be independently CRπ"x or N, provided that only two of Xπ-i, Xn-2, Xn-3, and Xn-4 can be N simultaneously. Each OfYn-1 and Y11-2 can be independently CRπ"y or N, provided that at least one OfYn-1 and Yn-2 must be N. In other words, the ring having Yn-1 and Yn-2 ring atoms can be a pyrimidinyl or pyridyl. Each R11'1 can be independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl. Each R11"2 can be independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -
N(alkyl)(cycloalkyl), -NH(heterocycloalkyl), -NH(heteroaryl), -NH-alkyl-heterocycloalkyl, - NH-alkyl-heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, cycloalkyl-alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aminosixlfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalky^alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalky^carbonylamino, (heterocycloalky^alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkoxycarbonylaminoalkylamino, (heteroary^arylcarbonylaminoalkylamino, heteroaralkylcarbonylaminoalkylamino, (heteroary^arylsulfonylaminoalkylcarbonylaminoalkylamino, arylsulfonylanxinoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl, m can be 0, 1, 2, 3, or 4, and when m >2, two adjacent R11"1 groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety, n can be 0, 1, 2, or 3, and when n >2, two adjacent R " groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety. Each of Rπ"x and Rπ"y can be independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cycloalkyl)alkylcarbonylamino, (cycloalkyl)alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, aralkylcarbonylamino, aralkylsulfonylamino, (heterocycloalkyl)carbonylamirio, (heterocycloalkyl)sulfonylamino, (heterocycloalkyl)alkylcarbonylamino, (heterocycloalkyl)alkylsulfonylamino, hetβroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylamino, heteroaralkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, (cycloalkyl) alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalkyl) alkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl.
[054] As defined above in formula II, when m >2, two adjacent R11"1 groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety. That is, tlie 2- pyridyl ring can fuse with a 4- to 8-membered cyclic moiety to form a moiety such as 7H- [l]pyτindinyl, 6,7-dihydro-5H-[l]pyrindinyl, 5,6,7,8-tetrahydro-quinolinyl, 5,7-dihydro- furo[3,4-b]pyridinyl, or 3,4-dihydro-lH-thiopyrano[4,3-c]pyridinyl. The fused ring moiety can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl; see the defmitoix of "alkyl" below), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, eye Io alkylcarbonylamino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino, heterocycloalkyl- alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, ϊialo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[055] Similarly, when n _≥2, two adjacent R11"2 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety, thereby forming a ring fused with the pyridyl or pyrimidinyl group. Some examples of such a moiety are shown below:
Figure imgf000030_0001
[056] The 4- to 8-membered cyclic moiety formed by two adjacent R11"2 groups can be optionally substituted with substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl; see the defmiton of "alkyl" below), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylarnino, cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl- carbonylamino, heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[057] Compounds of formula II and methods for producing the same are known in the art. For instance, WO 04/022054, which is incorpoarated in its entrity by reference, describes synthetic methods for producing inhibitors of formula II. Examples of compounds of formula II include, but are not limited to, 215) 4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-pyrimidin-2-3/lamine;
216) 4-(2-pyridin~2-yl-pyrazolo[ 1 ,5 -a]pyridin-3 -yl)-pyrimidin-2-ylamine;
217) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[ 1 ,5-a]pyridin-3-yl]-pyrimidin-2-ylamine;
218) 2-(6-methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-pyrazolo[l,5-a]pyridine; 219) 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine; 220) 2-(6-methyl-pyridin-2-yl)-3-(2-morpholin-4-yl-pyrimidin-4-yl)-pyrazolo[l,5- c]pyrimidine; 221) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyrazin-3-yl]-pyrimidin-2-ylamine;
222) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[ 1 ,5-a]pyrimidm-3-yl]-pyrimidm-2-ylamine;
223) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine; or a pharmaceutically acceptable salt or N-oxide thereof.
[058] In another embodiment, the antagonists have the structure shown in formula III:
Figure imgf000031_0001
[059] In formula III, each OfXm-1, Xm-2, Xπi-3, and Xm-4 can be independently CR or N, provided that only two of Xπi-i, Xm-2, X111-3, and Xm-4 can be N simultaneously. Each of Y11I-
\ and Ym-2 can be independently CR.m~y or N, provided that at least one of Yπn and Ym-2 must be N. Each of R111"1 can be independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxiy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocyclo alkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl. Each of R111"2 can be independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -N(alkyl)(cyclocalkyl), - NH(heterocycloalkyl), -NH(heteroaryl), -NH-alkyl-hetero cycloalkyl, -NH-alkyl- heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyFjalkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalky^alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalk:yl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonyl amino, heteroaralkylcarbonylamino, alkoxycarbonylaminoalkylamino, (heteroaryl)arylcarbonylaminoalkylamino, heteroaralkylcaLxbonylaminoalkylamino, (heteroaryl)arylsulfonylaminoalkylcarbonylaminoalkyl-amino, arylsulfonylaminoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl, m can be 0, 1, 2, 3, or 4, and when m >2, two adjacent R111"1 groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety, n can be 0, 1, 2, or 3, and when n ≥2, two adjacent R111"2 groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety. Each of Rm"x and RrII"y can be independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino ., nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarbonyl, aroyl, aralkylcarbonyl, heterocyeloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkyl sulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cyclo alkyl)alkylcarbonylamino, (cycloalkyl)alkylsulfonylamino, arylcarbonylamino, arylsαlfonylamino, aralkylcarbonylamino, aralkylsulfonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)sulfonylamino, (heterocycloalky^alkylcarbonylamino, (heterocycloalkyOalkylsulfonylamiαo, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylamino, heteroaxalkylsulfonylarm'no, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, (cycloalkyl)alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalkyl)a.lkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl; or a pharmaceutically acceptable salt or NT-oxide thereof.
[060] Compounds of formula III and methods for producing the same are known in the art. For instance, WO 04/21989, which is incorpoarated in its entrity by reference, descri/bes synthetic methods for producing inhitritors of formula III. Examples of compounds of formula III include, but are not limited to,
224) (2-Methoxy-ethyl)-{4-[2-(6-methyl-ρyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
225) (3-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]-pyrimidin-2-ylanαino}- propyl)-carbamic acid tert-butyl ester;
226) (3-Imidazol-l-yl-propyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
227) (4-Methoxy-benzyl)- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl] - pyrimidin-2-yl} -amine;
228) [2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridin- 6-yl] -methanol;
229) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- ajpyridine;
230) (4-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylairi.ino}- butyl)-carbamic acid tert-butyl ester;
231) (4-Amino-benzyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
232) (5-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylain-ino}- pentyl)-carbamic acid tert-butyl ester;
233) [3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-6-yl]- methanol; 234) [3-(2-amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-7-yl]- methanol;
235) [3-(2-Amino-pyrirnidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(2-moφholin-4-yl-ethyl)-amine;
236) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridin-8-yl]-(2-pyridm-2-yl-ethyl)-amine;
237) [3-(2-Arnino-pyrimidin-4-yl)-6-methy'l-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridin-8-yl]-(2-pyridin-3-yl-ethyl)-amine;
238) [3-(2-methanesulfonyl-pyrimidin-4-yl) -2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2- a]pyridin-6-yl]-methanol;
239) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a] pyridin- 8 -yl] -(2-pyridin-4-yl-ethyl)-amine ;
240) [3-(2-Aimno-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(3-moφholin-4-yl-propyl)-ainine;
241) [3-(4-Methyl-piperazin-l-yl)-propyl]-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-3-yl]-pyrimidin-2-yl}-amine;
244) [3-(4-Methyl-piperidin-l-yl)-propyl]-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-3-yl]-pyrimidin-2-yl} -amine;
245) [4-(2-Pyridin-2-yl-imidazo[ 1 ,2-a]pyridin-3-yl)-pyrimidin-2-yl]-pyridin-3-ylmethyl- amine;
246) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl]-pyriniidin-2-yl} -((R)- 1 - phenyl-ethyl)-amine;
247) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]ρyridin-3-yl]-ρyrimidin-2-yl} -((S)- 1 - phenyl-ethyl)-amine;
248) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(lH- tetrazol-5-yl)-amine;
249) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} -(2H- pyrazol-3-yl)-amine;
250) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} -(2- morpholin-4-yl-ethyl)-amine;
251) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} -(2-pyridin- 2-yl-ethyl)-amine;
252) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} -(2-pyridin- 3 -yl-ethyl)-amine; 253) {4- [2-(6-Methyl-ρyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl] -pyrimidin- 2-yl } -(2-pyridin- 4-yl-ethyl)-amine;
254) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]-pyrimidin-2-yl}-(3- morpholin-4-yl-propyl)-amine;
255) {4-[2-(6-Methyl-ρyridin-2-yl)-imidazo[ 1 ,2-a]ρyridin-3-yl]-pyrimidin-2-yl} -(3- piperidin- l-yl-propyl)-amine;
256) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidm-2-yl}- [l,3,4]thiadiazol-2-yl-amine;
257) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine; 258) 2-(6-Methyl-pyridm-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidaz:o[l,2-a]pyridine- 6-carboxylic acid methyl ester;
259) 2-(6-Meth.yl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrirnidin-4-yl)-imidazo[l,2-a]pyridine- 7-carboxylic acid ethyl ester;
260) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2- a]pyriniidin-7-ylamine ;
261) {7,7-Dimethyl-8-[5-(4-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamino}-butylcarbamoyl)-pentyl]-2-oxo-4-trifluoromethyl-7,S-dihydro-2H-l- oxa-8-aza-antliracen-5-yl} -methanesulfonic acid;
262) 2-(2,7-Difluoro-6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)-3,5,6-trifluoro-4-[(4- {4- [2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl] -pyrimidin-2-ylamino } - butylcarbamoyO-methylsulfanylJ-benzoic acid;
263) -(6-MEethyl-pyridin-2-yl)-3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo [ 1 ,2-a]pyridine;
264) 2-(6-Methyl-pyridin-2-yl)-3-(2-piperidin- 1 -yl-pyrimidin-4-yl)-imidazo [ 1 ,2-a]pyridine; 265) 2-(6-Methyl-pyridin-2-yl)-3-(2-pyrrolidin-l-yl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine; 266) 2-(6-Methyl-pyridin-2-yl)-3-[2-(lH-tetrazol-5-yl)-pyrimidin-4-yl]-irnidazo[l,2- a]pyridine;
267) 2-(6-3VIethyl-pyridin-2-yl)-3 -pyrimidin-4-yl-imidazo [ 1 ,2-a]pyridine;
268) 2-(6-]Methyl-pyridin-2-yl)-3-pyrimidin-4-yl-imidazo[l,2-a]pyrimidiri-7-ylarriine;
269) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-8- ylamine;
270) 3-(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carbonitrile;
271) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid; I'll) J-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid ([l,4]dioxan-2-ylrnethyl)-amide;
273) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
274) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid (2-dimethylamino-ethyl)-amide;
275) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid (2-methoxy-ethyl) -amide;
276) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid (2-thiophen-2-yl-ethyl)-amide;
277) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid [3-(4-methyl-piperazin-l-yl)-propyl]-amide;
278) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid amide;
279) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid cyclopropylamide;
280) 3-(2-Amino-pyrimidin-4-yl)-2-(6-rnethyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid ethylamide;
281 ) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridine-6- carboxylic acid hydroxyamide;
282) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid methoxy-amide;
283) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid methyl ester;
284) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid;
285) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l52-a]pyridine-7- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
286) 3-(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-ammo-etliyl)-arriide;
287) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-dimethylamino-ethyl)-amide;
288) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-hydroxy-ethyl)-amide; 289) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid (2-oxo-2-pyridin-3-yl-ethyl)-amide;
290) 3-(2- Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid (2-thiophen-2-yl-ethyl)-amide;
291) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (piperidin-3-yl-methyl)-amide;
292) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid 2,2-dimethylhydrazide;
293) 3-(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid amide;
294) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid cyclopropylamide;
295) 3-(2-Amino-pyrirnidin-4-yl)-2-(6-rnethyl-pyridin-2-yl)-irnidazo[l,2-a]pyridine-7- carboxylic acid ethyl ester;
296) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-irnidazo[l,2-a]pyridine-7- carboxylic acid ethylamide;
297) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid hydroxyamide;
298) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid methoxy-amide;
299) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-irnidazo[l,2-a]pyrimidin-7- ylamine;
300) 3-(2- Azetidin- 1 -yl-pyrimidin-4-yl)-2-(6-methyl-pyri din-2-yl)-imidazo [ 1 ,2-a]pyridine;
301) 3 -(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-rnetliyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridine-7-carboxylic acid ethyl ester;
302) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridine-6-carboxylic acid methyl ester;
303) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-7-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- ajpyridine;
304) 3-(2-Methanesulfonyl-pyrimidm-4-yl)-8-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- ajpyridine;
305) 3 ,3 -Dimethyl-N-[2-(6-methyl-pyridin-2-yl)-3 -(2-methylsulfanyl-pyrimidin-4-yl)- imidazo[ 1 ,2-a]pyrimidin-7-yl]-butyramide; 306) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridine-6-carbonitrile; 307) 3-(2-Methylsulfanyl-pyrimidin-4-yl)-2-pyridin-2-yl-imidazo[l,2-a]pyridine;
308) 3,6-Dichloro-N-(4- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]- pyrimidin-2-ylamino}-butyl)-2-(2,4,5,7-Tetrachloro-6-hydroxy-3-oxo-9,9a-dihydro-3K- xanthen-9-yl)-terephthalamic acid;
309) 3-[2-(2-Methyl-aziridin-l-yl)-pyrimidin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a] pyridine;
310) 3-[2-(4-Methyl-piperazin- 1 -yl)-pyrimidin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2- a] pyridine;
311) 3- {[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carbonylj-amino} -propionic acid methyl ester;
312) 3-{[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carbonyl] -amino} -propionic acid methyl ester;
313) 3- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino } - phenol;
314) 4-(2- {4- [2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3 -yl]-pyrimidin-2-ylamino } - ethyl)-benzenesulfonamide;
315) 4-(2-Pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-pyrimidin-2-ylamine;
316) 4-[2-(6-Chloro-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamine; 317) 4-[2-(6-Methyl-pyridin-2-yl)-7-trifluoromethyl-imidazo[l,2-a]pyridin-3-yl]-pyrirnidin- 2-yl-amine;
318) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamine;
319) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidine-2-carbonitrile;
320) 4-[2-(6-Methyl-pyridm-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidine-2-carboxylic acid amide;
321) 4-[6-Bromo-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
322) 4-[6-Chloro-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
323) 4-[6-Fluoro-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
324) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-morpholin-4-yl-ethylamino)-imidazo[l ,2-a] pyridin-3 -yl] -pyrimidin-2-ol;
325) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-2-yl-ethylainino)-imidazo[l,2-a] pyridin-3 -yl] -pyrimidin-2-ol; 326) 446-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-3-yl-ethylamino)-imidazo[l,2-a] pyridin-3 -yl] -pyrirnidin-2-ol;
327) 4-[6-Methyl-2-(6-tnethyl-pyridin-2-yl)-8-(2-pyridin-4-yl-ethylammo)-imidazo[l,2-a] pyridin-3 -yl] -pyrimidin-2-ol;
328) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-morpholin-4-yl-imidazo[l,2-a]pyiidin-3-yl]- pyrimidin-2-ol;
329) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-morpholin-4-yl-imidazo[ 1 ,2-a]pyridin-3-yl]- pyrimidm-2-ylamme;
330) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]-pyrimidin-2- ylamine;
331) 4-[7-AminomLethyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- yl-amine;
332) 4-[7-Methyl-2 -(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl] -pyrimidin-2- ylamine;
333) 4-[8-Benzyloxy-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ol;
334) 4-[8-Benzylox:y-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl- amine;
335) 4-[8-Bromo-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-
2-ol;
336) 4-[8-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
337) 6-Chloro-3 -(2-methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2- a]pyridine;
338) 5-Dimethylamino-naphthalene-l -sulfonic acid (4-{4-[2-(6-methyl-pyridin-2-yl)- imidazo[l,2-a]ρyrid.in-3-yl]-pyrimidin-2-ylammo}-butyl)-amide;
339) 6-(2,7-Difluoro-6-hydroxy-3-oxo-3H-xanthen-9-yl)-N-(4-{4-[2-(6-methyl-ρyridin-2-yl)- imidazo [ 1 ,2-a]pyridin-3 -yl] -pyrimidin-2-ylamino } -butyl)-isophthalamic acid; 340) 6-Amino-9-[2-carboxy-5-(4-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamin.o}-butylcarbamoyl)-phenyl]-xanthen-3-ylidene-ammonium;
341) 6-Bromo-2-(6-methyl-ρyridin-2-yl)-3 -(2-methylsulfanyl-pyrimidin-4-yl)-imidazo [ 1 ,2-a] pyridine;
342) 6-Fluoro-2-(6-methyl-ρyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a] pyridine;
343) 7-Amino-4-methyl-3-[(4-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamino } -butylcarbamoyl)-methyl] -2-oxo-2H-chromene-6-sulfonic acid; 344) Cyclobutyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} - amine;
345) Cyclopentyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidm-2- yl} -amine;
346) Cyclopropyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2- yl} -amine;
347) Cyclopropyl-methyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
348) Dimethyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl} - amine;
349) Isopropyl- {4-[2-(6-methyl-pyridm-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} - amine;
350) Methyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridm-3-yl]-pyrimidin-2-yl} - amine;
350a) N-(2-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ l,2-a]pyridin-3-yl]-pyrimidin-2- ylamino} -ethyl)-acetamide;
351 ) N-(4- {4- [2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl] -pyrimidin-2-ylamino } - butyl)-acetamide;
352) N,N-Dimethyl-N'-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-
2-yl} -ethane- 1 ,2-diamine;
353) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a] pyrimidin-7-yl] -3 -pyridin-3 -yl-propionamide;
354) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a] pyrimidin-7-yl]-nicotinamide;
355) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-ρyrimidin-4-yl)-imidazo[l,2-a] pyrimidin-7-yl] -propionamide;
356) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carbonyl] -methanesulfonamide;
357) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carbonyl] -methanesulfonamide;
358) N-[3 -(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyrimidin-7 - yl] -2-(3 -methoxy-phenyl)-acetamide;
359) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-p3τidin-2-yl)-imidazo[l,2-a]pyrimidin-7- yl] -3,3 -dimethyl-butyr amide; 360) N-[3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iniidazo[ 1 ,2-a]pyrimidin-7- yl] -3-pyridin-3 -yl-propionamide;
361) N-[3-(2-Amino-pyriniidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iinidazo[l,2-a]pyrimidin-7- yl]-acetamide;
362) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iinidazo[ 1 ,2-a]pyrimidin-7- yl] -nicotinamide;
363) N-[3 -(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyriciin-2-yl)-imidazo [ 1 ,2-a] pyrimidin-7-yl] -2-(3 -methoxy-phenyl)-acetamide;
364) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyric-iin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl]-3,3-dimethyl-butyramide;
365) N- [3 -(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyric-lin-2-yl)-imidazo [ 1 ,2-a] pyrimidin-7-yl]-3-pyridin-3-yl-propionamide;
366) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyri(-iin-2-yl)-imidazo[ 1 ,2-a] pyrimidin-7-yl]-nicotinamide;
367) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyriciin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl] -propionamide;
368) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-metliyl-pyridin-2-yl)-irnidazo[ 1 ,2-a]pyrimidin-7- yl] -propionamide ;
369) N-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]-pyrimidin-2-yl}- acetamide;
370) Nl-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3->/l]-pyrimidin-2-yl}-butane-
1,4-diamine;
371) Nl-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-3/l]-pyrimidin-2-yl}- propane- 1 ,3 -diamine;
372) N-(4- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3 -yl]-pyrimidin-2-ylamino} - butyl)-(BODIPY FL) amide; and
373) N-(4-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3 -yl]-pyrimidin-2-ylamino}- butyl)-(Texas Red-X) amide
374) N-[3-(2-amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iinidazo[ 1 ,2-a]pyrimidin-7- yl]-acetamide; and
375) N-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yO-pyrimidin-2-yl}- acetamide.
[061] In yet another embodiment, the antagonists have the structure shown in formula IV:
Figure imgf000042_0001
or an N-oxide or a pharmaceutically acceptable salt thereof.
[062] Each RIV"a can be independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl.
[063] R^'1 can be a bond, alkylene, alkenylene, alkynylene, or -(CH2)rl-O-(CH2)r2-, wherein each of rl and r2 is independently 2 or 3.
[064] R^"2 can be cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, or a bond.
[065] R1^3 can be -C(O)-, -C(O)O-, -OC(O)-, -C(O)-N(R1^)-, -N(R1^)-C(O)-, -0-C(O)- N(R1^)-, -N(R1^)-C(O)-O-, -0-S(O)P-N(R^13)-, -N(R1^)- S(O)P-O-, -N(R1^)-C(O)- N(R1^0)-, -N(RIV-b)-S(0)p-N(RIV-b)-, -C(O)-N(R1^)-S(OV, -S(O)P-N(R^)-C(O)-, -S(0)p- N(R^)-, -N(RIV-b)-S(O)p-, -N(R1^)-, -S(O)P-, -O-, -S-, or -(C(RIY"b)(RIV-c))q-, or a bond; wherein each of RIV'b and Rw"c is independently hydrogen, hydroxy, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; p is 1 or 2; and q is 1-4. [066] KW'Λ can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
[067] R^'5 can be hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulfinyl, amino, alkenyl, alkynyl, cycloalkyl, cycloalko:xy, cycloalkylsulfϊnyl, heterocycloalkyl, heterocycloalkoxy, heterocycloalkylsulfϊn^l, aryl, aryloxy, arylsulfinyl, heteroaryl, heteroaryloxy, or heteroarylsulfinyl.
[068] Rw"6 can be (1) a 5- to 6-membered heterocyclyl containing 1-3 hetero ring atoms selected from the group consisting of-O-, -S-, -N=, and -lNRIV"d-, wherein Rw'd can be hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkyl- alkyl, heteroaryl, or heteroaralkyl; said heterocyclyl being substituted with R[V"e and optionally substituted with one to two Rw'f; where Rw'e is oxo, thioxo, alkoxy, alkylsulfinyl, -NTH2, -NH(unsubstituted alkyl), or -N(unsubstituted alkyl)2, and RIV"f can be alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkiylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; or
[069] (2) a fused ring heteroaryl selected from the group consisting of:
Figure imgf000043_0001
Ring A can be an aromatic ring containing 0-4 hetero ring atoms, and ring B can be a 5- to 7- membered aromatic or nonaromatic ring containing 0-4 hetero ring atoms, provided that at least one of ring A and ring B contains one or more hetero rmg atoms. Ring A' can be an aromatic ring containing 0-4 hetero ring atoms, and ring B' can be a 5- to 7-membered saturated or unsaturated ring containing 0-4 hetero ring atoms, provided that at least one of ring A' and ring B' contains one or more hetero ring atoms. Each hetero ring atom can be - O- -S-, -N=, or -NR™"8-. Each X1 can be independently N or C. Each X2 can tie independently -O- -S-, -N=, -NRIV"g- or -CHR17"11- in which R1^ can be hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, he~teroaryl, or hetero aralkyl. Each of Rw'h and RIV"' can be independently alkyl, alkenyl, alkynyL, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonyl-amino, alkylsulfonylamino, arylsulfonylamirLO, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamo>4, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkyl-sulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl. n can be 0-2. m can be 0-3, and when m >2, two adjacent RIV"a groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety;
[070] hi compounds of formula IV, if R17"6 is 2-naphthyridinyl, 4-quinolinyl, imidazo[l,2- a]ρyridyl, or benzimidazolyl, then -R^"1-RIV"2-RIV"3-RIV'4 is not H, unsubstituted alkyl, -CH2-C(O)-N(H)-alkyl, -CH2-C(O)-N(alkyl)2, or benzyl.
[071] Compounds of formula IV and methods for producing the same are known in the art.
For instance, WO 04/072033, which is incorpoarated in its entrity by reference, describes synthetic methods for producing inhibitors of formula IV. Examples of compounds of formula IV include, but are not limited to,
376) 3-(3 -pyridin-2-yl-4-quinolin-4-yl-pyrazol- 1 -yl)-propylamine,
377) N-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-acetamide,
378) N-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-methanesulfonamide,
379) dimethyl- [3 -(3 -pyridin-2-yl-4-quinolin-4-yl-pyrazol- 1 -yl)-propyl] -amine,
380) 4-{3-pyridin-2-yl-l-[2-(lH-tetrazol-5-yl)-ethyl]-lH-pyrazol-4-yl}-quinoline,
381 ) 4-[3 -pyridin-2-yl- 1 -(3 -pyrrolidin- 1 -yl-propyl)- lH-pyrazol-4-yl] -quinoline,
382) 5-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-pyridin-2-ylamine,
383) 2,4-dimethoxy-5-(3-pyridin-2-yl- 1 H-pyrazol-4-yl)-pyrimidine,
384) 3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propionic acid,
385) 5-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)- 1 H-indole, 386) 2-[4-(2,3-dihydro-benzo[l,4]dioxm-6-yl)-lH-pyrazol-3-yl]-pyridine, 387) N-hydroxy-3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propionamide, 388) 2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol- 1 -yl)-ethylamine, 389) N-[2-(3 -pyridin-l-yM-quinolin^-yl-pyrazol- 1 -yl)-ethyl] -methanesulfonamide,
390) 2-methyl-4-methylsulfanyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyrimidine,
391 ) 2-(4-benzo [ 1 ,3 ]dioxol-5-yl- 1 H-pyrazol-3-yl)-pyridine,
392) 2-[4-(2,3-dihydro-benzofuran-5-yl)- lH-pyrazol-3-yl]-pyridine,
393) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[d]isoxazole,
394) 3-[4-benzo[l,3]dioxol-5-yl-3-(6-metliyl-pyridin-2-yl)-pyrazol-l-yl]-propionitrile, 395) N-{3-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-propyl}- methanesulfonamide,
396) 2-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-lH-pyrazol-3-yl]-6-methyl-pyridine, 397) [4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-acetonitrile, 398) N-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethyl}- methanesulfonamide,
399) 4-[3 -(6-methyl-pyridin-2-yl)- 1 H-pyrazol-4-yl] -2-methylsulfanyl-pyrimidine,
400) 4-(3-pyridin-2-yl-lH-pyrazol-4-yl)-2H-ρhthalazin-l-one,
401) l-[5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-2,3-dihydro-indol-l-yl]-ethanone,
402) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[ l,2,4]triazolo[l,5-a]pyridine,
403) 3-methyl-6-(3-pyridin-2-yl-lH-pyraz;ol-4-yl)-3H-quinazolin-4-one,
404) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-4H-benzo[l,4]oxazin-3-one,
405) 6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-qiιinoxaline,
406) 3 -(4-nitro-benzyl)-6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-3H-quinazolin-4-one, 407) 5-methyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyridine, 408) 4-methyl-7-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3,4-dihydro-lH-benzo[e][l,4]diazepine- 2,5-dione, 409) 2,3-dimethyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
410) 6-[3-(6-methyl-pyridin-2-yl)- 1 H-pyrazol-4-yl] -[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine, 41 Oa) 1 -methoxy-4-(3-pyridin-2-yl- lH-pyrazol-4-yl)-isoquinoline,
411) 2-methyl-6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)- [1 ,2,4]triazolo[l,5-a]pyridine, 41 Ia) 4-(3 -pyridin-2-yl- lH-pyrazol-4-yl)-2H-isoquinolin-l -one, 412) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-trifluoromethyl-pyridine,
412a) 2-(4-benzo[ 1 ,3]dioxol-5-yl- lH-pyra2ol-3-yl)-6-vinyl-pyridine, 413) 2-(4-benzo[ 1 ,3]dioxol-5-yl- 1 H-pyrazol-3-yl)-6-propenyl-pyridine, 414) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-ethyl-pyridine, 415) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-propyl-pyridine, 416) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-cyclopropyl-pyridine,
417) l-[6-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-pyridin-2-yl]-ethanol, 418) 4-methoxy-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoli:ne,
419) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinoline,
420) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin-4-ylamine,
421 ) 6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-3H-quinazolin-4-one3,
422) 7-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-pyrido[ 1 ,2-a]pyrimidin-4-one,
423) 6-[3-(6-cyclopropyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
424) 3-methyl-6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3H-quinazolin-4-one,
425) 4-(2- {2-[4-benzo[ 1 ,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol- 1 -yl]-ethoxy} - ethoxy)-bicyclo[2.2.2]octane-l-carboxylic acid,
426) 4-(2- {2-[4-benzo[ 1 ,3]dioxol-5-yl-3-(6-methyl-pyridin-2-;yl)-pyrazol- 1 -yl]-ethoxy} - ethoxy)-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester, 427) 4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-ρyr-azol-l-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester,
428) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-isopropyl-pyridine,
429) 2-(4-benzo[l,3]dioxol-5-yl-5-trifluoromethyl-lH-pyrazol-3-yl)-6-bromo-pyridine,
430) 6-[3-(5-fluoro-6-methyl-pyridm-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
431) 6-[3-(6-trifluoromethyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l ,2,4]triazolo[l,5-a]pyridine,
432) 6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoxaline,
432a) 6-[3-(6-cyclopropyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3-methyl-3H-quinazolin-4-one,
433) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-b]pyridazine,
433a) 6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoline,
434) 6-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-3-fluoro-2-methyl-pyridine,
435) 7-methoxy-3-methyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
436) (4-morpholin-4-yl-phenyl)-[6-(3-pyridin-2-yl-lH-pyrazol— 4-yl)-quinazolin-4-yl]-amine,
437) 4-isopropoxy-6-(3-pyridm-2-yl-lH-pyrazol-4-yl)-quinazo line,
438) 6-(3 -Pyridin-2-yl- lH-pyrazol-4-yl)-qumolin-4-ylamine,
439) {4-[4-benzo[ 1 ,3]dioxol-5-yl-3-(6-methyl-ρyridin-2-yl)-ρyxazol- 1 -yl]-cyclohexyl} - carbamic acid benzyl ester, 440) 4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohexylamine,
441) N- {4-[4-benzo[ 1 ,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-j>yrazol- 1 -yl]-cyclohexyl} - methanesulfonamide,
442) 6-[3-(5-fluoro-6-methyl-pyridm-2-yl)-lH-pyrazol-4-yl]-quLinoxaline, 443) 7-(3-ρyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]p3αidineJ
444) l-tert-butyl-3-[6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin-4-yl]-urea,
445) 5-(3-pyridm-2-yl-lH-pyrazol-4-yl)-benzo[l,2,5]thiadiazole, 446) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[l,2,5]oxadiazole,
447) 5-(3-Pyridin-2-yl-lH-pyrazol-4-yl)-benzooxazole,
448) 4-morpholin-4-yl-6-(3-pyridin-2-yl- 1 H-pyrazol-4-yl)-quinazoline, 449) 6-[3-(6-trifluoromethyl-pyridin-2-yl)- 1 H-pyrazol-4-yl]-quinoxaline,
45 O) 4-(4-methoxy-phenyl)-6-(3-pyridin-2-yl- lH-pyrazol-4-yl)-quinazoline,
451) 5-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-benzo[l ,2,5]thiadiazole,
452) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzothiazole,
453) 3-(3-methoxy-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
454) 5-methyl-thiophene-2-carboxylic acid [6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin-4- yl] -amide,
455) 5-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3-phenyl-benzo[c]isoxazole,
456) 3 -(4-methoxy-phenyl)-5 -(3 -pyridin-2-yl- lH-pyrazol-4-yl)-benzo [c]isoxazole, 45 V) 3-(4-chloro-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
458) 3-(4-ethyl-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
459) (4-methoxy-phenyl)-[6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin-4-yl]-methanone,
460) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3-thiophen-3-yl-benzo[c]isoxazole,
461 ) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid,
462) 5-(3-Pyridin-2-yl-lH-pyrazol-4-yl)-lH-mdazole-3-carboxylic acid methylamide,
463) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid dimethylamide,
464) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid (2,2-dimethyl- propyl)-amide,
465) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid phenylamide,
466) moφholin-4-yl-[5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazol-3-yl]-methanone,
467) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid benzylamide, and
468) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid cyclopentylamide.
[072] In another embodiment, the antagonists have the structure shown in formula V.
Figure imgf000048_0001
wherein Rv~! can be heteroaryl.
[073] Each Rv"a, independently, can be alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cya.no, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl.
[074] Xv can be cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a bond.
[075] Yv can be a bond, -CCO)-, -C(O)-O-, -0-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(O)-N(IT13)-, -N(Rv"b)-C(O)-, -O-C(O)-N(Rv-b)-, -N(Rv'b)-C(O)-O-, -C(O)-N(Rv"b)-O-, -O-N(Rv-b)-C(O)-, -O-S(O)p-N(Rv"b)-, -N(Rv"b)- S(O)p-O-, -S(O)p-N(Rv"b)-O-, -O-N(Rv"b)-S(O)p-, -N(Rv-b)-C(O)-N(Rv-c)-, -N(R.v-b)-S(O)p-N(Rv"c)-, -C(O)-N(Rv"b)-S(O)p-, -S(O)P-N(RV" b)-C(O)-, -C(O)-N(Rv-b)-S(O)p-N(Rv-c)-, -C(O)-O-S(O)p-N(Rv-b)-, -N(Rv"b)-S(O)p-N(Rv" C)-C(O)-,
-N(Rv-b)-S(O)p-O-C(O)-, -S(O)p-N(Rv-b)-, -N(Rv"b)-S(O)p-, -N(Rv"b)-, -S(O)P-, -O-, -S-, or -(C(Rv'b)(Rv"c))q-. Each of Rv~h and Rv"c , independently, can be hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, rieterocyclo alkyl, heteroaryl, or heteroaralkyl. p can be 1 or 2, and q can be 1-4.
[076] Rv"2 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (Tieterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl.
[077] Each of Av"! and Av"2, independently, can be N or NRv"b. It is to be understood that when Av~' is NRv"b, Av~2 is N, and vice versa. The variable, m, can be 0, 1, 2, or 3. In other words, the pyrimidinyl ring can be unsubstituted or substituted with 1-3 Rv"a groixps. Note that when m ≥2, two adjacent Rv"a groups can. optionally together to form a 4- to 8-membered optionally substituted cyclic moiety. That is, the pyrimidinyl ring can fuse with a cyclic moiety to form a moiety, that can be optionally substituted with one or more sub> stituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoronx ethyl), alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl, aryloxy, heteroaryloxy, aroyl, heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylthio, sulfoxy, sulfamoyl, oxo, or carbamoyl. Note also that if Xy is a bond, then Yy is a bond; Rv~2 is hydrogen or alkyl; m is 1, 2, or 3; and at least one Rv"a is substituted at the 2-p;yrimidinyl position (i.e., the position of the pyrimidinyl ring that is between the two nitrogen ring atoms).
[078] Compounds of formula V may be prep ared by a number of known metho ds from commercially available or known starting materials. In one method, compounds of formula V are prepared according to Scheme described below. Specifically, in Scheme V-Ia, optionally substituted 2-methylpyrimidine (II) is deprotonated by LDA before reacting with Rv"] -substituted carboxylic acid methoxy-methyl-amide (I) to form an Rv~'-(6- methylpyrimidinyl)-ketone (III), wherein Rv-1 has been defined above. The metrxoxy-methyl- amide can be prepared by reacting a corresponding acid chloride (i.e., R^-CO-G) with N, O-dimethylhydroxylamine hydrochloride. The Rv"1-(6-methylpyrimidinyl)-ke"tone (III) can then be treated with sodium nitrite in acetic acid to afford an α-keto-oxime (IV), "which can undergo a further reaction with an appropriate substituted (and optionally protected) aldehyde (VI) in the presence of ammonium acetate to yield a compound of formula V. Scheme V-Ia
Figure imgf000050_0001
1. NH4OAc
Figure imgf000050_0002
(IV)
(V)
[079] In another method, the above-described compounds of formula V can be prepared according to Scheme V-Ib below. Specifically, l,l-dimethoxy-propan-2-one can first react with dimethoxymethyl-dimethyl-amine at an elevated temperature to produce the intermediate 4-dimethylamino-l,l-dimethoxy-but-3-en-2-one, which can then react an Rv"a- substituted amidine to form an Rv"a-substituted pyrimidine-2-carbaldehyde (Ha). This carbaldehyde (Ha) can then react with aniline and diphenyl phosphite to form a resulting N,P- acetal, which can further couple with an R^-substituted aldehyde to produced an (Rv"'- methyl)-pyrimidinyl-ketone (Ilia). See, e.g., Journet et al., Tetrahedron Lett. 39:1717-1720 (1998). Treatment of the (R^-methyty-pyrimidinyl-ketone (Ilia) with sodium nitrite in acetic acid produces an α-keto-oxime (IVa), which can undergo a reaction with an appropriate substituted (and optionally protected) aldehyde (VI) to yield a compound of formula V as described in Scheme V-Ia above.
Scheme V-Ib
Figure imgf000051_0001
(Ilia) (Ua)
1. NH4OAc
Figure imgf000051_0002
[080] In another method, the above-described compounds of formula V can be prepared according to Scheme V-Ic below. Specifically, an
Figure imgf000051_0003
(Ilia) (described above) can be oxidized to form a pyrimidinyl-diketone (FVb), which can undergo reaction with an appropriate substituted (and optionally protected) aldehyde (VI) to yield a compound of formula V (V) as described above.
Scheme V-Ic
Figure imgf000052_0001
(Ilia) (IVb)
1. NH4OAc
Figure imgf000052_0002
(V)
[081] If compound (VI) is in its protected form, appropriate deprotecting agents can be applied to the resulting compound after the coupling reaction, of compound (IV) or (IVa) and compound (VI) to yield a compound of formula V (V). See, e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York (1981), for suitable protecting groups.
[082] Alternatively, a compound of formula V can be prepared by reacting intermediate (IV) or (IVa) with an aldehyde (VII) to yield a further intermediate (VIII), which can then react with compound (IX) to yield a compound of formula V. Note that moieties Y' and Y" are precursors of moiety Yv. See Scheme V-2 below, hi addition, desired substitutions at Rv"a can be obtained by selecting, for example, the appropriate compound (Ha) intermediate.
Scheme V-2
Figure imgf000053_0001
(V)
In some embodiments, moiety Xv in compound (VII) is a nitrogen-containing heterocycloalkyl (e.g., piperidine). The nitrogen ring atom can be protected by a nitrogen protecting group (e.g., Cbz, Boc, or FMOC) before coupling to compound (IV) or (IVa) and deprotected afterwards (see first step of Scheme 3) to yield compound (Villa). This compound can further react with various compounds (IX) to produce a compound of formula V. See second steps of Scheme V-3 below. It should be noted that compound (VIII) or compound (Villa) can be a compound of formula V as well.
Scheme V-3
Figure imgf000054_0001
(V)
[083] Similarly, when moiety X in compound (VII) is a cycloalkyl (e.g., cyclopentyl, cyclohexyl, or bicyclo[2.2.2]octane), it can be further functionalized to form a compound of formula V as depicted in Schemes V-4, V-5a, V-5b, and V-5c below. Scheme V-4
Pd/C
Figure imgf000055_0001
Figure imgf000055_0002
(V) Scheme V-5a
Figure imgf000056_0001
(V)
Figure imgf000056_0002
(V)
Scheme V-5b
Figure imgf000057_0001
(V) (V)
Figure imgf000057_0002
(V) (V)
Figure imgf000057_0003
(V)
(can be further modified according to Scheme 5c below)
Figure imgf000057_0004
(V)
Figure imgf000057_0005
(V)
(can be further modified according to Scheme 5c below)
Figure imgf000058_0001
(V) (V)
Figure imgf000058_0002
(V)
Trifluoroactic HATU, NH3 anhydride
(7)
DMF Pyridine, THF
Figure imgf000058_0004
Figure imgf000058_0003
(V) (V)
Figure imgf000058_0005
(V) (V)
Scheme V-5c
Figure imgf000059_0001
(V)
[084] As is well known to a skilled person in the art to which the present invention relates, desired substitutions can be placed on the pyrimidinyl ring in the last steps of the synthesis. See, e.g, Scheme V-6 below. Scheme V-6
Figure imgf000060_0001
(V) (V) (V)
[085] Compounds of formula V wherein Rv"b is not hydrogen can also be prepared by known methods. For example, compounds of formula V wherein Av"] is N and Av"2 is NH (or vice versa) can be treated with RbI (e.g., alkyl iodide) and CsCO3 to produce a compound of formula V wherein Rv"b is alkyl. See, e.g., Liverton, et al., J Med. Chem., 42: 2180-2190 (1999).
[086] As will be obvious to a skilled person in the art to which the present invention relates, some starting materials and intermediates may need to be protected before undergoing synthetic steps as described above. For suitable protecting groups, see, e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York (1981).
[087] Examples of compounds of formula V include, but are not limited to,
469) 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzamide;
470) 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzonitrile;
471) 4-[5-(2-methanesulfonyl-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
472) 4-[5-(2-methoxy-pyrimidin-4-yl)-4-(6-methLyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
473) 4-[5-(2-hydroxy-pyrimidin-4-yl)-4-(6-metriyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
474) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
475) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid; 476) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)- 1 H-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
477) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)- 1 H-imida^;ol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
478) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imida^zol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;
479) 4-[5-(2-amino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
480) {4-[5-(2-cyclopropylammo-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester;
481) N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-iinidazol- 2-yl] -bicyclo[2.2.2]oct- 1-yl} -acetamide;
482) N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-iinidazol- 2-yl] -bicyclo[2.2.2]oct-l -yl} -methanesulfonamide;
483) TSr-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-niethyl-pyridin-2-yl)-lH-in^iidazol- 2-yl]-bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;
484) 4-[5-quinoxalin-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
485) 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
486) 6-[2-tert-butyl-5-(2-cyclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
487) 6-[5-(2-byclopiOpyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
488) {4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanol;
489) 6-[5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
490) 6-[2-tert-butyl-5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
491) 4- [5 -quinoxalin-6-yl-4-(2-trifluoromethyl-pyrimidm-4-yl)- 1 H-imidazol-2-yl] - piperidine-1-carboxylic acid benzyl ester;
492) 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
493) 6-[5-(2-cyclopropyl-pyrimidin-4-yl)-2-(l-methanesulfonyl-piperidin-4-yl)-3H-irnidazol- 4-yl] -quinoxaline;
494) 4-[5-(2-methyl-pyrimidm-4-yl)-4-[l,2,4]triazolo[4,3-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol; 495) 4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
496) 4-[4-(2-methyl-pyrirnidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
497) 4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl] - bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
498) 4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexanol; and 499) 4- [4-(2-methyl-pyrimi din-4-yl)-5 -quinoxalin-6-yl- 1 H-imidazol-2-yl] - bicyclo[2.2.2]octan-l-ol.
[088] In still another embodiment, the antagonists have the structure shown in formula VI:
Figure imgf000062_0001
[089] In formula VI, each RVI"a, independently, can be alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, -NH2, -NH(unsubstituted alkyl), -N(unsubstituted alkyl)2, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarboixyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl.
[090] RVM can be a bond, alkylene, alkenylene, alkynylene, or -(CH2)ri-O-(CH2)r2-, wherein- each of rl and r2, independently, is 2 or 3. [091] Ryι~ι can be cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, arylene, heteroaryleae, or a bond.
[092] RVM can be -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(O)-N(RVI'b)-, -N(RVI"b)-C(O)-, -O-C(O)-N(RVI"b)-, -N(RVI'b)-C(O)-O-, -C(0)-N(RVI"b)-0-, -O-N(RVI" b)-C(O)-, -O-S(O)p-N(RVI"b)-, -N(RVW> S(O)P-O-, -S(O)p-N(RVI-b)-O-, -O-N(RVW>S(O)P-, -N(RVI-b)-C(O)-N(RVI-°)-, -N(RVI"b)-S(O)p-NCRVI"c)-, -C(O)-N(RVI-b)-S(O)p-, -S(O)p-N(RVI"b)-C(O)-, -C(O)-N(RVI"b)-S(O)p-N(RVI-c)-, -C(O)-O-S(O)p-N(Rvμb)-, -N(RVI"b)-S(O)p-N(RVI-c)-C(O)-, -N(RVI"b)-S(O)p-0-C(0)-, -S(O)p-N(RVI"b)-, -N(RVI"b)-S(O)p-, -N(RVW>, -S(O)p-, -O-, -S-, -(C(RVI-b)(RVI'c))q-, or a bond. Each of RVhb and RVI"C, independently, can be hydrogen, hydroxy, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl. p can be 1 or 2 and q can be 1-4.
[093] RVM can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocyclo alkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
[094] RVI"5 can be hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulflnyl, amino, alkenyl, alkynyl, cycloalkoxy, cycloalkylsulfmyl, heterocycloalkoxy, heterocycloalkylsulfinyl, aryloxy, arylsulfinyl, heteroaryloxy, or heteroarylsulfmyl.
[095] RVI"6 can be a 5- to 6-membered monocyclic heterocyclyl or a 8- to 11-membered bicyclic heteroaryl, and optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocyclo alkylsulfanyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl.
[096] The value of m can be 0-3, and when m ≥2, two adjacent Ra groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety.
[097] Compounds of formula VI are commercially available or may be prepared by a number of known methods from commercially available or known starting materials. [098] In one method, compounds of formula VI are prepared according to Scheme VI-I shown below. Specifically, a pyrimidine of formula II, which contains a 2-(α, /^-unsaturated carbonyl) substituent can cyclize with hydrazine to form a pyrazole core ring to produce a 2- (pyrazol-3-yl)-pyrimidine intermediate (III). Note that the pyrimidine of formula II can be prepared by known methods (see, e.g., Jameson, D. and Guise, L. Tetrahedron Letters, 32(18): 1999-2002). The intermediate (III) can be further substituted at the 4-position of the pyrazole core ring with a good leaving group such as halo (e.g., iodo or bromo) t>y reacting with a halogenation reagent (e.g., bromination reagent such as Br2 or iodination reagent such as N-iodosuccinimide) to form a 2-(4-halo-pyrazol-3-yl)-pyrimidine (IV). Note that halo is represented by moiety X in Scheme VI-I. The halo substituent forms an ideal platform for RVI"6 substitutions. For example, the iodo substituent can be converted into a boronic acid substituent (see compound (V) below), which can react with a RVI"6-halide (VI) C^ g-, an aryl halide or a heteroaryl halide) via Suzuki coupling reaction to form a compound of formula VI. Other substitution reactions can also be employed to produce a wide range of compounds of formula VI (see, e.g., via a reaction between the protected iodinated compound. (Wa) and phthalic anhydride to form a di-keto intermediate (VII), which can undergo a cyclization reaction with an Rg-substituted hydrazine to form a compound (VI); for reference, see J. Med. Chem., 44(16): 2511-2522 (2001). It should be noted that the pyrazole core ring should be properly protected (see, e.g., the N,N-dimethylaminosulfonyl group of compound (IVa)) to eliminate undesired side reactions.
Scheme VI-I
Figure imgf000065_0001
Figure imgf000065_0002
[O99] Exemplary reactions for preparing a compound of RVI"6 shown in Scheme VI-I are shown below in Scheme VI-2. Scheme VI-2
Figure imgf000066_0001
(Vl)
Figure imgf000066_0002
(Vl)
[0100] Alternatively, a compound of formula VI can be prepared according to Scheme VI-3 shown below. Specifically, a dirnethoxymethyl-substituted pyrimidine of formula (IEa) can be prepared by reacting dimethylformamide dimethylacetal with l,l-dimethoxy-propan-2-one to form 4-dimethylamino-l,l-dirnethoxy-but-3-en-2-one as an intermediate, which can further react with an RVI"a-substituted acetamidine (i.e., RVI"a-C(NH)-NH2) to produce a compound of formula (Ha). See Reilly, T.A. et al., J. Heterocyclic Chan. 24(4):955 <1989). The compound of formula (Ha) can then be deprotected in an acidic medium (e.g., aqueous HBr) and react with aniline and diphenylphosphite to form a compound of formula (lib), which can then react with an RVI"6-substituted aldehyde to form a compound of formula (lie). Further reaction of a compound of formula (lie) with N,N-dimethylformamide dimettiylacetal (DMFDMA), followed by hydrazine hydrate, yields a compound of formula VI. Scheme VI-3
Figure imgf000067_0001
HBr/H2O
Figure imgf000067_0002
1. DMF-DMA
2. NH2NH2
Figure imgf000067_0003
[0101] Another method for preparing a compound of formula VI is shown in Scheme VI-4 below. Note that in this Scheme, Ra' has the same meaning as RVI"a, which has been defined above, and X represents halo. Similar to the metlxod described in Scheme VI-I, this method requires halogenation at the RVI"6 position as an intermediate step. See Nesi, R. et al., J. Chem. Soc, Perkin Trans I, 8:1667-1770 (1980); Nagamitsu, T. et al., J. Org. Chem., 60(25):8126-8127 (1995); and Guanti, G. andRiv-a, R. Tetrahedron: Asymmetry, 12(8):1185-1200 (2001) for references for synthesis shown in the first four steps.
Scheme VI-4
Figure imgf000068_0001
1. NaOH
Figure imgf000068_0002
[0102] A compound of formula VI can also be prepared via a phenylacetyl pyrimidine compound (IX) as shown in Scheme VI-5 below. Specifically, a pyrimidine- carboxyaldehyde compound (VIII) is converted to the N5P acetal intermediate with aniline and diphenylphosphite. This acetal intermediate is then coupled to an aldehyde substituted with RVI"6 in basic condition (e.g., Cs2CO3) to afford an enamine intermediate, which is hydrolyzed to a ketone intermediate (DC). For reference, see, e.g., Journet et al., Tetrahedron Letters v. 39, p. 1717-1720 (1998). Cyclizing the ketone intermediate (IX) with N5N- dimethylformamide dimethyl acetal and hydrazine affords the pyrazole ring of the desired compound of formula VI. The pyrazole ring of a compound of formula VI can also be formed by cyclizing the ketone intermediate (IX) with an RVI"5-substituted carboxylic acid hydrazide (X). For reference, see, e.g., Chemistry of Heterocyclic compounds 35(11): 1319- 1324 (2000).
Scheme VT-5
Figure imgf000069_0001
RVI"5-CO-NHNH2 (X)
HCI1 THF
Δ
Figure imgf000069_0002
[0103] Another method of preparing the intermediate (IX) is depicted in Scheme VI-6 below. For reference, see, e.g., WO 02/066462, WO 02/062792, and WO 02/062787.
Scheme VI-6
Figure imgf000069_0003
(IX)
[0104] Examplanry methods for preparing a compound of formula VI wherein -RVI"1-RVI"2- RVI"3-RVM is not hydrogen are shown in Scheme VI-7 below. In reaction (A), a compound of formula VI wherein the 1 -position of the pyrazole core ring is unsubstituted undergoes a substitution reaction with X-RVI"1-RVI"2-RVI"3-RVI"4 where X is a leaving group such as trifluoromethylsulfonate, tosylate, and halide, e.g., Cl, Br, or I. Alternatively, a compound of formula VI wherein the 1 -position of the pyrazole core ring is unsubstituted can undergo a conjugate addition reaction as shown in reaction (B) below. As is well known to a skilled person in the art to which this invention relates, the electrophile or acceptor in the addition reaction generally contains a double bond connecting to an electron-withdrawing group or a double bond conjugating to groups such as carbonyl, cyano, or rαitro.
Scheme VI-7
X_RVI-1_RVI-2_RVI-3_RVI-4
Figure imgf000070_0002
-RVI-1 _RVI-2_RVI-3_RVI-4
RVI-1 _RVI-2_RVI-3_RVI-4
Figure imgf000070_0001
Figure imgf000070_0003
The -RVI"1-RVI"2-RVI"3-RVI"4 giOup can be further transformed into other functionalities as shown in Scheme VI-8 below. For example, a compound of formula VI wherein the -RVM- RVI~2-RVI"3-RVI"4 group is cyanoalkyl can be reduced to aminoallcyl, which can be further converted to other functionalities such as heteroaralkyl, heterocycloalkylalkyl, and carboxylic acid.
Scheme VI-8
Figure imgf000071_0001
[0105] Substituents at the pyrimidinyl ring (i.e., RVI"a) can also be converted into other functionalities. For example, a compound of formula VI wherein RVI"a is bromo (which can be obtained by employing a bromo-substituted compound of formula VI (Sigma- Aldrich, St. Louis, MO)) can be converted into other functionalities such as alkyl, alkenyl, cycloalkyl and the like, by known methods.
[0106] Likewise, substituents of the RVI"6 moiety can be further converted into other functionalities as well. A-S will be obvious to a skilled person in the art, some starting materials and intermediates may need to be protected before undergoing synthetic steps as described above. For suitable protecting groups, see, e.g., T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York (1981). [0107] Examples of compounds of formula VI include, but are not limited to,
500) 4-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-2-methyl-pyrimidine,
500a) 6-[3-(2-methyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-[l;,2,4]triazolo[l,5-a]pyridine,
501 ) 6-[3 -(2-trifluoromethyl-pyrimidin-4-yl)- 1 H-pyrazol-4-yl] -[ 1 ,2,4]triazolo [ 1 ,5-a]pyridine,
502) 6-[3-(2-methyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-quinoxaline,
502a) 6-[3-(2-trifluoromethyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-quinoxaline,
503) 6-[3-(2-cyclopropyl-pyrimidin-4-yl)- 1 H-pyrazol-4-yl] -quinoxaline, 504) 4-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-2-trifluoromethyl-pyrimidine, 505) 7-[3-(2-trifluoromethyl-pyrirnidin-4-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridme, and
506) 6-[3-(2-Trifluoromethyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-quinoline.
Routes of Administration
[0108] As defined above, an effective amount is the amount which is required to confer a therapeutic effect on the treated subject, e.g. a patient. For a compound of formulae (I, II, III, rV, V, and VI), an effective amount can range from about 1 mg/kg to about 150 mg/kg (e.g., from about 1 mg/kg to about 100 mg/kg). Effective doses will also vary, as recognized by those skilled in the art, dependent on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents and/or radiation therapy.
[0109] The compounds of formulae I, II, III, IV, V, and VI can be administered by any method that permits the delivery of the compounds to combat vascular injuries. For instance, the compounds of formulae I, II, III, IV, V, and VI can be admininistered via pills, tablets, capsules, aerosols, suppositories, liquid formulations for ingestion or injection or for use as eye or ear drops, dietary supplements, and topical preparations. A pharmaceutically acceptable composition includes the aqueous solution of the compound of formula I, II, III, IV, V, or VI, in an isotonic saline, 5% glucose or another well-known pharmaceutically acceptable excipient. Solubilizing agents such as cyclodextrins, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compounds. As to route of administration, the compositions can be administered orally, intranasally, transdermally, intradermally, vaginally, intraaurally, intraocularly, buccally, rectally, transmucosally, or via inhalation, or intravenous administration. The compositions may be delivered intravenously via a ballon catheter. The compositions can be administered to an animal (e.g., a mammal such as a human, non-human primate, horse, dog, cow, pig, sheep, goat, cat, mouse, rat, guinea pig, rabbit, hamster, gerbil, ferret, lizard, reptile, or bird).
[0110] The compounds of formulae I, U, III, IV, V, and VI also can be delivered by implantation (e.g., surgically) with an implantable device. Examples of implantable devices include, but are not limited to, stents, delivery pumps, vascular filters, and implantable control release compositions. Any implantable device can be used to deliver the compound provided that 1) the device, compound and any pharmaceutical composition including the compound are biocompatible, and 2) that the device can deliver or release an effective amount of the compound to confer a therapeutic effect on the treated patient within, a short or over an extended period of time.
[0111] Delivery of therapeutic agents via stents, delivery pumps (e.g., mini-osmotic pumps), and other implantable devices is known in the art. See for example, "Recent Developments in Coated Stents" by Hofrna et al., published in Current Interventional Cardiology Reports 2001, 3:28-36, the entire contents of which, including references cited therein, are incorporated herein. Other descriptions of implantable devices, such as stents, can "be found, e.g., in U.S. Patent Nos. 6,569,195 and 6,322,847; and PCT International Publication Numbers WO 04/0044405, WO 04/0018228, WO 03/0229390, WO 03/0228346, WO 03/0225450, WO 03/0216699, and WO 03/0204168, each of which is also incorporated herein by reference in its entirety.
[0112] Referring to Figure 1, a delivery device, such as stent 10, includes a compound 20 of formula I, II, III, IV, V, or VI. The compound, as a therapeutic agent, may be incorporated into or onto the stent using methodologies known in the art. In some embodiments, a stent can include interlocked meshed cables. Each cable can include metal wires for structural support and polyermic wires for delivering the therapeutic agent. The polymeric wire can be dosed by immersing the polymer in a solution of the therapeutic agent. Alternatively, the therapeutic agent can be embedded in the polymeric wire during the formation of the wire from polymeric precursor solutions. In other embodiments, stents or implatable devices can be coated with polymeric coatings that include the therapeutic agent. The polymeric coating can be designed to control the release rate of the therapeutic agent.
[0113] Controlled release of therapeutic agents can utilize various technologies. Devices are known having a monolithic layer or coating incorporating a heterogeneous solution and/or dispersion of an active agent in a polymeric substance (e.g., a polyester), where the diffusion of the agent is irate ϊϊmϊtϊngj as' the agent diffuses through the polymer to the polymer- fluid interface and is released into the surrounding fluid, hi some devices, a soluble substance is also dissolved or dispersed in, or chemically bonded to, the polymeric material, such that additional pores or channels are left after the material dissolves. A matrix device is generally diffusion limited as well, but with the channels or other internal geometry of the device also playing a role in releasing the agent to the fluid. The channels can be pre-existing or left behind by released agent or other soluble substances.
[0114] Erodible or degradable devices typically have the active agent physically immobilized in the polymer. The active agent can be dissolved and/or dispersed throughout the polymeric material. The polymeric material is often hydrolytically degraded over time through hydrolysis of labile bonds, allowing the polymer to erode into the fluid and releasing the active agent into the fluid. Hydrophilic polymers have a generally faster rate of erosion relative to hydrophobic polymers. Hydrophobic polymers are believed to have almost purely surface diffusion of active agent, having erosion from the surface inwards. Hydrophilic polymers are believed to allow water to penetrate the surface of the polymer, allowing hydrolysis of labile bonds beneath the surface, which can lead to homogeneous or bulk erosion of polymer.
[0115] The implantable device coating can include a blend of polymers each having a different release rate of the therapeutic agent. For instance, the coating can include a polylactic acid/polyethylene oxide (PLA-PEO) copolymer and a polylactic acid/polycaprolactone (PLA-PCL) copolymer. The polylactic acid/polyethylene oxide (PLA- PEO) copolymer can exhibit a higher release rate of therapeutic agent relative to the polylactic acid/polycaprolactone (PLA-PCL) copolymer. The relative amounts and dosage rates of therapeutic agent delivered over time can be controlled by changing the relative amounts of the faster releasing polymers relative to the slower releasing polymers. For higher initial release rates the proportion of faster releasing polymer can be increased relative to the slower releasing polymer. If most of the dosage is desired to be released over a. long time period, most of the polymer can be the slower releasing polymer. The stent can "be coated by spraying the stent with a solution or dispersion of polymer, active agent, and solvent. The solvent can be evaporated, leaving a coating of polymer and active agent. The active agent can be dissolved and/or dispersed in the polymer. In some embodiments., the co¬ polymers can be extruded over the stent body. [0116] In still other embodiments, compounds of formula I can be administered in conjunction with one or more other agents that inhibit the TGF/3 signaling pathway or treat the corresponding pathological disorders (e.g., fibrosis or progressive cancers) by way of a different mechanism of action. Examples of these agents include angiotensin converting enzyme inhibitors, nonsteroid, steroid anti-inflammatory agents, and chemotherapeutics or radiation, as well as agents that antagonize ligand binding or activation of the TGFjS receptors, e.g., anti-TGF/3, anti-TGF/3 receptor antibodies, or antagonists of the TGF/? type II receptors.
[0117] The invention will be further described in the following examples, which do not in any way limit the scope of the invention described in the claims.
Example 1 : Balloon Catheter Injury of the Rat Carotid Artery
[0118] The ability of compounds of formulae I, II, III, IV, V, and VI to prevent the stenotic fibrotic response was tested by administration of the test compounds (i.v., p.o., or s.c) to rats that have undergone balloon catheter injury of the carotid artery.
[0119] Sprague Dawley rats (400g, 3 to 4 months old) were anesthetized by i.p. injection with 10 mg/kg xylazine (XyIa- Ject, Phoenix Pharmaceuticals) and 80 mg/kg ketamine (Ketaset, Fort Dodge). The left carotid artery and the aorta were denuded with a 2F balloon catheter (Edwards Life Sciences) according to the procedure described in Clowes et al., Lab Invest. 49: 327-333 (1983). Test compounds of formulae I, II, III, TV, V, and VI were each administered to the treatment group (n=5-10 rats) (i.v., p.o., or s.c; qod, once per day, bid, tid or by continuous s.c. infusion 'via an Alzet mini-osmoticpump) starting the day of surgery and subsequently for 14 more days. The control group (n=5 rats) received the same volume of vehicle administered using the same regimen as the test compound- treated rats. The animals were sacrificed under anesthesia 14 days post-balloon injury. Exsanguination and then perfusion fixation was carried out under physiological pressure with 0.9% sodium chloride, injection USP (310 mOsmol/L, pH 5.6 (4.5-7.0)) and (10% neutral buffered formalin). The injured carotid artery was excised, post-fixed and embedded for histological and morphometic analysis. Sections (5 μm) were cut from the proximal, middle and distal segments of the denuded vessel and analyzed using image analysis software. The circumference of the lumen and the lengths of the internal elastic lamina (IEL) and the external elastic lamina (EEL) were determined by tracing along the luminal surface the perimeter of the neointima (IEL) and the perimeter of the tunica media (EEL), respectively. The lumen (area within the lumen), medial (area between the IEL and EEL) and intimal (area between the lumen and the IEL) areas were also determined using morphometric analysis. Statistical analysis used ANOVA to determine statistically significant differences between the means of treatment groups (p ≤0.05). Multiple comparisons between groups were then performed using the Dunnet's Multiple Comparisons test. The Student t test was used to compare the means between 2 groups, and differences were considered significant if P ≤0.05. All data are shown as mean + SEM.
[0120] Statistically significant decreases were seen in intimal area, intimal/medial ratio in injured arteries of test compound-treated rats compared to those of the vehicle-treated rats. Conversely, the lumen area, IEL and EEL lengths showed a statistically significant increase in injured arteries of test compound-treated rats compared to those of the vehicle-treated rats. These results show that inhibition of the TGF/3RI kinase prevents the stenotic response to balloon-catheter arterial injury by inhibiting the fibrotic expansion of the neointima and vessel remodeling.
Example 2: Cell-Free Assay for Evaluating Inhibition of Autophosphorylation of TGFjS Type I Receptor
[0121] The serine-threonine kinase activity of TGF/? type I receptor was measured as th.e autophosphorylation activity of the cytoplasrαic domain of the receptor containing an IST- terminal poly histidine, TEV cleavage site-tag, e.g., His-TGF/3RI. The His-tagged receptor cytoplasmic kinase domains were purified from infected insect cell cultures using the Gibco- BRL FastBac HTb baculovirus expression system.
[0122] To a 96-well Nickel FlashPlate (NEN Life Science, Perkin Elmer) was added 20 μl of 1.25 juCi 33P-ATP/25 μM ATP in assay buffer (50 mM Hepes, 60 mM NaCl, 1 mM MgCl2, 2 mM DTT, 5 mM MnCl2, 2% glycerol, and 0.0 15% Brij® 35). 10 μl of each test compound of formula I prepared in 5% domethyl sulfoxide (DMSO) solution were added to the FlashPlate. The assay was then initiated with the addition of 20 ul of assay buffer containing 12.5 prnol of His-TGFjSRI to each well. Plates were incαbated for 30 minutes at room temperature and the reactions were then terminated by a single xinse with Tris-buffered saline (TBS). Radiation from each well of the plates was read on a TopCount (Packard). Total binding (no inhibition) was defined as counts measured in the presence of DMSO solution containing no test compound and non-specific binding was defined as counts measured in the presence of EDTA or no-kinase control. [0123] Alternatively, the reaction performed using the above reagents and incubation conditions but in a microcentrifuge tube was analyzed by separation on a 4-20% SDS-PAGE gel and the incorporation of radiolabel into the 40 kDa His-TGFβRI SDS-PAGE band was quantitated on a Storm Phosphoimager (Molecular Dynamics).
[0124] Compounds of formulae I, II, III, IV, V, and VI typically exhibited low IC50 values of less than 10 μM; some exhibited IC50 values of less than 1 μM; and some even exhibited IC5O values of less than 50 nM.
Example 3: Cell-Free Assay for Evaluating Inhibition of Activin Type I Receptor Kinase Activity
[0125] Inhibition of the Activin type I receptor (AIk 4) kinase autophosphorylation activity by compounds of formulae I, II, III, IV, V, and VI, can be determined in a similar manner to that described above in Example 2 except that a similarly His-tagged form of AIk 4 (His- AIk 4) is used in place of the HiS-TGF1SRI.
Example 4: TGF/3 Type I Receptor Ligand Displacement FlashPlate Assay
[0126] 50 nM of tritiated 4-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinoline (custom-ordered from. PerkinElmer Life Science, Inc., Boston, MA) in assay buffer (50 mM Hepes, 60 mM NaCl2, 1 mM MgCl2, 5 mM MnCl2, 2 mM 1 ,4-dithiothreitol (DTT), 2% Brij® 35; pH 7.5) was premixed with a test compound of formula I, II, III, TV, V, or VI, in 1% DMSO solution in a v-bottom plate. Control wells containing either DMSO without any test compound or controL compound in DMSO were used. To initiate the assay, His-TGFβ Type I receptor in the same assay buffer (Hepes, NaCl2, MgCl2, MnCl2, DTT, and 30% Brij® added fresh) was added to a. nickel coated FlashPlate (PE, NEN catalog number: SMP 107), while the control wells contained only buffer (i.e., no His-TGF/3 Type I receptor). The premixed solution of tritiated 4-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinoline and the test compound was then added to the wells. The wells were aspirated after an hour at room temperature and radioactivity in wells (emitted from the tritiated compound) was measured using TopCount (PerkinElmer Lifesciences, Inc., Boston MA).
[0127] Compounds of formulae I, II, III, IV, V, and VI typically exhibited IQ values of less than 10 μM; some exhibited K1 values of less than 1 μM; and some even exhibited Ki values of less than 5O nM.
Example 5: Assay for Evaluating Cellular Inhibition of TGFjS Signaling and Cytotoxicity
[0128] Biological activity of the compounds of formulae I, II, III, IV, V, and VI was determined by measuring their ability to inhibit TGFβ-induced PAI-Luciferase reporter activity in HepG2 cells.
[0129] Specifically, HepG2 cells were stably transfected with the PAI-luciferase reporter grown in DMEM medium containing 10% FBS, penicillin (100 U/ml), streptomycin (100 μg/ml), L-glutamine (2 mM), sodium pyruvate (1 mM), and non-essential amino acids (Ix). The transfected cells were then plated at a concentration of 2.5 x 104 cells/well in 96-well plates and starved for 3-6 hours in media with 0.5% FBS at 370C in a 5% CO2 incubator. The cells were then stimulated with 2.5 ng/ml TGF/3 ligand in the starvation media containing 1 % DMSO either in the presence or absence of a test compound of formula I, II, III, IV, V, or VI and incubated as described above for 24 hours. The media was washed out the following day and the luciferase reporter activity was detected using the LucLite Luciferase Reporter Gene Assay kit (Packard, Cat. No. 6016911) as recommended. The plates were read on a Wallac Microbeta plate reader, the reading of which was used to determine the IC50 values of the test compounds for inhibiting TGFβ-induced PAI-Luciferase reporter activity in HepG2 cells. Compounds of formulae I, II, III, IV, V, and VI typically exhibited IC50 values of less 10 uM.
[013O] Cytotoxicity was determined using the same cell culture conditions as described above. Specifically, cell viability was determined after overnight incubation with the CytoLite cell viability kit (Packard, cat. no. 6016901). Compounds of formula I, II, III, IV, V, and VI typically exhibited LD25 values greater than 10 /xM.
Example 6: Assay for Evaluating Inhibition of TGFβ Type I Receptor Kinase Activity in Cells
[0131] The cellular inhibition of activin signaling activity by compounds of formula I, II, III, IV, V, or VI is determined in a similar manner as described above in Example 5, except that IOO ng/ml of activin is added to serum starved cells in place of the 2.5 ng/ml TGF 'β.
Example 7: Assay for TGF/3-Induced Collagen Expression
Preparation of Immortalized Collagen Promotor-Green Fluorescent Protein Cells
[013Z] Fibroblasts are derived from the skin of adult transgenic mice expressing Green Fluorescent Protein (GFP) under the control of the collagen IAl promoter (see Krempen, K. et al., Gene Exp. 8: 151-163 (1999)). Cells are immortalized with a temperature sensitive large T antigen that is in an active stage at 330C, and then expanded at 33°C before being transferred to 37°C at which temperature the large T antigen becomes inactive (see, e.g., Xu, S. et al., Exp. Cell Res., 220: 407-414 (1995)). Over the course of about 4 days and one split, the cells cease proliferating. The cells are then frozen in aliquots sufficient for a single 96- well plate.
Assay of TGFβ-induced Collagen-GFP Expression
[0133] Cells are thawed, plated in complete DMEM (contains non-essential amino acids, ImM sodium pyruvate and 2mM L-glutamine) with 10 % fetal calf serum, and then incubated for overnight at 37°C, 5% CO2. The cells are trypsinized in the following day and transferred into 96-well format with 30,000 cells per well in 50 μ\ complete DMEM containing 2 % fetal calf serum, but without phenol red. The cells are incubated at 37°C for 3 to 4 h-ours to allow them to adhere to the plate. Solutions containing a test compound of formula I, II, III, IV, V, or VI are then added to wells with no TGFjS (in triplicates), as well as wells with 1 ng/ml TGF/3 (in triplicates). DMSO is also added to all of the wells at a final concentration of 0.1%. GFP fluorescence emission at 530 ran following excitation at 485 urn is measured 48 hours after the addition of solutions containing a test compound on a CytoFluor microplate reader (PerSeptive Biosystems). The data are expressed as the ratio of TGFβ-induced to non-induced for each test sample.
OTHER EMBODIMENTS
[0134] It is to be understood that while the invention has been described in conjunction with the detailed description thereofl, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the following claims. Other aspects, advantages, and modifications are within the scope of the present invention.

Claims

CLAIMS:
1. A method of inhibiting intimal thickening by administering to a subject in need thereof an inhibitor of TGFb type I receptor or Alk4.
2. The method of claim 1, wherein the inhibitor has the structure shown in formula I:
Figure imgf000081_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein
R1"1 is aryl, heteroaryl, aralkyl, or heteroaralkyl; each Rτ"a is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thioxirea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsxilfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
X1-1 is cycloalkyl or heterocycloalkyl;
Yi-1 is a bond, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(O)-N(Rb)-, -N(Rb)-C(O)-, -0-C(0)-N(Rb)-, -N(Rb)-C(O)-O-, -O-S(O)p-N(Rb)-, -N(Rb)- S(O)P-O-, -N(Rb)-C(0)-N(Rc)-, -N(Rb)-S(0)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb)-C(O)-, -C(0)-N(Rb)-S(0)p-N(Rc)-, -C(0)-O-S(0)p-N(Rb)-, -N(Rb)-S(0)p-N(Rc)-C(0)-, -N(Rb)-S(O)p-O-C(O)-, -S(O)p-N(Rb)-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)P-, -O-, -S-, or -(C(Rb)(Rc))q-, wherein each of Rb and Rc is independently hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; wherein p is 1 or 2 and q is 1-4;
R1"2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heferocycloallcenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl; each of A1"1 and A1"2, independently, is O, S, N, or NRb, provided that at least one of A1"1 and A1"2 is N; and m is 0, 1, 2, or 3, and when m >2, two adjacent R!"a groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety.
3. The method of claim 1, wherein the inhibitor has the structure shown in formula II:
Figure imgf000082_0001
or a pharmaceutically acceptable salt or N-oxide thereof, wherein each OfXn-1, X11-2, X11-3, and Xn-4 is independently CRX or N, provided that no more than two of Xπ-i, X11-2, Xn-3, and Xn-4 can be N simultaneously; each Of Yn-1 and Yn-2 is independently CRy or N, provided that at least one of Yn-1 and Yn-2 must be N; each R11"1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocyclo alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaxyloxy, heteroarylsulfanyl, or heteroaroyl; each R11"2 is independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2, - NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -N(alkyl)(cycloalkyl), -NH(heterocycloalkyl), - NH(heteroaryl),
-NH-alkyl-heterocycloalkyl, -NH-alkyl-heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, cycloalkyl-alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cyeloalkytyalkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalky^carbonylamino, (heterocycloalkytyalkylcarbonylarnino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkoxycarbonylaminoalkylamino, (heteroaryl)arylcarbonylaminoalkylamino, heteroaralkylcarbonylaminoalkylamino, (heteroarytyarylsulfonylaminoalkylcarbonylaminoalkylammo, arylsulfonylaminoalkylamioo, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl; m is 0, 1, 2, 3, or 4, and when m Ξ≥2, two adjacent R1 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; n is 0, 1, 2, or 3, and when n >2, two adjacent R2 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; and each of Rx and Ry is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cycloalkyl)alkylcarbonylamino, (cycloalkyl)alkylsulfonylamino ., arylcarbonylamino, arylsulfonylamino, aralkylcarbonylamino, aralkylsulfonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)sulfonylamino, (heterocycloalkyl)alkylcarbonylamino, (heterocycloalkyl)alkylsulfonylainino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylamino, heteroaralkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfaanide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, (cycloalkyl)alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalkyl)alkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteiOarylsulfanyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl.
4. Trie method of claim 1, wherein the inhibitor has the structure shown in formula III
Figure imgf000084_0001
or a pharmaceutically acceptable salt or N-oxide thereof, wherein each of Xm-I, Xm-2, X111-3, and Xm-4 is independently CRIπ"x or NT, provided that no more than two of Xm-1, Xm-2, Xin-3, and Xm-4 can be N simultaneously; each of Ym-i and Ym-2 is independently CRπi"y or N, provided that at least one OfYm-1 and Ym-2 must be N; each R111"1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocyclo alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, iαeteroaryloxy, heteroarylsulfanyl, or heteroaroyl; each R111"2 is independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -N(alkyl)(cyclocalkyl), -NHOieterocycloalkyl), -NH(heteroaryl), -NH-alkyl-lieterocycloalkyl, -NH-alkyl-heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, anxinosulfonyl, alkylcarbonylamino, cycloalkylcaxbonylamino, (cycloalky^alkylcarbonylamino, arylcarbonylamino, aralkylcarboriylamino, (heterocycloalky^carbonylarnino, (heterocycloaUcyl)alkylcarbonylarnino, heteroarylcarbonylamino, heteroafalkylcarbonylamino, alkoxycarbonylaminoalkylamino, (heteroaryl)arylcarbonylaminoalkylamino, lαeteroaralkylcarbonylaminoalkylamino, (heteroary^arylsulfonylaminoalkylcarbonylaminoalkylamino, arylsulfonylaminoaUkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl; m is 0, 1, 2, 3, or 4, and when m >2, two adjacent R111"1 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety;
TTT O n is 0, 1, 2, or 3, and when n Ξ≥2, two adjacent R " groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; and each of Riπ"x and Riπ"y is independently hydrogen, alkyl, alkenyl, alkynyl, aLkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsuliϊnyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cycloaUcyl)alkylcarbonylamino, (cycloalkyl)alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, aralkylcarbonylamino, aralkylsulfonylaminσ, (heterocycloalky^carbonylamino, (heterocycloalkyl)sulfonylamino, (heterocycloalky^alkylcarbonylamino, (heterocycloalky^alkylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylamino, heteroaralkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloaUcyl)alkoxy, (cycloalkyl)alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalkyl) alkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteroarylsulfaαyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl.
5. The method of claim 1, wherein the inhibitor has the structure shown in formula IV
Figure imgf000086_0001
or an N-oxide or a. pharmaceutically acceptable salt thereof, wherein each RIV"a is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamirio, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocyclo alkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
RWA is a bond, alkylene, alkenylene, alkynylene, or -(CH2)rl-O-(CH2)r2-, wherein each of rl andr2 Is independently 2 or 3;
Rw~2 is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, or a bond;
R^3 is -C(O)-, -C(O)O-, -OC(O)-, -C(O)-N(R1^)-, -N(R1^)-C(O)-, -0-C(O)-N(R^" b)-, -N(R1^)-C(O)-O-, -0-S(O)P-N(R^'13)-, -N(RIV'b)- S(O)P-O-, -N(RIV"b)-C(O)-N(RIV"c)-, _N(RIV-b)-S(0)p-N(RIV-b)-3 -C(O)-N(Rw-b)-S(O)p-, -S(O)P-N(R1^)-C(O)-, -S(OVNCR1^)-, -N(R^)-S(O)P-, -N(R^-13)-, -S(O)P-, -O-, -S-, or -(C(RIV-b)(RIV-c))q-, or a bond; wherein each of Rw"b and R^"0 is independently hydrogen, hydroxy, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; wherein p is 1 or 2 and q is 1-4;
Rw'4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaraLkyl;
R™'5 is hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulfinyl, amino, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkylsulfinyl, heterocycloalkyl, heterocycloalkoxy, heterocycloalkylsulfinyl, aryl, aryloxy, arylsulfinyl, heteroaryl, heteroaryloxy, or heteroarylsulfmyl; j^rv-6 -s ^ a ^_ tQ 5_rnemiDered heterocyclyl containing 1-3 hetero ring atoms selected from the group consisting of -O-, -S-, -N=, and -NR^- wherein R^ is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl; said heterocyclyl being substituted with R^"6 and optionally substituted with one to two Rw"f; wherein Rw'e is oxo, thioxo, alkoxy, alkylsulfinyl, -NH2, -NH(unsubstituted alkyl), or -N(unsubstituted alkyl)2, and R^" is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfbnyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; or
(2) a fused ring heteroaryl selected from the group consisting of:
Figure imgf000087_0001
wherein ring A is an aromatic ring containing 0-4 hetero ring atoms, and ring B is a 5- to 7- membered aromatic or nonaromatic ring containing 0-4 hetero ring atoms, provided that at least one of ring A and ring B contains one or more hetero ring atoms; ring A' is an aromatic ring containing 0-4 hetero ring atoms, and ring B' is a 5- to 7-membered saturated or unsaturated ring containing 0-4 hetero ring atoms, provided that at least one of ring A' and ring B' contains one or more hetero ring atoms; each hetero ring atom is -O-, -S-, -N=, or - NR1^-; each X1 is independently N or C; each X2 is independently -O- -S-, -N=, -NR™"8- , or -CHR™"11-; wherein RW'B is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylallcyl, heteroaryl, or heteroaralkyl; each of R^"11 and R^'1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloaϊkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, hetero aryloxy, heteroarylsulfanyl, or tieteroaroyl; and n is 0-2; and m is 0-3, and when m >2, two adjacent Rw'& groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; provided that if Rw~6 is 2-naphthyridinyl, 4-quinolinyl, imidazo[l,2-a]pyridyl, or benzimidazolyl, then -R^'-R^-R^-R™'4 is not H, unsubstituted a,lkyl, -CH2-C(O)-N(H)-alkyl, -CH2-C(O)-N(alkyl)2, or benzyl.
6. The method of claim 1, wherein the inhibitor has the structure shown in formula V
Figure imgf000088_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein
Rv"! is heteroaryl; each Rv"a, independently, is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, ar;ylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
Xv is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a bond;
Yv is a bond, -C(O)-, -C(O)-O-, -0-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(0)-N(Rb)-, -N(Rb)-C(0)-, -O-C(O)-N(Rb)-, -N(Rb)-C(0)-0-, -C(0)-N(Rb)-0-, -O-N(Rb)-C(0)-, -O-S(O)p-N(Rb)-, -N(Rb)- S(O)p-O-, -S(O)p-N(Rb)-O-, -O-N(Rb)-S(O>p-, -N(Rb)-C(0)-N(Rc)-, -N(Rb)-S(O)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb)-C(O)-, -C(O>)-N(Rb)-S(O)p-N(Rc)-, -C(Oj-O-S(O)P-N(R")-, -N(Rb)-S(O)p-N(Rc)-C(O>, -N(Rb)-S(O)p-O-C(O)-, -S(O)p-N(Rb)-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)P-, -O-, -S-, or -(C(Rb)(Rc))o wherein each of Rb and Rc, independently, is hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; wherein p is 1 or 2 and q is 1-4;
Rv~2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkeayl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl; each of Av"! and Av~2, independently, is N or NRb; and m is 0, 1, 2, or 3, and when m >2, two adjacent R v"a groups can optionally join together to form a 4- to 8-membexed optionally substituted cyclic moiety, provided that if Xv is a bond, then Yv is a bond; Rv"2 is hydrogen or alkyl; m is 1, 2, or 3; and at least one Rv"a is substituted at the 2-pyrimidinyl position.
7. The method of claim 1, wherein the inhibitor has the structure shown in formula VI:
Figure imgf000090_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein each RVI"a, independently, is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, - NH2, -NH(unsubstituted alkyl), -N(unsubstituted alkyl)2, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
RVM is a bond, alkylene, alkenylene, alkynylene, or -(CH2)rl-O-(CH2)r2-, where each of rl and r2, independently, is 2 or 3;
RVI~2 is cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, arylene, heteroarylene, or a bond;
RVI"3 is -C(O)-, -C(O)-O-, -O-C(O)-, -S(OVO-, -O-S(O)P-, -C(O)-N(Rb)-, -N(Rb)-C(O)-, -O-C(O)-N(Rb)-, -N(Rb)-C(0)-0-, -C(O)-N(Rb)-O-, -O-N(Rb)-C(O)-, -O-S(O)p-N(Rb)-,
-N(Rb)- S(O)p-O-, -S(O)p-N(Rb)-O-, -0-N(Rb)-S(O)p-, -N(Rb)-C(O)-N(Rc)-, -N(Rb)-S(O)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb)-C(O>, -C(O)-N(Rb)-S(O)p-N(Rc)-, -C(O)-O-S(O)p-N(Rb)-, -N(Rb)-S(O)p-N(Rc)-C(O)-, -N(Rb)-S(O)p-O-C(O)-, -S(O)p-N(Rb)-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)P-, -O-, -S-, -(C(Rb)(Rc))q-, or a bond; wherein each of Rb and Rc is independently hydrogen, hydroxy, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; wherein p is 1 or 2 and q is 1-4; RVM is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
RVI"5 is hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulfinyl, amino, alkenyl, alkynyl, cycloalkoxy, cyclo alkylsulfinyl, heterocycloalkoxy, heterocycloalkylsulfinyl, aryloxy, arylsulfmyl, heteroaryloxy, or heteroarylsulfinyl;
RVI"6 is a 5- to 6-membered monocyclic heterocyclyl or a 8- to 11-membered bicyclic heteroaryl; each being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; and m is 0-3, and when m >2, two adjacent RVI~a groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety.
8. The method of claim 1, wherein the inhibitor is
1) 4-(4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl)-piperidine-l- carboxylic acid benzyl ester;
2) 4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidine- 1 -carboxylic acid benzyl ester;
3) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
4) 3 -[4-B enzo [1,3] dioxol-5 -yl-5 -(6-methyl-pyridin-2-yl)- 1 H-imidazol-2-yl] -pyrrolidine- 1 - carboxylic acid benzyl ester; 5) 2-(5-Benzo[l53]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine;
6) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid benzyl ester;
7) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
8) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]-pyrrolidine-l- carboxylic acid benzyl ester; 9) 2-(5-Benzo[l ,3] dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine;
10) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl]-6-methyl-pyridine;
11) 2-[5-Benzo[ 1 ,3 ]dioxol-5-yl-2-( 1 -phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl]-pyridine;
12) 2- [ 5 -B enzo [1,3] dioxol- 5-yl-2-( 1 -methanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl] - pyridine;
13) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
14) 4-(4-Benzo[ 1 ,3 ] dioxol-5-yl-5 -pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid 2-chloro-benzyl ester;
15) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 2,4-dichloro-b enzylamide;
16) l-[4-(4-Benzo[ l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-l-yl]- ethanone;
17) 2-[5-Benzo[l,3 ]dioxol-5-yl-2-(l-furan-2-yl-methyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
18) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-cyclohexyl}- carbamic acid benzyl ester;
19) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl] cyclohexylamine ;
20) N- {4-[4-Benzo [ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexyl } -C-phenyl-methanesulfonamide;
21) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid methyl ester;
22) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2]octane- 1 -carboxylic acid;
23) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester;
24) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-ethyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
25) 2-(5-Benzo[l ,3] dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine;
26) 4-(4-Benzo[l33]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-nitro-benzyl ester; 27) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4,5-dimethoxy-2-nitro-benzyl ester;
28) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyriciin-2-yl-lH-imidazol-2-yl)-piperidme-l-carboxylic acid 3-fluoro-benzylamide;
29) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-fluoro-benzylamide;
30) 4-(4-Benzo [ 1 ,3 ]dioxol-5-yl-5 -pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid benzylamide;
31) 2- {5-Benzo[l,3]dioxol-5-yl-2-[l-(toluene-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4-yl}- pyridine;
32) 4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid 4-methyl-benzylamide;
33) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-methoxy-benzylamide;
34) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 2-chloro-benzylamide;
35) 4-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyτidin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- benzoic acid;
36) 4-(4-Benzo [ 1 ,3] dioxol-5-yl-5 -pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid amide;
37) 4-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- benzonitrile;
38) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
39) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3 ,4-dicriloro-benzenesulfonyl)-piρeridin-4-yl]-3H- imidazol-4-yl} -pyridine;
40) {5-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- naphthalen- 1 -yl} -dimethyl-amine;
41) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(p3nidin-4-yl-methyl)-piperidin-4-yl)]-3H-imidazol-4- yl} -pyridine;
42) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
43) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-methoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine; 44) l-{4-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l- sulfonyl] -phenyl} -ethanone;
45) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-methyl-benzyl)-piperidin-4-yl]-3H-imiciazol-4-yl}- pyridine;
46) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3-fluoro-5-trifluoromethyl-benzyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
47) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-cyclohexylmethyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
48) 2-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-L -ylmethyl]- cyclopropanecarboxylic acid ethyl ester;
49) 2-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-l -ylmethyl]- pyrrolidine- 1-carboxylic acid tert-butyl ester;
50) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-piperidin-4- yl]-3H-imidazol-4-yl} -pyridine;
51) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-ethanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
52) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(butane-l-sulfonyl)-ρiperidin-4-yl]-3H-imidazol-4-yl}- pyridine;
53) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-nitro-phenyhnethanesulfonyl)-piperidia-4-yl]-3H- imidazol-4-yl} -pyridine;
54) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethenesulfonyl)-piperidin-4-yl]-3H-imidazol-
4-yl} -pyridine;
55) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-l-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
56) 1 -[4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidine- 1 - sulfonylmethyl]-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one;
57) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
58) 2- { 5 -Benzo [1,3] dioxol-5 -yl-2- [ 1 -(3 , 5 -dichloro-phenylmethanesulfonyl)-piperidin-4-yl] -
3H-imidazol-4-yl} -pyridine;
59) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(4-fluoro-phenylmethanesulfonyl)-piperidixi-4-yl]-3H- imidazol-4-yl} -pyridine;
60) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,4-dichloro-phenylmethanesulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl} -pyridine; 61) 2- {5-Benzo [ 1 ,3] dioxol-5-yl-2- £ 1 -(2-phenyl-ethanesulfonyl)-piperidin-4-yl] -3H-irni dazol- 4-yl} -pyridine;
62) 2-[5-Benzo[l ,3]dioxol-5-yl-2-( l-p-tolylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -pyridine;
63) 3-(4-Benzo[l,3]dioxol-5-yl-l-h.ydroxy-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l- carboxylic acid benzyl ester;
64) 3-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidine- 1 -carboxylic acid benzyl ester;
65) 4-[4-Benzo[l,3]dioxol-5-yl-l-h_ydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
66) 2-{5-Benzo[l,3]dioxol-5-yl-2-[ l-(pyridin-2-yl-methanesulfonyl)-piperidin-4-yl]-3H[- imidazol-4-yl} -pyridine;
67) 2-{5-Benzo[l,3]dioxol-5-yl-2-[ l-(2-naphthalen-l-yl-ethanesulfonyl)-piperidin-4-yl3-3H- imidazol-4-yl} -pyridine;
68) 2-[5-Benzo[l ,3]dioxol-5-yl-2-( 1 -phenylmethanesulfonyl-piperidin-3-yl)-3H-imidazol-4- yl] -pyridine;
69) 3-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
70) 2-{5-Benzo[l,3]dioxol-5-yl-2-[ l-(pyridin-4-yl-methanesulfonyl)-piperidin-4-yl]-3H[- imidazol-4-yl} -pyridine;
71) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-3-yl-methanesulfonyl)-piperidin-4-yl]-3HI- imidazol-4-yl} -pyridine;
72) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3-trifluoromethyl-phenylmethanesulfonyl)-pipericiin-4- yl]-3H-imidazol-4-yl} -pyridine;
73) 3-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl] - pyrrolidine- 1-carboxylic acid benzyl ester;
74) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[ 1 -(4-trifluoromethyl-phenylmethanesulfonyl)-piperidin-4- yl]-3H-imidazol-4-yl} -pyridine;
75) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l -(3,5-bis-trifluoromethyl-phenylmethanesulfonyl)- piperidin-4-yl]-3H-imidazol-4-yl}-pyridine;
76) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(biρhenyl-4-sulfonyl)-ρiperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
77) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l -(3,5-difluoro-phenylmethanesulfonyl)-ρiperidin-4-yl]- 3H-imidazol-4-yl} -pyridine; 78) 2-{5-Benzo[l,3]dioxoϊ-'5-"yl-2-[l:fø imidazol-4-yl} -6-methyl-pyridine;
79) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
80) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(biphenyl-4-ylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
81 ) 4-[5-Benzo[ 1 ,3]dioxol-5-yl- 1 -methyl-4-(6-methyl-pyridin-2-yl)- lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
82) 4-[4-Benzo[l,3]dioxol-5-yl-l-methyl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
83) {4-[4-Benzo[ 1 ,3]dioxol-5-yl- 1 -hydroxy-5-(6-methyl-pyridin-2-yl)- lH-imidazol-2-yl]- cyclohexylj-carbamic acid benzyl ester;
84) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[l -(3-phenoxy-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -6-methyl-pyridine;
85) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-ethanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
86) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-l-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl } -6-methyl-pyridine;
87) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(butane-l-sulfonyl)-piperidin-4-yl]-3H-imidazol-4-yl}- 6-methyl-pyridine;
88) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-3-ylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
89) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-4-ylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
90) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-difluoro-phenylmethanesulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
91) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3-trifluoromethyl-phenylmethanesulfonyl)-piperidin-4- yl] -3H-imidazol-4-yl} -6-methyl-pyridine;
92) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(thioρhene-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl } -6-methyl-pyridine;
93) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(butane-l-sulfonyl)-piperidin-3-yl]-3H-imidazol-4-yl}-
6-methyl-pyridine;
94) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-3-yl)-3H-imidazol-4- yl] -6-methyl-pyridine; 95)"2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(l-methyl-lH-imidazole-4-sulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
96) 2- { 5 -Benzo [1,3] dioxol-5 -yl-2- [ 1 -(5 -methyl-isoxazole-4-sulfonyl)-piperidin-4-yl] - 3H- imidazol-4-yl} -6-methyl-pyridine;
97) 4-[5-Benzo[l,3]dioxol-5-yl-l-liydroxy-4-(6-methyl-pyridm-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
98) Butane- 1 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl] -eye lohexyl} -amide;
99) N-{4- [4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexyrl}-C-pyridin-2-yl-methanesulfonamide;
100) Thiophene-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexyl}-amide;
101) 1 -Methyl- lH-imidazole-4-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl- pyridin-2-yl)-lH-imidazol-2-yl]-cyclohexyl} -amide;
102) 4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imiciazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
103) 4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imiciazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
104) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-bromo-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
105) 2-{5-Benzo[l53]dioxol-5-yl-2-[l-(thiophene-3-sulfonyl)-piρeridin-4-yl]-3H-imidazol-4- yl} -6-metliyl-pyridine;
106) 2-{5-Berizo[l,3]dioxol-5-yl-2-[l-(5-methyl-2-trifluoromethyl-furan-3-sulfonyl)- piperidin-4-yl]-3H-imidazol-4-yl}-6-methyl-pyridine;
107) 4- [2- ( 1 -phenylmethanesulfonyl-piperidin-4-yl)-5 -(6-methyl-pyridin-2-yl) - 1 H-imidazol-
4-yl]-pyridin-2-yl-fluoride;
108) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-trifluoromethyl-ρyridin-2-yl)-lH-imidaz:ol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
109) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-bromo-pyridin-2-yl)-l-hydroxy-lH-imi(iazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
110) 2-[5--Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -6-bromo-pyridine;
111) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.-2.2]oct- 1 -yl} -methanol; 112) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
113) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-2H-imidazol-2-yl]-piperidiτie-l- sulfonic acid dimethylamide;
114) l-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin- 1 -yl} -3 -phenyl-propan- 1 -one;
115) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[l -(propane-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
116) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonitrile;
117) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-ylamine;
118) N- {4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)- lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-C-phenyl-methanesulfonamide;
119) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct- 1 -yl} -methanesulfonaπxide;
120) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-niethyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-C-ρyridin-2-yl-methanesulfonamide;
121) 2-{5-Benzo[l,3]dioxol-5-yl-2-[4-(lH-tetrazol-5-yl)-bicyclo[2.2.2]oct-l-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
122) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetamide;
123) Thiophene-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
124) l-Methyl-lH-imidazole-4-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl- pyridin-2-yl)- 1 H-imidazol-2-yl] -bicyclo [2.2.2] oct- 1 -yl} -amide;
125) Thiophene-3 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
126) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethenesulfonyl)-ρiperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
127) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
128) Methanesulfonic acid 4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct-l-ylmeth.yl ester; 129) {4-[4-Benzo[l,3]dioxol-5-yl-'5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetonitrile;
130) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyri(iin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetic acid;
131) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyτidin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-ylmethyl}-methanesulfonamide;
132) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(biphenyl-4-sταlfonyl)-piperidin-4-yl]-3H-imidazol-4- yl } -6-methyl-pyridine;
133) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
134) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[l -(3,4-dichloro-"benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl}-6-methyl-pyridine;
135) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyτidin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-ylmethyl}-C-phenyl-methanesulfonamide; 136) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyxidin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] oct- 1 -ylmethyl } -C-pyridin-2-yl-methaxiesulfonamide; 137) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid benzylamide;
138) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (pyridin-2-ylrnethyl)-amide; 139) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid 3-chloro-4-fliαoro-benzylamide; 140) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (furan-2-ylmethyl)-amide;
141) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfoo.yl-pyrrolidin-3-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
142) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(butane-l-sulfonyl)-pyrrolidin-3-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
143) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(l-methyl-lH-imidazole-4-sulfonyl)-pyrrolidin-3-yl]- 3H-imidazol-4-yl}-6-methyl-pyridine;
144) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-pyrrolidin-3-yl)-3H-imidazol- 4-yl] -6-methyl-pyridine;
145) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-benzenesulfonyl)-pyrrolidin-3-yl]-3H- imidazol-4-yl} -6-methyl-pyridine; 146) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(2-nitro-phenylmethanesulfonyl)-piperidm-4-yl] -3 H- imidazol-4-yl} -6-methyl-pyridine;
147) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-naphthalen-2-yl-ethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl}-6-methyl-pyridine;
148) l-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-pipericaine- 1 -sulfonylmethyl} -7,7-dimethyl-bicyclo[2.2. l]heptan-2-one;
149) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(4-chloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
150) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methylamide;
151) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid ethylamide;
152) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid butylamide;
153) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid isopropylamide;
154) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2]octane- 1 -carboxylic acid (3 -imidazol- 1 -yl-propyl)-amide;
155) 2-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-
1 -sulfonylmethyl} -phenylamine;
156) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (l-methyl-5-methylsulfanyl-lH-[l,2,4]triazol-3-yl)- axnide;
157) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid cyclohexylamide;
158) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct- 1 -yl} -pyrrolidin- 1 -yl-methanone;
159) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid dimethylamide;
160) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid diethylamide;
1 61) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid dipropylamide;
162) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (5,7-difluoro-benzothiazol-2-yl)-amide; 163) 4-[4-Benzo[l ,3] dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane- 1-carboxylic acid benzothiazol-2-ylamide; 164) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane- 1-carboxylic acid (lH-benzoimidazol-2-yl)-amide; 165) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane- 1-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-amide; 166) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane- 1-carboxylic acid (pyridin-4-ylmethyl)-amide;
167) {4-[4-Benzo[l ,3 ]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin-l- yl}-(3-chloro-phenyl)-methanone;
168) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin-l- yl} -(4-fluoro-phenyl)-methanone;
169) {4-[4-Benzo[l ,3 ]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin-l- yl}-(4-methoxy-phenyl)-methanone;
170) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-cyclopropyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane- 1-carboxylic acid;
171) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane- 1-carboxylic acid methoxy-amide; 172) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane- 1-carboxylic acid hydroxyamide;
173) {4-[4-Benzo[l ,3 ]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-carbamic acid benzyl ester;
174) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane- 1-carboxylic acid hydrazide;
175) N-{4-[4-Benzo[l33]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-iniidazol-2-yl]- cyclohexylmethyl}-acetamide;
176) N-{4-[4-Benzo[l53]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmetliyl}-m.ethanesulfonamide;
177) N-{4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-C-phenyl-methanesulfonamide;
178) Butane- 1 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexylmethyl} -amide;
179) Propane-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl] -cyclohexylmethyl } -amide; 180) N- {4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-l H-imidazol-2-yl]- cyclohexylmethyl}-C-pyridin-2-yl-methanesulfonamide;
181) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-C-pyridin-4-yl-methanesulfonamide;
182) (4-Methoxy-benzyl)-{4-[5-(6-methyl-pyridin-2-yl)-2-(l-phenylmethanesulfonyl- piperidin-4-yl)-lH-imidazol-4-yl]-pyridin-2-yl}-amine;
183) 4-[5-(6-Methyl-pyridin-2-yl)-4-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
184) 4-[5-(6-Methyl-pyridin-2-yl)-4-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl- lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
185) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
186) 4-[4-(6-Methyl-ρyridin-2-yl)-5-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
187) 4-[4-(6-Methyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
188) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[l ,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2- yl] -bicyclo [2.2.2] octane- 1 -carboxylic acid;
189) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;
190) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
191) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l -carboxylic acid amide;
192) 4-[4-(6-Cyclopropyl-ρyridm-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridm-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
193) N- {4-[5-Benzo[l ,3]dioxol-5-yl-4-(6-meth.yl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-sulfamide;
194) Sulfamic acid 4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl ester;
195) {4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl- 1 H-imidazol-2-yl]-cyclohexyl} - carbamic acid benzyl ester;
196) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonyl}-methanesulfonamide; 197) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonyl}-benzenesulfonamide;
198) 4- [5-(3 -Methyl-4-oxo-3 ,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)- 1 H- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
199) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
200) N- {4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl} - acetamide;
201) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-"bicyclo[2.2.2]octane-
1-carboxylic acid methyl ester;
202) 4-[4-(6-Methyl-pyridm-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-"bicyclo[2.2.2]octane-
1-carboxylic acid;
203) 4-[4-(6-Methyl-pyridin-2-yl)-5-qumoxalin-6-yl-lH-imidazol-2-yl]-t)icyclo[2.2.2]octane-
1 -carboxylic acid hydroxyamide;
204) 4-[4-(6-Methyl-pyridm-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-lDicyclo[2.2.2]octane-
1-carboxylic acid amide;
205) N- {4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl} - methanesulfonamide;
206) 2,2,2-Trifluoro-N- {4-[4-(6-methyl-pyridin-2-yl)-5-quinoxalin-6-yl- 1 H-imidazol-2-yl]- cyclohexyl} -acetamide;
207) 4-[4-(5-Fluoro-6-methyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol- 2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
208) {4-[2- [ 1 -(Butane- 1 -sulfonyl)-piperidin-4-yl] -5-(6-methyl-pyridin-2- yl)- 1 H-imidazol-4- yl]-pyridin-2-yl}-(4-methoxy-benzyl)-amine;
209) 4-[2-[ 1 -(Butane- 1 -sulfonyl)-piperidin-4-yl]-5-(6-methyl-pyridin-2-yl)- lH-imidazol-4- yl]-pyridin-2-ylamine;
210) 2-[5-Benzo[ 1 ,3]dioxol-5-yl-2-(l -phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -6-ethyl-pyridine;
211) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
212) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide; 213) N-{4-[5-(6-Methyl-pyridin-2-yl)-4-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanesulfonamide; 2l4) N-{4-[5-(6-Methyl-pyridin-2-yl)-4-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetamide.
215) 4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-pyrimidin-2-ylamine;
216) 4-(2-pyridin-2-yl-pyrazolo[l,5-a]pyridin-3-yl)-pyrimidin-2-ylamine; 217) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-pyrimidin-2-ylamine;
218) 2-(6-methyl-pyridin-2-yl)-3-(2-metliylsulfanyl-pyrimidin-4-yl)-pyrazolo[l,5-a]pyridine;
219) 4-[2-(6-chloro-p)τidm-2-yl)-pyrazolo[l,5-c]pyrimidm-3-yl]-pyrimidin-2-ylamine;
220) 2-(6-methyl-pyridin-2-yl)-3-(2-morpholin-4-yl-pyrimidin-4-yl)-pyrazolo[ 1 ,5- c]pyrimidine;
221) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyrazin-3-yl]-pyrimidin-2-ylamine;
222) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyrimidin-3-yl]-pyrimidin-2-ylamine;
223) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine;
224) (2-Methoxy-ethyl)-{4-[2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
225) (3-{4-[2-(6-Methyl-pyridin-2-yl)-iinidazo[l52-a]pyridin-3-yl]-pyrimidin-2-ylamino}- propyl)-carbamic acid tert-butyl ester;
226) (3-Imidazol-l-yl-propyl)-{4-[2-(6-niethyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
227) (4-Methoxy-benzyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
228) [2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridin-
6-yl]-methanol;
229) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridine;
230) (4-{4-[2-(6-Methyl-pyridin-2-yl)-irriidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylammo}- butyl)-carbamic acid tert-butyl ester;
231) (4-Amino-benzyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
232) (5-{4-[2-(6-Methyl-pyridin-2-yl)-im.idazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}- pentyl)-carbamic acid tert-butyl ester;
233) [3-(2-Amino-pyrimidin-4-yl)-2-(6-rn.ethyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-6-yl3- methanol;
234) [3-(2-amino-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[ 1 ,2-a]pyridin-7-yl] - methanol; 235) [3-(2-Amino-pyrimidm-4'-yl):'6-methyl-2-(6-methyl-pyridin-2-yl)-iniidazo[l,2- a]pyridin-8-yl]-(2-morpholin-4-yl-ethyl)-amine;
236) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(2-pyridin-2-yl-ethyl)-amine;
237) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(2-pyridin-3-yl-ethyl)-amine;
238) [3-(2-methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridin-6-yl]-methanol;
239) [3 -(2- Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2- a]pyridin-8-yl]-(2-pyridin-4-yl-ethyl)-amine;
240) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridin-8-yl]-(3-morpholin-4-yl-propyl)-amine;
241 ) [3 -(4-Methyl-piperazin- 1 -yl)-propyl] - {4-[2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2- a]pyridin-3-yl]-pyrimidin-2-yl}-amine;
244) [3-(4-Methyl-piperidin-l-yl)-propyl]-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-3 -yl] -pyrimidin-2-yl} -amine;
245) [4-(2-Pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-pyrimidin-2-yl]-pyridin-3-ylmethyl- airline;
246) {4-[2-(6-Methyl-pyridm-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-((R)-l- phenyl-ethyl)-amine;
247) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-((S)-l- phenyl-ethyl)-amine;
248) {4-[2-(6-Methyl-pyridm-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(lH- tetrazol-5-yl)-amine;
249) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2H- pyrazol-3 -yl)-amine;
250) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2- morpholin-4-yl-ethyl)-amine;
251) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2-pyridm- 2-yl-ethyl)-amine;
252) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} -(2-pyridin- 3 -yl-ethyl)-amine;
253) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2-pyridin- 4-yl-ethyl)-amine; 254) {4-L2-(6-Melhyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl} -(3- moφholin-4 -yl-propyl)-amine;
255) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(3- piperidin- 1 -yl -propylamine;
256) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- [ 1 ,3 ,4]thiadiazol-2-yl-amine;
257) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,Z-a]pyridine;
258) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine- 6-carboxylic acid methyl ester;
259) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidm-4-yl)-imidazo[l,2-a]pyridine- 7-carboxylic acid ethyl ester;
260) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2- aJpyrimidin-V-ylamine;
261) {7,7-Dύmethyl-8-[5-(4-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridia-3-yl]- pyrimidin-2-ylamino}-butylcarbamoyl)-pentyl]-2-oxo-4-trifluoromethyl-7,8-dihy"dro-2H-l- oxa-8-aza-anthracen-5-yl} -methanesulfonic acid;
262) 2-(2,7-Difluoro-6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)-3,5,6-trifluoro-4-[(4- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]-pyrimidin-2-ylamino} - butylcarbamoyl)-methylsulfanyl]-benzoic acid;
263) -(6-Methyl-pyridm-2-yl)-3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[ 1 ,2-a]pyridine;
264) 2-(6-Methyl-pyridin-2-yl)-3-(2-piperidin-l-yl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine;
265) 2-(6-Methyl-pyridin-2-yl)-3-(2-pyrrolidin- 1 -yl-pyrimidin-4-yl)-irnidazo[ 1 ,2-a]pyridine; 266) 2-(6-Methyl-pyridin-2-yl)-3-[2-(lH-tetrazol-5-yl)-pyrimidin-4-yl]-imidazo[l,2- ajpyridine;
267) 2-(6-Methyl-pyridin-2-yl)-3-pyrimidin-4-yl-imidazo[ 1 ,2-a]pyridine;
268) 2-(6-Methyl-pyridin-2-yl)-3-pyrimidin-4-yl-imidazo[ 1 ,2-a]pyrimidin-7-ylairiine;
269) 3-(2-Arriino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridixi-8- ylamine;
270) 3-(2-Arriino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridirie-6- carbonitrile;
271) 3-(2-Arαino-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridirαe-6- carboxylic acid;
272) 3-(2-Arnino-pyrimidin-4-yl)-2-(6-methyl-ρyridin-2-yl)-imidazo[l,2-a]pyridirie-6- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide; Tl 5) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
274) 3-(2-Amino-pyrimidin-4-yl)-2 -(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid (2-dimethylamino-ethyl)-amide;
275) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid (2-methoxy-ethyl)-ainide;
276) 3-(2-7\mino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid (2-thiophen-2-yl-eth.yl)-atnide;
277) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid [3-(4-methyl-piperazin-l-yl)-propyl]-amide;
278) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid amide;
279) 3-(2-Amino-ρyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid cyclopropylamide;
280) 3-(2-Amino-pyrimidin-4-yl)-2-(6-metriyl-pyridin-2-yl)-irnidazo[l,2-a]pyridme-6- carboxylic acid ethylamide;
281) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid hydroxyamide;
282) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid methoxy-amide;
283) 3-(2-Amino-pyrimidin-4-yl)-2-(6-rnethyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid methyl ester;
284) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid;
285) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid ([l,4]dioxan-2-ylmetliyl)-amide;
286) 3-(2-Amino-pyrimidin-4-yl)-2-C6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-amino-ethyl)-amid.e;
287) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-dimethylamino-ettαyl)-amide;
288) 3-(2-Amino-ρyrimidin-4-yl)-2-(^6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridme-7- carboxylic acid (2-hydroxy-ethyl)-amide;
289) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-oxo-2-pyridin-3-yl-ethyl)-amide; 290) 3-(2-Aniino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-irnidazo[l,2-a]pyridine-7- carboxylic acid (2-thiophen-2-yl-ethyl)-amide;
291) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-inαidazo[l,2-a]pyridine-7- carboxylic acid (piperidin-3-ylmethyl)-amide;
292) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-in^iidazo[l,2-a]pyridine-7- carboxylic acid 2,2-dimethylhydrazide;
293) 3-(2-Amino-pyrimidin-4-yl)-2-(6-rnethyl-pyridin-2-yl)-intiidazo[l,2-a]pyridine-7- carboxylic acid amide;
294) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iirιidazo[l,2-a]pyridine-7- carboxylic acid cyclopropylamide;
295) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iinidazo[ 1 ,2-a]pyridine-7- carboxylic acid ethyl ester;
296) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-ρyridin-2-yl)-iπxidazo[ 1 ,2-a]pyridine-7- carboxylic acid ethylamide;
297) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-inxidazo[l,2-a]pyridine-7- carboxylic acid hydroxyamide;
298) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-inxidazo[l,2-a]pyridine-7- carboxylic acid methoxy-amide;
299) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iniidazo[ 1 ,2-a]pyrimidin-7- ylamine;
300) 3-(2-Azetidin-l-yl-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-irriidazo[l,2-a]pyridine;
301) 3-(2-Methanesulfonyl-pyrirnidin-4-yl)-2-(6-methyl-pyridiri-2-yl)-imidazo[l,2-a] pyridine-7-carboxylic acid ethyl ester;
302) 3 -(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridiri-2-yl)-imidazo [ 1 ,2- a]pyridine-6-carboxylic acid methyl ester;
303) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-7-methyl-2-(6-methLyl-pyridm-2-yl)-imidazo[ 1 ,2- a] pyridine;
304) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-8-methyl-2-(6-methLyl-pyridin-2-yl)-imidazo[l,2- a] pyridine;
305) 3,3-Dimethyl-N-[2-(6-methyl-pyridm-2-yl)-3-(2-methylsulfanyl-ρyrimidin-4-yl)- imidazo[ 1 ,2-a]pyrimidin-7-yl]-butyramide;
306) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridiπL-2-yl)-imidazo[l,2- a]pyridine-6-carbonitrile;
307) 3-(2-Methylsulfanyl-pyrimidin-4-yl)-2-pyridin-2-yl-imidazo[l,2-a]pyridine; 308) 3,6-Dichloro-N-(4-{4-[2-(6-methyl-ρyridin-2-yl)-imidazo[l,2-a]ρyridin-3-yl]- pyrimidin-2-ylamino}-butyl)-2-(2,4,5,7-Tetrachloro-6-hydroxy-3-oxo-9,9a-dihydro-3 H- xanthen-9-yl)-terephthalamic acid;
309) 3-[2-(2-Methyl-aziridin-l-yl)-pyrimidin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyridine;
310) 3-[2-(4-Methyl-piperazin-l-yl)-pyrimidin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a] pyridine;
311) 3-{[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridiiie-6- carbonyl] -amino} -propionic acid methyl ester;
312) 3-{[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridine-7- carbonyl] -amino} -propionic acid methyl ester;
313) 3-{4- [2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl]-pyrimidin-2-ylamino } - phenol;
314) 4-(2- {4- [2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl] -pyrimidin-2-ylarnino} - ethyl)-benzenesulfonamide;
315) 4-(2-Pyridin-2-yl-imidazo[ 1 ,2-a]pyridin-3-yl)-pyrimidm-2-ylamine;
316) 4-[2-(6-Chloro-pyridin-2-yl)-imidazo[l ,2-a]pyridm-3-yl]-pyrimidin-2-ylamine;
317) 4- [2-(6-Methyl-pyridin-2-yl)-7-trifluoromethyl-imidazo [ 1 ,2-a]pyridin-3 -yl]-pyrirnidin- 2-yl-amine;
318) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamine;
319) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidine-2-carbonitrile;
320) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidine-2-carboxylic acid amide;
321) 4-[6-Bromo-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
322) 4-[6-Chloro-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
323) 4-[6-Fluoro-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
324) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-morpholin-4-yl-ethylamino)-imidazo [ 1 ,2-a] pyridin-3-yl]-pyrimidin-2-ol;
325) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-2-yl-ethylamino)-imidazo[l,2-a] pyridin-3-yl]-pyrimidin-2-ol; 326) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-3-yl-ethylamino)-imidazo[l,2-a] pyridin-3-yl]-pyrimidin-2-ol; 327) 4-[6-Methyi-2-(6-methyl-ρyridin-2-yl)-8-(2-pyridin-4-yl-ethylamino)-imidazo[l,2-a] pyridin-3-yl]-pyrimidiri-2-ol;
328) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-morpholin-4-yl-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ol;
329) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-moφholin-4-yl-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2 -ylamine;
330) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
331) 4-[7-Aminomethyl-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2- yl-amine;
332) 4-[7-Methyl-2-(6-rnethyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
333) 4-[8-Benzyloxy-2-(6-rnethyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]-pyriniidin-2-ol; 334) 4-[8-Benzyloxy-Z-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyriniidin-2-yl- amine;
335) 4-[8-Bromo-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin- 2-ol;
336) 4-[8-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
337) 6-Chloro-3-(2-methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iniidazo[l,2- a] pyridine;
338) 5-Dimethylamino -naphthalene- 1 -sulfonic acid (4-{4-[2-(6-methyl-pyridin-2-yl)- imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} -butyl)-amide;
339) 6-(2,7-Difluoro-6-hydroxy-3-oxo-3H-xanthen-9-yl)-N-(4-{4-[2-(6-methyl-pyridin-2-yl)- imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylammo}-butyl)-isophthalamic acid; 340) 6-Amino-9-[2-carboxy-5-(4-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamino}-TDutylcarbamoyl)-plienyl]-xanthen-3-ylidene-aminonmm;
341) 6-Bromo-2-(6-methyl-pyridin-2-yl)-3 -(2-methylsulfanyl-pyrimidin-4-yl)-imidazo [ 1 ,2-a] pyridine;
342) 6-Fluoro-2-(6-methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a] pyridine;
343) 7-Amino-4-methyl-3-[(4-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamino}-"butylcarbamoyl)-methyl]-2-oxo-2H-chromene-6-sulfonic acid;
344) Cyclobutyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} - amine; 345) Cyclopentyl-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]-pyrimi(lin-2- yl} -amine;
346) Cyclopropyl- {4-[2-(6-methyl-pyridin-2 -yl)-imidazo[ 1 ,2-a]pyridin-3 -yl] -pyrimiclin-2- yl} -amine;
347) Cyclopropyl-methyl- {4-[2-(6-methyl-p;yridm-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
348) Dimethyl-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- amine;
349) Isopropyl-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- amine;
350) Methyl- {4- [2-(6-methyl-pyridin-2-yl)-irnidazo [ 1 ,2-a]pyridin-3 -yl] -pyrimidin-2- y\}- amine;
350a) N-(2- {4-[2-(6-Methyl-pyridin-2-yl)-inαidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2- ylamino } -ethyl)-acetamide;
351) N-(4- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}- butyl)-acetamide;
352) N,N-Dimethyl-N'-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyximidin- 2-yl} -ethane- 1 ,2-diamine;
353) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-meth.ylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a] pyrimidin-7-yl] -3 -pyridin-3 -yl-propionamide ;
354) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methiylsulfanyl-pyriinidm-4-yl)-imidazo[l ,2- a] pyrimidin-7-yl] -nicotinamide;
355) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methLylsulfanyl-pyrimidin-4-yl)-imidazo[1.2-a] pyrimidin-7-yl]-propionamide;
356) N-[3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carbonyl] -methanesulfonamide;
357) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carbonyl] -methanesulfonamide;
358) N-[3-(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyritnidin-7- yl]-2-(3-methoxy-phenyl)-acetamide;
359) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyrimidin-7- yl] -3 ,3 -dimethyl-butyramide;
360) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyrimidin-7- yl] -3 -pyridin-3-yl-propionamide; 3ό 1 ) JN-L3-(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]p;yrimidin-7- yl]-acetamide;
362) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]p3αimidin-7- yl]-nicotinamide;
363) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyrimidin-7-yl] -2-(3 -methoxy-phenyl)-acetamide ;
364) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidaz;o[ 1 ,2-a] pyrimidin-7-yl]-3,3-dimethyl-butyramide;
365) N-[3-(2-Methanesulfonyl-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidaz;o[l,2-a] pyrimidin-7-yl]-3-pyridin-3-yl-propionamide;
366) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidaz:o[l,2-a] pyrimidin-7-yl]-nicotinamide;
367) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidaz;o[l,2-a] pyrimidin-7-yl] -propionamide;
368) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyrimidin-7- yl] -propionamide;
369) N-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]-pyrimidin-2-y-l}- acetamide;
370) Nl-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-butane- 1,4-diamine;
37I) Nl- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-^l} - propane- 1 ,3 -diamine;
372) N-(4-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}- butyl)-(BODIPY FL) amide; and
373) N-(4-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}- butyl)-(Texas Red-X) amide
374) N-[3-(2-amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyrimidin-7- yl] -acetamide;
375) N- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl } - acetamide,
376) 3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propylamine, 377) N-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-acetamide, 378) N-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-methanesulfonanαide, 379) dimethyl-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-amine3
380) 4-{3-pyridin-2-yl-l-[2-(lH-tetrazol-5-yl)-ethyl]-lH-pyrazol-4-yl}-quinoline- 381) 4-[3-pyriSm-2-yϊ-ϊ-(3-pyifolϊ(din- 1 -yl-propyl)- 1 H-pyrazol-4-yl] -quinoline,
382) 5-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-pyridin-2-ylamine, 383) 2,4-dimethoxy-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyrimidine,
384) 3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propionic acid,
385) 5-(3 -pyridin-2-yl- 1 H-ρyrazol-4-yl)- 1 H-indole, 386) 2-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-lH-pyrazol-3-yl]-pyridine, 387) N-hydroxy-3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propionamide, 388) 2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-ethylamine, 389) N-[2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-ethyl]-methanesulfonamide, 390) 2-methyl-4-methylsulfanyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyrimidine, 391) 2-(4-benzo [1,3] dioxol-5-yl- 1 H-pyrazol-3-yl)-pyridine, 392) 2-[4-(2,3-dihydro-benzofuran-5-yl)-lH-pyrazol-3-yl]-pyridine,
393) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[d]isoxazole,
394) 3-[4-benzo [1,3] dioxol-5-yl-3 -(6-methyl-pyridin-2-yl)-pyrazol- 1 -yl] -propionitril e, 395) N-{3-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-propyl> - methanesulfonamide, 396) 2-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-lH-pyrazol-3-yl]-6-methyl-pyridine,
397) [4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-acetonitrile,
398) N- {2-[4-benzo[ 1 ,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-ρyrazol- 1 -yl]-ethyl} - methanesulfonamide, 399) 4-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-2-methylsulfanyl-pyrimidine,
400) 4-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-2H-phthalazin- 1 -one,
401) l-[5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-2,3-dihydro-indol-l-yl]-ethanone, 402) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyridine,
403) 3 -methyl-6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-3H-quinazolin-4-one,
404) 6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-4H-benzo [1,4] oxazin-3 -one,
405) 6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-quinoxaline,
406) 3-(4-nitro-benzyl)-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one, 407) 5-methyl-6-(3-pyridin-2-yl-lH[-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyridine,
408) 4-methyl-7-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-3 ,4-dihydro- lH-benzo [e] [ 1 ,4]diazepine- 2,5-dione,
409) 2,3-dimethyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
410) 6-[3-(6-methyl-pyridin-2-yl)- 1 H-pyrazol-4-yl]-[l ,2,4]triazolo[l ,5-a]pyridine, 41 Oa) 1 -methoxy-4-(3-pyridin-2-yl- lH-pyrazol-4-yl)-isoquinoline,
411) 2-methyl-6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)- [ 1 ,2,4]triazolo[ 1 ,5-a]pyridine, 41 Ia) "4-(3 -pyrϊdϊh-2-yl- 1 H-pyrazόl-4-yl)-2H-isoquinolin- 1 -one,
412) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-trifluoromethyl-pyridine, 412a) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-vinyl-pyridine,
413) 2-(4-benzo[l ,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-propenyl-pyridine,
414) 2-(4-benzo [ 1 ,3 ]dioxol-5 -yl- 1 H-pyrazol-3-yl)-6-ethyl-ρyridine,
415) 2-(4-benzo[l ,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-propyl-pyridine,
416) 2-(4-benzo[ 1 ,3]dioxol-5-yl- 1 H-pyrazol-3-yl)-6-cyclopropyl-pyridine,
417) l-[6-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-pyridin-2-yl]-ethanol,
418) 4-methoxy-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline,
419) 6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-quinoline,
420) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin-4-ylamine, 421) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
422) 7-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyrido[l,2-a]ρyrimidin-4-one,
423) 6-[3-(6-cyclopropyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[ 1 ,2,4]triazolo[ 1 ,5~a]pyridine, 424) 3-methyl-6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3H-quinazolin-4-one, 425) 4-(2-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethoxy}- ethoxy)-bicyclo[2.2.2]octane-l-carboxylic acid,
426) 4-(2-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethoxy}- ethoxy)-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester, 427) 4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-ρyrazol-l-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester, 428) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-isopropyl-pyridine,
429) 2-(4-benzo[l,3]dioxol-5-yl-5-trifluoromethyl-lH-pyrazol-3-yl)-6-bromo-pyridine,
430) 6-[3-(5-fluoro-6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l ,2,4]triazolo[l ,5-a]pyridine, 431) 6-[3-(6-trifluoromethyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
432) 6- [3 -(6-methyl-pyridin-2-yl)- 1 H-pyrazol-4-yl] -quinoxaline,
432a) 6-[3-(6-cyclopropyl-ρyridin-2-yl)-lH-pyrazol-4-yl]-3-methyl-3H-quinazolin-4-one,
433) 6-(3-pyridin-2-yl- 1 H-pyrazol-4-yl)- [ 1 ,2,4]triazolo[ 1 ,5-b]pyridazine, 433a) 6- [3 -(6-methyl-pyridin-2-yl)- 1 H-pyrazol-4-yl] -quinoline,
434) 6-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-3-fluoro-2-methyl-pyridine,
435) 7-methoxy-3 -methyl-6-(3-pyridin-2-yl- 1 H-pyrazol-4-yl)-3H-quinazolin-4-one,
436) (4-morpholin-4-yl-phenyl)-[6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin-4-yl]-amine,
437) 4-isopropoxy-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline,
438) 6-(3-Pyridin-2-yl-lH-pyrazol-4-yl)-quinolin-4-ylamine, 439") {4-[Vbenzotϊ73]'3ibxol3-yl-5-(S-meiJiyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohe carbaniic acid benzyl ester,
440) 4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohexylamine, 441 ) N- {4-[4-benzo[ 1 ,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol- 1 -yl]-cyclohexyl} - methanesulfbnamide, 442) 6-[3-(5-fluoro-6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoxaline,
443) 7-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine,
444) 1 -tert-butyl-3 - [ 6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-qumazolin-4-yl] -urea,
445) 5-(3 -pyridin-2-yl-lH-pyrazol-4-yl)-benzo[l,2,5]thiadiazole,
446) 5-(3 -pyridin-2-yl-lH-pyrazol-4-yl)-benzo[l,2,5]oxadiazole,
447) 5-(3 -Pyridin-2-yl- lH-pyrazol-4-yl)-benzooxazole, 448) 4-rαorpholin-4-yl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline, 449) 6-[3-(6-trifluoromethyl-pyridin-2-yl)-lH-pyrazol-4-yl]-qumoxaline, 450) 4-(4-methoxy-phenyl)-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline,
451) 5-[3 -(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-benzo[l ,2,5]thiadiazole,
452) 6-(3 -pyridin-2-yl- lH-pyrazol-4-yl)-benzothiazole, 453) 3-(3-methoxy-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
454) 5-methyl-thiophene-2-carboxylic acid [6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin-4- yl] -amide,
455) 5-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3-phenyl-benzo[c]isoxazole,
456) 3-(4~methoxy-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
457) 3-(4-chloro-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
458) 3-(4-ethyl-phenyl)-5-(3-ρyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
459) (4-methoxy-phenyl)-[6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-qumazolin-4-yl]-methanone,
460) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3-thiophen-3-yl-benzo[c]isoxazole,
461) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid,
462) 5-(3 -Pyridin-2-yl- lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid methylamide,
463) 5 -(3 -pyridin-2-yl- lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid dimethylamide,
464) 5 -(3 -pyridin-2-yl- lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid (2,2-dimethyl- propyl)-amide,
465) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid pheriylamide, 466) morpholin-4-yl-[5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazol-3-yl]-rnethanone,
467) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid benzylamide,
468) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid cyclopentylamide; 469) 4-f4-b'enzb['ϊ,3']di6xol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol^ benzamide;
470) 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzonitrile;
471) 4-[5-(2-methanesulfonyl-ρyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl] - bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
472) 4-[5-(2-methoxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
473) 4-[5-(2-hydroxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
474) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
475) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)- 1 H-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
476) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
477) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
478) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;
479) 4-[5-(2-amino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid;
480) {4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester;
481) N- {4-[5-(2-cyclopropylarnino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol- 2-yl]-bicyclo[2.2.2]oct-l-yl}-acetamide;
482) N-{4-[5-(2-cyclopropylarnino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-irnidazol— 2-yl]-bicyclo[2.2.2]oct- 1 -yl} -methanesulfonamide;
483) N- {4-[5-(2-cyclopropylarnino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)- lH-imidazol- 2-yl]-bicyclo [2.2.2]oct- 1 -yl} -2 ,2,2-trifluoro-acetamide;
484) 4-[5-quinoxalin-6-yl-4-(2 -trifluoromethyl-pyrimidin-4-yl)- 1 H-imidazol-2-yl] - bicyclo[2.2.2]octan-l-ol;
485) 4-[4-(2-cyclopropyl-pyrirnidrn-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
486) 6-[2-tert-butyl-5-(2-cyclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline; 487) S-[5-(2-B'ycl6propyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
488) {4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanol;
489) 6-[5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
490) 6-[2-tert-butyl-5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
491) 4-[5-quinoxalin-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
492) 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
493) 6-[5-(2-cyclopropyl-pyrimidin-4-yl)-2-(l-methanesulfonyl-piperidin-4-yl)-3H-imidazol- 4-yl] -quinoxaline;
494) 4-[5-(2-methyl-pyrimidin-4-yl)-4-[l,2,4]triazolo[4,3-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
495) 4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]Mazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
496) 4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]1riazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl]- bicyclo [2.2.2] octane- 1 -carboxylic acid;
497) 4-[4-(2-methyl-pyrimidin-4-yl)-5-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine-6-yl- 1 H-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
498) 4-[4-(2-methyl-pyrimidin-4-yl)-5-qumoxalin-6-yl-lH-imidazol-2-yl]-cyclohexanol, 499) 4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalirα-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol,
500) 4-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-2-methyl-pyrimidine,
500a) 6-[3-(2-metb.yl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
501) 6- [3-(2-trifluoromethyl-pyrimidin-4-yl)- lH-pyrazol-4-yl] -[ 1 ,2,4]triazolo [ 1 ,5-a]pyridine, 502) 6- [3 -(2-methyl-pyrimidin-4-yl)- 1 H-pyrazol- 4-yl] -quinoxaline,
502a) 6-[3-(2-trifluoromethyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-quinoxaline,
503) 6-[3-(2-cyclopropyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-quinoxaline,
504) 4-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-2-trifluorometliyl-pyrimidine,
505) 7- [3 -(2-trifluoromethyl-pyrimidin-4-yl)- 1 H-pyrazol-4-yl] -[1 ,2,4]triazolo [ 1 ,5 -a]pyridine, or
506) 6-[3-(2-Trifluoromethyl-pyrimidin-4-yl)-lH-pyi-azol-4-yl]-quinoline.
9. The method of claim 1 , wherein the inhibitor is administered locally.
10. The method of claim 1, wherein the inhibitor is administered via an implantable device.
11. "The method of "claim l"d',"wh'efeiή""the device is a delivery pump.
12. The method of claim 10, wherein the device is a stent.
13. A method of inhibiting vascular remodeling by administering to a subject in need thereof an inhibitor to TGFβ type I receptor orAlk4 .
14. The method of claim 13, wherein the inhibitor has the structure shown in formula I:
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein
R1"1 is aryl, heteroaryl, aralkyl, or heteroaralkyl; each R!"a is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkyl sulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
X1-1 is cycloalkyl or heterocycloalkyl;
Y1-1 is a bond, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(O)-N(Rb)-, -N(Rb)-C(O)-, -O-C(O)-N(Rb)-, -N(Rb)-C(O)-O-, -O-S(O)p-N(Rb)-, -N(Rb)- SCO)P-O-, -N(Rb)-C(O)-N(Rc)-, -N(Rb)-S(O)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb>C(O)-, -C(O)-N(Rb)-S(O)p-N(Rc)-, -C(O)-O-S(O)p-N(Rb)-, -N(Rb)-S(O)p-N(Rc)-C(O)-, -N(Rb)-S(O)p-O-C(O)-, -S(O)p-N(Rb)-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)P-, -O-, -S-, or -(C(Rb)(Rc))q-, wherein each of Rb and Rc is independently hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; p is 1 or 2; and q is 1-4;
R1"2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl; each of A*1"1 "and A'fΩj independently, is O, S, N, or NRb, provided that at least oxie of A 1"1 and A '"2 Is NT; and m is 0, 1, 2, or 3, and when m >2, two adjacent R'"a groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety.
15. The method of claim 13, wherein the inhibitor has the structure shown in formula II:
Figure imgf000119_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein each of Xn-1, Xn-2, Xn-3, and Xn-4 is independently CRX or N, provided that no more than two OfXn-1, IXn-2, Xπ-35 and X11-4 can be N simultaneously; each Of Yn-1 and Yn-2 is independently CRy or N, provided that at least one Of Yx1-1 and Y11-2 must be ISf; each R11"1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfπryl., alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsiαlfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; each R11"2 is independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2, - NΗ(alkyl), -N(alkyl)2, -NH(cycloalkyl), -N(alkyl)(cycloa]kyl), -NHCheterocycloalkyl), - NH(heteroaryl),
-NH-alkyl-heterocycloalkyl, -NH-alkyl-heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, cycloalkyl-alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)aUcoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulf anyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heferocycϊoaϊky^allc'yrsul'Faήyl1, h'eteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, arninosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkytyalkylcarbonylarnino., arylcarbonylamino, aralkylcarbonylamino, (heterocycloalky^carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, hetero aralkylcarbonylamino, alkoxycarbonylaminoalkylamino, (heteroaryl)arylcarbonylaminoalkylamino, heteroaralkylcarbonylaminoalkylamino, (heteroaryl)arylsulfonylaminoalk:ylcarbonylaminoalkylamino, arylsulfonylaminoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl; m is 0, 1, 2, 3, or 4, and when m >2, two adjacent R1 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; n is 0, 1, 2, or 3, and when n >2, two adjacent R2 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; and each of Rx and Ry is independently hydrogen, alkyl, alkenyl, allcynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cyclo alkyl) alkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cycloa-lkyl)alkylcarbonylamino, (cycloalkyT) alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, aralkylcarbonylamino, aralkylsulfonylamino, (heterocycloalkytycarbonylamino, (heterocycloalkyl)sulfonylamino, (heterocycloalky^alkylcarbonylamino, (heterocycloalky^alkylsulfonylamino, heteroarylcarbonylamino, hetero arylsulfonylamino, heteroaralkylcarbonylamino, heteroaralkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, (cycloalkyl)alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalkyl)alkyl, (heterocycloalky^allcoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl.
16. The method of claim 13, wherein the inhibitor has the structure shown in formula III
Figure imgf000121_0001
or a pharmaceutically acceptable salt or N-oxide thereof, wherein each OfXm-1, X111-2, X111-3, and Xm-4 is independently CRiπ"x or N, provided that only two of Xi11-], Xm-2, Xm-3, and Xm-4 can be N simultaneously; each OfYm-1 and Ym-2 is independently CRm"y or N, provided that at least one Of Y1n-1 and Ym-2 must be N; each R111"1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, allcylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfatrxide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; each R111"2 is independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -N(alkyl)(cyclocalkyl), -KHCheterocycloalkyl), -NH(heteroaryl), -NH-alkyl-heterocycloalkyl, -NH-alkyl-heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (lieterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl;, aminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalky^alkylcarfconylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkytycarbonylamino, (heterocycloalky^alkylcarbonylamino, heteroarylcarbonylamino, heterόara'lkylcarB'o'n^
(heteroaryl)arylcarbonylaminoalkylamino, heteroaralkylcarbonylaminoalkylamino, (heteroary^arylsulfonylaminoalkylcarbonylaminoalkylamino, arylsulfonylaminoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl; m is 0, 1, 2, 3, or 4, and when m ≥2, two adjacent R111"1 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; n is 0, 1, 2, or 3, and when n >2, two adjacent R111"2 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; arid each of Rm~x and Rm"y is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cyclo alkyl) alkylcarbonylamino, (cycloalkyl)alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, aralkylcarbonylamino, aralkylsulfonylamino, (heterocycloalkytycartoonylamino, (heterocycloalky^sulfonylamino, (heterocycloalky^alkylcarboiiylamino, (heterocycloalky^alkylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylanαino, heteroaralkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, (cycloalkyl)alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalkyl)alkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl; or a pharmaceutically acceptable salt or N-oxide thereof.
17. The method of claim 13, wherein the inhibitor has the structure shown in formula IV
Figure imgf000123_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein each RIV"a is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
RWA is a bond, alkylene, alkenylene, alkynylene, or -(CH2)rl-O-(CH2)r2-, where each of rl and r2 is independently 2 or 3;
Rw~2 is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, or a bond;
R^3 is -C(O)-, -C(O)O-, -OC(O)-, -C(O)-N(R1^)-, -N(R1^)-C(O)-, -0-C(O)-N(R^' b)-, -N(R1^)-C(O)-O-, -0-S(O)P-N(R^)-, -N(R1^)- S(0)p-0-, -N(RIV'b)-C(0)-N(RIV-c)-, -N(RIV"b)-S(0)p-N(RIV-b)-, -C(O)-N(R^)-S(O)P-, -S(OVN(R1^)-C(O)-, -S(OVN(R1^)-, -N(R1^)-S(OV, -N(R1^)-, -S(0)p-, -0-, -S-, or -(C(RIY"b)(Rrv"c))q-, or a bond; wherein each of R iv-b an^ ^TV-C -s independently hydrogen, hydroxy, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; wherein p is 1 or 2 and q is 1-4;
Rw~4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R™"5 is hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulfmyl, amino, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkylsulfinyl, heterocycloalkyl, heterocyclόali-bxy^Εeϊerocyclbalkylsiilfinyl, aryl, aryloxy, arylsulfinyl, heteroaryl, heteroaryloxy, or heteroarylsulfmyl;
Rw"6 is (1) a 5- to 6-membered heterocyclyl containing 1-3 hetero ring atoms selected from the group consisting of-O-, -S-, -N=, and -NR^-, wherein K1^'0 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl; said heterocyclyl being substituted with R17"6 and optionally substituted with one to two R17^; where R17"6 is oxo, thioxo, alkoxy, alkylsulfinyl, -NH2, -NH(unsubstituted alkyl), or -N(unsubstituted alkyl)2, and R1^ is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, hetero arylsulfanyl, or heteroaroyl; or
(2) a fused ring heteroaryl selected from the group consisting of:
Figure imgf000124_0001
wherein ring A is an aromatic ring containing 0-4 hetero ring atoms, and ring B is a 5- to 7- membered aromatic or nonaromatic ring containing 0-4 hetero ring atoms, provided that at least one of ring A and ring B contains one or more hetero ring atoms; ring A' is an aromatic ring containing 0-4 hetero ring atoms, and ring B' is a 5- to 7-membered saturated or unsaturated ring containing 0-4 hetero ring atoms, provided that at least one of ring A' and ring B' contains one or more hetero ring atoms; each hetero ring atom is -O-, -S-, -N=, or - NR1^s each X1 is independently N or C; each X2 is independently -O-, -S-, -N=, -NR17"6-, or -CHR17"11-; wherein Rw'g is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl; each of R17* and R™"1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cyc!oalfcyl,''cycl6affyTδxy,' cyclόalkyl'sulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; and n is 0-2; and m is 0-3, and when m >2, two adjacent R™"* groups can optionally join together to form a 4- to 8-memberecL optionally substituted cyclic moiety; provided that if R™"6 is 2-naphthyridinyl, 4-quinolinyl, imidazo[l,2-a]pyriciyl, or benzimidazolyl, then -R^'-R^-R^-R^ is not H, unsubstituted alkyl, -CH2-C(O)-N(H)-alkyl, -CH2-C(O)-N(alkyl)2, or benzyl.
18. The method of claim 13, wherein the inhibitor has the structure shown in fonnula V
Figure imgf000125_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein
Rv'! is heteroaryl; each Rv"a, independently, is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, tliioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylainino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfarnoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
Xv is cycloalkyl., heterocycloalkyl, aryl, heteroaryl, or a bond;
Yv is a bond, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(0)-N<Rb)-, -N(Rb)-C(0)-, -O-C(O)-N(Rb)-, -N(Rb)-C(0)-0-, -C(O)-N(Rb)-O-, -O-N(Rb)-C(O>)-, -O-S(O)p-N(Rb)-, -N(Rb> S(O)p-O-, -S(O)p-N(Rb)-O-, -O-N(Rb)-S(O)p-, -N(Rb)-C(O)-N(Rc)-, -N(Rb)-S(0)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb)-C(O)-, -C(0)-N(Rb)-S(O)p-N(Rc)-, -C(O)-O-S(O)p-N(RDK -N(Ri3)-S(0);^N(R.c)-C(O)-, -N(Rb)-S(O)p-O-C(O)-, -S(O)p-N(Rb)-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)p-, -O-, -S-, or -(C(Rb)(Re))q-, wherein each of Rb and Rc, independently, is hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; wherein p is L or 2 and q is 1-4;
Rv"2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl; each of Av"1 and Av~2, independently, is N or NRb; and m is 0, 1, 2, or 3, and when m >2, two adjacent Rv"a groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety, provided that if Xv is a bond, then Yv is a bond; R ,V-2 is hydro gen or alkyl; m is 1 , 2, or 3 ; and at least one R V- 'aa is substituted at the 2-pyrimidinyl position.
19. The method of claim 13, wherein the inhibitor has the structure shown in formula VI:
Figure imgf000126_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein each RVI"a, independently, is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, - NH2, -NH(unsubstituted alkyl), -N(unsubstituted alkyl)2, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, tieteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; "RVIJ1
Figure imgf000127_0001
aϊkenylene, alkynylene, or -(CH2)ri-O-(CH2)r2-, wherein each of rl and r2, independently, is 2 or 3;
RYI~2 is cycloalkylene, heterocycloalkylene, cycloalkenylene, heterocycloalkenylene, arylene, heteroarylene, or a bond;
RVI"3 is -C(O)-, -C(O)-O-, -0-C(O)-, -S(O)p-O-, -O-S(O)P-, -C(O)-N(Rb)-, -N(Rb)-C(0)-, -O-C(O)-N(Rb)-, -N(Rb)-C(0)-0-, -C(0)-N(Rb)-0-, -O-3^(Rb)-C(O)-3 -O-S(O)p-N(Rb)-,
-N(Rb)- S(O)p-O-, -S(O)p-N(Rb)-O-, -O-N(Rb)-S(O)p-, -N(Rb)-C(0)-N(Rc)-, -N(Rb)-S(0)p-N(Rc>, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb)-C(O)-, -C(O)-N(Rb)-S(O)p-N(Rc)-, -C(O)-O-S(O)p-N(Rb)-, -N(Rb)-S(0)p-N(Rc)-C(0)-, -N(Rb)-S(O)p-0-C(O)-, -S(O)p-N(Rb)-, -N(Rb)-S(0)p-, -N(Rb)-, -S(OV, -0"» -S-= -(C(Rb)(Rc))q-, or a bond; wherein each of Rb and Rc is independently hydrogen, hydroxy, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; wherein p is 1 or 2 and q is 1-4;
RVI"4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl) alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
RVI"5 is hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulfinyl, amino, alkenyl, alkynyl, cycloalkoxy, cycloalkylsulfinyl, heterocyclo alkoxy, heterocycloalkylsulfinyl, aryloxy, arylsulfinyl, heteroaryloxy, or heteroarylsulfinyl;
RVI"6 is a 5- to 6-membered monocyclic heterocyclyl or an 8- to 11-membered bicyclic heteroaryl; each being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; and m is 0-3 and when m ≥2, two adjacent RVI'a groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety.
20. The method of claim 13, wherein the inhibitor is
1) 4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)- lH-imidazol-2-yl)-piperidine- 1 - carboxylic acid benzyl ester; 2) 4-(4-BerizoiiV3ldioxol-5-yl-51-pyri3in-2-yl-lH-imidazol-2-yl) acid benzyl ester;
3) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-pipeτidine-l- carboxylic acid benzyl ester;
4) 3-[4-Beiαzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-pyrrolidine-l- carboxylic acid benzyl ester;
5) 2-(5-Benzo[ 1 J3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine; 6) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid benzyl ester;
7) 3-[4-Berαzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
8) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-pyrrolidine-l- carboxylic acid benzyl ester;
9) 2-(5-Benzo[l,3]dioxol-5-yl-2-piperidm-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine;
10) 2-[5 -B enzo [ 1 ,3] dioxol-5 -yl-2-( 1 -phenylmethanesulfonyl-piperidin-4-yl)-3 H-imidazol-4- yl] -6-metrryl-pyridine;
11 ) 2- [5 -B enzo [1,3] dioxol-5 -yl-2-( 1 -phenylmethanesulfonyl-piperidin-4-yl)-3 H-imidazol-4- yl]-pyridine;
12) 2-[5 -B enzo [1,3] dioxol-5-yl-2-( 1 -methanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
13) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]-6- methyl-pyridine ;
14) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 2-chloro-benzyl ester;
15) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 2,4-dichloro-benzylamide;
16) l-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-L -yl]- ethanone;
17) 2-[5-B enzo[ 1 ,3]dioxol-5-yl-2-(l -furan-2-yl-methyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
18) {4-[4-Ηenzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-cyclohexyl} - carbamic acid benzyl ester;
19) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl] cyclohexylamine; 20) N-'{4-[4-Benzo[i,3]dioxol-5-yl-5-(6-methyl-pyridm-2-yl)-lH-imidazol-2-yl]- cyclohexyl}-C-phenyl-methanesulfonamide;
21) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
22) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
23) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester;
24) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-ethyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
25) 2-(5-Benzo[l,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine;
26) 4-(4-Benzo[ 1 ,3] dioxol-5 -yl-5 -pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid 4-nitro-benzyl ester;
27) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4,5-dimethoxy-2-nitro-~benzyl ester;
28) 4-(4-Benzo [ 1 ,3] dioxol-5 -yl-5 -pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid 3-fluoro-benzylamide;
29) 4-(4-Benzo[ 1 ,3] dioxol-5 -yl-5 -pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid 4-fluoro-benzylamide;
30) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid benzylamide;
31) 2-{5-Benzo[l)3]dioxol-5-yl-2-[l-(toluene-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4-yl}- pyridine;
32) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-methyl-benzylamide;
33) 4-(4-Benzo [ 1 ,3] dioxol- 5 -yl-5 -pyridin-2-yl- lH-imidazol-2-yl)-piperidine- 1 -carboxylic acid 4-methoxy-benzylamid.e;
34) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 2-chloro-benzylamide;
35) 4-[4-(4-Benzo[l,3]diox:ol-5-yl-5-pyridin-2-yHH-imidazol-2-yl)-piperidine-l-sulfonyl]- benzoic acid;
36) 4-(4-Benzo[ 1 ,3]dioxol- 5-yl-5-pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid amide; 37) 4-[4-(4-Benzo[l,3]dioxiol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidme-l-sulfonyl]- benzonitrile; 38) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloτo-benzenesulfonyl)-ρiperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
39) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
40) {5-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- naphthalen- 1 -yl} -dimethyl-amine;
41) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-4-yl-methyl)-piperidin-4-yl)]-3H-imidazol-4- yl} -pyridine;
42) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
43) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-methoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
44) l-{4-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l- sulfonyl]-phenyl}-ethanone;
45) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-mettiyl-benzyl)-ρiperidm-4-yl]-3H-imidazol-4-yl}- pyridine;
46) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3-fluoro-5-trifluoromethyl-benzyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
47) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-cyclohexylmethyl-piperidm-4-yl)-3H-imidazol-4-yl]- pyridine;
48) 2-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-l-ylmethyl]- cyclopropanecarboxylic acid ethyl ester;
49) 2-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-l-ylmethyl]- pyrrolidine- 1-carboxylic acid tert-butyl ester;
50) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(2,2-dirnethyl-[ 1 ,3]dioxolan-4-ylmethyl)-piperidin-4- yl] -3H-imidazol-4-yl} -pyridine;
51) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-ethanes-ulfonyl-piρeridin-4-yl)-3H-imidazol-4-yl]- pyridine;
52) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(butane- 1 -sulfonyl)-piρeridin-4-yl]-3H-imidazol-4-yl} - pyridine;
53) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
54) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-pherxyl-ethenesulfonyl)-piperidin-4-yl]-3H-imidazol-
4-yl} -pyridine; 55) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-l-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
56) l-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l- sulfonylmethyl]-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one;
57) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
58) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-dichloro-phenylmethanesulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl} -pyridine;
59) 2- { 5 -Benzo[ 1 ,3] dioxol-5 -yl-2-[ 1 -(4-fluoro-phenylmethanesulfbnyl)-piperidin-4-yl] -3H- imidazol-4-yl} -pyridine;
60) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(3,4-dichloro-phenylmethanesulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl} -pyridine;
61) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-3H-imidazol-
4-yl} -pyridine;
62) 2-[5 -Benzo[l,3]dioxol-5-yl-2-(l-p-tolylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -pyridine;
63) 3-(4-Benzo[ 1 ,3]dioxol-5-yl- 1 -hydroxy-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidine- 1 - carboxylic acid benzyl ester;
64) 3-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid benzyl ester;
65) 4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1 -carboxylic acid benzyl ester;
66) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(pyridin-2-yl-methanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
67) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-naphthalen-l-yl-ethanesulfonyl)-piperidin-4-yl]-3H- imidazo 1-4-yl} -pyridine;
68) 2-[5 -Benzo[l ,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-3-yl)-3H-imidazol-4- yl] -pyridine;
69) 3-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-metliyl-pyridin-2-yl)-lH-iniidazol-2-yl]- piperidine-1 -carboxylic acid benzyl ester;
70) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(pyridin-4-yl-methanesulfonyl)-piperidin-4-yl]-3H- imidazo 1-4-yl} -pyridine;
71) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(pyridin-3-yl-methanesulfonyl)-piperidin-4-yl]-3H- imidazo 1-4-yl} -pyridine; 72) 2-{5-Benzotr'3']ϊϊoxoϊ:'S-yl-'2-[l-(3-trifluoromethyl-phenylmethan yl]-3H-imidazol-4-yl} -pyridine;
73) 3-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- pyrrolidine- 1-carboxylic acid benzyl ester;
74) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-trifluoromethyl-phenylmethanesulfonyl)-piperidin-4- yl] -3H-imidazol-4-yl} -pyridine;
75) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-bis-trifluoromethyl-phenylmethanesulfonyl)- piperidin-4-yl]-3H-imidazol-4-yl} -pyridine;
76) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l -(biphenyl-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
77) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-difluoro-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -pyridine;
78) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-2-yl-methanesulfonyl)-ρiperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
79) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
80) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(biphenyl-4-ylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
81) 4-[5-Benzo[l,3]dioxol-5-yl-l-methyl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine- 1-carboxylic acid benzyl ester;
82) 4-[4-Benzo[l,3]dioxol-5-yl-l-methyl-5-(6-methyl-ρyridin-2-yl)-lH-iniidazol-2-yl]- piperidine- 1-carboxylic acid benzyl ester;
83) {4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexyl}-carbamic acid benzyl ester;
84) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(3-phenoxy-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl}-6-methyl-pyridine;
85) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-ethanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
86) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-l-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
87) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(butane-l-sulfonyl)-piperidin-4-yl]-3H-imidazol-4-yl}- 6-methyl-pyridine;
88) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l -(pyridin-3-ylmethanesulfonyl)-ρiperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine; 89) 2-{5-Benzo[L3]'^^ imidazol-4-yl} -6-methyl-pyridine;
90) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-difluoro-phenylmethanesulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
91) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(3-trifluoromethyl-phenylmethanesulfonyl)-piperidin-4- yl] -3H-imidazol-4-yl} -6-methyl-pyridine;
92) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(thiophene-2-sulforiyl)-piperidm-4-yl]-3H-irnidazol-4- yl} -6-methyl-pyridine;
93) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(butane-l-sulfonyl)-piperidin-3-yl]-3H-imidazol-4-yl}-
6-methyl-pyridine;
94) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-3-yl)-3H-imidazol-4- yl] -6-methyl-pyridine;
95) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(l-methyl-lH-imidazole-4-sulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
96) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(5-methyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
97) 4-[5-Benzo[l,3]dioxol-5-yl-l-hydroxy-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
98) Butane- 1 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexyl} -amide;
99) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-iniidazol-2-yl]- cyclohexyl}-C-pyridin-2-yl-methanesulfonamide;
100) Thiophene-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexyl}-amide;
101) 1 -Methyl- lH-imidazole-4-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl- pyridin-2-yl)-lH-imidazol-2-yl]-cyclohexyl}-amide;
102) 4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
103) 4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
104) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-bromo-pyridin-2-y"l)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
105) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(thiophene-3-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine; 106) 2-'{5-Benzorø]dϊrø piperidin-4-yl]-3H-imidazol-4-yl}-6-methyl-pyridine;
107) 4-[2-(l-phenylmethanesulfonyl-piperidin-4-yl)-5-(6-methyl-pyridin-2-yl)-lH-imidazol-
4-yl]-pyridin-2-yl-fluoride;
108) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-trifluoromethyl-pyridin-2-yl)- lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
109) 4- [ 5 -B enzo [1,3] dioxol-5 -yl-4-(6-bromo-pyridin-2-yl)- 1 -hydroxy- 1 H-imidazol-2-yl] - piperidine-1-carboxylic acid benzyl ester;
110) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -6-bromo-pyridine;
111) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2]oct-l -yl} -methanol;
112) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
113) 4- [4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-2H-imidazol-2-yl]-piperidine- 1 - sulfonic acid dimethylamide;
114) 1- {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-irnidazol-2-yl]-piperidin- l-yl}-3-phenyl-propan-l-one;
115) 2- {5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-2-sulfonyl)-piperidiii-4-yl]-3H-imidazol-4- yl}-6-methyl-pyridine; 116) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imi(lazol-2-yl]- bicyclo [2.2.2]octane-l -carbonitrile;
117) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imi(lazol-2-yl]- bicyclo[2.2.2]oct-l-ylamine;
118) N- {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-iinidazol-2-yl]- bicyclo [2.2.2] oct- 1 -yl} -C-phenyl-methanesulfonamide;
119) N- {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] oct- 1 -yl} -methanesulfonamide;
120) N- {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2]oct- 1-yl} -C-pyridin-2-yl-methanesulfonamide;
121) 2- {5-Benzo[l,3]dioxol-5-yl-2-[4-(lH-tetrazol-5-yl)-bicyclo[2.2.2]oct-l-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
122) N- {4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetamide; 123) Thiophene-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
124) l-Methyl-lH-imidazole-4-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl- pyridin-2-yl)-lH-imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
125) Thiophene-3 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
126) 2- {5-Benzo[ 1 ,3]dioxo l-5-yl-2-[ 1 -(2-phenyl-ethenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl}-6-methyl-pyridine;
127) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(2-ρhenyl-ethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
128) Methanesulfonic acid 4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl] -bicyclo[2.2.2] oct- 1 -ylmethyl ester;
129) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetonitrile;
130) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetic acid;
131) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l -ylmethyl} -methanesulfonamide;
132) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(biphenyl-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
133) 2-{5 -Benzo [1,3] dioxo 1-5 -yl-2- [ 1 -(4-phenoxy-benzenesulfonyl)-piperidin-4-yl] -3H- imidazol-4-yl} -6-methyl-pyridine;
134) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(3,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
135) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct- 1 -ylmethyl} -C-phenyl-methanesulfonamide; 136) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l -ylmethyl} -C-pyridin-2-yl-methanesulfonamide; 137) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid benzylamide;
138) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (pyridin-2-ylmethyl)-amide; 139) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid 3-chloro-4-fluoro-benzylamide; 140) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6'-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (furan-2-ylmethyl)-amide;
141) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfonyl-pyrrolidin-3-yl)-3H-imidazol-4-yl]-6- methyl-pyridine ;
142) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(butane- l-sulfonyl)-pyrrolidin-3-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
143) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(l-methyl-lH-imidazole-4-sulfonyl)-pyrrolidm-3-yl]- 3H-imidazol-4-yl} -6-methyl-pyridine;
144) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylnxethanesulfonyl-pyrrolidin-3-yl)-3H-imidazol- 4-yl] -6-methyl-pyridine;
145) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(4-chloro-benzenesulfonyl)-pyrrolidin-3-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
146) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
147) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-naphtlialen-2-yl-ethanesulfonyl)-piperidm-4-yl]- 3H-imidazol-4-yl}-6-methyl-pyridine;
148) l-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine- l-sulfonylmethyl}-7,7-dimethyl-bicyclo[2.2.1]lieptan-2-one;
149) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
150) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methylamide;
151) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid ethylamide;
152) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid butylamide;
153) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid isopropylamide; 154) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (3-imidazol-l-yl-propyl)-amide; 155) 2-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine- 1 -sulfonylmethyl} -phenylamine;
156) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (l-methyl-5-methylsulfanyl-lH-[l,2,4]triazol-3-yl)- amide; 157) 4-[4-Benzo["ϊ ,3]dioxol-5-yr-5-(d':methyl-pyridin-2-yl)- lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid cyclohexylamide;
158) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct- 1 -yl} -pyrrolidin- 1 -yl-methanone;
159) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid dimethylamide;
160) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid diethylamide;
161) 4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-meth.yl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid dipropylamide;
162) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lEi-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid (5,7-difluoro-benzothiazol-2-yl)-arnide; 163) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid benzothiazol-2-ylamide; 164) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lEi-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (lH-benzoimidazol-2-yl)-amide; 165) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (2-hydroxy-l-methyl-2-phenyl-ethyl)-amide; 166) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid (pyridin-4-ylmethyl)-amide;
167) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin-l- yl } -(3 -chloro-phenyl)-methanone;
168) {4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)- 1 H-imidazol-2-yl]-piperidin- 1 - yl} -(4-fluoro-phenyl)-methanone;
169) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin-l- yl}-(4-methoxy-ρhenyl)-methanone;
170) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-cyclopropyl-pyridin-2-^l)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid;
171) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;
172) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
173) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmetliyl}-carbamic acid benzyl ester; 174) 4'-[4-Benzo[l,'3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydrazide;
175) N- {4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl} -acetamide;
176) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethylj-methanesmfonarnide;
177) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmemylj-C-phenyl-rnethanesulfonamide;
178) Butane- 1 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl] -cyclohexylmethyl} -amide;
179) Propane-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexylmethyl}-amide;
180) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohex:ylmethyl}-C-pyridin-2-yl-methanesulfonamide;
181)N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohex:ylmethyl}-C-pyridm-4-yl-methanesulfonamide;
182) (4-Methoxy-benzyl)- {4-[5-(6-methyl-pyridin-2-yl)-2-(l -phenylmethanesulfonyl- piperidin-4-yl)-lH-imidazol-4-yl]-pyridin-2-yl} -amine;
183) 4-[5-(6-Methyl-pyridin-2-yl)-4-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
184) 4-[5-(6-Methyl-pyridin-2-yl)-4-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
185) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
186) 4-[4-(6-Methyl-pyridin-2-yl)-5-[l52,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
187) 4-[4-(6-Methyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
188) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl- lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
189) N- -(4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridm-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;
190) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol; 191) 4-[4-(6-Cyclopropyl-pyridiix-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carbox:ylic acid amide;
192) 4-[4-(6-Cyclopropyl-pyridirL-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carbox:ylic acid hydroxyamide;
193) N-{4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct- 1 -yl} -sulfamide;
194) Sulfamic acid 4-[4-benzo[1.3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl ester;
195) {4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl} - carbamic acid benzyl ester;
196) N- {4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carbonyl} -methanesulfonamide;
197) N- {4-[4-Benzo[ 1 ,3]dioxol-5 -yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonyl} -benzenesulfonamide;
198) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester; 199) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
200) N-{4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl}- acetamide;
201) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane- 1-carboxylic acid methyl ester;
202) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane- 1-carboxylic acid;
203) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane- 1-carboxylic acid hydroxyamide;
204) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane- 1-carboxylic acid amide;
205) N-{4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl}- methanesulfonamide;
206) 2,2,2-Triiluoro-N-{4-[4-(6-inethyl-ρyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- cyclohexyl} -acetamide;
207) 4-[4-(5-Fluoro-6-methyl-pyτidin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol- 2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester; 208) {4-[2- [ 1 -(Butane- 1 -sύ"Iϊohyl)-pip"eridin-4-yl]-5 -(6-methyl-pyridin-2-yl)- 1 H-imidazol-4- yl]-pyridin-2-yl}-(4-methoxy-benzyl)-amine;
209) 4-[2-[l-(Butane-l-sulfonyl)-piperidin-4-yl]-5-(6-methyl-pyridin-2-yl)-lH-imidazol-4- yl] -pyridin-2-ylamine;
210) 2-[5-Benzo[l ,3]dioxol-5-yl-2-(l -phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl]-6-ethyl-pyridine;
211) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
212) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
213) N- {4- [5-(6-Methyl-pyridin-2-yl)-4-quinoxalin-6-yl- 1 H-imidazol-2-yl] - bicyclo[2.2.2]oct-l-yl}-methanesulfonamide;
214) N-{4-[5-(6-Methyl-pyridin-2-yl)-4-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetamide.
215) 4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-pyrimidin-2-ylamine;
216) 4-(2-pyridin-2-yl-pyrazolo[l,5-a]pyridin-3-yl)-pyrimidin-2-ylamme;
217) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-pyrimidin-2-ylamme;
218) 2-(6-methyl-pyridin-2-yl)-3-(2-methylsulfaxiyl-pyrimidin-4-yl)-pyrazolo[l,5-a]pyridine;
219) 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine;
220) 2-(6-methyl-pyridin-2-yl)-3-(2-moφholin-4-yl-pyrimidm-4-yl)-pyrazolo[l,5- c]pyrimidine;
221) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyrazin-3-yl]-pyrimidin-2-ylamine;
222) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[ 1 ,5-a]pyrimidin-3-yl]-pyrimidin-2-ylamine;
223) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine;
224) (2-Methoxy-ethyl)- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
225) (3- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-ρyrimidin-2-ylamino} - propyl)-carbamic acid tert-butyl ester;
226) (3-Imidazol-l-yl-propyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
227) (4-Methoxy-benzyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
228) [2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridin- 6-yl]-methanol; 229) 3-(2-Methanesulfonyl-^ a]pyridine;
230) (4-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}- butyl)-carbamic acid tert-butyl ester;
231) (4-Amino-benzyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]- pyrimidin-2-yl} -amine;
232) (5- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} - pentyl)-carbamic acid tert-butyl ester;
233) [3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-6-yl]- methanol;
234) [3-(2-ammo-pyrimidin-4-yl)-2-(6-metriyl-pyridm-2-yl)-imidazo[l,2-a]pyridin-7-yl]- methanol;
235) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(2-moipholin-4-yl-ethyl)-amine;
236) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(2-pyridin-2-yl-ethyl)-amine;
237) [3-(2-Amino-pyrimidin-4-yl)-6-metriyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(2-pyridin-3-yl-ethyl)- amine;
238) [3 -(2-methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2- a]pyridm-6-yl]-methanol;
239) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(2-pyridin-4-yl-ethyl)-amine;
240) [3-(2-Amino-pyrimidin-4-yl)-6-metliyl-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridin-8-yl]-(3-morpholin-4-yl-propyl)-amine;
241) [3 -(4-Methyl-piperazin- 1 -yl)-propyl] - {4- [2-(6-methyl-pyridin-2 -yl)-imidazo [1,2- a]pyridin-3-yl]-pyrimidin-2-yl}-amine;
244) [3-(4-Methyl-piperidm-l-yl)-propyl]-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-3-yl]-pyrimidin-2-yl}-amine;
245) [4-(2-Pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-pyrimidin-2-yl]-pyridin-3-ylmetriyl- amine;
246) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrirnidin-2-yl}-((R)-l- phenyl-ethyl)-amine;
247) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrirnidin-2-yl}-((S)-l- phenyl-ethyl)-amine; 248) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} -(1H- tetrazol-5-yl)-amine;
249) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2H- pyrazol-3 -yl)-amine;
250) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2- moφholin-4-yl-ethyl)-amine;
251) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2-pyriciin- 2-yl-ethyl)-amine;
252) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2-pyrid.in- 3 -yl-ethyl)-amine;
253) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2-pyridin- 4-yl-ethyl)-amine;
254) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(3- moφholin-4-yl-propyl)-amine;
255) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(3- piperidin- 1 -yl-propyl)-amine;
256) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidm-2-yl}- [1,3 ,4]thiadiazol-2-yl-amine;
257) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyτiciine;
258) 2-(6-Methyl-pyridin-2-yl)-3-(2-meth.ylsulfanyl-pyrimidm-4-yl)-iniidazo[l,2-a]pyrid.ine- 6-carboxylic acid methyl ester;
259) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-iinidazo[l,2-a]pyriciine- 7-carboxylic acid ethyl ester;
260) 2-(6-Methyl-pyridin-2-yl)-3-(2-metriylsulfanyl-pyrirnidin-4-yl)-irriidazo[l,2- a]pyrimidin-7-ylamme;
261) {7,7-Dimethyl-8-[5-(4-{4-[2-(6-methyl-ρyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamino} -butylcarbamoyl)-p entyl]-2-oxo-4-trifluoromethyl-7,8-dihydro-2H[- 1 - oxa-8-aza-anthracen-5 -yl} -methanesulfonic acid;
262) 2-(2,7-Difluoro-6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)-3,5,6-trifluoro-4-[(4-
{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}- butylcarbamoyl)-methylsulfanyl] -benzoic acid;
263) -(6-Methyl-pyridiri-2-yl)-3-(2-morpholin-4-yl-pyrirnidin-4-yl)-irnidazo[ 1 ,2-a]pyridine;
264) 2-(6-Methyl-pyridin-2-yl)-3-(2-piperidin-l-yl-pyrimidiri-4-yl)-irnidazo[l,2-a]pyridάne;
265) 2-(6-Methyl-pyridin-2-yl)-3 -(2-pyrrolidin- 1 -yl-pyrimidin-4-yl)-imidazo [ 1 ,2-a]pyridine; 266) 2-(6-Methyl-ρyridin-2-yl)-3-[2-(l H-tetrazol-5-yl)-ρyrimidin-4-yl]-imidazo[ 1 ,2- a]pyridine;
267) 2-(6-Methyl-pyridin-2-yl)-3 -pyrimidin-4-yl-imidazo[ 1 ,2-a]pyridine; 268) 2-(6-Methyl-pyridin-2-yl)-3-pyrimidin-4-yl-imidazo[l,2-a]pyrimidin-7-ylamine; 269) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-8- ylamine;
270) 3-(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carbonitrile;
271) 3-(2-Amino-pyrimidin-4-yl)-2-(6-metliyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid;
272) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l52-a]pyridine-6- carboxylic acid ([l,4]dioxan-2-ylmethyl)-aniide;
273) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
274) 3 -(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid (2-dimethylamino-ethyl)-amide;
275) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid (2-methoxy-ethyl)-amide;
276) 3 -(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridine-6- carboxylic acid (2-thioplien-2-yl-ethyl)-amide;
277) 3-(2-Amino-pyrimidin-4-yl)-2-(6-niethyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid [3-(4-methyl-piperazin-l-yl)-propyl]-amide;
278) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid amide;
279) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid cyclopropylamide;
280) 3-(2-Amino-pyrirnidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid ethylamide;
281) 3-(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridirie-6- carboxylic acid hydroxyamide;
282) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid methoxy-amide;
283) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-irriidazo[l,2-a]pyridine-6- carboxylic acid methyl ester; 284) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid;
285) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
286) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-amino-ethyl)-amide;
287) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-dimethylamino-ethyl)-amide;
288) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2- a]pyridine-7- carboxylic acid (2-hydroxy-ethyl)-amide;
289) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2- a]pyridine-7- carboxylic acid (2-oxo-2-pyridin-3-yl-ethyl)-amide;
290) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridine-7- carboxylic acid (2-thiophen-2-yl-ethyl)-amide;
291) 3-(2-Amino-pyrimidin-4-yl)-2-(6-metriyl-pyridin-2-yl)-irαidazo[l ,2- a]pyridine-7- carboxylic acid (piperidin-3-ylmethyl)-amide;
292) 3-(2-Amino-pyrimidin-4-yl)-2-(6-metliyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridine-7- carboxylic acid 2,2-dimethylhydrazide;
293) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridine-7- carboxylic acid amide;
294) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2- a]pyridine-7- carboxylic acid cyclopropylamide;
295) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[ 1 ,2- a]pyridine-7- carboxylic acid ethyl ester;
296) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid ethylamide;
297) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid hydroxyamide;
298) 3-(2-Arnino-pyriniidin-4-yl)-2-(6-methyl-pyridm-2-yl)-irnidazo[l,2-a]pyridirie-7- carboxylic acid methoxy-amide;
299) 3-(2-Amino-pyrimidin-4-yl)-2-(6-metriyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyrimidin-7- ylamine;
300) 3-(2-Azetidin-l-yl-pyrimidin-4-yl)-2-(6-rnethyl-pyridin-2-yl)-imida2o[l,2-a]pyridine; 301) 3-(2-Methanesulfonyl-pyrirnidin-4-yl)-2-(6-methyl-pyridin-2-yl)-inxidazo[l,2-a] pyridine-7-carboxylic acid ethyl ester; 302) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridine-6-carboxylic acid methyl ester;
303) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-7-rnethyl-2-(6-methyl-pyridin-2-yl)-iinidazo[l,Z- a] pyridine;
304) 3-(2-Methanesulfonyl-p3θimidin-4-yl)-8-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a] pyridine;
305) 3,3-Dimethyl-N-[2-(6-inethyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)- imidazo[l,2-a]pyrimidin-7-yl]-butyr amide;
306) 3-(2-Methanesulfonyl-pyriniidin-4-yl)-2-(6-niethyl-pyridin-2-yl)-imidazo[l,2- a]pyridine-6-carbonitrile;
307) 3-(2-Methylsulfanyl-pyrimidin-4-yl)-2-pyridin-2-yl-imidazo[l,2-a]pyridine;
308) 3,6-Dichloro-N-(4- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]- pyrimidin-2-ylamino}-butyl)-2-(2,4,5,7-Tetracliloro-6-hydroxy-3-oxo-9,9a-dihydro-3H- xanthen-9-yl)-terephthalamic acid;
309) 3-[2-(2-Methyl-aziridin-l-yl)-pyrimidin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a_] pyridine;
310) 3-[2-(4-Methyl-piperazin- 1 -yl)-pyrimidin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a] pyridine;
311) 3-{[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carbonyl]-amino} -propionic acid methyl ester;
312) 3-{[3-(2-Amino-pyrimi<im-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridine-7- carbonyl]-amino} -propionic acid methyl ester;
313) 3- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} - phenol;
314) 4-(2- {4-[2-(6-Methyl-p3rridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} - ethyl)-benzenesulfonamide;
315) 4-(2-Pyridin-2-yl-imidazo[l ,2-a]pyridin-3-yl)-pyrimidin-2-ylamine; 316) 4-[2-(6-Chloro-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamine;
317) 4-[2-(6-Methyl-pyridin-2-yl)-7-trifluoromethyl-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin— 2-yl- amine;
318) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamine;
319) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidine-2-carbonitrile;
320) 4-[2-(6-Methyl-pyridin.-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidine-2-carboxylic acid amide; 32Ϊ) 4-[6-Bromo-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
322) 4-[6-Chloro-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
323) 4-[6-Fluoro-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
324) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-morpholin-4-yl-etliylamino)-imidazo[l,2-a] pyridin-3 -yl] -pyrimidin-2-ol;
325) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-2-yl-ethylamino)-imidazo[l,2-a] pyridin-3-yl]-pyrimidin-2-ol;
326) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-3-yl-ethylamino)-imidazo[l,2-a] pyridin-3-yl]-pyrimidin-2-ol;
327) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-4-yl-ethylamino)-imidazo[ 1 ,2-a] pyridin-3 -yl] -pyrimidin-2-ol;
328) 4-[6-Methyl-2-(6-methyl-pyridm-2-yl)-8-morpholin-4-yl-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ol;
329) 4-[6-Methyl-2-(6-metriyl-pyridin-2-yl)-8-morpholm-4-yl-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamine;
330) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
331) 4-[7-Aminomethyl-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2- yl-amine;
332) 4-[7-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl] -pyrimidin-2- ylamine;
333) 4-[8-Benzyloxy-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ol; 334) 4-[8-Benzyloxy-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl- amine;
335) 4-[8-Bromo-6-methyl-2-(6-methyl-pyridin-2-yl)-imidaz;o[l,2-a]pyridin-3-yl]-pyrimidin- 2-ol;
336) 4-[8-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]p3τidin-3-yl]-pyrimidin-2- ylamine;
337) 6-Chloro-3-(2-methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a] pyridine;
338) 5-Dimethylamino-naphthalene-l -sulfonic acid (4-{4-[2-(6-methyl-pyridin-2-yl)- imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} -butyl)-amide; 339) 6-(2J-Difluoro-6-hydroxy-3-oxo-3H-xanthen-9-yl)-N-(4-{4-[2-(6-rnetliyl-ρyridm-2-yl)- imidazo[l,2-a]pyridin-3-yl]-pyrimidm-2-ylamino}-butyl)-isophthalamic acid;
340) 6-Ammo-9-[2-carboxy-5-(4-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[ l,2-a]ρyridin-3-yl]- pyrimidin-2-ylamino}-butylcarbamoyl)-phenyl]-xanthen-3-ylidene-ammonium;
341) 6-Bromo-2-(6-methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a] pyridine;
342) 6-Fluoro-2-(6-methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-'4-yl)-imidazo[l,2-a] pyridine;
343) 7-Amino-4-methyl-3-[(4-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylammo}-butylcarbamoyl)-metliyl]-2-oxo-2H-chromene-6-sτilfoiiic acid;
344) Cyclobutyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-yl} - amine;
345) Cyclopentyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3 -yl]-pyrimidin-2- yl} -amine;
346) Cyclopropyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3 -yl]-pyrimidin-2- yl} -amine;
347) Cyclopropyl-methyl-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
348) Dimethyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-yl} - amine;
349) Isopropyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-yl} - amine;
350) Methyl-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- amine;
350a) N-(2- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-p3rrimidin-2- ylamino} -ethyl)-acetamide;
351) N-(4- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyτimidin.-2-ylamino} - butyl)-acetamide;
352) N,N-Dimethyl-Nl-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-
2-yl} -ethane-1 ,2-diamine;
353) N-[2-(6-Metliyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a] pyrimidin-7-yl]-3-pyridin-3-yl-propionamide;
354) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a] pyrimidin-7-yl] -nicotinamide; 355) N-i2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidm-4-yl)-imidazo[l,2-a] pyrimidin-7-yl] -propionamide;
356) N-[3-(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-iinidazo[l,2-a]pyridine-6- carbonylj-methanesulfonamide;
357) N- [3 -(2- Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iinidazo [ 1 ,2-a]pyridine-7- carbonyl] -methanesulfonamide;
358) N-[3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyrimidin-7- yl]-2-(3-methoxy-phenyl)-acetamide;
359) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyrimidin-7- yl] -3 ,3 -dimethyl-butyr amide;
360) N-[3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iinidazo[l,2-a]pyrimidin-7- yl] -3 -pyridin-3 -yl-propionamide;
361 ) N-[3 -(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iτnidazo [ 1 ,2-a]pyrimidin-7- yl]-acetamide;
362) N-[3 -(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyrimidin-7- yl] -nicotinamide;
363) N- [3 -(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a] pyrimidin-7 -yl] -2-(3 -methoxy-ρhenyl)-acetamide;
364) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyri.din-2-yl)-imidazo[l,2-a] pyrimidin-7-yl]-3,3-dimethyl-butyramide;
365) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridiii-2-yl)-imidazo[l,2-a] pyrimidin-7-yl]-3-pyridin-3-yl-propionamide;
366) N-[3-(2-Methanesulfonyl-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyrimidin-7 -yl] -nicotinamide;
367) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl] -propionamide;
368) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyrimidin-7- yl] -propionamide;
369) N-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- acetamide;
370) Nl - {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3 -yl]-pyrimidin-2-yl} -butane-
1 ,4-diamine;
371) Nl-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- propane- 1 ,3-diamine; 372) N-(4- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} - butyl)-(BODIPY FL) amide; and
373) N-(4- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} - butyl)-(Texas Red-X) amide
374) N-[3-(2-ammo-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyrimidin-7- yl]-acetamide;
375) N- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} - acetamide.
376) 3-(3-pyridin-2-yl-4-qumolin-4-yl-pyrazol-l-yl)-propylamine,
377) N- [3 -(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol- 1 -yl)-propyl] -acetamide,
378) N-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-metlianesulfonamide,
379) dimethyl-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-amine,
380) 4-{3-pyridin-2-yl-l-[2-(lH-tetrazol-5-yl)-ethyl]-lH-pyrazol-4-yl}-quinoline,
381) 4-[3-pyridin-2-yl-l-(3-pyrrolidin-l-yl-propyl)-lH-pyrazol-4-yl]-quinoline,
382) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyridin-2-ylamine,
383) 2,4-dimethoxy-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyrimidine,
384) 3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propionic acid, 385) 5 -(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)- 1 H-indole, 386) 2-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-lH-pyrazol-3-yl]-pyridine, 387) N-hydroxy-3-(3-pyridm-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propionamide, 388) 2-(3 -pyridin-2-yl-4-quinolin-4-yl-pyrazol- 1 -yl)-ethylamine, 389) N-[2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-ethyl]-metlianesulfonamide, 390) 2-metliyl-4-methylsulfanyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyrimidine, 391) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-pyridine,
392) 2-[4-(2,3-dihydro-benzofuran-5-yl)-lH-pyrazol-3-yl]-pyridine,
393) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[d]isoxazole,
394) 3-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-proρionitrile, 395) N-{3-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-propyl}- methanesulfonamide,
396) 2-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-lH-pyrazol-3-yl]-6-methyl-pyridine, 397) [4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-acetonitrile, 398) N-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethyl}- methanesulfonamide,
399) 4-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-2-methylsulfanyl-pyrimidine,
400) 4-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-2H-phthalazin- 1 -one, 401) l-[5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-2,3-dihydro-indol-l-yl]-ethanone,
402) 6-(3-pyridin-2-yl- 1 H-pyrazol-4-yl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine, 403) 3-methyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one, 404) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-4H-benzo[l,4]oxazin-3-one, 405) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinoxaline,
406) 3-(4-nitro-benzyl)-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
407) 5-methyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyridine,
408) 4-methyl-7-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3,4-dihydro-lH-benzo[e][l,4]diazepine-
2,5-dione,
409) 2,3-dimethyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
410) 6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
41 Oa) 1 -rriethoxy-4-(3-pyridin~2-yl-lH-pyrazol-4-yl)-isoquinoline,
411) 2-methyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]ρyridine,
41 Ia) 4-(3-pyridin-2-yl-lH-pyrazol-4-yl)-2H-isoquinolin-l-one,
412) 2-(4-benzo[ 1 ,3] dioxol-5 -yl- 1 H-pyrazol-3 -yl)-6-trifluoromethyl-pyridine,
412a) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-vinyl-pyridine,
413) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-propenyl-pyridine,
414) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-ethyl-pyridine,
415) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-propyl-pyridine,
416) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-cyclopropyl-pyridine,
417) l-[6-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-pyridin-2-yl]-ethanol,
418) 4-methoxy-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline,
419) 6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-quinoline,
420) 6-(3 -pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin-4-ylamine, 421) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
422) 7-(3 -pyridin-2-yl-lH-pyrazol-4-yl)-pyrido[l,2-a]pyrimidin-4-one, 423) 6-[3-(6-cyclopropyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine, 424) 3-methyl-6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3H-quinazolin-4-one, 425) 4-(2-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethoxy}- ethoxy)-bicyclo[2.2.2]octane- 1 -carboxylic acid,
426) 4-(2-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethoxy} - ethoxy)-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester, 427) 4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester,
428) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-isopropyl-pyridine, 429) 2-(4-benzo[ 1 ,3]dioxol-5-yl-5-trifluoromethyl-lH-pyrazol-3-yl)-6-bromo-pyridine, 430) 6-[3-(5-fluoro-6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridirLe,
431) 6-[3-(6-trifluoromethyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l ,2,4]triazolo[l ,5-a]pyridine,
432) 6-[3-(6-methyl-pyridin-2-yl)- 1 H-pyrazol-4-yl]-quinoxaline,
432a) 6-[3-(6-cyclopropyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3-methyl-3H-quinazolin-4-oner, 433) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-b]pyridazine, 433a) 6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoline, 434) 6-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-3-fluoro-2-methyl-pyridine,
435) 7-methoxy-3-methyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
436) (4-morpholin-4-yl-phenyl)-[6-(3-pyridin-2-yl-lH-ρyrazol-4-yl)-quinazolin-4-yl]-amine, 437) 4-isopropoxy-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline,
438) 6-(3-Pyridm-2-yl-lH-pyrazol-4-yl)-quinolin-4-ylamine,
439) {4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohexyl}- carbamic acid benzyl ester,
440) 4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohexylaini]χe, 441) N-{4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohexyl} - methanesulfonarnide,
442) 6-[3-(5-fluoro-6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoxaline, 443) 7-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyridine,
444) l-tert-butyl-3-[6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolm-4-yl]-urea,
445) 5-(3-ρyridin-2-yl-lH-pyrazol-4-yl)-benzo[l ,2,5]thiadiazole,
446) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[l,2,5]oxadiazole,
447) 5-(3-Pyridin-2-yl-lH-pyrazol-4-yl)-benzooxazole, 448) 4-morpholin-4-yl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-q\iinazoline, 449) 6- [3 -(6-trifluoromethyl-pyridin-2-yl)- 1 H-pyrazol-4-yl] -quinoxaline, 450) 4-(4-methoxy-phenyl)-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolme, 451) 5-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-benzo[l,2,5]tbiadiazole,
452) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzothiazole,
453) 3-(3-methoxy-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
454) S-methyl-thiophene^-carboxylic acid [6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoLin-4- yl] -amide,
455) 5-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3-phenyl-benzo[c]isoxazole, 456) 3-(4-methoxy-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole, 457) 3-(4-chloro-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
458) 3 -(4-ethyl-phenyl)-5-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-benzo [cjisoxazole, 459) (4-methoxy-pE'enyϊ)- [6"-(3-pyridϊh-2-yl- 1 H-pyrazol-4-yl)-quinazolin-4-yl]-methanone,
460) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3-thiophen-3-yl-benzo[c]isoxazole,
461 ) 5 -(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)- 1 H-indazole-3 -carboxylic acid,
462) 5-(3-Pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid methylamide,
463) 5-(3-pyridiii-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid diethylamide,
464) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid (2,2-dimethyl- propyl)-amide,
465) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid phenylamide, 466) morpholin-4-yl-[5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazol-3-yl]-methanone,
467) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid benzylamide,
468) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid cyclopentylamide; 469) 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzamide;
470) 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzonitrile;
471) 4-[5-(2-methaiiesulfonyl-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
472) 4-[5-(2-methoxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] octane- 1 -carboxylic acid methyl ester;
473) 4-[5-(2-hydroxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
474) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l -carboxylic acid methyl ester;
475) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
476) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)- 1 H-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
477) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
478) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;
479) 4-[5-(2-ammo-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] octane- 1 -carboxylic acid;
480) {4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester; 481 ) N-|4-['5-(2-cycfoprbpyf amϊno-p'yrimidin-4-yl)-4-(6-metliyl-pyridin-2-yl)- 1 H-imidazol-
2-yl]-bicyclo[2.2.2]oct-l-yl}-acetamide;
482) N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-
2-yl]-bicyclo[2.2.2]oct-l-yl}-methanesulfonamide;
483) N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-
2-yl]-bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;
484) 4-[5-quinoxalin-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
485) 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
486) 6-[2-tert-butyl-5-(2-cyclopropyl-pyrimidm-4-yl)-3H-imidazol-4-yl]-quinoxaline;
487) 6-[5-(2-byclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
488) {4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanol;
489) 6-[5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline; 490) 6-[2-tert-butyl-5-(2-trifluoroniethyl-pyrimidm-4-yl)-3H-imidazol-4-yl]-quinoxaline; 491) 4-[5-quinoxalin-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
492) 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
493) 6-[5-(2-cyclopropyl-pyrimidin-4-yl)-2-(l-methanesulfonyl-piperidm-4-yl)-3H-imidazol-
4-yl] -quinoxaline;
494) 445.(2-methyl-pyrimidin-4-yl)-4-[l,2,4]triazolo[4,3-a]pyridm-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
495) 4.[4.(2-methyl-ρyrimidin-4-yl)-5-[l,254]triazolo[l,5-a]ρyridine-6-yl-lH-irnidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid amide;
496) 4-[4-(2-methyl-pyrirriidiri-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid;
497) 4-[4-(2-methyl-pyrimidm-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
498) 4-[4-(2-metb.yl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexanol,
499) 4-[4-(2-methyl-pyrimidm-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol,
500) 4-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-2-methyl-pyrimidine,
500a) 6-[3-(2-methyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
Figure imgf000154_0001
502) 6- [3 -(2-methyl-pyrimidin-4-yl)- 1 H-pyrazol-4-yl] -quinoxaline,
502a) 6-[3-(2-trifluoromethyl-pyrimidm-4-yl)-lH-pyrazol-4-yl]-quinoxaline,
503) 6-[3-(2-cyclopropyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-quinoxaline,
504) 4-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-2-trifluoromethyl-pyriniidine,
505) 7-[3-(2-trifluoromethyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine, or
506) 6-[3-(2-Trifluoromethyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-qumoline.
21. The method of claim 13, wherein the inhibitor is administered locally.
22. The method of claim 13, wherein the inhibitor is administered via an implantable device.
23. The method of claim 22, wherein the device is a delivery pump.
24. The method of claim 22, wherein the device is a stent.
25. An implantable device comprising an inhibitor of TGFb type I receptor or Alk4.
26. The device of claim 25, wherein the inhibitor has the structure shown in formula I:
Figure imgf000154_0002
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein
R1"1 is aryl, heteroaryl, aralkyl, or heteroaralkyl; each R!"a is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
X1-I is cycloalkyl or heterocycloalkyl; YIVis 1a bond,":C(0)-;-C(0)-O-, -O-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(O)-N(Rb)-, -N(Rb)-C(O)-, -O-C(O)-N(Rb)-, -N(Rb)-C(O)-O-, -O-S(O)p-N(Rb)-, -N(Rb)- S(O)P-O-, -N(Rb)-C(O)-N(Rc)-, -N(Rb)-S(O)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb)-C(O)-, -C(O)-N(Rb)-S(O)p-N(Rc)-, -C(O)-O-S(O)p-N(Rb)-, -N(Rb)-S(O)p-N(Rc)-C(O)-, -N(Rb)-S(O)p-O-C(O)-, -S(O)P-N(R")-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)P-, -O-, -S-, or -(C(Rb)(Rc))q-, wherein each of Rb and Rc is independently hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; p is 1 or 2; and q is 1-4;
R1"2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl; each of A1"1 and A1"2, independently, is O, S, N, or NRb, provided that at least one of A M and A 1^ iS N; and m is 0, 1, 2, or 3, provided that when m >2, two adjacent Rμa groups can optionally together to form a 4- to 8-membered optionally substituted cyclic moiety.
27. The device of claim 25, wherein the inhibitor has the structure shown in formula II:
Figure imgf000155_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein each OfXn-1, Xn-2, Xn-3, and Xπ-4 is independently CRX or N, provided that no more than two of Xn-1, Xn-2, Xn-3, and Xn-4 can be N simultaneously; each OfYn-1 and Yn-2 is independently CRy or N, provided that at least one OfYn-1 and Yn-2 must be N; each R11"1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfϊnyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyL sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycϊo'alkylsϋl'Fanyl, aryl'faryroxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; each R11"2 is independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2, - NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -N(alkyl)(cycloalkyl), -NH(heterocycloalkyl), - NH(heteroaryl), -NH-alkyl-heterocycloalkyl, -NH-alkyl-heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto^ alkoxy, cycloalkyloxy, cycloalkyl-alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsixlfanyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkytycarbonylamino, (heterocycloalkytyalkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkoxycarbonylaminoalkylamino, (heteroaryl)arylcarbonylaminoalkylammo, heteroaralkylcarbonylaminoalkylamino, (heteroary^arylsulfonylaminoalkylcarbonylaminoalkylamino, arylsulfonylaminoalkyl amino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl; m is 0, 1, 2, 3, or 4, and when m >2, two adjacent R1 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; n is 0, 1, 2, or 3, and when n ≥2, two adjacent R2 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; and each of Rx and Ry is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarboaiyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cycloalkyl)alkylcarbonylamino, (cycloaUcyl)alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, aralkylcarbonylamino, aralkylsulfonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)sulfonylamino, (heterocycloalkyl)alkylcarbonylamino, (heterocycloalkyl)alkylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylamino, heteroaralkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfarnoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloaϊkyl)alkoxy, (cycloalkyl)alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalkyl)alkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl.
28.. The device of claim 25, wherein the inhibitor has the structure shown in formula III
Figure imgf000157_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein each of Xm-i, Xm-2, X111-3, and X11I-4 is independently CRm"x or N, provided that only two OfXiII-1, Xm-2, Xm-3, and Xm-4 can be N simultaneously; each of Ym-1 and Ym-2 is independently CRm"y or N, provided that at least one ofVnn and Ym-2 must be N; each R111"1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; each R111"2 is independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -N(alkyl)(cyclocalkyl)5 - NH(heterocycloalkyl),
-NH(heteroaryl), -NH-alkyl-heterocycloalkyl, -NH-alkyl-heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, aryloxy, arylalkoxy, hetlπfcyclόallyloxy!," '(heterocycloalkyl)alk:oxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalky^alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino , (heterocycloalkytycarbonylamino, (heterocycloalky^alkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkoxycarbonylaminoalkylamino, (heteroary^arylcarbonylaminoalkylamino, heteroaralkylcarbonylaminoalkylamino, (heteroary^arylsulfonylaminoalkylcarbonylaminoalkylamino, arylsulfonylaminoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl; m is 0, 1, 2, 3, or 4, and when m ≥_2, two adjacent R111"1 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; n is 0, 1, 2, or 3, and when n Ξ≥2, two adjacent R111"2 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; and each of Rπi"x and Rm~y is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkyl)alkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cycloalkytyalkylcarbonylamino, (cycloalkyl)alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, aralkylcarbonylamino, aralkylsulfonylamino, (heterocycloalkytycarbonylamino, (heterocycloalkyl)sulfonylamino, (heterocycloalkytyalkylcarbonylamino, (rieterocycloalky^alkylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylamino, heteroaralkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, (cycloalkyl)alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloallcytyalkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl.
29. The device of claim 25, wherein the inhibitor has the structure shown in formula IV
Figure imgf000159_0001
or an N-oxide or a pharmaceutically acceptable salt thereo f, wherein each R™"8 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carh>oxy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfon;ylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloallcylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroarylox;y, heteroarylsulfanyl, or heteroaroyl;
R™'1 is a bond, alkylene, alkenylene, alkynylene, or -(CH2)F1 -O-(CH2)r2-, wherein each of rl and r2 is independently 2 or 3;
R^"2 is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, or a bond;
R^"3 is -C(O)-, -C(O)O-, -OC(O)-, -C(O)-N(R1^)-, -N(R1^)-C(O)-, -0-C(0)-N(RIV" b)-, -N(R1^)-C(O)-O-, -0-S(O)P-N(R^"13)-, -N(R^13)- S(O)p-0-, -N(RIV"b)-C(0)-N(RIV-c)-, -N(RIV-b)-S(0)p-N(RIV-b)-, -C(O)-N(R^)-S(O)P-, -S(O)P-N(R^)-C(O)-, -S(O)P-N(R^)-, -N(R1^)-S(OV, -N(R^'13)-, -S(O)p-, -0-, -S-, or -(C(RIV~b)(RIV-c))q-, or a bond; wherein each 0£j^iv-b 3J1(J R1V-0 jg independently hydrogen, hydroxy, alkiyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; and p is 1 or 2 and q is 1-4;
R^"4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkryl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
Rw~5 is hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulfinyl, amino, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloallkylsulfinyl, heterocycloalkyl, heferδ'e'yclόalkόxy, heterocycloalkylsulfinyl, aryl, aryloxy, arylsulfϊnyl, heteroaryl, heteroaryloxy, or heteroarylsulfinyl; j^iv-6 is (i) a 5_ tø 6-niembered heterocyclyl containing 1-3 hetero ring atoms selected from the group consisting of -O-, -S-, -N=, and -NR1^-, wherein Rw'd is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, tieteroaryl, or hetero aralkyl; said heterocyclyl being substituted with R^"6 and optionally substituted with one to two R1^; wherein R™"6 is oxo, thioxo, alkoxy, alkylsulfmyl, -NH2, -NH(unsubstituted alkyl), or -N(unsubstituted alkyl)2, and R1^ is alkyl, alkenyl, alkynyl, alkoxy, acyU halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mexcapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; or
(2) a fused ring heteroaryl selected from the group consisting of:
Figure imgf000160_0001
wherein ring A is an aromatic ring containing 0-4 hetero ring atoms and ring B is a 5- to 7- membered aromatic or nonaromatic ring containing 0-4 hetero ring atoms, provided that at least one of ring A and ring B contains one or more hetero ring atoms; ring A' is an aromatic ring containing 0-4 hetero ring atoms and ring B' is a 5- to 7-membered saturated or unsaturated ring containing 0-4 hetero ring atoms, provided that at least one of ring A' and ring B' contains one or more hetero ring atoms; each hetero ring atom is -O-, -S— s -N=, or - NR^"8-; each X1 is independently N or C; each X2 is independently -O- -S-, -N=, -NR1^- , or -CHR^"11-; where RIV"8 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, axalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl; each of R1^"11 and R^"1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcaPbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycldklkyT, cycroalfeyToxy7cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; and n is 0-2; and m is 0-3, and when m ≥2, two adjacent Rw'a groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; provided that if R^"6 is 2-naphthyridinyl, 4-quinolinyl, imidazo[l,2-a]pyridyl, or benzimidazolyl, then -R^-R^-R^-R™"4 is not H, unsubstituted alkyl, -CH2-C(O)-N(H)-alkyl, -CH2-C(O)-N(alkyl)2, or benzyl.
30. The device of claim 25, wherein the inhibitor has the structure shown in formula V
Figure imgf000161_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein
Rv"! is heteroaryl; each Rv~\ independently, is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
Xv is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a bond;
Yv is a bond, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(O)-N(Rb)-, -N(Rb)-C(O)-, -O-C(O)-N(Rb)-, -N(Rb)-C(O)-O-, -C(O)-N(Rb)-O-, -O-N(Rb)-C(O)-, -O-S(O)p-N(Rb)-, -N(Rb)- S(O)p-O-, -S(O)p-N(Rb)-O-, -O-N(Rb)-S(O)p-, -N(Rb)-C(O)-N(Rc)-, -N(Rb)-S(0)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb)-C(O)-, -C(O)-N(Rb)-S(O)p-N(Rc)-, -C(0)-σ-S(6%4ll&bj-; -N(RD)'-Si:O)' p-N(Rc)-C(O)-, -N(Rb)-S(O)p-0-C<O)-, -S(O)p-N(Rb)-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)p-, -O-, -S-, or -(C(Rb)(Rc))q-, wherein each of Rb and Rc, independently, is hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; p is 1 or 2 and q is 1-4;
Rv"2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocyclo alkenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl; each of A , v- "i and A , V- "2 , independently, is N or NR ; and m is 0, 1, 2, or 3, and when m >2, two adjacent R v"a groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety, provided that if Xv is a bond, then Yv is a bond; Rv"2 is hydrogen or alkyl; m is 1, 2, or 3; and at least one Rv'a is substituted at the 2-pyrimidinyl position.
31. The device of claim 25, wherein the inhibitor has the structure shown in formula VI:
Figure imgf000162_0001
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein each RVI"a, independently, is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, - NH2, -NH(unsubstituted alkyl), -N(unsubstituted alkyl)2, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfϊnyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylarnino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; ,.Jf Vi-I j™ a bond, alkylene, alkenylene, alkynylene, or -(CH2)rl-O-(CH2)r2-, where each of rl and r2, independently, is 2 or 3;
RVI"2 is cycloalkylene, heterocycloalkylene, cyclo alkenylene, heterocycloalkenylene, arylene, heteroarylene, or a bond;
RVI"3 is -C(O)-, -C(O)-O-, -0-C(O)-, -S(O)p-O-, -O-S(O)P-, -C(0)-N(Rb)-, -N(Rb)-C(O)-, -0-C(0)-N(Rb)-, -N(Rb)-C(0)-0-, -C(0)-N(Rb)-0-, -0-N(Rb)-C(0)-, -0-S(0)p-N(Rb)-,
-N(Rb)- S(O)p-O-, -S(0)p-N(Rb)-0-, -O-N(Rb)-S(O)p-, -N(Rb)-C(0)-N(Rc)-, -N(Rb)-S(0)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb)-C(O)-, -C(0)-N(Rb)-S(0)p-N(Rc)-, -C(O)-O-S(O)p-N(Rb)-, -N(Rb)-S(0)p-N(Rc)-C(0)-3 -N(Rb)-S(O)p-O-C(O)-, -S(O)p-NCRb)-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)p-, -0-, -S-, -(C(Rb)(Rc))q-, or a bond; wherein each of Rb and Rc is independently hydrogen, hydroxy, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; and p is 1 or 2 and q is 1-4;
RVI"4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocyclo alkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
RVI"5 is hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulfϊnyl, amino, alkenyl, alkynyl, cycloalkoxy, cycloalkylsulfinyl, heterocycloalkoxy, heterocycloalkylsulfinyl, aryloxy, arylsulfinyl, heteroaryloxy, or heteroarylsulfinyl;
RVI"6 is a 5- to 6-membered monocyclic heterocyclyl or a 8- to 11-membered tricyclic heteroaryl; each being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; and m is 0-3, and when m ≥2, two adjacent R VI"a groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety.
32. The device of claim 25, wherein the inhibitor is
1) 4-(4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl)-piperidine-l- carboxylic acid benzyl ester; 2) l4'-(4'-βenzotϊ3TSϊoxol-5-yl-5-pyndin-2-yl-lH-imidazol-2-yl)-piperi acid benzyl ester;
3) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
4) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-pyrrolidine-l- carboxylic acid benzyl ester;
5) 2-(5-Benzo[l,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine; 6) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidme-l-carboxylic acid benzyl ester;
7) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidme-l- carboxylic acid benzyl ester;
8) 3 - [4-Benzo [ 1 ,3 ]dioxol- 5 -yl-5-(6-methyl-pyridin-2-yl)- 1 H-imidazol-2-yl] -pyrrolidine- 1 - carboxylic acid benzyl ester; 9) 2-(5-Benzo[l,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine;
10) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl]-6-methyl-pyridine;
11) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl]-pyridine;
12) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
13) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
14) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 2-chloro-benzyl ester;
15) 4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidine- 1 -carboxylic acid 2,4-dichloro-benzylamide;
16) l-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-l-yl]- ethanone;
17) 2-[5-Benzo[ 1 ,3]dioxol-5-yl-2-(l -furan-2-yl-methyl-ρiperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
18) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-cyclohexyl}- carbamic acid benzyl ester;
19) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl] cyclohexylamine; 205Ε-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexyl}-C-ρhenyl-methanesulfonamide;
21) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
22) 4-[4-Beiizo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane- 1 -carboxylic acid;
23) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester;
24) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-ethyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
25) 2-(5-Benzo[l,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine;
26) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-nitro-benzyl ester;
27) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidme-l-carboxylic acid 4,5-dimethoxy-2-nitro-benzyl ester;
28) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 3-fluoro-benzylamide;
29) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-fluoro-benzylamide;
30) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid benzylamide;
31) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(toluene-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4-yl}- pyridine;
32) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-methyl-benzylamide;
33) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-methoxy-benzylamide;
34) 4-(4-Benzo [ 1 ,3 ]dioxol-5-yl-5 -pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid 2-chloro-benzylamide;
35) 4-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- benzoic acid;
36) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid amide;
37) 4-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- benzonitrile; I 385'2^-{5-Benzo[T3]Hiox6i-5-yl-2-[l-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
39) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
40) {5-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- naphthalen-l-yl}-dimethyl-amine;
41) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-4-yl-methyl)-piperidin-4-yl)]-3H-imidazol-4- yl} -pyridine;
42) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(propane-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
43) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-methoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
44) l-{4-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l- sulfonylj-phenyl} -ethanone;
45) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-methyl-benzyl)-piperidin-4-yl]-3H-imidazol-4-yl}- pyridine;
46) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3-fluoro-5-trifluoromethyl-benzyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
47) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-cyclohexylmethyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
48) 2-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-l-ylmethyl]- cyclopropanecarboxylic acid ethyl ester;
49) 2-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-l-ylmetb.yl]- pyrrolidine- 1-carboxylic acid tert-butyl ester;
50) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ l-(2,2-dimethyl-[ 1 ,3]dioxolan-4-ylmethyl)-piperidin-4- yl] -3H-imidazol-4-yl} -pyridine;
51) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-ethanesulfonyl-piperidm-4-yl)-3H-imidazol-4-yl]- pyridine;
52) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(butane- 1 -sulfonyl)-piρeridin-4-yl]-3H-imidazol-4-yl} - pyridine;
53) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
54) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethenesulfonyl)-piperidin-4-yl]-3H-imidazol- 4-yl} -pyridine; 55) 2-"{5-Berizdf 13 ]dioxol-5-yl-2-[ 1 -(propane- 1 -sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
56) 1 -[4-(4-Benzo [ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidine- 1- sulfonylmethyl]-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one;
57) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
58) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-dichloro-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -pyridine;
59) 2-{5-Benzo[13]dioxol-5-yl-2-[l-(4-fluoro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
60) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,4-dichloro-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -pyridine;
61 ) 2- {5-Benzo[ 1 ,3 ]dioxol-5-yl-2-[ 1 -(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-3H-imidazol- 4-yl} -pyridine;
62) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-p-tolylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -pyridine;
63) 3-(4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l- carboxylic acid benzyl ester;
64) 3-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid benzyl ester;
65) 4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
66) 2- {5-Benzo[ 1,3] dioxol-5-yl-2-[ 1 -(pyridin-2-yl-methanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
67) 2- {5-Benzo[ 1 ,3] dioxol-5-yl-2-[ 1 -(2-naphthalen- 1 -yl-ethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
68) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-3-yl)-3H-imidazol-4- yl]-pyridine;
69) 3-[4-Benzo[l,3]dioxol-5-yl-l-b.ydroxy-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
70) 2- {5-Benzo[ 1 ,3] dioxol-5-yl-2-[ 1 -(pyridin-4-yl-methanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
71) 2- {5-Benzo[ 1 ,3] dioxol-5-yl-2-[ 1 -(pyridin-3-yl-methanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine; 72) 2~'{5-Berizόp'3]diόxό'I-5-yl-2- [ 1 -(3-trifluoromethyl-phenylmethanesulfonyl)-piperidin-4- yl]-3H-imidazol-4-yl} -pyridine;
73) 3-[4-Benzo[l,3]dioxol-5-yl-l-h.ydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- pyrrolidine- 1-carboxylic acid benzyl ester;
74) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2- [ 1 -(4-trifluoromethyl-phenylmethanesulfonyl)-piperidin-4- yl]-3H-imidazol-4-yl} -pyridine;
75) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2- [ 1 -(3,5-bis-trifluoromethyl-phenylmethanesulfonyl)- piperidin-4-yl]-3H-imidazol-4-yl}-pyridine;
76) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(biphenyl-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
77) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(3,5-difluoro-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -pyridine;
78) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(pyridin-2-yl-methanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
79) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
80) 2-{5-Benzo[l,3]dioxol-5-yl-2-[ l-(biphenyl-4-ylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
81) 4-[5-Benzo[l,3]dioxol-5-yl-l-rnethyl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine- 1-carboxylic acid benzyl ester;
82) 4-[4-Benzo[l,3]dioxol-5-yl-l-methyl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine- 1-carboxylic acid benzyl ester;
83) {4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylj-carbamic acid benzyl ester;
84) 2-{5-Benzo[l,3]dioxol-5-yl-2-[ l-(3-phenoxy-phenylmethanesulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
85) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-ethanesulfonyl-ρiρeridin-4-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
86) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(propane-1 -sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
87) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(butane- 1 -sulfonyl)-ρiperidin-4-yl]-3H-imidazol-4-yl} - 6-methyl-pyridine;
88) 2-{5-Benzo[l,3]dioxol-5-yl-2-[ l-(pyridin-3-ylmethanesulfonyl)-ρiperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
Figure imgf000169_0001
imidazol-4-yl} -6-methyl-pyridine;
90) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-difluoro-phen^ylmethanesulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
91) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3-trifluoromethyl-ρlienylmethanesulfonyl)-piperidin-4- yl] -3H-imidazol-4-yl} -6-methyl-pyridine;
92) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(tliiophene-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
93) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(butane-l-sulfonyO-piperidin-3-yl]-3H-imidazol-4-yl}-
6-methyl-pyridine;
94) 2-[5-Benzo[l ,3]dioxol-5-yl-2-(l -phenylmethanesulfbnyl-piperidin-3-yl)-3H-imidazol-4- yl] -6-methyl-pyridine;
95) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(l-methyl-lH-imidazole-4-sulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
96) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(5-methyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
97) 4-[5-Benzo[l,3]dioxol-5-yl-l-hydroxy-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
98) Butane- 1 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexyl}-amide;
99) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexyl}-C-pyridin-2-yl-methanesulfonamide;
100) Thiophene-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexyl}-amide;
101) 1 -Methyl- lH-imidazole-4-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl- pyridin-2-yl)-lH-imidazol-2-yl]-cyclohexyl}-amide;
102) 4-[4-Benzo[l ,3]dioxol-5-yl- 1 -hydroxy-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
103) 4-[4-Benzo[ 1 ,3]dioxol-5-yl- 1 -hydroxy-5-(6-methyl-pyridin-2-yl)- lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
104) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-bromo-pyridin-2-yl)-lH-imidazol-2-yl]-ρiperidine-l- carboxylic acid benzyl ester;
105) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(thiophene-3-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine; 106) '"!'- {5-Benzό[T,3]dioxol-5-yl-2-[ 1 -(5-methyl-2-trifluoromethyl-f\iran-3-sulfonyl)- piperidin-4-yl]-3H-imidazol-4-yl}-6-methyl-pyridine;
107) 4-[2-(l-phenylmethanesulfonyl-piperidin-4-yl)-5-(6-methyl-pyridin-2-yl)-lH-imidazol- 4-yl] -pyridin-2-yl- fluoride;
108) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-trifluoromethyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
109) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-bromo-pyridin-2-yl)-l-hydrox3^-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
110) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-pipericiin-4-yl)-3H-imidazol-4- yl] -6-bromo-pyridine;
111) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imicaazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanol;
112) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
113) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-2H-imidazol-2-yl]-piperidine-l- sulfonic acid dimethylamide;
114) l-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-irnidazol-2-yl]-piperidin-
1 -yl} -3 -phenyl-propan- 1 -one;
115) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(propane-2-sulfonyl)-piperidirx-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
116) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] octane- 1 -carbonitrile;
117) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-ylamine;
118) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-metliyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-C-phenyl-methanesulfonamide;
119) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] oct- 1 -yl} -methanesulfonamide;
120) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-C-pyridin-2-yl-methanesulfonamide;
121) 2-{5-Benzo[l,3]dioxol-5-yl-2-[4-(lH-tetrazol-5-yl)-bicyclo[2.2.2]oct-l-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
122) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetamide;
Figure imgf000171_0001
acid (4-[4-beiizo [ 1 ,3 ]dioxol-5 -yl-5 -(6-methyl-pyridin-2-yl)- 1 H- imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl} -amide;
124) l-Methyl-lH-imidazole-4-sulfbnic acid {4-[4-benzo[ 1,3] dioxol-5 -yl-5 -(6-methyl- pyridin-2-yl)-lH-imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
125) Thiophene-3 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
126) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[l -(2-phenyl-emenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
127) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
128) Methanesulfonic acid 4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]oct-l-ylmethyl ester;
129) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetonitrile;
130) {4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetic acid;
131) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] oct- 1 -ylmethyl} -methanesulfonamide;
132) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(biphenyl-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
133) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl}-6-methyl-pyridine;
134) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
135) N- {4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-ylmethyl}-C-phenyl-methanesulfonamide;
136) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct- 1 -ylmethyl} -C-pyridin-2-yl-methanesulfonamide;
137) 4-[4_Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid benzylamide;
138) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (pyridin-2-ylmethyl)-amide;
139) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid 3-chloro-4-fluoro-benzylamide; 14O) 4-[4-Benzott,'3]aioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (furan-2-ylmethyl)-amide;
141) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfonyl-ρyrrolidin-3-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
142) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(butane- 1 -sulfonyl)-pyrrolidin-3-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
143) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(l-methyl-lH-imidazole-4-sulfonyl)-pyrrolidin-3-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
144) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-pyrrolidin-3-yl)-3H-imidazol-
4-yl] -6-methyl-pyridine;
145) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-benzenesulfonyl)-pyrrolidin-3-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
146) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
147) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(2-naphthalen-2-yl-ethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl}-6-methyl-pyridine;
148) l-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine- 1 -sulfonylmethyl} -7,7-dimethyl-bicyclo[2.2.1 ]heptan-2-one;
149) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(4-chloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
150) 4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridm-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methylamide;
151) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid ethylamide;
152) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid butylamide;
153) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid isopropylamide; 154) 4.[4-Benzo[l53]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (3-imidazol-l-yl-propyl)-amide; 155) 2-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine- 1 -sulfonylmethyl} -phenylamine;
156) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (l-methyl-5-methylsulfanyl-lH-[l,2,4]triazol-3-yl)- amide; 15I{7) "4'-[l-Be'nzot r';3iaioxδl-5-yl-5-(6-methyl-pyridin-2-yl)- 1 H-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid cyclohexylamide;
158) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazoi-2-yl]- bicyclo[2.2.2]oct- 1 -yl} -pyrrolidin- 1 -yl-methanone;
159) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid dimethylamide;
160) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid diethylamide;
161) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid dipropylamide;
162) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (5,7-difluoro-benzothiazol-2-yl)-aniide; 163) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid benzothiazol-2-ylamide; 164) 4-[4-Benzo[l:,3]dioxol-5-yl-5-(6-meth.yl-pyridm-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid (lH-benzoimidazol-2-yl)-amide; 165) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (2 -hydroxy- l-methyl-2-phenyl-etlxyl)-amide; 166) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid (pyridin-4-ylmethyl)-amide;
167) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin-l- yl}-(3-chloro-phenyl)-methanone;
168) {4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)- lH-imidazol-2-yl]-piperidin- 1 - yl} -(4-fluoro-phenyl)-methanone;
169) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin-l- yl } -(4-methoxy-phenyl)-methanone;
170) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-cyclopropyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid;
171) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;
172) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid hydroxyamide;
173) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-carbamic acid benzyl ester; l^^'-^-Benzotr^ϊdioxoβ-yl-S-Cό-methyl-pyridin-l-y^-lH-imidazol^-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydrazide;
175) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl} -acetamide;
176) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethylj-methanesulfonamide;
177) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-C-phenyl-methanesulfonamide;
178) Butane- 1 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl] -cyclohexylmethyl} -amide;
179) Propane-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-cyclohexylmethyl} -amide;
180) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-C-pyridin-2-yl-methanesulfonamide;
181) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-C-pyridin-4-yl-methanesulfonamide;
182) (4-Methoxy-benzyl)-{4-[5-(6-methyl-pyridin-2-yl)-2-(l-phenylmethanesulfonyl- piperidin-4-yl)-lH-imidazol-4-yl]-pyridin-2-yl}-amine;
183) 4-[5-(6-Methyl-pyridin-2-yl)-4-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl- lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
184) 4-[5-(6-Methyl-pyridin-2-yl)-4-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
185) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl- lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
186) 4-[4-(6-Methyl-pyridin-2-yl)-5-[ 1 ,2,4]triazolo[ 1 ,5-a]ρyridin-6-yl- lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
187) 4-[4-(6-Methyl-pyridin-2-yl)-5-[l ,2,4]triazolo[l ,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
188) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane- 1 -carboxylic acid;
189) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;
190) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol; 1 ø'ϊ )1!4-[i4-t6-Cycloprbpyl-'pyridin-2-yl)-5-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl- 1 H-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
192) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
193) N-{4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-sulfamide;
194) Sulfamic acid 4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl ester;
195) {4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl} - carbamic acid benzyl ester;
196) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonyl}-methanesulfonamide;
197) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonyl}-benzenesulfonamide;
198) 4-[5-(3-Metriyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH:- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester; 199) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
200) N-{4-[4-(6-Methyl-pyridm-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl}- acetamide;
201) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl- lH-imidazol-2-yl]-bicyclo[2.2.2]octane- 1-carboxylic acid methyl ester;
202) 4- [4-(6-Methyl-pyridin-2-yl)-5-qumoxalin-6-yl- 1 H-imidazol-2-yl] -bicyclo[2.2.2 ] octane- 1-carboxylic acid;
203) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane- 1-carboxylic acid hydroxyamide;
204) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane- 1-carboxylic acid amide;
205) N-{4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl}- methanesulfonamide;
206) 2,2,2-Trifluoro-N- {4-[4-(6-methyl-pyridin-2-yl)-5-quinoxalin-6-yl- 1 H-imidazol-2-yl] - eye lohexyl} -acetamide;
207) 4-[4-(5-Fluoro-6-methyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-irriidazol- 2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester; 20S)lt4-t2-[T-(Bufane-l-sulfonyl)-piperidin-4-yl]-5-(6-methyl-pyridin-2-yl)- lH-imidazol-4- yl]-pyridin-2-yl}-(4-methoxy-benzyl)-amine;
209) 4-[2-[l-(Butane-l-sulfonyl)-piperidin-4-yl]-5-(6-methyl-pyridin-2-yl)-l H-imidazol-4- yl]-pyridin-2-ylamine;
210) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl]-6-ethyl-pyridine;
211) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridirx-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
212) 4- [5-(3 -Methyl-4-oxo-3 ,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridirx-2-yl)- 1 H- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
213) N-{4-[5-(6-Methyl-pyridin-2-yl)-4-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanesulfonamide;
214) N-{4-[5-(6-Methyl-ρyridin-2-yl)-4-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetamide.
215) 4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-pyrimidin-2-ylamine;
216) 4-(2-pyridin-2-yl-pyrazolo[l,5-a]pyridin-3-yl)-pyrimidin-2-ylamine;
217) 4- [2-(6-methyl-pyridin-2-yl)-pyrazolo [1,5 -a]pyridin-3 -yl] -pyrimidin-2-ylamine;
218) 2-(6-methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-pyrazolo [ 1 ,5-a]pyridine;
219) 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine;
220) 2-(6-methyl-pyridm-2-yl)-3-(2-moφholin-4-yl-pyrimidin-4-yl)-pyrazolo[l,5- c]pyrimidine;
221 ) 4- [2-(6-methyl-pyridin-2-yl)-pyrazolo [ 1 , 5 -a]pyrazin-3 -yl] -pyrimidin-2-ylamine; 222) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyrimidin-3-yl]-pyrimidin-2-ylamine; 223) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine; 224) (2-Methoxy-ethyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
225) (3-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin.-2-ylamino}- proρyl)-carbamic acid tert-butyl ester;
226) (3-Imidazol-l-yl-propyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
227) (4-Methoxy-benzyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridiiι-3-yl]- pyrimidin-2-yl} -amine;
228) [2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridin-
6-yl]-methanol; 22'9)"3'-(2:Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- ajpyridine;
230) (4- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} - butyl)-carbamic acid tert-butyl ester;
231) (4-Amino-benzyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} - amine;
232) (5- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} - pentyl)-carbamic acid tert-butyl ester;
233) [3-(2-Amirio-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-6-yl]- methanol;
234) [3-(2-ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-7-yl]- methanol;
235) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(2-morpholin-4-yl-ethyl)-amine;
236) [3-(2-Amirio-pyrirnidin-4-yl)-6-methyl-2-(6-rn.ethyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(2-pyridin-2-yl-ethyl)-amine;
237) [3 -(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-irnidazo [ 1 ,2- a]pyridin-8-yl]-(2-pyridin-3-yl-ethyl)-amine;
238) [3-(2-methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-irnidazo[ 1 ,2- a]pyridin-6-yl] -methanol ;
239) [3-(2-Amin.o-pyrirnidin-4-yl)-6-niethyl-2-(6-methyl-pyridin-2-yl)-irnidazo[l,2- a]pyridin-8-yl]-(2-pyridin-4-yl-ethyl)-amine;
240) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(3-morpholin-4-yl-propyl)-amine;
241 ) [3-(4-Methyl-piperazin- 1 -yl)-propyl]- {4-[2-(6-methyl-pyridin-2-yl)-imidazo [1,2- a]pyridin-3 -yl] -p yrimidin-2-yl} -amine;
244) [3-(4-Methyl-piperidin-l-yl)-propyl]- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2- a]pyridin-3 -yl] -p yrimidin-2-yl} -amine;
245) [4-(2-Pyridin-2-yl-imidazo[ 1 ,2-a]pyridm-3-yl)-pyrimidin-2-yl]-pyridin-3-yhnethyl- amine;
246) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-((R)-l- phenyl-ethyl)-amine;
247) {4- [2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl]-pyrimidin-2-yl} -((S)- 1 - phenyl-ethyl)-amine; 241B)14-I2-(&-M'eayl-pyπdin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(lH- tetrazol-5-yl)-amine;
249) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} -(2H- pyrazol-3-yl)-amine;
250) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2- morpholin-4-yl-ethyl)-amine;
251) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2-pyridin- 2-yl-ethyl)-amine;
252) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2-pyridin- 3-yl-ethyl)-amine;
253) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} -(2-pyridin- 4-yl-ethyl)-amine;
254) {4-[2-(6-Methyl-ρyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(3- morpholin-4-yl-propyl)-amine;
255) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(3- piperidin- 1 -yl-propyl)-amine;
256) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- [1,3 ,4]thiadiazol-2-yl-amine;
257) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine; 258) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine- 6-carboxylic acid methyl ester;
259) 2-(6-Methyl-pyridin-2-yl)-3-(2-metliylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine- 7-carboxylic acid ethyl ester;
260) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[ 1 ,2- a]pyrimidin-7-ylamine;
261) {7,7-Dimethyl-8-[5-(4-{4-[2-(6-methyl-ρyridin-2-yl)-imidazo[l,2-a]ρyridin-3-yl]- pyrimidin-2-ylamino} -butylcarbamoyl)-p entyl]-2-oxo-4-trifluoromethyl-7, 8-dihydro-2H- 1 - oxa-8-aza-anthracen-5-yl} -methanesulfonic acid;
262) 2-(2,7-Difluoro-6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)-3,5,6-trifluoro-4-[(4- {4-[2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidm-2-ylamino}- butylcarbarnoyl)-methylsulfanyl] -benzoic acid;
263) -(6-Methyl-pyridin-2-yl)-3-(2-moφholin-4-yl-pyrirnidin-4-yl)-imidazo[l,2-a]pyridine; 264) 2-(6-Methyl-pyridm-2-yl)-3-(2-piperidin-l-yl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine; 265) 2-(6-Methyl-pyridin-2-yl)-3-(2-pyrrolidin- 1 -yl-pyrimidin-4-yl)-imidazo[ 1 ,2-a]pyridine; 2δ'6Jir2-(6-MetEyϊ-pyridin-2-yl)-3-[2-(lH-^ a]pyridine;
267) 2-(6-Methyl-pyridin-2-yl)-3 -pyrimidin-4-yl-imidazo [ 1 ,2-a]pyridine;
268) 2-(6-Methyl-pyridin-2-yl)-3-pyrimidin-4-yl-imidazo[l,2-a]pyrimidm-7-ylamine;
269) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-8- ylamine;
270) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyτidin-2-yl)-imidazo[l,2-a]pyridine-6- carbonitrile;
271) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyτidin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid;
272) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyτidin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
273) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
274) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyτidin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid (2-dimethylamino-ethyl)-amide;
275) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid (2-methoxy-ethyl)-amide;
276) 3-(2-Ainino-pyrimidm-4-yl)-2-(6-methyl-pyτidin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid (2-thiophen-2-yl-ethyl)-amide;
277) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyτidin-2-yl)-irriidazo[l,2-a]pyridirLe-6- carboxylic acid [3-(4-methyl-piperazin-l-yl)-propyl]-amide;
278) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid amide;
279) 3 -(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyτidin-2-yl)-imidazo [ 1 ,2-a]pyridine-6- carboxylic acid cyclopropylamide;
280) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyτidin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid ethylamide;
281) 3-(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyxidin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid hydroxyamide;
282) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyτidm-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid methoxy-amide;
283) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyτidin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid methyl ester; 284)'f3-(2-Amin6-pynήiidϊri-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]p^ carboxylic acid;
285) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]p3αidine-7- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
286) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid (2-amino-ethyl)-amide;
287) 3-(2-Aniino-pyrimidin-4-yl)-2-(6-metliyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid (2-dimethylamino-ethyl)-amide;
288) 3-(2-Aniino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-hydroxy-ethyl)-amide;
289) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-oxo-2-pyridin-3-yl-ethyl)-amide;
290) 3-(2-Arnino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]p3τidme-7- carboxylic acid (2-thiophen-2-yl-ethyl)-amide;
291) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (piperidin-3-ylmethyl)-amide;
292) 3-(2-Amino-pyrimidin-4-yl)-2-(6-rnethyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid 2,2-dimethylhydrazide;
293) 3-(2-Amino-pyrimidin-4-yl)-2-(6-rnethyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid amide;
294) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid cyclopropylamide;
295) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid ethyl ester;
296) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid ethylamide;
297) 3 -(2- Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridine-7- carboxylic acid hydroxyamide;
298) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid methoxy-amide;
299) 3 -(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyrimidin-7- ylamine;
300) 3-(2-Azetidm-l-yl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-irnidazo[l,2-a]pyridine;
301) 3 -(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a] pyridine-7-carboxylic acid ethyl ester; 302)'3'K2-MetHane'sulfonyl-pyπmidin-4-yl)-2-(6-methyl-pyridin-2- a]pyridine-6-carboxylic acid methyl ester;
303) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-7-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2- a] pyridine;
304) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-8-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2- a] pyridine;
305) 3,3-Dimethyl-N-[2-(6-methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)- imidazo[l,2-a]pyrimidin-7-yl]-butyramide;
306) 3 -(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [1,2- a]pyridine-6-carbonitrile;
307) 3 -(2-Methylsulfanyl-pyrimidin-4-yl)-2-pyridin-2-yl-imidazo [ 1 ,2-a]pyridine;
308) 3 ,6-Dichloro-N-(4- {4- [2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl]- pyrimidin-2-ylamino}-butyl)-2-(2,4,5,7-Tetrachloro-6-hydroxy-3-oxo-9,9a-dihydro-3H- xanthen-9-yl)-terephthalamic acid;
309) 3 - [2-(2-Methyl-aziridin- 1 -yl)-pyrimidin-4-yl]-2-(6-methyl-pyridin-2-yl)-im.idazo[ 1 ,2- a] pyridine;
310) 3-[2-(4-Methyl-piperazin-l-yl)-pyrimidin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a] pyridine;
311) 3-{[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carbonyl] -amino} -propionic acid methyl ester;
312) 3 - { [3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridine-7- carbonyl]-amino} -propionic acid methyl ester;
313) 3- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} - phenol;
314) 4-(2- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}- - ethyl)-benzenesulfonamide;
315) 4-(2-Pyridin-2-yl-imidazo[l,2-a]pyridin-3-yl)-pyrimidin-2-ylamine; 316) 4-[2-(6-Chloro-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamine;
317) 4-[2-(6-Methyl-pyridin-2-yl)-7-trifluoromethyl-imidazo[ 1 ,2-a]pyridm-3-yl]-pyrimidiiL-
2-yl-amine;
318) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrirnidin-2-ylamine;
319) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l52-a]pyridin-3-yl]-pyrimidine-2-carbonitrile;
320) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridm-3-yl]-pyrimidine-2-carboxylic acid amide; 32T) H-[6-6rbnϊ6-2K'6-met!Kyl-pyridm-2-yl)-imidazo[ 1 ,2-a]pyridm-3-yl]-pyrimidin-2- ylamine; 322) 4-[6-Chloro-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
323) 4-[6-Fluoro-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
324) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-morpholm-4-yl-ethylamino)-imidazo[l,2-a] pyridin-3-yl]-pyrimidin-2-ol;
325) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-2-yl-eth.ylamino)-imidazo[l,2-a] pyridin-3-yl]-pyrimidin-2-ol;
326) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-3-yl-etfcιylamino)-imidazo[ 1 ,2-a] pyridin-3 -yl] -pyrimidin-2-ol;
327) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-4-yl-etfcιylaiΗino)-imidazo[l,2-a] pyridin-3 -yl] -pyrimidin-2-ol;
328) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-morpholin-4-yl-inαidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ol;
329) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-morpholin-4-yl-iinidazo[ 1 ,2-a]pyridin-3-yl]- pyrimidin-2-ylaniine;
330) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
331) 4-[7-Aminomethyl-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a.]pyridin-3-yl]-pyrimidin-2- yl-amine;
332) 4-[7-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
333) 4-[8-Benzyloxy-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ol;
334) 4-[8-Benzyloxy-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl- amine;
335) 4-[8-Bromo-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l=(2-a]pyridm-3-yl]-pyrimidin-
2-ol;
336) 4-[8-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
337) 6-Chloro-3-(2-methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[ 1 ,2- a] pyridine;
338) 5-Dimethylammo-naphthalene-l-sulfonic acid (4-{4-[2-(6-rnethyl-pyridin-2-yl)- imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-butyl)-amide; 3f9|"6-(2';7-b1ifϊuorδl-6-hydroxy-3-oxo-3H-xanthen-9-yl)-N-(4-{4-[2-(6- imidazo[ 1 ,2-a]pyridin-3 -yl] -pyrimidin-2-ylamino } -butyl)-isophthalamic acid; 340) 6-Amino-9-[2-carboxy-5-(4-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamino}-butylcarbamoyl)-phenyl]-xanthen-3-ylidene-animonium;
341) 6-Bromo-2-(6-methyl-ρyridin-2-yl)-3 -(2-methylsulfanyl-pyrimidin-4-yl)-imidazo [ 1 ,2-a] pyridine;
342) 6-Fluoro-2-(6-methyl-pyridin-2-yl)-3-(2-metliylsulfanyl-pyrimidin-4-yl)-inαidazo[l,2-a] pyridine;
343) 7-Amino-4-methyl-3-[(4- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyricϊin-3-yl]- pyrimidin-2-ylamino } -butylcarbamoyl)-methyl] -2-oxo-2H-chromene-6-sulfonic acid;
344) Cyclobutyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl3-pyrimidin-2-yl} - amine;
345) Cyclopentyl-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- yl} -amine;
346) Cyclopropyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2- yl} -amine;
347) Cyclopropyl-methyl-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
348) Dimethyl-{4-[2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrinxidin-2-yl}- amine;
349) Isopropyl-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyriirLidin-2-yl'}- amine;
350) Methyl- {4- [2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3-yl] -pyrimidin-2-yl} - amine;
350a) N-(2-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamino} -ethyl)-acetamide;
351) N-(4-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidm-2-ylamino}- butyl)-acetamide;
352) N,N-Dimethyl-N'-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-y'l]-pyrirnidin-
2-yl}-ethane-l,2-diamine;
353) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a] pyrimidin-7-yl]-3-pyridin-3-yl-propionamide;
354) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazc»[l,2-a] pyrimidin-7-yl] -nicotinamide; 355)Η-[2-(6-MethyI-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a] pyrimidin-7-yl]-propionamide;
356) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carbonyl]-methanesulfonamide;
357) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-metliyl-pyridin-2-yl)-iinidazo[l,2-a]pyridine-7- carbonyl] -methanesulfonamide;
358) N- [3 -(2-Amino-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyrimidin-7- yl] -2-(3 -methoxy-phenyl)-acetamide;
359) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6--methyl-pyridin-2-yl)-irnidazo[l,2-a]pyrimidiri-7- yl]-3 ,3 -dimethyl-butyr amide;
360) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyrimidin-7- yl]-3-pyridin-3-yl-propionamide;
361) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyrimidiri-7- yl]-acetamide;
362) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyrimidiri-7- yl] -nicotinamide;
363) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl]-2-(3-methoxy-phenyl)-acetamide;
364) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl]-3,3-dimethyl-butyramide;
365) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl]-3-pyridm-3-yl-propionamide;
366) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl] -nicotinamide;
367) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl]-propionamide;
368) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-metliyl-pyridm-2-yl)-imidazo[l,2-a]pyriniidia-7- yl] -propionamide;
369) N-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- acetamide;
370) Nl-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-butane-
1,4-diamine;
371) Nl - {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-yl} - propane- 1 ,3 -diamine; 372)11'N-(4-{4>-[2-('6-MfetHyl-pyπdm-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}- butyl)-(BODIPY FL) amide; and
373) N-(4- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} - butyl)-(Texas Red-X) amide
374) N-[3-(2-amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyrimidin-7- yl]-acetamide;
375) N-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- acetamide.
376) 3-(3-pyridm-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propylaniine,
377) N-[3-(3-pyridin-2-yl-4-qumolin-4-yl-pyrazol-l-yl)-propyl]-acetamide,
378) N-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol- 1 -yl)-propyl]-methanesulfonamide,
379) dimethyl-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-amine, 380) 4-{3-pyridin-2-yl-l-[2-(lH-tetrazol-5-yl)-ethyl]-lH-pyrazol-4-yl}-quinoline, 381) 4-[3 -pyridin-2-yl- 1 -(3-pyrrolidin- 1 -yl-propyl)- 1 H-pyrazol-4-yl] -quinoline,
382) 5 -(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-pyridin-2-ylamine,
383) 2,4-dimethoxy-5-(3 -pyridin-2-yl- lH-pyrazol-4-yl)-pyrimidine,
384) 3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propionic acid, 385) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indole, 386) 2-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-lH-pyrazol-3-yl]-pyridine, 387) N-hydroxy-3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propionamide, 388) 2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-ethylamine,
389) N-[2-(3 -pyridin-2-yl-4-quinolin-4-yl-pyrazol- 1 -yl)-ethyl] -methanesulfonamide,
390) 2-methyl-4-methylsulfanyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyrimidine,
391) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-pyridine,
392) 2-[4-(2,3-dihydro-benzofuran-5-yl)- lH-pyrazol-3-yl] -pyridine,
393) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[d]isoxazole,
394) 3-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-propionitrile, 395) N-{3-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-propyl}- methanesulfonamide,
396) 2-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-lH-pyrazol-3-yl]-6-metliyl-pyridme, 397) [4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridm-2-yl)-pyrazol-l-yl]-acetonitrile, 398) N-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethyl}- methanesulfonamide,
399) 4-[3-(6-methyl-pyridin-2-yl)- 1 H-pyrazol-4-yl] -2-methylsulfanyl-pyrimidine,
400) 4-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-2H-ρhthalazm- 1 -one,
Figure imgf000186_0001
402) 6-(3-pyridin-2-yl- lH-pyrazol-4-yl)-[l ,2,4]triazolo[ 1 ,5-a]pyridine,
403) 3-methyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
404) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-4H-berizo[l,4]oxazm-3-one,
405) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinoxaline,
406) 3-(4-nitro-benzyl)-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
407) 5-methyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyridine,
408) 4-methyl-7-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-3 ,4-dihydro- 1 H-benzo [e] [ 1 ,4]diazepine- 2,5-dione,
409) 2,3-dimethyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one, 410) 6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l:,5-a]pyridine,
410a) 1 -methoxy-4-(3 -pyridin-2-yl- lH-pyrazol-4-yl)-isoquinoline, 411) 2-methyl-6-(3-pyridm-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyridine, 41 Ia) 4-(3 -pyridin-2-yl- lH-pyrazol-4-yl)-2H-isoquinolin-l -one,
412) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-trifluoromethyl-pyridine, 412a) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-vinyl-pyridine,
413) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-propenyl-pyridine, 414) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-ethyl-pyridine,
415) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-propyl-pyridine,
416) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-cyclopropyl-pyridine,
417) l-[6-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-pyridin-2-yl]-etlianol,
418) 4-methoxy-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline,
419) 6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-quinoline,
420) 6-(3-pyridin-2-yl- lH-pyrazol-4-yl)-qumazolin-4-ylamine,
421 ) 6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-3H-quinazolin-4-one,
422) 7-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyrido[l,2-a]pyrimidin-4-oixe,
423) 6-[3-(6-cyclopropyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
424) 3-methyl-6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3H-quinazolin-4-one, 425) 4-(2-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethoxy}- ethoxy)-bicyclo[2.2.2]octane-l-carboxylic acid,
426) 4-(2-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethoxy}- ethoxy)-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester, 427) 4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l -yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester,
428) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-isopropyl-pyridine, 429)i|'2-(4-benzδ[riS7dϊoxbl-5-yl-5-trifluoromethyl-lH-pyrazol-3-yl)-6-bromo-pyridine, 430) 6-[3-(5-fluoro-6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine;,
431) 6-[3-(6-trifluoromethyl-ρyridin-2-yl)-lH-pyrazol-4-yl]-[l ,2,4]triazolo[l ,5-a]pyridine.,
432) 6-[3-(6-methyl-pyridin-2-yl)- 1 H-pyrazol-4-yl]-quinoxaline,
432a) 6-[3-(6-cyclopropyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3-methyl-3H-qumazolin-4-one,
433) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l ,2,4]triazolo[l ,5-b]pyridazine, 433 a) 6-[3 -(6-methyl-pyridin-2-yl)- lH-pyrazol-4-yl] -quinoline,
434) 6-(4-benzo[l ,3 ]dioxol-5-yl-lH-pyrazol-3-yl)-3-fluoro-2-methyl-pyridine, 435) 7 -methoxy-3 -methyl-6-(3 -pyridin-2-yl- 1 H-pyr azol-4-yl)-3H-quinazolin-4-one,
436) (4-morpholin-4-yl-phenyl)-[6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-quinazolin-4-yl] -amine,
437) 4-isopropoxy-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline, 438) 6-(3-Pyridin-2-yl- 1 H-pyrazol-4-yl)-quinolin-4-ylamine,
439) {4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohexyl}- carbamic acid benzyl ester,
440) 4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohexylamine3,
441) N-{4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohexyl}- methanesulfonamide,
442) 6-[3-(5-fluoro-6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoxaline,
443) 7-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyridine,
444) l-tert-butyl-3-[6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin-4-yl]-urea,
445) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[l,2,5]thiadiazole,
446) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[l,2,5]oxadiazole,
447) 5-(3-Pyridin-2-yl-lH-pyrazol-4-yl)-benzooxazole, 448) 4-morpholin-4-yl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolme, 449) 6-[3-(6-trifluoromethyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoxaline, 450) 4-(4-methoxy-phenyl)-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline,
451) 5-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-benzo[l ,2,5]thiadiazole,
452) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzothiazole,
453) 3-(3-methoxy-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
454) 5-methyl-thiopliene-2-carboxylic acid [6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin_-4- yl] -amide,
455) 5-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3-phenyl-benzo[c]isoxazole,
456) 3-(4-methoxy-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
457) 3-(4-chloro-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
458) 3-(4-ethyl-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole, 459) |4-methoxy-pnenyl)-[i6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoπ
460) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3-thiophen-3-yl-benzo[c]isoxazole,
461) 5-(3 -pyridin-2-yl- 1 H-pyrazol- 4-yl)- 1 H-indazole-3 -carboxylic acid,
462) 5-(3-Pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid methylamide,
463) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid dimethylamide,
464) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid (2,2-dimethyl- propyl)-amide,
465) 5 -(3 -pyridin-2-yl- lH-pyrazol-4-yl)-l H-indazole-3 -carboxylic acid phenylamide, 466) morpholin-4-yl-[5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazol-3-yl]-methanone,
467) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid benzylamide,
468) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid cyclopentylamide; 469) 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzamide;
470) 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzonitrile;
471) 4-[5-(2-methanesulfonyl-pyrirnidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
472) 4-[5-(2-metlioxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
473) 4-[5-(2-hydroxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
474) 4-[5-(2-cyclopropylamino-pyτimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
475) 4-[5 -(2-cyclopropylamino-pyτimidin-4-yl)-4-(6-m.ethyl-pyridin-2-yl)- lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
476) 4-[5-(2-cyclopropylamino-pyiimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
477) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
478) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;
479) 4-[5-(2-amino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
480) {4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-carbarnic acid benzyl ester; 48 t) N- {4-[5-'[2-cyclopropylamino-pynmidin-4-yl)-4-(6-m.ethyl-pyridm-2-yl)- 1 H-imidazol-
2-yl]-bicyclo[2.2.2]oct-l-yl}-acetamide;
482) N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-iinidazol-
2-yl]-bicyclo[2.2.2]oct- 1 -yl} -methanesulfonamide;
483) N-{4-[5-(2-cyclopropylammo-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-
2-yl]-bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;
484) 4-[5-quinoxalin-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)- 1 H-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
485) 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
486) 6-[2-tert-butyl-5-(2-cyclopropyl-pyrimidin-4-yl)-3H-ixnidazol-4-yl]-quinoxaline;
487) 6-[5-(2-byclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
488) {4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-iniidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanol;
489) 6-[5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
490) 6-[2-tert-butyl-5-(2-trifluoromethyl-pyrimidin-4-yl)-3Η-imidazol-4-yl]-quinoxaline; 491) 4-[5-quinoxalin-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
492) 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yrl-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
493) 6-[5 -(2-cyclopropyl-pyrimidin-4-yl)-2-(l -methanesulf onyl-piperidin-4-yl)-3H-imidazol-
4-yl] -quinoxaline;
494) 4-[5-(2-methyl-pyrimidin-4-yl)-4-[l,2,4]triazolo[4,3-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
495) 4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
496) 4-[4-(2-methyl-pyrirnidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid;
497) 4-[4-(2-methyl-pyrimidin-4-yl)-5-[l,2,4]txiazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
498) 4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexanol;
499) 4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH:-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol,
500) 4-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-2-methyl-pyrimidine,
500a) 6-[3-(2-methyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-[l ,2,4]triazolo[l ,5-a]pyridine, 50 f) &-[3-(2-ffifIύδrόmetnyl:pyrirnidin-4-yl)- 1 H-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
502) 6- [3 -(2-methyl-pyrimidin-4-yl)- 1 H-pyrazol-4-yl] -quinoxaline,
502a) 6-[3-(2-trifluoromethyl-ρyrimidin-4-yl)-lH-pyrazol-4-yl]-quiiioxaline,
503) 6-[3-(2-cyclopropyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-quinoxaline,
504) 4-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-2-trifluoromethyl-pyrimidine,
505) 7-[3-(2-1rifluoromethyl-pyriniidin-4-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine, or
506) 6-[3-(2-Trifluoromethyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-quinoline.
33. The device of claim 25, wherein device is a delivery pump.
34. The device of claim 25, wherein the device is a stent.
35. A method of treating or preventing restinosis, vascular disease, or hypertension by administering to a subject in need thereof a compound of the formula 1, II, III, IV, V, or VI, or an N-oxide or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the structure:
Figure imgf000190_0001
wherein
R1"1 is aryl, heteroaryl, aralkyl, or heteroaralkyl; each RI-a is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aUcylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylstilfanyl, heterocyclo alkyl, heterocycloalkyloxy, heterocycloalkylsulfan.yl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfairyl, or heteroaroyl;
Xi-1 is cycloalkyl or heterocycloalkyl;
Y1-1 is a bond, -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(O)- N(Rb)-, -A(kbli)-C(05-7-0-d(b)-N(Rft)-, -N(Rb)-C(O)-O-, -0-S(Op-N(R13)-, -N(Rb)- S(0)p-O-, -N(Rb)-C(O)-N(Rc)-, -N(Rb)-S(O)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(0)p-N(Rb)-C(O)-, -C(0)-N(Rb)-S(0)p-N(Rc)-, -C(O)-O-S(O)p-N(Rb)-, -N(Rb)-S(O)p-N(Rc)-C(O)-, -N(Rb)-S(O)p-O-C(O)-, -S(O)p-N(Rb)-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)P-, -C-, -S-, or -(C(Rb)(Rc))q-, wherein each of Rb and Rc is independently hydrogen, hydroxy, alk;yl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl, p is 1 ox 2, and q is 1-4;
R1"2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl; each of A1"1 and A1"2, independently, is O, S, N, or NRb, provided that at lea.st one of A w and A l'2 is N; and m is 0, 1, 2, or 3, and when m >2, two adjacent R1"8 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; the compound of formula II has the structure:
Figure imgf000191_0001
wherein each OfXn-1, Xπ-2, Xn-3, and Xn-4 is independently CRX or N, provided that aio more than two of X H-1, X n-2, X H-3, and X U-4 can be N simultaneously; each OfYn-1 and Y11-2 is independently CRy or N, provided that at least one of Yn-1 and Yn-2 must be N; each R11"1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamiaio, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkylorxy, 'heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; each R11"2 is independently alkyl, alkenyl, alkynyl, acyl, halo, hydroxy, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -NCalkylXcycloalkyl), - NH(heterocycloalkyl), -NH(heteroaryl), -NH-alkyl-heterocycloalkyl, -NH-alkyl- heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl) alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, cycloalkyl-alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalky^alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkytycarbonylamino, (heterocycloalkytyalkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkoxycarbonylammoalkylamino, (heteroaryl)arylcarbonylaminoalkylamino, heteroaralkylcarbonylaminoalkylamino, (heteroary^arylsulfonylaminoalkylcarbonylaniirioalkylamino, arylsulfonylaminoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl; m is 0, 1, 2, 3, or 4, and when m >2, two adjacent R1 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; n is 0, 1, 2, or 3, and when n ≥2, two adjacent R2 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; and each of Rx and Ry is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfmyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalky^alkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cycloalky^alkylcarbonylamino, (cycloalky^alkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, aralkylcarbonylamino, aralkylsulfonylamino,
(heterocycloalky^carbonylamino, (heterocycloalkyl)sulfonylamino, "(lieϊerbcy"croallcyl)alk;ylcarbonylamino, (heterocycloalkytyalkylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylamino, heteroaralkylsulfonylami.no, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloalkyl)alkyl, (cycloalkyl)alkoxy, (cycloalkyl)alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalk;yl)alkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl-, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, heteroaralkyl, (heteroaryl)alk:oxy, or (heteroaryl)alkylsulfanyl; the compound of formula III has the structure:
Figure imgf000193_0001
wherein each of Xπn, Xm-2, Xπi-3, and Xra-4 is independently CRπi'x or N, provided that no more than two OfXm-1, Xπi-2, X111-3, and Xm-4 can be N simultaneously; each of Ym-i and Y1n-2 is independently CRiπ"y or N, provided that at least one OfYm-1 and Ym-2 must be N; each R111"1 is independently alkyl, alkenyl, alkynyl, alkozxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; each R111"2 is independently alkyl, alkenyl, alkynyl, acyU halo, hydroxy, -NH2, -NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -N(alkyl)(cyclocalkyl), - TSJH(heterocycIdalkyl), -lSIH(heteroaryl), -NH-alkyl-heterocycloalkyl, -NH-alkyl- heteroaryl, -NH(aralkyl), cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, aroyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, heteroaralkyl, heteroaroyl, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, aryloxy, arylalkoxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy, heteroaryloxy, heteroarylalkoxy, alkylsulfanyl, cycloalkylsulfanyl, (cycloalkyl)alkylsulfanyl, arylsulfanyl, aralkylsulfanyl, heterocycloalkylsulfanyl, (heterocycloalkyl)alkylsulfanyl, heteroarylsulfanyl, heteroarylalkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalky^alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkytycarbonylamino, (heterocycloalkytyalkylcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkoxycarbonylaminoalkylamino, (heteroaryl)arylcarbonylaminoalkylamino, heteroaralkylcarbonylaminoalkylamino, (heteroary^arylsulfonylaminoalkylcarbonylaminoalkylamino, arylsulfonylaminoalkylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, or carbamoyl; m is 0, 1, 2, 3, or 4, and when m ≥2, two adjacent R111'1 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; n is 0, 1, 2, or 3, and when n Ξ≥2, two adjacent R111"2 groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; and each of Rm"x and Rπi"y is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, cycloalkylcarbonyl, (cycloalkytyalkylcarbonyl, aroyl, aralkylcarbonyl, heterocycloalkylcarbonyl, (heterocycloalkyl)acyl, heteroaroyl, (heteroaryl)acyl, aminocarbonyl, alkylcarbonylamino, (amino)aminocarbonyl, alkylsulfonylaminocarbonyl, alkylsulfonylamino, cycloalkylcarbonylamino, cycloalkylsulfonylamino, (cycloalkytyalkylcarbonylamino, (cycloalkytyalkylsulfonylamino, arylcarbonylamino, arylsulfonylamino, aralkylcarbonylamino, aralkylsulfonylamino, (heterocycloalkytycarbonylamino, (heterocycloalkyl)sulfonylamino, (heterocycloalky^alkylcarbonylamino, (heterocycloalkytyalkylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfonylamino, heteroaralkylcarbonylamino, heteroaralkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, (cycloallcyϊ) aϊkyl, (cycloalkyl)alkoxy, (cycloalkyl)alkylsulfanyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, (heterocycloalkyl)alkyl, (heterocycloalkyl)alkoxy, (heterocycloalkyl)alkylsulfanyl, aryl, aryloxy, arylsulfanyl, aralkyl, aralkyloxy, aralkylsulfanyl, arylalkenyl, arylalkynyl, heteroaryl, heteroaryloxy, hetero arylsulfanyl, heteroaralkyl, (heteroaryl)alkoxy, or (heteroaryl)alkylsulfanyl; the compound of formula IV has the structure:
Figure imgf000195_0001
wherein each R™"* is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
R1^"1 is a bond, alkylene, alkenylene, alkynylene, or -(CH2)rl-O-(CH2)r2-, where each of rl and r2 is independently 2 or 3;
R^"2 is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, or a bond;
RIV-3 is -C(O)-, -C(O)O-, -OC(O)-, -C(0)-N(RIV-b)-, -N(RIV"b)-C(0)-, -O- C(O)-N(R1^)-, -N(R1^)-C(O)-O-, -O-S(O)p-N(RIV-b)-, -N(R1^)- S(0)p-0-, -N(RIV" b)-C(0)-N(RIV-c)-, -N(RIV-b)-S(0)p-N(RIV"b)-, -C(O)-N(RIV"b)-S(O)p-, -S(0)p-N(RIV'b)- " Cf(O)-; -S(O)p-N(Rlv-b)-, -N(RIV-b)-S(O)p-, -N(R1^)-, -S(O)P-, -O-, -S-, or - (C(RIV"b)(RIV'c))q-, or a bond; wherein each of Rw'h and Rw'c is independently hydrogen, hydroxy, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl; p is 1 or 2; and q is 1-4;
Rw~4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alk:yl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
Rw~5 is hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy., alkylsulfinyl, amino, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, cycloalkylsulfmyl, heterocycloalkyl, heterocycloalkoxy, heterocycloalkylsulfinyl, aryl, aryloxy, arylsulfinyl, heteroaryl, heteroaryloxy, or heteroarylsulfinyl;
R^" is (1) a 5- to 6-membered heterocyclyl containing 1-3 hetero ring atoms selected from the group consisting of -O-, -S-, -N=, and -NR^"0-, where JZ.w~d is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl; said heterocyclyl being substituted with R^"6 and optionally substituted with one to two Rw"f; where Rw'e is oxo, thioxo, alkoxy, alkylsulfmyl, -NH2, -NH(unsubstituted alkyl), or -N(unsubstituted a.lkyl)2, and R^ is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulflnyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, heterocycloalkyl, heterocyclo alkyloxy, heterocycloalkylsulfanyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; or
(2) a fused ring heteroaryl selected from the group consisting of:
Figure imgf000196_0001
wherein ring A is an aromatic ring containing 0-4 hetero ring atoms, and ring B is a 5- to 7-membered aromatic or nonaromatic ring containing 0-4 hetero ring atoms, provided that at least one of ring A and ring B contains one or more hetero ring atoms; ring A' is an aromatic ring containing 0-4 hetero ring atoms, and ring B' is a 5- to 7-membered saturated or unsaturated ring containing 0-4 hetero ring atoms, provided that at least one of ring A' and ring B' contains one or more hetero ring atoms; each hetero ring atom is -O-, -S-, -N=, or -NRIV"g-; each X1 is independently N or C; each X2 is independently -O- -S-, -N=, -NRIV'g- or -CHR™" h-; where Rw'e is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroaralkyl; each of Rw'h and R^"1 is independently alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; and n is 0-2; and m is 0-3, and when m >2, two adjacent Rw'& groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety; provided that if R^"6 is 2-naphthyridinyl, 4-quinolinyl, imidazo[l,2-a]pyridyl, or benzimidazolyl, then -R^-R^-R^-R™"4 is not H, unsubstituted alkyl, -CH2-C(O)-N(H)-alkyl, -CH2-C(O)-N(alkyl)2, or benzyl; the compound of formula V has the structure
Figure imgf000197_0001
wherein
R >v- "i is heteroaryl; each Rv"a, independently, is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfϊnyl, alkylsulfonyl, aminocarbonyl, aiKyicaroonyiammo, aryicar-Dυπylamino, heteroarylcarbonylami.no, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
Xv is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or a bond;
Yv is a bond, -C(O)-. -C(O)-O-, -O-C(O)-, -S(O)P-O-, -O-S(O)P-, -C(O)-N(Rb)-, -N(Rb)-C(O)-, -O-C(O)-N(Rb)-, -N(Rb)-C(O)-O-, -C(0)-N(Rb)-0-, -O- N(Rb)-C(O)-, -0-S(OVN(R13)-, -N(Rb)- S(O)P-O-, -S(O)p-N(Rb)-O-, -O-N(Rb)-S(O)p-, -N(Rb)-C(O)-N(R>, -N(Rb)-S(O)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb)-C(O)-, -C(O)-N(Rb)-S(O)p-N(RcK -C(O)-O-S(O)p-N(Rb)-, -N(Rb)-S(O)p-N(Rc)-C(O)-, -N(Rb)-S(O)p-O-C(O)-, -S(O)p-N(Rb)-, -N(Rb)-S(O)p-, -N(Rb)-, -S(O)P-, -O-, -S-, or -(C(Rb)(Rc))q-, wherein eacli of Rb and Rc, independently, is hydrogen, hydroxy, alkyl, alkoxy, amino, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl, p is 1 or 2, and q is 1-4;
Rv"2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, aralkyl, arylalkenyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, heteroaryl, heteroaralkyl, or (heteroaryl)alkenyl; each of Av"! and Av"2, independently, is N or NRb; and m is O, 1, 2, or 3, and when m >2, two adjacent R v"a groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety, provided that if Xv is a bond, then Yv is a bond; Rv"2 is hydrogen or alkyl; m is 1, 2, or 3; and at least one Rv"a is substituted at the 2-pyrimidinyl position; and the compound of formula VI has trie structure: RV VIl--3>3__p RVN I-4
Figure imgf000199_0001
wherein each RVI"a, independently, is alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, -NH2, -NH(unsubstituted alkyl), -N(unsubstituted alkyl)2, nitro, oxo, thioxo, cyano, guanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylsulfanyl, heterocycloalkylcarbonyl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl;
RVM is a bond, alkylene, alkenylene, alkynylene, or -(CH2)rl-O-(CH2)r2-, where each of rl and r2, independently, is 2 or 3;
RVI"2 is cycloalkylene, heterocycloalkylene, cyclo alkenylene, heterocycloalkenylene, arylene, heteroarylene, or a bond;
RVI"3 is -C(O)-, -C(O)-O-, -O-C(O)-, -S(O)p-O-, -O-S(O)P-, -C(0)-N(Rb)-, -N(Rb)-C(0>, -0-C(0)-N(Rb)-, -N(Rb)-C(0)-0-, -C(O)-N(Rb)-O-, -0-N(Rb)-C(0)-, -O-S(O)p-N(Rb)-, -N(Rb)- S(O)p-O-, -S(O)p-N(Rb)-O-, -O-N(Rb)-S(O)p-, -N(Rb)-C(0)-N(Rc)-, -N(Rb)-S(0)p-N(Rc)-, -C(O)-N(Rb)-S(O)p-, -S(O)p-N(Rb)-C(O)-,
Figure imgf000199_0002
-N(Rb)-S(O)p-O-C(O)-, -S(O)p-N(Rb>, -N(Rb)-S(O)p-, -N(Rb)-, -S(OV, -0-, -S-, -(C(Rb)(Rc))q-, or a bond; wherein each of Rb and Rc is independently hydrogen, hydroxy, alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaralkyl, p is 1 or 2, and q is 1-4; ''KVIJ4'is"iiydrogeή, alkyϊ, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, heterocycloalkenyl, (heterocycloalkenyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
RVI"5 is hydrogen, unsubstituted alkyl, halo-substituted alkyl, alkoxy, alkylsulfinyl, amino, alkenyl, alkynyl, cycloalkoxy, cycloalkylsulfinyl, heterocyclo alkoxy, heterocycloalkylsulfinyl, aryloxy, arylsulfήryl, heteroaryloxy, or heteroarylsulfϊnyl;
RVI"6 is a 5- to 6-membered monocyclic heterocyclyl or a 8- to 11-membered bicyclic heteroaryl; each being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, acyl, halo, hydroxy, amino, nitro, oxo, thioxo, cyano, gixanadino, amidino, carboxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylammo, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, alkoxycarbonyl, alkylcarbonyloxy, urea, thiourea, sulfamoyl, sulfamide, carbamoyl, cycloalkyl, cycloalkyloxy, cyclo alkylsulfanyl, heterocycloalkyl, heterocyclo alkyloxy, heterocycloalkylsulfanyl, cycloalkylcarbonyl, heterocycloalkylcarbonyl, aryl, aryloxy, arylsulfanyl, aroyl, heteroaryl, heteroaryloxy, heteroarylsulfanyl, or heteroaroyl; and m is 0-3, and when m Ξ≥2, two adjacent R VI"a groups can optionally join together to form a 4- to 8-membered optionally substituted cyclic moiety.
36. The method of claim 35, wherein restenosis is coronary restenosis, peripheral restenosis, carotid restenosis.
37. The method of claim 35, wherein vascular disease is intimal thickening, vascular remodeling, or organ transplant-related vascular disease.
38. The method of claim 37, wherein the vascular disease is intimal thickening or vascular remodeling.
39. The method of claim 35, wherein hypertension is primary or secondary hypertension, systolic hypertension, pulmonary hypertension or hypertension-induced vascular remodeling.
40. The method of claim 35, wherein the compound is l) 4-(4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl)-piperidine-l- carboxylic acid benzyl ester; 2) 4-(4-Benzo[ 1 ,3]dioxoI-5-yl-5-pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxyΗc acid benzyl ester;
3) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin.e-l- carboxylic acid benzyl ester;
4) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-pyrrolidine-l- carboxylic acid benzyl ester;
5) 2-(5-Benzo[l,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine; 6) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carbox>/lic acid benzyl ester;
7) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidirLe-l- carboxylic acid benzyl ester;
8) 3-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-pyrrolidixie-l- carboxylic acid benzyl ester;
9) 2-(5-Benzo[l,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-6-methyl-pyridine; 10) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imid-azol-4- yl] -6-methyl-pyridine;
11) 2-[5-Benzo[ 1 ,3]dioxol-5-yl-2-(l -phenylmethanesulfonyl-piperidin-4-yl)-3H-iinid-azol-4- yl] -pyridine;
12) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
13) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
14) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridm-2-yl-lH-imidazol-2-yl)-piperidine-l-carbo^cylic acid 2-chloro-benzyl ester;
15) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carbo^iylic acid 2,4-dichloro-benzylamide;
16) 1 -[4-(4-Benzo[ 1 ,33dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidin- 1-yl]- ethanone;
17) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-furan-2-yl-methyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
18) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-cyclotiexyl}- carbamic acid benzyl ester;
19) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl] cyclohexylamine; 20) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylJ-C-phenyl-methanesulfonamide;
21) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
22) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
23) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester;
24) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-ethyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
25) 2-(5-Benzo[ 1 ,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine;
26) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-nitro-benzyl ester;
27) 4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- 1 H-imidazol-2-yl)-piperidine- 1 -carboxylic acid 4,5-dimethoxy-2-nitro-benzyl ester;
28) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 3-fluoro-benzylamide;
29) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-fluoro-benzylamide;
30) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid benzylamide;
31) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(toluene-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4-yl}- pyridine;
32) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 4-methyl-benzylamide;
33) 4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidine- 1-carboxylic acid 4-methoxy-benzylamide;
34) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid 2-chloro-benzylamide;
35) 4-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- benzoic acid;
36) 4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxylic acid amide;
37) 4-[4-(4-Benzo[ 1 ,3]dioxol-5-yl-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidine- 1 -sulfonyl]- benzonitrile; 38)'t2-T5-Benzo[I,3]dioxoT-5-yl-2-[l-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
39) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
40) {5-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-sulfonyl]- naphthalen- 1 -yl} -dimethyl-amine;
41) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-4-yl-methyl)-piperidin-4-yl)]-3H-imidazol-4- yl} -pyridine;
42) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l -(propane-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
43) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-methoxy-benzenesulfonyl)-pipeτidin-4-yl]-3H- imidazol-4-yl} -pyridine;
44) l-{4-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l- sulfonyl] -phenyl} -ethanone;
45) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-methyl-benzyl)-piperidin-4-yl]-3H-imidazol-4-yl}- pyridine;
46) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3-fluoro-5-trifluoromethyl-benzyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
47) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-cycloliexylmethyl-piperidm-4-yl)-3H-imidazol-4-yl]- pyridine;
48) 2-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-l-ylmethyl]- cyclopropanecarboxylic acid ethyl ester;
49) 2-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidin-l-ylmethyl]- pyrrolidine- 1-carboxylic acid tert-butyl ester;
50) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[l -(2,2-dimethyl-[ 1 ,3]dioxolan-4-ylrriethyl)-piperidin-4- yl] -3H-imidazol-4-yl} -pyridine;
51) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-ethanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]- pyridine;
52) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(butane- 1 -sulfbnyl)-piperidin-4-yl] -3H-imidazol-4-yl} - pyridine;
53) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
54) 2- (5-Benzo[l ,3]dioxol-5-yl-2-[l-(2-phenyl-ethenesulfonyl)-piperidin-4-yl]-3H-imidazol- 4-yl} -pyridine; 55 j 2-X5-'feenzo['ϊ 31$^ yl} -pyridine;
56) l-[4-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l- sulfonylmethyl]-7,7-dimethyl-bicyclo[2.2.1]heptan-2-one;
57) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
58) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-dichloro-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -pyridine;
59) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(4-fluoro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
60) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,4-dichloro-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -pyridine;
61) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-3H-imιidazol- 4-yl} -pyridine;
62) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-p-tolylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -pyridine;
63) 3-(4-Benzo[ 1 ,3]dioxol-5-yl-l -hydroxy-5-pyridin-2-yl- lH-imidazol-2-yl)-piperidio.e- 1 - carboxylic acid benzyl ester;
64) 3-(4-Benzo[l,3]dioxol-5-yl-5-pyridin-2-yl-lH-imidazol-2-yl)-piperidine-l-carboxiylic acid benzyl ester;
65) 4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-vl]- piperidine-1 -carboxylic acid benzyl ester;
66) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(pyridin-2-yl-methanesulfonyl)-piperidin-4-yl] -3 H- imidazol-4-yl} -pyridine;
67) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-naphthalen-l-yl-ethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
68) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-3-yl)-3H-imidazol-4- yl]-pyridine;
69) 3-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1 -carboxylic acid benzyl ester;
70) 2- {5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-4-yl-methanesulfonyl)-ρiperidin-4-yl]-3 H- irnidazol-4-yl} -pyridine;
71) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(pyridin-3-yl-methanesulfonyl)-ρiρeridin-4-yl] -3 H- imidazol-4-yl} -pyridine; 72J'2-'{5-Benzo[l,3]diόxor-5-yl-2-[l-(3-trifluoromethyl-phenylmethanesulfonyl)-piperidin-4- yl]-3H-imidazol-4-yl}-pyridine;
73) 3-[4-Benzo[l ,3]dioxol-5-yl-l -hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- pyrrolidine-1-carboxylic acid benzyl ester;
74) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(4-trifluoromethyl-phenylmethanesulfonyl)-piperidin-4- yl]-3H-imidazol-4-yl} -pyridine;
75) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-bis-trifluorometliyl-phenylmethanesulfonyl)- piperidin-4-yl]-3H-imidazol-4-yl}-pyridine;
76) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(biphenyl-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -pyridine;
77) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(3,5-difluoro-phenylmethanesulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl} -pyridine;
78) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-2-yl-methanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
79) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
80) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(biphenyl-4-ylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -pyridine;
81) 4-[5-Benzo[l,3]dioxol-5-yl-l-methyl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
82) 4-[4-Benzo[l,3]dioxol-5-yl-l-methyl-5-(6-metliyl-pyridin-2-yl)-lH-irnidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
83) {4-[4-Benzo[ 1 ,3]dioxol-5-yl- 1 -hydroxy-5-(6-methyl-ρyridin-2-yl)- lH-imidazol-2-yl]- cyclohexylj-carbamic acid benzyl ester;
84) 2- {5 -Benzo [1,3] dioxol-5 -yl-2- [ 1 -(3 -phenoxy-phenylmethanesulfonyl)-piperidin-4-yl] - 3H-imidazol-4-yl}-6-methyl-pyridine;
85) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-ethanesulfonyl-piperidin-4-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
86) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-l-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
87) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(butane- 1 -sulfonyl)-ρiρeridin-4-yl]-3H-imidazol-4-yl} - 6-methyl-pyridine;
88) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l-(pyridin-3-ylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine; 89)"2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(pyridin-4-ylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
90) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,5-difluoro-phenylmethanesulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
91) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(3-trifluoromethyl'phenylmethanesulfonyl)-piperidin-4- yl]-3H4midazol-4-yl}-6-methyl-pyridine;
92) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(thiophene-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl } -6-methyl-pyridine;
93) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(butane-1 -sulfonyl)-piρeridin-3-yl]-3H-imidazol-4-yl} - 6-methyl-pyridine;
94) 2-[5-Benzo[ 1 ,3]dioxol-5-yl-2-(l -phenylmemanesulfonyl-piperidin-3-yl)-3H-imidazol-4- yl] -6-methyl-pyridine;
95) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(l-methyl-lH-imidazole-4-sulfonyl)-piperidin-4-yl]- 3H-imidazol-4-yl}-6-methyl-pyridine;
96) 2- {5-Benzo[l ,3]dioxol-5-yl-2-[l -(5-methyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
97) 4-[5-Benzo[l,3]dioxol-5-yl-l-hydroxy-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
98) Butane-1 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)~lH- imidazol-2-yl] -cyclohexyl} -amide;
99) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- cyclohexyl}-C-pyridin-2-yl-methanesulfonamide;
100) Thiophene-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH- imidazol-2-yl] -cyclohexyl} -amide;
101) 1 -Methyl- lH-imidazole-4-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl- pyridin-2-yl)-lH-imidazol-2-yl]-cyclohexyl}-amide;
102) 4-[4-Benzo[ 1 ,3]dioxol-5-yl- l-hydroxy-5-(6-methyl-pyridin-2-yl)- lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
103) 4-[4-Benzo[l,3]dioxol-5-yl-l-hydroxy-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
104) 4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-bromo-pyridin-2-yl)- lH-imidazol-2-yl]-piperidine- 1 - carboxylic acid benzyl ester;
105) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(thiophene-3-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine; 106) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(5-methyl-2-trifluoromethyl-furan-3-sulfonyl)- piperidin-4-yl]-3H-imidazol-4-yl}-6-methyl-pyridine;
107) 4-[2-( 1 -phenylmethanesulfonyl-piperidin-4-yl)-5-(6-methyl-pyridin-2-yl)-lH-imidazol- 4-yl]-pyridin-2-yl-fluoride;
108) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-trifluoromethyl-pyridin-2-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
109) 4-[5-Benzo[ 1 ,3]dioxol-5-yl-4-(6-bromo-pyridin-2-yl)- 1 -hydroxy- lH-imidazol-2-yl] - piperidine- 1-carboxylic acid benzyl ester;
110) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -6-bromo-ρyridine;
111) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanol;
112) 4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
113) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-2H-imidazol-2-yl]-piperidine-l- sulfonic acid dimethylamide;
114) l-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidm-
1 -yl} -3 -prienyl-propan- 1 -one;
115) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(propane-2-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-meth.yl-pyridine;
116) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonitrile;
117) 4_[4_Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridm-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-ylamine;
118) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-C-phenyl-methanesulfonamide;
119) N-{4-[4-Benzo[l53]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanesulfonamide;
120) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-C-pyridin-2-yl-methanesulfonamide;
121) 2-{5-Benzo[l,3]dioxol-5-yl-2-[4-(lH-tetrazol-5-yl)-bicyclo[2.2.2]oct-l-yl]-3H- imidazol-4-yl}-6-methyl-ρyridine;
122) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetamide;
Figure imgf000208_0001
imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
124) 1 -Methyl- lH-imϊdazole-4-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl- pyridin-2-yl)-lH-imidazol-2-yl]-bicyclo[2.2.2]oct-l-yl}-amide;
125) Thiophene-3-sulfbnic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl] -bicyclo [2.2.2] oct- 1 -yl} -amide;
126) 2-{5-Benzo[l,3]ciioxol-5-yl-2-[l-(2-phenyl-ethenesulfonyl)-piperidm-4-yl]-3H- imidazol-4-yl} -6-meth.yl-pyridine;
127) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-phenyl-ethanesulfonyl)-ρiperidin-4-yl]-3H- imidazol-4-yl}-6-methyl-pyridine;
128) Methanesulfonic acid 4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl] -bicyclo [2.2.2] oct- 1 -ylmethyl ester;
129) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl }-acetonitrile;
130) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl} -acetic acid;
131) N-{4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-iniidazol-2-yl]- bicyclo[2.2.2]oct-l-ylmethyl}-methanesulfonamide;
132) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(biphenyl-4-sulfonyl)-piperidin-4-yl]-3H-imidazol-4- yl} -6-methyl-pyridine ;
133) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-mettιyl-pyridine;
134) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(3,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-meth.yl-pyridine;
135) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-iniidazol-2-yl]- bicyclo[2.2.2]oct-l-ylmetb.yl}-C-phenyl-methanesulfonamide;
136) N- {4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo [2.2.2] oct- 1 -ylmethyl} -C-pyridin-2-yl-methanesulfonamide; 137) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid benzylamide;
138) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid (pyridin-2-ylmethyl)-amide; 139) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane- 1 -carboxylic acid 3-chloro-4-fluoro-benzylamide; 140) 4-[4-Benzo[l,3Jdioxol-5-yl-5-(6-metliyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (furan-2-ylmethyl)-amide;
141) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-methanesulfonyl-pyrrolidin-3-yl)-3H-imidazol-4-yl]-6- methyl-pyridine;
142) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(butane- l-sulfonyl)-ρyrrolidin-3-yl]-3H-imidazol-4- yl} -6-methyl-pyridine;
143) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(l-methyl-lH-imidazole-4-sulfonyl)-pyrrolidin-3-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
144) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenybΩ.ethanesulfonyl-pyrrolidin-3-yl)-3H-imidazol-
4-yl]-6-methyl-pyridine;
145) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(4-chloro-benzenesulfonyl)-pyrrolidin-3-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
146) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-nitro-phenylmethanesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
147) 2-{5-Benzo[l,3]dioxol-5-yl-2-[l-(2-naphthalen-2-yl-ethanesulfonyl)-piperidin-4-yl]-
3H-imidazol-4-yl}-6-methyl-pyridine;
148) l-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine- l-sulfonylmethyl}-7,7-dimethyl-bicyclo[2.2.1]lieptan-2-one;
149) 2- {5-Benzo[ 1 ,3]dioxol-5-yl-2-[ 1 -(4-chloro-benzenesulfonyl)-piperidin-4-yl]-3H- imidazol-4-yl} -6-methyl-pyridine;
150) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methylamide;
151) 4-[4_Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid ethylamide;
152) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid butylamide;
153) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid isopropylamide; 154) 4-[4_Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (3-imidazol-l-yl-propyl)-amide; 155) 2-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidine- 1 -sulfonylmethyl} -phenylamine;
156) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (l-meth.yl-5-methylsulfanyl-lH-[l,2,4]triazol-3-yl)- amide;
2O8 157) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH:-iniidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid cyclohexylamide;
158) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-pyrrolidin-l-yl-methanone;
159) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH:-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid dimethylamide;
160) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH:-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid diethylamide;
161) 4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid dipropylamide;
162) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid (5,7-difluoro-benzothiazol-2-yl)-amide;
163) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH:-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid benzothiazol-2-ylamide;
164) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH:-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (lH-benzoimidazol-2-yl)-amide;
165) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH:-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid (2-hydroxy-l -methyl-2-phenyl-ethyl)-amide;
166) 4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)- lEC-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid (pyridin-4-ylmethyl)-arnide;
167) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]-piperidin-l- yl}-(3-chloro-phenyl)-methanone;
168) {4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-l H-imidazol-2-yl]-piperidin- 1 - yl} -(4-fluoro-phenyl)-methanone;
169) {4-[4-Benzo[ 1 ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-l Η-imidazol-2-yl]-piperidin- 1 - yl}-(4-methoxy-phenyl)-methanone;
170) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-cyclopropyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
171) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH:-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;
172) 4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH[-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
173) {4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-ρyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethylj-carbamic acid benzyl ester; 174) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydrazide;
175) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl} -acetamide;
176) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethylj-methanesulfonamide;
177) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethylJ-C-phenyl-methanesulfonamide;
178) Butane- 1 -sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl] -cyclohexylmethyl} -amide;
179) Propane-2-sulfonic acid {4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH- imidazol~2-yl]-cyclohexylmethyl}-atnide;
180) N- {4-[4-Benzo[l ,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-C-pyridin-2-yl-methanesulfonamide;
181) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- cyclohexylmethyl}-C-pyridin-4-yl-methanesulfonamide;
182) (4-Methoxy-benzyl)-{4-[5-(6-methyl-pyridm-2-yl)-2-(l-phenylniethanesulfonyl- piperidin-4-yl)-lH-imidazol-4-yl]-pyridm-2-yl}-amme;
183) 4-[5-(6-Methyl-pyridin-2-yl)-4-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-iinidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
184) 4-[5-(6-Methyl-pyridm-2-yl)-4-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
185) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
186) 4-[4-(6-Methyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-iinidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
187) 4-[4-(6-Methyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]ρyridin-6-yl-lH-imIdazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid amide;
188) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl- lH-imidazol-2- yl] -bicyclo [2.2.2] octane- 1 -carboxylic acid;
189) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;
190) 4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yO- bicyclo[2.2.2]octan-l-ol; 191) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
192) 4-[4-(6-Cyclopropyl-pyridin-2-yl)-5-[l,2,4]triazolo[l,5-a]pyridin-6-yl-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
193) N-{4-[5-Benzo[l,3]dioxol-5-yl-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-sulfatnide;
194) Sulfamic acid 4-[4-benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl ester;
195) {4-[4-(6-Methyl-pyridin-2-yl)-5-qumoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl}- carbamic acid benzyl ester;
196) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonyl}-methanesulfonamide;
197) N-{4-[4-Benzo[l,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carbonyl}-benzenesulfonamide;
198) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester; 199) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
200) N- {4-[4-(6-Methyl-pyridm-2-yl)-5-quinoxalin-6-yl- lH-imidazol-2-yl]-cyclohexyl} - acetamide;
201) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-
1-carboxylic acid methyl ester;
202) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-
1-carboxylic acid;
203) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-
1-carboxylic acid hydroxyamide;
204) 4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-bicyclo[2.2.2]octane-
1-carboxylic acid amide;
205) N-{4-[4-(6-Methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexyl}- methanesulfonamide;
206) 2,2,2-Trifluoro-N-{4-[4-(6-methyl-pyridin-2-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- cyclohexyl} -acetamide;
207) 4-[4-(5-Fluoro-6-methyl-pyridin-2-yl)-5-[ 1 ,2,4]triazolo[l ,5-a]pyridin-6-yl-lH-imidazol-
2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester; 208) {4-[2-[l-(Butane-l-sulfonyl)-piperidin-4-yl]-5-(6-methyl-pyridin-2-yl)-lH-imidazol-4- yl] -pyridin-2-yl} -(4-methoxy-benzyl)-amine;
209) 4-[2-[l-(Butane-l-sulfonyl)-piperidin-4-yl]-5-(6-methyl-pyridin-2-yl)-lH-imidazol-4- yl] -pyridin-2-ylamine;
210) 2-[5-Benzo[l,3]dioxol-5-yl-2-(l-phenylmethanesulfonyl-piperidin-4-yl)-3H-imidazol-4- yl] -6-ethyl-pyridine;
211) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
212) 4-[5-(3-Methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-4-(6-methyl-pyridin-2-yl)-lH- imidazol-2-yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
213) N- {4-[5-(6-Methyl-pyridin-2-yl)-4-quinoxalin-6-yl- lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanesulfonamide;
214) N-{4-[5-(6-Methyl-pyridin-2-yl)-4-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-acetamide.
215) 4-[2-(6-Methyl-pyridin-2-yl)-pyrazolo[l ,5-a]pyridin-3-yl]-pyriraidin-2-ylamine;
216) 4-(2-pyridin-2-yl-pyrazolo[ 1 ,5-a]pyridin-3-yl)-pyrimidin-2-ylamine; 217) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyridin-3-yl]-pyrimidin-2-ylamine; 218) 2-(6-methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-pyrazolo[l,5-a]pyridine; 219) 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylaniine; 220) 2-(6-methyl-pyridin-2-yl)-3-(2-morpholin-4-yl-pyrimidm-4-yl)-pyrazolo[l,5- c]pyrimidine;
221) 4-[2-(6-methyl-pyridm-2-yl)-pyrazolo[l,5-a]pyrazin-3-yl]-pyrimidin-2-ylamine; 222) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-a]pyrimidm-3-yl]-pyrimidin-2-ylamine; 223) 4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[l,5-c]pyrimidin-3-yl]-pyrimidin-2-ylamine;
224) (2-Methoxy-ethyl)- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
225) (3- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino} - propyl)-carbamic acid tert-butyl ester;
226) (3-Imidazol-l-yl-propyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
227) (4-Methoxy-benzyl)-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
228) [2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridin- 6-yl] -methanol; 229) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridine;
230) (4- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino } - butyl)-carbamic acid tert-butyl ester;
231) (4-Amino-benzyl)- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
232) (5- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2-ylamino } - pentyl)-carbamic acid tert-butyl ester;
233) [3-(2-Arnmo-pyrirnidin-4-yl)-2-(6-methyl-pyridin-2-yl)-irnidazo[l,2-a]pyridin-6-yl]- methanol;
234) [3-(2-ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-7-yl] - methanol;
235) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridin-8-yl]-(2-morpholin-4-yl-ethyl)-amine;
236) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]ρyridin-8-yl]-(2-pyridin-2-yl-ethyl)-amine;
237) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridm-8-yl]-(2-pyridin-3-yl-ethyl)-amine;
238) [3-(2-methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridin-6-yl]-methanol;
239) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridin-8-yl]-(2-pyridin-4-yl-ethyl)-amine;
240) [3-(2-Amino-pyrimidin-4-yl)-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- ajpyridin- 8 -yl] -(3 -morpholin-4-yl-propyl)-amine;
241) [3-(4-Methyl-piperazin- 1 -yl)-propyl]- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a]pyridin-3 -yl] -pyrimidin-2-yl} -amine;
244) [3-(4-Methyl-piperidin-l-yl)-propyl]-{4-[2-(6-methyl-pyridm-2-yl)-imidazo[l,2- a]pyridin-3-yl]-pyrimidin-2-yl}-amine;
245) [4-(2-Pyridm-2-yl-imidazo[l,2-a]pyridm-3-yl)-pyrimidin-2-yl]-pyridm-3-ylmethyl- amine;
246) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-((R)-l- phenyl-ethyl)-amine;
247) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-((S)-l- phenyl-ethyl)-amine; 248) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(lH- tetrazol-5 -yl)-amine;
249) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]ρyridin-3-yl]-pyrimidin-2-yl}-(2H- pyrazol-3-yl)-amine;
250) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2- morpholin-4-yl-ethyl)-amine;
251) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]-pyrimidin-2-yl}-(2-pyridin- 2-yl-ethyl)-amine;
252) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(2-pyridin- 3 -yl-ethyl)-amine;
253) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidm-2-yl}-(2-pyridin- 4-yl-ethyl)-amine;
254) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}-(3- moφholin-4-yl-propyl)-amine;
255) {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-yl} -(3- piperidin- 1 -yl-propyl)-amine;
256) {4-[2-(6-Metliyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- [1 ,3,4]thiadiazol-2-yl-amine;
257) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine; 258) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfaiiyl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine- 6-carboxylic acid methyl ester;
259) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidm-4-yl)-imidazo[l,2-a]pyridine- 7-carboxylic acid ethyl ester;
260) 2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo [ 1 ,2- a]pyrimidin-7-ylamme;
261) {7,7-Dimethyl-8-[5-(4-{4-[2-(6-methyl-ρyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamino}-butylcarbarnoyl)-pentyl]-2-oxo-4-trifluoromethyl-7,8-dihydro-2H-l- oxa-8-aza-anthracen-5-yl} -methanesulfonic acid;
262) 2-(2,7-Difluoro-6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl)-3,5,6-trifluoro-4-[(4- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}- butylcarbamoyl)-methylsulfanyl]-benzoic acid;
263) -(6-Methyl-pyridm-2-yl)-3-(2-moipholin-4-yl-pyrimidm-4-yl)-irnidazo[l32-a]pyridine; 264) 2-(6-Methyl-pyridin-2-yl)-3-(2-piperidin-l-yl-pyrimidin-4-yl)-imidazo[l,2-a]pyridine; 265) 2-(6-Methyl-pyridin-2-yl)-3-(2-pyrrolidin-l-yl-pyrimidin-4-yl)-irnidazo[l,2-a]pyridine; 266) 2-(6-Methyl-pyridin-2-yl)-3-[2-(lH-tetrazol-5--yl)-pyrimidin-4-yl]-iniidazo[l,2- ajpyridine;
267) 2-(6-Methyl-pyridin-2-yl)-3-pyrimidin-4-yl-imidazo[l,2-a]pyridine;
268) 2-(6-Methyl-pyridin-2-yl)-3-pyrimidin-4-yl-imidazo[l,2-a]pyrimidin-7-ylamine;
269) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-8- ylamine;
270) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carbonitrile;
271) 3-(2-Aiiiino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridirie-6- carboxylic acid;
272) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
273) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
274) 3 -(2-Ammo-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid (2-dimethylamino-ethyl)-amide;
275) 3-(2-7\mmo-pyrimidin-4-yl)-2-(6-niethyl-pyridin-2-yl)-imidazo[l,2--a]pyridine-6- carboxylic acid (2-methoxy-ethyl)-amide;
276) 3 -(2- Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridine-6- carboxylic acid (2-thiophen-2-yl-ethyl)-amide;
277) 3-(2-Amino-pyrimidin-4-yl)-2-(6-niethyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid [3-(4-methyl-piperazin-l-yl)-propyl]-amide;
278) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid amide;
279) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carboxylic acid cyclopropylamide;
280) 3-(2-Amino-pyrirnidiri-4-yl)-2-(6-methyl-pyridin-2-yl)-irnidazo[l,2-a]pyridine-6- carboxylic acid ethylamide;
281) 3 -(2- Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridine-6- carboxylic acid hydroxyamide;
282) 3-(2-Amino-pyrirnidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridine-6- carboxylic acid methoxy-amide;
283) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iinidazo[l,2-a]pyridme-6- carboxylic acid methyl ester; 284) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridi3ie-7- carboxylic acid;
285) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-iinidazo[l,2-a]pyridLiie-7- carboxylic acid ([l,4]dioxan-2-ylmethyl)-amide;
286) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-amino-ethyl)-amide;
287) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridiiie-7- carboxylic acid (2-dimethylamino-ethyl)-amide;
288) 3-(2-Amino-pyrirnidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridiiie-7- carboxylic acid (2-hydroxy-ethyl)-amide;
289) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid (2-oxo-2-pyridin-3-yl-ethyl)-amide;
290) 3-(2-Ammo-pyrirnidin-4-yl)-2-(6-methyl-pyridm-2-yl)-irnidazo[l,2-a]pyridirie-7- carboxylic acid (2-thiophen-2-yl-ethyl)-amide;
291 ) 3 -(2- Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carboxylic acid (piperidin-3-ylmethyl)-amide;
292) 3-(2-Amino-pyrirnidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridirie-7- carboxylic acid 2,2-dimethylhydrazide;
293) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid amide;
294) 3 -(2- Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridine-7- carboxylic acid cyclopropylamide;
295) 3-(2-Ammo-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid ethyl ester;
296) 3-(2-Amino-pyrimidin-4-yl)-2-(6-metliyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid ethylamide;
297) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid hydroxyamide;
298) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridine-7- carboxylic acid methoxy-amide;
299) 3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[ 1 ,2-a]pyriinidin-7- ylamine;
300) 3-(2-Azetidin-l-yl-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridine;
301) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-ρyridin-2-yl)-irnidazo [ 1 ,2-a] pyridine-7-carboxylic acid ethyl ester; 302) 3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-metliyl-ρyridin-2-yl)-imidazo[l,2- a]pyridine-6-carboxylic acid methyl ester;
303) 3-(2-Methanesulforιyl-ρyrimidin-4-yl)-7-methyl-2-(6-niethyl-pyridin-2-yl)-imi<iazo[l,2- a] pyridine;
304) 3-(2-Methanesulfonyl-ρyrimidin-4-yl)-8-methyl-2-(6-methyl-pyridin-2-yl)-irnidazo[l,2- a] pyridine;
305) 3,3-Dimethyl-N-[2-(6-methyl-pyridin-2-yl)-3-(2-rnethylsulfanyl-pyrimidin-4-yl)- imidazo[l,2-a]pyrimidin-7-yl]-butyramide;
306) 3-(2-Methanesulfonyl-ρyrirnidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2- a]pyridine-6-carbonitrile;
307) 3 -(2-Methylsulfanyl-pyrimidin-4-yl)-2-pyridin-2-yl-imidazo [ 1 ,2-a]pyridine;
308) 3,6-Dichloro-N-(4- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamino}-bxιtyl)-2-(2,4,5,7-Tetrachloro-6-hydroxy-3-oxo-9,9a-dihydro-3H- xanthen-9-yl)-terephthalamic acid;
309) 3-[2-(2-Methyl-aziridin-l -yl)-pyrimidin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a] pyridine;
310) 3- [2-(4-Methyl-pip erazin- 1 -yl)-pyrimidin-4-yl] -2-(6-methyl-pyridin-2-yl)-imidazo [1,2- a] pyridine;
311) 3- { [3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridine-6- carbonyl] -amino} -propionic acid methyl ester;
312) 3-{[3-(2-Amino-pyrimidin--4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyri<iine-7- carbonyl] -amino} -propionic acid methyl ester;
313) 3-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylanαino}- phenol;
314) 4-(2-{4-[2-(6-Meth.yl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}- ethyl)-benzenesulfonam.ide;
315) 4-(2-Pyridin-2-yl-imidazo[ 1 ,2-a]pyridin-3-yl)-pyrimidin-2-ylamine;
316) 4-[2-(6-Chloro-pyridm-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamme;
317) 4-[2-(6-Methyl-pyxidin-2-yl)-7-trifluoromethyl-imidazo[ 1 ,2-a]pyridin-3-yl]-ρyτimidin- 2-yl-amine;
318) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylamine;
319) 4-[2-(6-Methyl-pyτidin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidine-2-carboaitrile;
320) 4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidine-2-carbox:ylic acid amide; 321) 4-[6-Bromo-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
322) 4-[6-Chloro-2-(6-methyl-pyridin-2-yl)-iinidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
323) 4-[6-Fluoro-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
324) 4-[6-Methyl-2-(6-niethyl-pyridin-2-yl)-8-(2-morpholin-4-yl-ethylammo)-imidazo[ 1 ,2-a] pyridin-3-yl]-pyrimidin-2-ol;
325) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-2-yl-ethylamino)-imidazo[l,2-a] pyridin-3-yl]-pyrimidin-2-ol;
326) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-3-yl-ethylamino)-imidazo[l,2-a] pyridin-3-yl]-pyrimidin-2-ol;
327) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-(2-pyridin-4-yl-ethylamino)-imidazo[l,2-a] pyridin-3-yl]-pyrimidin-2-ol;
328) 446-Methyl-2-(6-methyl-pyridin-2-yl)-8-morpholin-4-yl-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ol;
329) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-8-morpholin-4-yl-imidazo[l,2-a]pyridin-3-yl]- pyrimidin-2-ylamine;
330) 4-[6-Methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridm-3-yl]-pyrimidm-2- ylamine;
331) 4-[7-Aminomethyl-2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2- yl-amine;
332) 4-[7-Methyl-2-(6-methyl-pyri<lin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
333) 4-[8-Benzyloxy-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ol;
334) 4-[8-Benzyloxy-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl- amine;
335) 4-[8-Bromo-6-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidm-
2-ol;
336) 4-[8-Methyl-2-(6-methyl-pyrid.in-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2- ylamine;
337) 6-Chloro-3-(2-methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2- a] pyridine;
338) 5-Dimethylamino-naphthalene-l -sulfonic acid (4-{4-[2-(6-methyl-pyridin-2-yl)- imidazof 1 ,2-a]pyridin-3 -yl] -pyrimidin-2-ylamino } -butyl)-amide; 339) 6-(2,7-Difluoro-6-hydroxy-3-oxo-3H-xanthen-9-yl)-N-(4-{4-[2-(6-metliyl-pyridin-2-yl)- imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-butyl)-ϊsophthalamic acid;
340) 6- Amino-9-[2-carboxy-5 -(4- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3 -yl] - pyrimidin-2-ylamino } -butylcarbamoyl)-phenyl] -xanthen-3 -ylidene-ammonium;
341) 6-Bromo-2-(6-methyl-pyridin-2-yl)-3-(2-methylsulfaiiyl-pyrimidin-4-yl)-imidazo[l,2-a] pyridine;
342) 6-Fluoro-2-(6-methyl-pyridm-2-yl)-3-(2-methylsulfajayl-pyrimidin-4-yl)-imidazo[ 1 ,2-a] pyridine;
343) 7-Amino-4-methyl-3-[(4- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]- pyrimidin-2-ylamino}-butylcarbamoyl)-methyl]-2-oxo-2H[-chromene-6-sulfonic acid;
344) Cyclobutyl-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l-,2-a]pyridin-3-yl]-pyrimidin-2-yl}- amine;
345) Cyclopentyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridm-3-yl]-pyrimidin-2- yl} -amine;
346) Cyclopropyl- {4-[2-(6~methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]-pyrimidin-2- yl} -amine;
347) Cyclopropyl-methyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3-yl]- pyrimidin-2-yl} -amine;
348) Dimethyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-yl}- amine,
349) Isopropyl- {4-[2-(6-methyl-pyridin-2-yl)-imidazo[l ,2, -a]pyridin-3-yl]-pyrimidin-2-yl} - amine,
350) Methyl- {4-[2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrimidin-2-yl}- amine,
350a) N-(2-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-ρyrimidin-2- ylamino} -ethyl)-acetamide;
351) N-(4-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]p3rridin-3-yl]-pyrimidin-2-ylamino}- butyl)-acetamide;
352) N,N-Dimethyl-N'-{4-[2-(6-methyl-pyridin-2-yl)-imiciazo[l,2-a]pyridin-3-yl]-pyrimidm- 2-yl} -ethane-1 ,2-diamine;
353) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-p5τimidin-4-yl)-imidazo[l,2-a] pyrimidin-7-yl]-3-pyridin-3-yl-propionamide;
354) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-p3rrimidin-4-yl)-imidazo[l,2-a] pyrimidin-7-yl]-nicotinamide; 355) N-[2-(6-Methyl-pyridin-2-yl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[ 1 ,2-a] pyrimidin-7-yl]-propionamide;
356) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-6- carbonylj-methanesulfonamide;
357) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridine-7- carbonyl] -methanesulfonamide;
358) N-[3-(2-Ainino-pyriinidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyrimidin-7- yl]-2-(3-methoxy-phenyl)-acetamide;
359) N-[3-(2-Arnino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyrimidin-7- yl] -3 ,3 -dimethyl -butyr amide;
360) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyrimidin-7- yl] -3 -pyridin-3 -yl-propionamide;
361) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyrimidin-7- yl]-acetamide;
362) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyrimidin-7- yl] -nicotinamide ;
363) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a] pyrimidin-7-yl] -2-(3 -methoxy-phenyl)-acetamide;
364) N-[3-(2-Methanesulfonyl-pyrimidm-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl] -3,3 -dimethyl-butyr amide;
365) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl] - 3 -pyridin-3 -yl-propionamide;
366) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[ 1 ,2-a] pyrimidin-7-yl] -nicotinamide;
367) N-[3-(2-Methanesulfonyl-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a] pyrimidin-7-yl] -propionamide;
368) N-[3-(2-Amino-pyrimidin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazoπi,2-a]pyrimidin-7- yl] -propionamide;
369) N-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]pyridin-3-yl]-pyrirriidin-2-yl}- acetamide;
370) Nl - {4-[2-(6-Methyl-pyridin-2-yl)-imidazo [ 1 ,2-a]pyridin-3 -yl] -pyrimidin-2-yl} -butane-
1,4-diamine;
371) Nl-{4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l,2-a]ρyridin-3-yl]-pyrimidin-2-yl}- propane-1 ,3-diarnine; 372) N-(4- {4- [2-(6-Methyl-pyridin-2-yl)-imidazo[ 1 ,2-a]pyridin-3 -yl] -pyrimidin-2-ylamino } - butyl)-(BODIPY FL) amide; and
373) N-(4- {4-[2-(6-Methyl-pyridin-2-yl)-imidazo[l ,2-a]pyridin-3-yl]-pyrimidin-2-ylaniino} - butyl)-(Texas Red-X) amide
374) N-[3-(2-amino-pyrimidin-4-yl)-2-(6-methyl-pyridm-2-yl)-imidazo[l,2-a]pyrimidiix-7- yl]-acetamide;
375) N-{4-[2-(6-methyl-pyridin-2-yl)-imidazo[l,2-a]ρyridin-3-yl]-ρyrimidin-2-yl}- acetamide.
376) 3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l -yl)-propylamine,
377) N-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-acetamide,
378) N-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-methanesulfonamide,
379) dimethyl-[3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propyl]-amine,
380) 4-{3-pyridin-2-yl-l-[2-(lH-tetrazol-5-yl)-ethyl]-lH-pyrazol-4-yl}-quinoline,
381) 4- [3 -pyridin-2-yl- 1 -(3 -pyrrolidin- 1 -yl-propyl)- 1 H-pyrazol-4-yl]-quinoline,
382) 5-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-pyridin-2-ylamine, 383) 2,4-dimethoxy-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyrimidine, 384) 3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propionic acid, 385) 5-(3-pyridin-2-yl-lH-ρyrazol-4-yl)-lH-indole, 386) 2-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-lH-pyrazol-3-yl]-pyridine, 387) N-hydroxy-3-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-propionamide, 388) 2-(3-pyridin-2-yl-4-quinolin-4-yl-pyrazol-l-yl)-ethylamine,
389) N- [2-(3 -pyridin^-yM-quinolin^-yl-pyrazol- 1 -yl)-ethyl] -methanesulfonamide,
390) 2-methyl-4-methylsulfanyl-6-(3-pyridm-2-yl-lH-pyrazol-4-yl)-pyrimidine,
391) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-pyridine,
392) 2-[4-(2,3-dihydro-benzofuran-5-yl)-lH-pyrazol-3-yl]-pyridine,
393) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[d]isoxazole,
394) 3-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-propionitrile,
395) N-{3-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-propyl}- methanesulfonamide,
396) 2-[4-(2,3-dihydro-benzo[l,4]dioxin-6-yl)-lH-pyrazol-3-yl]-6-methyl-pyridine,
397) [4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-acetonitrile,
398) N-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethyl}- methanesulfonamide,
399) 4-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-2-methylsulfanyl-pyrimidine,
400) 4-(3-pyridin-2-yl- 1 H-ρyrazol-4-yl)-2H-phthalazin- 1 -one, 40 ϊ) f -t5!k3-pyri'a&'2-yl-ffl-pyrazoϊ-4-yl)-2,3-dihydro-indo 402) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyridme,
403) 3-niethyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
404) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-4H-benzo[ 1 ,4]oxazin-3-one,
405) 6-(3-pyridin-2-yl- 1 H-pyrazol-4-yl)-quinoxaline, 406) 3-(4-nitro-benzyl)-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
407) 5 -methyl-6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl) - [ 1 ,2,4]triazolo[ 1 ,5-a]pyridine,
408) 4-methyl-7-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl) -3 ,4-dihydro- 1 H-benzo[e] [ 1 ,4] diazepine- 2,5-dione,
409) 2,3-dimethyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one, 410) 6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
41 Oa) 1 -methoxy-4-(3-pyridin-2-yl-lH-pyrazol-4-yl)-isoquinoline,
411) 2-methyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyridine,
41 Ia) 4-(3 -pyridin-2-yl- lH-pyrazol-4-yl)-2H-isoquinolin-l -one,
412) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-trifluoromethyl-pyridine,
412a) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-vinyl-pyridine,
413) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-propenyl-pyridine,
414) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-ethyl-pyridine,
415) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-propyl-pyridine,
416) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-cyclopropyl-pyridine,
417) 1 -[6-(4-benzo[l ,3]dioxol-5-yl-lH-pyrazol-3-yl)-pyridin-2-yl]-ethanol,
418) 4-methoxy-6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-quinazoline,
419) 6-(3-pyridin-2-yl- 1 H-pyrazol-4-yl)-quinoline, 420) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolIn-4-ylamine, 421) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one, 422) 7-(3-pyridin-2-yl-lH-pyrazol-4-yl)-pyrido[l 32-a]pyrimidin-4-one, 423) 6-[3-(6-cyclopropyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
424) 3-methyl-6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3H-quinazolin-4-one,
425) 4-(2- {2-[4-benzo[ 1 ,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l -yl]-ethoxy} - ethoxy)-bicyclo [2.2.2] octane- 1 -carboxylic acid,
426) 4-(2-{2-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-ethoxy}- ethoxy)-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester,
427) 4-[4-benzo[l ,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol- 1 -yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester,
428) 2-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-6-isopropyl-pyridine, 429) 2-(4-benzo[l,3]dioxol-5-yl-5-trifluoromethyl-lH-pyrazol-3-yl)-6-bromo-pyridine,
430) 6-[3-(5-fluoro-6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine,
431) 6-[3-(6-trifluoromethyl-pyridin-2-yl)-lH-pyrazol-4-yl]-[l ,2,4]triazolo[l ,5-a]pyridine,
432) 6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoxaline,
432a) 6-[3-(6-cyclopropyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3-methyl-3H-quinazolm-4-one,
433) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-[l ,2,4]triazolo[l ,5-b]pyridazine,
433a) 6-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoline,
434) 6-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-3-fluoro-2-methyl-pyridine,
435) 7-methoxy-3-methyl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3H-quinazolin-4-one,
436) (4-moφholm-4-yl-phenyl)-[6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-qumazolm-4-yl]-amine,
437) 4-isopropoxy-6-(3-pyridin-2-yl- 1 H-pyrazol-4-yl)-quinazoline,
438) 6-(3-Pyridin-2-yl-lH-pyrazol-4-yl)-quinolin-4-ylamine,
439) {4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohexyl}- carbamic acid benzyl ester,
440) 4-[4-benzo[ 1 ,3] dioxol-5 -yl-3-(6-methyl-pyridin-2-yl)-pyrazol- 1 -yl]-cyclohexylamine, 441) N-{4-[4-benzo[l,3]dioxol-5-yl-3-(6-methyl-pyridin-2-yl)-pyrazol-l-yl]-cyclohexyl}- methanesulfonamide,
442) 6-[3-(5-fluoro-6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoxaline,
443) 7-(3-pyridin-2-yl- lH-ρyrazol-4-yl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine,
444) 1 -tert-butyl-3 - [6-(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-quinazolin-4-yl] -urea,
445) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[l ,2,5]thiadiazole, 446) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[l,2,5]oxadiazole,
447) 5-(3 -Pyridin-2-yl- 1 H-pyrazol-4-yl)-benzooxazole,
448) 4-morpholin-4-yl-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline,
449) 6-[3-(6-trifluoromethyl-pyridin-2-yl)-lH-pyrazol-4-yl]-quinoxaline, 450) 4-(4-methoxy-phenyl)-6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazoline, 451) 5-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-benzo[l,2,5]thiadiazole,
452) 6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzothiazole,
453) 3-(3-methoxy-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
454) 5-methyl-thiophene-2-carboxylic acid [6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quinazolin-4- yl] -amide,
455) 5-[3-(6-methyl-pyridin-2-yl)-lH-pyrazol-4-yl]-3-phenyl-benzo[c]isoxazole,
456) 3-(4-methoxy-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole,
457) 3 -(4-chloro-phenyl)-5 -(3 -pyridin-2-yl- 1 H-pyrazol-4-yl)-benzo [c] isoxazole,
458) 3-(4-ethyl-phenyl)-5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-benzo[c]isoxazole, 459) (4-methoxy-phenyl)-[6-(3-pyridin-2-yl-lH-pyrazol-4-yl)-quirιazolin-4-yl]-metlianone, 460) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-3-thiophen-3-yl-benzo[c]isoxazole,
461) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid,
462) 5-(3-Pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid methylamide,
463) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid dimethylamide,
464) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylio acid (2,2-dimethyl- propyl)-amide,
465) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid phenylamide, 466) moφholin-4-yl-[5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazol-3-yl]-methanone,
467) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid benzylamide,
468) 5-(3-pyridin-2-yl-lH-pyrazol-4-yl)-lH-indazole-3-carboxylic acid cyclopentylamide, 469) 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzamide; 470) 4-[4-benzo[l,3]dioxol-5-yl-5-(2-methylsulfanyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- benzonitrile; 471) 4-[5-(2-methanesulfonyl-pyrimidin-4-yl)-4-(6-methyl-pyridiπL-2-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
472) 4-[5-(2-methoxy-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-L H-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
473) 4-[5-(2-hydroxy-pyrimidm-4-yl)-4-(6-methyl-pyridin-2-yl)-lΗ-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
474) 4-[5.(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
475) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)- 1 H-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid;
476) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid amide;
477) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid hydroxyamide;
478) 4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]octane-l-carboxylic acid methoxy-amide;
479) 4-[5-(2-ammo-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)- 1 H-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
480) {4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-imidazol-2- yl]-bicyclo[2.2.2]oct-l-yl}-carbamic acid benzyl ester; 481) N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridiri-2-yl)-lH-imidazol-
2-yl]-bicyclo[2.2.2]oct-l-yl}-acetamide;
482) N-{4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-methyl-pyridin-2-yl)-lH-iniidazol-
2-yl] -bicyclo [2.2.2] oct- 1 -yl} -methanesulfonamide;
483) N- {4-[5-(2-cyclopropylamino-pyrimidin-4-yl)-4-(6-metliyl-pyridin-2-yl)- 1 H-imidazol-
2-yl]-bicyclo[2.2.2]oct-l-yl}-2,2,2-trifluoro-acetamide;
484) 4-[5-qumoxalin-6-yl-4-(2-trifluoromethyl-pyrimidin-4-yl)-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
485) 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-iinidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
486) 6-[2-tert-butyl-5-(2-cyclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
487) 6-[5-(2-byclopropyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
488) {4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]oct-l-yl}-methanol;
489) 6-[5-(2-trifluoromethyl-pyrimidin-4-yl)-3H-imidazol-4-yl]-quinoxaline;
490) 6-[2-tert-butyl-5-(2-trifluoromethyl-pyrimidm-4-yl)-3H-imidazol-4-yl]-quinoxaline; 491) 4-[5-quinoxalin-6-yl-4-(2-trifluorometb.yl-pyrimidin-4-yl)-lH-imidazol-2-yl]- piperidine-1-carboxylic acid benzyl ester;
492) 4-[4-(2-cyclopropyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-iinidazol-2-yl]-piperidine-l- carboxylic acid benzyl ester;
493) 6-[5-(2-cyclopropyl-pyrirnidin-4-yl)-2-(l-methanesulfonyl-piperidin-4-yl)-3H-imidazol-
4-yl] -quinoxaline;
494) 4-[5-(2-methyl-pyrimidm-4-yl)-4-[l,2,4]triazolo[4,3-a]pyridm-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol;
495) 4-[4-(2-methyl-pyrimidin-4-yl)-5-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine-6-yl- lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l -carboxylic acid amide;
496) 4-[4-(2-methyl-ρyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridiiie-6-yl-lH-iniidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid;
497) 4-[4.(2-methyl-ρyrimidin-4-yl)-5-[l,2,4]triazolo[l,5-a]pyridine-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octane-l-carboxylic acid methyl ester;
498) 4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]-cyclohexanol; and
499) 4-[4-(2-methyl-pyrimidin-4-yl)-5-quinoxalin-6-yl-lH-imidazol-2-yl]- bicyclo[2.2.2]octan-l-ol,
500) 4-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-2-methyl-pyrimidine,
500a) 6-[3-(2-methyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-[l52,4]triazolo[l,5-a]pyridine, 501) d-[3-(2-tπM'dfbm^
502) 6-[3-(2-methyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-quinoxaline,
502a) 6-[3 -(2-trifluoromethyl-pyrimidin-4-yl)- lH-pyrazol-4-yl] -quinoxaliire,
503) 6-[3-(2-cyclopropyl-pyrimidin-4-yl)-lH-pyrazol-4-yl]-quinoxaline,
504) 4-(4-benzo[l,3]dioxol-5-yl-lH-pyrazol-3-yl)-2-trifluoromethyl-pyrimidine,
505) 7-[3-(2-Mfluoromethyl-ρyrimidin-4-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyridine, or
506) 6-[3-(2-Trifluoromethyl-pyrimidin-4-yl)- 1 H-pyrazol-4-yl]-quinoline.
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